Convergent syntheses of polycyclic ethers. Illustrations of the utility of acetal-linked intermediates

Abstract

One of the most characteristic and spectacular class of compounds isolated from marine sources is the polycyclic ethers. Following the initial report of the structural determination of brevetoxin B, a variety of novel polycyclic ethers have begun to surface. These natural products include ciguatoxins, gambierol, gambieric acids, yessotoxins and gymnocins, each of which exhibit distinct biological properties such as cytotoxicity and neurotoxicity, as well as antiviral and antifungal activities. Because of these intriguing biological activities and their complex molecular architecture, the total synthesis of these compounds has been pursued by many laboratories over two decades. In particular, the development of novel convergent strategies to assemble the structural fragments is crucial for the successful construction of these nano-scale molecules. This Perspective will focus on a recent convergent methodology using an acetal-linkage as a key motif. Application of this methodology culminated in the total syntheses of gambierol and ciguatoxin CTX3C.

Total synthesis of ciguatoxin CTX3C: a venture into the problems of ciguatera seafood poisoning

“…The synthetic CTX3C was determined to be identical to the naturally occurring form in every respect, which confirmed the absolute stereochemistry of ciguatoxins 25. Thus, the power of our unified convergent [X + 2 + Y] coupling strategy31,32 for constructing the large and complex ladder‐like polyether system33,47 was clearly demonstrated.…”

“…Condensation of 1,4‐diol 13 and aldehyde 36 using catalytic Sc(OTf) 3 successfully delivered seven‐membered acetal 37 43. A reagent combination of Me 3 SiOTf and Me 3 SiSPh in the presence of 2,6‐di‐ t ‐butyl‐4‐methyl pyridine (DTBMP) cleaved the acetal of 37 to form O , S ‐acetal 38 through the regioselective cleavage of the less hindered CO bond 46,47. The C49‐spiroacetal remained intact in this acetal cleavage reaction.…”

“…First‐generation total synthesis demonstrated the power of the O , S ‐acetal strategy to build complex polyether structures 47. In order to synthesize ciguatoxin congeners with acid‐sensitive functionalities, such as CTX ( 4 ), we developed an alternative, direct, and milder route to the O , S ‐acetal without using highly acidic conditions.…”

Evolution of a Practical Total Synthesis of Ciguatoxin CTX3C

“…[19][20][21][22][23][24] The 12 ether rings, ranging from six-to nine-membered, are fused in a trans/ syn manner, and the five-membered ring is spirally attached at the end. Owing to the size and complexity of the molecule, efficient assembly of the structural fragments is crucial for its successful construction.…”

Phenylselenylation of Ethers using Diphenyl Diselenide–Tributylphosphine–Molecular Oxygen System under Mild Reaction Conditions

“…[1] For example,s elenoxides are often used for the stereoselective construction of olefins through the syn-selective b-elimination reactions. [3] Therefore, a-phenylselenyle thers have been utilized as key intermediates in total syntheses of naturalp roducts such as polyether antibiotics [4] and polyoxygenated diterpenes [5] etc. [3] Therefore, a-phenylselenyle thers have been utilized as key intermediates in total syntheses of naturalp roducts such as polyether antibiotics [4] and polyoxygenated diterpenes [5] etc.…”