A Short Synthesis of a Thromboxane B₂ Key Intermediate from (R)‐2,3‐Isopropylideneglyceraldehyde. γ‐Lactones as Templates for Chemoselective cis‐Annulation of Pyranosides

Abstract

A six-step synthesis of the bicyclic lactone pyranoside 1, which has served as a key intermediate in numerous syntheses of thromboxane Bl, from (R)-2,3-isopropylideneglyceraldehyde is described. In contrast to the previous syntheses of 1 the lactone part is prepared first and acts as a template in the annulation of the hemiketal unit. Further aspects of interest are the Felkin-Anh-controlled addition of vinyl cuprates to the acrylic ester 16 and the considerable rate difference in the formation of the y-lactones 13, 14, 19, and 21 from the corresponding hydroxy acids.The thromboxanes are central members of the arachidonic acid cascade ['] and exert an influence on platelet aggregation; whereas thromboxane A2 has been prepared in a total synthesis only several approaches to its stable metabolite thromboxane B2 have been reported.In the asymmetric syntheses the bicyclic lactone pyranoside 1 served as the key intermediate [3][4][5][6][7] to which the two side chains were attached by Wittig-type olefinations (Scheme 1). As a general strategy the tetrahydropyran part was adapted from various glucose derivatives 2-5 to which the y-lactone ring was subsequently annulated (Scheme 2).We describe a novel access to 1 which involves the synthesis of the y-lactone moiety prior to the formation of the tetrahydropyran unit. This leads to 6 as a precursor in which the moieties at C-4 and C-5 may be in cis or trans arrangement. The lactone 6 in turn can be prepared from the readly available (R)-2,3-isopropylideneglyceraldehyde As the lactone ring serves as a rigid template for the annulation of the second ring the cis stereoisomer may be expected to be preferably ketalized. Thus, if cisltmns mixtures of 6 are employed, the trans isomer will not cyclize and can hence easily be removed due to its higher polarity. As shown in Scheme 3 glyceraldehyde (7) was converted into the allylic alcohol lo['] as a 9: 1 mixture of 10a, b after reduction of the ketone 8 with Brown's chiral borohydride 9Lgl. A variety of alternative hydride donors (NaBHdj