Biocatalytic Cascade for the Synthesis of Enantiopure β‐Azidoalcohols and β‐Hydroxynitriles

Abstract

A three-step, two-enzyme, one-pot reaction sequence starting from prochiral α-chloroketones leading to enantiopure β-azidoalcohols and β-hydroxynitriles is described. Asymmetric bioreduction of α-chloroketones by hydrogen transfer catalysed by an alcohol dehydrogenase (ADH) established the stereogenic centre in the first step to furnish enantiopure chlorohydrin intermediates. Subsequent biocatalysed ring closure to the epoxide and nucleophilic ring opening with

Combining Designer Cells and Click Chemistry for a One‐Pot Four‐Step Preparation of Enantiopure β‐Hydroxytriazoles

“…We have decided to use the enzyme-catalyzed highly regioselective azidolysis of the epoxide ring (Scheme 1, 3 to 4), reported by us earlier, [10] as the central reaction of this system, allowing for the introduction of an azide into the substrates. A similar reaction was explored for the incorporation of azide using isolated enzymes and cofactor addition by Kroutil and co-workers [11] and by researchers from Codexis for the incorporation of cyanide for producing a statin intermediate. [12] We aimed at engineering cells that overexpress both enzymes used in the cascade, thus making the process cheaper and applicable on a larger scale.…”

“…[11] In view of the high enantiomeric excess of the products and the simple reaction setup (see also the paragraph below, covering the use of lyophilized cells) we envisage this new one-pot, whole cell cascade to be a valuable tool for the stereoselective preparation of an important class of chiral building blocks.…”

Whole‐Cell Cascade Biotransformations for One‐Pot Multistep Organic Synthesis

“…An early 2‐step artificial cascade is reduction of α‐chloroketone to chiral chlorohydrin by an ADH followed with ring‐closure to chiral epoxide by a halohydrin dehalogenase (HHDH) . HHDH could also catalyze the ring‐opening of epoxide with cyanide and azide to give β‐hydroxynitrile and β‐azidoalcohol, respectively, thus leading to two 3‐step cascades from α‐chloroketone to β‐hydroxynitrile and β‐azidoalcohol in vitro . This cascade transformation was carried out in a step‐wise manner to synthesize ethyl‐( R )‐4‐cyano‐3‐hydroxybutyrate, the key chiral synthon of atorvastatin .…”

Multi‐Enzymatic Cascade Reactions: Overview and Perspectives

“…[37] Additionally, the authors could extend the cascade by a nucleophilic epoxide ring-opening step, thus producing enantiopure b-hydroxy nitriles [38] and b-azido alcohols from the corresponding chloro ketones in a "three-step, two-enzyme, one-pot process" [Scheme 4 (b)]. [39] Recently, Janssen and co-workers reported a further extension of this concept: [40] The formation of b-azido alcohols using designer cells expressing both an ADH and a halohydrin dehalogenase was coupled with Cu(I)-catalyzed "click" cycloaddition of these azido alcohols to phenylacetylene in one pot [Scheme 4 (c)]. b-Hydroxytriazoles were obtained in moderate yields (18-65%) and high enantiomeric excess (97-99%).…”