Synthesis of N-Cbz-Substituted β³-Amino Ketones Utilizing 4-Substituted 1,3-Oxazinan-6-ones

Abstract

Stereoselective synthesis of N-Cbz-substituted β-amino ketones exploiting the versatile 1,3-oxazin-6-one scaffold is reported. The 4-substituted 1,3-oxazinan-6-ones were enolized and acylated diastereoselectively by addition of various acyl halides. Acidic decarboxylation was then employed to smoothly transform the 5-acylated products to chiral β-amino ketones. This methodology further highlights the utility of the 1,3-oxazinan-6-one as a scaffold to access valuable synthons that are used in the peptidomimetic field.

Key words

ketones - amino acids - acylation - ring opening - oxazinanones

• References and Notes

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• 11 General Procedure 1 5-Acylation of 1,3-Oxazinan-6-ones A solution of the 1,3-oxazinan-6-one 1–4 (0.1 M in dry freshly distilled THF) was cooled to –78 °C under an argon atmosphere. Then LiHMDS (1.1 equiv of a 1.0 M solution in THF) was added dropwise, and the solution was left to stir at –78 °C for 40 min. The acylating agent (3.0 equiv) was then added dropwise and stirring was continued for 3 h at –78 °C. The solution was then allowed to warm to –50 °C, and the reaction was then quenched with sat. NH₄Cl solution (5 mL). The solution was diluted with EtOAc (20 mL) and washed with H₂O (20 mL). The organic layer was dried (MgSO₄) and concentrated in vacuo to give an oil. The oil was subjected to flash column chromatography, eluting with 5–30% EtOAc–hexane. Data for (4S,5R)-N-Benzyloxycarbonyl-4-isopropyl-5-propionyl-1,3-oxazinan-6-one (5) General Procedure 1 was followed for the acylation of oxazinanone 1 (63 mg, 0.23 mmol) with propionyl chloride (59.8 μL, 0.68 mmol), to afford the desired 5-substituted 1,3-oxazinan-6-one 5 as a clear oil (crystallized on standing; 60 mg, 80% yield); mp 82–84 °C; R_f = 0.23 (20% EtOAc–hexane); [α]_D ²⁵ +116 (c 2.17, MeOH). ¹H NMR (300 MHz, CDCl₃): δ = 7.33 (s, 5 H), 5.93 (d, 1 H, J = 9.9 Hz), 5.17 (s, 2 H), 4.93 (d, 1 H, J = 9.9 Hz), 4.59 (t, 1 H, J = 7.2 Hz), 3.73 (d, 1 H, J = 7.2 Hz), 2.84–2.73 (m, 1 H), 2.58–2.47 (m, 1 H), 1.88–1.77 (m, 1 H), 1.09 (t, 3 H, J = 7.2 Hz), 0.89 (d, 3 H, J = 7.2 Hz), 0.85 (d, 3 H, J = 7.2 Hz). ¹³C NMR (75 MHz, CDCl₃): δ = 202.7 167.3, 154.5, 134.9, 128.3, 128.1, 127.8, 72.9, 68.2, 55.9, 55.1, 36.5, 31.0, 18.3, 18.1, 7.2. IR (film): ν_max = 2967, 2940, 1748, 1717, 1458, 1412, 1258, 1123, 979 cm^–1. HRMS (ESI^–): m/z calcd for C₁₈H₂₃NO₅ [M – H]^–: 332.1503; found: 332.1496.
• 12 General Procedure 2
  Formation of the β³-Amino Ketones The oxazinanone 15–24 was dissolved in a mixture of THF–2 M HCl (1:1, 0.013 M solution), and the reaction mixture was gently heated to 50 °C for 4–6 h. The THF was then removed under reduced pressure. The aqueous solution was taken up EtOAc and washed with H₂O (3 × 10 mL) followed by brine (1 × 10 mL). The organic layer was dried (MgSO₄) and evaporated in vacuo to give an oil. The oil was subjected to flash column chromatography, eluting with 5–20% EtOAc–hexane.
• 13 Data for (5R)-(N-Benzyloxylcarbonyl-5-amino)-6-methyl-heptan-2-one (15) General Procedure 2 was followed for the hydrolysis of the 1,3-oxazinan-6-one 5 (31 mg, 0.09 mmol), and afforded the β-amino ketone 15 as a white solid (24 mg, 92% yield); mp 75–77 °C; R_f = 0.50 (30% EtOAc–hexane); [α]_D ²⁵ –3.6 (c 1.09, MeOH). ¹H NMR (300 MHz, CDCl₃): δ = 7.32–7.27 (m, 5 H), 5.14 (d, 1 H, J = 8.9 Hz), 5.06 (s, 2 H), 3.83–3.76 (m, 1 H), 2.61 (br d, 2 H, J = 5.7 Hz), 2.47–2.33 (m, 2 H), 1.89–1.80 (m, 1 H), 1.00 (t, 3 H, J = 7.2 Hz), 0.89 (d, 3 H, J = 4.2 Hz), 0.87 (d, 3 H, J = 4.5 Hz). ¹³C NMR (75 MHz, CDCl₃): δ = 210.0, 155.7, 136.3, 128.1, 127.6, 127.5, 66.2, 53.2, 43.9, 35.8, 31.2, 19.1, 18.2, 7.3. IR (film): ν_max = 3325, 2940, 2878, 1709, 1682, 2539, 1454, 1416, 1308. HRMS (ESI⁺): m/z calcd for C₁₆H₂₃NO₃ [M + H]⁺: 278.1751; found: 278.1756. HPLC [Chiralpak AD-H, PE–2-PrOH (90:10), 25 °C, 254 nm]: t _R (major) = 7.1 min; t _R (minor) = 6.1 min, 97% ee.