Our data are consistent with the hypothesis that binding to sodium channels requires an elongated cigar-shaped molecule, approximately 30 A long. The four electrophysiological effects of the brevetoxins are not produced by a single structural feature, however, since they can be decoupled by using modified ligands, which are shown here to be partial sodium channel agonists. We propose a detailed model for the binding of brevetoxins to the channel which explains the differences in the effects of the brevetoxin analogs. These studies also offer the potential for developing brevetoxin antagonists.

No abstract

Better late than never! Two herbicidins, members of an important family of nucleoside antibiotics, have been synthesized for the first time. The route integrates a stereoselective C-glycosylation with several reagent-controlled stereoselective transformations and a surprisingly facile and highly diastereoselective late-stage N-glycosylation.

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).