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

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

References

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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.

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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, 7_anti-H), 1.68-1.71 (d, 1 H, J = 8.40 Hz, 7_sin-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.