Total Synthesis of Pectenotoxin‐2

Abstract

Pectenotoxin-2 (PTX2) is a shellfish toxin and has a non-anomeric spiroacetal, which is not stabilized by an anomeric effect. The selective construction of the non-anomeric spiroacetal has been a major problem in the synthesis of PTX2. Described herein is the stereoselective total synthesis of PTX2 via the isomerization of anomeric spiroacetal pectenotoxin-2b (PTX2b). The synthesis of PTX2b was achieved by a simple process including sulfone-mediated assembly of spirocyclic and bicyclic acetals and subsequent macrocyclization by ring-closing olefin metathesis. Finally, the selective construction of PTX2 was accomplished by the early termination of a dynamic transition process to equilibrium in the acid-catalyzed isomerization of anomeric PTX2b. [6,6]-Spiroacetal pectenotoxin-2c (PTX2c) was also synthesized from PTX2b. The cytotoxicity assay of the synthetic compounds against HepG2 and Caco2 cancer cells showed a potency of the order: PTX2≫PTX2b>PTX2c.

Pectenotoxin's ABCDE Ring System: A Complex Target to Test the Potential of Singlet Oxygen Super Cascades as Tools for Synthesis

“…The C7 center is readily epimerizable and its configuration changes www.eurjoc.orgfrom substrate to substrate, as evidenced by previous syntheses. [3][4][5] The structure and stereochemistry of product 2b were confirmed by undertaking a series of 1 H COSY, HMBC, HSQC, NOESY, and NOE experiments. Thus, the ambitious super cascade had worked, and the product it produced (i.e., 2b) represents the ABCDE ring skeleton of the pectenotoxins, albeit with the incorrect stereochemistry at C11; this fault was introduced by limitations to classical chemistry earlier in the substrate synthesis, not by the highly effective super cascade.…”

“…[3] Very recently, a total synthesis of PTX-2 was also achieved by Fujiwara et al [4] In addition to these complete works, substantial advances towards various fragments (within the A to F ring sections of the pectenotoxins) have been made by a number of other groups. [5] Our goal was a little different; we sought to use this complex and synthetically challenging structure as the testing ground to prove that nonclassical strategies that employ singlet oxygen have significant potential in synthesis and are not just limited to simple examples or situations.…”

The chemistry of the carbon-transition metal double and triple bond: Annual survey covering the year 2014

“…306) [766], the macrolactone fragments of FD-891 and FD-892 [767], 6-deoxypladienolide D [768], iriomoteolide 3a [769], aspicilin [770], cryptosporiopsin A [771], and aspergillide B (proposed and revised structures) [772]; (10) a macrocyclic lactone conjugated diyne system for preparation of ivorenolide B (e.g. 307) [773]; (11) a macrocyclic lactone bridged by several O-heterocyclic ring systems for total synthesis of pectenotoxin-2 [774]; (12) a macrocyclic lactone-pyrrolophane systems (e.g. 308)…”

Cobalt versus Osmium: Control of Both trans and cis Selectivity in Construction of the EFG Rings of Pectenotoxin 4

“…[2] Given their intriguing structure and biological activity it is not surprising that the pectenotoxins have attracted the interest of synthetic organic chemists.Despite the fact that an impressive set of synthetic methods have been focused on preparing these natural products [3] there have only been two successful syntheses of any pectenotoxins to date,b yE vans (PTX-4) [4] and Fujiwara (PTX-2). [5] We were attracted to the pectenotoxins because of the prevalence of multiply substituted THF rings bearing arange of stereochemical arrangements (compare rings C, Eand F). These targets provide ac hallenging test for methodology we have developed which uses catalytic osmium to construct THF rings with ah igh degree of stereochemical control.…”