Study on Multimodule Total Synthesis of Amphidinolactone B

The 26-membered macrolide amphidinolactone B (1) was isolated from dinoflagellate Amphidinium sp. and it exhibits cytotoxicity against L1210 murine leukemia and human epidermoid carcinoma KB cell lines with IC50 values of 3.3 and 5.3 μg/mL, respectively.1 However, the absolute configuration at C6 in amphidinolactone B (1) has not been assigned. We envisioned a multimodule total synthesis of the two C6 diastereomers of 1 in order to determine its C6 absolute configuration. According to our retrosynthetic bond disconnection shown below, amphidinolactone B (1) was disassembled into five bifunctional modules (fragments) 1–5 possessing orthogonal reactivities toward modular coupling reactions. For example, our Aphos-Y–Pd(OAc)2-catalyzed B-alkyl Suzuki–Miyaura cross-coupling reaction2 between the alkyl iodide 2 and the vinyl iodide 3 should facilitate formation of the C12–C13 bond under mild reaction conditions. The acetylide 4 was used for alkylation with the alkyl triflate 3 to form the C19–C20 bond; this was followed by a second acetylide addition with the aldehyde 53 to secure the C21–C22 bond. The resultant diastereomeric propargylic alcohol among C20–C22 should undergo the Au-catalyzed Meyer–Schuster rearrangement4 to form the conjugated enone. The latter should give the keto diol upon asymmetric dihydroxylation. Synthesis of the THF-derived vinyl iodide 3 and assembling of the target molecule will be discussed.