The Eschenmoser sulfide contraction method and its application in the synthesis of natural products

Tetrahedron xxx (2015) 1e70

Contents lists available at ScienceDirect

Tetrahedron journal homepage: www.elsevier.com/locate/tet

Tetrahedron report number XXX

The Eschenmoser sulfide contraction method and its application in the synthesis of natural products Syed Raziullah Hussaini a, *, Raghu Ram Chamala b, Zhiguo Wang a a b

Department of Chemistry and Biochemistry, The University of Tulsa, Keplinger Hall, 800 South Tucker Drive, Tulsa, OK 74104, United States Momentive Performance Materials (India) Pvt. Ltd., Survey No. 9, Electronic City West (Phase 1), Hosur Road, Bangalore 560 100, Karnataka, India

a r t i c l e i n f o Article history: Received 26 August 2014 Available online xxx Dedicated to Professor Albert Eschenmoser for his contributions to the field of organic chemistry

Keywords: Eschenmoser sulfide contraction method Eschenmoser coupling reaction Enaminones Sulfur extrusion Vinylogous amide Vinylogous urethane Vinylogous carbamate Thioamide Iodinative coupling Diazo coupling Thio-Reformatsky reaction

Contents 1.

2.

3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Historical perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.1. Sulfide contraction via oxidative precoupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.2. Sulfide contraction via alkylative precoupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. The Eschenmoser sulfide contraction reaction via oxidative precoupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. Evidence of oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. The Eschenmoser sulfide contraction reaction via alkylative precoupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Evidence of episulfide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Sulfur extrusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.1. Extrusion by thiophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.2. Extrusion without a thiophile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Modified versions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. The iodinative coupling variant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Reaction with diazo electrophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

* Corresponding author. E-mail address: [email protected] (S.R. Hussaini). http://dx.doi.org/10.1016/j.tet.2015.06.026 0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Hussaini, S. R.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.06.026

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S.R. Hussaini et al. / Tetrahedron xxx (2015) 1e70

4.

5. 6.

7.

3.3. Wittig reaction with thioimides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Bromine-induced cyclization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. The thio-Reformatsky reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Selenoamides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other improvements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Flow chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Sonication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stereochemistry of products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Assignment of stereochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Limitations of the Eschenmoser coupling reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Sulfide contraction via oxidative precoupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Sulfide contraction via alkylative precoupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.1. Issues with primary thioamides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.2. Steric issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.3. Competitive elimination reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.4. Issues when nitrogen of thioamide is N-acyl or N-aryl . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Challenges with the sulfur extrusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.1. Disulfides and thiol formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.2. Epimerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.3. Use of nitrogen complexing reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.4. Use of complementing Eschenmoser sulfide contraction reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.5. Use of protecting groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.6. Issues with six-membered thioamides as coupling partners . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.7. Issues with five-membered thioamides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.8. Miscellaneous issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Applications in the synthesis of natural products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1. Sulfide contraction via oxidative precoupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1.1. Vitamin B12 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1.2. Isobacteriochlorin macrocycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1.3. Vitamin B12 AeB-semicorrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2. Sulfide contraction via alkylative precoupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.1. Vitamin B12 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.2. Phycocyanobilin and homophycobiliverdin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.3. Anisomycin and deacetyl anisomycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.4. (
)-Pumiliotoxin C hydrochloride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.5. (
)-Saxitoxin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.6. Pyrrolizidine alcohols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.7. Acylative ring closure strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.8. Gephyrotoxin family of alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.9. Tropane and homotropane alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.10. Histrionicotoxin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.11. 5-Butyl-2-heptylpyrrolidines from glutamic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.12. Lythrancepine II and lythrancepine III . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.13. Peripentadenia alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.14. Alkylative cyclization strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.15. Plakoridine A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.16. Guanidine alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.17. ()-Adalinine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.18. Halichlorine and pinnaic acid core . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.19. Azaphenalene alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.20. C5-substituted hydroxyethyl indolizidines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.21. ()-Sedacryptine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.22. cis-Decahydroquinoline alkaloids: lepadin family . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.23. Monocyclic piperidine and pyrrolidine alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.24. Fuligocandins A and B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.25. Macrocycles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3. Sulfide contraction via iodinative coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3.1. Vitamin B12 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3.2. (þ)-Tolyporphin A O,O-diacetate (proposed structure) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4. Wittig reaction with thioimides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4.1. Iturinic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4.2. Isobacteriochlorin macrocylce . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.5. The thio-Reformatsky reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.5.1. N-Phosphorylated aziridine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.6. Coupling with diazo electrophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.6.1. Cephalotaxine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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7.6.2. Indolizomycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Extensions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.1. Synthesis of 1,3-dicarbonyl compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2. Sulfide contraction followed by retro-Claisen condensation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3. Synthesis of carbapenems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.4. Synthesis of thiopenem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.5. Pyridone synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.6. Formation of conjugated alkenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.7. Formation of an endocyclic double bond with benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.8. Sulfur heterocycles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions and outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographical sketch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix of functional groups

1. Introduction The Eschenmoser sulfide contraction reaction is a carbonecarbon bond forming reaction that prepares compounds shown in the Fig. 1 formula.1 When A is an oxygen atom, the compounds are called enaminones (an appendix of names and structures of less common functional groups encountered in this review has been placed after the author biographies).2 When A is an NR group they are called vinylogous amidines.1 The term enaminone includes vinylogous amides and vinylogous urethanes.2 Compounds with other electron withdrawing groups (R1C]A]EWG) can also be prepared by the Eschenmoser sulfide contraction method.3 The reaction is also known as the Eschenmoser coupling reaction, the Eschenmoser method, the Eschenmoser sulfide contraction, the Eschenmoser sulfide reaction4 and Eschenmoser olefination.5 Eschenmoser himself calls this transformation the sulfide contraction method6 or (thio)imidoester/enamine(enamide) condensation.7

Fig. 1. General structural formula of compounds that can be prepared by the Eschenmoser sulfide contraction method.

There are two major versions of the Eschenmoser sulfide contraction reaction. One involves oxidative precoupling while the other requires precoupling via alkylation. In both versions, a thioamide is one of the coupling partners (Scheme 1). Both processes are capable of making the vinylogous amidine system.1b,8 1.1. Historical perspective Before the development of the Eschenmoser sulfide contraction reaction, the imino ester (imidate) approach was the general method for the construction of vinylogous amidine structures in the synthesis of corrins (Scheme 2).8 Imino ester condensation could be performed by either acids or a base and required mild

3

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conditions. However, the reaction was sensitive to steric hindrance and failed to produce the vinylogous amidine system in the synthesis of metal-free corrins9 and vitamin B12.6a The Eschenmoser sulfide contraction reaction was an answer to address shortcomings of the imino ester approach. The development of the Eschenmoser reaction was motivated by the principle that intramolecular reactions occur more easily than intermolecular reactions. Thus, an intermolecular transformation that is unsuccessful due to deficiency in reactivity or by steric hindrance, may become possible by linking the two partners together through a temporary bridge (Fig. 2).6a,10 In the Eschenmoser sulfide contraction reaction, the two coupling partners are covalently joined, allowing them to achieve thioiminoester-enamide condensation intramolecularly. The reaction proved to be the method of choice in cases where bimolecular imino ester condensation failed. Structures 3 and 6 have two coupling partners covalently bound. This enables facile intramolecular reactions, which ultimately provide the vinylogous amidines (Scheme 3). In the oxidative coupling process the sulfur atom acts as a bifunctional template. It is easily introduced via oxidative coupling of a thioamide 1 with an enamide 2 and it can also be easily removed with the help of a thiophile (or heat). In the alkylative process, sulfur is introduced via the alkylation of a thioamide. After sulfur extrusion, enaminone 7 can be obtained. Alkylation with trialkyloxonium salts gives 8. Attack of an amine on 8 leads to the formation of the vinylogous amidine system 9.8,10,11 A vinylogous amidine can also be obtained by using a suitably substituted alkyl halide (O]NR in 5).10,12 1.1.1. Sulfide contraction via oxidative precoupling. Eschenmoser and his team developed the sulfide contraction via oxidative precoupling reaction for the synthesis of vitamin B12.8 However, the first scientific paper of the coupling process by Eschenmoser and co-workers appeared in 1967 in connection with their work on the synthesis of metal-free corrins.9 The imino ester approach, which previously provided cobalt-bound corrinoid compounds,9 could not be used because all efforts to remove cobalt to provide metalfree corrinoid compounds failed.13 In contrast to the imino ester approach, the Eschenmoser sulfide contraction reaction did not require a robust metal complex and could be carried out on the labile zinc(II) complex. The zinc ion could be removed easily from the cyclized corrin complex by treating the complex with trifluoroacetic acid (TFA) in CH3CN.9 Scheme 4 describes the process.9,10 Attempts to convert 10 into thiolactam 11 and to capture 11 as a zinc complex gave the

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Scheme 1. The two major versions of the Eschenmoser sulfide contraction reaction.

Scheme 2. The imino ester approach for the construction of vinylogous amidine structures in the synthesis of corrins.

Fig. 2. A representation of the principle that intermolecular reactions that are unsuccessful due to stereoelectronic reasons could become facile by making the process intramolecular.

the laboratories of Eschenmoser and R. B. Woodward.8,10,14 Analogous observations had previously been reported by Knott and Jeffreys in 1955.15 In an attempt to prepare sulfide dye of the type 24, Knott reacted dithiocarbamate 22 with bromoacetophenone 23 in the presence of Et3N (Scheme 5). However, instead of 24, 25 was obtained. Knott speculated that Et3N converts the salt 26 into the ylide 27, which via episulfide 28 provides the enaminone 25.15a Knott and Jeffreys explored the substrate scope of this transformation. They showed that it is possible to selectively react 29 with 30 to form 31, even though 30 also contains the thiocarbonyl functionality (Eq. 1).15d The preliminary reports on the alkylative precoupling process from Eschenmoser’s group appeared between 1968 and 1970.8,10,11,16 The reaction was developed for the synthesis of vitamin B12. Results on simple systems were reported with 2thiopyrrolidone and a-bromocarbonyl compounds. Some examples that were reported are shown below (Scheme 6). Bromoacetone and tert-butyl bromoacetate required a catalytic amount of base to induce the enolization that was necessary for the contrac-

Scheme 3. The Eschenmoser sulfide contraction reaction showing the intramolecular approach for the formation of vinylogous amidine systems.

macrocycle 12, presumably via 11. A series of operations was performed, which transformed 12 into 18. The authors speculated that the TFA equilibrates 12 with the corresponding thiolactam 13. Thiolactam 13 is oxidized by benzoyl peroxide to 14, which is attacked by the enamine to give the sulfur-bridged macrocycle 15. Acid-induced decomplexation of 15 allows the formation of intermediate 16 with the exocyclic double bond. Contraction of 16 to the episulfide (thiirane) 17, followed by rearrangement results in the formation of 5-mercapto-corrin ligand 18. The capture of 18 with zinc(II) provides the complex 19. Acid-catalyzed desulfurization with triphenylphosphine provided 20, which was decomplexed by TFA in CH3CN to give the metal-free corrin 21.9e11 1.1.2. Sulfide contraction via alkylative precoupling. The alkylative Eschenmoser coupling reaction was developed independently in

tion process.10,11,16 More details about the process appeared shortly after the initial reports.1a,14c

2. Mechanism 2.1. The Eschenmoser sulfide contraction reaction via oxidative precoupling The generally accepted mechanism for the oxidative process is shown in Scheme 7. Thioamide 1 is oxidized by benzoyl peroxide to give either a symmetrical disulfide or the O-benzoyl-S-oxide 36. The nucleophilic methylene carbon of the enamide 2 attacks the electrophilic sulfur of 36 forming 37, which undergoes tautomerization to give the sulfur-bridged intermediate 3. Intermediate 3 forms episulfide 39, either via an ene-type process, or via the electrocyclization of the structure 38. Attack of

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Scheme 4. The Eschenmoser oxidative precoupling process in the synthesis of metal-free corrins.

Scheme 5. First report of the sulfide contraction via an alkylative precoupling process.

(1)

a thiophile on the sulfur atom of 39 provides 40, which undergoes tautomerization to give the vinylogous amidine 4.1b,8e10,17 Another possibility is that the lone pair of electrons on the nitrogen adjacent to the episulfide 39 opens the ring giving

a thiolate, which after protonation gives thioether 41. Attack of a thiophile on 41 causes sulfur extrusion generating 40.1a The coupling of the enamide 2 with 36 can also be induced by a base.8

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Scheme 6. Preliminary reports of sulfide contraction of alkylative precoupling from the Eschenmoser group.

Chloride,18 bromide,15a iodide19 and triflate20 are used as leaving groups. The nucleophilic thioamide 44 reacts with an alkyl halide giving an iminium 45 (R2¼alkyl group) or an imine (R2]H in 44) thioether. Base deprotonates thioether 45 or 46 and the intermediates 47 and 48 are captured as an episulfide 49. The episulfide collapses, with or without the help of a thiophile (PR3), to give an enaminone. Conversion of thioethers 47 and 48 into episulfide 49 could also be an ene or electrocyclization process men-

Scheme 7. Mechanism of the Eschenmoser sulfide contraction reaction via an oxidative process.

2.1.1. Evidence of oxidation. In the oxidative coupling of thiolactam 1 and enamide 2, bis(imidoyl) disulfide 42 and 3 are identifiable intermediates (Scheme 8). The disulfide can be isolated when a thioamide is reacted with 0.5 equiv of benzoyl peroxide in the absence of an enamide 2. Intermediate 43, in the presence of a trace amount of HCl (or a base) reacts with an enamide giving the thio-bridged intermediate 3 and regenerating thioamide 1 that can be oxidized with benzoyl peroxide again. Heating 3 with a thiophile then provides the vinylogous amidine system 4.10,11,14b The intermediate O-benzoyl-Soxide (e.g., structure 14, Scheme 4) is another species that has been proposed by Eschenmoser and co-workers in lieu of 42. However, such a species has not been isolated.9,10

Scheme 8. Evidence of oxidation in the oxidative coupling process.

2.2. The Eschenmoser sulfide contraction reaction via alkylative precoupling The accepted mechanism of the Eschenmoser sulfide contraction reaction via an alkylative process is shown in Scheme 9.

tioned in Scheme 7 (3/39 and 38/39, respectively).1a,8,10,14c,15d,17,21 The conversion of 45 or 46 into 50 can also occur under acidic conditions. In this case the conversion of 45 or 46 into 8 is the same as the conversion of 37 into 4 in the oxidative precoupling reaction (Scheme 7).6a Vinylogous amidine products can be obtained directly (50, A] NR)10,12 or if the coupled products are enaminones (A]O Scheme 9), they can be converted into vinylogous amidines (Scheme 3). Other electron withdrawing groups (R5C]A]EWG) can also undergo this reaction.3 The process for the formation of a vinylogous amidine from a secondary enaminone system is shown in Scheme 10. Thus alkylation of 51 with Meerwein’s salt provides the enol 52. Treatment of 52 with an amine provides vinylogous amidinium salt 53 via a 1,4-addition followed by elimination. Compound 53 on reaction with t-BuOK provides the vinylogous amidine 54.1 The alkylation of thioamides (44/45 or 46, Scheme 9) is a reversible process with nucleophilic leaving groups. Two crossover experiments showed the reversibility of the process (Scheme 11).19 Heating 55 with ester 56, resulted in a 1:1 mixture of salts 55 and 57. Additionally, when 59 and 57 were heated and then subjected to the sulfide contraction followed by hydrolysis, it provided all four possible ketoesters 60e63. The alkylation of secondary thioamides (44/46, Scheme 9) with a-bromomonoesters proceeds more readily than the alkylation of tertiary thioamides (44/45). However, the subsequent sulfur extrusion of tertiary thioamides occurs more easily and under milder reaction conditions.21a,22 Steric crowding on the carbon atom, which is adjacent to both the sulfur and the nitrogen atom in thioethers, also assists sulfur extrusion.22a The formation of enaminones by the reaction of secondary thioamides and a-bromodicarbonyl compounds takes less time than tertiary thioamides. This was speculated to be due to the greater acidity of dicarbonyl compounds, which make the conversion of 44/45 or 44/46 the

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Scheme 9. Mechanism of the Eschenmoser sulfide contraction reaction via an alkylative process.

Scheme 10. Conversion of enaminones into vinylogous amidine systems.

Scheme 11. Crossover experiments showing the reversibility of thioamide alkylation with nucleophilic leaving groups.

rate determining step. The reactions of tertiary thioamides with abromodicarbonyl compounds are slower because of the greater steric hindrance in the alkylation step. Greater energy requirements due to steric hindrance shifts the equilibrium in the direction of the starting materials.21b

2.3. Evidence of episulfide The episulfide (39 in Scheme 7 or 49 in Scheme 9) mentioned in either pathway has been claimed to be observed in the Eschenmoser sulfide contraction reaction (Scheme 12). Unfortunately,

Scheme 12. Reported detection of episulfides in the Eschenmoser sulfide contraction reactions.

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detailed characterization of these episulfides was not reported.23 Similar non-definitive evidence was reported in 2012.24 In related sulfur extrusion reactions, episulfides have been isolated, characterized and sulfur extruded to give alkenes.25 Therefore, more work is needed to definitively show the intermediacy of episulfides in the Eschenmoser sulfide contraction reactions.

was rejected because the rates of the reactions are insensitive to large changes in the dielectric constant of the medium. Furthermore, cis-2-butene episulfides give cis-2-butene and trans-2butene episulfide gives trans-2-butene, suggesting the stereospecific nature of the process.29

2.4. Sulfur extrusion 2.4.1. Extrusion by thiophiles. Phosphines and phosphites are commonly used as thiophiles for the sulfur extrusion step (39/40 Scheme 7 or 49/50 Scheme 9). Use of a volatile trimethyl phosphite can simplify the workup as it can be readily removed along with trimethyl thiaphosphonate by co-evaporation with ethanol.18 Use of polymer-supported triphenylphosphine has also been reported. This reagent avoids the need of running multiple chromatographic columns for product purification.26 Other reagents, such as methylmercuryisopropoxide-boron trifluoride-triphenylphosphine,10 boron trifluoride (as a catalyst) and PPh3,8 Ni(ClO4)2,10 PPh3 and CF3CO2H,11 P(CH2CH2CN)3 and CF3CO2H,6a and partially deactivated W-2 Raney nickel27 have been used when the sulfide contraction was found to be challenging, or the products were thiols. Dual reagents, such as 681a and 69,20 which contain both a base and a thiophile, have also been used (Fig. 3). Compound 68 and 69 can be readily removed with an aqueous wash, thereby simplifying the product purification.

Fig. 3. Dual reagents containing both a base and a thiophile.

A proposed sulfur extrusion process that involves the opening of the episulfide ring in the Eschenmoser sulfide contraction process is shown in Scheme 13.1a Episulfide 39 opens, and after protonation, 41 is obtained. Thiol 41 is attacked by a thiophile, such as triphenylphosphine, giving 40 and PPh3SH. The latter is converted into triphenylphosphine sulfide under the reaction conditions.28

Scheme 13. Tentative mechanism for sulfur extrusion via thiol formation.

With phosphine and phosphite compounds, sulfur extrusion is commonly proposed to happen via a stereospecific extrusion of sulfur from an episulfide.1a,14c The proposal is based on the sulfur extrusion reaction of episulfides which give alkenes (the Eschenmoser sulfide contraction reaction gives enaminones or vinylogous amidines). Denney and Boskin studied this reaction (Scheme 14) and found that the desulfurization reaction proceeds by a nucleophilic attack by the phosphine on the sulfur to give the phosphine sulfide and the olefin in one step. The alternative stepwise pathway

Scheme 14. Mechanism of sulfur extrusion from episulfides.

The role of a thiophile in the Eschenmoser sulfide contraction reaction is probably more complex. Rapoport and co-workers studied the sulfide contraction reaction of thiolactam 70a with methyl bromoacetate 71 to yield enaminone 73 (Scheme 15 and Table 1). Base and thiophile were added to the reaction mixture after the formation of 72.22b The authors commented that the isolation of 76 (Scheme 15) suggested that the reaction proceeds via 74 and 75 and that the deprotonation at C-4 of 72 competes with the side-chain deprotonation, which provides 73. The isolation of lactam 70b also suggested the presence of 74, which was hydrolyzed during isolation.22b However, one could argue that 70b could also be obtained by the hydrolysis of 72. Table 1 shows the product distribution with and without the presence of thiophiles. In the absence of a thiophile (entry 1), more 70b and 76 were produced than in the presence of PPh3 (entries 2 and 4). More 73 was produced when phosphine was added before the base (compare entry 2 and 4).22b It was speculated that phosphine plays a role other than simple sulfur scavenging. It is possible for the phosphine to add into 72 and then for sulfur to coordinate to phosphorus, giving 77a. Formation of 77a enhances the side-chain deprotonation (the rate limiting step) at the expense of C-4 deprotonation. Once proton removal happens, the phosphine acts as a leaving group providing the episulfide and thus enaminone 73. It is also possible that after deprotonation, the enolate of 77a displaces sulfur and provide a thiaphosphetane intermediate 77b, which after expulsion of Ph3PS provides enaminone 73.30 Intermediates of type 77b are also suspected intermediates in thio-Wittig reactions31 and are also similar to the BartoneKellogg-type of intermediates.32 The hypothesis for the formation of 77a was tested by using morpholinophosphine which has the phosphine tethered to a base (entry 3). Since morpholinophosphine requires simultaneous amine and phosphine additions, the proton removal at C-4 is competitive with phosphine coordination and should provide more of 76 and 70b. As expected, the morpholinophosphine (entry 3) was found to be less effective than PPh3, Et3N system (entry 4) in producing enaminone 73. The authors cited thio-Claisen rearrangement of the S-allylthioiminium ion to further support their hypothesis that C-4 deprotonation is a competing process under the reaction conditions.22b Rapoport and co-workers did not report any other mechanistic data to support their hypothesis for the formation of 77a.22b Furthermore, the nucleophilicity of PPh3 is vastly different than morpholinophosphine. Therefore, more work is needed to better understand the above results33 (Table 1). Rapoport and co-workers have also speculated on another pathway for the formation of enaminones (Scheme 16). The

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Scheme 15. Studies on the role of a thiophile in the sulfide contraction reaction.

Table 1 Sulfur contraction studies Entry

Reaction conditions

1 2

Et3N Et3N, 5 min, PPh3

3

4 a b

PPh3, 5 min, Et3N

Products, % yield 70b

76

73

15 Nda

10 15b

30 60

18

nd

70

5

2

85

Scheme 16. Proposed mechanism involving Wittig-like intermediates.

Not determined. Sum of 70a and 76.

pathway proceeds through a betaine 79 and/or a thiaphosphetane 80 intermediate, leading to the formation of an enaminone.31 Equilibrium between an eipsulfide and a betaine have been observed in the case of thiocarbonyl compounds.34 This mechanism contradicts the observations reported above where 77a (Scheme 15) was suggested to facilitate the side-chain deprotonation.22b

2.4.2. Extrusion without a thiophile. Sulfur can extrude without a thiophile in some alkylative precoupling reactions. Compounds that show such behavior are typically relatively acidic, with pKa  w17 and they extrude sulfur when reacted with a base (Eqs. 2 and 3).1a,15a,21b,35 When the thioamide contains an electron withdrawing group like a carbonyl, the extrusion on the corresponding thioether (83) can occur without a base to give an enaminone (84) (Eq. 4).1a,22a

(2) -

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There are no mechanistic studies reported for the process of sulfur extrusion in the absence of a thiophile for the Eschenmoser sulfide contraction reaction. In some such reactions, elemental sulfur has been isolated.1a,15a A cheletropic mechanism has been suggested17,25a (Scheme 17) that shows the loss of one atom of sulfur, which could then combine to form the elemental sulfur.25a However, in related reactions in which sulfur extrusion occurs, the formation of a singlet sulfur atom has been reported to be an energetically unfavorable process.25a Still, if atomic sulfur is a very strong thiophile, traces of atomic sulfur generated during the reaction may play a role in the sulfur extrusion process.36 Another possible process for sulfur extrusion in the Eschenmoser sulfide contraction reaction is similar to the one shown in

However, in the intramolecular Eschenmoser sulfide contraction reactions, it proceeds in a disrotatory fashion. Padwa and coworkers have proposed that the weaker CeS bonds and thermodynamic stability of enaminones lowers the activation energy of the ring closure even though this represents a formal violation of the WoodwardeHoffmann rules (Eq. 5).17

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Scheme 17. Cheletropic loss of sulfur in the Eschenmoser sulfide contraction method.

Scheme 18. The thermal extrusion of sulfur from episulfides to form alkenes has been studied for 85.25a,37 At low concentrations, thermal ionization happens first and it is the rate determining step (86/87). The fast step involves the attack of a sulfur anion on another molecule of episulfide, giving intermediate 88. Intermediate 88 acquires further sulfur atoms sequentially until an S8 cycle is made. At high concentrations, a bimolecular mechanism is favored. Similar sulfur extrusion mechanisms may be operative in the Eschenmoser sulfide contraction reaction. According to the WoodwardeHoffmann rules, the retroelectrocyclization process proceeds in a conrotatory fashion.

An alternative non-stereospecific pathway for sulfur extrusion is shown in Scheme 19. The episulfide 90 may rupture due to electron donation from the nitrogen atom giving 92. The resulting thiolate can undergo fragmentation generating the alkene and the elemental sulfur.33 This mechanism is similar to the stepwise process initially proposed for sulfur extrusion in the presence of thiophiles1a (Scheme 13).

Scheme 19. A non-stereospecific sulfur extrusion pathway.

Scheme 18. Formation of alkenes by the thermal extrusion of episulfides.

Sulfur extrusion has also been reported in the absence of both the base and the thiophile (Eq. 4).1a,18,22a When DMSO is used as a solvent, secondary thioamides can be converted into enaminones at room temperature. It is speculated that the polar nature of the solvent not only facilitates the initial SN2 alkylation, but also the carbonecarbon bond formation. It exposes the carbanion toward the electrophilic sp2 carbon (Scheme 9).18 In the intermolecular Eschenmoser sulfide contraction reaction it is not uncommon to obtain a mixture of diastereomers.21b,35b However, this does not suggest that sulfur extrusion is a nonstereospecific reaction. In such cases the mixture can be explained as a result of the equilibrium that can establish between E and Z forms after the formation of enaminones. Such an equilibrium has been reported with quinazoline derivatives (Scheme 20).38 Similar observations have been noted earlier.39

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Scheme 20. E/Z equilibrium in CDCl3.

3. Modified versions 3.1. The iodinative coupling variant The Eschenmoser group invented the iodinative coupling variant method to overcome problems with the oxidative precoupling procedure. In some instances, the oxidative procedure either gave unsatisfactory results or failed completely. These difficulties could be overcome by using the iodinative variant. Initial examples of this process are shown in Scheme 21. The enamide 93 could be iodinated with iodine giving 94. Vinyl iodide 94 when reacted with thioamide 95 or 32 in the presence of a strong base, resulted in the formation of bridged compounds 96a and 96b. Sulfide contraction on these compounds gave vinylogous amidine 97a and 97b. Bromo derivatives of 94 underwent this reaction only to a limited extent.7,40

11

give the bridged product 96 (path a). However, mechanistic studies by Eschenmoser and co-workers on the coupling reaction between 94 and 95 suggested formation of oxidation products 104 and 105 and the anion 106 of enamide 93 (path b). Therefore, either both products 104 and 105 or only one of them, reacts with 106 giving the sulfur bridged-product 96a. However, the mechanism (path b) was found to be sensitive to reaction conditions and the structural features of the reactants. Therefore, pathway-a could not be ruled out with other starting materials.7,40 Another possibility proposed by Eschenmoser for the formation of a CeS bond requires the nucleophilic attack of sulfur on the conjugatively stabilized carbene 108 (Scheme 23). The unhindered nature of the carbene can allow easy access to the sulfur nucleophile, forming 96.7

Scheme 23. Generation of a conjugatively stabilized carbene.

Scheme 21. The iodinative coupling variant in the synthesis of vinylogous amidines.

The Eschenmoser group initially developed a working mechanism for the iodinative coupling variant (Scheme 22, path a). The base-induced tautomeric equilibration 94$100$101 followed by rapid SN2 attack by 102 on the unstable isomer 101 was expected to

The iodinative coupling process has been used in the synthesis of a series of corrins and related compounds.40,41 It has also been applied in the synthesis of natural products.6a,42

Scheme 22. Proposed mechanism for the iodinative coupling reaction.

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3.2. Reaction with diazo electrophiles In 1985, Sundberg and Pearce serendipitously discovered the formation of thioethers by the reaction of thioamides and diazo compounds. They tried to make an a-bromoketone derivative of 109 by treating 109 with HBr (Scheme 24). Their intention was to use the a-bromoketone derivative in the Eschenmoser sulfide contraction reaction. However, the reaction produced cyclic thioether 110. The same compound could be obtained by the treatment of 109 with BF3. When 110 was heated with Bu3P, and the resulting mixture was acetylated, it produced an equal mixture of 111 and 112. Compound 111 is the expected product of the Eschenmoser sulfide contraction reaction. The oxidized product 112 could be obtained exclusively when 110 was heated in the absence of a thiophile.43

carbenoids is considered the first step in both of the metalcatalyzed reactions.47 Danishefsky and co-workers also generated rhodium carbenoids from diazo compounds 118aee (Scheme 27). Cyclization resulted in

Scheme 27. Cyclization via rhodium catalysis.

Scheme 24. The Eschenmoser sulfide contraction with a diazo electrophile.

The conversion of 109 into 110 likely happens through the mechanism shown below (Scheme 25).33,44 Other mechanistic possibilities also exist.45 However, carbenoid formation is unlikely as the reaction is catalyzed by acids and not by transition metals.44,45,45d

the formation of intermediate 119. Reaction of enethiol 119 with partially deactivated W-2 Raney nickel gave bicyclic products 120aee.27 Padwa and co-workers also observed intramolecular cyclization while studying the reactions of thiocarbonyl ylides (Eq. 6). In this

Scheme 25. Possible mechanism for the formation of 110.

Fang and Danishefsky reported the use of metal carbenoids in the Eschenmoser sulfide contraction in 1989. Heating 1,3dithiolane 115 in the presence of tungsten hexacarbonyl resulted in the cyclized product 117. Heating hydrazone 116 with Rh2(OAc)4 provided 117 in a better yield (Scheme 26).46 Formation of metal

case, no intermediate of type 119 was observed.17,48 A similar rhodium-catalyzed reaction on diazo compounds was reported earlier with tetrahydro-furan-2-thione.49

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Scheme 26. Use of metal carbenoids in the Eschenmoser sulfide contraction reaction.

Until 2012, there was just one example where the metal carbenoid variant was used for the intermolecular process.50 Hussaini and co-workers filled this gap and showed many examples of the intermolecular process using the Grubbs first-generation and [PPh3]3RuCl2 catalysts.51 The successful examples included the conversion of primary, secondary and tertiary thioamides into their corresponding enaminones. An example of this work is shown in Eq. 7. The reaction was unsuccessful with sterically hindered thioamides.51a

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A tentative mechanism for the formation of enaminones from metal catalysts is shown below (Scheme 28). Carbenoid 123 is formed by the reaction of a metal catalyst 121 on diazo compound

13

122. Nucleophilic attack of thioamide 124 on carbenoid 123 generates ylide 125, which evolves into metal-free ylide 126 by the dissociation of the catalyst. Ylide 126 undergoes cyclization to provide episulfide 127. Expulsion of sulfur from 127 produces enaminone 128.51 The formation of thiol 119 in Scheme 27 can be explained as a result of the isomerization of its episulfide.52 It is mentioned in the literature that the reductive elimination of episulfide 127 to 128 (Scheme 28) is facilitated by the reaction of an additional diazo compound.49,50 However, with ruthenium carbenoids, only a small excess of diazo compounds was used while the reductive elimination through excess carbenoid requires at least two equivalents of a diazo compound.49 It is also known that dimerization is a competing pathway in the reaction of metal carbenoids.47a Therefore, the excess diazo compounds reported in these reactions probably dimerized rather than facilitated the reductive elimination of episulfides. One limitation of the use of diazo compounds in the sulfide contraction method is due to the regioselective formation of tosylhydrazones. During the synthesis of the benzazepine substructure, the regioselective formation of a tosylhydrazone was attempted on 130 (Scheme 29). Instead of the desired hydrazine on benzylic carbonyl, the reaction produced 131. The formation of the undesired regioisomer was confirmed by the conversion of 131 into diazo ketone 132 and its subsequent reaction with Rh2(OAc)4, which gave 133.47b Another issue with the metal-catalyzed Eschenmoser sulfide contraction is that the reaction can stop at the thioether stage and no enaminones are obtained. This was observed when thioamide 134 was reacted with ethyl diazoacetate in the presence of Grubbs1 catalyst. Instead of the desired enaminone 136, thioether 135 was obtained (Eq. 8).

Scheme 28. Proposed mechanism for the formation of enaminones in the metalcatalyzed coupling of thioamides and diazo compounds.

Scheme 29. Issue of regioselectivity in the hydrazone formation.

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The formation of thioether 135 indicated that the corresponding episulfide was not formed. It was speculated that the episulfide formation (Scheme 28, 126/127) failed because compared to diesters (126, R¼ester), the anion 126 is less stabilized in monoesters (126, R¼non-ester). As such, instead of an episulfide formation,

In the case of monothioimides, carbonyl olefination competes with thio-olefination (Eq. 9).55,57 When five-, six- and sevenmembered thioimides 141 were reacted with ester ylide 142, the reaction produced amide 143 along with small quantities of thioamide 144.

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a proton transfer occurred from the nitrogen atom (R1 or R2]H) to the anion 126 giving thioether.51a Such thioethers are also formed in the Eschenmoser sulfide contraction reaction via alkylative precoupling and they can be converted into enaminones by reacting them with a strong base and a thiophile.1a,53 3.3. Wittig reaction with thioimides The Wittig reaction with thioamides is also known as the thioWittig reaction.21a,31 However, the term thio-Wittig includes all reactions between thiocarbonyl and Wittig reagents.54 Therefore, this reaction is a subclass of the thio-Wittig reaction. Gossauer and co-workers discovered that thioamides can be coupled with resonance-stabilized ylides to give enaminones. When thioamide 137 was reacted with ylide 138, enaminone 139 was produced regioselectively (Scheme 30). The reaction was successful with fiveto seven-membered monothiocarboximides (monothioimide).55 Gossauer and co-workers also reported the synthesis of acyclic enaminones via the coupling of acyclic thioimides and resonancestabilized ylides.56 The enaminone products could be hydrolyzed to give 1,3-dicarbonyl compounds.56a

Another reaction that competes with the thio-Wittig reaction is the S-alkylation reaction (Scheme 32). When thioimide 137 was reacted with ylide 145, it gave 38% of enaminone 146 and 54% of S-alkylated product 149. Formation of 149 was proposed as a result of the removal of the NH proton by the ylide generating 147 and 148. The anion 147 is then S-alkylated with the phosphonium intermediate 148 producing thioether 149. Treatment of 149 with triphenylphosphine and 145 under the reaction conditions led to a quantitative recovery of starting materials. This indicates that the formation of 146 and 149 occurs through two independent pathways. Hence an alternative mechanism, involving S-alkylation and episulfide formation leading to 146 is, therefore, unlikely.31 Rapoport and co-workers concluded that the thio-Wittig reaction is dependent on the structure of both the thioamide and the ylide and is sensitive to steric effects.31 Compared to the reaction of 145, a higher yield of thio-Wittig product 139 was obtained when benzyl ester ylide 138 (Scheme 30) was coupled with 137. This is because ylide 145 acts more like a base than a nucleophile. As a base, it deprotonates the imide, generating 148, which then leads to the S-alkylated product 149.31 The Wittig reaction with thio-

Scheme 30. Wittig reaction between a thioimide and a resonance-stabilized ylide.

The proposed reaction mechanism for the thio-Wittig reaction resembles the Wittig reaction (Scheme 31). Thus, intermediates betaine 79 and thiaphosphetane 80 are involved.31

imides is sensitive to the structure of the thioamide substrate as well. The reaction of 137 gave Wittig product 146 and S-alkylated product 149. On the other hand, the reaction of regioisomer 150 (Fig. 4) with 145 resulted in oligomerization or decomposition. Calculations performed using modified neglect of diatomic overlap (MNDO) methods indicated that taking the thiocarbonyl out of conjugation increases the energy of its LUMO relative to 137, and as such no thio-Wittig product is observed with 150. A very favorable 1,4-addition is possible on 150 by the anion of 150, which could explain the formation of the oligomers.31,58 3.4. Bromine-induced cyclization

Scheme 31. Proposed mechanism of the thio-Wittig reaction.

Sundberg and Pearce reported a cyclization reaction, which likely goes through the Eschenmoser sulfide contraction. The proposed mechanisms (Scheme 33) involve bromination of the enol or bromination at the sulfur atom. The first mechanism is similar to

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Scheme 32. Competing S-alkylation pathway in the thio-Wittig reaction.

thioamides are unsuitable substrates in the Eschenmoser sulfide contraction reaction.60

(10) Fig. 4. Regioisomer 150 failed to undergo the thio-Wittig reaction.

the alkylative precoupling process (Scheme 9), while the second is similar to the oxidative precoupling process (Scheme 7). In either process, the product 155 is formed probably after the aromatization of intermediate 154.43 An intermolecular version of this reaction would be very useful because the synthesis of monohalogenated acarbonyl compounds can be challenging.21b

The mechanism of thio-Reformatsky reaction is speculated to be the one shown in Scheme 34.61 The zinc enolate 158 adds to the C] S generating 159. Intermediate 159 picks up a proton from adventitious moisture present in the reaction conditions to form 160 and 161. Expulsion of the hydrosulfide anion from the N,S-acetal 161

Scheme 33. Cyclization via the modified Eschenmoser sulfide contraction reaction.

3.5. The thio-Reformatsky reaction Michael and co-workers discovered that thioamide 156 coupled with 71 in the presence of zincecopper couple (Eq. 10). Even though the reported yield (47%) was modest, it was better than the Eschenmoser sulfide contraction reaction via alkylative precoupling under various conditions (5e33%). Therefore, the reaction complements the Eschenmoser sulfide contraction method.59 The thio-Reformatsky reaction is also successful with thioamides where the nitrogen atom is protected as a carbamate or an amide. Such

forms 162. Deprotonation of the iminium 162 gives 157 and liberates H2S. The production of H2S has been noted during such reactions.61 It is also possible that the intermediate 159 is protonated during the aqueous workup. As such, it would immediately lose H2S, leading to an iminium and, after tautomerization, to product 157.33 An alternative proposed mechanism for the thio-Reformatsky reaction involves the removal of the alpha proton by the excess Reformatsky reagent (Scheme 35). Sulfur leaves as zinc sulfide. This mechanism does not involve the generation of H2S.62 However, zinc

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Scheme 34. Tentative mechanism of the thio-Reformatsky reaction.

enolates are renowned for their low basicity, which makes the deprotonation step (159/163) unlikely.63

the enol was accomplished with a residence time of 70 s. The same reaction with a comparable yield took overnight using a conventional setup. Grob and co-workers studied the kinetics of sulfide contraction under flow conditions.65 The contraction step was found to be of first order for thioether and an activation energy EA of 91 kJ/mol was determined. The authors commented that this activation energy is the reason for the slow reaction kinetics at lower temperatures. This is why the application of pressurized high temperature conditions led to the rapid formation of the coupled product.65

Scheme 35. An alternate proposed mechanism for the thio-Reformatsky reaction.

4.2. Sonication 3.6. Selenoamides Hussaini and Hammond studied the Eschenmoser sulfide contraction reaction of selenoamides.64 They reported a faster alkylation step (Scheme 9) with selenoamides compared with thioamides. However, the contraction step was found to be much slower with selenium. The authors speculated that compared to an episulfide, the formation of an episelenide is less likely due to the greater size of the selenium atom. Only a few cyclic selenoamides were coupled with a-bromodicarbonyl compounds to give enaminones in low yields (Eq. 11).

In 2013, Hussaini and co-workers reported the use of sonication in the Eschenmoser sulfide contraction method under heterogeneous conditions.21b Use of sonication accelerated the formation of enaminones and the reaction time was reduced from days to hours. Sonication can accelerate reactions in a number of ways. In the case of secondary thioamides, the rate enhancement was found to be mainly due to the reduction in size of Na2CO3 particles. With tertiary thioamides the reduction in the particle size of Na2CO3 was not solely responsible for the rate enhancement. Other factors, such as high temperature and pressure were found to be important as well. The method was successful in coupling primary, secondary and tertiary thioamides with a-bromocarbonyls (Eq. 12).

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4. Other improvements 4.1. Flow chemistry Grob and co-workers studied the Eschenmoser coupling reaction under continuous-flow conditions.65 A thioamide, aromatic thiols and a thiourea were coupled with aromatic bromoketones. The flow reaction was found to be faster than the conventional method for the sulfide contraction step. For flow reactions, the following reaction conditions were used: 0.1 M solution of 164 in anhydrous 1,4-dioxane, 1.25 equiv of triisopropyl phosphite at 225  C, 100 bar pressure and 250e750 mL/min flow rate (Scheme 36). Under flow conditions, the conversion of thioether 164 into

(12) 5. Stereochemistry of products The E and Z isomers of enaminones can be observed in two conformations. These are shown in Fig. 5.38 When secondary thioamides are used in an intermolecular reaction, the Z isomer can be obtained exclusively. The rationale for this is the stability of the ZZ conformation that can form the NH/OC bond.1a,38 Similarly, in the

Scheme 36. Use of flow chemistry in the Eschenmoser sulfide contraction reaction.

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Tertiary thioamides reacting with monosubstituted electrophiles give mainly E products.51b,67b,71 The reaction of thioamide 168 with 169 produced single E isomers 170a and 170b (Eq. 15).67b The rationale for E selectivity is that the E isomer is the thermodynamic product. The E configuration minimizes the A1,3-strain.51b Fig. 5. ZZ, ZE, EZ, and EE conformers of enaminones.

vinylogous amidine system, the NH/NH]C bond is formed and the Z isomer can be obtained exclusively.1a Eschenmoser and co-workers showed that in intermolecular reactions, the coupling of secondary thioamides with monosubstituted electrophiles can selectively produce Z isomers (Eq. 13). The Z selectivity was explained as a result of the formation of a thermodynamically more stable product. As mentioned above, in the ZZ conformation, a compound can have intramolecular hydrogen bonding between the NH and the CO.1a The E/Z equilibrium has been observed spectroscopically in related systems (Scheme 20).38 Preference for the Z isomer in the alkylation of enaminones of secondary thioamides also suggests the possibility of such an equilibrium.66 The equilibrium should provide the thermodynamic Z product. Preference of Z isomers in the coupling of primary and secondary thioamides with a-halocarbonyl compounds has been observed in most instances.18,21b,51a,67

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With disubstituted electrophiles, more stable products are obtained predominantly.21b,51b,72 Thus, the reaction between thioamide 168 and diazodicarbonyl 171 gave enaminone 172 (Eq. 16). Simple molecular modeling calculations suggest that the Z isomer was 4.7 kcal/mol less stable than the E isomer.51b

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(13) When the electrophile is a disubstituted compound, the major or sole product is the one with a stronger hydrogen bond.21b,35a,67b Thus, coupling of thioamides 32 and 165 with 166 gave single isomers E-167a and E-167b (Eq. 14).21b Since these reports do not discuss relative H-bond strengths other explanations are also possible. Furthermore, the strength of an H-bond between an NeH and either an ester or a ketone carbonyl, such as in 167, is expected to be negligible. Perhaps only one of the carbonyl groups is coplanar with the enamine fragment in 167. This will allow only the coplanar group to be conjugated to the enamine. The other carbonyl-based group will twist out of plane to avoid A1,3-interactions with C3 of the pyrrolidine ring. Ketone is likely to be coplanar as this will allow the ester to avoid severe A1,3-interactions with C3 of the pyrrolidine ring.68 If ester is coplanar with the enamine then it would conjugate with the enamine. This would disrupt the ester resonance.69 Furthermore, ketone is a better electron acceptor than an ester. A better electron acceptor can maximize the overall stabilization between electron donor-acceptor systems. Electron donor-acceptor systems are maximally stabilized when electron donors are maximally rich and acceptors are maximally deficient.68 However, this explanation is not well-supported by the crystal structure of 167a, which shows the ester carbonyl to be nearly coplanar to the enamine.70

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5.1. Assignment of stereochemistry The stereochemical assignment of E and Z of enaminones is commonly done with the help of NOE analysis.51b However, in the case of tetrasubstituted enaminones it can be challenging. It was reported that no diagnostic NOE enhancements could be observed for 173 (Fig. 6).73 Nonetheless, the 2D NOESY analysis was used successfully in determining the stereochemistry of 174 (Fig. 6). Cross peaks between the benzylic hydrogens and the keto phenyl hydrogens indicated that the configuration of the double bond is E in 174.74

Fig. 6. Assignment of double bond configuration in tetrasubstituted enaminones using 2D NMR.

The stereochemical assignment of some trisubstituted enaminones can be challenging.67a Elliott and Wordingham reported observing only small NOE enhancements between the alkene CH and the allylic CH2 of compounds 51 and 175 (Fig. 7). They mentioned that since both the NH and the alkene CH protons are exchangeable, the NOE enhancements between them should not be used as an indication of E or Z stereochemistry.67a Enaminones produced from tertiary thioamides usually provide the characteristic NOE interactions.51b,67b The stereochemistry of 176 and related compounds was determined by observing the NOE enhancements between alkene CH and benzylic H’s.67b In vinylogous amidine systems the stereochemistry is also determined similarly.75

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comparison.67a For example, in the secondary enaminone 51, where the ZZ structure is favored due to hydrogen bonding, the C-3H’s appear at 2.59 ppm1a while in 180 these protons appeared at 3.04 ppm (Fig. 9). Therefore, the stereochemistry of 180 was assigned as E.78

Fig. 7. Use of NOE in assigning E/Z stereochemistry of trisubstituted enaminones.

Stereochemical assignments of tri- and tetrasubstituted enaminones can be determined by 1H NMR shift reagent studies.76 Two 1 H NMR shift reagents, Eu(fod)376a and Eu(dpm)3,76b,c have been reported. A large deshielding for C-3H’s in the presence of a 1H NMR shift reagent indicated that the carbonyl is near the C-3H atoms (177 E isomer, Fig. 8),76b,c while the absence of large deshielding effects for C-3H’s indicated that the two groups are opposite (178 Z isomer).76b The method was also successful in predicting the stereochemistry of tetrasubstituted enaminones (179 E isomer).76a Only one of the four groups should preferentially bind with the shift reagent to give unambiguous results.76a

Fig. 8. Use of 1H NMR shift reagents in the stereochemical assignment of enaminones.

When the NOE data is ambiguous, the NH chemical shift can be used to determine the stereochemistry of tri- and tetrasubstituted cyclic compounds that are secondary enaminones.21b,35a,51b,77 By comparison of the chemical shift of amine protons of compounds having an identical functional group, one can find the position of the non-identical groups. For example, the chemical shift of 11.53 of entry 3 (n¼1) when compared with entries 1 and 2 suggests that the stereochemistry of the compound is E (R1]CH3, R2]OEt) (Table 2). The NH hydrogen is significantly more deshielded in the E isomer as a result of stronger H-bonding with the ketone oxygen.77b

Fig. 9. Deshielding magnetic anisotropy effect of carbonyl function on C-3 hydrogens in determining the double bond configuration.

Before the use of NOE experiments became commonplace, IR frequencies were used to determine the stereochemistry of secondary enaminones.1a,55,77a,79 In the presence of an intramolecular NH/CO hydrogen bond, the NeH stretching frequencies are independent of the concentration of an enaminone. Thus, IR spectra were taken at various concentrations and if the NeH stretching band frequency remained constant, the stereochemistry was assigned as Z for trisubstituted enaminones.1a,55,79 The stereochemistry of vinylogous amidines can also be determined similarly.1a The IR absorption band for a carbonyl group can also be used in determining the E or Z stereochemistry of a secondary enaminone.35a Hydrogen bonding lowers the carbonyl frequency of a carbonyl group.80 Bachi and co-workers used this argument to support the assignment of E stereochemistry to diester 181 (Fig. 10). The IR absorption band for the a,b-unsaturated ester carbonyl 181 appeared at a frequency comparable to that of triester 182, concluding that the alkenic ester in 181 is not hydrogen bonded.35a The above mentioned 1H NMR and the IR frequency comparisons are still used to assign the stereochemistry of compounds that do not give good NOE interactions (see above).21b,67a No incorrect assignments have been reported as a result of these non-NOE-based methods and in some instances the stereochemical assignment has been confirmed by X-ray crystallography.70,81 As such, when used together, these methods are reliable in the determination of E/ Z stereochemistry of enaminones and vinylogous amidines.

Table 2 NH chemical shifts of enaminones

Entry

R1

R2

n¼1

n¼2

n¼3

1 2 3 4 5 6

OEt CH3 CH3 (CH2)2eCH3 CH(CH3)2 Ph

OEt CH3 OEt OEt OEt OEt

9.33 11.40 11.53 11.57 11.47 10.90

9.91 12.50 12.58 12.58 12.45 12.50

9.66 12.10 12.13 12.25 12.15 11.85

The 1H chemical shift of C-3H’s in the EZ isomer is subjected to the anisotropic effect of the carbonyl function. These H’s are significantly deshielded (w0.5 ppm) compared to the ZZ isomer and this observation can be used to determine the E and Z stereochemistry of enaminones.66,67,71,78 Because the 1H NMR of both isomers of a single enaminone is generally not available, chemical shift values of closely related compounds have been used for

Fig. 10. Determination of the E/Z stereochemistry of secondary enaminones using IR carbonyl absorption frequencies.

In addition to the above mentioned methods for the assignment of stereochemistry, the magnitude of the extinction coefficient in the UV spectrum had also been used in the past to support the stereochemical assignment of enaminones. The molar extinction coefficient of E isomers in general is much greater than the Z isomers.39c,71,78 Ultraviolet spectroscopy had been especially helpful in the structural assignment of complex vinylogous amidines such as corrins.9 Whenever possible, X-ray crystallography has been used for the unambiguous assignment of vinylogous amidines8 and enaminones.70,81

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6. Limitations of the Eschenmoser coupling reactions 6.1. Sulfide contraction via oxidative precoupling Oxidative coupling of substituted 2-thiopyrrolidones is an excellent method for making vinylogous amidines. However, unsubstituted thiopyrrolidones fail to undergo the Eschenmoser sulfide contraction process using the oxidative precoupling method. Thus, when thiolactam 32 and enamide 93 were reacted in the presence of benzoyl peroxide, thioether 96b could not be detected (Scheme 37). The cause of this failure is the formation of extremely labile 183 that, instead of acting as a coupling partner in the reaction, decomposes under the reaction conditions. Compared to 183, the substituted analog 105 is much more stable and gives 97a in excellent yield (90%). The iodinative coupling variant (Section 3.1) overcomes this issue and provides both 97a and 97b in excellent yields.40 The stability of disulfide is crucial in the oxidative precoupling method. Other labile groups, such as a methoxy instead of a cyanide group in 95 also fail to undergo the sulfide contraction via oxidative precoupling reaction with other enamides.7,82

Scheme 38. Limitation of the sulfide contraction via oxidative precoupling method due to the structural feature of enamides.

Scheme 37. Limitation of the sulfide contraction via oxidative precoupling method due to the structure of thioamides.

During the construction of the A/D secocorrin model, Eschenmoser and co-workers found that the disulfide 105 does not react with the enamide 184 under acidic or mild basic conditions to produce 185. Eventually, the use of t-BuOK was able to form the thioether 185 in 31% yield (Scheme 38). After optimization 45e50% yield of 185 could be obtained. Thioether 185 could be transformed into 186 using triphenylphosphine and the triphenylphosphineboron trifluoride complex. This issue suggests that the sulfide contraction via oxidative precoupling is also sensitive to the enamide structure (compare Schemes 37 with 38).7,82 The iodinative coupling variant overcomes this issue and provides 185 in 70% yield (Scheme 38).40

an a-bromodiester, an a-bromo-b-ketoester (Eq. 17) and a brominated lactam.21b,84

6.2. Sulfide contraction via alkylative precoupling

6.2.2. Steric issues. During the total synthesis of indolizomycin, Danishefsky and co-workers were unable to prepare enaminone 189 via the Eschenmoser sulfide contraction reaction on 188 and only starting materials were recovered. The result suggested that the alkylation of the thioamide did not occur.50,85 The authors speculated that the steric hindrance from the fused cyclopropane is responsible for the failure of the SN2 reaction. Since the alkylation of a thioamide is a reversible process (Section 2.2), it is not an unexpected result. The issue was resolved by using ethyl diazoacetate in the presence of catalytic Rh2(OAc)4 (Eq. 19).50

6.2.1. Issues with primary thioamides. It is mentioned that primary thioamides can undergo a competitive removal of the nitrogen proton during sulfur extrusion generating nitriles.20,21 The coupling of primary thioamides with a-bromo-b-ketoesters is also generally considered to be unsuitable in generating enaminones. In fact, the coupling is used to prepare thiazoles and is known as the Hantzsch thiazole synthesis.83 However, recent examples of the Eschenmoser sulfide contraction of primary thioamides have been reported with

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The problem with reversibility in the S-alkylation step (Section 2.2) of sterically hindered thioamides was tackled differently by Rapoport and co-workers (Eq. 19).20 The difficulty in the S-alkylation of sterically hindered thioamide 190 was attributed to the formation of a highly congested salt 192, which causes the equilibrium to shift to the side of thioamide 190. It was observed that by changing the leaving group (X) on the electrophile, the S-alkylation can be made irreversible. The trifluoromethanesulfonyl group was found to be the best leaving group among the ones that were tested and produced 192. The triflate salt 192 did not show any reversible formation to thioamide 190.20,21

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Eschenmoser sulfide contraction reaction on 193c also failed. In this case, no S-alkylation occurred when 193c was reacted with 194. The authors speculated that this could be due to larger steric hindrance of the silyloxy group compared with the acetyl group in 193a.86 The problem of the competing elimination reaction was addressed by performing the sulfide contraction reaction on a deprotected and epimerized thioamide 197 (Scheme 40). The elimination was suppressed when 197 was used as a substrate in the sulfide contraction reaction and enaminone 198 was obtained in good yield. Enaminone 198 was deprotected to give plakoridine A (199).86 6.2.4. Issues when nitrogen of thioamide is N-acyl or N-aryl. There are no reports of the Eschenmoser sulfide contraction reaction on thioamides where the nitrogen atom is protected as a carbamate or an amide. When Lee and co-workers applied the sulfide contraction reaction on 200, no formation of enaminone 201 could be observed. They speculated that the reaction failed probably because of the reduced nucleophilicity caused by the negative inductive effect of the BOC group.60 It can be argued that the delocalization of the nitrogen lone pair could be responsible for such a lack of reactivity. The thio-Wittig reaction gave the desired enaminone in low yield. Finally, a thio-Reformatsky reaction was used to form the enaminone (Eq. 20).60 Similar problems were reported earlier by Michael and co-workers for the sulfide contraction reaction of N-aryl thioamides.59,87

6.2.3. Competitive elimination reaction. During the total synthesis of plakoridine A, Ma and co-workers observed that if thioamides 193a and 193b were reacted with bromide 194 in the presence of silver triflate, followed by treatment with PPh3 and Et3N, it did not give the desired enaminone 195 and instead delivered a polysubstituted pyrrole 196 (Scheme 39). Attempts to perform the

(20) It is possible to make the N-acyl enaminone via carbamoylation of secondary enaminones that can be prepared by the Eschenmoser sulfide contraction reaction. Since these enaminones derived from secondary thioamides still have NeH functionality, they are amenable to carbamolylation.53 6.3. Challenges with the sulfur extrusion

Scheme 39. Formation of a substituted pyrrole during the Eschenmoser sulfide contraction reaction.

6.3.1. Disulfides and thiol formation. Knott observed that when 26 was treated with an aq NaOH solution, it led to the formation of disulfide 203 as a result of oxidation. The reaction indicated that episulfide 28 breaks down, at least in part, to the thiol anion 202, which is susceptible to oxidation, giving disulfide 203. The

Scheme 40. Successful application of the Eschenmoser sulfide contraction reaction in the synthesis of plakoridine A.

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breakdown of episulfide 28 into its anion can be reduced with weaker bases such as triethylamine. Thus, treatment of 26 with Et3N produced only a very low yield of 203.15a In some instances, the Eschenmoser coupling reaction provides enethiols (Schemes 4 and 27) instead of enaminones.9,17,27,50,88 This can be explained as a result of the formation of an anion of type 202 that provides enethiols after protonation. Sulfur extrusion in these instances has been carried out either with the help of a thiophile under acidic conditions9 or by reacting an enethiol with deactivated W-2 Raney Nickel.46 Attempted sulfur extrusion of pyrimidinone 204a also gave an unexpected product 206 (Scheme 42). The formation of product 206 can again be explained as a result of the formation of an enethiolate of type 202 (Scheme 41).22a The formation of 206 was avoided by replacing the hydrogen (R]H) with the methyl group (R]CH3). Apparently, steric crowding facilitates sulfur extrusion and 207 could be obtained.22a It was hypothesized that the rate and course of the contraction may be affected because of the conformations of the contracting intermediates. With R]H, conformation 208 is lower in energy and it leads to product 206 via the attack of the enol from ‘behind’ the C]N bond. With R]CH3, conformation 209 is preferred as the SeCH]C(OH)-residue points away from the methyl group on the ring. In this case, the enol carbon attacks the C]N bond from the ‘front’ and it leads to product 207.22a,36

21

tautomerism pathway to the tetrasubstituted alkene is disfavored due to the A1,3-strain (R]CH3). When R]H, the A1,3-strain is much less and there is a relatively less energetic penalty to make the tetrasubstituted alkene product 206 instead of the sulfur extrusion product 207.68 Hussaini and co-workers observed a similar episulfide opened product in a non-aromatic system. When 165 and 210 were sonicated in the presence of Na2CO3, only 28% of the desired enaminone 211 was obtained (Scheme 43). The major product of the reaction was a thiol 212. Unlike the examples above for the formation of

Scheme 43. Formation of an unexpected thiol in the sulfide contraction reaction.

Scheme 41. Formation of disulfides in the sulfide contraction method.

enethiols, in this case there is no a-carbonyl proton and therefore the product is the thiol 212, which is probably formed via 213.21b

Scheme 42. Steric crowding leading to a desired enaminone during the sulfur extrusion process.

It is possible that once 205 fragments with the help of the nearby nitrogen atom, the resulting zwitterionic intermediate of type 92 (Scheme 19) either tuautomerizes to give 206 (when R]H) or extrudes sulfur to give 207 (when R]CH3) (Scheme 42). The

6.3.2. Epimerization. In the synthesis of vitamin B12, thioamide 214 and enamide 215 were coupled to give thioether 216. When the resulting crude product 216 was heated at 120  C with trimethyl phosphite, a mixture (2:1) of epimeric (indicated with a * sign) vinylogous amidines (217) was obtained. Since both diastereomers could be used for the synthesis of vitamin B12, it was of no consequence.10,14a,89 Nonetheless, this example does show that the common conditions needed for the sulfide contraction process could result in epimerization. A similar phenomenon has been observed in other instances.75 In the case of 216, the sulfide contraction reaction can occur at a lower temperature (50  C) if Ni(ClO4)2 is used instead of P(OEt)3 and pure 217 could be obtained without any epimerization. However, in this case the yield drops to 32%.10,89 Nickel-catalyzed sulfide contraction has been used in other cases as well to perform the reaction under mild conditions.40b It is presumed that complexation with nickel shifts the balance of the thioether $ episulfide equilibrium in favor of episulfide formation (Eq. 21).82 This is because the coordinative bridging of nitrogen

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Scheme 44. Epimerization during the sulfide contraction process.

atoms with the metal would result in a steric acceleration of the process.14b

trimethyl phosphite, w20% yield of fuligocandin B (224) could be obtained as a result of the Eschenmoser sulfide contraction and Ndeprotection. Unfortunately, the product (224) was found to be a racemic mixture. The authors speculated that the racemization probably happens because of basic conditions, which cause tautomerization. Indeed, when 223 was heated in DMSO, in the absence of both the base and the thiophile, 225 was obtained in an enantiopure form. Compound 225 was converted into (þ)-fuligocandin B by carefully chosen N-deprotection conditions.18

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Shiosaki and Rapoport alkylated thiolactam 70a with triflate 218 (Scheme 45). When the salt was reacted with PPh3 and Et3N, it gave a mixture of diastereomers 220 in which optical purity at C-2 had been compromised. Attempts to improve the ee by using a secondary amine or a hindered base led to unwanted reaction products. It was found that lowering the temperature at which the sulfide contraction was performed from 20  C to 0  C greatly improved the ee. Decreasing the base strength also improved the ee. The best conditions were obtained when PPh3 was added before the base. Then the base N-methylpiperidine was added at 0  C. Vinylogous carbamate 220 was obtained in 70% yield possessing 96% ee.90 Similar observations about racemization and its control via low temperature sulfide contractions were recorded during the synthesis of (þ) and ()-anatoxin.91

Scheme 45. Issue of enantiomeric purity in the sulfide contraction.

During the synthesis of fuligocandin B, Bergman and co-workers attempted the coupling of monothiocarbonyl 221 with chloride 222 (Scheme 46).18 They found that in the presence of DABCO and

Scheme 46. Challenges in the enantioselective synthesis of fuligocandin B.

6.3.3. Use of nitrogen complexing reagents. In the synthesis of the A/D secocorrin model, the sulfide contractionesulfur extrusion on 185 did not occur with P(OEt)3, which was effective during the synthesis of vitamin B12 (Section 6.3.2, Scheme 44). Heating 185 with P(OEt)3 at 130  C (with the catalytic amount or an equivalent amount of KOt-Bu and DIPEA or with a trace of p-TsOH) gave back unchanged starting material. Heating 185 with P(OEt)3 at 200  C (without solvent) resulted in a complex mixture, which contained eight products in addition to the unchanged starting material.82 When the sulfide contraction was attempted with nickel(II) perchlorate at 115  C, 185 did give 186 (Eq. 22). However, it was unknown whether the reaction could be conducted at a lower temperature. Due to instability of perchlorates at high temperatures, the reaction was not optimized and attempts were continued to find a metal-free alternative for the sulfide contractionesulfur extrusion reaction. Furthermore, the reaction with Raney Nickel also did not give 186 and instead a nickel complex 226 was obtained (Eq. 22). Formation of 226 suggested that a similar process

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may be involved with nickel(II) perchlorate. If so, it was unlikely to achieve the sulfide contraction at room temperature with nickel(II) perchlorate.82

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When more basic phosphines (PPh3 and PEt3) were employed, a slow reaction was observed and under optimized conditions (heating at 152  C for six days), 25% of 186 was obtained (Eq. 23). A breakthrough in the sulfur elimination reaction occurred when boron trifluoride (in the form of the PPh3 adduct) was used in the transformation. In DMF, the reaction was completed faster and at a much lower temperature (3 days at room temperature followed by 16.5 h at 45  C). The product 186 was obtained in 27% yield along with an isomer in 49% yield. Encouraged by this result, better conditions were sought and it was found that when the reaction was heated in benzene at 80  C for three hours, 186 could be obtained in 70e80 % yield.7,14b,82 It was supposed that BF3 facilitates the sulfide contraction by complexation of one or more nitrogen atoms. The process is similar to the nickel(II) desulfurization process shown in Eq. 21.7,14b,82

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Perhaps the most difficult challenge, and its solution posed by the sulfide contraction-sulfur extrusion process, was observed during the synthesis of vitamin B12 (A/B variant). Under a variety of conditions using P(OEt)3 as the thiophile, the reaction did not proceed as desired (Eq. 24).12 The cause of these failures was the easy formation of the type II thioether 229 from the type I thioether 227 under the acidic conditions used for desulfurization (Eq. 25). Type II ether 229 is relatively stable and lacks structural features required (thioiminoester substructure) for the desired CeC bond forming reaction.12 It was found that the type I thioether 227 could be converted into type II 229 and type III 230 thioethers under basic conditions (Eq. 26). The type III thioether 230 is a tautomer of the type I thioether 227 and unlike the type II thioether 229, it does retain the C]N bond of ring C that is needed for the sulfide contraction.12 The type III thioether 230 could be desulfurized to the vinylogous amidine 228 (corrigenolide) by means of the boron trifluoride-catalyzed process (Eq. 27). However, the reaction required utmost care and the very best experimental skills. Complete exclusion of oxygen and moisture and every conceivable precaution with respect to purity of reagents was necessary for the preparation of 228. In Woodward’s words, ‘The first preparation of corrigenolide afforded striking testimony of the experimental skill of its discoverer, Dr. Yoshito Kishi.’y Therefore, it was difficult to develop this procedure into a reproducible method for the relatively largescale preparation of 228 that was needed. Also, even under the best conditions, the coupling of C and D rings did not produce more than 40% yield.12,92

y Yoshito Kishi is an emeritus professor at Harvard University. He is considered to be one of the masters of organic synthesis in our time.

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(25)

(26)

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Eschenmoser and co-workers discovered that if the type I thioether 227 is converted into a methyl-mercury derivative 231, then the latter can be converted into 228 by the boron trifluoridecatalyzed procedure (Scheme 47). The event provided valuable quantities of 228, which were used in the forward exploration during the synthesis of vitamin B12.10,12

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6.3.4. Use of complementing Eschenmoser sulfide contraction reactions. During the synthesis of isobacteriochlorins and (metalfree) C,D-tetradehydrocorrins via sulfide contraction, Eschenmoser and co-workers observed that thioether 234a, prepared via alkylative precoupling, did not undergo sulfide contraction under all the conditions that were attempted (Scheme 48). The failure was

Scheme 47. Conversion of a type I thioether into corrigenolide 228.

The above procedure for sulfur extrusion was not always reproducible. The reaction was sensitive to the aging of the triphenylphosphine/boron trifluoride reagent. An either too old or too freshly prepared adduct did not give desired results. Furthermore, the yield of 228 could not be increased to more than 40%.12 Ultimately, the transformation was realized when thioether 229 was heated with tris(2-cyanoethyl)phosphine and TFA in sulfolane (Eq. 28). The choice of solvent in this procedure was critical and gave 85% of the desired product 228. The isolation and purification of 228 also presented obstacles as the compound was found to be a participant in equilibrium among a number of tautomeric species. The equilibrium was easily established during chromatographic steps. This problem was finally surmounted by performing all chromatographic purifications in the complete absence of oxygen.12

attributed to 234b that has to be formed before the episulfide formation. ‘A structure of type 234b, especially its NHdeprotonated form, would be destabilized as a consequence of the conjugative destabilization that is expected to occur in vinylogues of hydrazine.’41d,93 Eschenmoser and co-workers circumvented the above issue by performing B/C coupling via the oxidative method (Scheme 49). Thus, enaminone 236 and thioamide 237 were coupled under oxidative conditions to give thioether 238. When thioether 238 was treated with TFA/sulfolane in the presence of a thiophile, it afforded the tetracycle 239 as a mixture of diastereomers. Under the above sulfide contraction conditions, the ester 238a first hydrolyzes (238b) and decarboxylates (238c) before undergoing the sulfide contraction step.41d

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Scheme 48. Failure of the sulfide contraction step in the coupling of B and C rings.

Scheme 49. Synthesis of 240 via oxidative precoupling process.

However, the oxidative precoupling method was proven to be inefficient in coupling 236 with 241. The solution was found when the modified iodinative coupling (Section 3.1) process was utilized (Scheme 50). Thioamide 241 was oxidized to disulfide 242, and 236 and 242 were coupled by the action of iodine to give 243. Thioether 243 underwent sulfide contraction and was isolated as nickel complex 244. Compound 244 was transformed into C,Dtetrahydrocorrin 245.41d 6.3.5. Use of protecting groups. The sulfide contraction of a secondary thioamide typically requires harsher conditions than a tertiary thioamide. Robinson and co-workers overcame this issue by protecting secondary thioamides as tertiary thioamides. After performing the sulfide contraction reaction on these tertiary thioamides, the nitrogen was deprotected to generate the desired enaminones.94 Thus, thiolactam 246 was converted into acrylate adduct 247 on treatment with methyl acrylate and a catalytic amount of sodium hydroxide. Adducts 247, being tertiary

thioamides, could be converted into enaminones 248 under mild Eschenmoser sulfide contraction conditions. Finally, methyl acrylate was cleaved using KHMDS to give 249 (Scheme 51). Quaternization of thioethers have also been used to facilitate sulfide contraction. Knott reacted bromide 250 with thiazole 251 in the presence of a base to give sulfide 252. Sulfide 252 was converted into thiacyanine 253 by quaternization with either methyl iodide or methyl sulfate (Scheme 52).15b In the case of complex electrophiles, other side products could also form in the sulfide contraction reaction. When thioamide 254 was heated with bromide 255 in the presence of sodium bicarbonate, it gave 256 as the sole recognizable product in 58% yield (Scheme 53). When 254 and 255 were heated first and then the reaction was treated with PPh3 and Et3N, it gave better results and enaminone 257a could be isolated in 30% yield. The yields were improved drastically (257b) when the tertiary thioamide 70a was employed in the reaction. Tertiary thioamides are known to perform better in the sulfide contraction step (Section 2.2).5,96

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Scheme 50. Synthesis of C,D-tetrahydrocorrin 245 via the Eschenmoser iodinative sulfide contraction reaction.

6.3.6. Issues with six-membered thioamides as coupling partners. In 2001, Michael and co-workers reported the influence of ring size on the outcome of the Eschenmoser sulfide contraction reactions. Thioamides 258, 165 and 259 were reacted with ethyl bromomalonate and a base to give putative thioethers 260aec (Scheme 54). Thioethers 260a and 260b on heating provided 261a and 261b, while thioether 260c on heating did not give the enaminone 261c and instead thiazolidinone 262 was obtained.97

Scheme 51. Formation of secondary enaminones under mild conditions (i) BrCH2CO2Et, t-BuOK, Ph3P, xylene; reflux95 (ii) CH2]CHCO2CH3, NaOH; (iii) BrCH2CO2Et, Et3N, Ph3P; (iv) KHMDS.

Scheme 54. Formation of thiazolidinone in the sulfide contraction reaction. Scheme 52. Sulfide contraction via quaternization.

Scheme 53. Secondary versus tertiary thioamides in the sulfide contraction method.

Michael and co-workers speculated about the formation of 262 by invoking Brown’s hypothesis.97,98 According to Brown’s hypothesis, ‘Double bonds, which are exo to a 5-ring are less reactive and more stable (relative to the saturated derivatives) than related double bonds, which are exo to a 6-ring. Reactions that involve the formation or retention of an exo double bond in a 5-ring derivative will be favored over corresponding reactions that involve the formation or retention of an exo double bond in a 6-ring derivative. Reactions that involve the loss of an exo double bond will be favored in the 6-ring as compared to the corresponding 5-ring derivative.’98b Therefore, the sulfide contraction of 260a to give 261a should be favored in comparison with the sulfide contraction of 260c to give 261c. The difference in the stability of endocyclic double bonds in five- and six-membered rings is generally small. Therefore, in the case of 260b, it provides enaminone 261b, while

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the phenyl group in 260c swings the outcome of the reaction due to stereoelectronic reasons.97 In an attempt to avoid the cyclization to thiazolidinone, the a proton to phenyl was replaced by an ester group 263a (Fig. 11). However, the reaction did not produce the corresponding enami€ nchnone 265a was obtained. none 264 and instead thioisomu Replacing ester with the phenyl group 263b also gave a thio€ nchnone 265b. When thioamide 263c was attempted, inisomu stead of thiazolidinone 266, a more exotic species 267 was obtained. Compound 267 is a meso-dimer, which is derived from € nchnone 265c or thiazolidinone 266 by oxidative couthioisomu pling at C-2.97

without any difficulty using sodium iodide, triethylamine and PPh3 in CHCl3 to give 269. Under the same reaction conditions, thiolactam 165 gave a mixture of enaminone 270 and the bicyclic product 271. Russowsky and co-workers observed that by using a stronger base DBU in the absence of a thiophile, enaminone 270 could be obtained as the only product. Encouraged by this result, they tested the coupling of 165 with other a-bromocarbonyl compounds (272aec) (Scheme 56). However, instead of enaminones 273aec, thiazolidinones 274aec were obtained. When thiopyrrolidone 32 was reacted with 272aec, only decomposition was observed.67b Similar observations were reported by Lhommet and co-workers earlier.72

€ nchnones and the dimer 267 in the attempted Eschenmoser sulfide contraction reaction of six-membered thioamides. Fig. 11. Formation of thioisomu

Russowsky and co-workers also observed a difference in reactivity between the five- and six-membered thioamides (Scheme 55).67b,99 The sulfide contraction of thiolactam 32 proceeded

Scheme 56. Failure of the sulfide contraction reaction with a six-membered thioamide.

Scheme 55. Difference in the reactivity of five- and six-membered thioamides.

The above results were rationalized in terms of the relative ease of deprotonation in thioether intermediates 275 and 276 (Fig. 12). Because of the relative angle between the proton at C3 and the C]

Fig. 12. Explanation based on competing deprotonations for the formation of 274 and decomposition products.

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N bonds, the proton is difficult to deprotonate in 275. On the other hand, proton at C6 is easy to deprotonate when R1 is an electron withdrawing group (phenyl, in the case of 269). When R1 is an electron donating group (alkyl group), proton at C6 is difficult to deprotonate and under the reaction conditions, no sulfide contraction takes place and the thioether decomposes. In 276, both C3 and C7 protons can deprotonate readily due to conformational aspects of the system. When R1 is an electron withdrawing group, the proton at C7 can deprotonate more readily than the proton at C3. Removal of a proton at C7 leads thioether 276 to the sulfur extrusion pathway that provides 270. When R1 is an electron donating group, deprotonation at C3 is easier than it is at C7, leading to the pathway that provides bicyclic thiazolidinones 274aec.67b The rationalization for the formation of different products does not explain why 270 is formed selectively in the absence of a thiophile. It also does not explain why changing the base from Et3N to DBU produced more of the enaminone 270.67b More work is needed to answer these questions. A similar situation was observed by Hart and co-workers when they tried to perform the sulfide contraction on thioamide 277b to prepare 279 via thioether 278 (Scheme 57).100

Scheme 57. Synthesis of an enaminone with the help of DABCO.

When the conversion of 278 to 279 was attempted at room temperature, only 12% of 279 was formed in addition to lactam 277a (74%). Variations of the base and solvents did not improve the yield. Further studies on model compound 280 indicated that the base kinetically deprotonates Ha rather than Hb on thioether 280 (Scheme 58) to give the N,S-acetal 281. The pKa’s of Ha and Hb, and the hydrogen iodide salt of DABCO, are balanced such that warming the sample leads to occasional Hb deprotonation to afford 282, which eventually provides 283. Therefore, heating of 278 was attempted, and indeed it gave 279 in 65% yield (Scheme 57).100

29

The outcome was explained as a result of deprotonation at C-8 followed by the attack of the intermediate ketene N,S-acetal on the ketone. The difference in reactivity (shown in Schemes 57 and Scheme 59) was attributed to the differing electrophilicity of ketone and ester carbonyl groups.100 Similar observations were reported by Ireland and co-workers earlier.19 Mechelke and Meyers have also reported the formation of similar thiophene products.101 Gerasyuto and Hsung also faced the problem of an undesired byproduct formation as a result of the deprotonation of ring protons.102 When 288 was reacted with PPh3 and Et3N, enaminone 289 was not obtained (entry 1) (Scheme 60). The addition of a stronger base DBU and refluxing gave 289 along with 290 (entry 2). It was assumed that the formation of 290 could be curbed by using a weaker base. Indeed, in the presence of DIPEA, an excellent yield of the desired enaminone 289 was obtained (entry 3). 6.3.7. Issues with five-membered thioamides. Failure of the sulfide contraction can also occur in five-membered rings. Eschenmoser and co-workers observed that when episulfide 291 was heated in the absence of a thiophile it produced the bicycle 292 (Fig. 13). In the presence of a thiophile, the expected enaminone 293 was obtained.1a Eschenmoser and co-workers reported that in the case of abromoketones, the tendency of the S-alkylated thioether is to produce cyclized structures (292 in Fig. 13 and 295 in Scheme 61). In polar solvents, such as ethanol, cyclization is preferred and in less polar solvents, such as chloroform and dichloromethane, an enaminone is formed preferentially. In the case of 295 the cyclization was reversible and 295 could be converted into enaminone 51 via thioether 296 (Scheme 61).1a Hart and co-workers observed the formation of pyrroles 302 and 303 when the Eschenmoser sulfide contraction method was attempted on thiolactam 297 to give 298 (Scheme 62). Formation of 302 and 303 was explained as a result of adjacent deprotonation of the thioalkyliminium salt 300, which gave 301. Thioether 301 underwent b-elimination to produce 302, which after decarboxylation gave 303.103 This problem was overcome by replacing the b-acyloxy group with a methoxy or a benzyloxy group. These are worse leaving groups than the b-acyloxy group. Treatment of thiolactam 304 with triflate 299, followed by a reaction with the base and the thiophile gave enaminone 305 (66%) along with pyrrole 306 (17%) (Eq. 29). Thus, the desired enaminone could be obtained in a reasonable yield.103

(29)

Scheme 58. Reversible deprotonation in the sulfide contraction.

When the above sulfide contraction protocol was attempted on thioamide 284, none of the desired enaminone 286 was obtained and thiophene 287 was produced instead (Scheme 59).

6.3.8. Miscellaneous issues. The sulfur extrusion step caused issues in the sulfide contraction reaction of certain aromatic compounds as well. Roth and co-workers observed that when 307 was reacted with 272a, thienopyrimidines 308a and 308b were produced

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Scheme 59. Challenges in the sulfide contraction reaction of six-membered rings.

performed in one pot. Use of relatively stronger bases such as K2CO3, Et3N, NaH or EtONa resulted in lower yields.35a The authors did not mention why the use of a stronger base resulted in lower yields. Perhaps the competing dimerization of 166 or Claisen condensation is more efficient in the presence of stronger bases, causing the yield of enaminone 181 to be lowered. Alkylation of 166 at the CH3 position may also occur with a strong base such as NaH.

Scheme 60. Selective formation of an enaminone in the sulfide contraction reaction.

(30)

When the products of the Eschenmoser sulfide contraction reaction are unstable, they may be treated with acids to yield iminium salts. Varga and co-workers used this strategy and found the salt 314 to be more stable than the enaminone 313 (Scheme 64).104 Complexation with metal has also been used to form stabilized products (Scheme 50 and Section 7.3.1). Fig. 13. Formation of a bicyclic product in the absence of a thiophile in the Eschenmoser sulfide contraction reaction in five-membered rings.

7. Applications in the synthesis of natural products 7.1. Sulfide contraction via oxidative precoupling

Scheme 61. Reversible cyclization in the Eschenmoser sulfide contraction reaction.

(Scheme 63). Presumably the tautomeric form 309 reacted with 272a forming the thioether 310, which converted into 308.22a Bachi and co-workers observed that stronger bases can reduce the yield of 181 in the sulfide contraction via alkylative precoupling (Eq. 30). The best results were obtained with NaHCO3 as a base when both the alkylation and the contraction steps were

7.1.1. Vitamin B12. The first application of the Eschenmoser sulfide reaction was in the synthesis of metal-free corrins (Section 1.1.1). Later, the reaction was applied in the synthesis of vitamin B12. The project was a joint effort between R. B. Woodward and A. Eschenmoser research groups. Two strategies were developed for the construction of a common intermediate corrin cobalt complex 320 (Scheme 65). These are commonly called A/B and A/D variants. The term A/B and A/D represents the two rings that are involved in the final closing of the ring to the macrocyclic corrin system.6a In both variants, all alkenic bridges between A, B, C and D cycles were created by the Eschenmoser sulfide contraction reaction.7 The use of sulfide contraction via oxidative precoupling was originally developed for the B/C coupling in the A/B variant. The reaction was developed because the imino ester-enamine condensation (Section 1.1, Scheme 2) of ring B with C failed to provide the vinylogous amidine 217 (Fig. 14). Eschenmoser and co-workers identified two reasons for this failure. First, the methylene carbon of 215 is not nucleophilic enough to react with mildly electrophilic

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Scheme 62. Formation of aromatic products in the Eschenmoser sulfide contraction method.

it was better to desulfurize crude 96a directly after the removal of benzoic acid by a base.14b The vinylogous amidine 97a obtained by this route was converted into 240.105

Scheme 63. Formation of a bicyclic product with 6-mercaptoisocytosine in the sulfide contraction.

Scheme 64. Conversion of the enaminone 313 into the stable iminium salt.

imino esters in neutral or basic media. Secondly, the lactone-lactam is less prone to undergo condensation with 215 due to steric hindrance caused by the substituents on ring C. Attempts to achieve a condensation via acid catalysis did not succeed due to the instability of the enamide 215 towards the acids.6a,10 The Eschenmoser sulfide contraction method was used to overcome these issues because it tethers the two rings through a temporary sulfur bridge (Section 1.1). Thus, thioamide 214 was oxidized with benzoyl peroxide in the presence of a trace of HCl and enamide 215 (Scheme 66). The resulting crude thio-bridged product 216 was heated with trimethyl phosphite to give a mixture of (2:1) epimeric vinylogous amidines 217. Both diastereomers could be used for the synthesis of vitamin B12 as it too is configurationally labile at the very same position (shown here with the symbol *).10,14a,89 Compound 217 was used in both versions (A/B and A/D) of the synthesis of vitamin B12. 7.1.2. Isobacteriochlorin macrocycle. The sulfide contraction reaction was used during the preparation of the isobacteriochlorin macrocycle 240. Isobacteriochlorin systems fall into the category of porphinoid natural products.105 During the synthesis of 240, thioamide 95 was coupled with enamide 93 in the presence of benzoyl peroxide to give the mixed sulfide 96a (Scheme 67). Preperatively,

7.1.3. Vitamin B12 AeB-semicorrin. The first synthesis of vitamin B12 AeB-semicorrin was disclosed by Mulzer and co-workers in 1997. The synthesis was carried out with the hope of developing a flexible and convergent AeBþCeD strategy, where varying the CeD portion could give access to compounds, which have similar AeB rings (Fig. 15 and vitamin B12 (Scheme 65)).75 Key reactions that led to the formation of coupling partners are shown in Scheme 68. A CoreyeKwiatkowskieHornereWadswortheEmmons reaction between 321 and 322 generated enone 324 via the b-keto phosphonate carbanion 323. Enone 324 was converted into stannylmethyl ether 325, which after a tinelithium exchange, followed by a [2,3]-WittigeStill rearrangement, gave 326. The tetrasubstituted homoallylic alcohol 326 was converted into 327, which underwent the EschenmosereClaisen rearrangement to provide g,d-unsaturated amide 328. Treatment of amide 328 with mchloroperbenzoic acid gave hydroxyl lactone 329 as a mixture of diastereomers. Lactone 329 was converted into amide 330, which on reaction with KCN followed by Lawesson’s reagent provided thioamide 331 as a mixture of diastereomers.75 The crucial coupling between 330 and 331 was achieved using Eschenmoser’s oxidative precoupling method for sulfide contraction. Thus, treatment of 330 and 331 with benzoyl peroxide gave the sulfide 332. Heating 332 with triethyl phosphite in a sealed tube furnished the AeB-semicorrin 333 as a mixture of four diastereomers (Scheme 69).75

7.2. Sulfide contraction via alkylative precoupling 7.2.1. Vitamin B12. The first application of the sulfide contraction via alkylative precoupling appeared in the total synthesis of vitamin B12. In the A/B variant of the synthesis of vitamin B12 (Scheme 65), B and C rings were coupled via the alkylative precoupling process (Scheme 70). The B/C component 316 was deprotonated and alkylated with 315 to give type I thioether 227 (Scheme 70). This thioether was very labile and prone to isomerization giving thioether type II 229 under various conditions. Because of this, the usual sulfur extrusion conditions did not succeed and it was necessary to find suitable conditions that could transform type II thioether 229 into 228. The transformation was realized with tris(2cyanoethyl)phosphine and TFA.8,10,12,106 Compound 228 was transformed into thioamide 317 (Scheme 65) in a few steps. Sulfide contraction via alkylative precoupling was also applied in the A/D variant (Scheme 65) of the vitamin B12 synthesis. The

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Scheme 65. The two approaches to vitamin B12 synthesis.

dithio derivative 334 was coupled with 318 via the sulfide contraction method to give 336 (Scheme 71). Compound 336 was elaborated into corrin cobalt complex 320 (Scheme 65).1b,6a,42a 7.2.2. Phycocyanobilin and homophycobiliverdin. Phycocyanobilin is a tetrapyrrolic chromophore of a photosynthetically active algal

protein C-phycocyanin.107 Gossauer and Hirsch synthesized the racemic dimethyl ester of phycocyanobilin 341c and its methyl derivative, homophycobiliverdin (341b) (Scheme 72). The key reaction was the coupling of thioamides 337a and 337b with bromides 338a and 338b using the Eschenmoser sulfide contraction reaction giving products 339a and 339b, respectively.

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cis-octahydroquinolone 351, which was elaborated to bromoketone 352. The bromoketone 352 was dehydrobrominated with lithium bromide-lithium carbonate to give enone 353. Conjugate addition with the Gilman reagent provided the methyl ketone 354 as a single diastereomer. Ketone 354 was converted into thioamide 355 in a few steps. Thioamide 355 was used for making the CeC bond at the C2 position of 355 via the sulfide contraction method. Reaction of 355 with bromoacetone produced thiazole 356, which was treated with NaHCO3 and heated in the presence of PPh3, t-BuOH and KOt-Bu to give the vinylogous amide 357. Vinylogous amide 357 was converted into racemic pumiliotoxin C (349) in a few steps.111 Fig. 14. Failed imino ester-enamine condensation strategy that led to the development of the Eschenmoser sulfide contraction via oxidative precoupling.

Hydrogenolysis of 339b gave ester 339c. Esters 339a and 339c were coupled with the aldehyde 340 to give 341a and 341c. Careful hydrolysis of 341a provided homophycobiliverdin (341b) in a low yield.108 7.2.3. Anisomycin and deacetyl anisomycin. Anisomycin (342) is an antibiotic, which is isolated from cultures of various Streptomyces. It is a potent inhibitor of protein biosynthesis in certain yeast and mammalian cells.109 Felner and Schenker described the synthesis ()-anisomycin (342) using the sulfide contraction method (Scheme 73).110 Sulfide contraction of thioamide 343 with bromide 344 provided the enaminone 345 as a single diastereomer. Cleavage of the ester group followed by hydrogenation gave diastereomers 346 and 347. Amine 347 was elaborated to give deacetyl anisomycin (348) and anisomycin (342). 7.2.4. (
)-Pumiliotoxin C hydrochloride. Pumiliotoxin C (349) is a toxin that was isolated from Dendrobate frogs. Some of the key reactions used in the synthesis of pumiliotoxin C are shown below (Scheme 74). Beckmann rearrangement of oxime 350 provided the

7.2.5. (
)-Saxitoxin. Saxitoxin (358) (Scheme 75) is one of the most toxic non-protein substances. The compound is responsible for paralytic shellfish poisoning.112 Kishi and co-workers reported the first total synthesis of saxitoxin.112,113 The Eschenmoser sulfide contraction was used to couple thiolactam 359 with bromide 166. A cleavage reaction of b-keto, b’-imino ester system of 360 under basic conditions gave 361. The enaminone 361 was reacted with benzyloxyacetaldehyde and silicon tetraisothiocyanate to give thiourea 363, presumably via 362. Thiourea 363 was elaborated to urea 364. Urea 364 was found to be very labile towards protic acids that were necessary for the cyclization process on model systems. To increase the acid stability of 364, the ketal group was converted into a thioketal group under carefully controlled conditions. Cyclization of 365 gave the tricycle 368. It was proposed that acetic acid enolized 365 into 366, which then underwent an electrocyclization process in which the urea group approached the carbon from the sterically less hindered side to give 367. Protonation-deprotonation of 367 gave 368. The rate of cyclization with acetic acid was slow, and for practical purposes the reaction was conducted in AcOH/TFA mixture. The resulting product was obtained as a 5:1 mixture of epimers in favor of the desired product. The formation of the undesired epimer was attributed to a competing cyclization pathway

Scheme 66. Coupling of rings B and C by the sulfide contraction method.

Scheme 67. Synthesis of the isobacteriochlorin macrocycle 240 by means of the sulfide contraction reaction.

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Fig. 15. Compounds containing AeB rings that are similar to vitamin B12.

in the presence of TFA. Urea 368 was converted into racemic saxitoxin (358) after a few more steps. 7.2.6. Pyrrolizidine alcohols 7.2.6.1. (
)-Isoretronecanol and (
)-trachelanthamidine. Isoretronecanol (369) and trachelanthamidine (370) (Scheme 76) are members of the pyrrolizidine family of alkaloids. They display potent biological activity. Isoretronecanol was isolated from Crotalaria spectabilis, Crotalaria retusa and Lindelofia anchusoides. Trachelanthamidine was isolated from Trachelanthus korolkovi and Cytisus laburnum.114 Pinnick and Chang reported the total synthesis of isoretronecanol and a formal synthesis of trachelanthamidine

(Scheme 75).95 The Eschenmoser sulfide contraction reaction of thioamide 32 and ethyl bromoacetate provided enaminone 371, which was converted into 372. Cyclization of diester 372, followed by the reduction gave pyrrolizidine 374. Attempts to reduce the lactam carbonyl before the reduction of the enamine double bond failed. However, after enamine reduction, reaction of 374 with LiAlH4 was successful in reducing the lactam carbonyl to provide isoretronecanol 369. Selective reduction of 374 with diborane was unsuccessful in obtaining 375 in a reasonable yield. The reduction was finally achieved with phosphoryl chloride/sodium borohydride. Formation of ester 375 completed the formal synthesis of trachelanthamidine (370).

Scheme 68. Synthesis of coupling partners 330 and 331.

Scheme 69. The use of the Eschenmoser sulfide contraction method in AeB coupling.

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Scheme 70. Sulfide contraction via alkylative precoupling in the A/B variant of the total synthesis of vitamin B12.

Scheme 71. C/D coupling via the alkylative version of the Eschenmoser sulfide contraction in the A/D variant of the vitamin B12 synthesis.

7.2.6.2. Laburnine and tashiromine. The pyrrolizidine alkaloid laburnine (376a) (Scheme 77) was first isolated in 1949 from Cytisus laburnum, and then from the leaves of the rainforest tree, Planchonella anteridifera, found in New Guinea. Tashiromine (376b), an indolizidine alkaloid, was isolated in 1990 from the stems of a leguminous plant, Maackia tashiroi, a deciduous shrub found in subtropical Asia. One of the pivotal steps in the synthesis of both of these alkaloids included an Eschenmoser reaction to install the crucial tetrasubstituted exocyclic double bond.115

The Eschenmoser reaction of thione 377 with bromides 378a and 378b yielded chiral b-enamino diesters 379a and 379b, respectively as an inseparable diastereomeric mixture of E/Z isomers in 75/25 and 65/35 ratios (Scheme 77). Hydrogenation of the exocyclic double bond proceeded diastereoselectively to give the stereocenters with the desired configuration 380. In the case of 379b, the debenzylation was avoided by lowering the amounts of 10% Pd/C from 0.2 to 0.04 equiv. For 379a, the reduction and debenzylation rates were very close and the use of 10% Pt/C was

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Scheme 72. Synthesis of dimethyl ester of phycocyanobilin and homophycobiliverdin.

Scheme 73. Synthesis of deacetyl anisomycin and anisomycin via the sulfide contraction method.

Scheme 74. Synthesis of pumiliotoxin C hydrochloride.

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Scheme 75. Synthesis of saxitoxin.

necessary to avoid the debenzylation reaction. Hydrogenolysis of the a-methylbenzyl amine and the subsequent ring closure afforded bicyclic lactam esters, which on the metal hydride reduction yielded the target alkaloids.115

The reason for the unexpected diastereoselectivity in the reduction of 379a and 379b was explained as a result of enolate intermediate 381a (Scheme 78). Enolate 381a was formed by the addition of an equivalent of MH2 from the Si face of 379, resulting in an R configuration at the C-20 stereocenter. The conformation 381b was favored for the hydride attack as it had a minimum 1,3-allylic strain. Protonation from the Re face at C-2 formed product 380. Molecular modeling showed the presence of a ‘gear effect’ between

Scheme 76. Synthesis of isoretronecanol and trachelanthamidine.

Scheme 78. Rationale for the diastereoselective reduction of the intermediates in the synthesis of (þ)-laburnine and (þ)-tashiromine.

Scheme 77. Synthesis of laburnine and tashiromine.

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the C-20 -alkyl and the substituents of the C*. The gear effect is minimized when H of C* is in front of the bulky C-2-alkyl group ‘R’ resulting in the presence of mainly one conformer. A preferential presence of one conformer was speculated to be responsible for the diastereoselective reduction.115 However, since the stereogenic methoxycarbonyl group is prone to epimerization, it is not a good indicator of stereoselectivity for the hydrogenation.68 7.2.6.3. Apomitomycin B. Apomitomycin B belongs to the family of mitomycins. Mitomycins are potent antibacterial and anti-cancer compounds. They have been in use as drugs since the 1960s. These compounds are isolated from extracts of the genus Streptomyces, a gram-positive soil bacterium.116 Only a handful of total syntheses of these compact, densely functionalized natural products have been reported.117 A few examples of mitomycins are shown below (Fig. 16).

Dibromide 383 was coupled with thioamide 384 using the Eschenmoser sulfide contraction method. Enaminone 385 was obtained as a mixture of cis and trans isomers. An intramolecular Goldberg amination using sodium hydride and copper(I) bromide gave pyrroloindole 386 as a single compound. Under the reaction conditions, the cis isomer was epimerized to the trans isomer, which is thermodynamically more stable. The sequence of nitration, reduction and subsequent oxidation afforded the quinone 382.116 The methodology was also used to prepare other derivatives of apomitomycin B.118 7.2.7. Acylative ring closure strategy 7.2.7.1. Ipalbidine. The (þ)-ipalbidine (387) (Scheme 80) was isolated from Ipomoea alba L.119 A formal synthesis of racemic ipalbidine was reported, which used the Eschenmoser sulfide contraction reaction. The N-alkylated thioamide 388 was selected

Fig. 16. Examples of the mitomycin family of alkaloids.

Kametani and co-workers reported the synthesis of apomitomycin B derivatives, including 382.118 Compound 382 is considered a potential intermediate in the synthesis of mitomycin synthesis (Scheme 79). Key features of this synthesis are shown below.

Scheme 79. Synthesis of an apomitomycin B derivative.

for the Eschenmoser sulfide contraction because tertiary thioamides undergo this reaction under milder reaction conditions. Also, in the case of a secondary enaminone, the authors were unable to attach the appropriate substituent for the annulation step. A sulfide contraction reaction of thioamide 388 with methyl bromoacetate 71 produced enaminone 389 as a single diastereomer. An acylative ring closure by the intramolecular reaction between the enamine and the ester was unsuccessful. To overcome this issue, the ester was hydrolyzed and the salt 390 was converted into a mixed anhydride. The mixed anhydride was not isolated as it underwent cyclization under the reaction conditions. The bicyclic product 391 was converted into target product 392 in a few steps. This constituted the formal synthesis of racemic ipalbidine (387).71 The acylative ring closure of enaminones, prepared via the Eschenmoser sulfide contraction method, was also applied in the formal syntheses of elaeocarpus alkaloids (Fig. 17).120 Michael and co-workers also utilized this methodology for the construction of a partially saturated indole nucleus.121

Scheme 80. Synthesis of ipalbidine.

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elaeocarpine (393)

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elaeokanine A (395) Fig. 17. Elaeocarpus alkaloids prepared by the acylative ring closure of enaminones.

subsequent decarboxylation and reduction of the enaminone double bond yielded 404. Ketone 404 was converted into the racemic target alkaloid (398).123 The authors also reported the enantioselective synthesis of the ()-indolizidine alkaloid 167B (398). The enantiomerically pure b-amino menthylester 405 was accessed at an early stage in the synthesis. By extending the Davies’ methodology, 405 was then converted into thiolactam 406. The rest of the synthesis was similar to the racemic synthesis.122

Fig. 18. Indolizidine 167B (398).

7.2.8. Gephyrotoxin family of alkaloids 7.2.7.2. Indolizidine 167B. Originally isolated as a trace component from the skin secretions of an unidentified frog belonging to n, Panama) and later identified in the genus Dendrobates (Isla Colo n, Panama), the sima single population of D. speciosus (Isla Colo plest amphibian indolizidine alkaloid, indolizidine 167B (398) (Fig. 18), shows interesting neurophysiological effects as a noncompetitive blocker of nicotinic acetylcholine receptor channels in muscle and ganglia membranes.122

7.2.8.1. Gephyrotoxin. Gephyrotoxin (407) (Scheme 82) was first isolated from the skin of frogs, Dendrobates histrionicus. The compound shows an array of interesting neurological activities.124 Fujimoto and Kishi synthesized the (þ)-enantiomer of the compound and thereby showed that the absolute configuration of the natural isomer should be opposite to the (þ)-isomer on each stereocenter. The Eschenmoser sulfide contraction method was applied on thioamide 408 to give enaminone 409 (Scheme 82). Deacylation

Scheme 81. Synthesis of indolizidine 167B.

Michael et al. in 1998 reported the racemic synthesis of the indolizidine alkaloid 167B (398), which featured a key ring closure step of the nucleophilic vinylogous urethane 400, formed exclusively as an E isomer from the sulfide contraction reaction of the thiolactam 399 (Scheme 81). Chemoselective hydrolysis of the saturated ester in 400 rendered the carboxylate salt 401. The carboxylate salt 401 was thoroughly dried and converted in situ to the mixed anhydride 402, which, after heating, underwent acylative cyclization to yield a b-oxo ester 403. Compound 403 on

of 409 gave the ester 410, which was elaborated to (þ)-gephyrotoxin (407).125 7.2.8.2. Dihydrogephyrotoxin. Dihydrogephyrotoxin (411) (Scheme 83) was also isolated from frogs belonging to the Dendrobatid family. Hart and Kanai cyclized 412 and established the new stereocenter in 414 via 413.126 Carbinolamide 412 exists in a chair conformation in which both vinyl groups are axially disposed due to the A1,3-starin. It was hypothesized that due to the

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Scheme 82. Enantioselective synthesis of (þ)-gephyrotoxin.

Scheme 83. Synthesis of dihydrogephyrotoxin.

Scheme 84. Synthesis of D7-mesembrenone.

same reasons, 413 exists in a conformation that results in the stereoselective cyclization. Tricycle 414 was elaborated to give thiolactam 415. The sulfide contraction reaction on 415 provided 416 as a single diastereomer. Hydroboration-oxidation of 416 was carried out and the resulting alcohol was protected as the silyl ether 417. Hydrogenation of 417 over platinum on alumina gave product in 96:4 in favor of the desired diastereomer 418. Tricycle 418 was converted into racemic dihydrogephyrotoxin (411) after a few steps. Tricycle 418 was also elaborated to provide the racemic gephyrotoxin (407).

7.2.8.3. D7-Mesembrenone. D7-Mesembrenone (419) (Scheme 84) is the constituent of Sceletium namaquense. Michael and coworkers prepared this compound in racemic form via a one-pot procedure involving S-alkylation, sulfur extrusion and intramolecular cyclization of the resulting enaminone. When thioamide 420 was reacted with chloromethyl vinyl ketone 421 under the Eschenmoser sulfide contraction method conditions, 422 was not isolated and instead D7-Mesembrenone (419) was formed. The spontaneous ring closure of 422 is presumably via an intramolecular 1,4-addition and requires the participation of 423.127 Alternatively, the mechanism of cyclization may involve an initial tautomerization of 423 into an enol that then undergoes a 6-pelectrocyclization giving 419.68 7.2.9. Tropane and homotropane alkaloids

Fig. 19. Enantiomers of anatoxin-a.

7.2.9.1. Anatoxin-a. Anatoxin-a (Fig. 19) is a homotropane alkaloid. It was isolated from the strains of fresh water blue-green b. Because it is a strong alga Anabaena flos-aquae (Lyngb.) de Bre nerve-depolarizing agent, it played a central role in neurotransmission research despite the difficulties of obtaining this natural

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product. The first synthesis of optically pure (þ)-anatoxin-a (natural) (424a) and ()-anatoxin-a (424b), reported by Rapoport and co-workers, utilized the Eschenmoser sulfide contraction sequence to install the functionalized side chain onto the pyroglutamate derivative. Later the functionalized side chain, by nucleophilic attack on the iminium ion, generated by decarbonylation of an aamino acid, formed the bicyclic homotropane structure.22b The optically pure thiopyroglutamate 70a, synthesized from Lglutamic acid, was S-alkylated with methyl bromoacetate resulting in a thioiminium salt, which was treated with triphenylphosphine followed by triethylamine to furnish the enaminone 73 (Scheme 85). Catalytic hydrogenation of the double bond in 73 proceeded

41

favoring cis-disubstituted pyrrolidine 433. Acid 433 was further elaborated to afford (þ)-anatoxin-a (424a).22b Earlier, the authors also reported the synthesis of (
)-anatoxin by iminium ion cyclization of the racemic 5-substituted proline.128 In 1990, Rapoport and co-workers reported an enantiodivergent synthesis of either (þ)-anatoxin-a (424a) or an unnatural ()-anatoxin-a (424b) from a common advanced intermediate, 2,5difunctionalized homotropane 439 (Scheme 87). Homotropane 439 was prepared from an inexpensive L-glutamic acid. The diastereomeric mixtures that were formed at several stages of the synthesis were funneled into either (þ)-anatoxin-a (424a) or ()-anatoxin-a (424b). Apart from iminium ion-mediated cycliza-

Scheme 85. Synthesis of ()-anatoxin-a (424b).

with the excellent transfer of amino acid chirality to furnish cis/ trans isomers in the ratio of 98:2 favoring the cis amino diester 425. The reduction with sodium cyanoborohydride was less selective with the formation of the 3:1 mixture of cis and trans isomers. Debenzylation under catalytic hydrogenation conditions was avoided by substituting protic solvents with ethyl acetate. Diester 425 was elaborated to acid 426. Compound 426 underwent cyclization by nucleophilic attack on the iminium ion 427, generated by decarbonylation of a-amino acid to form azabicyclononane derivative 428, which was further elaborated to ()-anatoxina (424b).22b Rapoport and co-workers adapted a convergent approach, and once again relied on the sulfide contraction reaction to install the requisite six-carbon side chain at once in their (þ)-anatoxina (424a) synthesis (Scheme 86). The required thiopyroglutamate 429 for (þ)-anatoxin-a was synthesized from D-glutamic acid, which was allowed to react with triflate 430 to form the thioiminium salt, which after sulfur extrusion gave the vinylogous carbamate 431 as a mixture of diastereomers. Transfer hydrogenolysis of the isomeric mixture caused debenzylation, decarboxylation and isomerization and produced the disubstituted 1pyrroline 432. Catalytic reduction of 432 resulted in an excellent transfer of chirality furnishing a 98:2 mixture of cis/trans isomers

tion, the sulfide contraction sequence played a pivotal role in facilitating access to the common intermediate 439.91 The synthesis of vinylogous carbamate 435 (Scheme 87) by the Eschenmoser sulfide contraction reaction closely followed that of the benzyl ester analogue 431 and gave a 4:1 mixture of doublebond isomers. Stereoselective reduction of the double bond occurred to give the cis isomer and a 4:1 mixture of epimers at C6 436. After acidic hydrolysis and chromatographic separation of keto acids, 437a and 437b, each isomer was subjected to cyclization conditions separately to give the mixture of 438a, 438b and 438c, 438d homotropanes, respectively. These homotropanes on debenzylation and simultaneous BOC protection gave 439a, 439b and 439c, 439d, respectively. Selective manipulation of either the C2 ester or C5 acetyl groups, channeled all four diastereomers (439aed) into either 440a or its enantiomer 440b. Compounds 440a and 440b were further transformed to (þ)-anatoxin-a or ()-anatoxin-a, respectively. The installation of a substituted side chain by the sulfide reaction also allowed entry into functionalized derivatives of anatoxin.91 7.2.9.2. ()-Cocaine. ()-Cocaine (Scheme 88) consists of one of the important members of tropane alkaloids isolated from the leaves of Erythroxylon coca. Cocaine is believed to be associated

Scheme 86. Synthesis of (þ)-anatoxin-a (424a).

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Scheme 87. Enantiodivergent synthesis of (þ)-anatoxin-a and ()-anatoxin-a.

Scheme 88. Synthesis of cocaine.

with its inhibition of dopamine reuptake and the consequent increase of dopamine levels in the synapse, leading to the continuous stimulation of the neurons, causing a feeling of euphoria. Cocaine is one of the eight possible stereoisomers of methyl 3-(benzoyloxy)8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate, and the major challenge in its synthesis, apart from controlling the stereochemistry, is the construction of the azabicyclo ring system.129 Rapoport et al. reported an enantiospecific route for the synthesis of optically pure natural ()-cocaine and unnatural (þ)-cocaine from D- and L-glutamic acids, respectively (Scheme 88). The Dthiopyroglutamate 429 was allowed to react with the triflate 441 under Eschenmoser sulfide contraction conditions. This afforded the vinylogous carbamate 442 as a 5.5:1 mixture of isomers.

Transfer hydrogenolysis-hydrogenation of the olefin intermediate 442 resulted in debenzylation, decarboxylation, and hydrogenation. The acid 443 thus obtained was esterified and N-Boc protected to give cis-5-substituted D-proline ester 444. The 8-azabicyclo [3.2.1]octane framework in 445, obtained by the Dieckmann cyclization of the diester 444, gave the b-keto ester 445 predominantly in the enol form. The key intermediate N-Boc nortropene (þ)-447, formed from the decomposition of tosylhydrazone of 446, which in turn was made by the decarboxylation of the methyl ester in 445, was later elaborated to form the natural ()-cocaine. The Eschenmoser sulfide contraction method and subsequent catalytic hydrogenation thus played a crucial role in the formation of 8-azabicyclo[3.2.1]octane framework in N-Boc

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Scheme 89. Synthesis of (þ)-euphococcinine.

nortropene (þ)-447, the key intermediate for the synthesis of the target alkaloid. Following the same protocol, unnatural (þ)-cocaine was also prepared, starting from L-glutamic acid and DL-malic acid.129 7.2.9.3. (þ)-Euphococcinine. (þ)-Euphococcinine (Scheme 89) is a homotropane alkaloid. It was first isolated in 1967 from an Australian coastal plant, Euphorbia atoto. Later, it was also found in the animal kingdom and was shown to be a potent feeding deterrent to spiders and ants. Euphococcinine forms a part of the chemical defensive arsenal of ladybugs and Mexican bean beetles. The unique bicyclic structure of euphococcinine attracted considerable synthetic interest, and one of the main challenges included the construction of the quaternary center bearing nitrogen, with control over the absolute stereochemistry.101

Mannich cyclization, but also resulted in concomitant loss of the chiral auxiliary to afford (þ)-euphococcinine (448) in a single step.101 7.2.10. Histrionicotoxin. The histrionicotoxin alkaloid (456) has been isolated from dendrobatid frogs and it is thought to be of an ant origin.130 Kishi and co-workers reported the first total synthesis of (
)-histrionicotoxin (456) (Scheme 90). The Eschenmoser sulfide contraction of 457 with ethyl 2-bromoacetoacetate gave the enaminone 458. It was necessary to elaborate the lower side-chain before elaborating the top side-chain. Thus, the primary acetate of 458 was saponified selectively to give 459. Alcohol 459 was oxidized and the Wittig reaction on the resulting aldehyde gave 460. Enyne 460 was elaborated to give racemic histrionicotoxin.131

Scheme 90. Synthesis of (
)-histrionicotoxin.

Treating cis-1-amino-2-indanol-derived chiral bicyclic lactam 449 with Belleau’s reagent provided thiolactam 450 (Scheme 89). The Eschenmoser sulfide contraction sequence on 450 with the abromo Weinreb amide 451 as a coupling partner provided the desired sulfide contraction product 452. Hydrogenation of compound 452 afforded a single diastereomer, which upon treating with MeLi provided the desired ketone 453. Exposing compound 453 to amphoteric conditions, not only facilitated a smooth intramolecular

7.2.11. 5-Butyl-2-heptylpyrrolidines from glutamic acid. Both enantiomers of trans-5-butyl-2-heptylpyrrolidine are major components of the venom of the ant Solenopsis fugax. Shiosaki and Rapoport synthesized these enantiomers, in addition to both of the enantiomers of the cis isomer 466, in an enantioselective manner (Scheme 91). The synthesis enabled the assignment of absolute configuration of the natural products. Thioamide 70a and triflate 218 were coupled using the Eschenmoser sulfide

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Scheme 91. Synthesis of 5-butyl-2-heptylpyrrolidines.

contraction reaction. Removal of benzyl ester and reduction through transfer hydrogenolysis-hydrogenation resulted in 461. Pyrrolidine ester 461 was elaborated to 462. Amino nitrile 462 provided thioamide 463 when reacted with LDA followed by the addition of excess sulfur. Amino nitrile 462 was crucial for the synthesis of 463 as formation of thioamide 463 on the precursor of 462 failed under various conditions. The Eschenmoser sulfide contraction was applied a second time to give 465. Transfer hydrogenolysis-hydrogenation of enaminone 465 gave cis-5butyl-2-heptylpyrrolidine 466 in an enantioselective form. The trans isomer was prepared from the intermediate 462. The other two enantiomers of cis- and trans-5-butyl-2-heptylpyrrolidine were prepared using a similar strategy.90 7.2.12. Lythrancepine II and lythrancepine III. Lythrancepine II (467) and lythrancepine III (468) (Scheme 92) belong to the Lythraceae family of alkaloids. Hart and co-workers synthesized these compounds and confirmed their structures.101,132 Thiolactam 469 was converted into enaminone 470 via the sulfide contraction reaction. Reduction of 470 with NaBH3CN gave a mixture of diastereomers 471a and 471b. Ester 471a was elaborated to diiodide 472. Intramolecular Ullman reaction on 472 afforded 473. As model studies indicated complications with hydrogenolysis (such as the cleavage

of the CeN bond), deprotection of the benzyl group was accomplished with BBr3. This provided racemic lythrancepine II (467). Acetylation of the product (467) gave racemic lythrancepine III (468).101,132 7.2.13. Peripentadenia alkaloids. Peripentadenine (474) and dinorperipentadenine (475) (Scheme 93) were isolated from the elaeocarpaceous tree Peripentadenia mearsii. Michael and co-workers employed an Eschenmoser sulfide contraction reaction and the chemoselective reduction of the enaminone as the key reactions for the synthesis of peripentadenine (474) and dinorperipentadenine (475).133 The thiolactam 476 was allowed to react with 477 under neat conditions, and the salt thus obtained was reacted with PPh3 and Et3N, which introduced the alkylidene side chain to yield the key intermediate 478. Conversion of this enaminone 478 into 474 and 475 was carried out by synthetic ‘loops’. In the sequence 478/479/480/483, chemoselective reduction of the nitrile group in 478 was achieved by hydrogenation over activated nickel. The other key reaction in this sequence was the chemoselective reduction of 480 to 483 with lithium aluminum hydride. In contrast to the model studies, the loop 479/482 was also successful and the amino group did not interfere with the reduction process. For the last loop, the chemoselective reduction of the enaminone

Scheme 92. Synthesis of lythrancepine II and lythrancepine III.

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sulfide contraction reaction of the intermediate thiolactam 486 (Scheme 94). The vinylogous cyanamide 487 was formed as a single geometrical isomer (presumably the E isomer). Chemoselective reduction of the ester in 487 and its subsequent ring closure afforded the unsaturated quinolizidine ring system 489 via in situ generated tosylate 488. Catalytic hydrogenation of 489 under acidic conditions gave mainly 490 while the sodium cyanoborohydride reduction gave an equal mixture of 490 and 491. An isomer mixture could be equilibrated with NaH to increase the ratio to 1.9:1 in favor of 491. Compounds 490 and 491 were then elaborated to form the respective target alkaloids.3 7.2.14.2. (
)-Lupinine and (
)-epilupinine. The alkaloids, (
)-lupinine (492) and its diastereomer (
)-epilupinine (493) are the simplest of the large group of alkaloidal metabolites of the Leguminosae (Fabaceae). They were synthesized from the Nsubstituted piperidine-2-thione 486 via enaminone intermediate 494 (Scheme 95). Thioamide 486 was subjected to the sulfide contraction sequence to form the enaminone 494. Chemoselective reduction of the saturated ester in 494 to primary alcohol, followed by in situ conversion of alcohol to alkyl iodide and immediate cyclization, afforded the bicyclic enaminone 495. Stereoselective cishydrogenation of 495 afforded (
)-lupinoate ester 496, which underwent a facile, thermodynamically favored, base-catalyzed epimerization to give (
)-epilupinoate ester 497. Both 496 and 497 are reduced to (
)-lupinine and (
)-epilupinine, respectively.134 Scheme 93. Synthesis of peripentadenine and dinorperipentadenine.

double bond was accomplished with lithium aluminum hydride. In the model studies, this reaction was shown to undergo a competitive retro-Michael reaction, giving the N-dealkylated product. A similar retro-Michael reaction was observed in the conversion of 478 to 479, but the dealkylated product was found only in a small amount (4%). Conversion of 481 to 482 was reported in literature and acylation of 482 was considered to be trivial and was not reported. Demethylation of 483 with BBr3 gave the alkaloids peripentadenine (474) and dinorperipentadenine (475) in racemic forms.133 7.2.14. Alkylative cyclization strategy 7.2.14.1. Lamprolobine and epilamprolobine. The alkaloid (þ)-lamprolobine (484) (Fig. 20), initially isolated in 1968 from the

(484)

(485)

Fig. 20. (þ)-Lamprolobine (484) and ()-epilamprolobine (485) alkaloids.

Australian tree Lamprolobium fruticosum and later from Lupinus holosericeus, Sophora chrysophylla and S. velutina, is an uncommon member of the quinolizidine alkaloids found in Leguminosae. ()-Epilamprolobine (485) was isolated from Sophora tomentosa and S. chrysophylla.3 In 1992, Michael et al. reported the racemic synthesis of lamprolobine (484) and epilamprolobine (485), which featured the

7.2.14.3. (5R,8R,8aS)-Indolizidine 209I. Indolizidine 209I (498) (Scheme 96) is a 5,8-disubstituted indolizidine alkaloid isolated from the skins of dendrobatid poison frogs Oophaga pumilio.130 Michael and co-workers reported a formal synthesis of this compound. The sulfide contraction was used to couple thioamide 500 with bromide 451. The enaminone 501 was obtained as a single diastereomer. Hydrolysis of 501 gave alcohol 502. Cyclization of 502 was conducted by its in situ conversion to the iodide 503 and by heating the reaction mixture. The bicyclic product 504 was hydrogenated to give the cis-hydrogenated product 505 as the only isolable isomer. The diastereoselectivity was explained to be due to an equatorial preference for the propyl chain in the six-membered transition state. This arrangement directs the hydrogenation to occur from the less hindered face of the double bond. Treatment of Weinreb amide 505 with the Grignard reagent followed by hydrolysis furnished 506. A model study suggested that the alkylation of a Weinreb amide could not be achieved without the reduction of the enaminone double bond in 504. Epimerization of 506 provided 507, which constituted as the formal synthesis of ()-indolizidine 209I (498).135 A similar strategy was used for the formal synthesis of indolizidine ()-209B (499).136 7.2.15. Plakoridine A. Unprecedented tyramine-containing pyrrolidine alkaloids, plakoridine A (199) and plakoridine B (508) (Fig. 21), isolated from the extracts of Okinawan marine sponges (genus plakortis), contain a fully substituted and functionally diverse pyrrolidine ring system.137 Ma et al.’s synthesis of plakoridine A,86 which was found to be weakly cytotoxic against the murine lymphoma L1210 cell line,137 provides an unusual example where the sulfide contraction method was used on a fully substituted and functionalized thiolactam.86 The key reactions for the synthesis of fully functionalized advanced pyrrolidinone intermediate 513 included the 1,4-addition of 509 to (E)-2-hexenoate to give 510, the aldol reaction of 510 with ethyl glyoxalate to give 512, and deprotection/cyclization of 512 to give 513 (Scheme 97). At this point, the stage was all set to install the enone moiety at the second position of compound 193c via the Eschenmoser sulfide contraction. However, it was found necessary

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(485)

(484)

Scheme 94. Synthesis of lamprolobine and epilamprolobine.

Fig. 21. Plakoridine A and B. Scheme 95. Synthesis of lupinine and epilupinine.

Scheme 96. Formal synthesis of indolizidine ()-209I.

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Scheme 97. Synthesis of plakoridine A.

to deprotect the sterically bulky TBS group and epimerize the C-4 in 193b for the successful application of the Eschenmoser sulfide contraction on 197. Desilylation on the resulting enaminone afforded plakoridine A (199).86 A model study for the synthesis of plakoridine A also used the Eschenmoser sulfide contraction method.138 7.2.16. Guanidine alkaloids 7.2.16.1. Guanidine core. Several guanidine alkaloids are found in different species of warm water sponges. The flagship alkaloid ptilomycalin A (514) (Scheme 98) and related guanidines have been

reported to possess substantial cytotoxic, antiviral and antifungal activities. Hiemstra and co-workers reported the synthesis of guanidine core. The N-acyliminium ion coupling of 515 with ethoxy lactam 516 in the presence of TMSOTf provided 517a as an equal mixture of diastereomers. Lawesson’s reagent converted 517a into thiolactam 517b selectively and without affecting the ketone. The Eschenmoser sulfide contraction was achieved in a stepwise manner. Reaction of 517b with 2-bromoacetophenone and Et3N gave thioether 518. Treatment of 518 with PPh3 and heat brought about the contraction and gave 519 as a sole isomer about the double bond. The enaminone was elaborated to a mixture of 520a

Scheme 98. Synthesis of ptilomycalin A.

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and 520b. The mixture of mono- and diacetal 520a and 520b was subjected to guanylation to give protected guanidines 521a and 521b. Reaction of this mixture with methanolic HCl resulted in double cyclization and dehydration and gave the product 522 along with other guanidines. Separation of crude 522 via chromatography gave pure 522 in 33% yield. A more polar fraction, which presumably contained 2,5-trans-disubstituted pyrrolidine derivatives of 521a and 521b, was also converted into 522 by reacting it with ammonia and ammonium acetate.139 Presumed trans-isomers 521a and 521b isomerize to cis isomers under the influence of ammonia, which then cyclize to guanidine.140 This conversion provided an additional 20% yield of 522.139 7.2.16.2. Batzelladine A side chain. Isolated from the Caribbean sponge Batzella sp., batzelladine alkaloids (batzelladines AeI, exemplified by batzelladine A (523), Fig. 22) are polyguanidine marine natural products. They feature a structurally and biologically fascinating group of natural products. There is at least one fused tricyclic

thione using the sulfide contraction method and vinylogous carbamates 525a and 525b were obtained as a 1:4 mixture of E:Z isomers (Scheme 99). The mixture of 525a and 525b was then converged to form the tricyclic urea 526. Hydrogenolysis of benzyl carbamate in 526, followed by the ring-opening of the lactone with NaOMe, and subsequent acetylation of the resultant primary alcohol afforded 527. Selective O-methylation of urea 527 followed by deacetylation provided 528, which was further elaborated to 529 to incorporate the oligomethylene side chain. The optical rotation of the L-aspartic acid-derived guanidinium formate salt 530, obtained by treating the O-methyl isourea 529 with excess ammonia, was found to be identical to that reported for the bicyclic fragment obtained from the chemical degradation of natural batzelladine A. Finally, TIPS-protected 529 was converted into 524, to complete the first synthesis of the bicyclic guanidine core, which could allow access not only to batzelladines A and B, but also to the related crambescin alkaloids.141

Fig. 22. Batzelladine A (523) and its fragment 524.

Scheme 99. Synthesis of the bicyclic guanidine fragment 2 of batzelladine A.

guanidine moiety, and an additional bicyclic guanidine fragment (batzelladines A and B) or a second tricyclic guanidine fragment (batzelladines FeI) in these compounds. Batzelladines A and B are of therapeutic interest for the treatment of HIV because of their inhibition of HIV glycoprotein gp120 to the CD4 receptor. Batzelladines CeE are cytotoxic, while batzelladines FeI induces dissociation of protein kinase p56lck from the CD4 receptor.141 In 2001, Gin et al. reported a non-racemic synthesis of a selectively protected bicyclic guanidine fragment 524 (Fig. 22), starting from L-aspartic acid, which established the absolute configuration at the C13 stereocenter. The oligomethylene side chain at C13 could be used to attach the tricyclic guanidine fragment of batzelladine A. The a-bromolactone 525 was allowed to react with pyrrolidine-2-

7.2.16.3. Batzelladine A core. Elliott and co-workers chose to investigate Kishi’s diastereoselective three-component coupling reaction used in saxitoxin synthesis (Section 7.2.5) for the enantioselective synthesis of a bicyclic guanidine core with latent functionality that can be elaborated to attach the tricyclic core of the batzelladines A (Fig. 22) and B. Synthesis of appropriate alkylidene pyrrolidine 532, required for the evaluation of the threecomponent coupling reaction, featured the Eschenmoser sulfide contraction method for the installation of the alkylidene functionality (Scheme 100). Thionation of ethyl (S)-pyroglutamate followed by the Eschenmoser sulfide contraction with ethyl-2bromoacetoacetate furnished a good yield of vinylogous carbamate 173 as a single isomer about the double bond. Chemoselective

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diastereomers 533a and 533b in the ratio of 2.3:1. The major diastereomer 533a was converted into guanidinium formate salt 534. Under the reaction conditions, the unexpected desilylation also occurred. The authors speculated that this happened due to anchimeric assistance by the neighboring guanidine’s nitrogen. Guanidine nitrogen attacks the silicon, which causes the oxygenesilicon bond to break.73,142

Scheme 100. Synthesis of the bicyclic core of batzelladine A.

7.2.17. ()-Adalinine. Shown to be present in all of the life cycle stages of Adalia bipunctata and as well as in the adult related species A. decempunctata, ()-adalinine (535) (Scheme 101), a chiral quaternary carbon-containing a piperidine alkaloid, was isolated as a minor component from the secretions of the European twospotted ladybird beetle, A. bipunctata.143 The sulfide contraction reaction of the optically active pyrrolidine-2-thione 536, afforded (Z)-enaminone 175 (Scheme 101). Enaminone 175 was converted into 537. The subsequent stereoselective 1,4-addition with pentylmagnesium bromide afforded 538 with the requisite quaternary carbon center. The d-amino ester 538 was later elaborated to 539. Samarium iodide-promoted regioselective CeN cleavage144 and cyclization gave 540 via the acyclic intermediate.143 In this transformation, samarium iodide acts as a one-electron reducing agent, while pivalic acid acts as a proton source. Compound 540 was elaborated to ()-adalinine (535).143

Scheme 101. Synthesis of adalinine.

reduction of the aliphatic ester followed by silylation provided compound 531, which on deacylation furnished the annulation precursor 532 as a Z isomer. Three-component annulation of 532 with silicon tetraisothiocyanate and acetaldehyde gave a mixture of

7.2.18. Halichlorine and pinnaic acid core. Marine alkaloids halichlorine (541) and pinnaic acids (542a) and (542b) (Fig. 23) present unique tetra- and bicyclic ring systems, respectively with a common azaspiro[4.5]decane core possessing three of the five

Fig. 23. Alkaloids possessing a common azaspiro[4.5]decane core.

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stereocenters present in the alkaloids. Halichlorine and pinnaic acids are isolated from the Japanese sponge Halichondria okadai and Okinawan bivalve Pinna muricata, respectively. Halichlorine significantly inhibits the induction of vascular cell adhesion molecule-1 (VCAM-1) and pinnaic acids are found to specifically inhibit cytosolic phospholipase A2 (cPLA2) activity. Ihara’s stereoselective approach to the azaspirocyclic core of the alkaloids included: a radical-translocationecyclization sequence to provide a spirocyclic structure with consecutive quaternary and tertiary stereogenic centers, an Eschenmoser sulfide contraction reactionehydrogenation to install a C5 stereocenter, and methylation at C14 using a stereochemical bias of the fused ring systems.145 Appropriately substituted lactam 543 underwent radical translocation/cyclization to furnish the spirolactams 544a and 544b as a 91:9 mixture of diastereomers, respectively (Scheme 102). In this reaction, it was assumed that the aryl radical homolytically dissociated the CeH bond next to the nitrogen atom by a [1,5]-radical translocation. The resulting a-aminyl radical reacted with the intramolecular olefin providing 544a and 544b. The stereoselectivity of the reaction was explained as a result of the possible conformation of the activated complex. The steric

Scheme 102. Radical translocation/cyclization reaction in the synthesis of halichlorine and pinnaic acid core.

repulsion between the ester and an axially oriented proton in the piperidine ring makes the activated complex leading to 544b higher in energy.145 Alternatively, the stereochemical outcome could be explained as a result of the A1,3-strain between the benzyl group on the nitrogen atom and one of the methylenes of the tether in the reactive conformer B. Conformer A experiences relatively less allylic strain and is therefore the preferred reactive conformer.68 Debenzylation of the major diastereomer 544a followed by thionation with Lawesson’s reagent gave thiolactam 545 (Scheme 103). Next, stereoselective installation of the substituent at C5 included the sulfide contraction reaction with ethyl-2bromoacetoacetate followed by deacylation with NaOEt to furnish the Z isomer 546. Stereoselective hydrogenation of 546 gave 547 with the required C5 stereochemistry of the target alkaloids. To take advantage of the facial bias in fused ring systems (concave vs convex) for the stereoselective introduction of methyl group at C14, tert-butyl ester in compound 547 was selectively hydrolyzed. This was followed by lactamization to give the fused tricyclic lactam 548. Reduction of the ethyl ester, silylation, and the stereoselective methylation, which occurred from the less bulky convex face (bface), yielded 549 as the only diastereomer. Reductive cleavage of the amide bond in 549 gave the azaspirocyclic core of halichlorine and pinnaic acids 550 possessing four of the five stereogenic centers.145 7.2.19. Azaphenalene alkaloids. Ladybug beetles (Coccinellidae) play an important role in controlling populations of agricultural pests such as aphids, mealy bugs, and scale insects. In 1971, Tursch and co-workers first isolated coccinelline (551b) along with its free base precoccinelline (551a), from the orange fluid released from the joints of Ladybug beetles (Coccinellidae) by a reflex bleeding mechanism, as their defense to protect themselves from their natural predators such as ants and quails (Fig. 24). The fluid also contains other stereoisomers, hippodamine (552a) and its N-oxide convergine (552b), and myrrhine (553) (its N-oxide not known to occur in nature), which were isolated later.102,146 The sulfide contraction method was utilized to synthesize the enaminone 289 from the thiolactam prepared from the lactam 554 (Scheme 104). The S-alkylation of the resulting thiolactam, with methyl bromoacetate provided the thioimidate 288, which was subsequently treated with PPh3/DIPEA to afford the desired enaminone 289. Compound 289 was then converted into enal 555,

Scheme 103. Synthesis of the core structure of halichlorine and pinnaic acid.

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Fig. 24. Azaphenalene alkaloids from Ladybug beetles.

Scheme 104. Synthesis of azaphenalene alkaloids.

the precursor for the pivotal aza-[3þ3] annulation. Treatment of enal 555 with piperidinium trifluoroacetate salt afforded the desired aza-annulation product 556, a common intermediate, which was later elaborated to achieve all of the stereoisomers and their Noxides of the target alkaloids.102,146 The mechanism of aza-[3þ3] annulation is shown in Scheme 105. First iminium salt 557 is formed, which undergoes a N-1,4addition to give 558. A 1,2-addition cyclize the bicycle giving 559. The tricycle 559 tautomerizes giving 560, which after elimination of the protonated piperidine gives the aza-tricycle 556. Modeling studies revealed that the formation of anti stereochemistry at the ring junction was the result of a lower energy transition state during the N-1,4-addition.102

Scheme 105. Proposed mechanism for the aza-[3þ3] annulation in the synthesis of azaphenalene alkaloids.

7.2.20. C5-substituted hydroxyethyl indolizidines. The simple alkylindolizidines detected in the skin of neotropical poison frogs

belonging to the family Dendrobatidae are attractive synthetic targets because of their extremely low abundance and strong biological activity, including neuromodulation, enzyme inhibition and antitumor, immunoregulatory and antiviral activity.104 Varga and co-workers developed a synthetic strategy, involving the sulfide contraction method, for the synthesis of 5-substituted indolizidines. Amide 563, prepared via the intramolecular Schmidt reaction of azide 561,147 was treated with Lawesson’s reagent to form the 5-thioindolizidinone 312 (Scheme 106).104 The sulfide contraction sequence was employed to attach the appropriate side chain. The unstable enaminoketone 313 formed after the sulfide contraction reaction was treated with perchloric acid to form the stable iminium salt 314, which was then subjected to the Clemmensen reduction to give the (
)-n-propylindolizidine 564 in low yield (10%). Similarly, a more stable enamino ester 565 was prepared (E:Z ratio is 1:3), which underwent catalytic hydrogenation and metal hydride reduction to give the C5-substituted hydroxyethyl indolizidine 567 in racemic form.104 7.2.21. ()-Sedacryptine. Wee et al. synthesized the 2,6disubstituted 3-hydroxypiperidine moiety containing alkaloid ()-sedacryptine (568) (Scheme 107) by a chiral building block approach.148 Earlier they reported the synthesis and utilization of the cis-bicyclic, functionalized, chiral non-racemic building block 569 in the synthesis of an indolizidine alkaloid, which provides a stereochemical bias for the stereoselective installation of the substituents on the piperidine ring.149 Their synthetic strategy utilized the sulfide contraction method to install the side chain at the sixth position of the piperidine ring. Efficient thionation of the bicyclic lactam 569, followed by alkylation with 2bromoacetophenone, and subsequent extrusion of sulfur by PPh3 yielded the enaminone 570 (Scheme 107). Catalytic hydrogenation of the enamide double bond in 570 yielded a 90:10 ratio of diastereomers. The major isomer (b-H) was then N-debenzylated and immediately protected with methyl chloroformate to give the carbamate 571. The carbonyl of the phenacetonyl side chain of 571 was then exclusively and stereoselectively reduced using the CBS

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Scheme 106. Synthesis of C5-substituted hydroxyethyl indolizidines.

Scheme 107. Synthesis of sedacryptine.

catalyst to give the carbinol 572. Carbinol 572 was elaborated to ()-sedacryptine (568).148 7.2.22. cis-Decahydroquinoline alkaloids: lepadin family. Eight members of the lepadin family, isolated from different sources such as tunicate Clavelina lepadinformis, flatworm Prostheceraeus villatus, tropical marine tunicate Didemnum sp., and Australian Great Barrier Reef ascidian Aplidium tabascum show various biological activities. Their intriguing structures have five stereogenic centers on the decahydroquinoline core with diverse relative stereochemical relationships. As such, they are attractive and challenging synthetic targets, especially lepadin F with its 1,3-anti relative configuration for C2,8a (Fig. 25). 151 Hsung et al.’s synthetic efforts towards lepadin F are shown in Scheme 108. Although 574 was anticipated to undergo

stereoselective reduction from the non-sterically hindered face of the C4a,8a double bond, only the C5 carbonyl underwent reduction to alcohol 576, or a deoxygenation occurred to give 576. This prompted the authors to switch to an alternative route. In the new route, the required functionality at C5 was installed, prior to the C4a,8a reduction. The Eschenmoser’s episulfide contraction yielded the a,b-unsaturated ester 578, exclusively as an E-isomer, and the subsequent one-step stereoselective reduction of C4a,8a and C5,10 olefins gave the ester 579 as a 5:1 mixture (with respect to C5 stereocenter) of separable diastereomers. The major diastereomer 579 (C5-aH) was elaborated further through a series of transformations that culminated in the enantioselective total synthesis of (þ)-lepadin F (573).150 7.2.23. Monocyclic piperidine and pyrrolidine alkaloids. Neto and co-workers synthesized racemic norallosedamine (580) (Scheme 109) using the Eschenmoser sulfide contraction reaction.67b A number of reaction conditions were screened for the formation of a-thionium salt. The best conditions were found when NaI was used as the additive. The use of NaI as an additive has been reported earlier in the Eschenmoser sulfide contraction reaction.19 The athionium salt was not isolated and subjected to contraction giving enaminone 581 as a single diastereomer. Various hydrides and hydrogenation catalysts were screened for the reduction of enaminone 581. In many instances, formation of a completely reduced product 580 competed with the formation of partially reduced product 582. The best yield of 580 was achieved with NaBH4/EtOH as the reducing system and 580 was obtained as a single diastereomer. Formation of 582 was best achieved when 581 was hydrogenated with PtO2 and catalytic HClO4. Other reducing agents, NaBH3CN/HCl and NaBH(OAc)3 also provided 582.

Fig. 25. Lepadin F: A representative of the lepadin family of alkaloids.

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Scheme 108. The Eschenmoser sulfide contraction in the synthesis of lepadin F.

Scheme 109. Synthesis of sedamine alkaloids. Scheme 110. Preparation of starting materials in the synthesis of fuligocandins A and B.

Formation of 582 marks the formal synthesis of four isomers of sedamine (580, 583e585).67b A similar strategy of sulfide contraction followed by reduction of the enaminone double bond was used to furnish the formal syntheses of elaeocarpine (393) and isoelaeocarpine (394) (Fig. 17),151 an antimalarial lead compound (
)-deoxyfebrifugine (586),152 an AD/HD drug (
)-erythro-methylphenidate (587),153 and racemic pyrrolidine alkaloids: hygrine (588a), dehydrodarlinine (588b), dehydrodarlingianine (588c), and N-methylruspolinone (588d) (Fig. 26 ).78

synthesize the thiolactam 221 but also for the synthesis of fuligocandin B 224, the preparation of the other reacting partner, i.e., an appropriately substituted indole derivative (enolizable a-halocarbonyl) 222 (Scheme 110). Although initial monothionation attempts using the literature methods resulted in poor selectivity, the known monothiocarbonyl 221 was finally obtained in 85% yield by employing the P2S5-Py2 complex (Scheme 110). After futile attempts to synthesize 222a by combining the monoylide 592 with the indole-3-carboxaldehyde 591a in a Wittig reaction, N-pro-

Fig. 26. Alkaloids prepared by the sulfide contraction followed by an enaminone reduction strategy.

7.2.24. Fuligocandins A and B. Bergman et al. employed the Eschenmoser episulfide contraction on the pyrrolo-1,4benzodiazepine 221 derivative, synthesized readily from L-proline and isatoic anhydride,154 for the synthesis of both fuligocandin A (589) (Scheme 110) and B (224) (Scheme 111).18 The challenge in this strategy was not only the selective monothionation of 590 to

tection with benzenesulfonyl chloride (591b) or p-nitrobenzenesulfonyl chloride (591c) facilitated a smooth Wittig reaction to give 222b and 222c, respectively.18 Combining 221 and chloroacetone under standard Eschenmoser sulfide contraction conditions (tert-butoxide or triethylamine as a base, and triphenylphosphine as sulfur scavenger, in benzene or

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Scheme 111. Synthesis of fuligocandins A and B.

xylene at elevated temperatures) failed to yield fuligocandin A. The authors hypothesized that a polar aprotic solvent like DMSO would facilitate the initial SN2 alkylation. The solvent would also expose the carbanion toward the electrophilic sp2 carbon of the imine, facilitating the CeC bond formation. These conditions were applied and 593a was obtained (Scheme 111). Treatment of 593a with DBU provided fuligocandin A in a moderate yield. The use of DABCO as a base and trimethyl phosphite as a sulfur scavenger provided better results and racemic fuligocandin A was obtained in excellent yield (98%) as a Z isomer (Scheme 111). The unstable thioimidate intermediate 593a, although isolable after the alkylation step, gave best results in a one-pot alkylationeepisulfide contraction process.18 The use of the same reaction conditions for the synthesis of fuligocandin B resulted in a low yield of the alkaloid. However, the authors observed the rapid episulfide contraction of 593b and 223 in hot DMSO to yield 49% and 57% of vinylogous amides 225 and 594 (Scheme 111). Not very surprisingly, the racemization occurred in the last N-deprotection step (594/224) under basic conditions (Cs2CO3/MeOH). However, the extremely mild N-deprotection conditions for 2- and 4-nitrobenzenesulfonamides, developed by Fukuyama, using thiolates, converted 594 to the desired Z,E-isomer-(þ)-(224) with a specific rotation of þ140, which is in agreement with the reported value.18 The general applicability of alkylationesulfur extrusion in DMSO with DABCO as a base was investigated and the method was found to be suitable in coupling secondary thioamides with primary halides. Secondary halides, ahaloesters and a-halo malonates were found to be unsuitable coupling partners.18,155 7.2.25. Macrocycles. Ireland et al. reported an intramolecular Eschenmoser sulfide contraction, a novel ring-forming reaction, for the formation of b-enamino lactones (cyclic vinylogous carbamates). Mild hydrolysis of the b-enamine moiety unveiled the masked ketone to form b-ketolactones. This strategy was applied

successfully for the synthesis of a macrocyclic lactone, diplodialide A (595) (Fig. 27).19

Fig. 27. Macrocylic lactone (
)-diplodialide A (595).

Before testing the applicability of this strategy for the construction of diplodialide A, the feasibility of the intramolecular Eschenmoser sulfide contraction reaction was first demonstrated in the synthesis of five- and six-membered b-enamino lactones, and then in the synthesis of macrocyclic b-ketolactones. The chloro esters obtained from the acylation of the hydroxythioamide 596 and 598 were treated with NaI and the Eschenmoser’s basethiophile reagent, bis-(3-dimethylaminopropyl)phenylphosphine (68), to afford the five- and six-membered b-enamino lactones 597 and 599 (Scheme 112). The corresponding thioiminium salts obtained after the intramolecular alkylative coupling with thioamide moiety in 596 and 598 underwent an irreversible deprotonation step, as evidenced by the formation of b-enamino lactones 599a and 599b with no sign of epimerization.19 However, application of this protocol, due to the possible reversible alkylation of the intermediate thioiminium salts (Section 2.2), posed a problem in the construction of macrocyles. Therefore, a modified procedure was adopted. The preformed a-chloro ester € nigs base, and was added slowly to the refluxing solution of NaI, Hu triethyl phosphite. This extruded the sulfur of the thioiminium salt as it was being formed and after an aqueous workup, the desired macrocycles were obtained in moderate yields. The conditions were also compatible with a variety of ancillary functional groups

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7.3. Sulfide contraction via iodinative coupling

Scheme 112. Intramolecular sulfide contraction.

such as acetylenic and olefinic linkages, esters, ketals, and ketones (Scheme 113). However, thioamides 606 and 607 did not afford any identifiable products.19

Scheme 113. Formation of lactones via the sulfide contraction method Conditions, 1. ClCH2COCl, py, 2. NaI, P(OEt)3, i-Pr2NEt, D, NaH2PO4.

Later, the aforementioned conditions were used in the successful construction of diplodialide A (Scheme 114). The b-acetoxy thioamide 608 was prepared and subjected to the sulfide contraction sequence to afford acetoxy lactone 609, albeit in a low yield, which after the elimination of the acetoxy group yielded (
)-diplodialide A (595).

Scheme 114. Synthesis of diplodialide A.

7.3.1. Vitamin B12. For the A and B ring coupling of the A/B variant, two strategies were developed.106 The one that involved the Eschenmoser sulfide contraction is shown in Scheme 115. Thioamide 317 was converted into a zinc complex, which was reacted with iodine to form the bridged intermediate 610. Decomplexation with TFA followed by sulfide contraction with triphenylphosphine or tris(2-cyanoethyl)phosphine provided the corrin core, which was recomplexed with zinc to give 611. Zinc complex 611 was elaborated to corrin cobalt complex 320.11,12,106 During the synthesis of vitamin B12, rings A and B of the A/D variant were coupled through the iodinative coupling variant of the sulfide contraction method (Scheme 116). The base enabled the formation of thioether 614, which was complexed with cadmium. Contraction with PPh3 and TFA followed by recomplexation provided 615.6a,42a The metal complexation probably helps with the sulfide contraction step.40b The problem of the A/D junction in the A/B variant generated the principle of conservation of orbital symmetry.156 Eschenmoser’s group investigation of the construction of A and D junction in the A/ D variant provided a stringent test for these newly developed WoodwardeHoffmann rules. The ring closure between A and D was carried out on 319, which was obtained on reacting 615 with DBU. The photo-induced cycloisomerization (a sigmatropic reaction followed by an electrocyclization reaction) on 319 gave the corrin chromophore 616 (Scheme 117) and provided an elegant alternative to the A/B variant. In the A/D variant, all of the four ring precursors of 320 were prepared from a single racemic starting material.6a,14b,42a 7.3.2. (þ)-Tolyporphin A O,O-diacetate (proposed structure). Kishi’s group used the Eschenmoser iodinative coupling reaction for the synthesis of (þ)-tolyporphin A O,O-diacetate (617) (Fig. 28).42b,157 The reaction was first used in the coupling of A/B and D/C coupling (Scheme 118). Thus, a base-induced coupling of thioamide 618 with enamides 619 and 621 in the presence of NIS, followed by sulfide contraction with triethyl phosphite provided the vinylogous amidine 620 and 622.42b Iodinative coupling was used again to join A and D rings (Scheme 119).42b The product 625 was elaborated to form the proposed structure of (þ)-tolyporphin A O,O-diacetate (617). The proposed structure was incorrect. However, after comparing the NOESY analysis of the prepared compound with the acetylated natural product, Kishi’s team was able to propose a revised structure of (þ)-tolyporphin A and (þ)-tolyporphin A O,O-diacetate. The revised structures had an opposite configuration at the C-7 and C17 stereocenters (Fig. 28).158 A similar iodinative sulfide contraction process was used to synthesize another derivative of isobacteriochlorin.41d 7.4. Wittig reaction with thioimides 7.4.1. Iturinic acid. Iturinic acid (626) (Scheme 120) belongs to a group of peptide antibiotics that are found as a mixture in Bacillus subtilis.159 Gossauer and co-workers utilized the Wittig reaction with thioimides as the key step in the synthesis of racemic iturinic acid (626) (Scheme 120).56b Thioimide 627 was reacted with 143 to give 628. The resulting enaminone 628 was reduced with Adam’s catalyst under acidic conditions to give the ester 629. Hydrolysis of 629 provided iturinic acid 626, which was esterified to ethyl ester 631 as ester 631 was easier to characterize.56b 7.4.2. Isobacteriochlorin macrocylce. Heme (haem) d1 (632a) (Scheme 121) is present in the bacterial enzyme cytochrome cd1. Its structural similarity with vitamin B12 (Scheme 65) suggests that

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Scheme 115. A and B coupling through the Eschenmoser iodinative coupling reaction in the A/B variant of the vitamin B12 synthesis.

Scheme 116. Use of the iodinative coupling process in the synthesis in the A/D variant of the vitamin B12 synthesis.

both compounds may share many steps of the same biosynthetic pathway. Until 1997, the absolute configuration at C-2 and C-7 centers of heme d1 (632a) was unknown. Battersby and co-workers reasoned that if heme d1 (632a) and vitamin B12 and its biosynthetic precursors share the same biosynthetic pathway then they are likely to have the same absolute configuration at C-2 and C-7. In order to test this hypothesis, stereoselective synthesis of 632b was conducted and it was found to have the predicted absolute configuration.160 This suggested that heme d1 (632a) and vitamin B12 do share the same biosynthetic pathway. For the synthesis of 632b, advanced intermediates isobacteriochlorins (644a) and (644b) were prepared using the Wittig reaction with thioimides (Scheme 121).161 Both the monothioimides 634 and 635 were made from (R)-succinimide 633. Imide 633 on treatment with

excess Lawesson’s reagent gave 90% of dithioimide along with the trithio product and the monothioimide 635. The dithioimide and the trithioproduct were converted into 634 by controlled hydrolysis using mercuric chloride. Monothioimide 635 was prepared by reacting 633 with Lawesson’s reagent. Base-catalyzed thio-Wittig reaction of 636 with thioimides 634 and 635 produced the corresponding 637 and 638 as single diastereomers. The nitrile group in the phosphonium salt 636 was found to be crucial for the successful coupling process. The coupled products 637 and 638 were converted into thioamides 639 and 640. The Eschenmoser sulfide contraction via alkylative precoupling reaction on 639 provided enaminone 641. Deprotection with TFA, followed by decarboxylation gave 642. The eastern thiolactam 640 was reacted with trimethyl orthoformate and TFA to provide the formyl

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Scheme 117. The crucial cycloisomerization reaction in the coupling of A and D rings in the A/D variant of the vitamin B12 synthesis.

Fig. 28. Proposed structure of (þ)- tolyporphin A O,O-diacetate synthesized by the iodinative coupling method.

thioimino ether 643. In this one pot process, deprotection of tertbutyl ester, decarboxylation, S-methylation and formylation of pyrrole was achieved. Acid-catalyzed condensation of the western 642 with the eastern block 643 generated the seco-system, which was irradiated to effect a photochemical 18p-electron antarafacial cyclization generating isobacteriochlorin 644a. The oxo function in 644a could be introduced via oxidation with Cu(OAc)2 providing 644b.161 Isobacteriochlorin 644b was elaborated to metal-free heme d1 632b.160 Similar methods involving: thio-Wittig reaction, sulfide contraction via alkylative precoupling and photochemical cyclization, were used to prepare other substituted isobacteriochlorins. These compounds were prepared to help study the biosynthesis of vitamin B12.162

Scheme 118. Coupling of A/B and D/C through the Eschenmoser iodinative coupling reaction.

Scheme 119. A/D coupling in the preparation of (þ)-tolyporphin A O,O-diacetate (617).

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Scheme 120. Synthesis of iturinic acid (626).

7.5. The thio-Reformatsky reaction 7.5.1. N-Phosphorylated aziridine. The 2,3-dihydro-1H-pyrrolo[1,2a]indole core is common to mitomycins (Section 7.2.6C). Michael and co-workers approached the asymmetric synthesis of this core via the thio-Reformatsky of 645 with ethyl bromoacetate (Scheme 122). An intramolecular Heck reaction was used to cyclize enaminone 646 into 647. The reaction required a judicious combination of base, solvent, ligand and the additive. Ketal 647 was converted into 648 with the hope that 648 could be oxidized to the sulfate on which the SN2 reaction of azide could be attempted. However, 648 could not be oxidized under Sharpless conditions (cat. RuCl3/NaIO4 as oxidant). Fortunately, direct SN2 reaction of azide on 648 was successful and the corresponding alcohol, formed after the expulsion of SO2, was converted into mesylate 649. The Staudinger reaction on 649 with PPh3 gave unprotected and unstable aziridine 650 in low yield. This problem was solved by employing trimethyl phosphite in the reaction and reacting the dimethyl phosphoramidate intermediate immediately with NaH to give N-phosphorylated mitosene analog 651.163 A similar strategy was employed in the formal asymmetric synthesis of 7-methoxyaziridinomitosene (652).164 7.6. Coupling with diazo electrophiles 7.6.1. Cephalotaxine. Cephalotaxine (653) (Scheme 123) is the most abundant alkaloid of Cephalotaxus drupacea, which is an evergreen shrub.165 Cephalotaxine (653) contains a unique benzazepine moiety that is fused with two five-membered rings.166 Danishefsky and co-workers prepared enamine 670, which provided the formal synthesis of 653. The key points of their strategy are shown.47b Hydrolytic succinoylation of dihydroisoquinoline 654 provided a mixture of acylated products 655 and 666. The mixture was treated with 1,2-ethanediol and BF3 to afford a single thioacetal 667. Compound 667 was elaborated to hydrazone 668, which on treatment with Rh2(OAc)4 gave enamide 669, which was reduced to give enamine 670. Formation of 669 was also possible with the tungsten hexacarbonyl-mediated cyclization of thioacetyl derivative of 668 (see Scheme 26, for a similar example).47b A similar alkaloid, chilenine (671), was also synthesized using the W(CO)6 and rhodium(II) acetate-mediated coupling process.46 7.6.2. Indolizomycin. Indolizomycin (672) (Scheme 124) is a bioengineered antibiotic. The structural complexity of indolizomycin (672) is due to the presence of a bridgehead hemiaminal flanked by fused cyclopropyl and epoxy functions. Furthermore, indolizomycin (672) undergoes decomposition after a few hours under neutral conditions at room temperature. These challenges compelled Danishefsky and co-workers to undertake the total synthesis of indolizomycin.50 The key transformations are shown. Rhodiumcatalyzed annulation of 673, followed by treatment with deactivated Raney nickel gave the enaminone 674. Compound 674 was

Scheme 121. Synthesis of metal-free heme d1 via thio-Wittig and sulfide contraction strategy.

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Scheme 122. Synthesis of an N-phosphorylated aziridine.

Scheme 123. Formal synthesis of cephalotaxine.

alkylated with (CH3)3OBF4 and the resulting iminium species was reduced with NaBH4. The crude product 675 underwent vinylogous McCluskey fragmentation when treated with TEOCl 676. Selection of the TEOC protecting group was crucial for the success of the total synthesis. Epoxidation of 677, followed by Wharton fragmentation gave the allylic alcohol 679. Compound 679 was converted into 680 and through the 1O2 ene reaction (681) followed by reduction with PPh3, enal 682 was obtained. Julia olefination on 682 provided 684, which was elaborated to DL-indolizomycin (672).50,88 The rhodiumcatalyzed sulfide contraction reaction was also used by Danishefsky and co-workers to prepare indolizidine, iso-A58365A.27 8. Extensions 8.1. Synthesis of 1,3-dicarbonyl compounds Eschenmoser and co-workers showed that the alkylative precoupling process can also be applied to thiocarboxylic acids. The mechanism, similar to the alkylative precoupling process, involving thioether formation followed by sulfide contraction was supposed to be operative (Scheme 125). The products of this reaction are enolizable b-dicarbonyl compounds. Eschenmoser’s process

complements other methods for the preparation of 1,3-dicarbonyl compounds, such as the Claisen condensation reaction. For example, the Claisen condensation reaction can fail due to steric hindrance or give a constitutionally non-specific product in a mixed condensation. In such systems, the Eschenmoser method is shown to tolerate steric hindrance better (due to greater carbonesulfur bond lengths) and provides constitutionally specific products due to greater nucleophilicity of the sulfur atom.1a,14c,21a The initial report11,16 describing the synthesis of 1,3-dicarbonyl compounds used PPh3 as the thiophile. Later, in some instances it was replaced by other phosphine reagents to improve the sulfur extrusion process.1a The reaction also required either a strong base or lithium salts for the sulfide contraction step. Three main complementary procedures that were discussed are shown in Table 3 along with some of the examples presented in Eschenmoser’s original publication.1a The use of lithium salts allows the synthesis of labile dicarbonyl compounds under mild conditions. As an example, sulfide contraction was carried out on the polyfunctional and labile compound 691 to provide the dicarbonyl 692 (Eq. 31). Method C with K-tamylate as a base failed to provide 692. Use of bis-(3dimethylaminopropyl)phenylphosphine 68 as a base and

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Scheme 124. Key reactions in the synthesis of

DL-indolizomycin.

Scheme 125. Proposed mechanism for the synthesis of 1,3-dicarbonyl compounds via the Eschenmoser coupling reaction. Table 3 Comparison of three methods used for the synthesis of 1,3-dicarbonyl compounds. R1

R2

R3

CH3CH2CH2 CH3CH2CH2 CH3CH2CH2

H CH3 CH

CH3CH2 CH3 p-BrC6H4

a b c

Yield Method A %a

Method B %b

Method C %c

93 80 d

72 52 80

75 75 79

Bis-(3-dimethylaminopropyl)phenylphosphine 68, LiBr, CH3CN, 70  C, 17 h. Bu3P, Et3N, LiClO4, benzene/RT, 3 days. Bu3P, K-t-amylate, LiClO4, 70  C, 3 h.

a thiophile provided easier separation of 1,3-dicarbonyl compounds. At the end of the reaction, it could be removed along with its phosphine sulfide by extraction with a dilute acid.1a

(32)

8.2. Sulfide contraction followed by retro-Claisen condensation € ggen and Krolikiewicz discovered that C-substitution of Vorbru nucleosides can be achieved via the Eschenmoser sulfide contrac-

(31)

Another method, for the preparation of 1,3-dicarbonyl compounds is the hydrolysis of vinylogous products that can be obtained from the Eschenmoser sulfide contraction reaction via alkylative precoupling (Eq. 32).19,20

tion followed by the retro-Claisen condensation. (Scheme 126).167 Yamane and co-workers also reported similar results near that € ggen and Krolikiewicz described this reaction as time.168 Vorbru sulfide contraction followed by a retro-aldol condensation

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reaction.167b However, Eschenmoser pointed out that the correct term should be a retro-Claisen condensation. The reaction is suitable for both pyrimidine and purine nucleosides. Methyl or substituted methyl compounds were obtained using this approach.167,168

61

Conversion of 700 into 701 was speculated to occur via a sulfide contraction reaction, which is reminiscent of the Eschenmoser sulfide contraction reaction (Scheme 128). Deprotonation by NaH and the intramolecular attack of the resulting anion 703 on the carbonyl gives episulfide 704. The episulfide 704 collapses with the help of the thiophile to give the sodium

Scheme 126. Methylation of a purine nucleoside.

8.3. Synthesis of carbapenems

salt 705. The salt is trapped in situ by (PhO)2POCl to give the carbapenem 701.169

Horikawa and co-workers reported a process for the formation of carbapenems (Scheme 127) that is closely related to the sulfide contraction reaction via alkylative precoupling. Alcohol 698 was treated with thionyl chloride and pyridine to form the corresponding chloride 699. The crude chloride was reacted with the base affording 700. Thiazone 700 was reacted with NaH in the presence of PPh3 followed by the addition of (PhO)2POCl to give 701. Without isolation, 701 was reacted with thiols to give the corresponding carbapenems 702 via an addition-elimination reaction.169

8.4. Synthesis of thiopenem Nelson and co-workers reported a carbene-mediated penem formation reaction (Scheme 129). The reaction was thought to proceed via stabilized carbene 709 that reacts intramolecularly with the thiocarbonate generating episulfide 710. Sulfur extrusion by the thiophile gives the thiopenem 712. Nelson and co-workers also reported another method for the formation of the thiopenem system, which is reminiscent of the

Scheme 127. Synthesis of carbapenems.

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was used in the synthesis of a sulopenem antibiotic (718) on a 266kg scale.24 Two reaction mechanisms were proposed for the conversion of 715 into 717 (Scheme 131). The one that is well precedented involves the formation of zwitterion intermediate 719. The subsequent intramolecular ring contraction provides 716 as a mixture of diastereomers. Spontaneous desulfurization of one of the diastereomers gives the penem 717 while the other diastereomer requires the addition of a thiophile for the desulfurization.24 The difference in the reactivity of two diastereomers of 716 is probably due to steric reasons. 8.5. Pyridone synthesis Scheme 128. Proposed mechanism for the ring contraction in the synthesis of carbapenems.

Peters and co-workers reported a novel process for the formation of pyridone. The reaction is related to the Eschenmoser sulfide contraction via an alkylative precoupling process. Bromide 720 was reacted with thioamide 32 to give 721 (Scheme 132). Salt 721, when

Scheme 129. Carbene-mediated penem formation.

Eschenmoser sulfide contraction reaction. The process required chloride 715, which was prepared as a 1:1 mixture of diastereomers by the chlorination of alcohol 714. Alcohol 714 was prepared by Nalkylation of b-lactam 706 with glyoxylic acid ester 713 (Scheme 130). The chloride 715 on reaction with Hunig’s base afforded a mixture of penem 717 and a compound that, on the basis of mass spectral data, was tentatively assigned as episulfide 716. Reaction of 716 with the thiophile produced penem 717. The reaction sequence

reacted with a combination of pentamethylpiperidine (PMP) and P(OEt)3, underwent a domino sulfide contraction/d-lactam formation providing 722 and the regioisomer 723.170 The proposed mechanism is initiated by the base-induced deprotonation of salt 721 (Scheme 133). The carbanion 724 attacks the imino group generating the episulfide 725. Subsequent dlactam formation gives 726. The tetracycle 726 is desulfurized by the thiophile giving the pyridone 722. The other regioisomer 723 is

Scheme 130. Synthesis of thiopenem via carbene.

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S.R. Hussaini et al. / Tetrahedron xxx (2015) 1e70

Scheme 131. Proposed mechanism for the formation of penem 717.

63

Contraction of thioethers containing an aromatic carbonyl group gave the double bond between C4eC5, while the contraction of thioethers containing ester groups, produced the C4eN3 double bond (Scheme 135). In the case of 730, it is obvious that the aromatic nature of the diazepine ring drives the reaction and the thermodynamic product is formed. No explanation was given for the formation 732 over the usual exocyclic products. Perhaps, under the reaction conditions, initially formed 728 tautomerizes into

Scheme 132. Pyridone synthesis via the Eschenmoser-type reaction.

Scheme 133. Proposed mechanism for the formation of the pyridone.

formed by the intramolecular reaction of 725 on the more hindered ester.170 Alternatively, it is the iminium form of 724 and 725 that participates in the reaction.68 8.6. Formation of conjugated alkenes Hsung and co-workers reported a reaction where the enaminthione 727 was coupled with methyl bromoacetate under the Eschenmoser sulfide contraction reaction conditions to give conjugated ester 578 (Scheme 134). The Wittig-type olefination of 577 with Ph3P]CHCHO failed to give the desired unsaturated 578. The reaction was used to prepare the alkaloid (þ)-lepadin F.150

732. In the case of ketones, a stronger hydrogen bond between the NH and ketone carbonyl prevents such tautomerization and 728 instead tautomerizes into 730. In the past, the chemistry of 5H-2,3benzodiazepines was limited to only carbon-heteroatom bonds. The new method was used to overcome this deficiency and prepared CeC bonds on 5H-2,3-benzodiazepines.171 8.8. Sulfur heterocycles Thiophene products that are usually unwanted side products in the Eschenmoser sulfide contraction reaction (Section 6.3.6 and 6.3.7), have been prepared by taking advantage of this un-

Scheme 134. Formation of conjugated double bonds via the sulfide contraction method.

8.7. Formation of an endocyclic double bond with benzodiazepines Sizonenko and co-workers found that the Eschenmoser sulfide contraction reaction of benzodiazepines does not give the usual exocyclic product 728, but instead gives the endocyclic products.

€ nsch and co-workers prepared thiopheneexpected reaction. Wu annulated 3-benzazepines 734 using this reaction (Scheme 136). The proposed mechanism involved the S-alkylation of thioamide 733 to give 735a. Deprotonation at the carbon adjacent to the iminium carbon produced 735b. An intramolecular attack by the enamine 735b on the ester carbonyl provided the tricyclic product

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S.R. Hussaini et al. / Tetrahedron xxx (2015) 1e70

9. Conclusions and outlook

Scheme 135. Formation of an endocyclic double bonds in benzodiazepines.

Even though much progress has been made since the discovery of the sulfide contraction reaction in 1955, the mechanism of the Eschenmoser sulfide contraction reaction is still not completely understood. More work is needed to understand the role of thiophiles and the extrusion process. To this day, pioneering studies by Eschenmoser and co-workers provide the most diverse set of reagents and conditions for the sulfur extrusion. The Eschenmoser sulfide contraction method remains a useful tool in organic synthesis. The alkylative precoupling method is used most frequently and most diversely. Even though the oxidative precoupling method is being mostly replaced by the iodinative method, it is still found to be useful in the synthesis of corrins and related compounds. Alkylative precoupling is mostly used in the synthesis of enaminones. Enaminones can themselves be used as coupling partners in the oxidative precoupling method (Schemes 49 and 50). The modified versions of the Eschenmoser sulfide contraction method have complemented the original alkylative and oxidative precoupling methods and, in doing so, they have broadened the substrate scope. More modifications are anticipated to further expand the substrate scope, and to render products in shorter time and under milder conditions. It is expected that the Eschenmoser sulfide contraction reaction will remain a useful method for the construction of CeC bonds for many years to come. Acknowledgements

Scheme 136. Formation of thiophene-annulated products.

736, which on deprotonation gave tetrahydro-3-benzazepines 734.172  ski and co-workers reported a different outcome with Jagodzin secondary b-keto thioamides. The reaction of thioamides of type 737 on reaction with ethyl bromoacetate and its derivatives gave thiazolidine derivative 738 (Scheme 137). The reaction was used to prepare a number of compounds of general formula 738 at room temperature. A possible mechanism based on the proposed hypothesis is shown below.68,173

Scheme 137. Synthesis of the thiazolidine derivatives.

We would like to thank Dr. J. Bergman of Karolinska Institute, Sweden, Dr. H. Hiemstra of the University of Amsterdam, Netherlands, Dr. G. Kim of Chungnam National University, South Korea, Dr. H. Lee of Korea Institute of Chemical Technology, South Korea, Dr. J. P. Michael of the University of the Witwatersrand, South Africa, Dr. M. C. Elliott of Cardiff Ukniversity, UK, and Dr. J. Petersen of SynDevRx, USA, for their assistance in providing additional information about their research. We are thankful to Dr. W. Fuhrer for his help in clarifying some terms and for connecting us with Dr. A. Eschen€ rich. Dr. Eschenmoser not only offered detailed moser of ETH Zu explanations of the concepts published in his papers, but he also helped us understand the work of other authors who could not be reached. We are also grateful to Dr. Eschenmoser for sharing his unpublished work with us. We are thankful to Dr. Mark Moloney of The University of Oxford, and Dr. Nan Zheng of the University of Arkansas, for providing useful comments on some aspects of the manuscript. References and notes €tschi, E.; Eschenmoser, A. Helv. Chim. Acta 1971, 54, 1. (a) Roth, M.; Dubs, P.; Go 710; (b) Nicolaou, K. C.; Sorensen, E. J. In Classics in Total Synthesis: Targets, Strategies, Methods; VCH: New York, 1996; p 99. 2. Greenhill, J. V. Chem. Soc. Rev. 1977, 6, 277. 3. Michael, J. P.; Jungmann, C. M. Tetrahedron 1992, 48, 10211. 4. Wang, Z. Eschenmoser coupling In. Comprehensive Organic Name Reactions and Reagents; Wiley: 2009; Vol. 1, p 1001; chapter 218. 5. Davies, D. E.; Doyle, P. M.; Hill, R. D.; Young, D. W. Tetrahedron 2005, 61, 301. 6. (a) Eschenmoser, A.; Wintner, C. E. Science 1977, 196, 1410; (b) Eschenmoser, A. Studies on organic synthesis In. XXIIIrd International Congress of Pure and Applied Chemistry: Special Lectures Presented at Boston, USA, 26e30 July 1971; Butterworths: London; 1971; Vol. 2, p 69 The published lecture is also accessible in the internet: ETH e-collection; Eschenmoser, A. Studies on Organic Synthesis, 1971; http://dx.doi.org/10.3929/ethz-a-010165162 (Online Publication Date: 2014). € hler, N.; Go € tschi, E.; 7. Yamada, Y.; Wehrli, P.; Miljkovic, D.; Wild, H.-J.; Bu €liger, P.; Gleason, J.; Pace, B.; Ellis, L.; Hunkeler, W.; Schneider, P.; Golding, B.; Lo € ller, K.; Neier, R.; Fuhrer, W.; Nordmann, R.; Srinivasachary, K.; Keese, R.; Mu Eschenmoser, A. Helv. Chim. Acta 2015 in press. 8. Eschenmoser, A. Pure Appl. Chem. 1969, 20, 1. 9. Fischli, A.; Eschenmoser, A. Angew. Chem., Int. Ed. Engl. 1967, 6, 866. 10. Eschenmoser, A. Proc. Robert A. Welch Foundation Conf. Chem. Res. 1968, 12, 9. 11. Eschenmoser, A. Q. Rev. Chem. Soc. 1970, 24, 366.

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Biographical sketch

Syed Raziullah Hussaini was born in Karachi, Pakistan. He received his bachelors and masters degrees from the University of Karachi in 1995 and 1996, respectively. He joined the HEJ Research Institute of Chemistry, Pakistan in 1997. In 2000, he moved to the United Kingdom and completed his DPhil from the University of Oxford in 2004 under the guidance of Dr. Mark G. Moloney. His research involved the selective synthesis of 2,5-substituted pyrrolidines. In 2004 he conducted postdoctoral studies with Professors R. B. Grossman at the University of Kentucky where he worked on elucidating the biosynthesis of the loline alkaloid. In 2005 he moved to Emory University and performed postdoctoral research with Professor S. Blakey. His research projects involved the discovery of new organometallic and organocatalytic reactions. In 2006 he joined the lab of Professor P. Crooks at the University of Kentucky where he conducted research in medicinal chemistry. From 2007 to 2009 he worked at the University of Louisville, teaching various graduate and undergraduate courses and conducted research in organic synthesis with Professor G. B. Hammond. Since 2009, he has been working as an Assistant Professor at the Department of Chemistry and Biochemistry, The University of Tulsa. His research interests include the development of selective CeC bond forming methods and their application in the synthesis of bioactive compounds.

Raghu Ram Chamala was born in Hyderabad, Andhra Pradesh (currently Telangana State), India. Raghu was raised and educated in Hyderabad, where he obtained a Bachelor’s degree (B. Sc.eBotany, Zoology, and Chemistry) from Andhra Vidyalaya College of Arts, Science, and Commerce (popularly known as A. V. College), which is affiliated to Osmania University. He was then trained and employed as a healthcare technician at Hariprasad Memorial Hospital, Hyderabad. After passing the national entrance examination conducted by University of Pune and National Chemical Laboratory, he moved to University of Pune in Maharashtra, India, to pursue a Master’s degree (M.Sc.) in organic chemistry, where he worked with Professors Dilip D. Dhavale and Shriniwas L. Kelkar on monobromination of phenols. During this time he received the Krishna Iyer Doraiswami Scholarship. Later, Raghu moved to the University of Kentucky, United States and joined Professor Robert B. Grossman’s research group to pursue doctoral studies. He earned a Ph.D. in chemistry for investigations involving the total synthesis of yohimbine alkaloids. During his Ph.D. studies he received the Research Challenge Trust Fund Fellowship for three consecutive academic years. He then joined Professor Mahesh K. Lakshman’s research group at the City College of the City University of New York, NY, as a postdoctoral researcher, and worked on purine nitrogen atom-directed, Ru- and Pd-catalyzed CeH bond activation chemistries of nucleobases and nucleosides. He also worked on the synthesis of benzotriazolyl ethers and developed novel cyclic and acyclic nucleoside mimics. He then moved to his current position as an advanced scientist at Momentive, Bangalore, India, where he is currently working on the synthesis and characterization of aminosiloxanes, and their applications in the industry.

Zhiguo Wang was born in Jinan, Shandong, China. He received his bachelor’s degree from Peking University in 2006. From 2008 to 2012 he did his graduate level study in Clarkson University and the University of Oklahoma. He then joined the University of Tulsa in 2013, where he is now a graduate student in Dr. Hussaini’s group.

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S.R. Hussaini et al. / Tetrahedron xxx (2015) 1e70

Appendix of functional groups Functional group

Structure

N,S-acetal

Alkylidenepyrrolidine

1,2-Benzodiazepine

O-benzoyl-S-oxide

Benzazepine

Carbapenem

Disulfide

R1eSeSeR2

Dithiocarbamate

1,3-Dithiolane

Enaminone (includes vinylogous amides (R1¼alkyl or aryl) and vinylogous urethanes R1¼Oalkyl or Oaryl)

Enaminthione

Enethiol Synonym: Enthiol

Episulfide Synonym: Thiirane, olefin sulfides, thioalkylene oxides, thiacyclopropanes

Bis(imidoyl) disulfide Synonym: Bis-imidoyl-disulfide

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69

(continued ) Functional group

Structure

Imino ester Synonyms: Iminoester, imidate, imino ether, carboximidate

Indolizidine Synonyms: Octahydroindolizine, dconiceine, 1-azobicylco[4.3.0]nonane

Monothiodicarboximide Synonym: Monothioimide

Penem

2-Pyridone

1-Pyrroline Synonym: 1-pyrroline, isopyrroline, D1pyrroline, 3,4-dihydro-2H-pyrrole

Pyrrolizidine Synonym: Hexahydropyrrolizine, 1azabicyclo[3.3.0]octane Quinazoline Synonym: 1,3-benzodiazine, 1,3diazanapthalene, 5,6-benzopyrimidine, NSC 72372, phenmiazine Quinolizidine

Tetrahydrofuran-2-thione

Thiazole

Thioamide Primary thioamide (R2]R3]H) Secondary thioamide (R2 or R3]H) Tertiary thioamide (R2]R3]alkyl group)

Thiocarbonyl

Thioether

ReSeR

Thioimidoester (Synonyms: Thioimido ester, thioiminoester, thioimino ester, thioimidate) (continued on next page)

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S.R. Hussaini et al. / Tetrahedron xxx (2015) 1e70

(continued ) Functional group

Structure

Thiolactam

Tyramine

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