| During the course of this work the new approach toward previously unavailable configurationally stable allocolchicinoids, which are functional analogs of the important antimitotic compound (−)-colchicine, using benzannulation reaction of Fischer carbene complexes with alkynes has been developed. These compounds bear natural substitution pattern on ring A and controlled variability of functionalization on ring C and can be synthesized from 3,4,5-trimethoxybenzoic acid. Either atropisomer of allocolchicinoids can be prepared stereoselelectively, dependent on the conditions of the benzannulation reaction, by asymmetric induction from the existing center of chirality on ring B. Highly efficient central-to-axial chirality transfer under thermodynamic conditions is realized in steric vs. hydrogen bonding controlled thermal equilibration.; Successful protection-deprotection routine has been developed for the oxygen functionality on ring B. This will allow for the modification of the side chain with new substituents, which are incompatible with the carbene complex preparation conditions. Enantiomerically enriched carbene complexes are prepared from the corresponding chiral nonracemic vinyl bromides. Their benzannulation reaction affords enantiomerically enriched allocolchicinoids.; A complementary strategy is reported for the synthesis of ring C functionalized allocolchicinoids, which is based on a Diels-Alder reaction—aromatization sequence and is best applicable when electron-withdrawing substitution of ring C is desired. Properly substituted dienes, incorporating the natural substitution pattern on ring A, can be prepared from 3,4,5-trimethoxybenzoic acid. They undergo Diels-Alder reactions with various dienophiles. Subsequent aromatization affords a set of differently functionalized ring C allocolchicinoids, including those that are configurationally stable, with high regioselectively and in moderate to good yields. An intramolecular Diels-Alder reaction-aromatization sequence allows for access to allocolchicinoids with reversed regiochemical introduction of ring C substituents. Solvent-dependent equilibrium of rotamers was investigated. A regioselective Diels-Alder reaction-aromatization sequence is utilized as the key step in the first stereoselective total synthesis of (−)-allocolchicine, accomplished in 10 steps and 8% overall yield from 3,4,5-trimethoxybenzoic acid. |
