Glecaprevir
was identified as a potent HCV NS3/4A protease inhibitor,
and an enabling synthesis was required to support the preclinical
evaluation and subsequent Phase I clinical trials. The enabling route
to glecaprevir was established through further development of the
medicinal chemistry route. The key steps in the synthesis involved
a ring-closing metathesis (RCM) reaction to form the 18-membered macrocycle
and a challenging fluorination step to form a key amino acid. The
enabling route was successfully used to produce 41 kg of glecaprevir,
sufficient to support the preclinical evaluation and early clinical
development.
The phorboxazole natural products are among the most potent inhibitors of cancer cell division, but they are essentially unavailable from natural sources at present. Laboratory syntheses based upon tri-component fragment coupling strategies have been developed that provide phorboxazole A and analogues in a reliable manner and with unprecedented efficiency. This has been orchestrated to occur via the sequential or simultaneous formation of both of the natural product's oxazole moieties from two serine-derived amides, involving oxidation-cyclodehydrations. The optimized preparation of three pre-assembled components, representing carbons 3-17, 18-30, and 31-46, has been developed. This article details the design and syntheses of these three essential building blocks. The convergent coupling approach is designed to facilitate the incorporation of structural changes within each component to generate unnatural analogues, targeting those with enhanced therapeutic potential and efficacy.
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