| Part one. New methodology has been devised for the generation and subsequent cyclization of iminyl and amidyl radicals under mild conditions. The process involves either the treatment of oximes with 2,6-dimethylbenzenesulfinyl chloride, or the treatment of hydroxamic acids with t-butylsufinyl chloride (-50°C to room temperature), to give the corresponding nitrogen radicals, followed by cyclization onto pendant olefins. Radical traps can be used to terminate the cyclizations, thus introducing functionality that provides multiple options for further manipulation. In a more convenient procedure, both the iminyl and amidyl radical cyclizations can be initiated using commercially available diethyl chlorophosphite which generally provides similar or significantly higher yields of products. This new variation of the methodology was successfully applied to a formal total synthesis of the alkaloid peduncularine. The key intermediate 114 was synthesized in only 4 steps in 35% overall yield, compared to the original 12 steps, 6% overall yield.; Part two. In work directed towards the total synthesis of the marine alkaloid chartelline A (1), a model system 50 containing a spirocyclic beta-lactam moiety and alpha,beta-unsaturated imine was constructed from isatin in 5 steps. In this synthesis, a Staudinger imine-ketene cycloaddition and a chemoselective addition of lithio t-butylacetylide to an N-activated gamma-lactam were used as key steps.; A convergent retrosynthetic strategy was investigated, in which indole 56 containing a spirocyclic beta-lactam, and imidazole 57 with a C-9 quaternary center are to serve as the key intermediates. The requisite starting 4,5,6-tribromoisatin (86) was produced in 6 steps and 52% overall.; We then developed an efficient procedure for synthesis the imidazole subunit 57 starting from histidine in 11 steps and 20% overall yield. In this approach, a dimethylation of imidazole ester 131, a Stille cross-coupling of imidazole bromide 137, and a one-carbon homologation of alpha-gem-dimethyl aldehyde 140 to imidazole alkyne 145 served as key steps.; Some preliminary studies on the coupling of model indole subunit 146 and imidazole subunit 145 were performed, giving the desired vinylogous amide 148 in good overall yield. Effort will now be made to explore the macrocyclization of vinylogous amide 148 and to subsequently complete a total synthesis of chartelline A. |
