Study On Chemoenzymatic Synthesis Of D-biotin Intermediate Lactone

d-Biotin(Vitamin H or coenzyme R)is a water-soluble vitamin B which is essential to the normal physiological activities of animals and human life.d-Biotin intermediate 1 {(3aS,6aR)-tetrahydro-1,3-dibenzylhexahydro-1H-Furo[3,4-d]imidazole-2,4-dione} is extremely vital to the synthesis of d-biotin,the main technical difficulties in the synthesis of d-biotin is the synthesis of optical purity d-Biotin intermediate(6aS,6aR)-lactone.In this paper,we described a novel chemoenzymatic synthetic route of(3aS,6aR)-lactone 1.We first obtained the diols 3 {2-Imidazolidinone,4,5-bis(hydroxymethyl)-1,3-bis(phenylmethyl)} by reducing diester 2 {4,5-Imidazoli dinedicarboxylic acid,2-oxo-1,3-bis(phenylmethyl)-4,5-dimethyl ester},then we got the(4S,5R)-monoacetate 4 {(4S,5R)-2-Imidazolidinone,4-[(acetyloxy)methyl]-5-(hydroxymethyl)-1,3-bis(phenylmethyl)} by Lipozyme RM IM catalyzed enantioselective transesterification of diols 3 in the organic solvent.Finally,the target production d-Biotin intermediate(3aS,6aR)-lactone was obtained by Jones oxidation,basic hydrolysis and lactonization.The synthesis of d-biotin intermediate lactone 1 was shown as the below scheme:We chose the synthetic route of(4S,5R)-monoacetate 4 by enantioselective transesterification of diols 3 with Lipozyme RM IM comparing with the two synthetic routes.Then we found that the best enzyme is Lipozyme RM IM,and the preferable acyl donor is vinyl acetate and the suitable organic solvent is Dioxane/Toluene(1:3).Effects of various biocatalysis parameters were studied.The optimize result was as following:the concentration of diols 3 was 100mmol/L,the ratio of diols 3 and vinyl acetate was 1:6,the concentration of enzyme was 1%,35? and 200rpm were a good choice.In this condition,the yield and e.e.of(4S,5R)-monoacetate 4 reached 90%and 98%after 6h.The enzyme activity was reserved 80%with a good selectivity after 10 cycles of reaction.