Early phase clinical manufacture of LP-184

Abstract: LP-184 is an acylfulvene class natural product derivative that exerts it action via alkylation of DNA. Previous routes to LP-184 used Acylfulvene, which is derived from illudin S, as feedstocks for early investigational batches. Access to these feedstocks were stymied by the inconsistent fermentation of O. olearius ( Jack-o-Lantern mushroom) to produce the ultimate feedstock of illudin S. To solve the manufacturing supply for upcoming clinical trials, we developed a de novo total synthesis of Acylfulvene and LP-184 to circumvent the reliance of natural sources. Several innovations had to be developed in order to realize the de novo total synthesis of the API, which includes a kilo-scale synthesis of a diazo ketone, selective methylation of a ketone over an enone via in situ protection, a Lewis acid mediated regioselective ring opening and use of serine as a formaldehyde scavenger.