A synthesis of an amphidinolides G and H C3-C18 subunits is reported. The C10-C18 segment 4 was prepared by a Negishi cross-coupling, whereas the synthesis of the C3-C9 fragment 5 employed an asymmetric cyanosilylation as the key step. The two segments were coupled by lithiation of iodide 4 and trapping of the anion with amide 5. The allylic epoxide moiety could be synthesized from the protected anti-mesylate 22.The amphidinolides are a structurally diverse group of bioactive secondary metabolites isolated from the symbiotic marine dinoflagellate Amphidinium sp. 1 Amphidinolides G (1) and H (2) are polyketide-based 27-and 26-membered macrolides, respectively, that were first isolated in 1991 by Kobayashi et al. 2 These two compounds putatively arise from the same seco acid. The gross structures of 1 and 2 have been elucidated primarily by means of 2D NMR data, whereas the absolute stereochemistry was determined on the basis of X-ray diffraction analysis and degradation 3 (Figure 1).Both amphidinolides G (1) and H (2) were shown to be among the most potent cytotoxic amphidinolides. Whereas amphidinolide H (2) exhibits extremely potent cytotoxic activity against L1210 murine lymphoma and KB epidermoid carcinoma cells (IC 50 = 0.00048 and 0.00052 µg/mL, respectively), amphidinolide G (1) showed approximately a 10-fold decrease in activity with IC 50 values of 0.0054 and 0.0046 µg/mL, respectively. 4 Amphidinolide H (2) has been implicated in binding to actin subdomain 4 as a potential mode of action. 5Because of their remarkable biological activity and challenging structure, amphidinolides G and H represent an attractive target for synthetic efforts. Although several syntheses of fragments of amphidinolides G and H and the structurally related amphidinolide B have been published, 1,6,7 to our knowledge no total synthesis of either of these amphidinolides has been accomplished so far.Our proposed synthetic route to amphidinolide H (2) divides the structure into the three major fragments 3, 4, and 5, allowing a convergent assembly of the molecule (Figure 2). To couple these fragments, we could establish the bond between C9 and C10 by nucleophilic addition of an alkyl-lithium species derived from fragment 4 into Weinreb amide 5. We propose an aldol coupling to construct the C18-C19 bond and a Wittig olefination with commercially available craig.crews@yale.edu. Supporting Information Available: Experimental procedures and characterization data for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript ylide 6 across C2 and C3. Finally, a macrolactonization should complete the carbon skeleton of amphidinolide G (1) or amphidinolide H (2).Our synthetic efforts toward the C10-C18 fragment 4 began with ketone 7, which was prepared from (-)-pseudoephedrine propionamide under the conditions developed by Myers 8 (Scheme 1). Ketone 7 was further elaborated to propargylic alcohol 8...