The current manufacturing process for BDQ relies on the reaction of the quinoline derivative 1 with the ketone 2 (Scheme 1a). The Bedaquiline Assembly (BA) reaction couples the lithiated quinoline 1a with the ketone 2 via a 1,2-addition to form products 3, ent-3, 4, and ent-4. This mixture of four stereoisomers is distributed in two pairs of diastereomers, syn-(RS, SR) and anti-(RR, SS). BDQ is the (1R,2S) stereoisomer 3, and it is the most active against TB. It is important to acknowledge that the other isomers present reduced activity toward the bacteria. Lesser activity is observed if BDQ (3) is combined with its enantiomer ent-3, evidencing the importance of having an efficient purification process that produces the enantiopure active pharmaceutical ingredient (API). Isolation of BDQ (3) from the complex mixture obtained in the 1,2-addition step is achieved through a 4step sequence of crystallizations (see Supporting Information Scheme S1), which includes precipitating out the less soluble anti-diastereomer pair (4 and ent-4), precipitation of the desired syn-diastereomer pair (3 and ent-3) to remove unreacted starting materials, chiral resolution with (R)-BINOL-phosphoric acid and treatment of the obtained solid with a base to yield enantiopure BDQ (3), and a final fumarate salt formation and final recrystallization to yield the API BDQ (3) fumarate. This complex purification process results in a significant loss of material and is required due to the low conversion and selectivity of the 1,2-addition.