Hybrid Organo- and Biocatalytic Process for the Asymmetric Transformation of Alcohols into Amines in Aqueous Medium

Abstract

A hybrid organo-and biocatalytic system for the asymmetric conversion of racemic alcohols into amines was developed. Combining an organocatalyst, AZADO, an oxidant, NaOCl, and an enzyme, transaminase, we implemented a one-pot oxidation-transamination sequential process in aqueous medium.The method showed broad substrate scope and was successfully applied to conventional secondary alcohols and sterically hindered -substituted cycloalkanols, where a highly stereoselective dynamic asymmetric bioamination enabled to set up both contiguous stereocenters with very high enantio-and diastereomeric ratio (>90% yield, >99% ee and up to 49:1 dr). KEYWORDS: One-pot reaction, organocatalysis, biocatalysis, asymmetric synthesis, amino alcohols, transaminase, AZADO. yield. On the other hand, treatment of 3a,b with di-tert-butyl dicarbonate led to the orthogonally protected derivatives (1R,2R)-5a,b. Actually, orthogonally protected amino alcohols are highly valuable molecules in both asymmetric catalysis and medicinal chemistry. 17 Debenzylation of 5a,b gives entry to N-protected amino alcohols (1R,2R)-6a,b, thus completing the practical syntheses of an interesting set of derivatives by means of quantitative and simple processes. Scheme 2. Organo-enzymatic platform towards valuable optically active -aminocycloalkanol derivatives. i) H2, Pd-C 10%, MeOH; ii) (Boc)2O, CH2Cl2, iii) CF3CO2H, CH2Cl2; iv) H2, Pd-C 10%, (Boc)2O, MeOH. CONCLUSIONSIn conclusion, we disclosed an expedient, stereoselective and operationally simple protocol for the synthesis of a variety of optically active amines, through the unprecedented one-pot combination of: i) organocatalyzed oxidation of secondary alcohols; ii) subsequent enantioselective bioamination of the transiently formed ketones. In all cases, the desired final amines were isolated in high yields and with excellent diastereo-and enantiomeric excesses. Likewise, it is worth noting the use of a one-pot methodology, in which the aqueous reaction medium from the organocatalyzed reaction feeds the 15 enzymatic amination. This methodology, which exploits the advantages of merging two catalytic worlds such as organo-and enzymatic catalysis, represents one of the few contributions of this kind of combination in water. Moreover, it is a robust alternative to the existing methodologies, with proven efficacy for a broad variety of secondary alcohols.

Overcoming the Incompatibility Challenge in Chemoenzymatic and Multi‐Catalytic Cascade Reactions

“…2-Keto-3-deoxy sugar acids are interesting building blocks for bio-based chemicals because theyc an be derived from sugar.S ieber et al suggested an ew route for their synthesis by the coupling of the chemical oxidation of sugars with an enzymatic dehydration step. [30] Similar to the work of Gonzalez-Sabína nd co-workers( see above), [24] the synthetic challenge was to achieve an oxidation under mild reaction conditions and the combination with an enzymatic step without intermediary steps for product recovery.S ieber and coworkers chose ag old catalyst for the oxidation (Scheme 3d). Both reactions proceed in aqueous systems.…”

“…Gonzáles‐Sabin and co‐workers successfully applied a non‐stereoselective oxidation using the organocatalyst 2‐azaadamantane N ‐oxyl (AZADO) together with NaOCl as mediator for the oxidation of a series of 2‐(benzyloxy)cycloalkanoles (Scheme e). The reaction conditions were mild enough to be compatible with the subsequent reductive amination by several ( S )‐selective and ( R )‐selective transaminases . Interestingly, the tendency of several 2‐(benzyloxy)cycloalkanones to undergo spontaneous racemization under slightly basic conditions allowed for the use of stereoselective amination to establish a dynamic kinetic resolution, giving rise to a series of diastereomerically pure 2‐(benzyloxy)cycloalkylamines in high isolated yield, good to excellent diastereomeric purity (up to 98:2), and very high optical purity (>99 % ee ).…”

Stereoselective Synthesis of 1‐Arylpropan‐2‐amines from Allylbenzenes through a Wacker‐Tsuji Oxidation‐Biotransamination Sequential Process

“…[15] For instance, Rebolledo and co-workers have reported the catalytic chemical oxidation of 1arylpropan-2-ols mediated by AZADO to produce the corresponding 1-arylpropan-2-ones, which were later subjected to asymmetric biotransamination using ATAs. [16] Multienzymatic strategies for the synthesis of optically active 1-arylpropan-2-amines from alcohols rely on the combination of two stereocomplementary alcohol dehydrogenases (ADHs) for the oxidation of racemic 1-arylpropan-2-ols to subsequently perform the biotransamination reaction [17] or the reductive amination catalysed by an AmDH. [18] Alternatively, a redox-neutral cascade has been described starting from racemic 1-phenylpropan-2-ol based on the use of a single non selective ADH for alcohol oxidation and subsequent reductive amination employing the reductive aminase from Aspergillus oryzae.…”

Asymmetric Amination of α‐Chiral Aliphatic Aldehydes via Dynamic Kinetic Resolution to Access Stereocomplementary Brivaracetam and Pregabalin Precursors

“…[5] UCB pharma has developed several synthetic routes for the preparation of the 2-oxo-pyrrolidine derivative, [6][7][8] however, these exclusively chemical methods come along with poor stereoselectivity and hence elaborate chromatography steps in order to obtain the far more active (2S,4R)-stereoisomer in pure form. Interestingly, despite of their popularity for the synthesis of chiral amines used for APIs and their successful application also on industrial scale, [24][25][26][27][28][29][30][31] transaminases (TA) [32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51] have not yet been considered as the biocatalyst of choice to prepare key intermediates of Pregabalin and Brivaracetam by deracemisation of the corresponding aldehydes. This process has been improved in terms of yield and economical aspects by replacing chemical resolution by a lipasecatalysed one.…”