Amino acid Schiff base methodology for the synthesis of glycosidase inhibitors: Polyhydroxylated pyrrolidines and indolizidines
AdvisorPolt, Robin L.
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PublisherThe University of Arizona.
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AbstractThe concise enantioselective syntheses of iminolyxitol and iminoribitol glycosidase inhibitors starting from benzophenone imines, of D-serine and L-alanine esters are presented. The reductive alkenylation of the Schiff bases followed by substrate-directed dihydroxylation and cyclization under various amino dehydration conditions (Ph₃P, CCl₄, or TEMPO oxidation/NaCNBH₃ reduction) gave the polyhydroxylated pyrrolidines in excellent overall yields (23% for 1 → 8a, 12% for 1 → 8b, 13% for 11 → 18a). In addition, synthesis of indolizidine glycosidase inhibitor 8- epi-swainsonine has been achieved. This approach featured trihydroxylated pyrrolidine 8a as an advanced intermediate in the synthesis of polyhydroxylated indolizidine alkaloid 25a, and highlighted efficiency in protecting group manipulation and stereocontrol in allylation with various allyltin reagents. In particular, a tandem protection-deprotection method converted pyrrolidine 8a to its corresponding partially protected analog which upon Swern oxidation and highly diastereoselective allylation afforded the required 3-carbon homologue. Subsequent hydroboration and cyclization furnished the polyhydroxylated indolizidine alkaloid in a limited number of steps and a good overall yield (29% for 8a → 25a). In a parallel sequence of reactions, pyrrolidine 8b was converted to 1,2-di-epi-swainsonine triacetate 25b in 32% overall yield.
Degree ProgramGraduate College