Total Synthesis of Brevetoxin B. 2. Completion

In the preceding communication1 we defined phosphonium salt 3 and aldehyde 2 (Figure 1) as key intermediates for the total synthesis of brevetoxin B (1) and described the construction of advanced intermediate 4 (Scheme 1 ) required for the synthesis of 3. Herein we delineate the chemistry that led to the advancement of 4 to 3» the coupling of 3 with 2, and the completion of the total synthesis of brevetoxin B (1).The initial task of completing the ABCDEFG ring framework of brevetoxin B from intermediate 4 proceeded as summarized in Scheme 1, Thus regio-and stereospeciflc epoxide opening2 by the internal hydroxyl group of 4 under acid conditions afforded 5, which was silylated to give 6 (76% over two steps).Ozonolysis of 6 led to the corresponding aldehyde 7, which was reacted with MeMgCl, and the produced alcohol was oxidized (Dess-Martin) to afford methyl ketone 8 (91% overall yield).3,4Desilylation of the latter compound with TBAF followed by esterification with bromoacetyl chloride afforded bromo ester 10 via alcohol 9 in 73% overall yield.Arbuzov reaction of 10 with (MeO)jP then led to phosphonate 1 1 , which underwent intramolecular condensation with die carbonyl group under the influence of ^E t N -LiCl5 to give lactone 12 (89% over two steps).Deoxygenation of the latter compound via a two-step reductive process (DIBAL-H followed by BF3*Et2 0 -EtaSiH) led to heptacyclic polyether 14 via compound 13 (93% overall).Finally, a conventional sequence (Li/liquid NH3 induced dcbenzylation, selective monotosylation of the primary alcohol, iodide displacement, silylation, and reaction with PI13P) afforded the requisite phosphonium salt 3 (67% overall)-3,4 X-ray crystallographic analysis6 of the crystalline iodide 18 (mp 192-193 °C, from acetonitrile) confirmed the stereochemistry of all asymmetric centers o f the brevetoxin B ABCDEFG fragments shown in Scheme 1 (see ORTEP drawing, Figure 2 ), The final stages o f the total synthesis of brevetoxin B (1) are described in Scheme 2. The ylide generated from 3 reacted with aldehyde 23 (TBS = 'BuMeaSi; TPS -'BuPh2Si) to afford the Z-ole fin 19, which without further purification was selec tively monodesilylated to furnish alcohol 20 in 75% overall yield.