Abstract
We report that a subtle balance of carbanion reactivity, leaving group activation, and pKa of the catalyst is required for efficient self-condensation of thiomalonates to thioacetoacetates in up to 71% yield under “biomimetic” conditions originally proposed by Kobuke and Yoshida (Tetrahedron Lett. 1978, 19, 367).
Highlights
The Claisen condensation of malonyl thioesters is one of the central processes in the biosynthesis of polyketide natural products [1]
These Kobuke-Yoshida (KY) conditions [5,6] contrast sharply with the harsher conditions required in other model systems for polyketide synthesis [7,8,9] but not polyketide cyclization [10,11,12]
We report that Mg2+-imidazolecatalyzed thiomalonate dimerization is possible in up to 71% yield under refined conditions by precise fine tuning of the properties of carbanion intermediate, thiolate leaving group, and catalyst, and show that future applicability of this approach toward biomimetic polyketide synthesis is problematic
Summary
The Claisen condensation of malonyl thioesters is one of the central processes in the biosynthesis of polyketide natural products [1]. Kobuke and Yoshida have, demonstrated more than twenty years ago that Claisen condensation of n-butyl thiomalonate 1a and phenyl thioacetate 2e can be catalyzed by imidazole and magnesium cations in THF at room temperature to give n-butyl thioacetoactate 3a in 87 h and 60% yield (Scheme 1) [5].
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