Lithiation–borylation methodology in the total synthesis of natural products

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. Boronic esters are versatile intermediates that readily accept nucleophiles and then undergo 1,2-migration, expelling a neighbouring leaving group. Such reactivity enables carbon chains to be grown one atom at a time with high stereocontrol. This Review examines the fundamentals of lithiation–borylation methodology and its application to natural product synthesis.