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Enantioselective Single and Dual α-C–H Bond Functionalization of Cyclic Amines via Enzymatic Carbene Transfer

[Image: see text] Cyclic amines are ubiquitous structural motifs found in pharmaceuticals and biologically active natural products, making methods for their elaboration via direct C–H functionalization of considerable synthetic value. Herein, we report the development of an iron-based biocatalytic s...

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Autores principales: Ren, Xinkun, Couture, Bo M., Liu, Ningyu, Lall, Manjinder S., Kohrt, Jeffrey T., Fasan, Rudi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9837850/
https://www.ncbi.nlm.nih.gov/pubmed/36542059
http://dx.doi.org/10.1021/jacs.2c10775
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author Ren, Xinkun
Couture, Bo M.
Liu, Ningyu
Lall, Manjinder S.
Kohrt, Jeffrey T.
Fasan, Rudi
author_facet Ren, Xinkun
Couture, Bo M.
Liu, Ningyu
Lall, Manjinder S.
Kohrt, Jeffrey T.
Fasan, Rudi
author_sort Ren, Xinkun
collection PubMed
description [Image: see text] Cyclic amines are ubiquitous structural motifs found in pharmaceuticals and biologically active natural products, making methods for their elaboration via direct C–H functionalization of considerable synthetic value. Herein, we report the development of an iron-based biocatalytic strategy for enantioselective α-C–H functionalization of pyrrolidines and other saturated N-heterocycles via a carbene transfer reaction with diazoacetone. Currently unreported for organometallic catalysts, this transformation can be accomplished in high yields, high catalytic activity, and high stereoselectivity (up to 99:1 e.r. and 20,350 TON) using engineered variants of cytochrome P450 CYP119 from Sulfolobus solfataricus. This methodology was further extended to enable enantioselective α-C–H functionalization in the presence of ethyl diazoacetate as carbene donor (up to 96:4 e.r. and 18,270 TON), and the two strategies were combined to achieve a one-pot as well as a tandem dual C–H functionalization of a cyclic amine substrate with enzyme-controlled diastereo- and enantiodivergent selectivity. This biocatalytic approach is amenable to gram-scale synthesis and can be applied to drug scaffolds for late-stage C–H functionalization. This work provides an efficient and tunable method for direct asymmetric α-C–H functionalization of saturated N-heterocycles, which should offer new opportunities for the synthesis, discovery, and optimization of bioactive molecules.
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spelling pubmed-98378502023-01-14 Enantioselective Single and Dual α-C–H Bond Functionalization of Cyclic Amines via Enzymatic Carbene Transfer Ren, Xinkun Couture, Bo M. Liu, Ningyu Lall, Manjinder S. Kohrt, Jeffrey T. Fasan, Rudi J Am Chem Soc [Image: see text] Cyclic amines are ubiquitous structural motifs found in pharmaceuticals and biologically active natural products, making methods for their elaboration via direct C–H functionalization of considerable synthetic value. Herein, we report the development of an iron-based biocatalytic strategy for enantioselective α-C–H functionalization of pyrrolidines and other saturated N-heterocycles via a carbene transfer reaction with diazoacetone. Currently unreported for organometallic catalysts, this transformation can be accomplished in high yields, high catalytic activity, and high stereoselectivity (up to 99:1 e.r. and 20,350 TON) using engineered variants of cytochrome P450 CYP119 from Sulfolobus solfataricus. This methodology was further extended to enable enantioselective α-C–H functionalization in the presence of ethyl diazoacetate as carbene donor (up to 96:4 e.r. and 18,270 TON), and the two strategies were combined to achieve a one-pot as well as a tandem dual C–H functionalization of a cyclic amine substrate with enzyme-controlled diastereo- and enantiodivergent selectivity. This biocatalytic approach is amenable to gram-scale synthesis and can be applied to drug scaffolds for late-stage C–H functionalization. This work provides an efficient and tunable method for direct asymmetric α-C–H functionalization of saturated N-heterocycles, which should offer new opportunities for the synthesis, discovery, and optimization of bioactive molecules. American Chemical Society 2022-12-21 /pmc/articles/PMC9837850/ /pubmed/36542059 http://dx.doi.org/10.1021/jacs.2c10775 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Ren, Xinkun
Couture, Bo M.
Liu, Ningyu
Lall, Manjinder S.
Kohrt, Jeffrey T.
Fasan, Rudi
Enantioselective Single and Dual α-C–H Bond Functionalization of Cyclic Amines via Enzymatic Carbene Transfer
title Enantioselective Single and Dual α-C–H Bond Functionalization of Cyclic Amines via Enzymatic Carbene Transfer
title_full Enantioselective Single and Dual α-C–H Bond Functionalization of Cyclic Amines via Enzymatic Carbene Transfer
title_fullStr Enantioselective Single and Dual α-C–H Bond Functionalization of Cyclic Amines via Enzymatic Carbene Transfer
title_full_unstemmed Enantioselective Single and Dual α-C–H Bond Functionalization of Cyclic Amines via Enzymatic Carbene Transfer
title_short Enantioselective Single and Dual α-C–H Bond Functionalization of Cyclic Amines via Enzymatic Carbene Transfer
title_sort enantioselective single and dual α-c–h bond functionalization of cyclic amines via enzymatic carbene transfer
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9837850/
https://www.ncbi.nlm.nih.gov/pubmed/36542059
http://dx.doi.org/10.1021/jacs.2c10775
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