Asymmetric total synthesis of highly symmetric squalene-derived cytotoxic polyethers

Abstract

The efficient total synthesis of the cytotoxic meso polyether teurilene (1), rarely occurring in nature, was achieved through the effective combination of the concept of two-directional synthesis and rhenium(VII) chemistry. In the key rhenium (VII)-promoted syn oxidative cyclization reaction of the two-directional substrate 16, trans-syn diastereoselectivity (steric control) has been observed in contrast to our early observation of cis-syn diastereoselectivities (chelation control) for bishomoallylic tertiary alcohols 24-27 possessing the neighboring tetrahydrofuran (THF) ring. This synthesis in only 10 steps from commercially available methyl tiglate is significantly shorter than the previous one requiring 25 steps. The total syntheses of four possible Cs symmetric (3 and 47-49) and one C2 symmetric (4) compounds for biogenetically squalene-derived pentaTHF polyether, glabrescol, was also achieved in relatively few steps by taking advantage of its intrinsic symmetry and one- and two-directional modes of double THF ring formations with vanadium catalyst, tert-butyl hydroperoxide (TBHP), and trifluoroacetic acid (TFA). Thus, the meso structure 3 originally proposed by Jacobs et al. has been revised to the optically pure C2 symmetric structure 4 through its enantioselective total synthesis. © 2002 Wiley-Liss, Inc.