Ethyl retinoate synthesis

Babler and Schlidt [86] described a route to a versatile C15 phosphonate, used for a stereoselective synthesis of all E retinoic acid and p-carotene. Base-catalyzed isomerization of the vinyl-phosphonate afforded the corresponding allyl-phosphonate as the sole product. Homer-Emmons olefination with ethyl 3-methyl-4-oxo-2-butenoate concluded the facile synthesis of all E ethyl retinoate. The C15 phosphonate was synthesized starting from the epoxide of P-ionone. Subsequent isomerization with MgBr2, afforded the C14 aldehyde in 93%... 

A stereoselective synthesis of all-trans-stereomer of ethyl retinoate (111) was reported by Babler and Schlidt [56] starting from the easily available -ionone 112 (Scheme 30). The key step of the synthesis was a base-catalyzed isomerization of the vinylphosphonate 113, which was obtained in the Horner-Wittig reaction of the aldehyde 114 and tetraethyl bisphosphonate, to give the allylic phosphonate 115 as the sole product. The Horner-Wittig reaction of the latter with ethyl trans-3-methyl-4-oxo-2-butenoate concluded a facile synthesis of the all-trans-polyenic retinoate 111. 

An attempt was made to synthesize the bicyclic retinoids (247) directly by Simmons-Smith cyclopropanation of ethyl retinoate (24). Only isomerized starting material was obtained (Dawson et aL, 1981b). It was therefore necessary to develop a separate, multistage procedure for the synthesis of (247). Initially, cyclopropanated p-cyclocitral (243) was reacted with the weakly nucleophilic anion of the phosphonate (244), generated by means of sodium hydride in di-methylsulfoxide. This procedure, too, failed to give the desired molecule (247), and the product obtained was merely the derivative (245) containing an expanded ring. 

In a comparable approach, Valla et al. [73] described the synthesis of 9-methylene analogues of retinol, retinal, retinonitrile and retinoic acid, using the p-methylenealdehyde derived from P-ionone. Homer-Emmons condensation with ethyl 4-(diethoxyphosphoryl)-3-methylbut-2-enoate carbanion afforded the ester in 55% yield, as a mixture of 13E/13Z isomers (50/50). This ethyl 9-methylene-retinoate was saponified with ethanolic NaOH to give the corresponding 9-methylene-retinoic acid in 55% yield (13 /13Z 50/50). The retinol analogue was obtained by DIBAL-H reduction of the ethyl ester (75%, 132T/13Z isomers 65/35). 

These French chemists described a synthesis of ethyl 9-methylene-13E and 13Z-retinoates via the Julia strategy [74]. The required new C15 sulfone was prepared by O-silylation of P-ionone, followed by catalytic condensation (ZnBr2) of the enol with PI1SCH2CI. 

Ethyl-2-(/J)-hydroxy-2-(T,2, 3. 4 -tetrahydro-T,T.4, 4 -tetramethyl-6 -naphthalenyl) acetate 53 (Figure 16.14) and the corresponding acid 54 were prepared as intermediates in the synthesis of the retinoic acid receptor gamma-specific agonist [86]. Enantioselective microbial reduction of ethyl 2-oxo-2-(T,2, 3. 4 -tetrahydro-T,T,4, 4 -tetramethyl-6-naphthalenyl) acetate 55 to alcohol 53 was carried out using Aureobasidiumpullulans SC 13849 at a 98% yield and with an EE of 96%. At the end of the reaction, hydroxyester 53 was adsorbed onto XAD-16 resin and, after filtration, recovered in 94% yield from the resin with acetonitrile extraction. The recovered (/ )-hydroxyester 53 was treated with Chirazyme L-2 or pig liver esterase to convert it to the corresponding (/ )-hydroxyacid 54 in quantitative yield. The enantioselective microbial reduction of ketoamide 55 to the corresponding (/ )-hydroxyamide 52 by A. pullulans SC 13849 has also been demonstrated [86]. 

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