Total synthesis of (-)-callystatin A

A highly convergent and stereocontrolled total synthesis of (−)-callystatin A 1, a member of the leptomycin family of cytotoxic natural products, is described in this thesis. Chapter one summarizes the biological activity, structural elucidation and efforts of several research groups toward the total synthesis of (−)-callystatin A. Chapter one also describes the structural similarities between (−)-callystatin A and (+)-discodermolide, recognition of which initiated our interest in the total synthesis. Chapter two details the Smith total synthesis of callystatin A. Our short synthesis of (−)-callystatin A focused on Julia olefination for coupling the key intermediates. Synthesis of the C(8-9) olefin was particularly challenging. The sulfone substrate (+)-144 was prone to α-elimination, which could be only partially suppressed by the addition of HMPA. The Sylvester Julia benzothiazoylyl sulfone gave no selectivity, and ultimately it was Kocienski\u27s phenyl-tetrazole sulfone used in combination with dimethoxyethane solvent which gave the best results. Synthesis of the C(12-13) double bond was accomplished by the more traditional two-step procedure of Marc Julia and Lygothe. Retrosynthetically, breaking the molecule at C(12-13) afforded aldehyde (+)-150, and sulfone (+)-151. Disconnection at the C(8-9) alkene gave aldehyde (+)-136 and sulfone (+)-144 . Further disconnection of aldehyde (+)-136 suggested a Still modified Wittig olefination for the costruction of the Z-trisubstituted double bond at C(8-9). Union of fragments (+)-144 and (+)- 136 furnished the alkene in 35% yield, as a cis/ trans mixture of C(6-7) olefins, favoring the trans by 6:1. Coupling of (+)-150 to (+)-151 to prepare the full carbon backbone entailed sulfone alkylation and sodium-mercury amalgam mediated elimination. The yoeld for the two steps was 70% with the E isomer favored 2.5:1. Oxidation of the C(17) and C(1) alcohols followed by deprotection of the C(19) alcohol gave the shortest total synthesis of (+)-callystatin A.* Synthesis of aldehyde (+)-151 exploited the Evans extended aldol reaction, which gave the entire polypropionate carbon framework in a single step. Remarkably, the extended aldol reaction proceeded without epimerization at C(16). Single crystal x-ray analysis of carbonyl (+)-91 shows that the chiral auxiliary prevents co-planar alignment of the carbonyls, making the C(16) hydrogen less acidic than conventional wisdom would suggest.* In the course of these synthetic investigations, a novel reduction was discovered. Construction of the C(15-22) fragment (+)-(151) employed successive Evans aldol reactions, followed by an unprecedented lactolization with simultaneous removal of the chiral auxiliary.* The Smith total synthesis was accomplished in 32 steps from commercially available materials, 9 steps shorter than the previously completed Kobayahi and Crimmins syntheses. The longest linear sequence was 15 steps compared with the 19 steps of Kobayashi and Crimmins. Our overall yield was 2.23% with an average yield per step of 78%. *Please refer to dissertation for diagrams