Telaprevir discovery synthesis

The original discovery synthesis of the P2 domain of telaprevir utilized bicycloproline derivative 56 (Scheme 10),"° which was prepared in racemic form using a four-step, two-pot protocol starting from 2-cyclopentenone, as described by Monn and Valli." In this approach, enantiomerically pure 56 was obtained via chiral HPLC separation." Reduction of the ketone of 56 produced secondary alcohol 57, which was further reduced to 58 under Barton-McCombie deoxygenation conditions. The synthesis of P2 fragment 59 was completed by hydrogenolysis of the benzyl carbamate. 

The overall synthetic strategy toward the tetrapeptide scaffold of telaprevir requires four key amino acid building blocks (45-49, Scheme 8), which can be coupled using standard peptide coupling methods. As in the synthesis of boceprevir, the P2 domain (48), which contains the bicyclic proline mimic, is the most synthetically challenging fragment of telaprevir, particularly in the context of a scalable route for commercialization. Likewise, the synthesis of the PI ketoamide domain (49) has required significant revision and optimization in the transition from discovery to process scale. 

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