An Efficient Synthesis of Chiral Cyclic β-Amino Acids via Asymmetric Hydrogenation

Abstract

Cyclic β-amino acids, homoproline, homopipecolic acid and 3-carboxy-methylmorpholine were obtained in high enantiomeric excesses by transition metal-catalyzed asymmetric hydrogenation of cyclic β-acylamino-alkenoates. These compounds were synthesized by a thio-Wittig reaction on N-protected thiolactames.

Key words

β-aminoacids - asymmetric synthesis - rhodium - ruthenium - iridium

References

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Yields from the corresponding N-protected thiolactames: compound 2: 60% (E: 100%); compound 3: 55% (E:Z = 87:13). The reaction failed with hindered protective groups such as Boc.

20

Compound 4 was obtained as the pure E-isomer using the reaction of a Peterson reagent (Me₃SiCHLi-CO₂Et) with the N-protected δ-lactone.

21

Typical Procedures: Ruthenium: [(COD)Ru(2-methylallyl)₂] (0.01 mmol, 3.2 mg, 1 equiv) and (S,S)-MeO-Biphep (0.012 mmol, 7 mg, 1.2 equiv) were stirred under argon for 30 min in acetone (1 mL), 0.16 N HBr in MeOH (140 µL, 2.2 equiv) was then slowly added and the solution was stirred for 30 min at r.t. The unsaturated enamido ester (100 equiv) was then added and the solution was transferred into an autoclave. The autoclave was then purged three times with hydrogen and filled with hydrogen at the required pressure. The mixture was stirred at r.t. for 24 h. After release of the hydrogen, the solvent was evaporated. The residue was passed through a short silica gel plug to give the reducted β-amino esters.
Rhodium: [(R,R)-(Me-DuPHOS)Rh(COD)(OTf)] (0.01 mmol, 6.6 mg, 1 equiv) was stirred under argon in degassed CH₂Cl₂ (1 mL) at r.t. The unsaturated enamido ester (100 equiv) in CH₂Cl₂ was then added and the solution was transferred into an autoclave and treated as previously described.
Iridium: [(COD)Ir(Cl)]₂ (0.05 mmol, 3.4 mg, 0.5 equiv) and (S)-BINAP (0.012 mmol, 7.5 mg, 1.2 equiv) were stirred under argon in a glass tube for 30 min in degassed CH₂Cl₂ (2 mL), the unsaturated enamido ester (100 equiv) was then added, the glass tube was transferred into an autoclave and treated as previously described.
Physical Data: compound 5: [α]_D ²⁰ +58.5 (c 2.3, CH₂Cl₂), ee: 97.3%. IR (KBr): 2955, 1737, 1698, 1452, 1385, 1194 cm^-1. ¹H NMR (200 MHz, CDCl₃), two conformers: δ = 1.23, 1.25 (2 t, 3 H, J = 7.1 and 7.2 Hz), 1.73-2.11 (m, 4 H), 2.01, 2.10 (2 s, 3 H), 2.31, 2.41, 2.54, 2.94 (4 dd, 2 × 2 H, J = 3.9, 9.5, 15.4 and 3.6, 10.3, 15.4 Hz), 3.43 (m, 2 H), 4.12 (2 q, 2 H, J = 7.1 and 7.2 Hz), 4.23, 4.38 (2 m, 1 H). ¹³C NMR (50 MHz, CDCl₃): δ = 14.2, 23.0, 23.9, 30.1, 37.6, 47.9, 53.8, 60.4, 169.3, 171.5. MS (CI, NH₃): m/z (%) = 217 (100) [M + 1], 200(23). Compound 6: [α]_D ²⁰ +13.7 (c 4.0, CHCl₃), ee: 95.1%. IR (KBr): 2976, 1735, 1701, 1413, 1392, 1163 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 1.23 (t, 3 H, J = 7.1 Hz), 1.40-1.60 (m, 6 H), 2.51 (dd, 2 H, J = 8.0 and 14.3 Hz), 2.81 (dd, 1 H, J = 7.4 and 14.3 Hz), 2.83 (t, 1 H, J = 11.5 Hz), 3.66 (s, 3 H), 4.07 (br s, 1 H), 4.09 (q, 2 H, J = 7.2 Hz), 4.72 (br s, 1 H). ¹³C NMR (50 MHz, D₂O): δ = 21.5, 21.9, 28.2, 40.0, 44.6, 54.6, 177.7. MS (CI): m/z = 144. Anal. Calcd for C₁₁H₁₉NO₄: C, 57.62; H, 8.35; N, 6.11. Found: C, 57.48; H, 8.53; N, 6.02.
(2 R )-2-Carboxymethylpiperidine: The ester 6 (0.5 mmol) was saponified at r.t. with KOH (2.75 mmol, 5.5 equiv) in solution in a EtOH (3.5 mL)-H₂O (0.75 mL) mixture for 48 h. After evaporation, the solid residue was then treated with HBr in HOAc (33%) for 24 h. After elimination of the HOAc under vacuo, the residue was chromatographed on Dowex H⁺ 50X8 resin (2 M aq NH₃) to give a white solid (70%): mp 95 °C (hexane); [α]_D ²⁰ -28 (c 0.60, H₂O), lit. [6] 93 °C; S compound [α]_D ²⁰ +33.5 (c 0.60, H₂O). IR (KBr): 3500-3200, 3011, 2980, 1736, 1639, 1433, 1185 cm^-1. ¹H NMR (200 MHz, D₂O): δ = 1.41 (m, 3 H), 1.76 (m, 3 H), 2.37 (d, 2 H, J = 6.7 and 15.0 Hz), 2.89 (td, 1 H, J = 12.6 and 12.7), 3.28 (m, 2 H). ¹³C NMR (50 MHz, D₂O): δ = 21.5, 21.9, 28.2, 40.0, 44.6, 54.6, 177.7. MS (CI): m/z = 144. Compound 8: [α]_D ²⁰ +30.2 (c 1.15, CH₂Cl₂), ee: 85.5%. IR (KBr): 2980, 1735, 1698 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 1.25 (t, J = 7.1 Hz, 3 H), 1.44 (s, 9 H), 2.54 (dd, J = 5.5 and 15.0 Hz, 1 H), 2.81 (dd, J = 8.8 and 15.0 Hz, 3 H), 4.11 (q, J = 7.1 Hz, 2 H), 4.36 (m, 1 H). ¹³C NMR (50 MHz, CDCl₃): δ = 14.2, 28.4, 33.8, 39.5, 48.1, 60.7, 66.9, 68.9, 80.3, 154.5, 171.3. MS (EI): m/z (%) = 273 (1), 217 (5), 200 (3), 172 (24), 142 (43), 130 (32), 86 (46), 57 (100), 41 (26). Anal. Calcd for C₁₃H₂₃NO₅: C, 57.13; H, 8.48; N, 5.12. Found: C, 57.06; H, 8.63; N, 5.04.

23

(3 S )-4- tert -Butoxycarbonyl-3-carboxymethylmor-pholine: mp 82 °C (hexane-i-Pr₂O, 8:2); [α]_D ²⁰ +35.7 (c 1.94, CH₂Cl₂), ee: 99%. IR (KBr): 3700-2500, 1713, 1694 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 1.47 (s, 9 H), 2.56 (dd, J = 6.0 and 15.4 Hz, 1 H), 2.83 (dd, J = 8.5 and 15.4 Hz, 1 H), 2.90-3.90 (m, 6 H), 4.34 (m, 1 H). ¹³C NMR (50 MHz, CDCl₃): δ = 28.2, 33.4, 39.4, 48.0, 66.7, 68.8, 80.5, 154.5, 175.9. MS (EI): m/z (%) = 245 (1), 190 (2), 172 (3), 130 (14), 114 (13), 100 (5), 86 (33), 70 (13), 57 (100). Anal. Calcd for C₁₁H₁₉NO₅: C, 53.87; H, 7.81; N, 5.71. Found: C, 53.95; H, 7.91; N, 5.59.