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Novel chemoenzymatic synthesis of an enantiopure allo-inosamine hexaacetate from benzyl azide
Tetrahedron Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Novel chemoenzymatic synthesis of an enantiopure allo-inosamine hexaacetate from benzyl azide Victoria de la Sovera a, Pablo Garay a, Natalia Thevenet a, Mario A. Macías b, David González a, Gustavo Seoane a, Ignacio Carrera a,⇑ a b
Laboratorio de Síntesis Orgánica, Departamento de Química Orgánica, Facultad de Química—Universidad de la República, General Flores 2124, 11800 Montevideo, Uruguay Cryssmat-Lab, Cátedra de Física, DETEMA., Facultad de Química—Universidad de la República, General Flores 2124, 11800 Montevideo, Uruguay
a r t i c l e
i n f o
Article history: Received 7 April 2016 Revised 18 April 2016 Accepted 19 April 2016 Available online xxxx Keywords: Aminocyclitol Inosamines cis-Cyclohexadienediols Allylic azide
a b s t r a c t A facile and short chemoenzymatic synthesis of ( ) 1L-5-amino-5-deoxy-allo-inositol hexaacetate is described using benzyl azide as starting material. The key transformations consist of an enzymatic dioxygenation using the toluene dioxygenase enzymatic complex, followed by an allylic azide double sigmatropic [3,3] shift to introduce the nitrogen functionality in the ring in a stereoselective manner. Azide reduction and further regioselective oxidation of the diene moiety afforded the desired inosamine in only eight steps from benzyl azide. Ó 2016 Elsevier Ltd. All rights reserved.
Aminocyclitols (or aminocarbasugars) are a group of aminocycloalkane polyols that have gained great importance because of their remarkable biological activities.1 Functioning as mimics of natural carbohydrates they present a wide range of biological activities such as alpha-glucosidase inhibitors,2 antibiotics,3 antifungals,4 and potential therapeutics for diseases of carbohydrate metabolism.5 In addition, some aminocyclitols are advanced key structural motifs in the total synthesis of several Amaryllidaceae alkaloids.6 Figure 1 shows some structural examples: amino-inositols 1–3 are part of antibiotic KA-3093,7 methoxyhygromycin,8 and minosaminomycin9 respectively. Also compounds 4–5 present interesting biological activities for Gaucher disease.5,10 Due to these interesting biological properties, the enantioselective preparation of aminocyclitols has attracted the attention of the synthetic community in the last decades.1a In particular, ciscyclohexadienediols prepared by biotransformation of arenes using bacterial dioxygenases have been widely used as starting materials for aminocyclitol synthesis (Fig. 2A).11 These substrates already possess two hydroxyl groups and the additional ones may be introduced by further stereoselective oxidations. Regarding the nitrogen functionality, several different methodologies have been used for its strereocontrolled introduction into the ring as reviewed recently by Lewis and co-workers11b Acyl nitroso cycloaddition to the diene moiety;12 alkene regio- and stereoselective epoxidation ⇑ Corresponding author. Tel.: +598 29247881; fax: +598 29240106. E-mail address: [email protected] (I. Carrera).
followed by ring-opening with a nitrogen nucleophile6b,12b,13 and also alkene aziridination13b,e,l,14 are the three main strategies that have been used for this aim (Fig. 2A). Recently we described the structures of novel interesting azido dienediols obtained from the biotransformation of benzyl azide by the toluene dioxygenase (TDO) enzymatic complex expressed in Escherichia coli JM109 (pDTG601).15 In addition to the expected diol 11, the exocyclic diene 12 was found; its formation was explained by an spontaneous stereoselective double sigmatropic
Figure 1. Representative aminocyclitol units present in important biologically active products.
http://dx.doi.org/10.1016/j.tetlet.2016.04.072 0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: de la Sovera, V.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.04.072
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Figure 2. (A) Previous strategies for introducing nitrogen functionality in cis-cyclohexadienediols for aminocyclitol synthesis. (B) Stereoselective azide functionalization via double allylic azide sigmatropic shift used in this work.
[3,3] shift from 11 (Fig. 2B). This type of rearrangement was previously reported by Boyd et al. on cyclic dienediols from microbial origin.16 Production of 12 was optimized in a bioreactor scale to render a yield of 1.0–1.6 g/L.15 In this work we use the azido dienediol 12 as starting material for the enantioselective preparation of ( ) 1L-5-amino-5-deoxyallo-inositol hexaacetate. The proposed synthetic design allows for a facile and straightforward inosamine preparation since the nitrogen containing functionality is already present and with the right configuration in the starting material. The same inosamine skeleton with the proper stereochemistry has led to the synthesis of interesting derivatives such as a methylenedioxoacetal related to hygromycin A,17 and the corresponding azido analog.18 However, to the best of our knowledge, the target aminocyclitol has only one previous enantioselective synthesis in the literature19 and other racemic approaches.20 As a first approach we studied oxidative conditions to selectively oxidize the exo- or endo-cyclic olefins in diol 12. Standard dihydroxylation procedures using RuCl3 or OsO4, as well as epoxidation using m-CPBA, afforded mixtures of products with poor regio-selectivities. Ozonolysis in DCM/Py afforded the best results to oxidize the exo-olefin to give the corresponding ketone, which was reduced under Luche conditions,21 and acetylated to give 13 as a chromatographically inseparable 7:3 mixture of diastereomers in an overall yield of 40% (Fig. 3). In order to be able to separate the diastereomeric mixture for further spectroscopic characterization, we decided to change the protecting groups of the triol moiety. To our disappointment, transesterification of 13 with K2CO3/MeOH followed by diol protection with the isopropylidene group afforded products 14a and 14b where the azide group underwent an allylic [3,3] rearrangement. According to our previous findings, we reasoned that this sigmatropic shift is favored by hydrogen bonding between the azide and the vicinal free hydroxyl group.15a At this stage, we became concerned that this rearrangement could also take place
Figure 3. First approach toward aminocyclitol synthesis using diol 12. (a) E. coli JM109 (pDTG601) then 1 week at rt, 1.0–1.6 g/L; (b) O3, DCM: Py 78 °C; (c) NaBH4 CeCl37H2O, MeOH; (d) Ac2O, Et3N, DMAP, DCM, 0 °C, overall b-d 40%.
Figure 4. (A) (a) K2CO3, MeOH; (b) 2,2-dimethoxypropane, acetone, p-TsOH. (B) The [3,3] sigmatropic shift is promoted by the hydrogen bond generated in the alpha hydroxy azide moiety and can jeopardize the stereochemical integrity of the product.
immediately after the ozonolysis/reduction of 12, in which case the allylic azide in triol 15 (Fig. 4B) would be shifted to give 16. Since in both structures there is a vicinal hydroxyazide, an equilibrium could take place and jeopardize the enantiomeric integrity of the product (15 and 16 are enantiomers when the three hydroxyl groups are syn). In view of these results we decided to change our synthetic design reducing first the azide group in 12, in order to avoid the above mentioned sigmatropic shifts. Figure 5 shows our second approach. Staudinger conditions on 12 smoothly produced the desired amine in 98% yield, which was fully protected to give triacetate 17. Unexpectedly, oxidation of 17 using previous ozonolysis conditions gave a complex mixture of products affording the desired ketone only in traces. However, we were delighted to find that, epoxidation conditions in 17 using m-CPBA in the presence of fluoride salts (NaF/KHF2)22 as additives afforded epoxide 18 in a 63% yield, whose stereochemistry (epoxide syn to the acetamido group) was proposed according to J coupling analysis. Trace amounts of another diastereomer with the same regiochemistry were also found in the reaction mixture (probably with the epoxide anti to the acetamido group). The obtained regio- and stereoselectivity of 18 could be explained by coordination of the epoxidation agent with the acetamide function acting as a directing group. Then acidic hydrolysis of 18 followed by acetylation, gave tetraol 19 with complete regiocontrol.
Please cite this article in press as: de la Sovera, V.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.04.072
V. de la Sovera et al. / Tetrahedron Letters xxx (2016) xxx–xxx
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diffraction data were collected and the crystal structure was solved and refined. Agencia Nacional de Investigación e Innovacion (ANII) is acknowledged for financial support (Project FCE 6045). Also, we would like to thank the Comisión Académica de Posgrado (Universidad de la República) for a PhD scholarship for Victoria de la Sovera and Prof. Alejandra Rodríguez (Facultad de Química, Polo Tecnológico de Pando – UdelaR) for the High Resolution Mass Spectroscopy analysis. We also thank María Agustina Vila (Laboratorio de Biocatálisis y Biotransformaciones – UdelaR) for the preparation of cis-cyclohexadienediol 12. Mario A. Macías thanks ANII for his postdoctoral contract (No. PD_NAC_2014_1_102409). Supplementary data Figure 5. Final approach to ( )-allo inosamine hexaacetate. (a) E. coli JM109 (pDTG601), then 1 week at rt 1.0–1.6 g/L; (b) i. Ph3P, THF ii. H2O, 98%; (c) Ac2O, Et3N, DMAP, DCM, quant.; (d) m-CPBA, NaF/KHF2, DCM, 63%; (e) H2O, DowexÒ 50WX8; (f) Ac2O, Et3N, DMAP, DCM, overall e-f 80%; (g) O3, DCM: Py 78 °C then NaBH4/MeOH; (h) Ac2O, Et3N, DMAP, DCM, overall g-h 53%.
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.04. 072. References and notes
Figure 6. Molecular structure of 19 showing the anisotropic displacement ellipsoids drawn at the 30% probability level (hydrogen atoms are depicted as spheres with arbitrary radii).
Stereochemical assignment of 19 was confirmed by X-ray diffraction analysis (Fig. 6), which demonstrates that the epoxide in 18 was opened by the attack of water on the allylic position. Ozonolysis of the exocyclic olefin in 19, followed by sodium borohydride reduction and acetylation afforded the desired inosamine hexaacetate with an overall yield of 53% for the last three steps. In summary we describe the first enantioselective synthesis of an aminocyclitol using benzyl azide as a starting material. The key transformations consist of an enzymatic dioxygenation using the toluene dioxygenase enzymatic complex, followed by an allylic azide double sigmatropic [3,3] shift to introduce the nitrogen functionality in the ring in a stereoselective manner. Azide reduction and further regioselective oxidation of the diene moiety afforded the desired inosamine in only eight steps from benzyl azide. Acknowledgments We would like to thank Prof. L. Suescun and the organization of the course IUCr-UNESCO Bruker OpenLab Uruguay 2, where X-ray
1. (a) Diaz, L.; Delgado, A. Curr. Med. Chem. 2010, 17, 2393; (b) Delgado, A. Eur. J. Org. Chem. 2008, 2893. 2. (a) Trapero, A.; Egido-Gabás, M.; Bujons, J.; Llebaria, A. J. Org. Chem. 2015, 80, 3512; (b) Compain, P.; Martin, O. R. Iminosugars: from Synthesis to Therapeutic Applications; John Wiley & Sons: Chicester, UK, 2007; (c) Chen, X.; Zheng, Y.; Shen, Y. Curr. Med. Chem. 2006, 13, 109; (d) Schmidt, D. D.; Frommer, W.; Junge, B.; Müller, L.; Wingender, W.; Truscheit, E.; Schafer, D. Naturwissenschaften 1977, 64, 535. 3. (a) Houghton, J. L.; Green, K. D.; Chen, W.; Garneau-Tsodikova, S. ChemBioChem 2010, 11, 880; (b) Jaines, B. H.; Elliot, N. C.; Schicho, D. L. J. Antibiot. (Tokyo) 1992, 45, 1705; (c) Legler, G. Adv. Carbohydr. Chem. Biochem. 1990, 48, 319. 4. Vértsey, L.; Fehlhaber, H.-W.; Schulz, A. Angew. Chem., Int. Ed. Engl. 1994, 33, 1844. 5. (a) Trapero, A.; González-Bulnes, P.; Butters, T. D.; Llebaria, A. J. Med. Chem. 2012, 55, 4479; (b) Serra-Vinardell, J.; Díaz, L.; Casas, J.; Grinberg, D.; Vilageliu, L.; Michelakakis, H.; Mavridou, I.; Aerts, M. F. G.; Decroocq, C.; Compain, P.; Delgado, A. ChemMedChem 2014, 9, 1744. 6. (a) Gonzalez, D.; Martinot, T. A.; Hudlicky, T. Tetrahedron Lett. 1999, 40, 3077; (b) de la Sovera, V.; Bellomo, A.; Gonzalez, D. Tetrahedron Lett. 2011, 52, 430. 7. Dictionary of Natural Products, 1st ed.; 2–6 Boundary Row, London SE18HN, UK, 1994. 8. Palaniappan, N.; Dhote, V.; Ayers, S.; Starosta, A. L.; Wilson, D. N.; Reynolds, K. A. Chem. Biol. 2009, 16, 1180. 9. Iinuma, K.; Kondo, S.; Maeda, K. U. J. Antibiot. (Tokyo) 1975, 28, 613. 10. Díaz, L.; Casas, J.; Bujons, J.; Llebaria, A.; Delgado, A. J. Med. Chem. 2011, 54, 2069–2079. 11. (a) Duchek, J.; Adams, D. R.; Hudlicky, T. Chem. Rev. 2011, 111, 4223; (b) Griffen, J. A.; White, J. C.; Kociok-Köhn, G.; Lloyd, M. D.; Wells, A.; Arnot, T. C.; Lewis, S. E. Tetrahedron 2013, 69, 5989; (c) Pilgrim, S.; Kociok-Köhn, G.; Lloyd, M. D.; Lewis, S. E. Chem. Commun. 2011, 4799. 12. (a) Hudlicky, T.; Olivo, H. F. Tetrahedron Lett. 1991, 32, 6077; (b) Hudlicky, T.; Olivo, H. F.; Andersen, C.; Nugent, T.; Price, J. D. J. Chem. Soc., Perkin Trans. 1 1991, 290; (c) Akgün, H.; Hudlicky, T. Tetrahedron Lett. 1999, 40, 3081. 13. (a) Carless, H. A. J.; Malik, S. S. Tetrahedron: Asymmetry 1992, 3, 1135; (b) Hudlicky, T.; Abboud, K. A.; Entwistle, D. A.; Fan, R.; Maruya, R.; Thorpe, A. J.; Bolonick, J.; Myers, B. Synthesis 1996, 897; (c) Lallemand, M.-C.; Desjardins, M.; Freeman, S.; Hudlicky, T. Tetrahedron Lett. 1997, 38, 7693; (d) Banwell, M. G.; Haddad, N.; Hudlicky, T.; Nugent, T. C.; Mackay, M. F.; Richards, S. L. J. Chem. Soc., Perkin Trans. 1 1997, 1779; (e) Desjardins, M.; Lallemand, M.-C.; Freeman, S.; Hudlicky, T.; Abboud, K. A. J. Chem. Soc., Perkin Trans. 1 1999, 621; (f) Orsini, F.; Sello, G.; Bernasconi, S.; Fallacara, G. Tetrahedron Lett. 2004, 45, 9253; (g) Fonseca, G.; Seoane, G. A. Tetrahedron: Asymmetry 2005, 16, 1393; (h) Bellomo, A.; Giacomini, C.; Brena, B. G. S.; Gonzalez, D. Synth. Commun. 2007, 37, 3509; (i) Bellomo, A.; Bonilla, J. B.; López-Pardos, J.; Martín-Lomas, M.; González, D. Tetrahedron: Asymmetry 2009, 20, 2061; (j) de la Sovera, V.; Bellomo, A.; Pena, J. M.; Gonzalez, D.; Stefani, H. A. Mol. Diversity 2011, 15, 163; (k) Hudlicky, T.; Mandel, M.; Rouden, J.; Lee, R. S.; Bachmann, B.; Dudding, T.; Yost, K. J.; Merola, J. S. J. Chem. Soc., Perkin Trans. 1 1994, 1553; (l) Paul, B. J.; Willis, J.; Martinot, T. A.; Ghiviriga, I.; Abboud, K. A.; Hudlicky, T. J. Am. Chem. Soc. 2002, 124, 10416; (m) Freeman, C.; Liu, L.; Banwell, M. G.; Brown, K. J.; Bezos, A.; Ferro, V.; Parish, C. R. J. Biol. Chem. 2005, 280, 8842. 14. (a) Hudlicky, T.; Abboud, K. A.; Bolonick, J.; Maurya, R.; Stanton, M. L.; Thorpe, A. J. Chem. Commun. 1996, 1717; (b) Paul, B. J.; Hobbs, E.; Buccino, P.; Hudlicky, T. Tetrahedron Lett. 2001, 42, 6433; (c) Schilling, S.; Rinner, U.; Chan, C.; Ghiviriga, I.; Hudlicky, T. Can. J. Chem. 2001, 79, 1659; (d) Paul, B. J.; Martinot, T. A.; Willis, J.; Hudlicky, T. Synthesis 2001, 952. 15. (a) Thevenet, N.; de la Sovera, V.; Vila, M. A.; Veiga, N.; Gonzalez, D.; Seoane, G.; Carrera, I. Org. Lett. 2015, 17, 684; (b) Vila, M. A.; Pazos, M.; Iglesias, C.; Veiga, N.; Seoane, G.; Carrera, I. ChemBioChem 2016, 17, 291–295.
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16. Boyd, D. R.; Sharma, N. D.; Belhocine, T.; Malone, J. F.; McGregor, S. T.; Atchison, J.; McIntyre, P. A. B.; Stevenson, P. J. J. Phys. Org. Chem. 2013, 12, 997–1008. 17. Hecker, S. J.; Lilley, S. C.; Minich, M. L.; Werner, K. M. Bioorg. Med. Chem. Lett. 1992, 2, 1015–1018. 18. Nakajima, M.; Hasegawa, A.; Lichtenthaler, F. W. Justus Liebigs Ann. Chem. 1964, 680, 21–31. 19. Braun, H.; Burger, W.; Kresze, G.; Schmidtchen, F. P. Tetrahedron: Asymmetry 1990, 1, 403.
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Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Novel chemoenzymatic synthesis of an enantiopure allo-inosamine hexaacetate from benzyl azide Victoria de la Sovera a, Pablo Garay a, Natalia Thevenet a, Mario A. Macías b, David González a, Gustavo Seoane a, Ignacio Carrera a,⇑ a b
Laboratorio de Síntesis Orgánica, Departamento de Química Orgánica, Facultad de Química—Universidad de la República, General Flores 2124, 11800 Montevideo, Uruguay Cryssmat-Lab, Cátedra de Física, DETEMA., Facultad de Química—Universidad de la República, General Flores 2124, 11800 Montevideo, Uruguay
a r t i c l e
i n f o
Article history: Received 7 April 2016 Revised 18 April 2016 Accepted 19 April 2016 Available online xxxx Keywords: Aminocyclitol Inosamines cis-Cyclohexadienediols Allylic azide
a b s t r a c t A facile and short chemoenzymatic synthesis of ( ) 1L-5-amino-5-deoxy-allo-inositol hexaacetate is described using benzyl azide as starting material. The key transformations consist of an enzymatic dioxygenation using the toluene dioxygenase enzymatic complex, followed by an allylic azide double sigmatropic [3,3] shift to introduce the nitrogen functionality in the ring in a stereoselective manner. Azide reduction and further regioselective oxidation of the diene moiety afforded the desired inosamine in only eight steps from benzyl azide. Ó 2016 Elsevier Ltd. All rights reserved.
Aminocyclitols (or aminocarbasugars) are a group of aminocycloalkane polyols that have gained great importance because of their remarkable biological activities.1 Functioning as mimics of natural carbohydrates they present a wide range of biological activities such as alpha-glucosidase inhibitors,2 antibiotics,3 antifungals,4 and potential therapeutics for diseases of carbohydrate metabolism.5 In addition, some aminocyclitols are advanced key structural motifs in the total synthesis of several Amaryllidaceae alkaloids.6 Figure 1 shows some structural examples: amino-inositols 1–3 are part of antibiotic KA-3093,7 methoxyhygromycin,8 and minosaminomycin9 respectively. Also compounds 4–5 present interesting biological activities for Gaucher disease.5,10 Due to these interesting biological properties, the enantioselective preparation of aminocyclitols has attracted the attention of the synthetic community in the last decades.1a In particular, ciscyclohexadienediols prepared by biotransformation of arenes using bacterial dioxygenases have been widely used as starting materials for aminocyclitol synthesis (Fig. 2A).11 These substrates already possess two hydroxyl groups and the additional ones may be introduced by further stereoselective oxidations. Regarding the nitrogen functionality, several different methodologies have been used for its strereocontrolled introduction into the ring as reviewed recently by Lewis and co-workers11b Acyl nitroso cycloaddition to the diene moiety;12 alkene regio- and stereoselective epoxidation ⇑ Corresponding author. Tel.: +598 29247881; fax: +598 29240106. E-mail address: [email protected] (I. Carrera).
followed by ring-opening with a nitrogen nucleophile6b,12b,13 and also alkene aziridination13b,e,l,14 are the three main strategies that have been used for this aim (Fig. 2A). Recently we described the structures of novel interesting azido dienediols obtained from the biotransformation of benzyl azide by the toluene dioxygenase (TDO) enzymatic complex expressed in Escherichia coli JM109 (pDTG601).15 In addition to the expected diol 11, the exocyclic diene 12 was found; its formation was explained by an spontaneous stereoselective double sigmatropic
Figure 1. Representative aminocyclitol units present in important biologically active products.
http://dx.doi.org/10.1016/j.tetlet.2016.04.072 0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: de la Sovera, V.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.04.072
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Figure 2. (A) Previous strategies for introducing nitrogen functionality in cis-cyclohexadienediols for aminocyclitol synthesis. (B) Stereoselective azide functionalization via double allylic azide sigmatropic shift used in this work.
[3,3] shift from 11 (Fig. 2B). This type of rearrangement was previously reported by Boyd et al. on cyclic dienediols from microbial origin.16 Production of 12 was optimized in a bioreactor scale to render a yield of 1.0–1.6 g/L.15 In this work we use the azido dienediol 12 as starting material for the enantioselective preparation of ( ) 1L-5-amino-5-deoxyallo-inositol hexaacetate. The proposed synthetic design allows for a facile and straightforward inosamine preparation since the nitrogen containing functionality is already present and with the right configuration in the starting material. The same inosamine skeleton with the proper stereochemistry has led to the synthesis of interesting derivatives such as a methylenedioxoacetal related to hygromycin A,17 and the corresponding azido analog.18 However, to the best of our knowledge, the target aminocyclitol has only one previous enantioselective synthesis in the literature19 and other racemic approaches.20 As a first approach we studied oxidative conditions to selectively oxidize the exo- or endo-cyclic olefins in diol 12. Standard dihydroxylation procedures using RuCl3 or OsO4, as well as epoxidation using m-CPBA, afforded mixtures of products with poor regio-selectivities. Ozonolysis in DCM/Py afforded the best results to oxidize the exo-olefin to give the corresponding ketone, which was reduced under Luche conditions,21 and acetylated to give 13 as a chromatographically inseparable 7:3 mixture of diastereomers in an overall yield of 40% (Fig. 3). In order to be able to separate the diastereomeric mixture for further spectroscopic characterization, we decided to change the protecting groups of the triol moiety. To our disappointment, transesterification of 13 with K2CO3/MeOH followed by diol protection with the isopropylidene group afforded products 14a and 14b where the azide group underwent an allylic [3,3] rearrangement. According to our previous findings, we reasoned that this sigmatropic shift is favored by hydrogen bonding between the azide and the vicinal free hydroxyl group.15a At this stage, we became concerned that this rearrangement could also take place
Figure 3. First approach toward aminocyclitol synthesis using diol 12. (a) E. coli JM109 (pDTG601) then 1 week at rt, 1.0–1.6 g/L; (b) O3, DCM: Py 78 °C; (c) NaBH4 CeCl37H2O, MeOH; (d) Ac2O, Et3N, DMAP, DCM, 0 °C, overall b-d 40%.
Figure 4. (A) (a) K2CO3, MeOH; (b) 2,2-dimethoxypropane, acetone, p-TsOH. (B) The [3,3] sigmatropic shift is promoted by the hydrogen bond generated in the alpha hydroxy azide moiety and can jeopardize the stereochemical integrity of the product.
immediately after the ozonolysis/reduction of 12, in which case the allylic azide in triol 15 (Fig. 4B) would be shifted to give 16. Since in both structures there is a vicinal hydroxyazide, an equilibrium could take place and jeopardize the enantiomeric integrity of the product (15 and 16 are enantiomers when the three hydroxyl groups are syn). In view of these results we decided to change our synthetic design reducing first the azide group in 12, in order to avoid the above mentioned sigmatropic shifts. Figure 5 shows our second approach. Staudinger conditions on 12 smoothly produced the desired amine in 98% yield, which was fully protected to give triacetate 17. Unexpectedly, oxidation of 17 using previous ozonolysis conditions gave a complex mixture of products affording the desired ketone only in traces. However, we were delighted to find that, epoxidation conditions in 17 using m-CPBA in the presence of fluoride salts (NaF/KHF2)22 as additives afforded epoxide 18 in a 63% yield, whose stereochemistry (epoxide syn to the acetamido group) was proposed according to J coupling analysis. Trace amounts of another diastereomer with the same regiochemistry were also found in the reaction mixture (probably with the epoxide anti to the acetamido group). The obtained regio- and stereoselectivity of 18 could be explained by coordination of the epoxidation agent with the acetamide function acting as a directing group. Then acidic hydrolysis of 18 followed by acetylation, gave tetraol 19 with complete regiocontrol.
Please cite this article in press as: de la Sovera, V.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.04.072
V. de la Sovera et al. / Tetrahedron Letters xxx (2016) xxx–xxx
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diffraction data were collected and the crystal structure was solved and refined. Agencia Nacional de Investigación e Innovacion (ANII) is acknowledged for financial support (Project FCE 6045). Also, we would like to thank the Comisión Académica de Posgrado (Universidad de la República) for a PhD scholarship for Victoria de la Sovera and Prof. Alejandra Rodríguez (Facultad de Química, Polo Tecnológico de Pando – UdelaR) for the High Resolution Mass Spectroscopy analysis. We also thank María Agustina Vila (Laboratorio de Biocatálisis y Biotransformaciones – UdelaR) for the preparation of cis-cyclohexadienediol 12. Mario A. Macías thanks ANII for his postdoctoral contract (No. PD_NAC_2014_1_102409). Supplementary data Figure 5. Final approach to ( )-allo inosamine hexaacetate. (a) E. coli JM109 (pDTG601), then 1 week at rt 1.0–1.6 g/L; (b) i. Ph3P, THF ii. H2O, 98%; (c) Ac2O, Et3N, DMAP, DCM, quant.; (d) m-CPBA, NaF/KHF2, DCM, 63%; (e) H2O, DowexÒ 50WX8; (f) Ac2O, Et3N, DMAP, DCM, overall e-f 80%; (g) O3, DCM: Py 78 °C then NaBH4/MeOH; (h) Ac2O, Et3N, DMAP, DCM, overall g-h 53%.
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.04. 072. References and notes
Figure 6. Molecular structure of 19 showing the anisotropic displacement ellipsoids drawn at the 30% probability level (hydrogen atoms are depicted as spheres with arbitrary radii).
Stereochemical assignment of 19 was confirmed by X-ray diffraction analysis (Fig. 6), which demonstrates that the epoxide in 18 was opened by the attack of water on the allylic position. Ozonolysis of the exocyclic olefin in 19, followed by sodium borohydride reduction and acetylation afforded the desired inosamine hexaacetate with an overall yield of 53% for the last three steps. In summary we describe the first enantioselective synthesis of an aminocyclitol using benzyl azide as a starting material. The key transformations consist of an enzymatic dioxygenation using the toluene dioxygenase enzymatic complex, followed by an allylic azide double sigmatropic [3,3] shift to introduce the nitrogen functionality in the ring in a stereoselective manner. Azide reduction and further regioselective oxidation of the diene moiety afforded the desired inosamine in only eight steps from benzyl azide. Acknowledgments We would like to thank Prof. L. Suescun and the organization of the course IUCr-UNESCO Bruker OpenLab Uruguay 2, where X-ray
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