Unified Synthesis of 10-Oxygenated Lycopodium Alkaloids: Impact of C10-Stereochemistry on Reactivity.

The pronounced impact of the C10 stereochemistry on the successful construction of a polycyclic Lycopodium alkaloid scaffold has been explored. A wide range of reaction conditions and functionality were investigated to control a keto sulfone Michael addition to construct the C7-C12 linkage. An unexpected, overriding impact of the C10 stereochemistry in stereoselectivity and reaction rate in the Michael addition was observed. Furthermore, divergent reactivity of a conformationally accelerated, intramolecular Mannich cyclization based on the C10 stereochemistry was discovered. The successful execution of this synthetic route resulted in the total synthesis of all three known 10-oxygenated Lycopodium alkaloids: 10-hydroxylycopodine, paniculine, and deacetylpaniculine.

Enantioselective approach to quinolizidines: total synthesis of cermizine D and formal syntheses of senepodine G and cermizine C.

The formal syntheses of C5-epi-senepodine G and C5-epi-cermizine C have been accomplished through a novel diastereoselective, intramolecular amide Michael addition process. The total synthesis of cermizine D has been achieved through use of an organocatalyzed, heteroatom Michael addition to access a common intermediate. Additional key steps of this sequence include a matched, diastereoselective alkylation with an iodomethylphenyl sulfide and sulfone-aldehyde coupling/reductive desulfurization sequence to combine the major subunits. The utility of a Hartwig-style C-N coupling has been explored on functionally dense coupling partners. Diastereoselective conjugate additions to α,ß-unsaturated sulfones have been investigated, which provided the key sulfone intermediate in just six steps from commercially available starting materials. The formal syntheses of senepodine G and cermizine C have been accomplished through an intramolecular cyclization process of a N-Boc-protected piperidine sulfone.

Stereoselective synthesis of the eastern quinolizidine portion of himeradine A.

The synthesis of the C(15)-C(17)/N(1')-C(11') quinolizidine portion of himeradine A is disclosed. An intramolecular, heteroatom Michael addition was employed to establish the C(6') stereogenic center with high diastereoselectivity. The quinolizidine ring was constructed using microwave-induced cyclization at the N(1')-C(2') position. The C(17) stereogenic center was introduced through a diastereoselective Overman rearrangement.

Improved protocol for asymmetric, intramolecular heteroatom Michael addition using organocatalysis: enantioselective syntheses of homoproline, pelletierine, and homopipecolic acid.

An improved protocol for the construction of enantioenriched pyrrolidine, indoline, and piperidine rings using an organocatalyzed, intramolecular heteroatom Michael addition is described. Application to the enantioselective synthesis of homoproline, homopipecolic acid, and pelletierine has been accomplished.