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A synthetic approach towards the cytotoxic polyene polyol macrolide amphidinolide B (1), based on elaboration of the C1C13 carboxylic acid 4 and the C14C25 alcohol 3 units, their esterification to the iodostannyl ester 2, and an intramolecular Stille sp2–sp2 coupling reaction, is described. In spite of adequate precedent and model experiments, circumstances conspired and the aforementioned coupling reaction was not realised in this case.

The C-1 ∼ C-13 segment (2) of amphidinolide B (1), a potent cytotoxic 26-membered macrolide, has been synthesized.

The C-14–C-26 segment 2 of amphidinolide B 1, a potent cytotoxic 26-membered macrolide, has been synthesized.

The C1—C13 fragment of amphidinolide B (1) was synthesized from D-erythrose (3). The Evans alkylation reaction protocol allowed the introduction of the stereogenic center at the C11 position, which was unambiguously confirmed by a single X-ray crystallographic analysis.

The total syntheses of amphidinolide B1 and the proposed structure of amphidinolide B2 have been accomplished. Key aspects of this work include the development of a practical, non-transition-metal-mediated method for the construction of the C13-C15 diene, the identification of α-chelation and dipole minimization models for diastereoselective methyl ketone aldol reactions, the discovery of a spontaneous Horner-Wadsworth-Emmons macrocyclization strategy, and the development of a novel late stage method for construction of an allylic epoxide moiety. The originally proposed structure for amphidinolide B2 and diastereomers thereof display potent antitumor activities with IC50 values ranging from 3.3 to 94.5 nM against human solid and blood tumor cells. Of the different stereoisomers, the proposed structure of amphidinolide B2 is over 12-fold more potent than the C8,9-epimer and C18-epimer in human DU145 prostate cancer cells. These data suggest that the epoxide stereochemistry is a significant factor for anticancer activity.

The C1—C13 fragment of amphidinolide B (1) was synthesized from D-erythrose (3). The Evans alkylation reaction protocol allowed the introduction of the stereogenic center at the C11 position, which was unambiguously confirmed by a single X-ray crystallographic analysis.

[reaction: see text] An asymmetric synthesis of a C(7)-C(20) synthon of amphidinolide B is described. The synthesis entails the construction of C(7)-C(13) and C(14)-C(20) fragments and makes extensive use of catalytic asymmetric bond constructions to establish the requisite stereochemical relationships. Fragment coupling proceeds by Suzuki cross-coupling and installs the trisubstituted diene unit that is among amphidinolide B's defining structural features.

The efficient synthesis of the C(19)-C(26) subunit of amphidinolide B(1) and B(2) has been completed using a boron-mediated aldol reaction. The synthesis of the C(19)-C(26) subunit of amphidinolide B(3) has also been accomplished through an unexpected anti aldol reaction using a titanium-mediated process. In addition, the first reported examples of a stereochemical discrepancy between the Evans' boron-mediated oxazolidinone and the Crimmins' titanium-mediated oxazolidinethione aldol reactions are disclosed. A working hypothesis is put forth to explain the results.

The biosynthetic origins of amphidinoide B (1) were investigated on the basis of 13C-NMR data of 13C-enriched samples obtained by feeding experiments with [1-(13)C], [2-(13)C], and [1,2-(13)C2] sodium acetates in cultures of a dinoflagellate Amphidinium sp. These incorporation patterns suggested that 1 was generated from three successive polyketide chains, an isolated C1 unit from C-2 of acetates, six branched C1 units from C-2 of acetates, and an "m-m" and an "m-m-m" unit derived only from C-2 of acetates. The labeling patterns of amphidinolide B (1) were different from those of amphidinolide H (2), a 26-membered macrolide closely related to 1.

A synthetic approach towards the cytotoxic polyene polyol macrolide amphidinolide B (1), based on elaboration of the C1C13 carboxylic acid 4 and the C14C25 alcohol 3 units, their esterification to the iodostannyl ester 2, and an intramolecular Stille sp2–sp2 coupling reaction, is described. In spite of adequate precedent and model experiments, circumstances conspired and the aforementioned coupling reaction was not realised in this case.

Regioselective hydroboration of a 4-methyl-2-alkene, oxidation of the resulting mixture of isomeric alcohols, and finally diastereoselective reduction of the ketone are the key steps in the stereoselective synthesis of C19-C26 fragment of amphidinolide B which was coupled with the C14-C18 fragment leading to the first synthesis of the entire C14-C26 moiety of this important molecule.

A novel macrolide, amphidinolide-B with potent antineoplastic activity has been isolated from the marine dinoflagellate Amphidinium sp. and its structure elucidated on the basis of spectroscopic studies.