Thieme Chemistry Journals Awardees – Where Are They Now?
A Stereoselective Tripeptide Catalyst for Conjugate Addition Reactions of Acetophenones to Dicyanoolefins

Abstract

Peptides of the type H-Pro-Pro-Xaa-NH₂ were evaluated as catalysts for conjugate addition reactions of acetophenones to cyanoolefins. Tripeptide H-d-Pro-Pro-Glu-NH₂ with a carboxylic acid moiety in the side chain of Xaa was identified as a catalyst that provides γ,γ-dicyanoacetophenones in yields of up to 90% and stereoselectivies of up to 88:12 er.

Key words

peptides - organocatalysis - proline - nitriles - conjugate addition reactions

• References and Notes

• 1 Fleming FF. Nat. Prod. Rep. 1999; 16: 597-597
• 2 Carey FC, Sundberg RJ. In Advanced Organic Chemistry . Part B, 5th ed. Springer; New York: 2008
• 3 Vicario JL, Badia D, Carrillo L, Reyes E. In Organocatalytic Enantioselective Conjugate Addition Reactions: A Powerful Tool for the Stereocontrolled Synthesis of Complex Molecules. RSC Publishing; Cambridge: 2010

For examples, see:
• 4a Huang H, Bihani M, Zhao JC.-G. Org. Biomol. Chem. 2016; 14: 1755-1755
• 4b Penon O, Carlone A, Mazzanti A, Locatelli M, Sambri L, Bartoli G, Melchiorre P. Chem. Eur. J. 2008; 14: 4788-4788
• 5 Enders D, Demir AS, Rendenbach BE. M. Chem. Ber. 1987; 120: 1731-1731
• 6 Gilli P, Pretto L, Bertolasi V, Gilli G. Acc. Chem Res. 2008; 42: 33-33
• 7a Krattiger P, Kovasy R, Revell JD, Ivan S, Wennemers H. Org. Lett. 2005; 7: 1101-1101
• 7b Messerer M, Wennemers H. Synlett 2011; 499-499
• 8a Wiesner M, Neuburger M, Wennemers H. Chem. Eur. J. 2009; 15: 10103-10103
• 8b Wiesner M, Upert G, Angelici G, Wennemers H. J. Am. Chem. Soc. 2010; 132: 6-6
• 8c Wiesner M, Revell JD, Tonazzi S, Wennemers H. J. Am. Chem. Soc. 2008; 130: 5610-5610
• 9 Grünenfelder CE, Kisunzu JK, Wennemers H. Angew. Chem. Int. Ed. 2016; 55: 8571-8571
• 10a Duschmalé J, Wennemers H. Chem Eur. J. 2012; 18: 1111-1111
• 10b Kastl R, Wennemers H. Angew. Chem. Int. Ed. 2013; 52: 7228-7228
• 11 For an early report on aldol and conjugate addition reactions catalyzed by peptides, see: Martin HJ, List B. Synlett 2003; 1901-1901

For examples of reactions between acetophenones and cyanoolefins, see:
• 12a Moirangthem N, Thingom B, Moirangthem SD, Laitonjam WS. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 2013; 937-937
• 12b Wei Y, Guo R, Dang Y, Nie J, Ma J.-A. Adv. Synth. Catal. 2016; 358: 2721-2721
• 12c Yue L, Du W, Liu Y.-K, Chen Y.-C. Tetrahedron Lett. 2008; 49: 3881-3881
• 12d Kojima S, Suzuki M, Watanabe A, Ohkata K. Tetrahedron Lett. 2006; 47: 9061-9061

For examples of amine-catalyzed addition reactions with acetophenones, see:
• 12e Liu K, Cui H.-F, Nie J, Li X.-J, Ma J.-A. Org. Lett. 2007; 9: 923-923
• 12f Liu J, Yang Z, Liu X, Wang Z, Liu Y, Bai S, Lin L, Feng X. Org. Biomol. Chem. 2009; 7: 4120-4120
• 12g Li W, Wu W, Yang J, Liang X, Ye J. Synthesis 2011; 1085-1085
• 12h Liu T.-Y, Cui H.-L, Zhang Y, Jiang K, Du W, He Z.-Q, Chen Y.-C. Org. Lett. 2007; 9: 3671-3671
• 13 Duschmalé J, Wiest J, Wiesner M, Wennemers H. Chem. Sci. 2013; 4: 1312-1312
• 14 Notably, this peptide is also a powerful catalyst for conjugate addition reactions between aldehydes and β-nitroolefins (ref. 8).
• 15 The peptide catalyst B (0.2 equiv, 20 μmol) was dissolved in MeOH (400 μL). The acetophenone 1 (5 equiv, 500 μmol) and dicyanostyrene 2 (1 equiv, 100 μmol) were added, and the reaction mixture was stirred for 3 d. The reaction mixture was subjected to flash chromatography (hexane–EtOAc, 20:1 to 4:1) to isolate the product after removal of all volatiles under reduced pressure. (S)-2-(3-Oxo-1,3-diphenylpropyl)malononitrile (Table 2, Entry 1) ¹H NMR (300 MHz, CDCl₃): δ = 8.01–7.92 (m, 2 H), 7.71–7.58 (m, 1 H), 7.51 (dd, J = 8.3, 6.9 Hz, 2 H), 7.41 (s, 3 H), 4.63 (d, J = 5.0 Hz, 1 H), 3.95 (dt, J = 8.2, 5.3 Hz, 1 H), 3.75–3.56 (m, 2 H).