Catalytic asymmetric formal synthesis of beraprost

Abstract

SummaryThe first catalytic asymmetric synthesis of the key intermediate for beraprost has been achieved through an enantioselective intramolecular oxa-Michael reaction of an α,β-unsaturated amide mediated by a newly developed benzothiadiazine catalyst. The Weinreb amide moiety and bromo substituent of the Michael adduct were utilized for the C–C bond formations to construct the scaffold. All four contiguous stereocenters of the tricyclic core were controlled via Rh-catalyzed stereoselective C–H insertion and the subsequent reduction from the convex face.

Asymmetric Synthesis of Ethers by Catalytic Alkene Hydro­alkoxy­lation

“…Enantioselective syntheses of the biologically active compound (-)-raxofelast (128) and the natural products beraprost (127) and erythrococcamide B (129) were achieved. 62 Similar reactions of ,-unsaturated esters were also reported by Hintermann and co-workers, which were catalyzed by cinchonine 66e (Scheme 32, a). 38b Furthermore, nitrile 133 and benzodioxanyl acetate 135 could be obtained with good results (Scheme 32, b).…”

A Practical Synthesis of a Key Intermediate of Beraprost

“…1 H NMR spectra were recorded on a Bruker DRX-400 (400 MHz) spectrometer or a Bruker DRX-500 (500 MHz) spectrometer. 13 C NMR spectra were obtained on a JNM-EX400…”

“…The filtrate was evaporated to dryness and purified by flash column chromatography (dichloromethane/petroleum ether, 1:2) to give the pure compound 3 as a colourless solid: Yield 61.2 g (55%); m.p. 165.5-167.5 ºC; 1 H NMR (400 MHz, CDCl 3 ): δ 2.72 (s, 2H), 5.67 (s, 2H), 6.32 (s, 2H), 7.56 (s, 4H); 13…”

“…7 Due to its clinical importance, a number of synthetic routes to benaprost have been reported. [8][9][10][11][12][13][14][15][16][17][18][19][20][21] Among these synthetic methods, the most practical synthesis was reported by Nagase's group, utilising an ortho-selective metal-halogen exchange and subsequent copper-catalysed cyclisation to construct the cyclopenta[b]benzofuran core (Scheme 1). 12 The butyric side chain of beraprost could be introduced by several methods.…”

Kinetic Resolution of 2H-Azirines by Asymmetric Allylation Reactions

“…On the other hand, incorporation of allyl groups into one molecule has remarkable influence on its biological activity and molecular versatility . Allyl groups can also be easily transformed into alkyl, hydroxyl, carboxyl, and many other diversified functional groups or used to broaden the carbon chain, which provides rich postfunctionalization possibilities of important molecules.…”