Diastereoselective Reduction of the Enone Intermediate of Travoprost

Abstract

A scalable process for the diastereoselective reduction of the prochiral enone intermediate 1 has been developed with DEANB/(R)-methyl CBS as reducing agent, to obtain the key intermediate alcohol 15R-isomer 2, used in a process for the manufacture of Travoprost (3). Various advantages of this process against the DMSB reduction assisted by (R)-methyl CBS have been studied. Specific comparison has been made to highlight the salient features of the chosen process on yield and optical purity with those of the DMSB reduction.

Chemoenzymatic Synthesis towards the Active Agent Travoprost

“…Prostaglandins, discovered in the early 1930s, act as hormone‐like messengers by controlling a broad range of essential biological processes in the body, thus making them highly attractive molecules for the pharmaceutical industry . A considerable number of pharmaceuticals containing prostaglandins and their analogues are on the market, including the active agent travoprost ( 1 , Travatan, Alcon, Fort Worth, TX), which is a highly efficient therapeutic for the treatment of glaucoma and ocular hypertension . Glaucoma is an optic neuropathy leading to irreparable optic‐nerve damage and loss of vision if untreated …”

“…As already mentioned above the selective reduction in the ω ‐side chain to attain enantiopure prostaglandins and other analogues is challenging . An alternative synthetic strategy that avoids the late‐stage reduction in the ω ‐side chain was reported by Lennon and co‐workers .…”

“…[1,2] Ac onsiderable number of pharmaceuticals containing prostaglandins and their analogues are on the market, including the active agent travoprost (1,T ravatan, Alcon, Fort Worth, TX), which is ah ighlye fficient therapeutic for the treatment of glaucoma and ocular hypertension. [3] Glaucomai sa no ptic neuropathy leadingt oi rreparable optic-nerve damage and loss of vision if untreated. [4] The increasing number of studies dealing with synthetic approaches towards the total synthesis of prostaglandins and their analogues stresses the growing demando ft hese active agents.…”

“…Previous approaches towards the synthesiso ft ravoprost (1) led to racemic (AE)-travoprost (1) [12] and those using the Corey method( in which the so-called Corey lactone 2 acts as an intermediate that is sequentially attached by two sidechains in aH orner-Emmons and Wittig alkenylation) [8] suffer from low selectivity in the late-stage reduction of the keto functiona t positon1 5i nthe w-side chain of intermediate 3 (Figure 1). [3] In 2002, an ew strategy for the synthesis of travoprost (1)w as published by Lennon and co-workers, [13] based on the threecomponent coupling (3-CC) between A, B,a nd C. [14] Travoprost (1)w as obtainedi n4 .0-6.9 %y ield over 22 steps, with the longest linear sequence of eleven steps. [13] In 1994 Lipshutz and Wood [15] described anotherp rotocol for at hree-component couplinga pproacht owards prostaglandins starting with at erminal alkyne in aone-pot reaction sequence (Scheme 1).…”

“…As already mentioned above the selectiver eduction in the w-side chain to attain enantiopure prostaglandins ando ther analogues is challenging. [3] An alternative synthetic strategy that avoidst he late-stage reduction in the w-side chain was reported by Lennon and co-workers. [13,36] Their route required three synthons:t he silyl-protected bicycle 9,t he enantiopure vinyl iodide 10,a nd the commerciallya vailableW ittig reagent (4-carboxybutyl)-triphenylphosphonium bromide (11), the latter of which gives access to the w-side chain (Figure 2).…”