A Convergent Synthesis of the 11-Oxa Prostaglandin Analogue AL-12182

Abstract

[reaction: see text] The 11-oxa prostaglandin analogue AL-12182 1 has potent topical ocular hypotensive activity. A convergent and concise general synthesis of this class of prostanoid was developed employing a stereoselective coupling reaction between a tetrahydrofuran core electrophile and a nucleophilic omega side chain component, providing a route that should be suitable for commercial scale production. The tetrahydrofuran core was assembled from dimethyl d-malate using a stereoselective beta-hydroxy ester dianion alkylation reaction.

Highly stereoselective gram scale synthesis of all the four diastereoisomers of Boc-protected 4-methylproline carboxylates

“…Then a chemoselective reduction of the ester group adjacent to the hydroxyl group was achieved with borane-dimethyl sulde complex to afford diol 11 in 90% yield. 11 Then protection of diol 11 followed by hydrolysis of the methyl ester with lithium hydroxide gave acid 12, which was directly coupled with chiral (S)-oxazolidinone auxiliary in the presence of pivaloyl chloride and triethyl amine to afford Evans' chiral auxiliary 6 (72% yield, three steps).…”

Modular Total Synthesis of Rhizopodin: A Highly Potent G‐Actin Dimerizing Macrolide

“…The initial steps in this successful strategy are shown in Scheme . Starting from known ester 33 , which was available in three steps from D ‐malic acid,25 ether 34 was obtained by treatment with methyl iodine in almost quantitative yield, which was then directly exposed to lithiated tert ‐butyl acetate.…”

Large-Scale Carbonyl Reductions in the Pharmaceutical Industry

“…Other reagents such as BH 3 ·SMe 2 (stoichiometric)/NaBH 4 (catalytic), Zn­(BH 4 ) 2 (prepared in situ from LiBH 4 and ZnCl 2 ), , borane (prepared in situ from LiBH 4 and BF 3 ·THF), LiBH 4 , (reactivity between LAH and NaBH 4 ; either commercial or prepared in situ from NaBH 4 and LiBr, , ), and Red-Al (Vitride, sodium bis­(2-methoxyethoxy)aluminum hydride; 65–70 wt% in PhMe) have also been employed.…”

“…Fox and co-workers at Dowpharma have published the synthesis of 11-oxa prostaglandin analogue 131 , a drug candidate for the reduction of intraocular pressure in the treatment of glaucoma (Scheme ) . The first step of the synthesis involved the chemoselective reduction of dimethyl d -malate ( 129 ) at the methyl ester adjacent to the hydroxyl group.…”

“…Fox and co-workers at Dowpharma have published the synthesis of 11-oxa prostaglandin analogue 131, a drug candidate for the reduction of intraocular pressure in the treatment of glaucoma (Scheme 33). 87 The first step of the synthesis involved the chemoselective reduction of dimethyl D-malate (129) at the methyl ester adjacent to the hydroxyl group. To accomplish this reduction, neat BH 3 •SMe 2 was added to a THF solution of 129 at 12−16 °C followed by the addition of NaBH 4 (5 mol%) in five portions.…”