Synthesis of small molecules is a major task in the chemical industry. Small molecules serve as precursors for e.g. pharmaceuticals, agrochemicals and organic materials and their efficient and preferably catalytic synthesis is essential for our society. Thus, the development of new and superior catalysts providing small molecules in excellent yields and stereoselectivities is important. An attractive class of catalysts are secondary amine organocatalysts: These provide products under mild reaction conditions, are often cheap and non-toxic and can be combined with other modern organic methods such as photo- or electrochemical processes. Yet, these catalysts typically require high loadings of 10–30 mol%, which hamper their use in industrial settings. Hence, general concepts to improve secondary amine catalysts are necessary. Conformationally Tailored Peptidic Catalysts Enable New Asymmetric Transformations Tobias Schnitzer, Jasper S. Möhler, A. Budinská and Helma Wennemers Laboratory of Organic Chemistry, ETH Zürich, Vladimir-Prelog-Weg 3, 8093 Zürich, Switzerland. 1. Peptidic Catalysts of the H-Pro-Pro-Xaa Type – Substrate Scope, Reaction Mechanism & Conformational Analysis Peptides are among the most reactive and stereoselective 2° amine catalysts… R 2 NO 2 NO 2 R 2 NO 2 R 3 R 2 NO 2 COOEt H O NO 2 R 1 R 2 HO NO 2 R 1 H O NO 2 R 1 R 2 H O NO 2 R 1 R 2 2) BH 3 THF . R 3 COOEt H O R 1 H N O O NH O O O O R OH 78 - 82% ee 66 - 99% yield H R O H O R 1 1) 1 mol% Cat I ≤ 1 mol% Cat II 1mol% Cat II 5 mol% Cat III 10 mol% Cat IV 5 mol% Cat V 88 - 98% ee d.r. 4:1 - >99:1 84% - 99% yield 92 - 98% ee d.r. 5:1 - 19:1 80% - 99% yield 94 - 99% ee d.r. 2:1 - 5:1 59% - 98% yield 89 - 97% ee d.r. 3:1 - 10:1 72% - 90% yield 95 - 99% ee 67% - 90% yield N O NH H N O CONH 2 CO 2 H Cat I N O NH H N O CONH 2 Cat II CO 2 H N O NH H N O CO 2 H Cat III CONH 2 N O NH H N O Ph p-Me-C 6 H 4 Cat IV N O NH H N O CONH 2 CONH 2 Cat V a) P. Krattinger, R. Kovasy, J. D. Revell, S. Ivan, H. Wennemers, Org. Lett. 2005, 7, 1101. b) M. Wiesner, M. Neuenburger, H. Wennemers, Chem. Eur. J. 2009, 15, 10103. c) M. Wiesner, J. D. Revell, S. Tonazzi, H. Wennemers, J. Am. Chem. Soc. 2008, 130, 5610. d) J. Duschmale, H. Wennemers, Chem. Eur. J. 2012, 18, 1111. e) R. Kastl, H. Wennemers, Angew. Chem. Int. Ed. 2013, 52, 7228. f) C. Grünenfelder, J. Kisunzu, H. Wennemers, Angew. Chem. Int. Ed. 2016, 55, 8571. Reaction Mechanism and peptide conformation studied in depth… H O R 1 + H O R 1 R 2 NO 2 R 2 NO 2 1 mol% Peptide CHCl 3 / i PrOH 9:1 NH * N R 2 R 1 N O O * * * CO 2 H H R 1 H O H 2 O N * R 1 R 2 NO 2 CO 2 H H O R 2 NO 2 R 1 O O H 2 O rate- and enantioselectivity no product inhibition intramolecular protonation H-Pro-Pro-Xaa type catalysts are excellent model systems to derive design principles to improve peptidic & 2° amine catalysts Ground state Enamine more flexible rigid a) M. Wiesner, G. Upert, G. Angelici, H. Wennemers, J. Am. Chem. Soc. 2010, 132, 6. b) J. Duschmale, J. Wiest, M. Wiesner, H. Wennemers, Chem. Sci. 2013, 4, 1312. c) F. Bächle, J. Duschmale, C. Ebner, A. Pfaltz, H. Wennemers, Angew. Chem. Int. Ed. 2013, 52, 12619. d) C. Rigling, J. K. Kisunzu, J. Duschmale, D. Häussinger, M. Wiesner, M. O. Ebert, H. Wennemers, J. Am. Chem. Soc. 2018, 140, 10829. e) T. Schnitzer, H. Wennemers, Helv. Chim. Acta 2019, 102, e1900070. 2. Optimization of Peptidic Catalysts 3. Optimization of 2° Amine Catalysts a) T. Schnitzer, H. Wennemers J. Am. Chem. Soc. 2017, 139, 15356. b) T. Schnitzer, H. Wennemers Synthesis 2018, 22, 4377. c) T. Schnitzer, H. Wennemers J. Org. Chem. 2020, 85, 7633. About 75% of all peptidic catalysts contain at least one proline residue… cis trans Design principle: High population of trans amide: high reactivity, chemo- & stereoselectivity Tools: H O R 2 R 1 NO 2 R 2 NO 2 + H O R 1 i O NH N H N O CONH2 CO2H Low catalyst loading 500 ppm Solvent-free conditions Ring-size analogues of Pro g-substituted Pro derivatives Applications: High stereoselectivity a) T. Schnitzer,* J. S. Möhler,* H. Wennemers Chem. Sci. 2020, 11, 1943. b) J. S. Möhler,* T. Schnitzer,* H. Wennemers Chem. Eur. J. 2020, DOI: 10.1002/chem.202002966. The enamine intermediate is involved in the rate- and stereodetermining step… Design principle: High population of endo pyramidalized enamine: high reactivity & stereoselectivity Tools: Access to g-nitroaldehydes bearing N-heterocycles Bicyclic Pro derivatives Application: 4. Reversal of the Diastereoselectivity a) T. Schnitzer, A. Budinská, H. Wennemers Nat. Catal. 2020, 3, 143. Design principle: s-cis enamine leads to anti-configured product Tool: d,d-disubstituted Pro derivatives 5. Conclusion s-cis s-trans syn anti R 1 N CO 2 H * N CO 2 H * R 2 H O R 2 R 1 NO 2 H O R 2 R 1 NO 2 R R R R Application: N O NH H N O X R N O HN H N O X R N O N 3 O N O O H O R 2 R 1 NO 2 R 2 NO 2 + H O R 1 CHCl 3 / i PrOH 9:1 O NH N H N O CONH2 CO2H sovent-free 0.1–0.3 mol% H O R 1 + H O R 1 R 2 NO 2 R 2 NO 2 dioxane/MeCN 1:1 5 mol% Peptide N H O N H N O CO 2 H O NH CONH 2 N H Me Me O Access to anti-configured g-nitroaldehydes N H O N H N O X R O N R 1 Peptidic catalysts: trans / cis N O O Conformational tuning of organocatalysts enables both, improved catalytic performance and emergence of new reactivity. The Wennemers Group Thanks! 88% yield 5.5:1 d.r., 98% ee H O i Pr NO 2 57% yield >20:1 d.r., 98% ee H O Et NO 2 98% yield 3.5:1 d.r., 98% ee H O Et NO 2 CF 3 O 98% yield 4.0:1 d.r., 96% ee H O NO 2 6 H O Et NO 2 94% yield 2.0:1 d.r., 96% ee 96% yield 6.5:1 d.r., 98% ee H O Et NO 2 97% yield 4.0:1 d.r., 97% ee H O Et NO 2 OMe 92% yield 4.5:1 d.r., 96% ee H O NO 2 OMe 2 O 99% yield 14:1 d.r., 98% ee H O Me NO 2 98% yield 26:1 d.r., 97% ee H O Et NO 2 80% yield >100:1 d.r., 97% ee H O Et NO 2 98% yield 39:1 d.r., 97% ee H O n Bu NO 2 H O Me NO 2 93% yield 6:1 d.r., 99% ee 99% yield 45:1 d.r., 99% ee H O Et NO 2 92% yield 28:1 d.r., 97% ee H O Et NO 2 OMe 94% yield >100:1 d.r., 97% ee H O i Pr NO 2 F O O H O R 1 + Het NO 2 0.5 mol% Peptide CHCl 3 / i PrOH 9:1 O R 1 NO 2 Het H N H N O O NH CONH 2 CO 2 H 91% yield 27:1 d.r., 98% ee 92% yield 9:1 d.r., 92% ee 87% yield >50:1 d.r., 96% ee 53% yield 13:1 d.r., 89% ee 95% yield >50:1 d.r., 98% ee 81% yield 12:1 d.r., 99% ee 71% yield, 18:1 d.r., 90% ee 84% yield 13:1 d.r., 96% ee O n Pr NO 2 N H O Bn NO 2 N H O Et NO 2 N N H O Pent NO 2 H N N Me O Oct NO 2 H N N Trt O NO 2 H 2 N CO 2 Me Boc O i Pr NO 2 H HN O NO 2 H NH 3 Et rate- and enantioselectivity determining step E + endo fast R N R 1 H E R 1 O E + exo slow N R 1 R H E R 1 O More than 100 organocatalysts are known that form syn-configured g-nitroaldehydes but no general access to anti-configured products is known… 2° Amine catalysts: N endo / exo s-cis / s-trans N R H