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

被引:86
作者
NICOLAOU, KC [1 ]
THEODORAKIS, EA [1 ]
RUTJES, FPJT [1 ]
SATO, M [1 ]
TIEBES, J [1 ]
XIAO, XY [1 ]
HWANG, CK [1 ]
DUGGAN, ME [1 ]
YANG, Z [1 ]
COULADOUROS, EA [1 ]
SATO, F [1 ]
SHIN, J [1 ]
HE, HM [1 ]
BLECKMAN, T [1 ]
机构
[1] UNIV CALIF SAN DIEGO, DEPT CHEM & BIOCHEM, LA JOLLA, CA 92093 USA
关键词
D O I
10.1021/ja00146a009
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
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.
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页码:10239 / 10251
页数:13
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