An Efficient Method for Constructing Cyclic β-Amino Acids Bearing Quaternary Stereocenters

^◊ These authors contributed equally to this work

Abstract

This paper describes an efficient method for constructing cyclic β-amino acids bearing quaternary stereocenters. NaHMDS-promoted asymmetric α-alkylation was employed to obtain the key intermediates with quaternary stereogenic centers, which were subsequently reduced by NaBH₄ in 10% methanol in THF, with high yields and high diastereoselectivities. By removing the allyl ester group and the chiral auxiliary, the corresponding cyclic β-amino acid hydrochlorides were finally obtained.

Key words

β-amino acids - quaternary stereocenters - asymmetric alkylation - sulfimines - diastereoselectivity

• References and Notes

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• 34 Allyl (1S)-1-Benzyl-2-[(tert-butylsulfinyl)imino]cyclopentanecarboxylate (3a); Typical Procedure In a round-bottomed flask, a solution of compound 4a (2.00 g, 7.37 mmol) in freshly distilled THF (25 mL) was mixed with a 2 M solution of NaHMDS in THF (5.53 mL) under N₂ at 0 °C. After 15 min, BnBr (2.77 g, 16.2 mmol) was added dropwise, and the mixture was stirred at r.t. overnight. When the substrate was completely consumed (TLC), the reaction was quenched with sat. aq NH₄Cl (100 mL) and the mixture was extracted with EtOAc (3 × 100 mL). The combined organic phases were dried (Na₂SO₄), filtered, and concentrated in vacuo. The residue was purified by flash column chromatography [silica gel; PE–EtOAc (5:1)] to give a colorless oil; yield: 2.11 g (79%); [α]_D ²³ –102.4 (c 1.0, CHCl₃). IR (KBr): 3062, 3029, 1733, 1640, 1495, 1474, 1390, 1263, 1219, 1146, 1084, 931, 795, 770, 703 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.26–7.18 (m, 3 H), 7.17–7.11 (m, 2 H), 5.89 (ddt, J = 17.1, 10.4, 5.9 Hz, 1 H), 5.28 (ddq, J = 24.0, 10.4, 1.3 Hz, 2 H), 4.58 (ddt, J = 5.9, 4.6, 1.3 Hz, 2 H), 3.32 (d, J = 13.7 Hz, 1 H), 3.16–3.04 (m, 2 H), 2.52 (ddd, J = 14.9, 9.4, 7.9 Hz, 1 H), 2.26 (dt, J = 12.7, 6.4 Hz, 1 H), 1.89–1.74 (m, 2 H), 1.56–1.47 (m, 1 H), 1.29 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 188.5, 172.1, 137.2, 131.8, 130.4, 128.4, 126.9, 119.1, 66.3, 62.8, 58.4, 40.9, 33.4, 31.9, 22.9, 22.7. HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₀H₂₇NNaO₃S⁺: 384.1604; found: 384.1603. Allyl (1S,2R)-1-Benzyl-2-[(tert-butylsulfinyl)amino]cyclopentanecarboxylate (2a); Typical Procedure In a round-bottomed flask, NaBH₄ (0.441 g, 11.7 mmol) was added to a solution of compound 3a (2.11 g, 5.83 mmol) in 10:1 THF–MeOH (60 mL) under N₂ at 0 °C, and the mixture was stirred at r.t. for 0.5 h. When the substrate was completely consumed (TLC), the reaction was quenched with sat. aq NH₄Cl (100 mL), and the mixture was extracted with EtOAc (3 × 100 mL). The combined organic phases were dried (Na₂SO₄) and concentrated in vacuo. The residue was purified by flash column chromatography [silica gel, PE–EtOAc (4:1)] to give a colorless oil; yield: 1.93 g (91%); [α]_D ²⁵ –99.4 (c 0.31, CHCl₃). IR (KBr): 2958, 2926, 2856, 1729, 1456, 1261, 1074, 702 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.21 (ddd, J = 10.1, 8.5, 5.4 Hz, 3 H), 7.06 (d, J = 6.6 Hz, 2 H), 5.81 (ddt, J = 16.4, 10.5, 5.9 Hz, 1 H), 5.30–5.16 (m, 2 H), 4.57–4.44 (m, 2 H), 4.35 (d, J = 1.7 Hz, 1 H), 3.84 (dd, J = 11.9, 3.9 Hz, 1 H), 3.23 (d, J = 13.8 Hz, 1 H), 2.54 (d, J = 13.8 Hz, 1 H), 2.36–2.23 (m, 1 H), 1.95 (dd, J = 12.2, 6.5 Hz, 1 H), 1.86–1.73 (m, 4 H), 1.27 (s, 9 H).¹³C NMR (101 MHz, CDCl₃): δ = 175.4, 137.5, 131.7, 129.9, 128.4, 126.8, 119.1, 65.7, 59.9, 57.9, 55.8, 36.1, 29.4, 28.7, 22.8, 19.5. HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₀H₂₉NNaO₃S⁺: 386.1760; found: 386.1758. (1S,2R)-2-Amino-1-benzylcyclopentanecarboxylic Acid Hydrochloride (1a); Typical Procedure In a round-bottomed flask, morpholine (0.923 mL, 10.6 mmol) and Pd(PPh₃)₄ (0.307 g, 0.27 mmol) were added to a solution of compound 2a (1.93 g, 5.31 mmol) in THF (30 mL), and the mixture was stirred at r.t. for 5 h. When the substrate was completely consumed (TLC), the mixture was washed with 1 M aq HCl (150 mL) and extracted with EtOAc (3 × 150 mL). The combined organic phases were dried (Na₂SO₄), filtered, and concentrated in vacuo. The residue was purified by flash column chromatography [silica gel, CH₂Cl₂–MeOH (50:1)] to give the free β-amino acid. The free β-amino acid was then treated with 4 M HCl in 1,4-dioxane (17 mL), and the solution was stirred at r.t. for 3 h. When the free acid was completely consumed (TLC), EtOAc was added to induce precipitation, and the mixture was filtered to give 1a as a pale-yellow solid; yield: 1.18 g (87% over two steps); mp 215–217 °C; [α]_D ²⁵ –43.2 (c 0.54, H₂O). IR (KBr): 2829, 2579, 1737, 1625, 1336, 1191, 1107, 1059, 860 cm^–1. ¹H NMR (400 MHz, D₂O): δ = 7.50–7.35 (m, 3 H), 7.35–7.25 (m, 2 H), 3.99 (t, J = 7.9 Hz, 1 H), 3.15 (d, J = 12.9 Hz, 1 H), 2.88 (d, J = 12.9 Hz, 1 H), 2.31 (ddd, J = 12.8, 8.8, 4.7 Hz, 1 H), 2.10–1.72 (m, 5 H). ¹³C NMR (101 MHz, D₂O): δ = 178.1, 136.0, 129.9, 128.7, 127.4, 57.2, 56.1, 36.0, 29.2, 27.8, 19.0. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₃H₁₈NO₂ ⁺: 220.1332; found: 220.1334.