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Biocatalytic One-Carbon Ring Expansion of Aziridines to Azetidines via a Highly Enantioselective [1,2]-Stevens Rearrangement

Miller, David C. and Lal, Ravi G. and Marchetti, Luca A. and Arnold, Frances H. (2021) Biocatalytic One-Carbon Ring Expansion of Aziridines to Azetidines via a Highly Enantioselective [1,2]-Stevens Rearrangement. . (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20210821-140525422

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Abstract

We report enantioselective one-carbon ring expansion of aziridines to make azetidines as a new, abiologcal activity of engineered ‘carbene transferase’ enzymes. A laboratory-evolved variant of cytochrome P450BM3, P411-AzetS, not only overrides the inherent reactivity of aziridinium ylides to undergo cheletropic extrusion of ethylene, it also exerts unparalleled stereocontrol (99:1 er) over a [1,2]-Stevens rearrangement, a notoriously challenging reaction class for asymmetric catalysis. These unprecedented selectivities enable an entirely new strategy for the synthesis of chiral azetidine products from readily available synthetic precursors. The utility of this reaction is highlighted by the synthesis of an enantiopure azetidine on gram scale. The exquisite selectivity of the enzyme enables new-to-nature ring-expansion chemistry that overcomes a longstanding synthetic problem.


Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription
https://doi.org/10.33774/chemrxiv-2021-8fq9b-v2DOIDiscussion Paper - version 2
https://doi.org/10.33774/chemrxiv-2021-8fq9bDOIDiscussion Paper - version 1
ORCID:
AuthorORCID
Miller, David C.0000-0002-4560-8824
Lal, Ravi G.0000-0001-6943-4147
Arnold, Frances H.0000-0002-4027-364X
Additional Information:The content is available under CC BY 4.0 License. Research was sponsored by the U.S. Army Research Office and accomplished under contracts W911NF-19-D-0001 and W911NF-19-2-0026 for the Institute for Collaborative Bio-technologies. D.C.M. was supported by a Ruth Kirschstein NIH Postdoctoral Fellowship (F32GM128247). The authors acknowledge Dr. Sabine Brinkmann-Chen, Nathaniel Gold-berg, and Dr. Nicholas Porter for assistance preparing the manuscript. The author(s) have declared they have no conflict of interest with regard to this content. The author(s) have declared ethics committee/IRB approval is not relevant to this content.
Funders:
Funding AgencyGrant Number
Army Research Office (ARO)W911NF-19-D-0001
Army Research Office (ARO)W911NF-19-2-0026
NIH Postdoctoral FellowshipF32GM128247
Subject Keywords:Azetidines; Asymmetric Catalysis; Directed Evolution; Biocatalysis; [1.2]-Stevens Rearrangements
Record Number:CaltechAUTHORS:20210821-140525422
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20210821-140525422
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:110345
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:21 Aug 2021 16:57
Last Modified:21 Aug 2021 16:57

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