- Email: [email protected]
Towards a stereoselective synthesis of α,α-disubstituted proline analogues
Accepted Manuscript Towards a stereoselective synthesis of α,α-disubstituted proline analogues Sukant K. Das, Mohammad Mujahid, Per I. Arvidsson, Hendrik G. Kruger, Tricia Naicker, Thavendran Govender PII: DOI: Reference:
S0040-4039(15)01229-0 http://dx.doi.org/10.1016/j.tetlet.2015.07.065 TETL 46554
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
5 May 2015 11 June 2015 21 July 2015
Please cite this article as: Das, S.K., Mujahid, M., Arvidsson, P.I., Kruger, H.G., Naicker, T., Govender, T., Towards a stereoselective synthesis of α,α-disubstituted proline analogues, Tetrahedron Letters (2015), doi: http://dx.doi.org/ 10.1016/j.tetlet.2015.07.065
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
Towards a stereoselective synthesis of α,α-disubstituted proline analogues Sukant K. Das a, Mohammad Mujahid a, Per I. Arvidsson a,b, Hendrik G. Kruger a, Tricia Naicker a* and Thavendran Govender a* a
Catalysis and Peptide Research Unit, University of KwaZulu Natal, Durban, South Africa, [email protected] or [email protected] Science for Life Laboratory, Drug Discovery and Development Platform and Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden b
A RT I C L E I N F O
A BS T RA C T
Article history: Received Received in revised form Accepted Available online
A mild organocatalytic protocol for the syntheses of α,α-disubstituted proline analogues has been developed. The 3-ketoproline scaffold was functionalised using various aromatic nitrostyrenes in the presence of a bifunctional organocatalyst. The resulting quaternary proline derivatives could easily be transformed into α-alkyl-β-hydroxyproline analogues. Furthermore, the methodology could also be applied to the synthesis of 3-ketoproline functionalized peptides with high selectivity and good yields.
Keywords: α,α-disubstituted amino acid β-ketoester substituted proline organocatalysis Michael addition
Introduction -Disubstituted (quaternary) -amino acids are a class of nonnatural amino acids that have received considerable attention within biological and medicinal chemistry. 1-4 -Disubstituted -amino acids are inert toward racemization, and their restricted conformational freedom contributes to their significance as unnatural building blocks in peptide design;5 i.e. the incorporation of such amino acids into the peptide backbone is an important tool to reduce the intrinsic flexibility of the peptide.5, 6,7 Similarly, proline – the only naturally occurring amino acid that forms a tertiary amide bond when incorporated in peptides and proteins, is crucial for the formation of secondary structures such as -turns or polyproline helices.7-9 The ability of proline to induce turns and reduce conformational flexibility in peptides can have a significant effect on its biological conformation, thereby influencing ligand binding and protein activity.9, 10 Unsurprisingly, α,αdisubstituted proline analogues represent a class of artificial amino acid residues that has been heavily exploited in the design of peptides with well-defined backbone conformations.9, 11, 12 In addition to multiple biological applications, 13-15 the pyrrolidine motif of proline is a crucial element in many widely used organocatalysts.16-18 Hence, there is a large interest in synthetic methodologies for the preparation of substituted prolines with inherent functional diversity from both the biomedical and asymmetric catalysis research communities. Surprisingly, the catalytic asymmetric synthesis of α,α-disubstituted proline analogues have been rather neglected. Their synthesis generally relies on the use of stoichiometric amounts of
2009 Elsevier Ltd. All rights reserved .
external/internal chirality inducers. 19 Cao and Williams synthesized α,α-disubstituted proline analogues by the enzymatic resolution of racemic N-Boc protected 3-ketoproline followed by deprotonation using LDA and subsequent alkylation.20 To our knowledge, only one report on the direct catalytic asymmetric transforamtion of 3ketoproline derivatives has been reported. In this case, Maruoka and co-workers employed a phase transfer catalyst for functionalisation, which limited the range of electrophiles to benzylic bromides.21 Herein, we describe an organocatalytic methodology for the preparation of α,α-disubstituted proline analogues by the asymmetric α-substitution of the 3-ketoproline backbone. In addition, further synthetic transformations of the N-Boc protected 3-ketoproline core to enhance its functional diversity for the incorporation into peptides are also outlined.
Results and Discussion It should be noted that 2-oxocyclopentanecarboxylate (cyclopentane analogue of 3-ketoproline) is amongst the most widely used substrate class in asymmetric catalysis due to its inherent keto-enol tautomerism, e.g. undergoing Michael addition under organocatalytic conditions.22-24 Most commonly, these substrates have been activated with bifunctional organocatalysts;25-30 hence we selected cinchonine and quinine derived organocatalysts I and II, respectively, for the benchmark Michael addition reaction of 3-ketoproline and nitrostyrene (Scheme 1).
OMe
2 N
X HN
CF3
HN R
O
NO2 +
CO2Et
N Boc
Ph
N I R=H, X=O II R=OMe, X=O solvent
CF3
O Ph
2a
1
NO2
CO2Et N Boc
The relative configuration of the optically active Michael adduct 3c O was determined to be (S,S)NO by single X-ray crystallography (Figure 2 1).31 The stereochemistry of the remaining products were assigned by analogy. CO2Et
N Boc
OMe
3a
Scheme 1. Organocatalytic asymmetric Michael addition of nitrostryrene with N-Boc protected 3-ketoproline. Initially, we examined the reaction using DCM as it was widely reported for this type of Michael addition. To our delight, using 20 mol% of catalyst I at 20 oC, the product was obtained with good yield (69%) and high enantioselectivity (82% ee). A limited solvent and catalyst optimisation (see ESI), revealed that toluene gave comparable yields (70%) but offered improved enantioselectivity (87% ee). Catalyst II gave the product in improved yield (75%), with excellent enantioselectivity (95% ee) and diastereoselectivity (>99:1 dr). All diastereoselectivities were determined from the crude 1H NMR spectra. Further optimisation reactions were carried out in toluene using catalyst II, however varying the reaction temperature or catalyst loading had little effect on the obtained yield and no effect on the reaction selectivity. O
NO2 CO2Et
N Boc 1
+ Ar 2a-i
O Ar 20 mol% Cat. (II) Toluene, 24 h, 20 oC
NO2
CO2Et
N Boc
3a-i
Scheme 2. Organocatalytic asymmetric Michael addition of N-Boc protected 3-ketoproline using quinine derived catalyst II. With the optimized reaction conditions in hand, the generality of the reaction of 3-ketoproline backbone (1) with various nitroolefins was investigated (Scheme 2 and Table 1). The reaction of β-ketoester (1) with substituted electron-rich, electron-poor and heteroaromatic aromatic nitroolefins, afforded the corresponding adducts in good yields (67-75%) with excellent enantio- and diastereoselectivities (86-95% ee, >99:1 dr) (Table 1). It appeared that the electronic properties of the substituents on the aromatic rings had limited influence on the enantioselectivities. However, the reaction did not tolerate substituents at the ortho position (2-chloro nitrostyrene) of the aromatic ring and in this case only recovered starting material was detected. Additionally, aliphatic electron deficient olefins displayed very low reactivity (acrylonitrile and 2methylenemalononitrile). Table 1. Substrate scope for the asymmetric Michael reaction. Entry Substrate (Ar) Yield (%) ee (%)[a] 1 Ph (3a) 75 95 2 4-MePh (3b) 70 90 3 4-OMePh (3c) 70 91 4 3,4-(OMe)2Ph (3d) 71 86 5 4-ClPh (3e) 74 89 6 3-ClPh (3f) 69 89 7 4-BrPh (3g) 69 91 8 3-BrPh (3h) 67 87 9 2-furyl (3i) 71 89 a
All products displayed >99:1 dr and ee was determined by chiral HPLC (see ESI). Reaction conditions: 1 (0.155 mmol), 2 (0.186 mmol), toluene (0.5 mL), 20 oC, 24 h.
O NO2 CO2Et N Boc
Figure 1. X-Ray structure of product 3c. The products resulting from the Michael reaction are rich in functionality, and can serve as valuable synthetic intermediates. Deprotection of the Boc group using TFA afforded proline derivative 4 in good yield. Mild reduction of the keto group using NaBH4 gave the α-alkyl-β-hydroxyproline (5) as a single diastereomer (Scheme 3). O Ph NO2 N CO Et 2 Boc
4 h, 0 oC-RT
3a
OH
O Ph
TFA, DCM,
NO2 N H
CO2Et
NaBH4, EtOH 3 h, 0 oC
* N H
Ph NO2
CO2Et
5, 70%, dr 99:1
4
Scheme 3. Deprotection of the Boc group on 3a and reduction using NaBH4. To demonstrate the synthetic utility of the 3-ketoproline scaffold as a peptide turn inducer, compound 1 was deprotected and subjected to N-terminal peptide coupling (Scheme 4). The dipeptidic products (6) underwent the organocatalysed Michael addition reaction with nitrostyrene under the optimised conditions to yield α,α-disubstituted proline peptide products (7) in high diastereoselectivity and good yield. Both Cbz- and Boc-protection of the peptide (6a and 6b) were well tolerated, however, Fmoc protected peptide (6c) suffered from very low conversion. This decrease in reactivity was attributed to the steric hindrance of the large Fmoc moiety. It should be noted that attempts to form a peptidic bond using the N-terminus of Michael addition product, 4, was extremely low yielding (< 5%) which is a known challenge of sterically crowded α,α-disubstituted amino acids. O
O CO2Et
N Boc
a) TFA, DCM, RT
CO2Et
b) PG-Phe-OH, N Coupling conditions Phe-PG
NO2 Ph 20 mol% Cat. (II) Toluene, 24 h, 20 oC
O Ph * * N CO2Et Phe-PG
NO2
1 6a PG=Cbz 6b PG=Boc 6c PG=Fmoc
7a PG=Cbz, 72%, dr 99:1 7b PG=Boc, 73%, dr 99:1 7c PG=Fmoc, <10%,
Scheme 4. Organocatalysed asymmetric Michael reaction of peptide β-ketoesters (6a-c).
These transformations illustrate that the asymmetric α,αdisubstituted proline products can be easily modified/functionalised to give other valuable building blocks
Conclusion In conclusion, we have developed an effective organocatalytic method for the synthesis of chiral α,α-disubstituted proline analogues. The reaction products were easily transformed into α,αdisubstituted amino alcohols, as well as peptide analogues. Novel
3 chiral α,α-disubstituted prolines represent valuable building blocks with utility in biomedical research, peptide/protein design and catalysis.
References and notes 1. ati iela, . a -de-Villegas, M. a. D. Tetrahedron: Asymmetry 1998, 9, 3599. 2. Ohfune, Y.; Shinada, T. Eur. J. Org. Chem. 2005, 24, 5143. 3. Vogt, H.; Brase, S. Org. Biomol. Chem. 2007, 5, 406. 4. Metz, A. E.; Kozlowski, M. C. J. Org. Chem. 2015, 80, 7. 5. Tanaka, M. Chem. Pharm. Bull. 2007, 55, 358. 6. Venkatraman, J.; Shankaramma, S. C.; Balaram, P. Chem. Rev. 2001, 101, 3152. 7. Kay, B. K.; Williamson, M. P.; Sudol, P. FASEB J. 2000, 14, 231. 8. Young, T. S.; Schultz, P. G. J. Biol. Chem. 2010, 285, 11039. 9. Mothes, C.; Caumes, C.; Guez, A.; Boullet, H.; Gendrineau, T.; Darses, S.; Delsuc, N.; Moumne, R.; Oswald, B.; Lequin, O.; Karoyan, P. Molecules 2013, 18, 2307. 10. Fatas, P.; Jimenez, A. I.; Isabel Calaza, M.; Cativiela, C. Org. Biomol. Chem. 2012, 10, 640. 11. Thomas, K. M.; Naduthambi, D.; Tririya, G.; Zondlo, N. J. Org. Lett. 2005, 7, 2400. 12. Tang, H.-C.; Lin, Y.-J.; Horng, J.-C. Proteins 2014, 82, 76. 13. Sharma, S.; Singh, R.; Rana, S. Int. J. Bioautomation 2011, 15, 223. 14. Kumar, R.; Sharma, R.; Bairwa, K.; Roy, R. K.; Kumar, A.; Baruwa, A. Der Pharmacia Lettre 2010, 2, 388. 15. Vitali, A. Curr. Protein Pept. Sci. 2015, 16, 147. 16. Jensen, K. L.; Dickmeiss, G.; Jiang, H.; Albrecht, L.; Jorgensen, K. A. Acc. Chem. Res. 2012, 45, 248.
17. Gaunt, M. J.; Johansson, C. C. C.; McNally, A.; Vo, N. T. Drug Discovery Today 2007, 12, 8. 18. Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. 19. Calaza, M. I.; Cativiela, C. Chem. Eur. J. 2008, 20, 3448. 20. Williams, R. M.; Cao, J. H. Tetrahedron Lett. 1996, 37, 5441. 21. Ooi, T.; Miki, T.; Maruoka, K. Org. Lett. 2005, 7, 191. 22. Andres, J. M.; Manzano, R.; Pedrosa, R. Chem. Eur. J. 2008, 14, 5116. 23. Rigby, C. L.; Dixon, D. J. Chem. Commun. 2008, 3798. 24. Scheffler, U.; Mahrwald, R. Chem. Eur. J. 2013, 19, 14346. 25. Yu, X.; Wang, W. Chem. Asian J. 2008, 3, 516. 26. Novacek, J.; Waser, M. Eur. J. Org. Chem. 2014, 4, 802. 27. Shirakawa, S.; Tokuda, T.; Kasai, A.; Maruoka, K. Org. Lett. 2013, 15, 3350. 28. Enders, D.; Urbanietz, G.; Hahn, R.; Raabe, G. Synthesis 2012, 2012, 773. 29. Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004, 126, 9906. 30. Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672. 31. CCDC 1044272 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif
Supplementary Material Supplementary information includes the experimental procedures, optimization table, NMR spectra and chiral HPLC chromatographs.
Graphical Abstract
To create your abstract, type over the instructions in the template box below. Fonts or abstract dimensions should not be changed or altered.
Towards a stereoselective synthesis of α,αdisubstituted proline analogues
Leave this area blank for abstract info.
CF3
O N
HN HN CF3
O CO2Et N Boc
NO2
MeO
N
O Ar NO2
+ Ar
Toluene, 20 oC
N CO2Et Boc
up to 75% yield, 99:1 dr, 95% ee
S0040-4039(15)01229-0 http://dx.doi.org/10.1016/j.tetlet.2015.07.065 TETL 46554
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
5 May 2015 11 June 2015 21 July 2015
Please cite this article as: Das, S.K., Mujahid, M., Arvidsson, P.I., Kruger, H.G., Naicker, T., Govender, T., Towards a stereoselective synthesis of α,α-disubstituted proline analogues, Tetrahedron Letters (2015), doi: http://dx.doi.org/ 10.1016/j.tetlet.2015.07.065
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
Towards a stereoselective synthesis of α,α-disubstituted proline analogues Sukant K. Das a, Mohammad Mujahid a, Per I. Arvidsson a,b, Hendrik G. Kruger a, Tricia Naicker a* and Thavendran Govender a* a
Catalysis and Peptide Research Unit, University of KwaZulu Natal, Durban, South Africa, [email protected] or [email protected] Science for Life Laboratory, Drug Discovery and Development Platform and Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden b
A RT I C L E I N F O
A BS T RA C T
Article history: Received Received in revised form Accepted Available online
A mild organocatalytic protocol for the syntheses of α,α-disubstituted proline analogues has been developed. The 3-ketoproline scaffold was functionalised using various aromatic nitrostyrenes in the presence of a bifunctional organocatalyst. The resulting quaternary proline derivatives could easily be transformed into α-alkyl-β-hydroxyproline analogues. Furthermore, the methodology could also be applied to the synthesis of 3-ketoproline functionalized peptides with high selectivity and good yields.
Keywords: α,α-disubstituted amino acid β-ketoester substituted proline organocatalysis Michael addition
Introduction -Disubstituted (quaternary) -amino acids are a class of nonnatural amino acids that have received considerable attention within biological and medicinal chemistry. 1-4 -Disubstituted -amino acids are inert toward racemization, and their restricted conformational freedom contributes to their significance as unnatural building blocks in peptide design;5 i.e. the incorporation of such amino acids into the peptide backbone is an important tool to reduce the intrinsic flexibility of the peptide.5, 6,7 Similarly, proline – the only naturally occurring amino acid that forms a tertiary amide bond when incorporated in peptides and proteins, is crucial for the formation of secondary structures such as -turns or polyproline helices.7-9 The ability of proline to induce turns and reduce conformational flexibility in peptides can have a significant effect on its biological conformation, thereby influencing ligand binding and protein activity.9, 10 Unsurprisingly, α,αdisubstituted proline analogues represent a class of artificial amino acid residues that has been heavily exploited in the design of peptides with well-defined backbone conformations.9, 11, 12 In addition to multiple biological applications, 13-15 the pyrrolidine motif of proline is a crucial element in many widely used organocatalysts.16-18 Hence, there is a large interest in synthetic methodologies for the preparation of substituted prolines with inherent functional diversity from both the biomedical and asymmetric catalysis research communities. Surprisingly, the catalytic asymmetric synthesis of α,α-disubstituted proline analogues have been rather neglected. Their synthesis generally relies on the use of stoichiometric amounts of
2009 Elsevier Ltd. All rights reserved .
external/internal chirality inducers. 19 Cao and Williams synthesized α,α-disubstituted proline analogues by the enzymatic resolution of racemic N-Boc protected 3-ketoproline followed by deprotonation using LDA and subsequent alkylation.20 To our knowledge, only one report on the direct catalytic asymmetric transforamtion of 3ketoproline derivatives has been reported. In this case, Maruoka and co-workers employed a phase transfer catalyst for functionalisation, which limited the range of electrophiles to benzylic bromides.21 Herein, we describe an organocatalytic methodology for the preparation of α,α-disubstituted proline analogues by the asymmetric α-substitution of the 3-ketoproline backbone. In addition, further synthetic transformations of the N-Boc protected 3-ketoproline core to enhance its functional diversity for the incorporation into peptides are also outlined.
Results and Discussion It should be noted that 2-oxocyclopentanecarboxylate (cyclopentane analogue of 3-ketoproline) is amongst the most widely used substrate class in asymmetric catalysis due to its inherent keto-enol tautomerism, e.g. undergoing Michael addition under organocatalytic conditions.22-24 Most commonly, these substrates have been activated with bifunctional organocatalysts;25-30 hence we selected cinchonine and quinine derived organocatalysts I and II, respectively, for the benchmark Michael addition reaction of 3-ketoproline and nitrostyrene (Scheme 1).
OMe
2 N
X HN
CF3
HN R
O
NO2 +
CO2Et
N Boc
Ph
N I R=H, X=O II R=OMe, X=O solvent
CF3
O Ph
2a
1
NO2
CO2Et N Boc
The relative configuration of the optically active Michael adduct 3c O was determined to be (S,S)NO by single X-ray crystallography (Figure 2 1).31 The stereochemistry of the remaining products were assigned by analogy. CO2Et
N Boc
OMe
3a
Scheme 1. Organocatalytic asymmetric Michael addition of nitrostryrene with N-Boc protected 3-ketoproline. Initially, we examined the reaction using DCM as it was widely reported for this type of Michael addition. To our delight, using 20 mol% of catalyst I at 20 oC, the product was obtained with good yield (69%) and high enantioselectivity (82% ee). A limited solvent and catalyst optimisation (see ESI), revealed that toluene gave comparable yields (70%) but offered improved enantioselectivity (87% ee). Catalyst II gave the product in improved yield (75%), with excellent enantioselectivity (95% ee) and diastereoselectivity (>99:1 dr). All diastereoselectivities were determined from the crude 1H NMR spectra. Further optimisation reactions were carried out in toluene using catalyst II, however varying the reaction temperature or catalyst loading had little effect on the obtained yield and no effect on the reaction selectivity. O
NO2 CO2Et
N Boc 1
+ Ar 2a-i
O Ar 20 mol% Cat. (II) Toluene, 24 h, 20 oC
NO2
CO2Et
N Boc
3a-i
Scheme 2. Organocatalytic asymmetric Michael addition of N-Boc protected 3-ketoproline using quinine derived catalyst II. With the optimized reaction conditions in hand, the generality of the reaction of 3-ketoproline backbone (1) with various nitroolefins was investigated (Scheme 2 and Table 1). The reaction of β-ketoester (1) with substituted electron-rich, electron-poor and heteroaromatic aromatic nitroolefins, afforded the corresponding adducts in good yields (67-75%) with excellent enantio- and diastereoselectivities (86-95% ee, >99:1 dr) (Table 1). It appeared that the electronic properties of the substituents on the aromatic rings had limited influence on the enantioselectivities. However, the reaction did not tolerate substituents at the ortho position (2-chloro nitrostyrene) of the aromatic ring and in this case only recovered starting material was detected. Additionally, aliphatic electron deficient olefins displayed very low reactivity (acrylonitrile and 2methylenemalononitrile). Table 1. Substrate scope for the asymmetric Michael reaction. Entry Substrate (Ar) Yield (%) ee (%)[a] 1 Ph (3a) 75 95 2 4-MePh (3b) 70 90 3 4-OMePh (3c) 70 91 4 3,4-(OMe)2Ph (3d) 71 86 5 4-ClPh (3e) 74 89 6 3-ClPh (3f) 69 89 7 4-BrPh (3g) 69 91 8 3-BrPh (3h) 67 87 9 2-furyl (3i) 71 89 a
All products displayed >99:1 dr and ee was determined by chiral HPLC (see ESI). Reaction conditions: 1 (0.155 mmol), 2 (0.186 mmol), toluene (0.5 mL), 20 oC, 24 h.
O NO2 CO2Et N Boc
Figure 1. X-Ray structure of product 3c. The products resulting from the Michael reaction are rich in functionality, and can serve as valuable synthetic intermediates. Deprotection of the Boc group using TFA afforded proline derivative 4 in good yield. Mild reduction of the keto group using NaBH4 gave the α-alkyl-β-hydroxyproline (5) as a single diastereomer (Scheme 3). O Ph NO2 N CO Et 2 Boc
4 h, 0 oC-RT
3a
OH
O Ph
TFA, DCM,
NO2 N H
CO2Et
NaBH4, EtOH 3 h, 0 oC
* N H
Ph NO2
CO2Et
5, 70%, dr 99:1
4
Scheme 3. Deprotection of the Boc group on 3a and reduction using NaBH4. To demonstrate the synthetic utility of the 3-ketoproline scaffold as a peptide turn inducer, compound 1 was deprotected and subjected to N-terminal peptide coupling (Scheme 4). The dipeptidic products (6) underwent the organocatalysed Michael addition reaction with nitrostyrene under the optimised conditions to yield α,α-disubstituted proline peptide products (7) in high diastereoselectivity and good yield. Both Cbz- and Boc-protection of the peptide (6a and 6b) were well tolerated, however, Fmoc protected peptide (6c) suffered from very low conversion. This decrease in reactivity was attributed to the steric hindrance of the large Fmoc moiety. It should be noted that attempts to form a peptidic bond using the N-terminus of Michael addition product, 4, was extremely low yielding (< 5%) which is a known challenge of sterically crowded α,α-disubstituted amino acids. O
O CO2Et
N Boc
a) TFA, DCM, RT
CO2Et
b) PG-Phe-OH, N Coupling conditions Phe-PG
NO2 Ph 20 mol% Cat. (II) Toluene, 24 h, 20 oC
O Ph * * N CO2Et Phe-PG
NO2
1 6a PG=Cbz 6b PG=Boc 6c PG=Fmoc
7a PG=Cbz, 72%, dr 99:1 7b PG=Boc, 73%, dr 99:1 7c PG=Fmoc, <10%,
Scheme 4. Organocatalysed asymmetric Michael reaction of peptide β-ketoesters (6a-c).
These transformations illustrate that the asymmetric α,αdisubstituted proline products can be easily modified/functionalised to give other valuable building blocks
Conclusion In conclusion, we have developed an effective organocatalytic method for the synthesis of chiral α,α-disubstituted proline analogues. The reaction products were easily transformed into α,αdisubstituted amino alcohols, as well as peptide analogues. Novel
3 chiral α,α-disubstituted prolines represent valuable building blocks with utility in biomedical research, peptide/protein design and catalysis.
References and notes 1. ati iela, . a -de-Villegas, M. a. D. Tetrahedron: Asymmetry 1998, 9, 3599. 2. Ohfune, Y.; Shinada, T. Eur. J. Org. Chem. 2005, 24, 5143. 3. Vogt, H.; Brase, S. Org. Biomol. Chem. 2007, 5, 406. 4. Metz, A. E.; Kozlowski, M. C. J. Org. Chem. 2015, 80, 7. 5. Tanaka, M. Chem. Pharm. Bull. 2007, 55, 358. 6. Venkatraman, J.; Shankaramma, S. C.; Balaram, P. Chem. Rev. 2001, 101, 3152. 7. Kay, B. K.; Williamson, M. P.; Sudol, P. FASEB J. 2000, 14, 231. 8. Young, T. S.; Schultz, P. G. J. Biol. Chem. 2010, 285, 11039. 9. Mothes, C.; Caumes, C.; Guez, A.; Boullet, H.; Gendrineau, T.; Darses, S.; Delsuc, N.; Moumne, R.; Oswald, B.; Lequin, O.; Karoyan, P. Molecules 2013, 18, 2307. 10. Fatas, P.; Jimenez, A. I.; Isabel Calaza, M.; Cativiela, C. Org. Biomol. Chem. 2012, 10, 640. 11. Thomas, K. M.; Naduthambi, D.; Tririya, G.; Zondlo, N. J. Org. Lett. 2005, 7, 2400. 12. Tang, H.-C.; Lin, Y.-J.; Horng, J.-C. Proteins 2014, 82, 76. 13. Sharma, S.; Singh, R.; Rana, S. Int. J. Bioautomation 2011, 15, 223. 14. Kumar, R.; Sharma, R.; Bairwa, K.; Roy, R. K.; Kumar, A.; Baruwa, A. Der Pharmacia Lettre 2010, 2, 388. 15. Vitali, A. Curr. Protein Pept. Sci. 2015, 16, 147. 16. Jensen, K. L.; Dickmeiss, G.; Jiang, H.; Albrecht, L.; Jorgensen, K. A. Acc. Chem. Res. 2012, 45, 248.
17. Gaunt, M. J.; Johansson, C. C. C.; McNally, A.; Vo, N. T. Drug Discovery Today 2007, 12, 8. 18. Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. 19. Calaza, M. I.; Cativiela, C. Chem. Eur. J. 2008, 20, 3448. 20. Williams, R. M.; Cao, J. H. Tetrahedron Lett. 1996, 37, 5441. 21. Ooi, T.; Miki, T.; Maruoka, K. Org. Lett. 2005, 7, 191. 22. Andres, J. M.; Manzano, R.; Pedrosa, R. Chem. Eur. J. 2008, 14, 5116. 23. Rigby, C. L.; Dixon, D. J. Chem. Commun. 2008, 3798. 24. Scheffler, U.; Mahrwald, R. Chem. Eur. J. 2013, 19, 14346. 25. Yu, X.; Wang, W. Chem. Asian J. 2008, 3, 516. 26. Novacek, J.; Waser, M. Eur. J. Org. Chem. 2014, 4, 802. 27. Shirakawa, S.; Tokuda, T.; Kasai, A.; Maruoka, K. Org. Lett. 2013, 15, 3350. 28. Enders, D.; Urbanietz, G.; Hahn, R.; Raabe, G. Synthesis 2012, 2012, 773. 29. Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004, 126, 9906. 30. Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672. 31. CCDC 1044272 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif
Supplementary Material Supplementary information includes the experimental procedures, optimization table, NMR spectra and chiral HPLC chromatographs.
Graphical Abstract
To create your abstract, type over the instructions in the template box below. Fonts or abstract dimensions should not be changed or altered.
Towards a stereoselective synthesis of α,αdisubstituted proline analogues
Leave this area blank for abstract info.
CF3
O N
HN HN CF3
O CO2Et N Boc
NO2
MeO
N
O Ar NO2
+ Ar
Toluene, 20 oC
N CO2Et Boc
up to 75% yield, 99:1 dr, 95% ee