(+)-Methyl β-methoxy-β-phenylpropionate (VIII) was prepared from (+)-mandelic acid and from (+)-β-hydroxy-β-phenylpropionic acid (I). In this way the configuration of I was correlated with that of mandelic acid

A. Deljac

B. Urbas

K. Balenović

English

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CROATICA CHEMICA ACTA 31 (1959) 153 CCA - 162 541.63:547.1588.l Absolute Configuration of ~-ffydroxy-~-phenylpropionic acid* K. BaLenov:ic, B. Urbas, and A. Deljac Chemical Laboratory, Faculty of Science, University of Zagreb, Strossmayerov trg 14, Zagreb, Croatia, Yugoslavia Received December 11, 1959 (+ )-Methyl ~-methoxy-~-phenylpropionate (VIII) was prepared from (+)-mandelic acid a'.nd from (+)-~-hydroxy-~-phenylpropionic acid (I). In this way the configuration of I was c-0rrelated with that o:f mandelic acid. Laevorotatory ~-hydroxy-~-phenylpropionie acid (I) has been found in Lobelia inflata L. Degradation of Lobelia alkaloids and sedamine from Sedum acre L. also afforded optically active acids (I).** Knowledge of the absolute configuration of I is therefore important for the determination of the steric structure of these alkaloids. Recently, Lukes et al.1 found that (+)-P-hydroxy-p-phenylethylamine (II) could be obtained from ( + )-P-hydroxy-~-phenylpropionic acid as well as from ( + )-mandelic acid. Mislow2 had found earlier that (-)-mandelic acid belonged to the D-series of a-hydroxy acids; the dextrorotatory acid I has, therefore, the configumtion III. This determination of the absolute configuration was repeated and confirmed3 by the preparation of the same ( + )-5-phenyloxazoli-done-(2) (IV) from the dextrorotatory acid I and from ( + )-mandelic acid. III COCHN2 I CHpCH I Ph VI PhCHOHCH2NH2 II Ph-CH--CH2 I I I ' 0 NH "'-co/ IV CH2C02CH~ I CHpCH I Ph VII '" Communication No. 75 from this Laboratory; 74th Communication: Chem. & Ind. 1959, 1449. ** cf. e. g. lit. cit.a 154 K. BALENOVIC, B. URBAS, .AND A. DEl,JAC. In the present paper we wi,sh to report another useful way for the cor-relation of the configurations of a- and ~-hydroxy acids by the following series of stereospecific reactions [( + )-mandelic acid as model}: ( + )-Mandelic acid \,Vas converted to ( + )-a-methoxyphenylacetic acid (V) with methyl iodide and silver oxide4 and into the diazoketone VI in · the usual way. Application of the Arndt-E1stert reaction to VI failed under no,rmal conditions, but the homo-geneous Wolff rearrangement5 afforded (+ )-methyl ~-methoxy-~-phenyl­propionate (VII). We prepared the same compound from (+)-~-hydroxy-~­-phenylpropionic acid with methyl iodide and silver oxide. These results CO'l'roborate the earlier established configuration of ( + )-P--hydroxy-~.:.phenylpropionic acid1•3• Application of this series of reactions to the determination of the con:liiguratiJon of some othell.' P-hydroxy acids has re<:ently been descri.beds. EXPERIMENTAL ( + )-a-Methoxyphenylacetic acid (V) ( + )-Mandelic acid of 94°/o optical purity (5.3 g., 0.035 moile, [a]D + 1480) , was dissolved in benzene (30 ml.) and methyl iodide -(20 g., 0.14 mole) and methylated according to McKenzie.' To this solution silver 'oxide (20 g., 0.08 mole) was gradually added over a period of one hour, with stirring. The silver oxide was freshly prepared and washed successively with water, methanol and benzene. The reaction mixture wa,s refluxed for 8 hours (bath temp. 50-550), then cooled fo room temperature, the silver iodide filtered off, washed with benzene (10 ml.) and the combined mother liquo,rs evapomted in vacua to dryness. The methyl a-methoxyphenylacetate thus obtained was a yellow oil (5.6 g., 90°/o). It was dissolved in methanol (50 ml.), and a solution of sodi,um hydroxide (2 g.) in water (3 ml.) added. After standing for 24 hours at room temperature (+ )-a-methoxyphenyl acetic acid was isolated from the hydrolysate in the usual way (4.1 g., 710/o). Recrystallization from benzene -petroleum ether gave colourless crystals with [a]~ + 1220 (c, 2.36 in ethanol), and m. p. 62-640. McK.enzie4 reported m. p. 63-640 and [a]j; + 1500 (o, 6.76 in ethanol). (-)-3-Diazo-1-methoxy-1-phenylpropan-2-one (VI) A mixture of (+)-a-methoxyphenylacetic acid (3 g., 0.018 mole, [a]D + 1220) and freshly distiHed thionyl chloride (20 ml.) was refluxed for 2 hours at 50-600. The excess of thionyl chloride was evaporated in vacua, and the last traces removed by repeatedly dissolving the crude a-methoxypheny1acetyl chloride in benzene and evaporating to dryness. The chloride was dissolved in benzene (50 ml.) and added, with stirring, to an ethereal solution of diazomethane (300 ml.) prepared from 35 g. of nitrosomethylurea. After standing at oo overnight the solvents were removed in vacua and (-)-3-diazo-1-methoxy-1-phenylpropan-2-one (VI) remained as a yellow oil (3.3 g., 970/o), showing [a]~ -830 (c, 3.5 in ethyl acetate). ( + )-MethyL P-methoxy-p-phenylpropionate (VII) (-)-3-Diazo-1-methoxy-1-phenylpropan-2-one (VI) (3.3 g., 0.017 mole) was dis·soived in a mixture o.f absolute methanol (15 ml.) and acetonitrile (15 ml.). To this mixture Cu-(I)-iodide (0.3 g.) was addeds, and the mixture warmed on a water b~th to 35.0 for a few minutes until nitrogen evolution began. Heating was discontinued :and the reaction mixture was left standing :at room temperature for three hours. After one hour of heating at 500 the nitrogen ·evolution ceased. The reaction mixture was filtered, poured in.to water (100 ml.), and extracted with benzene (3 X 50 ml.) . The combined benzene ilayers were washed with water, dried (anhydrous Na2S04) and evaporated in vacua. The remaining greenish oily residue (3.1 g.) was dissolved j ~ benzene and filtered through a column of neutral aluminium oxide (50 g., activity ABSOLUTE CONFIGURATION OF p-HYDROXY-p-PHENYL PROPIONIC ACID 155 JII according to Brockmann). 'rhe first benzene filtrates (50 ml.) were evaporated ·to dryness and 2.28 g. (680/o) of (+)-methyi p-methoxy-p-phenylpropionate (VID were ,obtained showing the b. p . 5~00/0.01 mm. and [a]~ + 400 (c, 2.57 in benzene); .colourless oily liquid. Anal. 9.19 mg. subst.: 22.90 mg. C02, 5.8'7 mg. H20 C11H1403 (194.22) calc'd.: C 68.03; H 7.260/o found: C 68.00; H 7.156/o ·{+)-Methyl ~-methoxy-~-phenylpropionate (VII) -from ( + )-~-hydroxy-~-phenylpropionic acid The resolution of inactive ~-hydroxy-p-phenylpropionic acid prepared according to E. Fischer et al.1 was accomplished with morphine according to. McKenzie and Humphriess. To .a solution of (+)-~-hydroxy-~-phenylpropionic acid [0.6 g., 0.0036 mole, la]~ + 19.50 (ethanol), optical purity 1000/o] in benzene (15 ml.) and methyl iodide (2.5 g., 0.017 mole) silver oxide (2..7 g., 0.011 mole) was added and the reaction mixture refluxed for 8 hours. (+)-Methyl ~-methoxy-B-phenylpropionate was isolated in the ;usual way, showing the b. p. 50-550/0.007 mm. and [a]~ + 61.00 (c, 2.935 in benzene) . Anal. 9.520 mg. subst.: 23.562 mg. C02, 6.028 mg. H20 C11H140 3 (194.22) calc'd.: C 68.03; H 7.260/o found: C 67.54; H 7.090/o Acknowledgment. The authors are indebted to dr. Z. Stefanac for the micro-:ana[yses. REFERENCES J. R. Luke s, K. B 1 ah a, and I. Kovar, Chem. & Ind. 1958, 527. ·2. K. Mis 1 ow, J. Am. Chem. Soc. 72 (1951) 3954. 3. C. S c h 6 p f and W. W ii s t, Ann. 626 (1959) 150. 4. cf. A. McKenzie, J. Chem. Soc., 75 (1899) 753, 964. 5. P . Y ates and J. Fugger, Chem & Ind. 1957, 1511. ·6. K. Balenovic and B. Urbas, Chem, & Ind. 1959, 1448. 'l. E . Fis c h er, H. S c he i b 1 er, and R. Groh, Ber. 43 (1910) 2020. :8. A. Mc. Kenzie and H . B. P. Humphries, J. Chem. Soc. 97 (1910) 121. IZVOD Apsolutna konfiguracija B-hidl'9ksi-B-fenilpropionske kiseline K. Balenovic, B . Urbas i A . Deljac Opisana je priprava (+)-metil B-metoksi-B-fenil-propionata (VII) iz (+)-bade-move kiseline i iz (+ )-B-hidroksi-p-fenilpropionske kiseline (I). Na taj nacin je -0dredena konfiguracija spoja I. KEMIJSKI ZAVOD ;P_RI,RODOSLOVNO-MATEMA TICKI FAKULTET ZAGREB Primljeno 11. proslnca 1959. 

Absolute Configuration of β-Hydroxy-β-phenylpropionic acid*

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