Application of Chiral Transfer Reagents to Improve Stereoselectivity and Yields in the Synthesis of the Anti-Tuberculosis Drug Bedaquiline

Bedaquiline (BDQ) is an important drug for treating multidrug-resistant tuberculosis (MDR-TB), a worldwide disease that causes more than 1.6 million deaths yearly. The current synthetic strategy adopted by the manufacturers to assemble this molecule relies on a nucleophilic addition reaction of two complex starting materials, but suffers from low conversion and no stereoselectivity, which subsequently increases the cost of manufacturing BDQ. M4ALL has developed a new approach to this process that not only allows high conversion of starting materials, but also results in good diastereo- and enantioselectivity towards the desired BDQ stereoisomer. A variety of chiral lithium amides derived from amino acids were studied, and it was found that lithium (R)-2-(methoxymethyl)pyrrolidide, obtained from D-proline, results in high assay yield of the syn-diastereomer pair (82 %) and with considerable stereocontrol (d.r. = 13.6:1, e.r. = 3.6:1, 56 % ee) providing bedaquiline in up to 64 % assay yield before purification steps towards the final API. This represents a considerable improvement in the BDQ yield compared to previously reported conditions and could be critical to further lowering the cost of this life-saving drug.