Gold and Biocatalysis for the Stereodivergent Synthesis of Nor(pseudo)ephedrine Derivatives: Cascade Design Toward Amino Alcohols, Diols, and Diamines

Abstract

The combination of gold(I) and enzyme catalysis has provided access to a series of nor(pseudo)ephedrine derivatives in a regio‐ and stereoselective manner. The approach involves developing IPrAuNTf2‐catalyzed hydration of 1‐phenylprop‐2‐yn‐1‐yl acetate or N‐(1‐phenylprop‐2‐yn‐1‐yl)acetamide, followed by (dynamic) asymmetric biotransamination or bioreduction of the corresponding keto ester or keto amide intermediates. Enzyme actions were completely selective towards the modification of the methyl ketones in a highly stereoselective manner, allowing the synthesis of enantio‐ and diastereomerically enriched products using either racemic or optically active starting materials. Thus, a series of amino alcohol, diol, and diamine derivatives were produced from propargyl esters or amides (57 to 86% isolated yield), the biocatalyst of choice determining the (stereo)selectivity of the overall cascade process (70–99% diastereomeric excess and >98% enantiomeric excess), and providing access to nor(pseudo)ephedrine compounds in a straightforward manner.

One-pot chemo- and photo-enzymatic linear cascade processes

“…Recently, Gotor-Fernandez et al 71 reported a chemo-enzymatic process by combining a gold( i ) catalyst and enzymes to transform propargylic derivatives into a variety of nor(pseudo)ephedrine derivatives in a regio- and stereoselective way. Ephedrine-type alkaloids are an important family of nitrogen-containing compounds with multiple applications in medicinal chemistry as mimics of adrenaline.…”

Substrate-Specific Evolution of Amine Dehydrogenases for Accessing Structurally Diverse Enantiopure (R)-β-Amino Alcohols

“…Besides some chemical synthetic routes, − biocatalytic strategies have also been receiving considerable attention − mostly due to their high stereoselectivity and the mild reaction conditions. Particularly, amine dehydrogenase-catalyzed asymmetric reductive amination − and kinetic resolution − are two attractive processes to access chiral amines.…”

Hot off the Press

“…The regio- and stereo-selective synthesis of nor(pseudo)ephedrine derivatives has been achieved using a combination of gold( i ) and enzyme catalysis. 32 The process involved the gold( i )-catalysed hydration of 1-phenylalkynes, followed by asymmetric biotransamination with an amine transaminase (Scheme 4) or bioreduction with an alcohol dehydrogenase. Mutagenesis studies have allowed the rational design of novel methionine sulfoxide reductase A (MsrA) biocatalysts that can perform the kinetic resolution of bulky sulfoxides.…”