Stereoselective syntheses of the C(1)-C(9) fragments 18 and 28 of amphidinolide C have been developed. The first generation sequence involves a diastereoselective chelate-controlled [3 + 2]-annulation reaction of 6 and 7, while the second generation synthesis involves an intramolecular hetero-Michael cyclization of 8.The amphidinolides are a structurally diverse group of natural products isolated from the symbiotic marine dinoflagellate Amphidinium sp. Kobayashi and coworkers have characterized more than 30 members of this family since 1986, many of which exhibit potent cytotoxicitity against human cancer cell lines. 1 Not surprisingly, the amphidinolides have attracted considerable interest from the synthetic community. Total syntheses of many members of this class have been reported, with several resulting in stereochemical reassigments. 2 Amphidinolide C 3 (1) is one of the most cytotoxic members of this family, exhibiting in vitro cytotoxicities of 0.0058 and 0.0046 μg/mL against murine lymphoma L1210 and epidermoid carcinoma KB cells, respectively. Interestingly, the structurally related amphidinolides C2 4 (2) and F 5 (3) display significantly reduced activities against these cell lines (0.8 and 3 μg/mL, respectively, for 2; 1.5 and 3.2 μg/mL, respectively for 3), suggesting that the C(25)-C(34) side chain plays an important role in the bioactivity of amphidinolides C, C2, and F. As such, amphidinolide C is an important target for synthesis and exploration as a lead compound for drug development. Several efforts on the synthesis of 1-3 have appeared, including a report from our laboratory on the synthesis of the C(11)-C(29) fragment of amphidinolide F. 3b,6A retrosynthetic analysis of 1-3 is presented in Figure 1. We envisage that these targets can be assembled from the major fragments 4 and 5 via a late-stage cross-coupling and macrolactonization sequence (or esterification followed by macrocyclization via intramolecular cross-coupling). Both fragments 4 and 5 possess trans-tetrahydrofuran ring systems that appeared to be excellent targets for synthesis via chelate-controlled [3+2]-annulation 7 reactions of aldehydes and allylsilanes. synthesis of an advanced precursor to 4 via a [3+2]-annulation sequence. 6a At the outset, we envisaged that the C(1)-C(9) fragment 5 could be assembled efficiently via the chelatecontrolled [3+2]-annulation reaction of crotylsilane 6 9 and an appropriate aldehyde coupling partner. In practice, a first-generation synthesis of 5a (X = H) was developed that proceeds via the [3+2]-annulation reaction of 6 and 7. Owing to the length of this first generation synthesis, we also developed a second generation sequence culminating in the synthesis of 5b (X = H) via the intramolecular hetero-Michael addition of 8. Both syntheses are presented herein.Allylsilane 6 was prepared in 75-91% ee by the known enantioselective Rh(II) catalyzed insertion of the diazoester derived from 9 into the Si-H bond of phenyldimethylsilane (Scheme 1). 9 We initially targeted aldehydes 11 for use i...