J.Am. Chem. Soc. 133, 16794–16797 (2011)

Despite the wide use of organometallic nucleophiles in synthetic organic chemistry, there are only a few chiral examples of these useful reagents. This stands in stark contrast to the wide variety of chiral electrophilic reagents that have been developed. The most important property of chiral reagents — configurational stability — is often mutually exclusive with the features that are valued in organometallic reagents: high reactivity and ease of preparation. Now, Varinder Aggarwal and co-workers from the University of Bristol have described the use of ate complexes of boronic esters as chiral nucleophiles for asymmetric synthesis.

Aggarwal and co-workers recognized that chiral boronic esters would be configurationally stable and easy to synthesize, but that they were unreactive. They reasoned, however, that addition of an aryl lithium to a chiral boronic ester might result in formation of a reactive boronate complex — which would be able to react stereoselectively with a variety of electrophiles. The initial attempts — using p-methoxyphenyllithium to activate an alkyl boronic ester followed by reaction with iodine — were promising, giving an almost completely stereospecific reaction. Other electrophilic partners — such as an azodicarboxylate — were less successful, giving the product as an almost racemic mixture.

This result was assumed to be due to a competing single-electron reaction pathway, which involved an achiral alkyl radical intermediate. Tuning the electronic properties of the aryllithium was sufficient to bias the reaction in favour of the stereoselective two-electron pathway. The new methodology was shown to work with a wide variety of electrophile partners to produce chiral alkyl halides, alcohols and amines among others.