Studies toward the total synthesis of (-)-apoptolidin

A total synthesis of the apoptosis-inducing natural product, apoptolidin, was developed and the construction of the aglycone was initiated. A model system of the 20-membered macrocycle was studied to determine the feasibility of ring closure. Achiral subunits were used to first couple the northern half to the southern half via a Suzuki coupling followed by Yamaguchi macrolactonization to successfully close the ring. Once accomplished, the chiral subunits for the northern portion of the ring were constructed. Initial attempts involved a stereo-controlled thio-Claisen rearrangement of an allene to give the desired alkyne. The inability to optimize this thio-Claisen methodology led to an aldol approach using Evans' auxiliary to control the stereochemistry. The desired alkyne was then coupled to the vinyl iodide using a Suzuki method to afford the carbon skeleton for the northern component of the macrolide. Esterification and a subsequent Suzuki coupling were the key steps in affording the aglycone.