Central-to-axial chirality transfer in the benzannulation reaction of optically pure Fischer carbene complexes in the synthesis of allocolchicinoids

A method for the synthesis of allocolchicinoids is explored that involves the benzannulation reaction of Fischer chromium carbene complexes with alkynes. The benzannulation reaction is employed to install the aromatic C-ring via the reaction of an α,β-unsaturated carbene complex in which the carbene complex is attached to a seven-membered ring that is to become the B-ring of the allocolchicinoids. Two different regioisomeric series can be accessed depending on which position the carbene complex is on the seven-membered ring. A key issue that is addressed is the stereochemistry of the newly formed axis of chirality that results from a stereo-relay from an existing chiral center on the seven-membered ring at the position destined to be C(7) in the allocolchicinoids. The level of stereochemistry is dependent on the position of the carbene complex on the seven-membered ring. A mechanism is proposed to account for this stereochemical dependence and to account for the observed effects of temperature and solvent on the stereoselectivity. Finally, the benzannulation reactions of optically pure complexes are examined and quite surprisingly one, but not both, of the diastereomeric products is racemized. The racemization can be prevented with the proper choice of solvent and temperature. A mechanism is proposed to account for the racemization of only one of the diastereomers of the product that involves the intermediacy of an o-quinone methide chromium tricarbonyl complex.

The optical purity of the carbene complex is lost in only one of the two diastereomeric products which is attributed to the intermediacy of an o-quinone methide chromium tricarbonyl complexed intermediate.