New synthesis of unnatural amino acids using methyl nitroacetate as a glycine template and efforts towards the total synthesis of geissoschizine utilizing a nickel-catalyzed cyclization

A new synthetic route has been developed that provides rapid access to an increasingly diverse range of non-natural amino acids through a direct linear sequence utilizing methyl nitroacetate as a glycine template. First, α,β-unsaturated nitroacetates were assembled utilizing the Lehnert modification of the Knoevenagel condensation, followed by an uncatalyzed 1,4 addition with an organozinc or organocuprate. The zinc compounds were prepared in situ by transmetallating an organolithium or a Grignard reagent with zinc chloride or through a zinc insertion into a carbon halogen bond using the Rieke protocol. The transmetallation-derived organozincs were reactive enough to be used without further modification, however the Rieke-derived organozincs required conversion to the corresponding cuprates. Further elaboration at the α-carbon using previously developed methods for alkylating nitroacetates, such as palladium-catalyzed allylic allylation, and phosphine promoted Michael addition to enones and acrylates, proceeded smoothly. Chemoselective reduction of the nitro moiety to the primary amine was done efficiently using Sn° in AcOH. Also, utilizing doubly 13C-labeled methyl nitroacetate, which can be synthesized from the tail-to-tail dimerization of 13C-labeled nitromethane, in the same sequence provided the corresponding doubly 13C-labeled amino acids.; Geissoschizine is a key biosynthetic intermediate for a variety of indole alkaloid families and has drawn a significant amount of attention from the synthetic community. A novel approach to the geissoschizoid skeleton has been developed utilizing the methodology previously developed in our laboratory for the nickel-catalyzed cyclization of alkynyl enoates. The synthesis proceeds by the cyclization an appropriately functionalized piperidine to produce the quinolizidine core with the necessary D-ring functionality, and the exocyclic double in the desired (E)-configuration. The piperidine was efficiently synthesized, through an ozonolysis/double reductive amination sequence, from a protected cyclopentenol. The indole moiety was regioselectively introduced into the quinolizidine core, in the epi series, using the methodology recently developed by Rawal and co-workers. This completed the formal synthesis of geissoschizine.