Cephalostatin analogs

A twofold intramolecular Heck reaction of the dibromobenzene derivative 19 has been used to construct the heptacyclic skeleton 20 of cephalostatin analogs. This reaction required a precise control of the reaction time and temperature. The conversion proceeded best with a catalytic amount of the palladacycle from tris(< -tolyl)phosphine and palladium acetate, and gave exclusively (in 80% yield) the heptacycle 20 with an unusual m-annelation of the two newly formed rings (Scheme 10). ... 

Shawakfeh, KQ., Al-Said, N.H., and Al-Zoubi, R.M. (2008) Synthesis of bis-diosgenin pyrazine dimers new cephalostatin analogs. 

The right half of cephalostatin 7 was synthesized32 in an analogous manner to that of tetrahydrocephalostatin 12. The silyl ether of 55 was dihydroxylated to give a pair of inseparable diastereomers in a 4 1 ratio, the major product 57 corresponding to the natural C-25 stereochemistry (Scheme 26). However, no reaction was observed with conditions used for spiroketalization (Scheme 22, vide supra), while harsher conditions led to undesired products. As in the earlier work, the brominated derivative 58 of the desired 5/5 spiroketal was formed by treatment with NBS. A diastereomeric byproduct was also obtained, occurring from cyclization of the minor epimer of 57. 

So far, all the publications related to total synthesis have been from Fuchs group, who first reported [12] a symmetrical dimer corresponding to the right half of cephalostatin 1 but lacking the D ring alkene and C17 alcohol. The dimer can be considered an analog of cephalostatin 12, whose existence had yet to be disclosed then. 

The cephalostatins are a group of cytotoxic dimeric steroid derivatives from the marine worm Cephalodiscus gilchristi. Tietze and Krahnert prepared a group of natural product analogs using multiple Heck reactions using derivative 106 obtained from the Hajos-Wiechert reaction their approach is outlined below. ... 

Deslongchamps and coworkers [176] have used this method for the construction of the 5,5-spiroacetal in analogues of hippuristanol 362, in an analogous manner to Suarez et al. and Shair et al. s [177, 178] earlier syntheses of the cephalostatin and ritterazine scaffolds (Scheme 87). The 5,5-spiroacetals 364a and 364b were obtained as a 1 2.8 mixture in high yield. 

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