An Alternative Enzymatic Route to the Ergogenic Ketone Body Ester (R)-3-Hydroxybutyl (R)-3-Hydroxybutyrate

Recent studies have highlighted the therapeutic and ergogenic potential of the ketone body ester, (R)-3-hydroxybutyl-(R)-3-hydroxybutyrate. In the present work, the enzymatic synthesis of this biological active compound is reported. The (R)-3-hydroxybutyl-(R)-3-hydroxybutyrate has been produced through the transesterification of racemic ethyl 3-hydroxybutyrate with (R)-1,3-butanediol by exploiting the selectivity of Candida antarctica lipase B (CAL-B). The needed (R)-1,3-butanediol was in turn obtained from the kinetic resolution of the racemate achieved by acetylation with vinyl acetate, also in this case, thanks to the enantioselectivity of the CAL-B used as catalyst. Finally, the stereochemical inversion of the unreacted (S) enantiomers of the ethyl 3-hydroxybutyate and 1,3-butanediol accomplished by known procedure allowed to increase the overall yield of the synthetic pathway by incorporating up to 70% of the starting racemic reagents into the final product.

Early Steps in the Biosynthetic Pathway of Rishirilide B

The biological active compound rishirilide B is produced by Streptomyces bottropensis. The cosmid cos4 contains the complete rishirilide B biosynthesis gene cluster. Its heterologous expression in the host Streptomyces albus J1074 led to the production of rishirilide B as a major compound and to small amounts of rishirilide A, rishirilide D and lupinacidin A. In order to gain more insights into the biosynthesis, gene inactivation experiments and gene expression experiments were carried out. This study lays the focus on the functional elucidation of the genes involved in the early biosynthetic pathway. A total of eight genes were deleted and six gene cassettes were generated. Rishirilide production was not strongly affected by mutations in rslO2, rslO6 and rslH. The deletion of rslK4 and rslO3 led to the formation of polyketides with novel structures. These results indicated that RslK4 and RslO3 are involved in the generation or selection of the starter unit for rishirilide biosynthesis. In the rslO10 mutant strain, two novel compounds were detected, which were also produced by a strain containing solely the genes rslK1, rslK2, rslK3, rslK4, and rslA. rslO1 and rslO4 mutants predominately produce galvaquinones. Therefore, the ketoreductase RslO10 is involved in an early step of rishirilide biosynthesis and the oxygenases RslO1 and RslO4 are most probably acting on an anthracene moiety. This study led to the functional elucidation of several genes of the rishirilide pathway, including rslK4, which is involved in selecting the unusual starter unit for polyketide synthesis.

Pd/C-catalyzed synthesis of oxamates by oxidative cross double carbonylation of alcohols and tertiary amines through C–N bond cleavage

Palladium-catalyzed oxidative cross double carbonylation reaction between tertiary amines and alcohols using oxidant O2 and KI as the additive affords oxamates. Oxamate are as a intermediate in biological active compound and glycol synthesis.