Novel approches to Strychnos and Aspidosperma alkaloids

All Strychnos and Aspidosperma alkaloids possess a core pyrrolo[2,3-d]carbazole ABCE tetracycle. In order to develop an efficient and divergent methodology for the synthesis of Strychnos alkaloids, a streamlined synthetic sequence to the ABCE tetracycle has been developed. It features a Mitsunobu activation of an N-hydroxyethyl gramine intermediate and subsequent intramolecular aza-Baylis-Hillman reaction. This method was first applied in the total synthesis of (+/-)-alstolucine B. Additional key steps in the synthesis included (1) chemoselective intermolecular and intramolecular Michael additions and (2) a Swern indoline oxidation. The second application of this method was in the first total synthesis of (-)-melotenine A, a novel rearranged Aspidosperma alkaloid with potent biological activity. Additional key steps in the synthesis included (1) a Piers annulation of a vinyl iodide and a methyl ketone to prepare the D ring and (2) a site-selective intermolecular vinylogous aldol reaction to functionalize the E ring. A unified, biomimetic approach to bis-Strychnos alkaloids has also been designed and applied to the first asymmetric syntheses of (-)-strychnogucine B, (-)-sungucine and (-)-isosungucine from (-)-strychnine in 6-8 steps. These complex alkaloids possess intriguing biological activities ranging from anti-malarial to selective cytotoxicity for cancer cells that are resistant to apoptotic stimuli. Key steps in the syntheses included (1) an optimized, DBU-mediated synthesis of isostrychnine from strychnine; (2) the Polonovski-Potier reaction of strychnine N-oxide for southern fragment activation; (3) the BF3.etherate-mediated Mannich coupling of northern and southern fragments; (4) a Cs2CO3-mediated alkene isomerization reaction; and finally (5) a NaBH3CN-mediated reduction of allylic bromides intermediates to install the requisite ethylidene moieties found in the bis-Strychnos targets. In order to gain efficient access to Aspidosperma alkaloids that possess unique architectural complexity and pharmacological activity for further study, an asymmetric domino Michael/Mannich/N-alkylation sequence for the rapid assembly of the tetrahydrocarbazole (ABE) framework of Aspidosperma alkaloids has been developed. This novel approach was utilized in the concise total syntheses of classical targets (-)-aspidospermidine, (-)-tabersonine, and (-)-vincadifformine in 10-11 steps. Additional key steps in the syntheses include (1) the ring-closing metathesis reaction to forge the dehydropiperidine D ring and (2) the Bosch-Rubiralta spirocyclization to prepare the pyrrolidine C ring. Finally, efforts toward the total syntheses of complex bis-Aspidosperma alkaloids (-)-melodinine K, (-)-conophylline, and (-)-conophyllidine are discussed. These congeners possess unique biological activities ranging from cytotoxicity to the extraordinary ability to differentiate pancreatic stem cells into beta-cells, which are responsible for the production of insulin and therefore may be used as therapy in the treatment of type 1 diabetes.