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 b een developed. The key strategic element is the aza-Cope-Mannich rearr angement (Scheme II) of formaldiminium ions derived from azabicyclo[3. 2.1]octanols 5 (Scheme I). This reorganization occurs with perfect ste reochemical fidelity in high yield to form the intricate skeleton of t his 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 prepa red the akuammicine degradation product (+/-)-dehydrotubifoline in 12 chemical operations and approximately 6% overall yield from 2-cyclopen tenone (Schemes VI-VIII). A related sequence that employed a tert-buto xycarbonyl group to protect the aromatic nitrogen led to the synthesis of the tetracyclic enecarbamate 63 (Scheme IX). Additional refinement s of the aza-Cope-Mannich strategy allowed the total synthesis of (+/- )-akuammicine to be accomplished by way of 10 isolated intermediates a nd in nearly 8% overall yield from 2-cyclopentenone (Scheme X). Notabl e 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.