Chemoenzymatic Platform for Synthesis of Chiral Organofluorines Based on Type II Aldolases

Jason Fang,Diptarka Hait,Martin Head‐Gordon,Michelle C Y Chang

doi:10.1002/ange.201906805

Jason Fang, Diptarka Hait + Show 2 more

Open Access

https://doi.org/10.1002/ange.201906805

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Journal: Angewandte Chemie	Publication Date: Jul 19, 2019
Citations: 14	License type: cc-by

Affiliation: University of California, Berkeley

Abstract

AbstractAldolases are C−C bond forming enzymes that have become prominent tools for sustainable synthesis of complex synthons. However, enzymatic methods of fluorine incorporation into such compounds are lacking due to the rarity of fluorine in nature. Recently, the use of fluoropyruvate as a non‐native aldolase substrate has arisen as a solution. Here, we report that the type II HpcH aldolases efficiently catalyze fluoropyruvate addition to diverse aldehydes, with exclusive (3S)‐selectivity at fluorine that is rationalized by DFT calculations on a mechanistic model. We also measure the kinetic parameters of aldol addition and demonstrate engineering of the hydroxyl group stereoselectivity. Our aldolase collection is then employed in the chemoenzymatic synthesis of novel fluoroacids and ester derivatives in high stereopurity (d.r. 80–98 %). The compounds made available by this method serve as precursors to fluorinated analogs of sugars, amino acids, and other valuable chiral building blocks.

Highlights

Aldolases are C-C bond forming enzymes that have become prominent tools for sustainable synthesis of complex synthons
Fluorine has unique elemental characteristics that have served as the basis for its rising use in the design of synthetic compounds with a breadth of functions ranging from materials to pharmaceuticals.[1]
While many synthetic methodologies are known for the site-selective introduction of fluorine onto various scaffolds,[2] fluorine biocatalysis is less mature yet offers many potential advantages with respect to chemo, regio, and stereoselectivity of enzymatic approaches.[3]

Summary

Introduction

Aldolases are C-C bond forming enzymes that have become prominent tools for sustainable synthesis of complex synthons. The challenge is magnified for fluorine stereocenters, such that asymmetric fluoro-aldol reactions have been reported only recently.[5c] For these reasons, aldolase enzymes that catalyze the addition of a carbonyl donor to an aldehyde acceptor have been explored as an alternative to chemical methods.[6] Pyruvate aldolases in particular furnish a useful, denselyfunctionalized α-ketoacid motif.

Results

Conclusion