Amphidinolide E (1) is a unique 18-membered macrolide isolated from the Y-5' strain of the dinoflagellate Amphidinium sp. [1] It exhibits cytotoxic activity against L1210 (IC 50 = 2.0 mg mL À1 ) and L5178Y (IC 50 = 4.8 mg mL À1 ) murine leukemia cells in vitro. Owing to its unique structural features and limited availability, amphidinolide E (1) has been the target of intense synthetic studies. [2] We report herein the results of our recent efforts towards the total synthesis of 1.
According to our retrosynthetic analysis, 1 could be synthesized by lactonization of the seco acid A, which we intended to prepare by the Julia coupling of fragments B and C. In this way, potential problems arising from the intrinsic lability at C2 of 1 would only be faced at the end of the synthetic sequence. We also decided to introduce the triene side chain relatively early in the synthesis, thus forestalling difficulties which might arise from manipulations of the unstable macrolide intermediates. Fragment B may be obtained from the known tartrate acetonide precursors, and fragment C may be prepared from fragment D. Fragment D may in turn be obtained by radical cyclization of the b-alkoxy acrylate derivative E, which should be accessible from fragment F (Scheme 1).
For the synthesis of fragment B, methyl (S)-3-hydroxy-2methylpropanoate (2; commercially available) was converted into the corresponding TBDPS ether, from which vinyl boronic acid 3 was obtained through reduction, oxidation, Corey-Fuchs homologation, [3] and hydroboration-hydrolysis. [4] Suzuki coupling [5] of 3 with the known vinyl iodide 4 [6] proceeded smoothly, and the resulting diene was transformed into aldehyde 5 by removal of the TBS protecting group and oxidation (Scheme 2).
The known diol 6 [7] served as the starting material in the synthesis of fragment C. DDQ oxidation of 6 provided the corresponding PMP cyclic acetal, which was converted into aldehyde 7 by MOM protection of the remaining hydroxy group and reduction with DIBAL. Roush crotylation [8] of 7 by treatment with boronate 8 provided a product mixture that contained mainly the desired homoallylic alcohol 9 (d.r. 16:1). TIPS protection of 9 and oxidative deprotection of the acetal with CAN produced diol 10. Selective tosylation of the primary hydroxy group in 10, treatment with ethyl propiolate, and substitution of the tosylate group with iodide led to the balkoxy acrylate 11. Radical cyclization [9] of 11 proceeded smoothly in the presence of tris(trimethylsilyl)silane and triethylborane, and the oxolane product 12 was obtained in high yield (Scheme 3). Hydroboration-oxidation of alkene 12 produced the corresponding primary alcohol, which was converted into the corresponding aldehyde. At this point, a variety of methods were tested to find an effective way to build up the Scheme 1. Retrosynthetic analysis of 1.