Abstract
Our synthesis of the CDE ring fragment of pectenotoxin-4 utilised two key steps to make the complex bicyclic ketal unit: (i) a rhodium-catalysed vinyl group 1,4-addition as the major C-C bond forming step; (ii) a stereoselective Sharpless Asymmetric Dihydroxylation (SAD) of the resulting 1,1-disubstituted homoallylic alcohol. Subsequent acid-catalysed cyclisation afforded the desired [5,6]-bicyclic ketal of the target molecule. This methodology was shown to be compatible with the desired E ring fragment 35 in order to construct the CDE fragment 37 of pectenotoxin-4.
Highlights
We chose to use model C ring boronate 15 as a substitute for the real ABC ring fragment required in the synthesis of PTX-4 (Scheme 2)
(R)-tetrahydrofurfuryl alcohol 16 was oxidised to the corresponding aldehyde 17, and vinyl Grignard reagent was Scheme 3 Synthesis of the model E ring enone 19
We have developed a novel route to the CDE fragment (C-12 to C-30) of PTX-4
Summary
The pectenotoxins (PTXs) are a family of polyether macrolides containing a spiroketal (AB ring), three substituted tetrahydrofurans (C, E and F rings) and 19 or more stereocentres decorating the 40-carbon chain.1 These intriguing natural products were rst isolated in 1985 by Yasumoto and coworkers,2 and have been shown to exhibit potent biological activity, including selective cytotoxicity against tumour cell lines.3The architectural complexity of these highly functionalised macrolactones have garnered signi cant interest within the synthetic chemistry community,4 only two total syntheses of these molecules have been completed to date: PTX4 by Evans in 2002 (ref. 5) and PTX-2 by Fujiwara in 2014.640 EFG fragment via stereodivergent catalytic cobalt and osmium oxidative cyclisations (Scheme 1a).8The major challenge remaining in our synthesis of PTX-4 is uniting these two complex fragments to synthesise the nal [5,6]-bicyclic ketal, the D ring. A subsequent stereoselective dihydroxylation–ketalisation sequence should afford the desired [5,6]-bicyclic ketal structure of the D ring of PTX-4 (Scheme 1b).
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