ASYMMETRIC-SYNTHESIS OF 3-OXACARBACYCLIN AND 3-OXAISOCARBACYCLIN BY ACOMMON ENANTIOSELECTIVE DEPROTONATION BASED ROUTE

Asymmetric total syntheses of 3-oxacarbacyclin (4) and 3-oxaisocarbacy clin (5) have been achieved by a new and common route. The key step of these syntheses is an enantioselective deprotonation of the prochiral ketone 25 with Lithium (R,R)-bis(phenylethyl)amide (12) in the presen ce of LiCl. Treatment of the thus formed enolate 26 with ClSiEt3 gave the enol ether 27 of 92% ee in 94% yield. Deprotonation of the analogo us prochiral ketone 9 with 12 in the presence of LiCl followed by reac tion of the enolate 13 with ClSiEt3 led to isolation of the silyl enol ether 8b of 92% ee in 95% yield. A study of the deprotonation of 9 wi th the chiral Lithium amides 14-19 showed that 12 in combination with LiCl is the optimal base in terms of enantioselectivity and accessibil ity. The alpha-side chain in 4 and 5 was established by a Mukaiyama re action of 27 with the unsaturated aldehyde 28, leading to ketone 39 of 90% de, in combination with a stereoselective Pd-catalyzed allylic re arrangement of acetate 47 to the isomeric acetate 48 and a Mitsunobu r eaction of the allylic alcohol 49, The key step in the construction of the alpha-side chain in 4 is a Horner-Wadsworth-Emmons reaction of ke tone 7c with the 8-phenylnormenthol-containing phosphonoacetate 56 whi ch gave ester 60 of 90% de. Eater 60 was obtained diastereomerically p ure by chromatography in 72% yield from 7c. Reduction of 60 furnished the allylic alcohol 62 which was converted to 4 in a standard fashion. It is at the stage of the alpha,beta-unsaturated ester 60 where diver gence into synthesis of 5 was made. Selective isomerization of 60 to t he beta,gamma-unsaturated ester 66 of 97% ie in 91% yield was accompli shed by deprotonation of 60 with 12 to enolate 65 and its subsequent r egioselective protonation. By a similar reaction sequence the isomeric alpha,beta-unsaturated ester 61 was converted to the beta,gamma-unsat urated ester 69 of 97% ie in 88% yield. Reduction of 66 afforded the h omoallylic alcohol 71 which was converted to 5 in a standard fashion.