Journal
NATURE CHEMISTRY
Volume 12, Issue 7, Pages 629-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41557-020-0464-x
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Funding
- Tamaki Foundation
- Chugai Pharmaceuticals
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Polyketide natural products are an important class of biologically active compounds. Although substantial progress has been made on the synthesis of repetitive polyketide motifs through the iterative application of a single reaction type, synthetic access to more diverse motifs that require more than one type of carbon-carbon bond connection remains a challenge. Here we describe a catalytic, multicomponent method for the synthesis of the privileged polyketide 1,3-dienyl-6-oxy motif. The method allows for the formation of two new carbon-carbon bonds and two stereodefined olefins. It generates products that contain up to three contiguous sp(3) stereocentres with a high stereoselectivity in a single operation and can be used to generate chiral products. The successful development of this methodology relies on the remarkable efficiency of the ruthenium-catalysed alkene-alkyne coupling reaction between readily available vinyl boronic acids and alkynes to provide unsymmetrical 3-boryl-1,4-diene reagents. In the presence of carbonyl compounds, these reagents undergo highly diastereoselective allylations to afford the desired 1,3-dienyl-6-oxy motif and enable complex polyketide synthesis in a rapid and asymmetric fashion. A ruthenium-catalysed multicomponent reaction provides rapid and tunable access to 1,3-dienyl-6-oxy polyketide motifs. An initial alkene-alkyne coupling produces unsymmetrical 3-boryl-1,4-dienes. Allylation of aldehydes and ketones with these products is highly diastereoselective and results in the formation of two carbon-carbon bonds, two stereodefined olefins and up to three contiguous sp(3) stereocentres.
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