Graduate Thesis Or Dissertation
 

Studies toward the total synthesis of sanglifehrin A

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  • Studies toward synthesis of subunits of sanglifehrin A, an immunosuppressant featuring a highly substituted [5,5]-spirolactam moiety as well as a 22-membered macrocycle are described. The macrolactone contains a peptidic backbone characterized by an unusual [beta]-substituted (S)-piperazic acid and (S)-m-hydroxyphenylalanine units. These studies resulted in the synthesis of advanced intermediate 358 which contains all of the carbon atoms of the C1-C25 macrolactone of sanglifehrin A, and 251 which bears the C31-C41 carbon skeleton of the [5,5]-spirolactam moiety of sanglifehrin A. A Masamune anti-aldol reaction of aldehyde 294 and ester 285 furnished alcohol 295 in a second generation approach to carboxylic acid 242, while a third generation route toward 242 improved the yield and required fewer synthetic steps. An asymmetric, catalytic phase-transfer method was used to introduce an [alpha]-amino function into 331 in the synthesis of (S)-m-hydroxyphenylalanine derivative 244. Assembly of 244, piperazic acid 113 and L-valine derivative 336 into tripeptide 241 using a racemization-free peptide coupling method is described. The synthesis of C31-C37 aldehyde 253 exploited double asymmetric crotylation to set in place the correct configuration of alternating hydroxyl and methyl groups at C33, 34, 35 and 36.
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