The final strategy for the total synthesis of brevetoxin B (1) according to the retro synthetic analysis shown in Scheme 1 is described. Starting with the tetracyclic ring system 8 [DEFG], the construction of the C ring was accomplished via an intramolecular conjugate addition (7 -13). A hydroxy epoxide cyclization was then utilized for the formation of ring B (6 -^ 21). Ring A was introduced via an intramolecular phosphonate ester-ketone condensation (5 -*• 27) to produce, after side chain elaboration, the desired heptacyclic phosphonium iodide 4. Formation of the tricyclic aldehyde 3 [UK] starting from diol 34 is also described. Wittig coupling of 3 and 4 followed by selective deprotection, hydroxy dithioketal cyclization, and radical desulfurization produced the undecacyclic system 48 representing the complete brevetoxin B skeleton (46 -2 -47 -48). Allylic oxidation of ring A (48 49) followed by side chain elaboration of the K ring side chain (49 -* 50 -■ 51 -* 52) led to the TBS protected brevetoxin B (52) which upon exposure to HF*pyridine treatment afforded natural brevetoxin B (1).
A bstract: The first generation strategies toward the total synthesis of brevetoxin B (1) are presented and the syntheses of the key intermediates 3, 4, 5, 67, 83, and 94-98 required for the projected construction are described. The earliest and most convergent strategy required the application of the hydroxy epoxide cyclization and the intramolecular conjugate addition as key reactions for the construction of the fused tetrahydropyran ring systems (4) [ABC], (7) [FG], and (8 ) [UK], The oxocene ring (H) was formed via a Wittig reaction followed by a hydroxy dithioketal cyclization to produce the hexacyclic fragment [FGHUK] ( 6 -5), The 12-membered dithionolactone 18 was envisioned as the precursor of the dioxepane system of the molecule via a projected bridging reaction, to construct simultaneously both oxepane rings. However, the dithionation of dilactone 17 proved unsuccessful. In a subsequently evolved strategy, a new photolytic approach toward the dioxepane region was developed, starting from the acyclic dithiono progenitor 20 (20 -* 23). Application of this reaction to the brevetoxin B skeleton afforded the desired oxepene (96 -* 97), which after deprotection produced oxepanone 98. A specifically designed reductive hydroxy ketone cyclization (98 -199) was then employed in an attempt to close the remaining ring [E], but, again, without success. The novel rearrangement of hydroxy ketone 87 to the pentacyclic system 89 was observed in a less elaborate skeleton. The scope and generality of these silicon-induced reductive cyclizations are also described.
With its imposing structure, brevetoxin B (1), produced by Gymnodinium breve Davis, stood as a formidable challenge to synthetic chemists since its discovery and structural elucidation in 1981.1 Brevetoxin's beautifully arranged molecular assembly includes 11 transfused rings, each containing an oxygen atomf with each fusion consisting of a C-C bond separating two adjacent ring oxygens and with all adjacent substituents flanking the oxygens placed syn to each other except on ring K. Its unprecedented architecture, its association with the "red tide" catastrophes,2 and its potent neurotoxicity and interference with the function of sodium channels attracted serious attention from chemists3 and biologists4 alike. We now wish to announce, in this and the following communication,5 the total synthesis of brevetoxin B (1) in its naturally occurring form. Figure 1 outlines the strategic bond disconnections and retrosynthetic analysis of 1. The adopted strategy benefited from convergency (oxocene disconnections) and synthetic technolo gies developed in these laboratories specifically for constructing oxocene6 and tetrahydropyran7 systems.
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 Murai 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 6ß was then converted to the desired isomer 6a 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 of 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.
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