Kinetic Resolution of α-Nitrolactones by Catalytic Asymmetric Hydrolysis or Ester–Amide Exchange Reaction

Abstract

C ₁-Symmetric chiral ammonium salt catalysts induced a kinetic resolution of racemic α-nitrolactones through an asymmetric ester–amide exchange reaction. The corresponding amides were obtained with high enantioselectivities and high S (= k _fast/k _slow) values. This reaction system is a useful approach for obtaining carbocyclic quaternary α-nitroamides as chiral building blocks.

Key words

nitrolactones - kinetic resolution - hydrolysis - ester–amide exchange - quaternary amino acids - Brønsted acid catalysis

• References and Notes

• 1 Fuji Y, Nakao R, Sugihara S, Fujita K, Araki Y, Kudoh T, Hayakawa I, Mizoguchi H, Sakakura A. Synlett 2020;
• 2 For a review, see: Cativiela C, Ordóñez M. Tetrahedron: Asymmetry 2009; 20: 1
• 3a Okino T, Hoashi Y, Furukawa T, Xu X, Takemoto Y. J. Am. Chem. Soc. 2005; 127: 119
• 3b Okino T, Hoashi Y, Takemoto Y. J. Am. Chem. Soc. 2003; 125: 12672
• 4 See the Supporting Information for details.

For reviews, see:
• 5a Kagan HB, Fiaud JC. Top. Stereochem. 1988; 18: 249
• 5b Keith JM, Larrow JF, Jacobsen EN. Adv. Synth. Catal. 2001; 343: 5
• 5c Robinson DE. J. E, Bull SD. Tetrahedron: Asymmetry 2003; 14: 1407
• 5d Vedejs E, Jure M. Angew. Chem. Int. Ed. 2005; 44: 3974
• 6 Because the absolute configuration of the recovered (+)-5a was 6aS, the absolute configuration of (–)-6a was assigned as 3R.
• 7 Because the reaction in Scheme 2 was conducted by using a mixture of 4b (25 mol%) and TFA (20 mol%), 5 mol% of 4b probably acted as a catalyst to promote the asymmetric hydrolysis of (±)-5a.
• 8 Qian Y, Ma G, Lv A, Zhu H.-L, Zhao J, Rawal VH. Chem. Commun. 2010; 46: 3004
• 9 Li W, Wu W, Yu F, Huang H, Liang X, Ye J. Org. Biomol. Chem. 2011; 9: 2505
• 10 Ogura Y, Akakura M, Sakakura A, Ishihara K. Angew. Chem. Int. Ed. 2013; 52: 8299
• 11 Ammonium salts of 4 were used as catalysts because the free amines 4 preferentially promoted the hydrolysis of 5a.
• 12 Asymmetric Ester–Amide Exchange Reaction of (±)-5a (Table [2], Entry 12); Typical Procedure TfOH (0.5 μL, 5.6 μmol) and N ¹-benzylglycinamide (7c; 7.7 mg, 0.051 mmol) were added to a solution of catalyst 4c (2.1 mg, 5.1 μmol) in toluene (1.2 mL) at rt, and the mixture was stirred for 5 min. The suspension was then cooled to –78 °C, (±)-5a (13.2 mg, 0.051 mmol) was added, and the resulting mixture was stirred at –78 °C for 24 h. The reaction was quenched by the addition of TFA (7.7 μL, 0.10 mmol), and the resulting mixture was purified by column chromatography [silica gel, hexane–acetone (3:1)] to give (–)-8ac (yield: 6.6 mg, 31%) and (+)-5a (yield: 8.5 mg, 64%). (1S,2R,3S,4R)-N-[2-(Benzylamino)-2-oxoethyl]-3-(2-hydroxyphenyl)-2-nitrobicyclo[2.2.1]hept-5-ene-2-carboxamide [(–)-8ac] White solid; mp 86.0–88.0 °C; [α]_D ²² –142.1 (c 0.19, CHCl₃) (95% ee). IR (film): 3324, 1655, 1539, 1456 cm^–1. ¹H NMR (600 MHz, CDCl₃): δ = 7.50 (br s, 1 H), 7.4–7.2 (m, 3 H), 7.2–7.1 (m, 3 H), 7.1–7.0 (m, 2 H), 6.81 (t, J = 5.2 Hz, 1 H), 6.71 (dd, J = 0.8, 5.6 Hz, 1 H), 6.66 (dd, J = 2.0, 3.2 Hz, 1 H), 6.3–6.1 (m, 1 H), 6.08 (dd, J = 1.6, 3.6 Hz, 1 H), 4.31 (dd, J = 6.2, 15.0 Hz, 1 H), 4.2–4.1 (m, 2 H), 3.81 (br s, 1 H), 3.49 (dd, J = 5.1, 16.6 Hz, 1 H), 3.41 (dd, J = 5.2, 16.6 Hz, 1 H), 3.18 (br s, 1 H), 2.48 (d, J = 6.4 Hz, 1 H), 1.98 (d, J = 6.4 Hz, 1 H).¹³C NMR (100 MHz, CDCl₃): δ = 168.2, 166.3, 154.7, 143.2, 137.2, 134.8, 128.7, 128.7, 127.6, 127.4, 127.4, 125.0, 121.0, 116.1, 104.5, 52.6, 49.0, 46.8, 46.2, 43.6, 43.6. HRMS (FAB): m/z [M + H]⁺ calcd for C₂₃H₂₄N₃O₅: 422.1710; found: 422.1698.
• 13 The dimethylammonium group of the catalyst is more acidic than the thiourea group. In the Diels–Alder reaction,¹ we proposed the formation of a hydrogen bond between the dimethylammonium group and the lactone group of 3-nitrocoumarin. In contrast, in the current reaction, the dimethylammonium group is proposed to interact preferentially with the amino group of 7c, because 7c is more basic than substrate 5.