Combining Photochemical Oxyfunctionalization and Enzymatic Catalysis for the Synthesis of Chiral Pyrrolidines and Azepanes

Abstract

Chiral heterocyclic alcohols and amines are frequently used building blocks in the synthesis of fine chemicals and pharmaceuticals. Herein, we report a one-pot photoenzymatic synthesis route for N-Boc-3-amino/hydroxy-pyrrolidine and N-Boc-4-amino/hydroxy-azepane with up to 90% conversions and >99% enantiomeric excess. The transformation combines a photochemical oxyfunctionalization favored for distal C-H positions with a stereoselective enzymatic transamination or carbonyl reduction step. Our study demonstrates a mild and operationally simple asymmetric synthesis workflow from easily available starting materials.

Figure 1

Examples of bioactive compounds containing a 3-amino/hydroxy-pyrrolidine or 4-amino/hydroxy-azepane moiety (highlighted in blue).

Figure 2

A. Examples of literature-reported biocatalytic syntheses of enantioenriched 3-aminopyrrolidines and 3-hydroxypyrrolidines. (i). Amine-transaminase (ATA)-catalyzed transamination or keto reductase (KRED)-catalyzed carbonyl reduction of N-protected-3-pyrrolidinone, (ii). ATA-mediated kinetic resolution of racemic N-Boc-3-aminopyrrolidine, (iii). Chemoenzymatic multipot preparation of chiral N-benzyl-3-aminopyrrolidine, with racemic resolution of N-protected-d,l-asparagine esters with proteases as the key step. B. Summarized reaction scheme of the one-pot photoenzymatic conversion of pyrrolidine or azepane into chiral N-Boc-protected 3-amino/hydroxypyrrolidines and 4-amino/hydroxyazepanes.