Total Synthesis of Entecavir: A Robust Route for Pilot Production

Abstract

A practical synthetic route for pilot production of entecavir is described. It is safe, robust, and scalable to kilogram scale. Starting from (S)-(+)-carvone, this synthetic route consists of a series of highly efficient reactions including a Favorskii rearrangement-elimination-epimerization sequence to establish the cyclopentene skeleton, the Baeyer–Villiger oxidation/rearrangement to afford the correct configuration of the secondary alcohol, and a directed homoallylic epoxidation followed by epoxide ring-opening to introduce the hydroxyl group suitable for the Mitsunobu reaction. In addition, the synthesis contains only four brief chromatographic purifications.

Strong and Confined Acids Enable a Catalytic Asymmetric Nazarov Cyclization of Simple Divinyl Ketones

“…Moreover, a Luche reduction of 2a furnished allylic alcohol 10 in excellent diastereoselectivity (dr > 20:1), which could then be utilized in a Mitsunobu reaction to install a purine-derivative and afford compound 12 with excellent C1 enantiopurity. 12 In conclusion, we have developed a powerful catalytic, asymmetric Nazarov cyclization of simple, acyclic, aliphaticsubstituted divinyl ketones using a strong and confined Brønsted acid. We propose that the confinement of the IDPi scaffold induces the reactive s-trans/s-trans conformation of the divinyl ketone substrate, thereby promoting the cyclization to give a variety of versatile enones in good yields and excellent enantio-, regio-, and diastereoselectivities.…”

“…Moreover, a Luche reduction of 2a furnished allylic alcohol 10 in excellent diastereoselectivity (dr > 20:1), which could then be utilized in a Mitsunobu reaction to install a purine-derivative and afford compound 12 with excellent C1 enantiopurity. 12…”

“…The α-methylene unit of 2a could be isomerized to the fully substituted, thermodynamically more stable cyclopentenone 3a with an excess amount of methanesulfonic acid, again retaining the excellent enantioselectivity. Moreover, a Luche reduction of 2a furnished allylic alcohol 10 in excellent diastereoselectivity (dr > 20:1), which could then be utilized in a Mitsunobu reaction to install a purine-derivative and afford compound 12 with excellent C1 enantiopurity …”

Nucleobase coupling by Mitsunobu reaction towards nucleoside analogs

“…MR has seen extensive use for nucleobase alkylation, mostly in the context of drug development, including scale up attempts, namely for the synthesis of the antiviral drug entecavir, in gram 21,22 and even kilogram 23 scales. The application of MR in large scale has so far been limited by the complex nature of the resulting reaction mixtures, which makes them difficult to purify.…”

“…This conclusion should be envisioned as specific for this reaction, as there are examples of regioselective N 1 coupling by MR with THF. 78 While in many cases the yield of MR with pyrimidines is quite good, 23,59,[75][76][77] there are no reported cases of nearly quantitative yields of N 1 -linked products, most probably due to the formation of O-2 derivatives.…”