Kinetic Resolution of 5-Substituted Oxazinones with Bifunctional Chiral Base/Squaramide Organocatalysts

Abstract

5-Substituted oxazinones provide N-protected β²-amino acid esters upon alcoholytic ring opening. Thus far, this access to enantiopure β²-amino acids has been restricted to the use of enzymes (hydrolases) as catalysts for the kinetic resolution of racemic 5-substituted oxazinones, and branched alkyl or ortho-substituted aryl groups on the substrate oxazinone’s 5-position were typically not tolerated. We herein report that certain bifunctional chiral base/squaramide organocatalysts, in particular those derived from cis-1,2-diaminocyclohexane or 9-amino-9-epi-quinine, allow the first organocatalytic kinetic resolution of this ‘difficult’ class of oxazinone substrates, affording N-protected β²-amino acid esters with selectivity factors up to 43.

Key words

asymmetric catalysis - kinetic resolution - oxazinone - organocatalysis - squaramides

• References and Notes

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• 10 The preparation of the catalysts and substrates used is described in the Supporting Information. Analytical data of cis-DACH derived squaramide catalyst II, 3-[3,5-bis(trifluoromethyl)anilino]-4-([(1R,2S)-2-(piperidin-1-yl)cyclohexyl]-amino)cyclobut-3-ene-1,2-dione: Pale yellow solid; mp 157–159 °C. ¹H NMR (300 MHz, CD₃OD): δ = 1.49–1.55 (m, 12 H), 1.62–1.99 (m, 3 H), 2.93 (br s, 5 H), 7.52 (s, 1 H), 8.14 (s, 2 H). ¹³C NMR (75 MHz, CD₃OD): δ = 18.76, 22.88, 23.14, 24.64, 28.03, 31.80, 50.63, 50.92, 65.24, 115.05, 115.10, 123.22 (q, J = 270.3 Hz), 132.47 (q, J = 32.9 Hz), 141.17, 163.80, 169.63, 181.02, 184.10. FT-IR (ATR): 2937 (w), 1791 (w), 1685 (w), 1598 (m), 1544 (m), 14733 (m), 1436 (m), 1375 (s), 1330 (m), 1274 (s), 1244 (w), 1174 (s), 1124 (s), 933 (m), 877 (m), 731 (m) cm^–1. MS (ESI): m/z [M + H]⁺ = 490.1. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₂₅F₆N₃O₂: 490.1929; found: 490.193. [α]₅₈₉ –7.9, [α]₅₄₆ –6.7 (c = 0.5 in MeOH, at 20 °C).
• 11 Kinetic resolutions: The reaction was carried out in abs. toluene at room temperature and under an inert atmosphere. The oxazinone (75.0 mmol, 1.0 equiv) and allyl alcohol (5.1 μL, 1.0 equiv) were dissolved in abs. toluene (1.0 mL), and 5.0 mol% of the catalyst were added. Conversions/yields and enantiomeric excesses (ee) were determined by HPLC on chiral stationary phase as described in the Supporting Information.