A Novel Convergent Synthesis of the Antiglaucoma PGF_2α Analogue Bimatoprost

Abstract

The 17-phenyl PGF(2α) analogue bimatoprost (10a) is the most efficacious ocular hypotensive agent currently available for the treatment of glaucoma or ocular hypertension. A novel convergent synthesis of 13,14-en-15-ol prostamideF(2α) analogues was developed employing Julia-Lythgoe olefination of the structurally advanced phenylsulfone (+)-(5Z)-15 with an enantiomerically pure aldehyde ω-chain synthon (-)-(S)-16a. Subsequent hydrolysis of protecting groups and final amidation of the diol 26a yielded bimatoprost (10a). The main advantage of the current strategy is the preparation of high-purity bimatoprost (10a). The novel convergent strategy allows the synthesis of a whole series of 13,14-en-15-ol prostamideF(2α) analogues with the desired C-15 asymmetric center configuration from a common and structurally advanced prostaglandin intermediate (+)-(5Z)-15. The preparation and identification of two synthetic impurities, 15-epi isomer (10b) of bimatoprost and a new prostaglandin related amide (+)-(5Z)-18, are also described.

A Novel Convergent Synthesis of the Potent Antiglaucoma Agent Tafluprost

“…Based on our previous work on ω-chain elongation of the prostaglandin phenylsulfone 16 with the aldehyde ω-chain synthons of travoprost and bimatoprost [ 28 , 29 ], we envisaged that the Julia–Lythgoe olefination [ 35 , 36 , 37 ] of the sulfone 16 with the α-hydroxy protected aldehyde 17 should give a mixture of β-hydroxysulfones 18 ( Scheme 2 ), which via reductive dehydroxy-desulfonylation and deprotection/protection of methyl-OBO and hydroxyl groups followed by oxidation of the 15-ol and deoxydifluorination of 13,14-en-15-one could enable construction of the ω-chain trans -13,14-en-15-deoxy-15,15-difluoro moiety. Irrespective of stereochemical configuration of the C-2 carbon atom in the aldehyde 17 , corresponding to the C-15 carbon atom in tafluprost ( 5 ), the deprotection of tert -butyldimethylsilyl protected hydroxyl group and its oxidation to a 15-one followed by its deoxydifluorination should lead to the non-chiral C-15 gem-difluorinated carbon atom in the final prostaglandin analog 5 .…”

“…Thus, the ω-chain elongation of the phenylsulfone 16 by S N 2 alkylation with enantiomerically pure alkyl halides allowed the synthesis of 13,14-dihydro-15-ol PGF 2α analogs, such as latanoprost ( 2 ) [ 27 ]. The Julia–Lythgoe olefination of the sulfone 16 with enantiomerically pure aldehyde ω-chain synthons allowed the synthesis of trans -13,14-en-15-ol PGF 2α analogs, such as travoprost ( 3 ) and bimatoprost ( 4 ) [ 28 , 29 ]. One of the main reasons for choosing this method of phenylsulfone 16 ω-chain elongation was formation of trans -13,14-ene as the only product of olefination.…”

Prostaglandin Total Synthesis Enabled by the Organocatalytic Dimerization of Succinaldehyde

“…[34] This extension of our methodology to prostaglandin-based pharmaceutically-relevant compounds allowed us to demonstrate expedient access to life-changing medicines in short step count -7 or 8 for bimatoprost and latanoprost, respectively -vs. 17 or 19 via the Corey lactone. [35,36] The hemiacetal of enal 6 could either be converted to its methyl acetal 24 (as a mixture of diastereoisomers) or to lactone 19 using a Stahl oxidation. [37] The advantage of the latter approach was that lactone 19 could be recrystallised to > 99 : 1 e.r.…”

Chemoenzymatic Synthesis towards the Active Agent Travoprost

“…Tremendous effort has been invested in the enantiomerically pure synthesis of 4‐hydroxy‐2‐cyclopentenones and their O ‐silyl‐derivatives, such as building block A , owing to it being a valuable synthetic intermediate for the synthesis of prostaglandins . These building blocks also function as cornerstones in the synthesis of numerous other natural compounds, including alkaloids, terpenes, and many more …”

“…The increasing number of studies dealing with synthetic approaches towards the total synthesis of prostaglandins and their analogues stresses the growing demand of these active agents . In this context, extensive efforts have been dedicated to the development of synthetic strategies, which have allowed an easy access to diverse prostaglandin derivatives, for example, Woodward, Corey, Danishefsky, Aggarwal, Nicolaou, and co‐workers have developed new methods for establishing the complex structures of these diverse molecules.…”