TOTAL SYNTHESIS OF BREVETOXIN-B .3. FINAL STRATEGY AND COMPLETION

The final strategy for the total synthesis of brevetoxin B (1) according to the retrosynthetic 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 [IJK] 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).