Revised Synthetic Route

Revised specifications and methods of analysis (including analytical improvements as well as new synthetic routes/processes and new formulations)... 

Salts of the tetrafluoroaluminate (TFA) anion have been known for many years. Yet aqueous routes to pure materials have not been established despite the substantial amount of literature available on the subject. The present review will discuss the various synthetic methods that have been employed and will demonstrate a revised method for preparing pure TFA salts. These materials are important because TFA is able to stimulate various guanosine nucleotide-binding proteins (G-proteins) and inhibit P-type ATPases by serving as a nonhydrolyzing phosphate mimic. Additionally, various TFA salts serve as precursors to aluminum trifluoride, which is used as a catalyst for chlorofluorocarbon isomerizations and fluorinations. 

A useful synthesis (ref.ll)of patchouli alcohol, an important fragrant constituent of patchouli oil, from (+)-camphor, that onetime important natural product which was employed as a plasticiser for nitrocellulose (itself a semi-synthetic polymer), was complicated by structural revision of the sesquiterpene alcohol. Dihydrocarvone (14) obtained by saturation of the ring double bond in carvone, a major constituent of oil of spearmint has been employed for two very different sesquiterpenes, the ketone campherenone (15) and the alcohol, occidentalol (16). In the first case an enol acetate was converted to a bicyclic intermediate by earlier established methodology and the route emulated a plausible biogenetic sequence giving racemic campherenone (ref.12) as shown. Any chirality in (14) is apparently lost. 

Though improvements continue to appear, such as a revised route to the lactone portion,52 and no doubt will continue to appear, this is a staggering achievement involving 43 chemists and you are particularly directed to the fifth paper in the series.51 Commenting on the synthesis as a whole they say The success of this project and its chemistry paves the way for other, perhaps even more complex, natural products to be prepared for early-phase clinical evaluations and sends a positive message to both the isolation and synthetic academic community and possibly other pharmaceutical companies that your work need not just be of academic interest and it may be worth taking a few risks. ... 

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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