P etasis- B orono M annich Reaction ( PBM Reaction)

1. Petasis-Borono Mannich Reaction(PBM Reaction) Hua Wu LSPN Seminar 17-03-2016

2. Outline • Background and Introduction • General Protocols • Reaction Scope and Synthetic Application • Asymmetric Petasis Reaction • Summary

3. Background and Outline Ph.D., 1983, University of Pennsylvania Research Associate and Adjunct Lecturer, University of Pennsylvania, 1984-1987 Working in University of Southern California (USC) Prof. Nicos A. Petasis Research Field: New Synthetic Methods and Strategies, organotitanium, organoboron • Petasis-Borono Mannich Reaction (Petasis Reaction) • Petasis-Ferrier Rearrangement Reaction • c. Petasis-Tebbe Olefination Petasis, N. A. et al. Tetrahedron Lett. 1996, 37, 141. Cp2TiCl2 + 2 CH3MgCl → Cp2Ti(CH3)2 + 2 MgCl2

4. Background and Introduction What is the Petasis Reaction ?

5. Backgroud and Introduction Discovery of Mannich Reaction

6. Backgroud and Introduction First Example of Petasis Reaction In 1993, Nicos A. Petasis (USC) described the preparation of tertiary allylic amines from paraformaldehyde, secondary amines, and vinyl boronic acids under acid-free conditions. Yields ranged from 75-96%. Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34, 583. • Reaction of vinyl boronic acids with secondary amines and paraformaldehyde gives tertiary allylamines. • b. This 3-CR (3-component reaction) can also been described as a boronic acid Mannich.

7. Backgroud and Introduction Mechanism Investigation The precise mechanism of the first PBM is still disputed: · Petasis noted that in the absence of acid, it was unlikely that significant amounts of the iminium salt would form. Also, boronic acids did not readily add to preformed iminium salts, though they did react with diamines. Based on these observations, Petasis proposed the formation of an intermediate ammonium borate complex followed by internal delivery of the vinyl nucleophile.

8. General Protocols However, the vast majority of cases in the literature employ an aldehyde substrate containing a directing group near the carbonyl, indicating a necessity for formation of two-center ionic complex. Reviews: Dömling, A. Chem. Rev. 2006, 106, 17-89. Multicomponent Reactions. Zhu, J.; Bienaymé, H., eds. Wiley-VCH; Weinheim, 2005. Orru, R. V. A.; de Greef, M. Synthesis2003, 10, 1471-1499. Ugi, I. Pure Appl. Chem. 2001, 73, 187-191. Bienaymé, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem. Eur. J. 2000, 6, 3321-3329. Ugi, I. J. Prakt. Chem. 1997, 339, 499-516. Ugi, I.; Dömling, A.; Hörl, W. Endeavour1994, 18, 115-122.

9. General Protocols Theoretical Study on the Mechanism：DFT Calculation Highly stereocontrolled as anti-amino alcohols diastereomer. Tao, J. C. Li, S. H. Chin. J. Chem. 2010, 28, 41

10. Aldehydes Used in Petasis Reaction a. Order of reactivity: glycolaldehyde > glyoxylic acid > salicylaldehyde. b. Vinyl boronic acids are in general more reactive than their aryl counterparts.

11. Effect of Esterification Tetracoordinate boron intermediate is more difficult to form with sterically hindered boronate ester. Southwood, T. J.; Curry, M. C.; Hutton, C. A. Tetrahedron2006, 62, 236.

12. Glyoxylic Acid Synthesis of Vinyl a-Amino Acids Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445. The methodology was applied to primary and secondary amines, and bulky amines were also reported to react under these conditions.

13. Glyoxylic Acid Synthesis of Enantiopure a-Amino Acids The Petasis reaction exhibits high degrees of stereocontrol when a chiral amine or aldehyde is used as a substrate. When certain chiral amines, such as (S)-2-phenylglycinol, are mixed with an α-keto acid and vinyl boronic acid at room temperature, the corresponding allylamine is formed as a single diastereomer. Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445.

14. Glyoxylic Acid Synthesis of a-Amino Acids Koolmeister, T.; Sodergren, M.; Scobie, M. Tetrahedron Lett. 2002, 43, 5965 Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron 1997, 53, 16463. antiplatelet agent Kalinski, C.; et al. Synthesis 2008, 4007.

15. Glyoxylic Acid Petasis-type Reaction Naskar, D.; Neogi, S.; Roy, A.; Mandal, A. B. Tetrahedron Lett. 2008, 49, 6762. Naskar, D.; Roy, A.; Seibel, W.L., Portlock, D.E. Tetrahedron Lett. 2003, 44, 5819-5821.

16. Imino Amides Synthesis of a-Functionalized Glycine Derivatives An efficient approach was developed for the α-arylation of imino amides with arylboronic acids. Zhao, L.; Liao, X. H.; Li, C. J. Synlett 2009, 2953.

17. Glycolaldehyde Synthesis of Enantiopure a-Amino Alcohol When a α-hydroxy aldehyde is used as a substrate in the synthesis of β-amino alcohols, a single diastereomer is generated. This reaction forms exclusively anti-product. optically pure glyceraldehydes Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998, 120, 11798–11799. Unconventional aldehyde equivalent a potent immunosuppressive agent Sugiyama, S.; Arai, S.; Kiriyama, M.; Ishii, K. Chem. Pharm. Bull. 2005, 53, 100.

18. Glycolaldehyde L-xylose Ritthiwigrom, T.; Pyne, S. G. Org. Lett. 2008, 10, 2769. Ritthiwigrom, T.; Willis, A. C.; Pyne, S. G. J. Org. Chem. 2010, 75, 815. Synthesis of amino polyols and amino sugars Petasis, N.A. (2005). Zhu, J.; Bienayme, H., ed. Multicomponent Reactions. Wiley-VCH. pp. 199-223.

19. Salicylaldehyde Synthesis of Alkylaminophenol Petasis, N. A.; Boral, S. Tetrahedron Lett. 2001, 42, 539.

20. Salicylaldehyde Synthesis of 2H-Chromenes Catalytic amount of dibenzyamine Wang, Q.; Finn, M. G. Org. Lett. 2000, 2, 4063.

21. 2-Pyridine Carbaldehydes Mandai, H.; Murota, K.; Sakai, T. Tetrahedron Lett. 2010, 51, 4779.

22. Asymmetric PBM

23. Chiral Amine The first report in the asymmetric version of this reaction was made by Petasis, using an enantiomerically pure amine with boronic acids. Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron 1997, 53, 16463.

24. Chiral Amine Chiral Benzoamines Jiang, B.; Yang, C.-G.; Gu, X.-H. Tetrahedron Lett. 2001, 42, 2545. Chiral Pyrrolidines Nanda, K. K.; Trotter, B. W. Tetrahedron Lett. 2005, 46, 2025-2028.

25. Chiral Aldehyde Chiral a-Hydroxyl Aldehyde Au, C. W. G.; Pyne, S. G. J. Org. Chem. 2006, 71, 7097. This method has been applied to the synthesis of hyacinthacine B3 and purported hyacinthacine B7. Batey, R.A.; Mackay, D.B. Tetrahedron Lett. 2000, 41, 9935–9938.

26. Chiral Boronic Ester The chiral amine was observed to be responsible for the stereochemical outcome. Koolmeister, T.; Sodergren, M.; Scobie, M. Tetrahedron Lett. 2002, 43, 5969. Southwood, T. J.; Curry, M. C.; Hutton, C. A. Tetrahedron 2006, 62, 236.

27. Asymmetric Catalytic PBM Chiral Boronic Ester Ligand Lou, S.; Moquist, P. N.; Schaus, S. E. J. Am. Chem. Soc. 2007, 129, 15398. Not a real Petasis Reaction !

28. Asymmetric Catalytic PBM Lou, S.; Schaus, S. E. J. Am. Chem. Soc. 2008, 130, 6922.

29. Mechanistic studies Mechanistic studies using NMR and ESI-MS analysis of reaction mixtures at room temperature indicated single ligand exchange. Lou, S.; Schaus, S. E. J. Am. Chem. Soc. 2008, 130, 6922.

30. Asymmetric Catalytic PBM N-acylated quinoline salts Yamaoka, Y.; Miyabe, H.; Takemoto, Y. J. Am. Chem. Soc. 2007, 129, 6686.

31. Asymmetric Catalytic PBM Synthesis Chiral Aminophenols Bifunctional Chiral Thiourea Catalyst Yuan, W. C. et al. Org. Lett., 2012, 14, 976–979

32. Mechanistic Investigantion

33. Summary and Outlook Petasis reaction has become an attractive method for the preparation of an assortment of compounds, among which amino acids, heterocycles and alkylaminophenols are the most easily accessible.

34. THANKS !