Part I: Total Synthesis of Marine Macrolide Amphidinolide F and Synthetic Studies Toward Amphidinolide C; Part II: Computational Study on Proline Sulfonamide-catalyzed Aldol Reaction

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-C 8 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 C 9-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.