UNIVERSIDADE DE SÃO PAULO INSTITUTO DE QUÍMICA DE SÃO CARLOS α,β-unsaturated Diazoketones as Useful Platforms in the Synthesis of Heterocycles Antonio C. B. Burtoloso antonio@iqsc.usp.br Recent Advances on the Synthesis of Bioactive Natural Metabolites, November 12 th, 2015
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Bernardim, B.; Hardman-Baldwin, A. M.; Burtoloso, A. C. B.. RSC Adv. 2015, 5, 13311 Rosset, I. G.; Dias, R. M. P.; Pinho, V. D.; Burtoloso, A. C. B. J. Org. Chem. 2014, 79, 6748. Bernardim, B.; Lordello, L.; Burtoloso, A. C. B. Curr. Top. Med. Chem. 2013, 13, 2099. Rosset, I. G.; Burtoloso, A. C. B. J. Org. Chem. 2013, 78, 9464. Pinho, V. D.; Burtoloso, A. C. B. Tetrahedron Lett. 2012, 53, 876. Bernardim, B.; Pinho, V. D.; Burtoloso, A. C. B.. J. Org. Chem. 2012, 77, 9926. Pinho, V. D.; Burtoloso, A. C. B. J. Org. Chem. 2011, 76, 289. 3
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New Applications from α,β-unsaturated Diazoketones: 1) Total synthesis of Ergot alkaloids 5
2) Cycloadditions from Unsaturated diazoketones: 3) Construction of New Bicyclic Nitrogen Scaffolds from Unsaturated diazoketones: 6
4) Asymmetric additions from Unsaturated diazoketones: 7
Why our Interest in Unsaturated Diazoketones? Dendrobates pumilio Daly, J, W.; Spande, T. F.; Garraffo, H. M. J. Nat. Prod. 2005, 68, 1556. dendrobatid and mantellid frogs 8
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How to prepare? 10
Danheiser Methodology Danheiser, R. L.; Miller, R. F.; Brisbois, R. G.; Park, S. Z. J. Org. Chem. 1990, 55, 1959.
SYNTHESIS OF NEW HORNER-WADSWORTH-EMMONS REAGENTS 2-3 steps 12
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Entry Activation Method Activation Conditions Yield (%) 1 Acyl chloride 1. SOCl 2, 25 C, 3h 18 2 Acyl chloride 1. SOCl 2, 50 C, 3h 0 3 Acyl chloride 1. SO 2 Cl 2, 25 C, 3h 5 4 Acyl chloride PCl 5, THF, 25 C, 1h 0 5 Acyl chloride 1. (COCl) 2, 25 o C, 2h 20 6 Acyl chloride 1. (COCl) 2, DCM, 25 C, 2h 25 7 Acyl chloride 1. (COCl) 2, CHCl 3, reflux, 2h 60-70 8 Acyl phosphonium 1. PPh 3, NBS, THF, 0 C, 1h 0 9 Acyl urea 1. DCC, THF, 25 C, 1h 0 10 Acyl mesylates 1. MsCl, CH 3 CN, TEA, 0 C, 1h 0 11 Mixed anhydride 1. ClCO 2 Et, TEA, DCM, 0 C, 1h 0 12 Mixed anhydride 1. TFAA, CHCl 3, reflux, 2h 0 Pinho, V. D.; Burtoloso, A. C. B. J. Org. Chem. 2011, 76, 289-292. 14
Entry Method Base Solvent T( o C) Yield (%) 1 a,b A Ba(OH) 2 THF 0 (2h) 57 2 a,c B NaH THF -78 (1 h) to 0 (1 h) 60 3 a,c C NaH PhMe -78 (1 h) to 0 (1 h) 62 4 a,c D LiHMDS THF -78 (1 h) to 0 (1 h) 38 5 a,c E NaHMDS THF -78 (1 h) to 0 (1 h) 60 6 a,c F KHMDS THF -78 (1 h) to 0 (1 h) 56 7 a,c G BuLi THF -78 (1 h) to 0 (1 h) 60 8 a,d H DIPEA CH 3 CN 25 (24 h) 37 9 a,e I K 2 CO 3 THF 25 (48 h) 14 10 f J NaH THF -78 (1 h) to 0 (1 h) 91 a. 1.0 equiv of phosphonate A; b. 0.8 equiv of the base; c. 1.1 equiv of the base; d. 3.0 equiv of the base and 1.0 equiv of LiCl as additive; e. 1.0 equiv of 18-crown-6 ether as additive; f. 2.0 equiv of the phosphonate A and 2.2 equiv of NaH. Pinho, V. D.; Burtoloso, A. C. B. J. Org. Chem. 2011, 76, 289-292. 15
complete E selectivity Pinho, V. D.; Burtoloso, A. C. B. J. Org. Chem. 2011, 76, 289-292. 16
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Drawback: Solution: Inverting stechiometry: 18
APPLICATIONS 19
APPLICATION IN THE SYNTHESIS OF SUBSTITUTED 2- AND 3-PYRROLIDINONES 20
APLICATION IN THE SYNTHESIS OF SUBSTITUTED 2- AND 3-PYRROLIDINONES 21
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Total Synthesis of Preussin Rosset, I.; Burtoloso, A. C. B. J. Org. Chem. 2014, 79, 6748-6753. All 8 stereoisomers are active! antifungic, antiviral, and anticancer activities 24
Total Synthesis of Preussin 25
APLICATION IN THE SYNTHESIS OF SUBSTITUTED INDOLIZIDINES: SYNTHESIS OF INDOLIZIDINES 167B E 209D AND HYDROXYLATED INDOLIZIDINES 26
Bernardim, B.; Pinho, V. D.; Burtoloso, A. C. B. J. Org. Chem. 2012, 77, 9926. Pinho, V. D.; Burtoloso, A. C. B. Tetrahedron Lett., 2012, 53, 876-878. 27
Non-competitive blockers of neuromuscular transmission Pinho, V. D.; Burtoloso, A. C. B. Tetrahedron Lett., 2012, 53, 876-878.
IMPROVEMENT IN THE WOLFF REARRANGEMENT 29
Studies in the Wolff Rearrangement Entry Catalyst Temperature ( C) Yield (%) 1 40mol% AgBz 50 28 2 40mol% AgBz 50 50 3 30mol% CF 3 CO 2 Ag 50 26 4 30mol% CF 3 SO 3 Ag 50 28 5 30mol% CF 3 SO 3 Ag 50 41 6 50mol% AgBz 50 66 7 50mol% CF 3 CO 2 Ag 50 71 8 50mol% CF 3 SO 3 Ag 50 76 9 50mol% AgNO 3 50 51
White LED 18W Bernardim, B.; Hardman-Baldwin, A. M.; Burtoloso, A. C. B. RSC Adv. 2015, 5, 13311 31
Optimized Reaction Conditions Bernardim, B.; Hardman-Baldwin, A. M.; Burtoloso, A. C. B.. RSC Adv. 2015, 5, 13311
Substrate scope: ESTERS Bernardim, B.; Hardman-Baldwin, A. M.; Burtoloso, A. C. B.. RSC Adv. 2015, 5, 13311
Substrate scope: AMIDES
Non-competitive blockers of neuromuscular transmission Pinho, V. D.; Burtoloso, A. C. B. Tetrahedron Lett., 2012, 53, 876-878.
HYDROXYLATED INDOLIZIDINES 37
Bernardim, B.; Pinho, V. D.; Burtoloso, A. C. B. J. Org. Chem. 2012, 77, 9926.
Bernardim, B.; Pinho, V. D.; Burtoloso, A. C. B. J. Org. Chem. 2012, 77, 9926.
Mitochondria-target nitroxide that has been proven to be of extremely effectiveness at scavenging reactive oxygen species, such as superoxide and nitric oxide. 1) Wipf, P.; Xiao, J.; Jiang, J.; Belikova, N. A.; Tyurin, V. A.; Fink, M. P.; Kagan, V. E. J. Am. Chem. Soc. 2005, 127, 12460 12461. Peter Wipf 2) Frantz, M.-C.; Pierce, J. G.; Pierce, J. M.; Kangying, L.; Qingwei, W.; Johnson, M.; Wipf, P. Org. Lett. 2011, 13, 2318 2321. Bernardim, B.; Burtoloso, A. C. B. Tetrahedron, 2014, 70, 3291 41
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Rosset, I. G.; Burtoloso, A. C. B. J. Org. Chem. 2013, 9464. 45
Rosset, I. G.; Burtoloso, A. C. B. J. Org.Chem. 2013, 9464. 46
New Applications from α,β-unsaturated Diazoketones: 1) Total synthesis of Ergot alkaloids 47
2) Cycloadditions from Unsaturated diazoketones: 48
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3) Construction of New Bicyclic Nitrogen Scaffolds from Unsaturated diazoketones: 50
4) Asymmetric additions from Unsaturated diazoketones: 5) Asymmetric aza-michael additions from Unsaturated diazoketones:??? 51
CONCLUSION 52
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ACKNOWLEDGMENTS 57
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220,000. 11,000,000. 65
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