Synthesis of an enantiomerically pure sterol side‐chain precursor by enantioselective reduction of 1,3‐dihydroxy‐3‐methyl‐2‐butanone with baker's yeast

Abstract

Sterol side-chain precursor 1,3-Dihydroxy-3-methyl-2-butanone (l), accessible in 5 steps from 2-methyl-3-butyn-2-01, is reduced by baker's yeast to (R)-(+)-3-methyl-1,2,3-butanetriol (2) with a high enantioselectivity. This chiral building block for the synthesis of various sterols with a modified side chain thus becomes available in 73% yield with an enantiomeric excess of 90%.(R)-( + )-2,3-Dihydroxy-3-methylbutyl p-toluenesulfonate (3) is a preferred side-chain precursor for the synthesis of (24R)-24,25-dihydroxy vitamin D3'-'). It is prepared by tosylation of the triol 2, a homochiral compound available in 7 steps from the chiral pool starting from D-mannitol's4,5). Being interested in a reduction of the reaction steps and an improvement of the overall yield, we have elaborated an alternative to the established reaction sequence. 3The reduction of the ketone 1 with baker's yeast (Saccharomyces cerevisiae) affords the desired triol 2 in a yield of 73% with an enantiomeric excess of 90%. This product is easily converted into the desired enantiomerically pure tosylate 3 in a yield of 70% by reaction with p-toluenesulfonyl chloride in pyridine and recrystallization from benzene". The optical purity has been determined by polarimetry and differential scanning calorimetry 'I.The starting ketone 1 is available in five steps from the industrially produced 2-methyl-3-butyn-2-01 via 1 -bromo-3-methyl-l -butyn-3-o17), 4-bromomethylene-5,5-dimethyl-1,3-dioxolane8)', l-bromo-3-hydroxy-3-methyl-2-butanone8), and l-acetoxy-3-hydroxy-3-methyl-2-butanone') in an overall yield of 60%.It seems worth mentioning that the preferred formation of the (R)-trio1 2 does not correspond to Prelog's according to which the ( S ) enantiomer should be obtained. ExperimentalMelting points were determined on a Boetius micro melting point apparatus and are corrected. -Optical rotations were measured at 546 and 578 nm in a I-dm cell using a photoelectric polarimeter Polamat A (Carl Zeiss, Jena) and extrapolated to 589 nm. -Differential scanning microcalorimetry (DSC) 12313) was performed with a DSC-1B (Perkin-Elmer). -'H-NMR spectra were recorded at 100 MHz with a Tesla BS-567 spectrometer with tetramethylsilane as internal standard. -Celite (Type 545; Serva, Heidelberg) was used for filtration and silica gel 60 (0.063-0.2 mm; E. Merck, Darmstadt) for column chromatography.(R)-( + )-3-Methyl-1,2,3-butanetriol(2): Fresh baker's yeast (Saccharomyces cerevisiae; 25.0 g) was suspended in a solution of sucrose (37.5 g) in water (200 ml) by stirring at 30°C. After 1 h, the dihydroxy ketone 1 (1.25 g, 10.6 mmol), dissolved in water (5 ml), was added slowly within 60 min. The reaction mixture was stirred at 25-30°C for 24 h, then a second portion of sucrose (37.5 g) in water (125 ml) and a second portion of 1 (1.25 g, 10.6 mmol) in water (5 ml) were added. After a total incubation time of 3 d, the reaction mixture was stirred for 30 min with Celite (10 g) and filtered. The filtrate was continuously extracted for 30 h with ethyl acetate in a percolator....