An Efficient Access to Conformationally Rigid Amino Acid Analogues with a Piperidine Skeleton

Abstract

Two unnatural conformationally constrained cyclic amino acid derivatives with the piperidine skeleton were synthesized in enantiomerically pure forms. The key step in the synthesis of these amino acids is the highly diastereoselective functionalization of the oxo group in a 4-oxo-pipecolic acid derivative.

Key words

reductive amination - constrained amino acids - pipecolic acid - piperidine - stereoselectivity

References and Notes

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9

(2 S ,4 R ,6 R )-4-Amino-6- tert -butyl- N -methylpiperidine-2-carboxamide (4)
NH₄OAc (3.27 g, 42.4 mmol) and NaBH₃CN (266 mg, 4.24 mmol) were added to a solution of ketone 2 (50 mg, 0.24 mmol) in anhyd MeOH (6 mL) in the presence of MS 4 Å. The resulting mixture was stirred at r.t. for 30 h. The mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by chromatography on basic alumina with CH₂Cl₂ to give the corresponding amine 4 as orange oil with the contamination of 4% 4S-epimer (epi-4). Yield 36 mg (72%); [α]_D ^²0 -29.0 (c 1.0, CH₂Cl₂). ^¹H NMR (600 MHz, CDCl₃): δ = 0.92 (s, 9 H), 1.65-1.75 (m, 1 H), 1.79-1.90 (m, 1 H), 2.42-2.44 (m, 1 H), 2.53-2.56 (m, 1 H), 2.75-2.83 (m, 5 H), 3.43-3.47 (m, 1 H), 6.64 (br s, 1 H). ^¹³C NMR (150 MHz, CDCl₃): δ = 26.1, 26.5, 33.4, 41.9, 44.0, 44.2, 57.8, 61.6, 172.7. ESI-MS: m/z calcd for C₁₁H₂₃N₃O: 214.1919 [M + H]⁺, 236.1738 [M + Na]⁺; found: 214.1901 [M + H]⁺, 236.1721 [M + Na]⁺. MS (EI): m/z (%) = 144 (60), 100 (40), 80 (100).

14

(2 S ,6 R )-Isobutyl-6- tert -butyl-4-(cyanomethylene)-2-(methylcarbamoyl)piperidine-1-carboxylate (7) To a solution of LDA (3.4 mL, 6.12 mmol) in anhyd THF (10 mL) at r.t. under argon was added a solution of diethyl cyanomethylphosphonate (0.8 mL, 5.1 mmol), and the mixture was stirred for 10 min. A solution of compound 6 (532 mg, 1.7 mmol) in anhyd THF (20 mL) was added, and the resulting mixture was stirred at r.t. until conversion was complete (ca. 60 min, as monitored by TLC). The reaction was quenched with H₂O (30 mL) and extracted with CH₂Cl₂ (3 × 15 mL). The combined organic extracts were dried with anhyd Na₂SO₄, filtered, evaporated under reduced pressure and subsequently purified by chromatography on silica gel (cyclohexane-EtOAc, 1:1) to give compound 7 as an inseperable mixture of E/Z (1:1) isomers (determined by crude ^¹H NMR). Yield 548 mg (96%); [α]_D ^²0 -31.0 (c 1.0, CHCl₃). ^¹H NMR (300 MHz, CDCl₃): δ = 0.80-0.94 (m, 15 H), 1.70-1.73 (m, 1 H), 1.84-2.07 (m, 4 H), 2.61-2.77 (m, 2 H), 2.77 (s, 3 H), 3.85-3.92 (m, 2 H), 4.19-4.29 (m, 1 H), 4.89 (br s, 1 H), 4.90 (br s, 1 H, olefinic proton for the other isomer). ^¹³C NMR (75 MHz, CDCl₃): δ = 19.2, 26.4, 27.1, 28, 37.8, 41.1, 56.0, 57.5, 60.5, 73.0, 115.3, 125.0, 158.0, 162.2, 171.7. ESI-MS: m/z calcd for C₁₈H₂₉N₃O₃: 336.2287 [M + H]⁺, 358.2106 [M + Na]⁺; found: 336.2271 [M + H]⁺, 358.2092 [M + Na]⁺.

15

(2 S ,4 R ,6 R )-Isobutyl-6- tert -butyl-4-(cyanomethyl)-2-(methylcarbamoyl)piperidine-1-carboxylate (8)
A 1.0 M solution of L-Selectride^® in THF (3.76 mL, 3.76 mmol) was added dropwise to a 1:1 E/Z mixture of compound 7 (315 mg, 0.94 mmol) dissolved in anhyd THF (20 mL) at -78 ˚C under argon, and the mixture was stirred for 20 h at -78 ˚C. The reaction mixture was warmed up to 0 ˚C, and then sat. aq NH₄Cl (30 mL) was added carefully with stirring at 0 ˚C. After extraction with EtOAc (3 × 15 mL), the combined organic layers were dried with anhyd Na₂SO₄, filtered, and the solvents evaporated in vacuo followed by purification of the residue by silica gel column chromatography (cyclohexane-EtOAc, 70:30) to afford 8 (exclusively one diastereomer from ^¹H NMR) as yellow oil. Yield 211 mg (67%); [α]_D ^²0 -43.0 (c 1.0, CHCl₃). ^¹H NMR (600 MHz, CDCl₃): δ = 0.85 (s, 9 H), 0.93 (d, ^³ J _H,H = 6.7 Hz, 6 H), 1.19-1.24 (m, 1 H), 1.35-1.41 (m, 1 H), 1.91-1.98 (m, 1 H), 2.18-2.25 (m, 2 H), 2.37-2.40 (m, 1 H), 2.55 (br s, 1 H), 2.73 (d, ^³ J _H,H = 6.0 Hz, 3 H), 3.78-3.80 (m, 1 H), 3.93-3.95 (m, 1 H), 4.13-4.15 (m, 1 H), 4.80-4.83 (m, 1 H), 6.86 (br s, 1 H). ^¹³C NMR (151 MHz, CDCl₃): δ = 19.4, 24.8, 25.1, 25.8, 26.6, 28.3, 29.7, 30.1, 37.2, 52.6, 57.9, 72.9, 118.0, 159.8, 172.9. ESI-MS: m/z calcd for C₁₈H₃₁N₃O₃: 338.2443 [M + H]⁺, 360.2263 [M + Na]⁺; found: 338.2442 [M + H]⁺, 360.2265 [M + Na]⁺.

16

(2 S ,4 R ,6 R )-Isobutyl-4-(2-aminoethyl)-6- tert -butyl-2-(methylcarbamoyl)piperidine-1-carboxylate (5)
A solution of 8 (50 mg, 0.15 mmol) in anhyd THF (2 mL) was added to a suspension of LiAlH₄ (5 mg, 0.15 mmol, 1 equiv) in anhyd THF (3 mL) at 0 ˚C. The reaction was stirred for 1 h at r.t. and then quenched with aq 2 M HCl (2 mL) at 0 ˚C. The compound was extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with sat. aq NaHCO₃ (5 mL), brine (5 mL), dried over Na₂SO₄, and evaporated. Purification of the residue was done by silica gel column chromatography (cyclohexane-EtOAc, 70:30) to afford 5 as colorless oil. Yield 41 mg (82%); [α]_D ^²0 -28.0 (c 1.0, CHCl₃). ^¹H NMR (300 MHz, CDCl₃): δ = 0.84 (s, 9 H), 0.91-0.95 (m, 8 H), 1.13-1.27 (m, 3 H), 1.75-1.98 (m, 3 H), 2.22-2.33 (m, 2 H), 2.72-2.81 (m, 5 H), 3.79-3.98 (m, 3 H), 4.75-4.77 (m, 1 H), 6.88 (br s, 1 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 19.5, 26.0, 28.0, 28.4, 28.6, 30.6, 31.2, 37.2, 39.2, 41.0, 50.3, 53.3, 72.7, 159.7, 173.5. ESI-MS: m/z calcd for C₁₈H₃₅N₃O₃: 342.2756 [M + H]⁺; found: 342.2758 [M + H]⁺.