A Formal Total Synthesis of Eleutherobin Using the Ring-Closing Metathesis (RCM) Reaction of a Densely Functionalized Diene as the Key Step: Investigation of the Unusual Kinetically Controlled RCM Stereochemistry

摘要

Asymmetric oxyallylation reactions and ring-closing metathesis have been used to synthesize compound 3,a key advanced intermediate used in the total synthesis of eleuthero-bin reported by Danishefsky and co-workers.The aldehyde 6,which is readily prepared from commercially available R-(-)-carvone in six steps in 30% overall yield on multigram quantities,was converted into the diene 5 utilizing two stereoselective titanium-mediated Hafner-Duthaler oxyallylation reactions.The reactions gave the desired products (8 and 12) in high yields (73 and 83%,respectively) as single dia-stereoisomers,with the allylic alcohol already protected as the p-methoxy-phenyl (PMP) ether,which previous work has demonstrated actually aids ring-closing metathesis compared to other protective groups and the corresponding free alcohol.Cyclization under forcing conditions,using Grubbs' second-generation catalyst 13,gave the ten-membered carbocycle (E)-14 in 64% yield.This result is in sharp contrast to similar,but less functionalized,dienes,which have all undergone cycli-zation to give the Z stereoisomers exclusively.A detailed investigation of this unusual cyclization stereochemistry by computational methods has shown that the E isomer of the ten-membered carbocycle is indeed less thermodynamically stable than the corresponding Z isomer.In fact,the selectivity is believed to be due to the dense functionality around the ruthenacyclobu-tane intermediate that favors the trans-ruthenacycle,which ultimately leads to the less stable E isomer of the ten-membered carbocycle under kinetic control.During the final synthetic manipulations the double bond of ene-dione (E)-16 isomerized to the more thermodynamically stable enedione (Z)-4,giving access to the advanced key-intermediate 3,which was spectro-scopically and analytically identical to the data reported by Danishefsky and co-workers,and thereby completing the formal synthesis of eleutherobin.