Chemoenzymatic synthesis of statine side chain building blocks and application in the total synthesis of the cholesterol-lowering compound solistatin.

The synthesis and enzymatic reduction of several 6-substituted dioxohexanoates are presented. Two-step syntheses of tert-butyl 6-bromo-3,5-dioxohexanoate and the corresponding 6-hydroxy compound have been achieved in 89% and 59% yield, respectively. Regio- and enantioselective reduction of these diketones and of the 6-chloro derivative with alcohol dehydrogenase from Lactobacillus brevis (LBADH) gave the (5S)-5-hydroxy-3-oxo products with enantiomeric excesses of 91%, 98.

Chemoenzymatic synthesis of the chiral side-chain of statins: application of an alcohol dehydrogenase catalysed ketone reduction on a large scale.

The chemoenzymatic synthesis of the tert-butyl (S)-6-chloro-5-hydroxy-3-ketohexanoate is described. Our approach relies on a highly regio- and enantioselective reduction of a beta,delta-diketohexanoate ester catalysed by NADP(H)-dependent alcohol dehydrogenase of Lactobacillus brevis (LBADH). A detailed description of the scale-up of the enzymatic synthesis of the hydroxyketo ester is given which includes a scale-up of the substrate synthesis as well, i.

Directed evolution of an industrial biocatalyst: 2-deoxy-D-ribose 5-phosphate aldolase.

Aldolases are emerging as powerful and cost efficient tools for the industrial synthesis of chiral molecules. They catalyze enantioselective carbon-carbon bond formations, generating up to two chiral centers under mild reaction conditions. Despite their versatility, narrow substrate ranges and enzyme inactivation under synthesis conditions represented major obstacles for large-scale applications of aldolases.

Enzyme-catalyzed regio- and enantioselective ketone reductions.

In this chapter, examples are given of the application of highly reactive prochiral ketones as substrates for enzymatic reductions. 3,5-Dioxocarboxylates are polyketide-like compounds that can be used to synthesize all of the possible stereoisomers of the corresponding 1,3-diols by means of regio- and enantioselective enzymatic reduction. The results obtained from an investigation into the usefulness of the resulting hydroxyl ketones and 1,3-diols in organic synthesis led to the development of non-natural functionalized ynones as a starting material for the enzymatic route to enantiopure propargylic alcohols.

Asymmetric total synthesis of (-)-callystatin A and (-)-20-epi-callystatin A employing chemical and biological methods.

An efficient asymmetric total synthesis of the potent cytotoxic marine natural product (-)-callystatin A and its 20-epi analogue has been achieved. The synthetic pathway involved the preparation of three fragments to be coupled with each other at the end of the route. The first fragment 3 was obtained using a biocatalytic enantioselective reduction of a 3,5-dioxocarboxylate as the key step.

Asymmetric total synthesis of (-)-callystatin A employing the SAMP/RAMP hydrazone alkylation methodology.

[structure: see text] The asymmetric total synthesis of (-)-callystatin A has been achieved. The key steps generating the stereogenic centers rely on the asymmetric alpha-alkylation of aldehydes or ketones exploiting the SAMP/RAMP hydrazone alkylation methodology, as well as an enzymatic enantioselective reduction of a 3,5-dioxocarboxylate. For the construction of the alkene moieties, highly selective Wittig or Horner-Wadsworth-Emmons reactions were employed.

Diastereomer-differentiating hydrolysis of 1,3-diol-acetonides: a simplified procedure for the separation of syn- and anti-1,3-diols.

[reaction: see text] A new method to facilitate the separation of diastereomeric syn- and anti-1,3-diols is described. The method relies on the different hydrolysis rates of the corresponding diastereomeric acetonides. Treatment of a dichloromethane solution of syn- and anti-1,3-diol-acetonide with a catalytic amount of diluted aqueous hydrochloric acid leads to the selective cleavage of the anti diastereomer.