Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 60, Issue 39, Pages 21412-21417Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202106938
Keywords
asymmetric catalysis; biocatalysis; directed evolution; ketones; nitrogen heterocycles
Categories
Funding
- National Institute of General Medical Sciences of the National Institutes of Health [R01GM125887, DP2-GM137417]
- Rothenberg Innovation Initiative at Caltech
- Ruth L. Kirschstein NIH Postdoctoral Fellowship [F32GM131620]
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The engineered TrpB enzyme can catalyze the asymmetric alkylation of ketones, addressing a significant challenge in synthetic chemistry. Through directed evolution, high selectivity is achieved in the alkylation of propiophenone and 2-fluoroacetophenone. Control over stereochemistry at the new chiral center is demonstrated, showing potential for efficient synthesis of non-canonical prolines and other chirally dense nitrogen heterocycles.
The beta-subunit of tryptophan synthase (TrpB) catalyzes a PLP-mediated beta-substitution reaction between indole and serine to form L-Trp. A succession of TrpB protein engineering campaigns to expand the enzyme's nucleophile substrate range has enabled the biocatalytic production of diverse non-canonical amino acids (ncAAs). Here, we show that ketone-derived enolates can serve as nucleophiles in the TrpB reaction to achieve the asymmetric alkylation of ketones, an outstanding challenge in synthetic chemistry. We engineered TrpB by directed evolution to catalyze the asymmetric alkylation of propiophenone and 2-fluoroacetophenone with a high degree of selectivity. In reactions with propiophenone, preference for the opposite product diastereomer emerges over the course of evolution, demonstrating that full control over the stereochemistry at the new chiral center can be achieved. The addition of this new reaction to the TrpB platform is a crucial first step toward the development of efficient methods to synthesize non-canonical prolines and other chirally dense nitrogen heterocycles.
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