Hydroxy esters, preparation from lactones

Catalytic hydrogenation of the acetate 98, readily prepared from 97, gave the dihydro and the tetrahydro acetates 99 and 100, respectively. The former was also obtained in two steps from the aminolactone 97 via compound 101 while the latter was synthesized in racemic form as shown from either the hydroxy ester 29 or lactone 34 which were available from previous work (Schemes 4 and 6). The last sequence of reactions also produced the epimeric racemic tetrahydroacetate (30) already described in the degradative experiments on securinine (Scheme... 

Corey et al. [36] developed an efficient and mild lactonization method using 2-pyridinethiol ester. Slow addition of 2-pyridinethiol esters, prepared from to-hydroxy acids by reaction with 2,2 -dipyridyl disulfide and Ph3p or 2-fhiopyridyl chloroformate and EljN, to refluxing xylene under dilution conditions yielded... 

Cyclization of hydroxy esters, i.e., lactonization, is an internal transesterification that can be carried out in the presence of lipases in organic solvents. The method, used for the synthesis of macrocyclic lactones [101], has been applied to the preparation of optically active lactones from racemic hydroxy esters [102]. This enzymatic transesterification has also been used to prepare enantiomerically pure hydroxy lactones from racemic dihydroxy esters [103-105], as shown in Scheme 15. 

Cuscutic resinoside A (1 tetradecanoic acid, (115)-[[6-deoxy-3-(9-(6-deoxy-a-L-mannopyranosyl)-4-0-[(2/ ,3R)-3-hydroxy-2-niethyl-l-oxobutyl]-a-L-nianno-pyranosyl]oxy]-intramol. l,2 -ester) was obtained from the ethyl acetate-soluble fraction of a methanol extract prepared from the seeds of Cuscuta chinensis Lam. The purification of this compound employed a combination of column and preparative-scale HPLC. The structure was deduced from spectroscopic evidence and acid hydrolysis 14). The degradative process gave convolvuUnolic acid, nilic acid, and L-rhamnose. The sugar components were identified by GC analysis after being converted to their thiazolidine derivatives. This disaccharide has a unique macrocyclic lactone, which is placed between C-1 and C-2 of the first rhamnose moiety. 

Linkers that enable the preparation of y-lactones by cleavage of hydroxy esters from insoluble supports are discussed in Section 3.5.2. Resin-bound y-lactones have been prepared by Baeyer-Villiger oxidation of cyclobutanones [39], by intramolecular addition of alkyl radicals to oximes [48], by electrophilic addition of resin-bound sele-nenyl cyanide or bromide to 3,y-unsaturated acids (Figure 9.2 [100]), and by palladium-mediated coupling of resin-bound aryl iodides with allenyl carboxylic acids (Entry 10, Table 5.7 [101]). 

While diketene remains a very important synthetic precursor, there has been increasing interest in the chemistry of a-methylene-/3-lactones, 3-methylene-2-oxetanones. However, unlike diketene, which can be readily synthesized by the dimerization of aldehydic ketenes, there are few methods for the synthesis of a-methylene-/3-lactones in the literature. Recent strategies for the preparation of the compounds are discussed in Section 2.05.9.2. The kinetic resolution of racemates of alkyl-substituted a-methylene-/3-lactones has been carried out via a lipase-catalyzed transesterification reaction with benzyl alcohol (Equation 21) <1997TA833>. The most efficient lipase tested for this reaction was CAL-B (from Candida antarctica), which selectively transesterifies the (A)-lactone. At 51% conversion, the (R)-f3-lactone, (R)-74, and (A)-/3-hydroxy ester, (S)-75, were formed in very high enantio-selectivities (up to 99% ee). 

Acylation of a simple thiol with an alkyl carboxylate is not a very suitable method for preparation of S-alkyl thiocarboxylates. Transesterification is, however, possible if either the thiol or the carboxylic ester is activated. The enhanced reactivity of boron, aluminum and silicon thiolates has been utilized for the synthesis of a large variety of thiocarboxylic S-esters, including hydroxy derivatives (from lactones). a,P-Unsaturated thiol esters, e.g. cinnamoyl or 2-butenoyl derivatives, are also accessible. Michael addition, an undesirable side reaction of thiols, is completely avoided if alkyl trimethylsilyl sulfides ortris(arylthio)boranes are applied. ... 

Indium enolates, prepared conveniently by transmetalation of hfhium enolates with IriCl j, react wifh aldehydes to give fhe corresponding -hydroxy esters [80]. Ultrasound irradiation promotes fhe Reformatsky reaction of aldehydes and ethyl bromoacetate wifh indium [81]. Indium-mediated Reformatsky reaction of phenyl a-bromoalkanoates wifh ketones or aldehydes gives di-, tri-, and tetrasubstituted -lactones (Scheme 8.57) [82]. Indium-mediated reaction of imines with ethyl bromoacetate gives 3-unsubstituted -lactams (Scheme 8.58) [83]. An indium-Refor-matsky reagent prepared from 2-(chlorodifluoroacetyl)furan couples with aldehydes (Scheme 8.59) [84]. 

A, 1,6 rearrangement of macrocyclic lactone 14, prepared from ( + )-carene via enantiomeri-cally pure hydroxy ester 13, is used in the construction of the tricyclic ingenol precursor 16. which allows the rare in-out bridged bicyclic stereochemistry to be controlled. The stereochemistry of 16 arises from a boatlike transition state559. 

The next objective of the synthesis was the lactone 122, a compound that is also readily available from annotinine (1). Borohydride reduction of the enol acetate 123 derived from 121 yielded a mixture of the hydroxy esters 124 and 125. This mixture was hydrolysed to the corresponding acids, 126 and 127, and the acids treated with p-toluene-sulfonic acid in boiling benzene. The product was a mixture of the desired lactone 122 and the hydroxy acid 127 in approximately equal amounts. Another less attractive method of preparation of 124 was described in the course of the structural study of annotinine (1). 

Scheme 8 Alcohol (94), prepared from (72, was converted to hydroxy hemiacetal (95) upon treatment with potassium carbonate in aqueous isopropanol. Selective oxidation and acetylation yielded ester (96), whose conversion to lactone (97) was achieved without dificulty. Dehydration of (97), followed by cuprate addition, provided (98), whose conversion to phytuberin has already been accomplished.

Although synthons 100 are extremely useful for construction of lactones associated with HMG—CoA reductase inhibitors, they are not limited exclusively to that role. Simple methylation a to the ester group generates useful building blocks for the synthesis of such polyfiinctionalized natural products as scytophycin C or roxaticin. The requisite hydroxy P- ketoester 120 is prepared from 45a as shown in Scheme 15 [54]. 

Some efficient preparations of lactones from open chain precursors involve the use of special catalysts. For example, co-hydroxy esters react at elevated temperatures with ZrOj or Zr02 treated with TMS-Cl to give 2-oxocanone in 35% <92CL57l> and 77% yield <93BCJ1305>, respectively. The use of the silylated ZrOj has been the subject of a patent application <93MIP9325308>. This is a direct, relatively high yield route to oxocanone however, the scope of the reaction and the sensitivity to other functional groups have not been explored. 

The ester 169 was converted into 170 through a Michael type three-carbon extension. The carboxylic acid 172 was derived from 170 through the ketophos-phonate 171. The C11-C15 segment 174 was prepared from (R)-3-hydroxy-butyric acid (173). Esterification of 172 with 174 using DCC and DMAP gave 175, which was converted into 176 through an intramolecular Horner-Emmons reaction. The lactone 176 was transformed to the Tatsuta intermediate 163. 

Simvastatin Zocor , Merck) is prepared from lovastatin. The methylbutyroyl ester is first hydrolysed with lithium hydroxide, whereby the lactone is opened as well. The latter is cydised again by azeotropic distillation with toluene. After regioselective protection of the hydroxy-group in the lactone ring, the intermediate is esterified with dimethylbutyryl chloride, and the silyl protecting group is finally cleaved off. 

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