SYNTHESIS APPLICATIONS OF CATIONIC AZA-COPE REARRANGEMENTS .24. THE AZA-COPE-MANNICH APPROACH TO STRYCHNOS ALKALOIDS - SHORT STEREOCONTROLLED TOTAL SYNTHESES OF (+/-)-DEHYDROTUBIFOLINE AND (+/-)-AKUAMMICINE

A direct approach for the total synthesis of Strychnos alkaloids has been developed. The key strategic element is the aza-Cope-Mannich rearrangement (Scheme II) of formaldiminium ions derived from azabicyclo[3.2.1]octanols 5 (Scheme I). This reorganization occurs with perfect stereochemical fidelity in high yield to form the intricate skeleton of this complex alkaloid group. Critical to the success of this synthesis endeavor was the evolution of an efficient sequence for assembling the azabicyclo[3.2.1]octanol rearrangement substrates (Scheme V). Using a pivaloyl group to protect the nitrogen of the aromatic ring, we prepared the akuammicine degradation product (+/-)-dehydrotubifoline in 12 chemical operations and approximately 6% overall yield from 2-cyclopentenone (Schemes VI-VIII). A related sequence that employed a tert-butoxycarbonyl group to protect the aromatic nitrogen led to the synthesis of the tetracyclic enecarbamate 63 (Scheme IX). Additional refinements of the aza-Cope-Mannich strategy allowed the total synthesis of (+/-)-akuammicine to be accomplished by way of 10 isolated intermediates and in nearly 8% overall yield from 2-cyclopentenone (Scheme X). Notable features of this final sequence are (a) the convergent carbonylative coupling of vinylstannane 64 and aryl iodide 65 to afford enone 66, (b) the use of the 1,3-dimethylhexahydro-2-oxo-1,3,5-triazine group to protect the primary aniline nitrogen, and (c) the strategic use of an intramolecular epoxide aminolysis to assemble the azabicyclooctanol 71. Incorporation of oxidation at the terminal carbon of the ethylidene appendage should allow this total synthesis approach to be extended to more complex Strychnos alkaloids such as strychnine.