Asymmetric Catalysis
Peptides as asymmetric catalysts
Peptides play crucial roles in nature and everyday life, e.g., as hormones, neurotransmitters, toxins, anti-ageing agents and artificial sweeteners. Despite their numerous functions, not a single peptide or other small molecule with catalytic activity is known in nature. Our group is intrigued by the question of whether short peptides can function as effective stereoselective catalysts.
With a combination of combinatorial screening and rational design we established tripeptides of the general type H-Pro-Pro-Xaa as effective catalysts for C–C bond forming reactions. Their modular nature allowed to develop highly stereoselective catalysts for a range of aldol and related conjugate addition reactions including even “difficult” electrophiles that yielded, e.g., access to products with quaternary stereogenic centers with exquisite yields and stereoselectivities. The peptidic catalysts are so reactive that many of the reactions proceed in the presence of as little as ≤1 mol% of the catalyst. They are also so robust that the immobilized peptide H-D-Pro-Pro-Glu-NH-TentaGel can be reused after filtration at least 30 times without loss in activity and stereoselectivity and can even be used in a flow reactor for the continuous synthesis of more than 100 g (>450 mmol) of addition products. Mechanistic investigations using a combination of kinetic, NMR-spectroscopic, and ESI-MS studies provided deep insight into the key features of the catalytic cycle and enabled the rationalization of the exquisite performance of the peptidic catalysts. Our studies also revealed a direct correlation between the trans/cis ratio of the Pro-Xaa amide bond and the enantio- and diastereoselectivity of structurally related peptidic catalysts. These insights led to the identification of H-D-Pro-Pip-Glu-NH2 as a highly reactive and stereoselective amine-based catalyst that allows C−C bond formations to be performed in the presence of as little as 0.05 mol% of the catalyst, which is the lowest catalyst loading yet achieved for organocatalyzed reactions that rely on an enamine-based mechanism.
The research highlights the value of peptidic catalysts for organic synthesis and the potential role of peptides in the chemical evolution of enzymes. We are currently probing the features of peptidic catalysts further and are extending our studies to other challenging and relevant reactions.
Selected Publications
C. Rigling, J. K. Kisunzu, J. Duschmalé, D. Häussinger, M. Wiesner, M. O. Ebert, H. Wennemers "Conformational Properties of a Peptidic Catalyst: Insights from NMR Spectroscopic Studies"
J. Am. Chem. Soc. 2018, 140, 10829-10838
T. Schnitzer, H. Wennemers "Influence of the trans/cis Conformer Ratio on the Stereoselectivity of Peptidic Catalysts”
J. Am. Chem. Soc., 2017, 139, 15356-15362.
T. Schnitzer, M. Wiesner, P. Krattiger, J. D. Revell, H. Wennemers, "Is More Better? A Comparison of Tri- and Tetrapeptidic Catalysts"
Org. Biomol. Chem. 2017, 15, 5877 – 5881.
C. Grünenfelder, J. Kisunzu, H. Wennemers "Peptide-Catalyzed Stereoselective Conjugate Addition Reactions of Aldehydes to Maleimide"
Angew. Chem. Int. Ed. 2016, 55, 8571 – 8574.
J. Duschmalé, S. Kohrt, H. Wennemers, "Peptide Catalysis in Aqueous Emulsions"
Chem. Commun. 2014, 50, 8109–8112
F. Bächle, J. Duschmalé, C. Ebner, A. Pfaltz, H. Wennemers, "Organocatalytic Asymmetric Conjugate Addition of Aldehydes to Nitroolefins: Identification of Catalytic Intermediates and the Stereoselectivity-Determining Step by ESI-MS"
Angew. Chem. Int. Ed. 2013, 52, 12619–12623
J. Duschmalé, J. Wiest, M. Wiesner, H. Wennemers, "Effects of internal and external carboxylic acids on the reaction pathway of organocatalytic 1,4-addition reactions between aldehydes and nitroolefins"
Chem. Sci. 2013, 4, 1312–1318
R. Kastl, H. Wennemers, "Peptide-Catalyzed Stereoselective Conjugate Addition Reactions Generating All-Carbon Quaternary Stereogenic Centers"
Angew. Chem. Int. Ed. 2013, 52, 7228–7232
Y. Arakawa, H. Wennemers, "Enamine Catalysis in Flow with an Immobilized Peptidic Catalyst"
ChemSusChem 2013, 6, 242–245
M. Wiesner, J. D. Revell, H. Wennemers, "Tripeptides as Efficient Asymmetric Catalysts for 1,4-Addition Reactions of Aldehydes to Nitroolefins – A Rational Approach"
Angew. Chem. Int. Ed. 2008, 47, 1871–1874
P. Krattiger, R. Kovasy, J. D. Revell, S. Ivan, H. Wennemers, "Increased Structural Complexity Leads to Higher Activity: Peptides as Efficient and Versatile Catalysts for Asymmetric Aldol Reactions"
Org. Lett. 2005, 7, 1101–1103
Thioesterenolate chemistry
Thioesters are abundant in nature and are versatile functional groups for further transformations. Yet, they are underutilized in organic synthesis since the stereoselective introduction of thioester building blocks, such as thioester enolates, is challenging.
Inspired by natural polyketide synthases, which use malonic acid half thioesters (MAHTs) as thioester enolate equivalents, we developed organocatalytic methods for stereoselective addition reactions of MAHTs and protected variants (monothiomalonates, MTMs) to electrophiles. Addition reactions proceed with excellent yields and stereoselectivities in the presence of low amounts (1-5 mol%) of bifunctional organocatalysts which activate the nucleophile and electrophile in a manner akin to the dual activation mode observed in natural systems. Addition products include synthetically versatile compounds bearing, e.g., 4° stereogenic centers and two adjacent fully substituted centers as well as β-aminothioesters that allow for coupling reagent-free solid phase peptide synthesis.
Recently we extended the methodology to fluorinated MAHTs that enabled for the first time enantioselective fluoroacetate aldol reactions, a transformation which provides access to fluorinated analogues of medicinally relevant acetate-derived compounds, such as polyketides and statins but had so far remained elusive. We were also able to utilize fluorinated MTMs as nucleophiles for stereoselective additions to nitroolefins and Mannich type reactions. The addition products were readily converted into fluorinated nitrogen heterocycles or incorporated into peptides. Conformational investigations revealed that -fluoro-carbonyl derivatives adopt a distinct conformation, which is the result of the gauche effect and a preferential antiperiplanar arrangement of C–F and C=O moieties.
Further mechanistic studies are currently on-going to shed light onto the catalytic cycle of the addition reactions. We are also exploring the possibility of implementing new α-substituents in MAHTs and MTMs and examining alternative ways of preparing challenging MAHTs and MTMs compared to classical batch setups. With these substrates we plan to expand the scope and applications of organocatalytic stereoselective addition reactions with thioester enolate equivalents with special emphasis on the preparation of halogenated natural products.
Selected publications
E. Cosimi, N. Trapp, M.-O. Ebert, H. Wennemers, "Combined Experimental and Theoretical Study of Long-Range H-F Interactions in α-Fluoro Amides”
Chem. Commun. 2019, 55, 2253–2256
E. Cosimi,* O. D. Engl,* J. Saadi, M.-O. Ebert, H. Wennemers "Stereoselective Organocatalyzed Synthesis of α-Fluorinated β-Amino Thioesters and their Application in Peptide Synthesis”
Angew. Chem. Int. Ed. 2016, 55, 13127 – 13131
J. Saadi, H. Wennemers, "Enantioselective Aldol Reactions with Masked Fluoroacetates"
Nature Chem. 2016, 8, 276–280
O. D. Engl, S. P. Fritz, H. Wennemers, "Stereoselective Organocatalytic Synthesis of Oxindoles with Adjacent Tetrasubstituted Stereocenters"
Angew. Chem. Int. Ed. 2015, 54, 8193–8197
O. D. Engl, S. P. Fritz, A. Käslin, H. Wennemers, "An Organocatalytic Route to Dihydrocoumarins and Dihydroquinolinones in all Stereochemical Configurations"
Org. Lett. 2014, 16, 5454–5457
Kolarovic, A. Käslin, H. Wennemers, "Stereoselective Synthesis of Indolines via Organocatalytic Thioester Enolate Addition Reactions"
Org. Lett. 2014, 16, 4236–4239
Y. Arakawa, S. P. Fritz, H. Wennemers, "Organocatalytic Stereoselective Synthesis of Acyclic -Nitrothioesters with All-Carbon Quaternary Stereogenic Centers"
J. Org. Chem. 2014, 79, 3937–3945
Bahlinger, S. P. Fritz, H. Wennemers, "Stereoselective Metal-free Synthesis of β-Amino Thioesters Bearing Tertiary and Quaternary Stereogenic Centers"
Angew. Chem. Int. Ed. 2014, 53, 8779–8783
J. Lubkoll, H. Wennemers, "Mimicry of Polyketide Synthases - Enantioselective 1,4-Addition Reactions of Malonic Acid Half Thioesters to Nitroolefins"
Angew. Chem. Int. Ed., 2007, 46, 6841–6844