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

Published in: Journal,

DOI : 10.1021/acs.oprd.3c00287

Author : Robey, Juliana M. S.; Maity, Sanjay; Aleshire, Sarah L.; Ghosh, Angshuman; Yadaw, Ajay K.; Roy, Subho; Mear, Sarah Jane; Jamison, Timothy F.; Sirasani, Gopal; Senanayake, Chris H.; Stringham, Rodger W.; Gupton, B. Frank; Donsbach, Kai O.; Nelson, Ryan C.; Shanahan, Charles S.

Abstract : 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 mol. relies on a nucleophilic addition reaction of a quinoline fragment to a ketone, but it suffers from low conversion and no stereoselectivity, which subsequently increases the cost of manufacturing BDQ. The Medicines for All Institute (M4ALL) has developed a new reaction methodol. to this process that not only allows high conversion of starting materials but also results in good diastereo- and enantioselectivity toward 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 desired syn-diastereomer pair (82%) and with considerable stereocontrol (d.r. = 13.6:1, e.r. = 3.6:1, 56% ee), providing BDQ in up to 64% assay yield before purification steps toward 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.