Total Synthesis of Chiriquitoxin

Abstract

Tetrodotoxin (TTX, 1), a well-known marine natural product, was originally isolated as a toxic principle of puffer fish intoxication. The toxicity is attributed to a specific blockage for voltage-dependent sodium channels responsible for nerve and muscle excitability. Chiriquitoxin (CHTX, 2), a naturally occurring analog of TTX, was first isolated from the skin of harlequin Costa Rica frog, Atelopus chiriquiensis. The structure of CHTX including all absolute configurations was elucidated on the basis of extensive spectroscopic analyses by Yotsu-Yamashita and Yasumoto in 1990. CHTX possesses the same basic structure of TTX, except that it has a glycine residue attached to the C-11 position. Although CHTX was reported to interfere with both sodium and potassium channels, the details are still unsolved because of the limited availability of 2 from natural sources. Thus, we initiated synthetic studies toward the total synthesis of CHTX (2).

The synthesis commenced with allylic oxidation at C-5 position of hydroxylated compound 3. The resulting 9 was transformed into aldehyde 11 through epoxidation and ozonolysis of the vinyl group. Addition of lithium acetylide as a carboxylic acid equivalent to aldehyde 11gave a 10:1 diastereomeric mixture in favor of the desired product 12. Then, 12 was transformed into diacetate 15, and acetylenic moiety of 15 was cleaved with RuCl₃ and Oxone^Rfollowed by alkaline hydrogen peroxide to give the carboxylic acid intermediate, which underwent spontaneous opening of the epoxide, as expected. Subsequent silylation provided orthoester 16 in good overall yield. Selective deprotection of the acetonide and subsequent cleavage of the resulting 1,2-diol gave an aldehyde, which was protected as internal acetal.

Toward the total synthesis of CHTX (2), introduction of a glycine residue at the C-11 position by aldol reaction was examined. After one-pot transformation from trichloroacetamide of 17 into benzyl carbamate, MTM-protected aldehyde 21 was synthesized in 2 steps. Addition of lithium enolate generated from iminolactone 22 to aldehyde 21 proceeded in a highly stereoselective manner, yielding the desired anti-aldol adduct 23 as a single product. Hydrogenolytic deprotection of Cbz group of 23 and subsequent guanidinylation gave di-Boc guanidine 24. Since deprotection of the MTM group under the conventional conditions failed to give the expected alcohol, we developed a new deprotection method of MTM group by utilizing Pummerer reaction; oxidation of 24 with MCPBA was followed by treatment of the resulting sulfoxide 25 with TFAA to give mono-thioacetal 26. Then, sequential hydrolysis provided diol 27. Deprotection of all the protecting groups of 27 with aqueous HF provided 4,9-anhydroCHTX-13,6-lactone (28), which was further treated with aqueous pyridine to furnish CHTX (2). The NMR spectra of the synthesized 2 were identical to those of the natural chiriquitoxin.