Studies toward the total synthesis of azaspiracid-1 Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/cj82k955z

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  • Azaspiracid has generated an enormous amount of scientific interest in the fourteen years since its initial discovery. The structure contains a 6,5,6 bis-spiroketal, a [3.3.1] bicyclic ketal and a 6,5-spiroaminal linkage as key moieties. With 9 rings, 20 stereocenters and three alkenes, the azaspiracid immediately attracted the interest of the synthetic community. To date, two syntheses have been reported by the Nicolaou and Evans laboratories. An initial route to the C13-C19 aldehyde was plagued by a problematic 1,2 silyl migration. An improved route to the C13-C19 aldehyde was developed based on a modified protecting group strategy utilizing a PMP ketal. The improvements in the synthesis led to facile production of 250 mg of the key transoidal ABC ring bisspiroketal. This second generation route dramatically improved the efficiency of our synthesis, with the overall yield for the C13-C19 aldehyde increasing from 2% to 15%, which allowed the synthesis of over 250 mg the bisspiroketal. An optimized route to the FGHI spiroaminal was developed. A unique equilibration method for the construction of the anomerically-stabilized spiroaminal was discovered. After cleavage of the Cbz carbamate, an in situ tautomerization provided the desired doubly anomeric FGHI spiroaminal subunit. This transformed a total synthesis of FGHI spiroaminal into a process which could easily produce gram quantities of advanced intermediates requisite for the synthesis of azaspiracid. With an optimized synthesis of the FGHI ring system complete, a host of routes were investigated for the coupling of the C26-C40 fragment and C20-C25 fragment was developed. The C25-C26 bond was formed via an aldol condensation between FGHI methyl ester and the C20-C 26 aldehyde. A novel TAS-F-mediated elimination was developed to provide the C26-C44 olefin. The Horner-Wadsworth-Emmons coupling of the C4-C19 lactol and C20-C40 ketophosphonate furnished the contiguous C4-C45 framework of azaspiracid-1. Davis oxidation of C20 provided the requisite oxidation state. The only challenges remaining are desilylation at C25 and cross metathesis at C4 to complete a formal synthesis of azaspiracid.
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