Asymmetric synthesis of antimicrotubule biaryl hybrids of allocolchicine and steganacin.
The asymmetric synthesis of novel axially chiral biaryl compounds 5 a-f containing a seven- or eight-membered heterocyclic medium ring is described. These molecules can be considered to be structural hybrids of allocolchicine- and steganacin-type 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 the 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 stereoselective S(N)1-type cyclodehydration that probably involved a configurationally stable carbocationic intermediate, as supported by calculations. Alternatively, S(N)2-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,aR-configured compounds 5 a, b and 5 f; in particular, ethyl analogue 5 b showed a twofold antimicrotubule activity relative to colchicine.
Joncour
Agnès
A
Institut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France.
Décor
Anne
A
Liu
Jian-Miao
JM
Dau
Marie-Elise Tran Huu
ME
Baudoin
Olivier
O