11-Saxitoxinethanoic acid (SEA) is amember of the saxitoxin (STX) family of paralytic shellfish poisons,a nd contains an unusual CÀCb ond at the C11 position. Reported herein is atotal synthesis of SEA. The key to our synthesis lies in aMukaiyama aldol condensation reaction of silyl enol ether with glyoxylate in the presence of an anhydrous fluoride reagent, [Bu 4 N][Ph 3 SnF 2 ], whichd irectly constructs the crucial CÀCb ond at the C11 position in SEA. The Na V Chinhibitory activities of SEA and its derivatives were evaluated by means of cell-based assay. SEA showed an IC 50 value of (47 AE 12) nm,w hich is approximately twice as potent as decarbamoyl-STX (dcSTX).Saxitoxin (1;S TX;F igure 1), which was first isolated as ap aralytic shellfish poison, [1] is an inhibitor of voltage-gated sodium channels (Na V Ch). [2] So far, more than 50 analogues have been discovered [3] and they have attracted considerable interest from synthetic chemists. [1c,d,4] Among the STX analogues,o nly zetekitoxin AB (6;Z TX) [5] and 11-saxitoxinethanoic acid (7;S EA) [6] contain aC ÀCb ond at the C11 position. It is extremely difficult to understand how this CÀC bond arises in terms of proposed biosynthetic pathways for STXs. [7] We are interested in developing subtype-selective Na V Ch inhibitors,a nd in this work we focused on the synthesis of SEA (7)and its analogues as candidate Na V Ch modulators. [8] SEA was originally isolated from xanthid crab Atergatis floridus in 1995, [6] and it contains as axitoxin core with an acetic acid group at the C11 position. Then atural product is a9:1 mixture of stereoisomers.The toxicity of 7 was reported as 830 mouse units per mmol on i.p.i njection into mice,a nd corresponds to approximately one-third of the toxicity of 1. [3,6] Herein we describe the synthesis of 7 [9] and its derivatives 8 and 9.T he Na V Ch-inhibitory activity of these new STX derivatives in ac ell-based assay is also reported.We have recently developed as ynthesis of the fully protected saxitoxinol 11 [4g] by utilizing neighboring acylgroup-assisted construction of the five-membered cyclic guanidine structure in STXs under mild reaction conditions (Scheme 1). Thec ompound 11 is ak ey intermediate for the synthesis of STX and its derivatives,which have ahighly polar nature because of the two guanidine groups.W eh ave employed 11 in the syntheses of dcSTX (2), GTX III (4), and artificial STX derivatives. [4g, 8b] Herein, we envisage application of 11 to the synthesis of 7 through CÀCb ond formation at the C11 position.Regarding synthetic approaches to 7,t here are two possibilities to construct the CÀCb ond at the C11 position (Scheme 2), that is,d irect alkylation of the enolate 12 with halides in the presence of base,and Mukaiyama aldol reaction of the silyl enol ether 13 with glyoxylate.W ei nitially investigated the alkylation strategy.However,the conversions were extremely low and only trace amounts of the corresponding alkylation product were obtained.Then, the Mukaiyama aldol reaction was investigated for construc...
