CHEMISTRY

Corresponding Member of the Academy of Sciences of the USSR A. P. Terent’ev, R. A. Gracheva,
T. F. Dedenko

SYNTHESIS OF OPTICAL ISOMERS OF β-AMINOBUTYRIC ACID

Racemic β-aminobutyric acid is usually obtained by addition of ammonia to crotonic acid \((^1)\). Addition of benzylamine \((^2)\) to crotonic acid with subsequent hydrogenolysis of the N-substituted acid also leads to an optically inactive acid. At present, for the synthesis of β-amino acids, including β-aminobutyric acid, a method is widely used that consists in the interaction of aldehydes, malonic acid, and ammonia \((^3)\).

In optically active form, β-aminobutyric acid was first obtained by Fischer \((^4)\) by resolution of the racemate with camphorsulfonic acid. Racemic β-aminobutyric acid was obtained by him by hydrogenation of the phenylhydrazone of acetoacetic ester. Later \((^5)\), β-aminobutyric acid was resolved with the aid of optically active α-phenylethylamine. In 1952 Balenovich and co-workers \((^6)\) synthesized optically active \((+)\)-β-aminobutyric acid, applying the Arndt—Eistert reaction to \((-)\)-1-diazo-3-phthalimidobutan-2-one, obtained from \(L\)-alanine. The specific rotation of β-aminobutyric acid was \(+38.80^\circ\). Somewhat later the configuration of β-aminobutyric acid was established. \((+)\)-β-Aminobutyric and \(L\)-α-aminobutyric acids were converted to 2-phthalimidobutane, and, by analogy with α-amino acids, β-aminobutyric acid was assigned to the \(L\)-series \((^7)\).

\[ \begin{array}{ccc} \begin{array}{c} \mathrm{CH_2COOH}\\ |\\ \mathrm{H_2N{-}C{-}H}\\ |\\ \mathrm{CH_3} \end{array} & \longrightarrow & \begin{array}{c} \mathrm{CH_2CH_3}\\ |\\ \mathrm{C_6H_4(CO)_2N{-}C{-}H}\\ |\\ \mathrm{CH_3} \end{array} \longleftarrow \begin{array}{c} \mathrm{COOH}\\ |\\ \mathrm{H_2N{-}C{-}H}\\ |\\ \mathrm{CH_2CH_3} \end{array} \\[1em] (+)\ \text{3s-aminobutyric acid} && (-)\ \text{2s-aminobutyric acid} \end{array} \]

In the present work we propose a new method for the synthesis of both antipodes of β-aminobutyric acid, starting from crotonic acid and optically active α-phenylethylamine.

\[ \mathrm{CH_3CH{=}CHCOOH} + \begin{array}{c} \mathrm{C_6H_5\overset{*}{CH}CH_3}\\ |\\ \mathrm{NH_2} \end{array} \rightarrow \begin{array}{c} \mathrm{CH_3\overset{*}{CH}CH_2COOH}\\ |\\ \mathrm{NH\overset{*}{CH}CH_3}\\ |\\ \mathrm{C_6H_5} \end{array} \rightarrow \begin{array}{c} \mathrm{CH_3\overset{*}{CH}CH_2COOH}\\ |\\ \mathrm{NH_2} \end{array} \]

\[ \begin{array}{cccc} \text{(I)} & \text{(II)} & \text{(IIIa, IIIb, IIIc, IIId)} & \text{(IV)} \end{array} \]

When one of the antipodes of α-phenylethylamine is added to crotonic acid, two diastereomeric forms of N-substituted β-aminobutyric acid are formed. We separated the diastereomers IIIa and IIIb, using the greater solubility of one of them in acetone. When using α-phenylethylamine with \([\alpha]_D^{20} -41^\circ\), we isolated the N-substituted β-aminobutyric acids IIIa with \([\alpha]_D^{20} +21.99^\circ\) (yield 27%) and IIIb with \([\alpha]_D^{20} -44.82^\circ\) (yield 38.5%).

By hydrogenolysis of the N-substituted acids, \((+)\)-β-aminobutyric acid with \([\alpha]_D^{20} +35.69^\circ\) (92% optical purity) and \((-)\)-β-aminobutyric acid with \([\alpha]_D^{20} -33.91^\circ\) (87.4% optical purity) were obtained. In the case of addition

to crotonic acid, $\alpha$-phenylethylamine with $[\alpha]_D^{20} +41^\circ$ gave N-substituted $\beta$-aminobutyric acids—IIIc with $[\alpha]_D^{20} -18.29^\circ$ (yield 28.8%) and IIIa with $[\alpha]_D^{20} +30.69^\circ$ (yield 42.3%). Hydrolysis of the N-substituted acids IIIc and IIIa led to $\beta$-aminobutyric acids with $[\alpha]_D^{20} -34.91^\circ$ (90% optical purity) and with $[\alpha]_D^{20} +31.25^\circ$ (81% optical purity). The total yield of the N-substituted $\beta$-aminobutyric acids IIIa and IIIb (IIIc and IIId) in both cases is $\sim 70\%$.

Table 1

Experimental data*

* Literature data: (+) $\beta$-aminobutyric acid—m.p. 200°; $[\alpha]_D^{20} +35.3^\circ$ (C = 9.6; H₂O); $[\alpha]_D^{20} +14.7^\circ$ (C = 9.8; 1 N NaOH) (4); $[\alpha]_D^{20} +29.7^\circ$ (C = 10; 1 N HCl); $[\alpha]_D^{18} +38.8^\circ$ (C = 0.5; H₂O) (6); (−) $\beta$-aminobutyric acid—m.p. 220°; $[\alpha]_D^{20} -35.2^\circ$ (C = 10; H₂O) (4).

By the method proposed by us, one of the diastereomers is isolated in the predominant amount ($\sim$ by 14%). In order to decide the question of asymmetric induction in this reaction, we carried out hydrolysis of the mixture of diastereomers IIIa and IIIb (without separation) from $\alpha$-phenylethylamine

Table 2

Molecular rotations of $\beta$-aminobutyric acids from (+) $\alpha$-phenylethylamine*

* Values of the molecular rotations are given for only one antipode of $\beta$-aminobutyric acid.

with $[\alpha]_D^{20} -41^\circ$. After removal of the impurity of optically active $\alpha$-phenylethylamine, the rotation of the acidic solution of $\beta$-aminobutyric acid was measured. At the sodium D-line it proved to be $-4^\circ$. Thus, both experiments on the separation of diastereomers and experiments without separation indicate

for the fact that, on addition of optically active α-phenylethylamine to crotonic acid, asymmetric induction is observed.

For conclusions about the regularities of this reaction, further accumulation of experimental material is necessary.

For β-aminobutyric and N-substituted β-aminobutyric acids we have, for the first time, recorded optical rotatory dispersion curves. In Fig. 1 are shown the ORD curves of acids obtained using (−)-α-phenylethylamine; Table 2 gives the values of molecular rotations for β-aminobutyric acids isolated using (+)-α-phenylethylamine. To designate the configurations of optically active β-aminobutyric acids we used the ρ—σ system proposed by Terent’ev and co-workers (8).

Fig. 1. 1 — 3σ-aminobutyric acid in 2 N NaOH; 2 — (+)3σ-aminobutyric acid in 2 N HCl; 3 — (+)3σ-aminobutyric acid in H₂O; 4 — (+)3σ-(N-phenylethyl)-aminobutyric acid in H₂O; 5 — (+)3σ-(N-phenylethyl)-aminobutyric acid in 2 N HCl; 6 — (+)3σ-(N-phenylethyl)-aminobutyric acid in 2 N NaOH; 7 — (−)3ρ-(N-phenylethyl)-aminobutyric acid in H₂O; 8 — (−)3ρ-(N-phenylethyl)-aminobutyric acid in 2 N NaOH; 9 — (−)3ρ-(N-phenylethyl)-aminobutyric acid in 2 N HCl.

Experimental Part

Racemic β-N-phenylethylaminobutyric acid (III). To a solution of 2.2 g (0.026 mole) of crotonic acid in 6 ml of freshly distilled dry pyridine, 3 g (0.026 mole) of racemic α-phenylethylamine is added dropwise with shaking. The mixture is heated in an oil bath at 120–130° for 2 h. After cooling, the pyridine is distilled off in vacuo. The oily residue is treated with dry acetone; a white crystalline precipitate of β-N-phenylethylaminobutyric acid separates. Yield 3.4 g (65.4%); mp 189–190° (from acetone); \(R_f\) 0.69 (butanol : water : acetic acid = 4 : 5 : 1).

Found, %: C 69.15, 69.24; H 8.50, 8.59
Calculated, %: C 69.56; H 8.21

Racemic β-aminobutyric acid (IV). 0.5 g (0.002 mole) of III is dissolved in 10 ml of 30% ethyl alcohol. The mixture is hydrogenated over palladium black in a stream of hydrogen at 40° for 20 h. The catalyst is filtered off; the alcoholic solution of β-aminobutyric acid is evaporated to a volume of 1 ml. The acid is precipitated with acetone. Yield 0.2 g (100% based on III); mp 191–193° (2) (precipitated from 96% alcoholic solution with acetone); \(R_f\) 0.21 (butanol : water : acetic acid = 4 : 5 : 1).

Found, %: C 46.17, 46.32; H 8.85, 8.82
Calculated, %: C 46.60; H 8.74

(+) 3σ- and (−) 3ρ-N-phenylethylaminobutyric acids from α-phenylethylamine with \([\alpha]_D^{20} -41^\circ\). To a solution of 2.2 g (0.026 mole) of crotonic acid in 6 ml of dry, freshly distilled pyridine, 3 g (0.026 mole) of α-phenylethylamine with \([\alpha]_D^{20} -41^\circ\) is added dropwise with shaking. The reaction mixture is heated for 2 h in an oil bath at a temperature of 120–130°. The pyridine is distilled off in vacuo and freshly distilled acetone (~20 ml) is added to the residue. A white crystalline…

crystalline precipitate (IIIa). Yield 1.4 g (27%); mp 187–188°; \([\alpha]_D^{20}\) +21.99° (\(C = 1.4\); H\(_2\)O); \([\alpha]_D^{20}\) −32.1° (\(C = 0.9\); 2 N NaOH); \([\alpha]_D^{20}\) −6.66° (\(C = 1.2\); 2 N HCl); \(R_f\) 0.69 (butanol : water : acetic acid = 4 : 5 : 1). Ether is added to the acetone mother liquor; a white, oily substance (IIIb) precipitates, crystallizing upon trituration with absolute ether. Yield of IIIb—2 g (38.5%); mp 150–151°; \([\alpha]_D^{20}\) −44.82° (\(C = 1.5\); H\(_2\)O); \([\alpha]_D^{20}\) −71.08° (\(C = 1.4\); 2 N NaOH); \([\alpha]_D^{20}\) −28.19° (\(C = 1.4\); 2 N HCl).

(+)3σ- and (−)3ρ-Aminobutyric acids from α-phenylethylamine with \([\alpha]_D^{20}\) −41°. A solution of 0.5 g (0.002 mole) of the N-substituted acid with \([\alpha]_D^{20}\) +21.99° (IIIa) in 10 ml of 30% ethyl alcohol is hydrogenated over palladium black in a stream of hydrogen for 24 h. After separation of the catalyst, the solution is evaporated to a volume of 1 ml. The acid is precipitated with acetone. Yield 0.22 g (100% based on IIIa); mp 215–218°; \([\alpha]_D^{20}\) +35.69° (\(C = 2\); H\(_2\)O); \([\alpha]_D^{20}\) +12.65° (\(C = 0.9\); 2 N NaOH); \([\alpha]_D^{20}\) +16.26° (\(C = 1.2\); 2 N HCl); \(R_f\) 0.21 (butanol : water : acetic acid = 4 : 5 : 1). Upon hydrogenation of 0.5 g (0.002 mole) of the N-substituted acid with \([\alpha]_D^{20}\) −44.82° (IIIb) under the same conditions, 0.22 g of β-aminobutyric acid is obtained, mp 215–216°; \([\alpha]_D^{20}\) −33.94° (\(C = 1\); H\(_2\)O) (4); \(R_f\) 0.21 (in the same system).

(−)3ρ- and (+)3σ-N-Phenylethylaminobutyric acids from α-phenylethylamine with \([\alpha]_D^{20}\) +41°. From 2.2 g (0.026 mole) of crotonic acid in 6 ml of freshly distilled dry pyridine and 3 g (0.026 mole) of α-phenylethylamine with \([\alpha]_D^{20}\) +41°, 1.5 g (28.8%) of IIIc is obtained (from acetone); mp 187–189°; \([\alpha]_D^{20}\) −18.29° (\(C = 1.4\); H\(_2\)O); \([\alpha]_D^{20}\) +32.45° (\(C = 1.8\); 2 N NaOH); \([\alpha]_D^{20}\) +4.5° (\(C = 1.5\); 2 N HCl); \(R_f\) 0.69 (butanol : water : acetic acid = 4 : 5 : 1).

After addition of ether to the acetone solution, an oily substance (IIId) precipitates, which is treated by the method described above. Yield 2.2 g (IIId; 42.3%); mp 145–147°; \([\alpha]_D^{20}\) +30.69° (\(C = 1.5\); H\(_2\)O); \([\alpha]_D^{20}\) +53.43° (\(C = 1.4\); 2 N NaOH); \([\alpha]_D^{20}\) +18.96° (\(C = 1.4\); 2 N HCl); \(R_f\) 0.69 (in the same system).

(−)3ρ- and (+)3σ-Aminobutyric acids. Hydrogenation of 0.5 g (0.002 mole) of the N-substituted β-aminobutyric acid IIIc \([\alpha]_D^{20}\) −18.29° in 10 ml of 30% ethyl alcohol over palladium black in a stream of hydrogen under the conditions described above leads to β-aminobutyric acid with mp 215–216° (4); \([\alpha]_D^{21}\) −34.91° (\(C = 2.2\); H\(_2\)O) (4); \([\alpha]_D^{20}\) −12.66° (\(C = 1.2\); 2 N NaOH); \([\alpha]_D^{20}\) −18.5° (\(C = 1.2\); 2 N HCl) \(R_f\) 0.21 (butanol : water : acetic acid = 4 : 5 : 1).

Upon hydrogenation of 0.5 g (0.002 mole) of the N-substituted β-aminobutyric acid (IIId) with \([\alpha]_D^{20}\) +30.69°, β-aminobutyric acid is obtained, mp 215–217°; \([\alpha]_D^{20}\) +31.25° (\(C = 0.9\); H\(_2\)O); \([\alpha]_D^{20}\) +11.02° (\(C = 0.8\); 2 N NaOH); \([\alpha]_D^{20}\) +14.4° (\(C = 0.9\); 2 N HCl); \(R_f\) 0.21 (in the same system).

Moscow State University
named after M. V. Lomonosov

Received
19 I 1965

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