A Simple Enantioconvergent and Chemoenzymatic Synthesis of Optically Active α‐Substituted Amides

Abstract

Enantiopure amides 1, substituted in the a position with an azide or a simple N, O, or S substituent (Scheme 1), form an important class of compounds and are key intermediates in medicinal chemistry. The a-azidoamide motif (1, Nu = N 3 ) is found in bioactive molecules, such as the antibiotic azidocillin (Scheme 1). The azide group is considered to be an isostere of the amino group, however, it has increased bulkiness and is not positively charged at physiological pH values. [1] The introduction of an azide function into the a position of peptides is also aimed at the synthesis of enzyme inhibitors that, after binding to their targets and subsequent Staudingertype ligation with biotin-phosphine, are subjected to streptavidin pull-down. [2] Furthermore, enantiopure a-azidoamides are important reagents for "click" chemistry [3] and valuable precursors in the synthesis of amino acids [4] and peptides. [5,6] The chiral scaffold of an amide with a simple O substituent (1, Nu = OR) in the a position can be found in numerous bioactive compounds, such as solimastat (Scheme 1), which is an inhibitor of matrix metalloproteinase, [7] and other anticancer [8] and anticonvulsant [9] agents. Bioactive molecules that bear a chiral amide motif with an S substituent (1, Nu =[*] Dr.

Inverting hydrolases and their use in enantioconvergent biotransformations

“…In some cases, a weak leaving group has to be converted into a better one via an additional activation step. This process has been verified for haloalkane dehalogenases [19].…”

“…The protocol is of high interest because it presents a DKR procedure that is not dependent on environmentally questionable heavy metal complexes. The first enantioconvergent process (Figure 2, type 4) based on haloalkane dehalogenases was recently developed for the chemoenzymatic synthesis of α-substituted amides, which are key intermediates in the production of pharmacologically active compounds [19]. In the first enzymatic kinetic resolution step, a homochiral mixture of α-bromo- and α-hydroxyamide was obtained using an inverting dehalogenase.…”

The effect of a unique halide‐stabilizing residue on the catalytic properties of haloalkane dehalogenase DatA from Agrobacterium tumefaciens C58

“…Haloalkane dehalogenases (HLDs) are bacterial enzymes that catalyze the hydrolytic dehalogenation of various halogenated compounds [1][2][3]. As a result of their broad specificity, HLDs have potential applica-tions in biocatalysis, bioremediation and biosensing [4][5][6][7][8]. Structurally, the HLDs belong to the a/b hydrolase superfamily.…”

One‐Pot Deracemization of sec‐Alcohols: Enantioconvergent Enzymatic Hydrolysis of Alkyl Sulfates Using Stereocomplementary Sulfatases

“… 1 – 3 Enantioconvergent processes are based on the transformation of a pair of enantiomers through opposite stereochemical pathways affecting retention and inversion of configuration. Depending on the stereochemical course of enzymatic and chemical reactions, three types of deracemization protocols were recently classified by Feringa et al 4 Two chemoenzymatic methods start with a biocatalytic kinetic resolution step, which yields a hetero- or homochiral 1:1 mixture of the formed product and nonconverted substrate enantiomer. The latter is subjected to a second (non-enzymatic) transformation with retention or inversion of configuration to yield a single stereoisomeric product.…”

“…For enzymes, the ability to act by retention or inversion is a rare feature, which has been found among epoxide hydrolases, 8 dehalogenases, 4 , 9 and sulfatases. 10 The latter catalyze the hydrolytic cleavage of (alkyl) sulfate esters by breakage of the S–O or the C–O bond leading to retention or inversion at the chiral carbon atom, 10b and thus makes them prime candidates for enantioconvergent processes.…”