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γ-Butyrolactone functionality possesses great importance in natural product chemistry and constitutes an essential part of many molecules with pharmacological applications. The existence of γ-butyrolactone ring as a constitutional unit in many natural products attracted lots of interests on the synthesis and configurational assignments of variously substituted γ-butyrolactones. In our synthetic study of massarilactone A, trans β-methyl-γ-allyl-γ-butyrolactone (3-methyl-6-hepten-4-olide) was selected to be a suitable early material. Several routes for racemic synthesis of cis and trans β-methyl-γ-allyl-γ-butyrolactone were known. At first, synthesis of optically active 3-methyl-6-hepten-4-olide was envisaged to be similar to that of eldanolide. But some preliminary work led us to realize that more efficient synthetic pathway should be devised for a large quantity of material. Here we wish to report a short and efficient synthesis of (3S,4R)-(+)-3-methyl-6-hepten-4-olide (1). In Scheme 1, commercially available (S)-(+)-3-hydroxy2-methylpropionate (2) was silylated with TBDMSCl and its ester function was reduced to aldehyde using DIBAH. Following addition of allylmagnesium bromide to the aldehyde produced a diastereomeric mixture of alcohols 3 and 4 which was easily separated by MPLC (3 : 4 = 1 : 1.4). Alcohol 3 had a right configuration for our purpose and alcohol 4 needs to be inverted at its hydroxyl site. Alcohol 3 was converted to cyanoalcohol 5 through a series of reactions including desilylation, selective tosylation and displacement to cyanide. Sequential desilylation, bismesylation and selective displacement of alcohol 4 with NaCN generated cyanomesylate intermediate which was then smoothly inverted to its acetate 6 using CsOAc. Finally, both cyanoalcohol 5 and acetate 6 were successfully transformed into the target material (3S,4R)-(+)-3-methyl-6hepten-4-olide (1) under hydrolytic condition with c-HCl. In conclusion, (3S,4R)-(+)-3-methyl-6-hepten-4-olide (1) was efficiently synthesized from (S)-(+)-3-hydroxy-2methylpropionate (2) as a staring material by 7 steps in overall yield of 37%. This protocol can also be applied effectively to the synthesis of optically active eldanolide and related compounds.

Efficient Synthesis of (3S,4R)-(+)-3-Methyl-6-hepten-4-olide