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Lithiation–borylation methodology in the total synthesis of natural products

Nature Synthesis volume 1, pages 117–126 (2022)Cite this article

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Abstract

Robust synthetic methods that show a broad substrate scope are of great utility in the synthesis of complex organic molecules. Within this arena, synthetic methods that employ boronic esters are especially useful because they undergo a wide variety of transformations with very high levels of stereoselectivity. In particular, boronic esters can undergo single or multiple homologations using enantioenriched metal carbenoids. The addition of a suitable enantioenriched lithium or magnesium carbenoid to a boronic ester, with subsequent 1,2-migration, gives a homologated boronic ester with high stereocontrol. This process, termed lithiation–borylation, can be iterative, which allows a carbon chain to be extended one atom at a time with remarkable precision. The iterative homologation has been likened to a molecular assembly line and resembles the way nature assembles natural products, for example, in polyketide synthase machinery. The application of lithiation–borylation chemistry to the synthesis of a broad variety of natural products is discussed in this Review.

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Fig. 1: Introduction to homologation of boronic esters.
Fig. 2: Preparation and use of metal carbenoid precursors.
Fig. 3: Exploiting selective invertive and retentive pathways of trapping benzylic carbamates in lithiation–borylation reactions.
Fig. 4: Homologation of boronic esters using primary alkyl substrates to construct alkaloid and polyketide natural products.
Fig. 5: Rapid construction of natural products through desymmetrization of bis-boronic esters.
Fig. 6: Enabling the rapid construction of natural products with high efficiency through iterative homologations (assembly-line synthesis).
Fig. 7: Synthesis of the originally proposed structures of baulamycins A and B.
Fig. 8: Determination of the relative and absolute configurations of baulamycins A and B through synthesis and NMR spectroscopic analysis52.

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Acknowledgements

R.C.M. thanks the Bristol Chemical Synthesis Centre for Doctoral Training, funded by the EPSRC (EP/L015366/1) and AstraZeneca. We thank EPSRC (EP/T033584/1) for financial support.

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  1. These authors contributed equally: Kay Yeung, Rory C. Mykura.

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  1. School of Chemistry, University of Bristol, Bristol, UK

    Kay Yeung, Rory C. Mykura & Varinder K. Aggarwal

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K.Y., R.C.M. and V.K.A. wrote the manuscript.

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Correspondence to Varinder K. Aggarwal.

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Yeung, K., Mykura, R.C. & Aggarwal, V.K. Lithiation–borylation methodology in the total synthesis of natural products. Nat Synth 1, 117–126 (2022). https://doi.org/10.1038/s44160-021-00012-1

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