Synthetic studies on laidlomycin

Abstract

Highly enantioselective synthesis of the key intermediate 258 to laidlomycin 1 was established. 258 was disconnected to give the left segment containing of protected anti-, syn-1,3,5-triol and the right segment containing 3 oxacycles: successive cis-, trans-THF ring and 6-memebered cyclic ketal.The backbone of right segment (C11-26) was achieved by two B-alkyl Suzuki-Miyaura coupling reactions. The requisite stereochemistry at C12 and C13 were secured by desymmetric benzoylation and Roush allylation respectively. cis-THF ring was obtained via both osmate-mediated oxidative cyclization route and VO(acac)2-mediated epoxidation followed by acidic cyclization route with (Z)-alkene. Shi epoxidation with (E)-alkene followed by acidic cyclization and oxidative lactonization in Anelli’s conditioin furnished desired trans-THF and lactone with high diastereoselectivity. The right segment 85 was synthesized from desymmetric benzoylation of 2-methylpropane-1,2,3-triol over 26 steps in 15% overall yield via two different epoxidation route.The left segment (C1-C10) was synthesized via Evans aldol reaction and anti-aldol coupling. The reduction of β-hydroxy ketone to anti-alcohol was conducted successfully via Evans-Tishchenko method to give 222 as a major with a 26 : 1 d.r..The key intermediate 258 was obtained in high yield via Horner-Wadsworth-Emmons reaction of 85 and β-ketophosphonate 257 derived from 222.