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 ,a R ‐configured compounds 5 a ,  b and 5 f ; in particular, ethyl analogue 5 b showed a twofold antimicrotubule activity relative to colchicine.