Asymmetric Synthesis of cis-2,5-Disubstituted Pyrrolidine, the Core Scaffold of β₃-AR Agonists

Abstract

A practical, enantioselective synthesis of cis-2,5-disubstituted pyrrolidine is described. Application of an enzymatic DKR reduction of a keto ester, which is easily accessed through a novel intramolecular N→C benzoyl migration, yields syn-1,2-amino alcohol in >99% ee and >99:1 dr. Subsequent hydrogenation of cyclic imine affords the cis-pyrrolidine in high diastereoselectivity. By integrating biotechnology into organic synthesis and isolating only three intermediates over 11 steps, the core scaffold of β3-AR agonists is synthesized in 38% overall yield.

Exploiting Enzymatic Dynamic Reductive Kinetic Resolution (DYRKR) in Stereocontrolled Synthesis

“…[58] The syn amino alcohol was obtained in remarkable diastereo- (99% de) and enantioselectivity (99% ee) (Scheme 18). The amino alcohol was eventually transformed into cis -2,5-pyrrolidine, a core scaffold of β 3 -andrenergic receptor agonists.…”

Synthesis of Vibegron Enabled by a Ketoreductase Rationally Designed for High pH Dynamic Kinetic Reduction

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Described here is an efficient stereoselective synthesis of vibegron enabled by an enzymatic dynamic kinetic reduction that proceeds in ah igh-pH environment. [3] Vibegron [4] (1)i sapotent and selective b 3 -AR agonist currently in phase III clinical trials.Itstructurally differs from acyclic b-hydroxylamine b 3 -AR agonists, [3a,b,4a] and possesses au nique cis pyrrolidine moiety linking the C2 and C5 substituents.T he discovery of the cis pyrrolidine backbone improved the pharmacological properties, [4a] but raised the synthetic complexity.In 2013, we reported an asymmetric synthesis [5] of cis-2,5disubstituted pyrrolidine 2,t he core scaffold of vibegron. [1] Before 2012, muscarinic antagonists were the standard-of-care prescribed pharmacological therapy,b ut these agents lack sufficient efficacy and have side effects owing to blockade of the M3 muscarinic receptor.

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“…[1] Before 2012, muscarinic antagonists were the standard-of-care prescribed pharmacological therapy,b ut these agents lack sufficient efficacy and have side effects owing to blockade of the M3 muscarinic receptor. Furthermore,t he transformation of hydroxy amino ester 4 into imine 6 introduced ar eduction-oxidationreduction sequence and ap rotection-deprotection step, [5] contributing to synthetic inefficiency.We envisioned that am ore concise synthesis of vibegron could be based on reducing acorresponding pyrrolidine imine formed by intramolecular Michael addition to aryl alkyne 8 (Scheme 2). [3] Vibegron [4] (1)i sapotent and selective b 3 -AR agonist currently in phase III clinical trials.Itstructurally differs from acyclic b-hydroxylamine b 3 -AR agonists, [3a,b,4a] and possesses au nique cis pyrrolidine moiety linking the C2 and C5 substituents.T he discovery of the cis pyrrolidine backbone improved the pharmacological properties, [4a] but raised the synthetic complexity.…”

“…In 2013, we reported an asymmetric synthesis [5] of cis-2,5disubstituted pyrrolidine 2,t he core scaffold of vibegron. In this approach (Scheme 1), the R,R (C1',C2) stereochemistry of 1 was efficiently established through an enzymatic dynamic kinetic (DK) reduction of b-keto ester 3.T he third stereogenic center, at the C5 position, was established by diastereoselective hydrogenation of imine 6.V ibegron (1)w as obtained after coupling with pyrimidinone acid sodium salt 7.…”

Why Leave a Job Half Done? Recent Progress in Enzymatic Deracemizations

“…Hence, the bioreduction over the carbonyl moiety using an alcohol dehydrogenase is probably one of the most typical biocatalytic DKR systems, being described since 70's. [6] Recent examples include (Scheme 10a) the reduction of: i) α-substituted β-keto esters with commercial and overexpressed ADHs, [80,81] ii) α-substituted 1,3-diketones using commercial enzymes, [82] iii) α-substituted ketones employing overexpressed ADHs, [83] and iv) α-substituted aldehydes with an immobilized biocatalyst. [84] In all cases a pH close to neutral was enough to develop an efficient racemization of the labile position adjacent to the carbonyl reacting group.…”