Synthesis of the Potent Antiglaucoma Agent, Travoprost

Abstract

A commercial synthesis of the antiglaucoma agent, travoprost 2, is described. A total of 22 synthetic steps are required to provide the single enantiomer prostanoid, with the longest linear sequence being 16 steps from 3-hydroxybenzotrifluoride. The route is based upon a cuprate-mediated coupling of the single enantiomer vinyl iodide 13 and the tricyclic ketone 5, of high stereochemical purity, to yield the single isomer bicyclic ketone 15. A Baeyer-Villiger oxidation provides the lactone 16 as a crystalline solid, thus limiting the need for chromatographic purification. DIBAL-H reduction, Wittig reaction, esterification, and silyl group deprotection complete the synthesis of travoprost.

An Enantioconvergent Synthesis of (R)-4-Aryloxy-1-butyne-3-ols for Prostanoid Side Chains

“…Confirmation of the absolute configuration of vinyl iodide 10a and hence alcohol 6a, was obtained by transformation to travoprost. [21] Conclusion A scaleable and high-yielding synthesis of (R)-4-aryloxy-1-butyne-3-ols starting from the corresponding racemic alcohols has been developed. These compounds are precursors to the wside chains of commercially important prostaglandin analogues.…”

Chemoenzymatic Synthesis towards the Active Agent Travoprost

“…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 . Their route required three synthons: the silyl‐protected bicycle 9 , the enantiopure vinyl iodide 10 , and the commercially available Wittig reagent (4‐carboxybutyl)‐triphenylphosphonium bromide ( 11 ), the latter of which gives access to the ω ‐side chain (Figure ).…”

“…Iodide 10 was prepared from the racemic alcohol rac ‐ 12 by a kinetic resolution step using Chirazyme L9 (hydrolase from Rhizomucor miehei, Roche Molecular Biochemicals, Mannheim, Germany). Mesylation of the undesired alcohol ( S )‐ 12 followed by an esterification with inversion of its configuration and an additional ester hydrolysis with Chirazyme L2 (hydrolase from Candida antarctica, Roche Molecular Biochemicals, Mannheim, Germany) yielded ( R )‐ 12 (58–65 % yield, >99 % ee ) …”

“…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).…”

Pharmaceuticals

“…5.102). [229] Enisoprost The challenge encompasses not only to make travoprost accessible by a route as convergent as possible without elaborate protecting-group chemistry, and in good yields; but also to generate five stereocentres correctly and with high stereoselectivity. In addition, the configuration of both double bonds must be given due consideration.…”