Convenient Synthesis of 3-(S)-Amino-γ-butyrolactone

Abstract

An efficient two step conversion of N-t-Boc-l-aspartic acid β-benzyl ester to enantiopure 3-(S)-amino-γ-butyrolactone is described. In this route, chemoselective reduction of the α-carboxylic group in the starting material via a mixed anhydride with NaBH₄ afforded the corresponding alcohol in 95% yield without any loss of the optical purity. Subsequent acidic hydrolysis of the N-protected β-amino alcohol not only deprotected the amino group, but also produced the desired γ-lactone in 98% yield with complete retention of the optical activity.

amino acids - amino alcohols - lactones - reductions - ring closure

References

1a Bovy PR, Rico JG, and Rogers TE. inventors; U.S. Patent  6 037 365.  ; Chem. Abstr. 2000, 132, 207753

1b Bovy PR, Rico JG, and Rogers TE. inventors; U.S. Patent  9 506 038.  ; Chem. Abstr. 1995, 123, 33068

1c Bovy PR, Rico JG, and Rogers TE. inventors; U.S. Patent  9 312 103.  ; Chem. Abstr. 1993, 120, 106764

2a Askew BC, Hartman GD, Duggan ME, Young SD, Hutchinson JH, Wai JS, Egbertson MS, Vassallo LM, Libby LA, Ihle NC, Krause AE, and Halczenko W. inventors; U.S. Patent  9 714 417.  ; Chem. Abstr. 1997, 126, 5353

2b Askew BC, Hartman GD, Duggan ME, Young SD, Hutchinson JH, Wai JS, Egbertson MS, Vassallo LM, Libby LA, Ihle NC, Krause AE, and Halczenko W. inventors; U.S. Patent  5 852 045.  ; Chem. Abstr. 1998, 130, 66809

2c Sato M, Mannaka A, Takahashi K, Kawashima Y, and Hatayama K. inventors; J. P. Patent  7 206 860.  ; Chem. Abstr. 1995, 124, 8804

2d Hartman GD, Prugh JD, Halczenko W, Egbertson M, and Ihle N. inventors; U.S. Patent  9 504 531.  ; Chem. Abstr. 1995, 123, 228162

3 Ruminski PG, Clare M, Collins PW, Desai BN, Lindmark RJ, Rico JG, Rogers TE, and Russell MA. inventors; U.S. Patent  9 708 145.  ; Chem. Abstr. 1997, 126, 264011

4 Mullican MD. Lauffer DJ. Gillispie RJ. Matharu SS. Kay D. Porrit GM. Evans PL. Golec JMC. Murcko MA. Bioorg. Med. Chem. Lett.  1994,  4(19):  2359 

5a Chu DT, and Li Q. inventors; U.S. Patent  5 252 747.  ; Chem. Abstr. 1993, 120, 298642

5b Ashina Y, Fukuda Y, and Fukuda H. inventors; E. P. Patent  443 498.  ; Chem. Abstr. 1991, 115, 256018

6 Nagai K. Tanaka R. Murakami H. Sano A. Arzneim-Forsch.  1967,  17:  1575 ; Chem. Abstr. 1967, 68, 67444

7 McGarvey GJ. Williams JM. Hiner RN. Matsubara Y. Oh T. J. Am. Chem. Soc.  1986,  108:  4943 

8 Rinehart KL. Harada K. Namikoshi M. Chen C. Harvis CA. Munro MHG. Blunt JW. Mulligan PE. Beasley VR. Dahlem AM. Carmichel WW. J. Am. Chem. Soc.  1988,  110:  8557 

9 Atmani A. El Hallaoui A. El Hajji S. Roumestant ML. Viallefont P. Synth. Commun.  1971,  21:  2383 

10 Hvidt T. Szarek WA. Maclean DB. Can. J. Chem.  1988,  66:  779 

11 Calvisi G. Catini R. Chiariotti W. Giannessi F. Muck S. Tinti MO. De Angelis F. Synlett  1997,  71 

12

Benzyl (3 S )-[( tert -butoxycarbonyl)amino]-4-hydroxy-butanoate(3). Prepared from N-t-boc-l-aspartic acid
β-benzyl ester following a literature procedure [13d] as a white solid. Yield 95%, ee > 98%. Enantiomeric excess was determined by HPLC using a normal phase Chiralpak AD column, hexanes-isopropanol 90:10, 1 mL/min, at 250 nm, mp 62-63.8 °C [α]_D ²⁵ -6.0 (c = 1, MeOH); lit. [13e] [α]_D -6.0 (c = 1, MeOH). ¹H NMR (250 MHz; CDCl₃), δ: 7.33 (s, 5 H), 5.28 (s, 1 H), 5.11 (s, 2 H), 4.00 (s, 1 H), 3.64 (d, J = 4.7 Hz, 2 H), 2.88 (s, 1 H), 2.64 (d, J = 6.2 Hz, 2 H), 1.42 (s, 9 H). ¹³C NMR (67.5 MHz; CDCl₃) δ: 172.06, 156.23, 135.99, 129.02, 128.76, 128.66, 107.82, 80.29, 67.05, 49.87, 36.47, 28.76. MS (FAB) (M + H⁺) calcd 310.16, found 310.10. Anal. Calcd. for C₁₆H₂₃NO₅: C, 62.12; H, 7.49; N, 4.53. Found C, 61.72; H, 7.39; N, 4.41.

13a Seki H. Koga K. Matsu H. Ohki S. Matsuo I. Yamada S. Chem. Pharm. Bull.  1965,  13:  995 

13b Soai K. Bull. Chem. Soc. Jpn.  1984,  57:  2327 

13c Soai K. Yokoyama S. Mochida K. Synthesis  1987,  647 

13d Kokotos G. Synthesis  1990,  299 

13e Rodriguez M. Linares M. Doulut S. Heitz A. Martinez J. Tetrahedron Lett.  1991,  32:  923 

14

3-( S )-amino-γ-butyrolactone hydrochloride(1) The amino alcohol 4 (1.26g, 4 mmol) was treated with 40 mL of 2 M HCl in diethyl ether. The temperature was kept at 0 °C for 6 h, then allowed to rise to room temperature, and stirred for 18 hours. The excess of HCl and ether were evaporated first under a stream of N₂ and then under vacuum. The residue, a white solid was filtered out, washed with ethyl ether (3 × 20 mL), and dried at room temperature. Yield 98%. mp 182-184 °C. [α]_D ²⁵ -59.3 (c = 1, H₂O); lit. [11] [α]_D ²⁰ + 56.7 (c = 1, H₂O) (R) form. ¹H NMR [250 MHz; (DMSO-d₆)] δ: 8.76 (s, 3 H), 4.5 (dd, J = 10.4 Hz, J = 6.6 Hz, 1 H), 4.36 (dd, J = 10.4 Hz, J = 2.7 Hz, 1 H), 4.10 (m, 1 H), 3.0 (dd, J = 18.3, J = 8.5 Hz, 1 H), 2.57 (dd, J = 18.3 Hz, J = 2.9 Hz, 1 H). ¹³C NMR: [67.5 MHz; (DMSO-d₆)] δ: 175.39, 71.05, 41.19, 33.42. MS (FAB) (M + H⁺) calcd. 102.1, found 102.1. Anal. Calcd. for C₄H₈ClNO₂: C, 34.92; H, 5.86; N, 10.18; Cl, 25.77. Found C, 34.99; H, 5.62; N, 10.08; Cl, 25.12.