Highly enantioenriched mixed benzoins are obtained selectively through a biocatalytical cross-coupling reaction of aromatic aldehydes using ThDP-dependent enzymes.

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[reaction: see text] Benzaldehyde lyase from the Pseudomonas fluorescens catalyzes the reaction of aromatic aldehydes with methoxy and dimethoxy acetaldehyde and furnishes (R)-2-hydroxy-3-methoxy-1-arylpropan-1-one and (R)-2-hydroxy-3,3-dimethoxy-1-arylpropan-1-one in high yields and enantiomeric excess via acyloin linkage. Aromatic aldehydes and benzoins are converted into enamine-carbanion-like intermediates prior to carboligation.

Alteration of the substrate specificity of thiamin diphosphate (ThDP)-dependent benzoylformate decarboxylase (BFD) by error-prone PCR is described. Two mutant enzymes, L476Q and M365L-L461S, were identified that accept ortho-substituted benzaldehyde derivatives as donor substrates, which leads to the formation of 2-hydroxy ketones. Both variants, L476Q and M365L-L461S, selectively catalyze the formation of enantiopure (S)-2-hydroxy-1-(2-methylphenyl)propan-1-one with excellent yields, a reaction which is only poorly catalyzed by the wild-type enzyme. Different ortho-substituted benzaldehyde derivatives, such as 2-chloro-, 2-methoxy-, or 2-bromobenzaldehyde are accepted as donor substrates by both BFD variants as well and conversion with acetaldehyde resulted in the corresponding (S)-2-hydroxy-1-phenylpropan-1-one derivatives. As deduced from modeling studies based on the 3D structure of wild-type BFD, reduction of the side chain size at position L461 probably results in an enlarged substrate binding site and facilitates the initial binding of ortho-substituted benzaldehyde derivatives to the cofactor ThDP.

A general and practical synthesis of both syn-and anti-α-amino β-hydroxy esters with high levels of selectivity by the use of Ru-SYNPHOS  catalysts is reported. The key transformations include asymmetric hydrogenations of α-N-substituted β-keto esters protected as α-amido or α-amino hydrochloride derivatives, respectively. The Ru II -catalyzed hydro-

Stereoselective reduction of 2-hydroxy ketones should in principle give access to syn-and anti-1,2-diols. anti-1,2-Diols are accessible in a highly selective way using zinc borohydride [ZnA C H T U N G T R E N N U N G (BH 4 ) 2 ] under chelation control (dr > 20:1). Diastereoselective reduction of unprotected or even protected 2-hydroxy ketones towards syn-1,2-diols could be achieved only with moderate selectivity of dr 5:1. Even when using sterically demanding protecting groups and/or polymer-supported borohydride reagents high selectivity could not be achieved. A new ionic liquid-dependent borohydride reduction method, although highly attractive with respect to reaction engineering, resulted in only moderate to good selectivity. An efficient twostep biocatalytic method for the synthesis of syn-1,2-diols is described. The method relies on the whole-cell Pichia glucozyma-catalyzed stereoselective reduction of the unprotected (R)-2-hydroxy ketones (dr > 10:1). The latter are accessible through thiamine diphosphate-dependent enzyme-catalyzed synthesis starting from simple aldehydes. Thus, biocatalytic transformations enable a process which is hardly accessible through present non-enzymatic methods.

Biocatalytical approaches have been investigated in order to improve accessibility of the bifunctional chiral building block (5S)-hydroxy-2-hexanone ((S)-2). As a result, a new synthetic route starting from 2,5-hexanedione (1) was developed for (S)-2, which is produced with high enantioselectivity (ee >99%). Since (S)-2 can be reduced further to furnish (2S,5S)-hexanediol ((2S,5S)-3), chemoselectivity is a major issue. Among the tested biocatalysts the whole-cell system S. cerevisiae L13 surpasses the bacterial dehydrogenase ADH-T in terms of chemoselectivity. The use of whole-cells of S. cerevisiae L13 affords (S)-2 from prochiral 1 with 85% yield, which is 21% more than the value obtained with ADH-T. This is due to the different reaction rates of monoreduction (1-->2) and consecutive reduction (2-->3) of the respective biocatalysts. In order to optimise the performance of the whole-cell-bioreduction 1 2 with S. cerevisiae, the system was studied in detail, revealing interactions between cell-physiology and xenobiotic substrate and by-products, respectively. This study compares the whole-cell biocatalytic route with the enzymatic route to enantiopure (S)-2 and investigates factors determining performance and outcome of the bioreductions.

The synthesis of arylated dihydropyrans and unsaturated lactones starting from enantiomerically pure alpha-hydroxy ketones (prepared by an enzyme-catalyzed benzoin condensation) is described. The key steps are a highly diastereoselective addition of vinyl metal compounds under chelate control and a ruthenium-catalyzed ring-closing olefin metathesis reaction. Elucidation of the relative configuration of the final products was achieved by NOE experiments.