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Progression toward a scalable synthesis of TORC1/2 inhibitor bulk drug, culminating in the first GMP manufacturing campaign, is described. Process research and development was needed to obtain the prerequisite stereocenter in high enantiomeric excess for kilogram-scale production. Through route selection, a six-linear step synthesis was developed which afforded the API in 20% overall yield. Development included an application of memory of chirality (MOC) to install a quaternary chiral center with near complete retention, a reductive cyclization to form a piperazinone core, and a palladium-catalyzed C–C bond-forming step.

[reaction: see text] A synthesis of a pectenotoxin 4 C1-C15 segment is reported. Suitable C1-C7 and C8-C15 segments were prepared, coupled, converted to I and the C3-hydroxy variant, and then cyclized. Key findings include the stereoselective conversion of the allene to the corresponding spirodiepoxide, oxidative cleavage of the p-methoxybenzyl ether, and cyclization of the spirodiepoxide to spiroketal II.

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