A comparative analysis of the total syntheses of the amphidinolide T natural products.

In this article we compare and contrast the strategies and tactics used in the syntheses of the amphidinolide T family of natural products that have been reported by Fürstner, Ghosh and ourselves. Similar approaches to the trisubstituted THF ring present in the targets are utilized in all of the syntheses, but each strategy showcases a different means of macrocyclization.

Total syntheses of amphidinolides T1 and T4 via catalytic, stereoselective, reductive macrocyclizations.

Described in this work are total syntheses of amphidinolides T1 and T4 using two nickel-catalyzed reductive coupling reactions of alkynes, with an epoxide in one case (intermolecular) and with an aldehyde in another (intramolecular). The latter was used to effect a macrocyclization, form a C-C bond, and install a stereogenic center with >10:1 selectivity in both natural product syntheses. Alternative approaches in which intermolecular alkyne-aldehyde reductive coupling reactions would serve to join key fragments were investigated and are also discussed; it was found that macrocyclization (i.e. intramolecular alkyne-aldehyde coupling) was superior in several respects (diastereoselectivity, yield, and length of syntheses). Alkyne-epoxide reductive couplings were instrumental in the construction of key fragments corresponding to approximately half of the molecule of both natural products. In one case (T4 series), the alkyne-epoxide coupling exhibited very high site selectivity in a coupling of a diyne. A model for the stereoselectivity observed in the macrocyclizations is also proposed.

P-chiral, monodentate ferrocenyl phosphines, novel ligands for asymmetric catalysis.

Eight P-chiral monodentate ferrocenyl phosphines (1a-h) were prepared in high enantiomeric excess (>95% ee in most cases) by way of an ephedrine-based oxazaphospholidine borane complex. Primary alkyl, secondary alkyl, and substituted aromatic substituents were successfully introduced at the phosphorus center, along with ferrocenyl and phenyl groups, generating phosphines of the general structure FcP(Ph)(R) (Fc = ferrocenyl, R = aryl, alkyl). The synthetic route employed provides facile access to a previously undeveloped class of chiral monophosphines. These compounds were evaluated as ligands in asymmetric catalytic reductive coupling of alkynes and aldehydes and were found to provide the desired chiral allylic alcohols with good regioselectivity and ee in many cases and with complete (E)-selectivity (>98:2) in all cases.

Synthesis of amphidinolide T1 via catalytic, stereoselective macrocyclization.

Two nickel-catalyzed reductive coupling reactions of alkynes were instrumental in a modular, stereoselective synthesis of amphidinolide T1 (1). The C13-C21 fragment was prepared from two simple starting materials that were joined in a catalytic alkyne-epoxide fragment coupling operation, whereas an intramolecular aldehyde-alkyne reductive coupling simultaneously formed the final carbon-carbon bond of the macrocycle and established the C13 carbinol configuration with complete selectivity in the desired fashion.