| Since its isolation in 2000, peloruside A (1) has been the subject of intense synthetic interest due to the combination of its stereochemically complex structure and intriguing biological activity. Published approaches to peloruside A are reviewed herein, with particular emphasis placed on the efficiency and novelty of the routes described. Comparison of these reports revealed that allylation, dihydroxylation, and aldol reactions were the most common means of introducing stereocenters.;Our convergent strategy for the synthesis of peloruside A (1) divided the molecule into two fragments, C1-C10 ketone 202 and C11-C20 aldehyde 160, both of which were efficiently accessed utilizing catalytic asymmetric methodology. The C1-C9 lactone 196, containing five stereocenters, was prepared in only six linear steps and 26% yield from meso-epoxydiol 165. The sequence featured a cobalt-catalyzed desymmetrizing Payne rearrangement and a highly diastereoselective chromium-catalyzed hetero-Diels-Alder (HDA) cycloaddition. Further elaboration of lactone 196 provided ketone 202 in a total of 11 linear steps and 12% overall yield from 165. Synthesis of the C11-C20 aldehyde 160 highlighted a novel internal opening of terminal propargyl epoxide 135, which established the C18 ethyl stereocenter. The C11-C20 aldehyde 160 was obtained in 9 linear steps and 8% yield from 1-penten-3-yne. Notably, the eight stereocenters of fragments 202 and 160 were installed without recourse to any of the reactions commonly used in other efforts toward peloruside A.;Completion of the synthesis of peloruside A (1) was also investigated. The small size of the protecting group on the C8 hydroxyl was critical for the successful union of ketone 202 with aldehyde 160 to afford the complete carbon skeleton of the natural product. Following this key fragment coupling, deprotection produced tetraol 219. Elaboration of this intermediate to peloruside A was complicated by undesired lactonization between a C1 carboxylic acid and the deprotected C5 hydroxyl. Thus, proper protection of the C5 hydroxyl has been identified as a crucial consideration for completing the synthesis of peloruside A.*.;*Please refer to dissertation for diagrams. |
