TOTAL SYNTHESIS OF BREVETOXIN-B .2. 2ND GENERATION STRATEGIES AND CONSTRUCTION OF THE DIOXEPANE REGION [DEFG]

The second generation strategy for the total synthesis of brevetoxin B (1) is presented. According to this strategy, the heptacyclic [ABCDEFG] phosphonium iodide 4 and the tricyclic [IJK] aldehyde 3 were defined as the precursors for the brevetoxin B skeleton. The Yamaguchi lactonization was successfully applied for the formation of the [EFG] and [DEFG] lactones (15 --> 7) and (29 --> 6), respectively. The required appendage on ring [E] was efficiently introduced via a Mural coupling, involving addition of a higher order organocuprate derived from iodide 20 to the lactone-derived enol triflate 16 (16 --> 25). The minor epimer of the resulting product 6 beta was then converted to the desired isomer 6 alpha via hydrogenation using an Ir(I) catalyst. A number of approaches were considered for further elaboration of lactone 6. Among them a convienient Cr/Ni-promoted coupling reaction was developed and applied to the introduction of the side chain on ring D. The scope and generality df this reaction was examined with a variety of aldehydes (e.g., 39, 59, and 62). Construction of 38 was thus achieved from vinyl triflate 36 and the ring B aldehyde 39. However, the projected intramolecular Michael addition (41 --> 42) and reductive hydroxy ketone cyclization (47 --> 48) failed to yield ring C. Fetizon cyclization afforded the pentacyclic lactone [CDEFG] (51 --> 52), which resisted further useful functionalization. Using the more elaborate aldehyde 62, the Cr/Ni coupling reaction afforded allylic alcohol 64, which then served as a precursor to the pentacyclic lactol 80. The latter compound also resisted advancement to more elaborate intermediates, leading to abandonment of this approach and the formulation of a new strategy.