Graduation date: 1992

More than 30 members of the diverse amphidinolide family of biologically active macrolides have been isolated over last three decades. From this family, amphidinolides C and F stand among the most complex and densely functionalized affiliates. Recently, we have accomplished the first total synthesis of amphidinolide F. The all-carbon framework of amphidinolide C has been synthesized. During endeavor toward the total syntheses of amphidinolides F / C, we have uncovered a "hidden symmetry element" present in the northern and southern domains of amphidinolides F / C. The southern C₁-C₈ and northern C₁₈-C₂₅ tetrahydrofuran segments were derived from a common intermediate. A scalable silver-catalyzed isomerization / cyclization on propargyl-benzoate / diol furnished the common intermediate in multigram quantity. The common intermediate provided access to over half of carbon backbone of the macrocycle as well as majority of stereochemistry present in amphidinolides F / C. Two strategically different techniques have been developed for the C₉-C₁₁ diene preparation. A metal-catalyst free Weinreb amide-vinyl lithium coupling / methylenation sequence furnished the diene motif. Alternately, diastereoselective addition of a dienyl iodide derived 2-lithio-1,3-diene species to an α-oxy aldehyde installed the C₉-C₁₁ diene and secured the C₈ stereochemistry in single operation. The dienyl iodide was prepared via a regioselective hydrostannylation on an enyne. A challenging alkylation between an α-branched sulfone and an α-silyloxy iodide generated the all-carbon frameworks of amphidinolides F / C. An efficient oxidative desulfurization incorporated the carbonyl moiety at C₁₅. The protecting group on C₁₈ alcohol was found to have significant effect on the sulfone-iodide alkylation / oxidative desulfurization sequence. Installation of chelating ethoxyethyl ether on C₁₈ alcohol helped the successful incorporation of C₁₅ ketone and solved the deprotection problem in advanced stage of synthesis. A detailed analytical and computational study on proline sulfonamide-catalyzed aldol reactions has been performed. The pKa value of a proline sulfonamide catalyst was determined experimentally via NMR titration technique. Computational study revealed the origin of enhanced stereoselectivity by proline sulfonamide catalysts over parent proline. The non-classical hydrogen bonding interactions were found to be responsible for improved diastereoselectivity. / Graduation date: 2013

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. / Graduation date: 2013