A Straightforward Synthesis of Enantiopure 2,6-Disubstituted Morpholines by a Regioselective O-Protection/Activation Protocol

Abstract

Enantiopure 2,6-disubstituted morpholines have been synthesized through the ring opening of chiral, nonracemic oxiranes with nitrogen nucleophiles, under solid-liquid phase-transfer catalysis (SL-PTC) conditions. The β-hydroxytosyl amides resulting from the ring opening of a first epoxide with TsNH₂ was used as nucleophile, after protection of the hydroxyl group, in the reaction with a second oxirane. The morpholine skeleton has been generated through standard functional group chemistry, followed by cyclization of the intermediate β-hydroxy-β′-tosyloxy-tosylamides carried out under SL-PTC conditions. N-Tosyl morpholines produced can be employed as building blocks in the synthesis of pharmaceuticals and as chiral tools.

Key words

morpholines - regioselectivity - phase-transfer catalysis - epoxides - ring opening

References and Notes

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1

Present address: Nerviano Medical Sciences, Viale Pasteur 10, 20014 Nerviano, Italy. E-mail: [e-mail].

13

Synthesis of (2 R ,6 R )-2-Phenoxymethyl-6-phenyl-4-(toluene-4-sulfonyl)morpholine (11d); Typical Cyclization (Step v): In a screw cap vial, a heterogeneous mixture of 10d (0.60 g, 1 mmol) and TEBA (23 mg, 0.1 mmol) solution in anhyd MeCN (10 mL), and anhyd Cs₂CO₃ (0.83 g, 2.5 mmol), was magnetically stirred at 25 ˚C for 3 h. Then the crude was diluted with CH₂Cl₂ (10 mL), and filtered through a celite pad. The solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (230-400 mesh, EtOAc-hexane, 1:4) to give 11d (373 mg, 88%) as a white solid; mp 146-148 ˚C; ee >99%; HPLC: 4.6/250 mm CHIRALPAK-AD column, 25 ˚C, i-PrOH-hexane (75:25), flow 0.8 mL/min; t _R = 11.9 min; [α]_D ^²0 -31.1 (c = 1.0, CHCl₃). IR (Nujol): 1598, 1587, 1493, 1345, 1236, 1167, 1131, 1122, 1065, 1051, 968, 813, 776, 757, 682 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.63 (d, 2 H, J = 8.2 Hz), 7.25-7.44 (m, 9 H), 6.97 (t, 1 H, J = 7.3 Hz), 6.91 (d, 2 H, J = 8.2 Hz), 4.73 (dd, 1 H, J = 10.4, 2.6 Hz), 4.09-4.21 (m, 2 H), 3.96-3.99 (m, 2 H), 3.83 (dd, 1 H, J = 11.5, 1.9 Hz), 2.43 (s, 3 H), 2.33 (t, 1 H, J = 11.0 Hz), 2.23 (t, 1 H, J = 11.0 Hz). ^¹³C NMR-APT (75 MHz, CDCl₃): δ = 158.86 (C_ArO), 144.46 (C_ArMe), 138.82 (C_Ar), 132.69 (C_ArS), 130.51, 129.97, 128.98, 128.67, 128.29, 126.54, 121.71, 115.17 (14 CH_Ar), 78.01 (OCHPh), 74.40 (OCH), 68.78 (CH₂OPh), 52.17 (CH₂N), 48.21 (CH₂N), 22.00 (Me). Anal. Calcd for C₂₄H₂₅NO₄S: C, 68.06; H, 5.95; N, 3.31. Found: C, 68.10; H, 5.99; N, 3.26. Physical, Spectroscopic and Analytical Data of Intermediate Compounds (Steps i-iv) in the Synthesis of Morpholine (11d):
3c: white solid; mp 105-106 ˚C (lit. [¹4] 107-108 ˚C); [α]_D ^²0
-70.5 (c = 1.0, CHCl₃). IR (Nujol): 3401, 3149, 1918, 1662, 1598, 1318, 1148, 1098, 1088, 1065 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.72 (d, 2 H, J = 8.3 Hz), 7.23-7.34 (m, 8 H), 4.99-5.01 (m, 1 H), 3.05 (dd, 1 H, J = 8.6, 3.6 Hz), 3.01 (dd, 1 H, J = 8.5, 4.6 Hz), 2.42 (s, 3 H), 2.31 (d, 1 H, J = 3.5 Hz). Anal. Calcd for C₁₅H₁₇NO₃S: C, 61.83; H, 5.88; N, 4.81. Found: C, 61.91; H, 5.92; N, 4.78.
7c (Diastereomeric mixture): wax. IR (Nujol): 3291, 2925, 2854, 1599, 1495, 1377, 1162, 1121, 1094, 1074, 1022, 982 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.73 (d, 2 H, J = 8.4 Hz), 7.16-7.32 (m, 7 H), 5.32 (dd, 1 H, J = 8.1, 3.1 Hz), 4.63-4.71 (m, 1 H), 4.33-4.37 (m, 1 H), 3.90-4.10 (m, 1 H), 3.47-3.51 (m, 1 H), 3.18-3.31 (m, 1 H), 2.99-3.12 (m, 1 H), 2.42 (s, 3 H), 1.48-1.81 (m, 6 H). Anal. Calcd for C₂₀H₂₅NO₄S: C, 63.97; H, 6.71; N, 3.73. Found: C, 63.90; H, 6.65; N, 3.68.
8d (Diastereomeric mixture): wax. IR (Nujol): 3431, 3062, 3030, 1599, 1496, 1245, 1157, 1076, 1027, 978, 815, 757, 702, 659 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.73 (d, 2 H, J = 8.4 Hz), 7.25-7.37 (m, 9 H), 6.94 (t, 1 H, J = 7.5 Hz), 6.90 (d, 2 H, J = 8.4 Hz), 5.28 (dd, 1 H, J = 9.6, 2.4 Hz), 4.48 (br s, 1 H), 4.35 (dd, 2 H, J = 6.9, 2.4), 4.13 (dd, 1 H, J = 9.6, 5.4 Hz), 3.99-4.08 (m, 1 H), 3.94 (dd, 1 H, J = 9.6, 6.0 Hz), 3.42-3.58 (m, 3 H), 3.10-3.18 (m, 2 H), 2.39 (s, 3 H), 1.48-1.81 (m, 6 H). ^¹³C NMR-APT (75 MHz, CDCl₃; major diastereoisomer): δ = 159.1 (C_ArO), 144.0 (C_ArMe), 139.7 (C_Ar), 136.0 (C_ArS), 130.1, 129.8, 129.1, 128.6, 128.1, 127.1, 121.3, 119.9 (14 × CH_Ar), 98.6 (OCHO_THP), 78.9 (OCHPh), 69.9 (CH₂OPh), 67.9 (CHOH), 65.2 (CH₂O_THP), 57.2 (CH₂N), 55.2 (CH₂N), 31.4, 25.4, 21.3 [3 × CH_{2 ( THP)}], 21.9 (Me). ^¹³C NMR-APT (75 MHz, CDCl₃; minor diastereoisomer, visible signals): δ = 130.3, 130.0, 128.5, 126.4, 121.7, 115.0 (CH_Ar), 73.6 (OCHPh), 69.3 (CHOH), 64.2 (CH₂O_THP), 59.0 (CH₂N), 54.1 (CH₂N), 31.3, 20.7 (CH₂O_THP). Anal. Calcd for C₂₉H₃₅NO₆S: C, 66.26; H, 6.71; N, 2.66. Found: C, 66.30; H, 6.67; N, 2.60.
9d (Diastereomeric mixture): wax. IR (Nujol): 3440, 2926, 2853, 1598, 1495, 1303, 1246, 1156, 1120, 1090, 908, 813 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.78 (d, 2 H, J = 8.3 Hz), 7.72 (d, 2 H, J = 8.2 Hz), 7.21-7.31 (m, 11 H), 6.93 (t, 1 H, J = 7.3 Hz), 6.66 (d, 2 H, J = 8.1 Hz), 5.00 (dd, 1 H, J = 8.5, 4.7 Hz), 4.82-4.87 (m, 1 H), 4.30-4.33 (m, 1 H), 4.07 (dd, 1 H, J = 11.0, 3.5 Hz), 3.99 (dd, 1 H, J = 11.0, 5.8 Hz), 3.65-3.73 (m, 2 H), 3.60 (dd, 1 H, J = 15.2, 6.0 Hz), 3.42 (dd, 1 H, J = 15.0, 8.6 Hz), 3.25-3.32 (m, 1 H), 3.17 (dd, 1 H, J = 15.0, 4.7 Hz), 2.42 (s, 3 H), 2.41 (s, 3 H), 1.25-1.56 (m, 6 H). ^¹³C NMR-APT (75 MHz, CDCl₃; major diastereoisomer): δ = 157.9 (C_ArO), 144.8, 143.7 (2 × C_ArMe), 139.0 (C_Ar), 135.7, 133.4 (2 × C_ArS), 129.7, 129.6, 129.3, 128.5, 128.2, 128.1, 127.6, 127.1, 121.0, 114.3 (18 × CH_Ar), 95.8 (OCHO_THP), 78.9 (OCHPh), 76.0 (CHOTs), 66.7 (CH₂OPh), 62.6 (CH₂O_THP), 55.8 (CH₂N), 50.0 (CH₂N), 30.5, 25.2, 19.6 [3 × CH_{2 ( THP)}], 21.6, 21.5 (2 × Me). ^¹³C NMR-APT (75 MHz, CDCl₃; minor diastereoisomer, visible signals): δ = 129.9, 126.6, 125.9, 121.3 (CH_Ar), 78.4 (OCHPh), 72.5 (CHOTs), 58.8 (CH₂O_THP), 55.5 (CH₂N), 51.1 (CH₂N), 29.6, 19.1 [CH_{2 ( THP)}]. Anal. Calcd for C₃₆H₄₁NO₈S₂: C, 63.60; H, 6.08; N, 2.06. Found: C, 63.54; H, 6.03; N, 2.10.
10d: wax; [α]_D ^²0 -12.0 (c = 1.0, CHCl₃). IR (Nujol): 3504, 2924, 1733, 1598, 1243, 1159, 1090, 1045, 917 cm^-¹. ^¹H NMR (300 MHz, CDCl₃) : δ = 7.81 (d, 2 H, J = 8.3 Hz), 7.69 (d, 2 H, J = 8.3 Hz), 7.20-7.31 (m, 11 H), 6.94 (t, 1 H, J = 7.3 Hz), 6.69 (d, 2 H, J = 8.1 Hz), 5.01-5.06 (m, 1 H), 4.96 (dd, 1 H, J = 9.3, 3.2 Hz), 4.07-4.18 (m, 2 H), 3.63-3.70 (dd, 1 H, J = 15.3, 6.7 Hz), 3.46-3.53 (dd, 1 H, J = 12.2, 6.2 Hz), 3.26-3.34 (dd, 1 H, J = 14.7, 9.3 Hz), 3.08-3.14 (dd, 1 H, J = 14.7, 3.3 Hz), 2.81 (br s, 1 H), 2.41 (s, 6 H). ^¹³C NMR-APT (75 MHz, CDCl₃): δ = 157.7 (C_ArO), 145.0, 144.1 (2 × C_ArMe), 141.0 (C_ArCHOH), 134.5, 133.0 (2 × C_ArS), 129.9, 129.7, 129.3, 128.5, 128.1, 127.9, 127.5, 125.8, 121.3, 114.4 (18 × CH_Ar), 78.4 (OCHPh), 72.4 (CHOTs), 66.5 (CH₂OPh), 58.8 (CH₂N), 51.1 (CH₂N), 21.6, 21.5 (2 × Me). Anal. Calcd for C₃₁H₃₃NO₇S₂: C, 62.50; H, 5.58; N, 2.35. Found: C, 62.44; H, 5.53; N, 2.39.