A strategy of tandem ketene-trapping/IMDA toward the total synthesis of the hirsutellones was attempted. The AB ring moiety of the hirsutellones was constructed with the proper tereochemistry.

Depending on the nature of the metal catalyst, ω-hydroxy propargylic acetates choose between alternative cycloetherification manifolds to produce functionalized heterocycles in high yields. AuCl catalyzes the formation of oxacyclic enol acetates, whereas [Cl2Pt(CH2CH2)]2 (Zeise’s dimer) will induce a propargylic substitution via an unprecedented SN2′-type allenic substitution from within a chelated square planar cationic Pt(II) complex.

A unique natural product termed palmerolide A was recently isolated from the antarctic marine tunicate Synoicum adareanum by Baker and co-workers.1 The structure and absolute stereochemistry of palmerolide A, expressed by formula 1 (Scheme 1), was solved by NMR studies and reveals a 20-membered macrolide decorated with a polyunsaturated N-acyl dienamine side chain distinct from the N-acyl enamine found in salicylihalamide and related natural products.2 Palmerolide is a differential cytotoxin with an activity profile that correlates to V-ATPase inhibitors.1 Subsequent in vitro studies confirmed that palmerolide A is indeed a potent inhibitor of bovine brain V-ATPase (IC50 _ 2 nM).1,3 Palmerolide was isolated from an organism found in one of the most inaccessible areas of the world, which in conjunction with commercial exploitation prohibited by the Antarctic Treaty will severely limit access to this compound from natural sources.4 Therefore, total synthesis remains as the only option to ensure investigation of palmerolide's promising antitumor properties. Herein, we present our synthetic efforts that led to the conclusion that (-)-palmerolide A is in fact a diastereomer of the proposed structure 1, that is, structure ent-24 (Scheme 4).

Platinum(II) and an unusual cationic gold(I) complex were identified as mild catalysts for the room temperature cycloisomerization or tandemhydroalkoxylation/acetal formation of unactivated internal alkynols. Under the appropriate conditions, 5-endo, 5-exo, 6-endo, and 6-exo cycloisomerization modes are all available.

An asymmetric synthesis of the backbone of the core of natural peloruside A is described. Key elements include reiterative application ofenantioselective allylation to establish the stereochemistry of the backbone and a double asymmetric aldol reaction to successfully couple two fragments.