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Synlett 2005(2): 319-321  
DOI: 10.1055/s-2004-836068
LETTER
© Georg Thieme Verlag Stuttgart · New York

Enantioselective Synthesis of [(1R,3-exo)-2-Benzyl-2-azabicyclo[2.2.1]hept-5-en-3-yl]methanol via Aza-Diels-Alder Reaction

Franco Fernándeza, Xerardo García-Mera*a, Maria Luísa C. Valeb, José Enrique Rodríguez-Borges*b
a Departamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
Fax: +34(981)594912; e-Mail: qoxgmera@usc.es;
b CIQ, Departamento de Química, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre, 687, 4169-007 Porto, Portugal
Fax: +351(22)6082959; e-Mail: jrborges@fc.up.pt;
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Publication History

Received 11 October 2004
Publication Date:
10 December 2004 (online)

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Abstract

The asymmetric aza-Diels-Alder reaction of the 8-phenylneomenthyl (or 8-phenylisomenthyl) glyoxylate-derived N-benzylimine with cyclopentadiene resulted in the enantioselective synthesis of the corresponding [(1R,3-exo)-2-benzyl-2-azabicy­clo[2.2.1]hept-5-en-3-yl]carboxylate. In both cases, the (1R,3-exo)-adduct was the main diastereomer and was isolated in 70% and 65% yield, respectively. Reduction of the (1R,3-exo)-adducts with LiAlH4 afforded [(1R,3-exo)-2-benzyl-2-azabicyclo[2.2.1]hept-5-en-3-yl]methanol, with recovery of the chiral auxiliaries with retention of configuration.

Key words

asymmetric synthesis - chiral auxiliaries - Diels-Alder reactions - induction

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9

General Procedure for the Synthesis of 1a. A solution of acryloyl chloride (2.10 mL, 25.8 mmol) in dry CH2Cl2 (40 mL) was added dropwise under argon to a solution of (+)-8-phenylneomenthol [(5a, 3.00 g, 12.9 mmol)], Et3N (3.6 mL, 26 mmol) and 4-(dimethylamino)pyridine (227 mg, 1.81 mmol) in dry CH2Cl2 (60 mL) at 0 °C. The mixture was stirred for 2 h at r.t. and was then treated with sat. NaHCO3 solution (125 mL) and extracted with Cl2CH2 (3 × 100 mL). The pooled organic layers were washed with sat. NaHCO3 solution (2 × 100 mL) and brine (100 mL), and were then dried with Na2SO4. The solvent was removed in a rotary evaporator, and purification of the resulting residue on a short column of silica gel using Et2O-EtOAc 9:1 as eluent afforded 6a as a yellow oil. Yield 3.29g (89%).
A mixture of 6a (2.35 g, 8.21 mmol), OsO4 (20.8 mg, 10 equiv), H2O (9 mL) and dioxane (30 mL) was stirred at r.t. for 5 min, during which time the mixture became dark brown. Then NaIO4 (3.51 g, 2 equiv) was added in portions over 30 min, and the mixture (now pale brown) was stirred at r.t. for another 2 h and then extracted thoroughly with Et2O. The combined organic extracts were dried (Na2SO4) and concentrated, affording a yellow oil that upon filtration through a short column of silica gel using hexane-EtOAc 3:1 as eluent afforded 7b as a mixture of the glyoxylate and its hydrate which was used without further purification. Yield 2.31 g (98%).
A solution of benzylamine (0.57 mL, 5.2 mmol) in dry Cl2CH2 (10 mL) was added under argon to a stirred suspension of 7b (1.5 g, 5.2 mmol) and 3 Å molecular sieves (4 g) in dry Cl2CH2 (30 mL) at 0 °C. When the addition was complete the reaction mixture was cooled to -78 °C and treated successively with TFA (0.4 mL, 1 equiv), BF3·OEt2 (0.65 mL, 1 equiv) and freshly distilled cyclopentadiene (1 mL, ca. 2 equiv). After 6 h a mixture of sat. aq NaHCO3 solution (13 mL) and then solid NaHCO3 (1.3 g) were added. The reaction mixture was allowed to reach r.t. and filtered. The organic layer was separated from the filtrate and washed with H2O and CH2Cl2 on a celite pad; the organic layer of the resulting mixture was separated, and the aqueous layer was extracted with CH2Cl2 (3 × 80 mL). The pooled organic layers were washed with sat. NaHCO3 solution (80 mL) and brine (90 mL), and were dried over Na2SO4.
Removal of the solvent on a rotary evaporator yielded an orange oil (2.3 g) which was purified by column chromatography (silica gel) using hexane-EtOAc 3:1 as eluent. Fractions 7-10 afforded a colorless oil (1.61 g) identified as the pure major adduct (1R,3-exo) 1a. Yield 70%.
Compound 1a: [α]D 25 +52.5 (c 1, CHCl3). IR (NaCl): ν = 3059, 2948, 1734 (CO), 1601, 1560, 1496, 1455, 1368, 1322, 1170, 1146, 1096, 1031, 978, 919, 846, 761, 733, 699, 661 cm-1. 1H NMR (CDCl3): δ = 0.84 (d, J = 6.5 Hz, 3 H, 5′-CH3), 0.88-1.05 (m, 2 H), 1.18 and 1.20 [2 s, 6 H, 8′-(CH3)2], 1.30-1.49 (m, 2 H), 1.50-1.79 (m, 4 H), 1.82-1.88 (m, 1 H), 1.94 (virtual d, J = 8.3 Hz, 1 H, 7 sin -H), 2.29 (br s, 1 H, 3 endo -H), 3.06 (br s, 1 H, 4-H), 3.55 (s, 2 H, CH2Ph), 3.88 (br s, 1 H, 1-H), 5.03 (br s, 1 H, 1′ eq -H), 6.25 (dd, J = 5.5 Hz, J = 1.8 Hz, 1 H, 5-H), 6.49 (dd, J = 5.5 Hz, J = 3.4 Hz, 1 H, 6-H), 7.10-7.45 (m, 10 H, C6H5). 13C NMR (CDCl3): δ = 22.57 (5′-CH3), 22.75 (C-3′), 26.11 (C-5′), 27.06 and 27.38 [8′-(CH3)2], 35.79 (C-4′), 40.14 (C-8′), 40.33 (C-6′), 47.00 (C-7), 48.95 (C-4), 51.63 (C-2′), 59.50 (NCH2-Ph), 64.52 (C-1), 65.96 (C-3), 71.64 (C-1′), 125.95 [aromatic C-4 (Ph)], 126.43 [aromatic C-2 + C-6 (Ph)], 127.47 [aromatic C-4 (Bn)], 128.35 [aromatic C-3 + C-5 (Ph)], 128.68 [aromatic C-2 + C-6 (Bn)], 129.39 [aromatic C-3 + C-5 (Bn)], 134.12 (C-5), 136.76 (C-6), 139.53 [aromatic C-1 (Bn)], 150.34 [aromatic C-1 (Ph)], 173.09 [C(O)O]. HRMS: m/z calcd for C30H37NO2: 443.2824. Found: 443.2817.

10

Compound 1b: yield 65%; [α]D 25 +53.5 (c 1, CHCl3). IR (NaCl): ν = 3021, 3062, 2966, 1732 (CO), 1598, 1560, 1494, 1464, 1452, 1386, 1366, 1358, 1324, 1241, 1217, 1202, 1187, 1172, 1078, 1043, 1018, 919, 859, 768, 741, 734, 704 cm-1. 1H NMR (CDCl3): δ = 0.93 (d, J = 7.1 Hz, 3 H, 5′-CH3), 1.172 and 1.177 [2 s, 6 H, 8′-(Me2)], 1.20-1.35 (m, 4 H), 1.36-1.50 (m, 2 H), 1.52-1.65 (m, 2 H), 1.82 (virtual d, J = 8.3 Hz, 1 H, 7 sin -H), 1.85-1.90 (m, 1 H), 1.95 (s, 1 H, 3 endo -H), 2.84 (br s, 1 H, 4-H), 3.42 and 3.52 (AB system, 2 H, J = 13.0 Hz), 3.82 (br s, 1 H, 1-H), 5.02 (td, 1 H, J t = 10.8 Hz, J d = 4.18 Hz, 1′ ax -H), 6.20 (dd, 1 H, J = 5.6 Hz, J = 1.8 Hz, 1 H, 5-H), 6.38 (dd, 1 H, J = 5.6 Hz, J = 3.3 Hz, 1 H, 6-H), 7.10-7.40 (m, 10 H, C6H5). 13C NMR (CDCl3): δ = 19.52 (5′-CH3), 21.79 (C-3′), 26.45 (C-5′), 27.51 and 27.89 [8′-(CH3)2], 31.52 (C-4′), 40.40 (C-8′), 38.30 (C-6′), 46.75 (C-7), 49.02 (C-4), 50.74 (C-2′), 59.31 (NCH2-Ph), 64.45 (C-1), 65.50 (C-3), 71.93 (C-1′), 125.53 [aromatic C-4 (Ph)], 126.03 and 126.12 [aromatic C-2 + C-6 (Ph)], 127.36 [aromatic C-4 (Bn)], 128.30 [aromatic C-3 + C-5 (Ph)], 128.54 and 128.60 [aromatic C-2 + C-6 (Bn)], 129.39 [aromatic C-3 + C-5 (Bn)], 134.05 (C-5), 136.80 (C-6), 139.63 [aromatic C-1 (Bn)], 151.32 [aromatic C-1 (Ph)], 173.08 [C(O)O]. HRMS: m/z calcd for C30H37NO2: 443.2824. Found: 443.2814.

11

Compound 2: yield 92%; colorless oil; [a]D 25 +71.5 (c 1, CHCl3). IR (NaCl): ν = 3364, 3060, 2985, 2870, 1495, 1452, 1367, 1324, 1208, 1134, 1028, 910, 717 cm-1. 1H NMR (CDCl3): δ = 1.25-1.28 (d, 1 H, J = 8.40 Hz, 7anti-H), 1.68-1.71 (d, 1 H, J = 8.40 Hz, 7sin-H), 1.82-1.86 (t, 1 H, J = 5.55 Hz, 3-H), 2.32 (br s, 1 H, OH), 2.69 (s, 1 H, 4-H), 3.32-3.44 (m, 4 H, CH2OH + CH2Ph), 3.69 (s, 1 H, 1-H), 6.10-6.13 (dd, 1 H, J = 5.65, 1.80 Hz, 5-H), 6.41-6.45 (dd, 1 H, J = 5.65, 3.24 Hz, 6-H), 7.16-7.28 (m, 5 H, C6H5). 13C NMR (CDCl3): δ = 46.13 (C-7), 47.16 (C-4), 59.34 (NCH2Ph), 64.43 (C-1), 64.98 (C-3), 65.66 (CH2OH), 127.55 (C-4′), 128.80 (C-2′ + C-6′), 129.43 (C-3′ + C-5′), 132.71 (C-5), 138.27 (C-6), 140.11 (C-1′). HRMS: m/z calcd for C14H17NO: 215.1310. Found: 215.1319.