Synthetic and Biological Studies of Compactin and Related Compounds. 3. Synthesis of the Hexalin Portion of Compactin

Article abstract of DOI:10.1021/jo00208a010

Several synthons for the hexalin moiety of compactin (1) have been prepared, and a procedure for production of the key alcohol 5 in enantiomerically homogeneous form is presented.Diels-Alder reaction of ethyl (Z)-crotonate and Danishefsky's diene affords cycloadduct 6 (78percent).Hydride reduction followed by silylation of the resulting primary alcohol gives enone 8 (72percent).Two-step cyclohexene annelation furnishes enone 11 (42-55percent), which is elaborated to diene 21 by using a modification of the Shapiro olefin synthesis (three steps, 60percent).Dithiane hydrolysis followed by L-Selectride (Aldrich) reduction of the resulting ketone affords axial alcohol 28.Compound 28 possesses the correct relative stereochemistry at the four contiguous asymmetric carbon atoms in the hexalin portion of 1, and the synthesis is suitable for large-scale preparation (ten steps, 10-14 percent, no isomer separations).Functional group manipulations give synthons 36-39.Acid-catalyzed dehydration of allylic alcohol 19 affords diene isomer 20 (11:1).A simple procedure for the preparation of large quantities of ethyl (Z)-crotonate is also presented.