Racemic acetic acid, synthesis

Scheme 14. Synthesis of racemic (3,5-di-ter -butylpyrazol-l-yl)(3, 5 -di-methylpyrazol-l-yl)acetic acid (3d) (47).

The first synthesis of an optically active isopavine, (—)-reframoline (29), has been achieved by the acid-catalyzed double cyclization process described previously. The properly substituted diarylamine 109 was resolved using (-t-)-di-benzoyltartaric acid to afford the (-I-) enantiomer. Conversion to the acetal 110 was accomplished without racemization. Subsequent acid-catalyzed cyclization yielded the levorotatory alkaloid 29 (Scheme 21) 112). 

The synthesis of racemic felodipine (Scheme 11.2) utilizes a stepwise Hantzsch dihydropyridine reaction (Berntsson et al., 1981). 2,3-Dichlorobenzylidineacetyl acetic acid... 

An alternative method for dialkyl peroxide synthesis is the nucleophilic addition of an alkyl hydroperoxide to an alkene under acid catalysis reported by Davies and coworkers (Scheme 31, path B) ". A similar reaction is the nucleophilic addition of alkylhy-droperoxides to vinyl ethers under acid catalysis, producing perketals. Perketals can be deprotected under mild conditions (THF/water/acetic acid) and this hydroperoxide protection-deprotection sequence has been used by Dussault and Porter as a means for the resolution of racemic hydroperoxides (see also Section II.A.2) . In this respect more detailed studies were carried out with the perketals 75, which were prepared via reaction of alkyl hydroperoxides with vinyl ethers (Scheme 33). Weissermel and Lederer reported that in the presence of teri-butyl hypochlorite, a-chlorodialkyl peroxides can be formed in yields between 12% and 45% (Scheme 31, path C)". a-Alkoxydialkyl peroxides and diperoxyacetals were prepared by Rieche and coworkers via acid catalyzed reaction of one or two equivalents of alkyl hydroperoxides with acetals, ketals or aldehydes (Scheme 31, path D)" or by methylation of the corresponding a-alkoxy hydroperoxides with diazomethane (yields 11%, 27%)" . The diperoxyacetals 76 were isolated in yields ranging from 39 to 77%. 

One Sanofi synthesis of enantiomerically pure (-i-)-clopidogrel (2) utilized optically pure (R)-(2-chloro-phenyl)-hydroxy-acetic acid (20), a mandelic acid derivative, available from a chiral pool. After formation of methyl ester 21, tosylation of (/ )-21 using toluene sulfonyl chloride led to a-tolenesulfonate ester 22. Subsequently, the Sn2 displacement of 22 with thieno[3,2-c]pyridine (8) then constructed (-i-)-clopidogrel (2). Another Sanofi synthesis of enantiomerically pure (-i-)-clopidogrel (2) took advantage of resolution of racemic a-amino acid 23 to access (S)-23. The methyl ester 24 was prepared by treatment of (S)-23 with thionyl chloride and methanol. Subsequent Sn2 displacement of (2-thienyl)-ethyl para-toluene-sulfonate (25) assembled amine 26. 

A closely related synthesis utilizes alkynic epoxides, which add hydrogen sulfide in the presence of a base to form thiophenes in good yield. For example, when the epoxide (184) was stirred in an aqueous solution of barium hydroxide with slow addition of hydrogen sulfide gas, and the product extracted after neutralization with acetic acid, the substituted thiophene (186) was obtained in 60-70% yield (53ZOB1569). In these experiments R1 = Me or Et, R2 = H or Me and R3 = Ph. The same synthetic method was used to produce a thiophene having an optically active substituent, with relatively little racemization. In this case R1 = EtC HMe while R2 and R3 = H, but the yield was equivalent (73JOC2361). This reaction also undoubtedly proceeds via an intermediate (185), a structure related to a 1 -mercapto-1,3-butadiene. 

A number of methods for the synthesis of piperazic acid (7) and related derivatives are currently available as a result of growing interest in natural product chemistry and in their potential in medicinal chemistry. Their chemistry and conformational properties have been comprehensively reviewed. 2451 Racemic piperazic acid is obtained by condensation of penta-2,4-dienoic acid with phthalazinedione and subsequent reductive deprotection of the resulting A,A -bis(phthaloyl)-l,2,3,6-tetrahydropyridazine-3-carboxylic acid.12431 Resolution of racemic piperazic acid is achieved by fractional crystallization of the ephedrine salt of Nl-(benzyloxycarbonyl)piperazic acid from ethyl acetate. 246,2471 A typical route to enantiomerically pure (3S)-piperazic acid 56 starts from chiral 2-amino-5-hydroxyvaleric acid 55 as shown in Scheme 12.1248 Convenient stereoselective syntheses have been reported for 5-hydroxy- and 5-chloropiperazic acids as important constituents of natural cyclic peptides and depsipep-tides.1249,2521... 

Dihydroxylation60 of (-)-82 in pyridine, a protocol used for our racemic synthesis was found to be difficult here mainly due to problems in the isolation of the tetraol product. We elected to go with the epoxidation protocol60 using various peroxy acetic acids, and the best result gave (-)-84 in 21% yield in addition to a hexacyclein 28% yield.63 64... 

The use of extracellular lipases of microbial origin to catalyze the stereoselective hydrolysis of esters of 3-acylthio-2-methylpropionic acid in an aqueous system has been demonstrated to produce optically active 3-acylthio-2-methyl-propionic acid [41-43], The synthesis of the chiral side chain of captopril by the lipase-catalyzed enantioselective hydrolysis of the thioester bond of racemic 3-acetylthio-2-methylpropionic acid (15) to yield 5 -(-)-(15) has been demonstrated [44], Among various lipases evaluated, lipase from Rhizopus oryzae ATCC 24563 (heat-dried cells), BMS lipase (extracellular lipase derived from the fermentation of Pseudomonas sp. SC 13856), and lipase PS-30 from Pseudomonas cepacia in an organic solvent system (l,l,2-trichloro-l,2,2-tri-fluoroethane or toluene) catalyzed the hydrolysis of thioester bond of undesired enantiomer of racemic (15) to yield desired S-(-) (15), R-(+)-3-mercapto-2-methylpropionic acid (16) and acetic acid (17) (Fig. 8A). The reaction yield of... 

They made a racemic sample using the Strecker synthesis of amino acids that you met in Chapter 12. The racemic amino acid was reacted with acetic anhydride to make the mixed anhydride and then with the sodium salt of naturally derived, enantiomerically pure alcohol menthol to give two diastereoisomers of the ester (see top of facing page). 

In 1982 Foley and Btichi (182a) described a biomimetic synthesis of racemic dibromophakellin (137) via an oxidative cyclization of dihydroor-oidih (138). The ethyl ester of (+)-citrulline (139) was reduced with sodium amalgam and the crude aldehyde obtained was condensed with cyanamid and cyclized with hydrochloric acid, respectively, to give 140. Compound 140 was hydrolyzed to the amine 141. Acylation with 2,3-dibromo-5-tri-chloroacetylpyrrole yielded dihydrooroidin (138). Exposure of the hydrochloride of 138 to bromine in acetic acid and addition of methanol, followed by treatment with potassium /eri-butanolate gave racemic 137, identical to... 

Oxidative cyclization. The final step in a synthesis of racemic ajmalicine (2) required oxidative cyclization of (I). This reaction was carried out in 2.5% aqueous acetic acid with an excess of 1 1 mercuric acelale-ethylenediaminetetraacetic acid disodium salt (EDTA, I, 373-374) followed by sodium borohydride reduction of iminium intermediates. 

---