908118-87-6Relevant articles and documents
Asymmetric synthesis of antimicrotubule biaryl hybrids of allocolchicine and steganacin
Joncour, Agnes,Decor, Anne,Liu, Jian-Miao,Tran Huu Dau, Marie-Elise,Baudoin, Olivier
, p. 5450 - 5465 (2008/03/12)
The asymmetric synthesis of novel axially chiral hiaryl compounds 5 a-f containing a seven- or eight-memhered heterocyclic medium ring is described. These molecules can he considered to he structural hybrids of allocolchicine- and sleganacin-lype natural products. The synthesis featured an atropo-diastereoselective biaryl Suzuki coupling in which a benzylic stereocenter efficiently transferred its stereochemical information to the biaryl axis. The coupling conditions were optimized. and two biphenylphosphane ligands (DavePhos and S-Phos) were found to give Ihe highest yields and diastereoselectivities. A three-element stereochemical model was proposed to explain the observed diastereoselectivities. In a second key step, the medium ring of the target molecules was formed by a stercoselective SN1-type cyclodehydration that probably involved a configurationally stable carbocationic intermediate, as supported by calculations. Alternatively. S N2-type cyclizations were employed on the same Suzuki coupling products to give the target molecules in a stereodivergent or stereoconvergent manner. These cyclization methods furnished the target hybrid analogues 5 a-f with ee values above 94%. All analogues were evaluated as antimicrotubule agents and against a panel of cancer-cell lines using colchicine (1) and N-acetylcolchinol (3) as references. Promising activities were found for R,a R-configured compounds 5 a, b and 5 f; in particular, ethyl analogue 5 b showed a twofold antimicrotubule activity relative to colchicine.
