Development of\na Scalable Process for the Synthesis\nof Cyclopropyl-Methyl-Proline with Complex Stereochemistry: A Key\nBuilding Block of Factor D Inhibitors

The development of a scalable process for a complex intermediate\nfeaturing a chiral, quaternary cyclopropane moiety presented significant\nchallenges. We report two generations of synthetic strategies appropriate\nfor the respective stages of development. The initial approach utilized\na stereoselective Simmons–Smith cyclopropanation of (<i>R</i>)-pyroglutamic acid ester, which predominantly yielded\nthe undesired stereoisomer. To circumvent this issue, we implemented\na strategy that combined isomerization, recycling of the undesired\nisomer, and selective crystallization to improve the yield of the\ndesired product. An important insight was that the Simmons–Smith\ncyclopropanation exhibited opposite stereoselectivity with a benzoyl\nester of a prolinol substrate, resulting in the desired stereoisomer\nas the major product. This understanding enabled the development of\na second-generation process that facilitated the large-scale production\nof the targeted intermediate, thus supporting the advancement of clinical\ntrials.