In summary, we have engineered a P450 monooxygenase for the generation of a key chiral epoxide building block 3a for the synthesis of delamanid. Through a single round of directed evolution, involving site-saturation mutagenesis of 24 library positions and subsequent shuffling of beneficial mutations, a P450 BM3 variant was identified with an order of magnitude increase in activity compared to the parent enzyme. The chiral epoxide 3a could be generated directly from the requisite alkene in a single step with up to 98% e.e., a transformation which is not possible using traditional asymmetric chemistry. We believe that these findings will serve as a valuable basis for those seeking to develop a more efficient and sustainable process chemistry route towards delamanid.