Unexpected Beneficial Effect of ortho-Substituents on the (S)-Proline-Catalyzed Asymmetric Aldol Reaction of Acetone with Aromatic Aldehydes

Abstract

An intriguing effect of electronegative 2,6-substituents on the stereochemical outcome of (S)-proline-catalyzed aldol reactions between benzaldehyde derivatives and acetone is reported. Remarkably high enantioselectivities can be achieved with such substrates.

Key words

aldehyde - aldol reaction - asymmetric catalysis - organocatalysis - proline

• References and Notes

• 1 Mahrwald R In Modern Aldol Reactions . Wiley-VCH; Weinheim: 2004
• 2a Eder U, Sauer G, Wiechert R. Angew. Chem., Int. Ed. Engl. 1971; 10: 496
• 2b Hajos ZG, Parrish DR. J. Org. Chem. 1974; 39: 1615
• 3a List B, Lerner RA, Barbas CF. III. J. Am. Chem. Soc. 2000; 122: 2395
• 3b Notz W, List B. J. Am. Chem. Soc. 2000; 122: 7386
• 3c List B, Pojarliev P, Castello C. Org. Lett. 2001; 3: 573

For recent reviews, see:
• 4a Berkessel A, Gröger H In Asymmetric Organocatalysis . Wiley-VCH; Weinheim: 2005
• 4b List B. Chem. Commun. 2006; 819
• 4c Dalko PI In Enantioselective Organocatalysis . Wiley-VCH; Weinheim: 2007
• 4d Mukherjee S, Yang JW, Hoffmann S, List B. Chem. Rev. 2007; 107: 5471

Some selected examples of designed catalysts:
• 5a Tang Z, Jiang F, Yu L.-T, Cui X, Gong L.-Z, Mi A.-Q, Jiang Y.-Z, Wu D. J. Am. Chem. Soc. 2003; 125: 5262
• 5b Szöllőssi G, London G, Baláspiri L, Somlai C, Bartók M. Chirality 2003; 15: 90
• 5c Hartikka A, Arviddson PI. Tetrahedron: Asymmetry 2004; 15: 1831
• 5d Guo H.-M, Cun L.-F, Gong L.-Z, Mi A.-Q, Jiang Y.-Z. Chem. Commun. 2005; 1450
• 5e Hartikka A, Arvidsson PI. Eur. J. Org. Chem. 2005; 4287
• 5f Tang Z, Yang Z.-H, Chen X.-H, Cun L.-F, Mi A.-Q, Jiang Y.-Z, Gong L.-Z. J. Am. Chem. Soc. 2005; 127: 9285
• 5g Samanta S, Liu J, Dodda R, Zhao C.-G. Org. Lett. 2005; 7: 5321
• 5h Guizetti S, Benaglia M, Pignataro L, Puglisi A. Tetrahedron: Asymmetry 2006; 17: 2754
• 5i Raj M, Vishnumaya Ginotra SK, Singh VK. Org. Lett. 2006; 8: 4097
• 6 Wasser M In Asymmetric Organocatalysis in Natural Product Syntheses. Springer; Wien: 2012
• 7 Nyberg AI, Usano A, Pihko PM. Synlett 2004; 1891
• 8 The absolute stereochemistry was assigned by comparison of the specific rotation with the one reported in the literature: Yanagisawa A, Matsumoto Y, Nakashima H, Asakawa K, Yamamoto H. J. Am. Chem. Soc. 1997; 119: 9319
• 9 Aromatic aldehydes commonly used in asymmetric aldol transformations were also tested, obtaining moderate yields and enantioselectivities. See Supporting Information, compounds 3b–j.
• 10a Gryko D, Lipinski R. Eur. J. Org. Chem. 2006; 3864
• 10b Luo S, Li J, Xu H, Zhang L, Cheng J.-P. Org. Lett. 2007; 9: 3675
• 10c Hu S, Jiang T, Zhang Z, Zhu A, Han B, Song J, Xie Y, Li W. Tetrahedron Lett. 2007; 48: 5613
• 11 Compound 5h has been described previously in literature obtained from the (S)-proline-catalyzed aldolization. It was obtained in 10% yield after 2 d of reaction time using 30 mol% of catalyst, see: Zhou Y, Shan Z. J. Org. Chem. 2006; 71: 9510
• 12 87% of (S)-proline was reisolated and reused in different experiments, maintaining its catalytic activity.
• 13 Ramachary DB, Sakthidevi R. Chem. Eur. J. 2009; 15: 4516
• 14 Ji C, Peng Y, Huang C, Wang N, Jiang Y. Synlett 2005; 986
• 15 Tang Z, Jiang F, Cui X, Gong L.-Z, Mi A.-Q, Jiang Y.-Z, Wu Y.-D. Proc. Natl. Acad. Sci. U.S.A. 2004; 101: 5755
• 16a Hoang L, Bahmanyar S, Houk KN, List B. J. Am. Chem. Soc. 2003; 125: 16
• 16b Bahamanyar S, Houk KN, Martin HJ, List B. J. Am. Chem. Soc. 2003; 125: 2475