Phenylbutyric anhydride

Reaction of exo-carbinol ( ) — 16 with racemic a-phenylbutyric anhydride afforded the dextrorotatory acid hence the chirality center has the absolute configuration (R). The behavior of the endo isomer 15 was also in accord with this finding the resolved levorotatory acid indicates that the asymmetric C atom has the absolute configuration (S). 

Phenylbutyric acid, 303, 333 a-Phenylbutyric anhydride, 317-318 Phenylcarbamate, 320 Phenyl chloroformate, 318-319 1 -Phenyl-5-chlorotetrazole, 319-320 /3-Phenylcinnamaldehyde, 249 Phenylcyanate, 320 a-Phenylcyclobutylmethylamine, 289... 

Long-range substituent effects of unknown mechanism influence the esterification of 5-en-3)3-ols by racemic a-phenylbutyric anhydride. Hydrolysis of the resulting esters gave a-phenylbutyric acid with modest optical activity, the sign depending upon the nature of C-17 substitution in the steroid employed. "... 

Based upon ORD studies on 78 and on the stereochemical outcome of the reaction of 76 with oc-phenylbutyric anhydride it was concluded... 

The absolute configurations of chelidonine, chelidonine acetate, and norchelidonine have been independently studied by application of a kinetic method of partial resolution during esterification with a-phenylbutyric anhydride, by CD analysis (662), and by H NMR analysis (785). The mass spectra and the NMR spectra of chelirubine, chelilutine, sanguinarine, and sanguilutine have been reported (770, 786). 

The absolute configuration of the chiral axis in the naturally occurring skyrin molecule has remained an outstanding question for many years. Recently, the stereochemistry of (-h) Skyrin and of atrovirin-B has been established as ( S) by making use of an extension to the Horeau method 398). Thus, reaction of each of these compounds with ( )-2-phenylbutyric anhydride led to an excess of residual (-l-)-2-phe-nylbutyric acid, which was also the case when (S)-2,2 -dihydroxy-l,r-binaphthyl was used as the substrate and esterified under the same conditions. 

Turning now to chemical methods used for stereochemical studies of carotenoids the modified Horeau method (32) has been successfully used to confirm the configuration of (2/ )- 3, 3-caroten-2-ol [(33), R=H] (38) and to establish the configuration of aleuriaxanthin (36) (34). However, no conclusive results could be obtained for plectaniaxanthin [(35), R = R =H] (28). In principle the Horeau method is based on partial resolution of racemic and meso a-phenylbutyric anhydride by means of an optically active secondary alcohol, which readts preferentially with one diastereomer. The unreacted anhydride is quantitatively determined by an appropriate procedure (32, 68, 94). 

AS(H) Asymmetric synthesis by the method of Horeau Tetrahedron Letters, 1961, 506). This involves reaction of the chiral alcohol with racemic 2-phenylbutyric anhydride. The absolute configuration at the hydroxyl-bearing chiral centre is determined by measurement of the specific rotation of the recovered unreacted 2-phenylbutyric acid. 

Table 8. Chemical and optical yields of the esterification of compounds 74-77 with 2-phenylbutyric anhydride.

To the enol ether (10 ) mol in pyridine (0.5 ml) Is added 2-phenylbutyric anhydride (2 x 10 " mol). After mixing and standing for 15-20 h at room temperature, a few drops of water are added, followed by heating on a steam bath during 30 min. The solution, after addition of water (2 ml) and benzene (3 ml), Is titrated with NaOH 0.1 N on phenolphthalein. The aqueous layer Is extracted (3 x) with benzene (10 ml) and subsequently acidified with HCI (2 ml), Then the optical rotation of the 2-phenylbutyric acid obtained is measured at 589 nm, 578 nm, 546 nm, 436 nm and 365 nm. The respective values are ... 

Pentyn-1-ol, 33, 68 Peracetic acid, 33, 79 -Phenetidine hydrochloride, 31, 11 a-Phenoxyacetoacetic acid, 33, 44 Phenylacetamide, 32, 92 Phenylacetic acid, 32, 93, 94 33, 70 imino ether hydrochloride, 32, 94 N-Phenylacetimidochloride, 31, 51 Phenylacetonitrile, 30, 44 32, 92 Phenylacetylene, 30, 72 7-Phenylallylsuccinic acid, 31, 85 7-Phenylallylsuccinic anhydride, 31, 86 Phenylazide, 31,16 Phenylazoacetoacetic acid, 32, 85 Phenyl benzoate, 32, 103 IttZtti-l-PHENYL-l,3-BUTADIENE, 30, 75 7-Phenylbutyric acid, 33, 91 a-PHENYL-a-CARBETHOXYGLUTARO-NITRILE, 30, 80, 82 tt-Phenylcinnamonitrile, 32, 63 Phenyldichlorophosphine, 31, 88 0-PhENYLENE CARBONATE, 33, 74 o-Phenylenediamine, 30, 56, 86... 

The Merck process group subsequently published a more detailed route amenable towards multikilogram scales (Blacklock et al., 1988). This synthesis begins with treatment of alanine with phosgene to produce A-carboxyanhydride (NCA) 16 (Scheme 10.3). Under basic aqueous conditions this anhydride is coupled with proline to produce, upon acidic work-up, the dipeptide alanyl-proline (14). Enalapril is then prepared in one synthetic step by a diastereoselective reductive amination between ethyl-2— oxo-4-phenylbutyrate (13) and 14. This reaction was the subject of extensive optimization, and it was found that the highest diastereoselectivity was obtained by hydrogenation over Raney nickel in the presence of acetic acid (25%), KF (4.0 equiv.), and 3 A molecular sieves (17 1 dr). Enalapril is then isolated in diastereomerically pure form as its maleate salt (Huffman and Reider, 1999 Huffman et al., 2000). 

An earlier work of Barker173 described the formation of 5,6-dihydro-4-methyl-6-oxo-2,4-diphenyl-l,3-oxazine through dehydration of 0-benzamido-/3-phenylbutyric acid with acetic anhydride. 

Kinetic resolution of ferrocene derivatives, mainly alcohols, had an important place during the early stage of stereochemical investigations of ferrocene derivatives. The reaction of (partially) resolved ferrocenylalkyl alcohols and amines with racemic 2-phenylbutyric acid anhydride (Korean s method) was the basis for the configurational assignment before the establishment of structures by X-ray crystallography [41]. There has been some debate on the reliability of the method [62, 63], and additional chirality information seems necessary for certainty. Recently, the kinetic resolution of 1-ferrocenylethanol by transesterification with vinyl acetate, catalyzed by a lipase from PseudomonasJluorescens, led to an enantiomeric excess of 90—96% of both enantiomers [64], opening new preparative aspects. 

Preparation. By refluxing a-phenylbutyric acid (suppliers Aldrich, Eastman) with acetic anhydride for 6 hrs. and removal of the solvent. 

Cyclic anhydrides react in the same sense their use in Friedel-Crafts syntheses has been reviewed by Berliner.505 For example, phthalic anhydride and benzene give o-benzoylbenzoic acid in yields exceeding 90% 560 succinic anhydride with benzene gives 4-oxo-4-phenylbutyric acid,561 and with anisole in the presence of aluminum chloride gives 4-(p-methoxyphenyl)-4-oxobutyric... 

Phenylbutyric acid added to the phosphonium anhydride (prepared according to Synth. Meth. 44, 166), the mixture warmed to room temp., and stirred for 4h -> a-tetralone. Y 93%. The method is generally milder and cleaner than the polyphos-phoric acid procedure, and without the problems of solubility, viscosity, and work-up. Intermolecular acylation failed. F.e.s. J.B. Hendrickson, M.S. Hussoin, J. Org. Chem. 54, 1144 9 (1989). 

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