A macrocyclization–transannulation strategy is the crux of an efficient total synthesis of the benzolactone enamide apicularen A (see scheme; Bn=benzyl). Key steps include a four‐component coupling, a Stille cross‐coupling to introduce the aromatic moiety, and the formation of the enamide from a hemiaminal. The size‐selective macrolactonization of the ethoxyvinyl ester shown was followed by transannular etherification in excellent yield.

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...

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Reactions between amide anions and propanal derivatives containing benzolactone components at their 3‐positions produced hemiaminals, which were dehydrated via the corresponding acetates to provide the apicularen A analogues 21, 29, 34, 38, and 41. Of these, 21 and 29 contain the intact enamide side chain of apicularen A but have modifications in the macrolactone core. On the other hand, compounds 34, 38, and 41 are characterized by the natural core structure but are modified in the enamide part. Biological studies showed that 21 and 29 are quite active but that the other three analogues show only minor activities. The 11‐deoxy analogue 21 turned out to be the most active compound against a mdr cell line. It can be concluded that the macrolactone part of apicularen A will tolerate modifications to some degree, whereas the enamide part is rather sensitive towards structural modifications. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

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