Exo-Selective Asymmetric Inverse-Electron Demand Hetero-Diels-Alder Reaction Catalyzed by Cu(II)-Hydroxy Oxazoline Ligands

Abstract

Cu(II) complexes of hydroxy oxazolines derived from (+)-(S)-ketopinic acid catalyze the asymmetric hetero-Diels-Alder cycloaddition of enol ethers and β,γ-unsaturated α-keto esters. The reaction takes place with unprecedented exo selectivity providing 2,4-trans-disubstituted chiral 2,3-dihydropyrans with up to 88% ee.

Key words

asymmetric catalysis - cycloaddition - copper - acetals - heterocycles

References and Notes

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16

We have not determined the absolute stereochemistry of the minor endo-adducts 10. For a description of these adducts see refs. 5 and 6.

17

Synthesis of Ligand 5: A solution of (S)-(+)-ketopinic acid (1; 1.0 g, 5.5 mmol) in SOCl₂ (4.5 mL) was refluxed for 2 h and the excess SOCl₂ was removed under reduced pressure. The residue dissolved in CH₂Cl₂ (3.8 mL) was added drop-wise to a solution of (R)-2-amino-2-phenylethanol (0.76 g, 5.5 mmol) and Et₃N (0.75 mL, 5.5 mmol) in CH₂Cl₂ (3 mL) at 0 ˚C under nitrogen. After 1 h, the mixture was diluted with EtOAc (150 mL), washed with 2 M HCl (2 × 30 mL), sat. aq NaHCO₃ (2 × 30 mL) and brine (30 mL), dried
over MgSO₄ and concentrated. The crude product was crystallized from hexane-CH₂Cl₂ to give 1.49 g (90%) of hydroxy amide; mp 140-142 ˚C; [α]_D ^²5 -6.2 (c = 0.78, CHCl₃). ^¹H NMR (300 MHz, CDCl₃): δ = 8.37 (d, J = 6.4 Hz, 1 H), 7.32 (m, 5 H), 5.15 (td, J = 5.4, 7.0 Hz, 1 H), 3.87 (m, 2 H), 2.81 (s, 1 H), 2.58 (m, 1 H), 2.51 (dd, J = 4.7, 8.5 Hz, 1 H), 2.17 (m, 1 H), 2.09 (t, J = 4.4 Hz, 1 H), 2.00 (d, J = 18.8 Hz, 1 H), 1.69 (ddd, J = 4.6, 9.2, 13.8 Hz, 1 H), 1.45 (m, 1 H), 1.22 (s, 3 H), 0.94 (s, 3 H). ^¹³C NMR (75.5 MHz, CDCl₃): δ = 217.3 (s), 169.8 (s), 139.0 (s), 128.7 (d), 127.6 (d), 126.5 (d), 67.1 (t), 64.5 (s), 55.7 (d), 50.3 (s), 43.6 (t), 43.2 (d), 28.4 (t), 27.7 (t), 20.8 (q), 20.3 (q). MS (FAB):
m/z (%) = 302 (100) [M⁺ + 1], 154 (71), 137 (58). HRMS: m/z calcd for C₁₈H₂₄NO₃: 302.1756; found: 302.1754.
Mesyl chloride (6.75 mmol) was added dropwise to a solution of hydroxy amide (1.03 g, 3.4 mmol), Et₃N (5.8 mL) and diisopropylethylamine (1.2 mL) in CH₂Cl₂ (17 mL) under nitrogen at 0 ˚C. The reaction was stirred overnight. After this time, the reaction mixture was diluted with EtOAc (200 mL), washed with H₂O (2 × 25 mL) and brine (25 mL), dried over MgSO₄, concentrated under reduced pressure and the product was purified by flash chromatography eluting with hexane-EtOAc to give 0.93 g (96%) of keto-oxazoline; mp 122-125 ˚C; [α]_D ^²5 +88.5 (c = 0.73, CHCl₃). ^¹H NMR (300 MHz, CDCl₃): δ = 7.29 (m, 5 H), 5.23 (dd, J = 8.0, 10.2 Hz, 1 H), 4.67 (dd, J = 8.5, 10.1 Hz, 1 H), 4.07 (t, J = 8.1 Hz, 1 H), 2.49-2.64 (m, 2 H), 2.16 (t, J = 4.4 Hz, 1 H), 2.07 (m, 1 H), 1.98 (d, J = 18.3 Hz, 1 H), 1.84 (ddd, J = 4.7, 9.2, 13.9 Hz, 1 H), 1.43 (ddd, J = 4.0, 9.2, 12.9 Hz, 1 H), 1.19 (s, 3 H), 1.13 (s, 3 H). ^¹³C NMR (75.5 MHz, CDCl₃): δ = 211.9 (s), 165.4 (s), 142.4 (s), 128.6 (d), 127.4 (d), 126.5 (d), 74.8 (t), 69.3 (d), 63.0 (s), 49.4 (s), 44.4 (d), 43.8 (t), 27.3 (t), 26.6 (t), 21.4 (q), 19.8 (q). MS (EI): m/z (%) = 283 (73) [M⁺], 268 (26), 255 (99), 240 (60), 214 (28), 210 (19), 165 (24), 120 (27), 104 (60), 91 (100), 77 (67), 67 (81). HRMS: m/z calcd for C₁₈H₂₁NO₂: 283.1572; found: 283.1571.
A solution of [LiAlH₄˙2THF] complex in toluene (1 M, 1.5 mL, 1.5 mmol) was added dropwise to a solution of keto-oxazoline (0.47 g, 1.67 mmol) in toluene (17 mL) under nitrogen at -40 ˚C. The reaction was stirred until the starting material was consumed (TLC). The reaction mixture was then diluted with EtOAc (150 mL), washed with brine (3 × 10 mL), dried over MgSO₄, concentrated under reduced pressure and the product was purified by flash chromato-graphy eluting with hexane-EtOAc to give 295 mg (62%) of compound 5 and 71 mg (15%) of its C2-epimer. Compound 5: [α]_D ^²5 +14.3 (c = 1.02, CHCl₃). ^¹H NMR (300 MHz, CDCl₃): δ = 7.25 (m, 5 H), 5.53 (br s, 1 H), 5.20 (dd, J = 7.7, 10.1 Hz, 1 H), 4.53 (dd, J = 8.4, 10.2 Hz, 1 H), 4.06 (dd, J = 3.5, 7.8 Hz, 1 H), 4.00 (t, J = 8.1 Hz, 1 H), 2.20 (m, 1 H), 1.83-1.96 (m, 2 H), 1.70-1.80 (m, 2 H), 1.27 (m, 1 H), 1.22 (s, 3 H), 1.14 (m, 1 H), 1.06 (s, 3 H). ^¹³C NMR (75.5 MHz, CDCl3): δ = 170.2 (s), 142.0 (s), 128.5 (d), 127.4 (d), 126.2 (d), 77.5 (d), 73.4 (t), 68.4 (d), 53.0 (s), 49.7 (s), 45.6 (d), 39.3 (t), 30.3 (t), 27.6 (t), 21.9 (q), 20.5 (q). MS (EI) m/z (%) = 285 (10) [M⁺], 270 (71), 257 (100), 242 (88), 216 (22), 202 (50), 174 (16), 151 (24), 120 (25), 104 (46), 91 (73), 77 (57). HRMS: m/z calcd for C₁₈H₂₃NO₂: 285.1729; found: 285.1718.
Experimental Procedure for the Enantioselective HDA Reaction: Copper triflate (9.0 mg, 0.025 mmol) in a Schlenk tube was dried at 90 ºC under vacuum for 1 h. The tube was filled in with nitrogen and ligand 5 (7.1 mg, 0.025 mmol) was added followed by anhyd EtOAc (0.75 mL). The mixture was stirred for 1 h and keto ester 8a (50 mg, 0.25 mmol) dissolved in EtOAc (0.4 mL) was added. After stirring for 30 min, the solution was cooled at 0 ˚C and ethyl vinyl ether (7a; 75 µL, 0.75 mmol) was added. After 3 h, the reaction mixture was filtered through a short pad of silica gel eluting with CH₂Cl₂ to give 61.4 mg (89%) of compound 9aa + 10aa (Table 1, entry 12). HPLC analysis (Chiralpak IC, 2% isopropanol-98% hexane, 1.0 mL/min): (+)-(2S,4R)-9aa: tR = 12.2 min, (-)-(2R,4S)-9aa: tR = 17.0 min, 10aa (enantiomer 1): tR = 27.6 min, 10aa (enantiomer 2): tR = 33.6 min. A pure sample of enantioenriched (+)-9aa was obtained by flash column chromatography, eluting with hexane-CH₂Cl₂ (1:9); [α]_D ^²5 +136 (c = 1.0, CHCl₃, 81% ee). ^¹H NMR (300 MHz, CDCl₃): δ = 7.16-7.29 (m, 5 H), 6.15 (dd, J = 1.8, 2.4 Hz, 1 H), 5.25 (t, J = 2.4 Hz, 1 H), 4.21 (q, J = 7.0 Hz, 2 H), 3.86 (dq, J = 9.9, 7.2 Hz, 1 H), 3.71 (ddd, J = 2.4, 6.3, 11.7 Hz, 1 H), 3.61 (dq, J = 9.9, 7.2 Hz, 1 H), 2.11 (dddd, J = 12.0, 6.3, 2.1, 1.8 Hz, 1 H), 1.76 (ddd, J = 12.0, 11.7, 2.4 Hz, 1 H), 1.25 (t, J = 7.0 Hz, 3 H), 1.18 (t, J = 7.2 Hz, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 162.9 (s), 143.4 (s), 140.8 (s), 128.7 (d), 127.6 (d), 126.8 (d), 115.3 (d), 97.1 (d), 64.2 (t), 61.1 (t), 34.9 (t), 34.0 (d), 15.1 (q), 14.2 (q). MS (EI): m/z (%) = 276 (1.5) [M⁺], 230 (15), 203 (6), 157 (25), 131 (100). HRMS: m/z calcd for C₁₆H₂₀O₄: 276.1362; found: 276.1364. Minor diastereomer 10aa: ^¹H NMR (300 MHz, CDCl₃): δ = 7.21-7.40 (m, 5 H), 6.13 (dd, J = 1.2, 3.0 Hz, 1 H), 5.15 (dd, J = 2.4, 8.1 Hz, 1 H), 4.26 (m, 2 H), 4.03 (dq, J = 9.6, 6.9 Hz, 1 H), 3.71 (ddd, J = 3.0, 6.9, 9.6 Hz, 1 H), 3.63 (dq, J = 9.6, 6.9 Hz, 1 H), 2.30 (dddd, J = 13.5, 6.9, 2.4, 1.2 Hz, 1 H), 1.96 (ddd, J = 13.5, 9.6, 8.1 Hz, 1 H), 1.31 (t, J = 7.2 Hz, 3 H), 1.23 (t, J = 6.9 Hz, 3 H).