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Iterative assembly line synthesis of polypropionates with full stereocontrol

Abstract

The polypropionate motif is ubiquitous, being characteristic of the most important family of natural products for human health, the polyketides. Numerous strategies have been devised to construct these molecules with high stereocontrol, but certain stereoisomers remain challenging to prepare. We now describe the development of an iterative assembly line strategy for the construction of polypropionates. An assembly line strategy for the synthesis of deoxypolypropionates has already been described. However, the introduction of carbinol units required the development of new building blocks and new reaction conditions. This has been achieved by the use of enantioenriched lithiated α-chlorosilanes [1-((2′-lithiochloromethyldimethylsilyl)-methyl)-2-(methoxymethyl)-pyrrolidine], thus enabling the programmed synthesis of polypropionates in a fully stereocontrolled manner, including the stereochemically challenging antianti isomers. The versatility of the approach is exemplified in its extension to the synthesis of 1,3-related polyols. The methodology now allows access to a much wider family of polyketide natural products with stereochemistry being dialled in at will.

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Figure 1: Iterative assembly line strategy for polyketide synthesis.
Figure 2: Issues associated with homologation of β-alkoxy boronic esters and possible solutions using a silyl group as a masked-oxygen functionality for iterative homologations.
Figure 3: Development of assembly line synthesis protocol for the construction of polypropionates.
Figure 4: Proposed catalytic cycle for photoredox cleavage of aminosilane 8a.

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Acknowledgements

Thge authors thank the European Research Council (FP7, ERC grant no. 670668), the EPSRC (EP/I038071/1) and Bristol University for financial support. T.B. acknowledges support from the Marie Curie Fellowship programme (EC FP7, no. 626828). The authors thank P.J. Unsworth for discussions and preliminary work.

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V.K.A. and E.L.M. conceived and directed the project. T.B. and J.M.F. conducted and designed the experiments and analysed the data. V.K.A., E.L.M. and T.B. co-wrote the paper.

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Correspondence to Varinder K. Aggarwal.

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The authors declare no competing financial interests.

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Bootwicha, T., Feilner, J., Myers, E. et al. Iterative assembly line synthesis of polypropionates with full stereocontrol. Nature Chem 9, 896–902 (2017). https://doi.org/10.1038/nchem.2757

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