Stereoselective Chemoenzymatic Synthesis of Optically Active Aryl-Substituted Oxygen-Containing Heterocycles

Abstract

A two-step stereoselective chemoenzymatic synthesis of optically active α-aryl-substituted oxygen heterocycles was developed, exploiting a whole-cell mediated asymmetric reduction of α-, β-, and γ-chloroalkyl arylketones followed by a stereospecific cyclization of the corresponding chlorohydrins into the target heterocycles. Among the various whole cells screened (baker's yeast, Kluyveromyces marxianus CBS 6556, Saccharomyces cerevisiae CBS 7336, Lactobacillus reuteri DSM 20016), baker's yeast was the one providing the best yields and the highest enantiomeric ratios (up to 95:5 er) in the bioreduction of the above ketones. The obtained optically active chlorohydrins could be almost quantitatively cyclized in a basic medium into the corresponding α-aryl-substituted cyclic ethers without any erosion of their enantiomeric integrity. In this respect, valuable, chiral non-racemic functionalized oxygen containing heterocycles (e.g., (S)-styrene oxide, (S)-2-phenyloxetane, (S)-2-phenyltetrahydrofuran), amenable to be further elaborated on, can be smoothly and successfully generated from their prochiral precursors.

Whole-Cell Biocatalyst for Chemoenzymatic Total Synthesis of Rivastigmine

“…As different alcohol dehydrogenases (ADHs) with different stereopreference and substrate specificity can be expressed in various microorganisms, also by varying metabolic growth conditions and phase [26][27][28][29][30], we envisaged the whole-cell bioreduction of prochiral aryl ketone 1 or 2 as the key step in obtaining the appropriate precursor (R)-3 or (R)-4, useful for the synthesis of the target eutomer of (S)-rivastigmine (5) (Scheme 2). In order to establish the feasibility of this strategy, we explored different experimental conditions in water and in DES-water mixtures using baker's yeast resting cells (RC) or Lactobacillus reuteri DSM 20016 whole cells.…”

“…The progress of the reactions was monitored by TLC and/or GC. The racemic alcohols 3, 4 were prepared by NaBH 4 reduction in EtOH in 91-95% yields [26][27][28][29][30]. The optically active alcohols 3 and 4, obtained from baker's yeast or Lactobacillus reuteri bioreductions, had analytical and spectroscopic data identical to the previously synthesized or commercially available racemic compounds.…”

Enantiodivergent Synthesis of Halohydrins by Engineering P450DA Monooxygenases

“…Chiral halohydrins are extremely versatile intermediates for building various drug molecules, biological molecules, and natural products, as they can be easily converted into a broad range of functional groups to construct various useful chiral compounds, such as chiral epoxides, azidoalcohols, amino alcohols, and hydroxynitriles . However, the development of convenient and economical methods to synthesize these motifs remains challenging.…”