Methyl retinoate synthesis

Reaction between the lithiate of cyclogeranyl sulphone (25) and the aldehyde ester 43, followed by tetrahydropyranylation of the hydroxy group of the coupling product, furnishes 44. Treatment of 44 with ten equivalents of f-BuOK in refluxing f-BuOH leads to methyl retinoate (19) (all- 13Z= 1 1). The versatility of the double elimination method is highlighted by a novel synthesis of vitamin A acetate (JO) (Scheme 15) [17,18]. 

Oxidation of methyl retinoate (43) with manganese(IV) oxide gave the 4-keto ester (317), which was converted to the acid (188), and to the 4-hydroxy ester (318). The latter compound has also been employed as an intermediate in the synthesis of 3,4-didehydro compounds (Henbest, 1957 Rao et aL, 1972 Barua and Ghosh, 1972). 

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%... 

Bu Lock, J.D., Quarrie, S.A., and Taylor, D.A., Synthesis of methyl frfl 5-retinoate-10-carbon-14 and fran -retinol-lO-carbon-14, 7. Labelled Compd., 9, 311, 1973. 

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. 

Several papers have described the synthesis of epoxyretinoids. The 5,6-epoxides of fmns-retinal (88) and its (9Z)-, (IIZ)-, and (13Z)-isomers were prepared by direct epoxidation of retinal with w-chloroperbenzoic acid. The 7,8-epoxides (89) of retinal, retinol, and retinoic acid and its methyl esters were synthesized from the jS-ionone epoxide (90). The exceedingly labile methyl 13,14-epoxy-13,14-dihydroretinoate (91) was made by addition of the epoxyaldehyde (92) to the phosphorane (93). Chromogen 574 , a product of the epoxidation of retinol first described in 1945, has now been identified as the... 

Wittig olefination was discovered in 1953 during studies on the reactions of pentaphenyl-phosphorane, and was described in the following year as a widely suitable method for olefin synthesis [33]. As early as 1956 a patent application appeared [34], in which the synthesis of retinoic acid esters from p-ionylideneacetaldehyde and (3-alkoxycarbonyl-2-methyl)allyl-triphenylphosphonium bromide was claimed, evidence of the fact that the inventors had rapidly realized the economic potential and industrial practicability of this novel reaction [35,36]. 

Two other metabolites (199) and (203) of (all-/ran5 )-retinoic acid (3) (Hanni et al., 1976 Hanni and Bigler, 1977) posses an oxidized methyl group in the ring. The carbon skeleton of (199) was built on the basis of a method that was successfully used for the synthesis of the trisporic acids, which have a similar structure (Yakovleva et al., 1978 Prisbylla et aL, 1979). 

Tosukhowong and Olson (1978) have described the synthesis, as shown in Fig. 16, and metabolism of 15-methylretinone, 15-methyl retinol, and 15-di-methyl retinol. The labeled compounds needed for the metabolic study were prepared in the following way. Starting with retinoic acid-6,7- 2, 15-meth-ylretinone-6,7- C (LX) was prepared by treatment with lithium and methyl... 

The synthesis of rrani-[13- C]retinoic acid (265) (Procedure B) may serve as an additional example of the use of an [ " C]acetone-based building block. Homer-Wads-worth-Emmons olefination of [2- C]acetone with methyl diethyl-phosphonoacetate afforded methyl 3-methyl-2-[3- C]butenoate t2631. Upon deprotonation, this coupled with /3-ionylideneacetaldehyde (264) to provide 265. thereby extending the carbon skeleton of 264 again by a labeled five-carbon unit Building block 263 was also shown to be accessible (Procedure C) through Reformatsky synthesis of [2- C]acetone with zinc and... 

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