A Stereoselective Synthesis of a 3,4,5-Substituted Piperidine of Interest as a Selective Muscarinic (M₁) Receptor Agonist

Dedicated to Steve Ley on the occasion of his 70th birthday

Abstract

A stereoselective synthesis of (1RS,2SR,6SR)-7-benzyl-6-cyclo­butyl-2-methoxymethyl-4,7-diaza-9-oxobicyclo[4.3.0]nonan-8-one, which is representative of a novel series of selective muscarinic (M₁) receptor agonists, is described.

Key words

piperidines - oxazolidinones - hydroboration - muscarinic receptors - trifluoroacetimidates

• References and Notes

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• 3 Davies, R. H. unpublished observations.
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• 6 (4SR,5RS)-4-(tert-Butyldimethylsilyloxymethyl)-4-cyclobutyl-5-propen-2-yl-1,3-oxazolidin-2-one (5): Propen-2-ylmagnesium bromide (0.5 M in toluene, 297 mL, 148.5 mmol, 3.75 equiv) was added over 1 h to aldehyde 6 (15.5 g, 39.6 mmol) in THF (800 mL) at –78 °C, and the reaction mixture was stirred at –78 °C for 2 h, then allowed to warm to r.t. overnight. The reaction mixture was stirred for another 36 h at r.t. before sat. aq NH₄Cl (500 mL) was added. The aqueous phase was extracted with Et₂O (3 × 500 mL) and the organic extracts were dried (MgSO₄) and concentrated under reduced pressure. Chromato­graphy (EtOAc–light petroleum, 1:10) of the residue gave the title compound 5 (8.5 g, 66%) as a single diastereoisomer as a white solid; mp 110–112 °C; R_f = 0.30 (EtOAc–light petroleum, 1:4). IR: 3240, 3137, 2952, 2935, 2892, 2859, 1756, 1465, 1384, 1344, 1254, 1106, 903, 840, 777 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.02 (s, 6 H, 2 × SiCH₃), 0.87 [s, 9 H, SiC(CH₃)₃], 1.69–2.18 (m, 6 H, 3 × CH₂), 1.80 (s, 3 H, 3′-H₃), 2.70 (pent, J = 8.2 Hz, 1 H, 4-CH), 3.43 (s, 2 H, 4-CH₂), 4.50 (s, 1 H, 5-H), 5.04 (s, 1 H, 1′-H), 5.13 (s, 1 H, 1′-H), 5.86 (s, 1 H, NH). ¹³C (100 MHz, CDCl₃): δ = –5.9, –5.8, 17.4, 18.1, 19.9, 22.4, 24.3, 25.7, 39.4, 63.9, 65.0, 82.2, 113.9, 138.0, 158.9. MS (CI+): m/z (%) = 343 (75) [M⁺ + 18], 326 (100) [M⁺ + 1]. HRMS: m/z [M⁺ + H] calcd for C₁₇H₃₂NO₃Si: 326.2152; found: 326.2150. Anal. Calcd for C₁₇H₃₁NO₃Si: C, 62.73; H, 9.60; N, 4.30; found: C, 62.76; H, 9.62; N, 4.20.
• 7 X-ray crystal data for oxazolidinone 5: CCDC 1413285; C₁₇H₃₁NO₃Si; unit cell parameters: a = 12.250(3), b = 13.606(3), c = 12.818(3); P21/c. Alcohol 32: CCDC 1413286; C₂₅H₃₀N₂O₃; unit cell parameters: a = 22.546(14), b = 9.314(10), c = 10.283(9); P21/c.
• 8a Yasuda A, Tanaka S, Oshima K, Yamamoto H, Nozaki H. J. Am. Chem. Soc. 1974; 96: 6513
• 8b Tanaka S, Yasuda A, Yamamoto H, Nozaki H. J. Am. Chem. Soc. 1975; 97: 3252
• 9 (4SR,5RS)-3-Benzyl-4-(tert-butyldimethylsilyloxymethyl)-4-cyclobutyl-5-[(SR)- and -(RS)-1-hydroxy-3-methoxyprop-2-yl]-1,3-oxazolidin-2-ones (4) and (25): Borane (1 M in THF, 8.2 mL, 8.22 mmol, 5 equiv) was added dropwise to alkene 24 (660 mg, 1.48 mmol) in THF (5 mL) at 0 °C and the reaction mixture was stirred at this temperature for 18 h before EtOH (7.1 mL), sat. aq NaOAc (23 mL) and H₂O₂ (30% in H₂O, 8 mL) were added. The reaction mixture was heated to reflux for 1 h then cooled. The aqueous phase was extracted with Et₂O (3 × 35 mL) and the organic extracts were dried (MgSO₄) and concentrated under reduced pressure. Chromatography (EtOAc–light petroleum, 1:4) of the residue gave the title compounds 4 and 25 (648 mg, 95%), as a mixture of diastereoisomers (4/25 ratio 85:15); R_f = 0.21 (EtOAc–light petroleum, 1:2). HRMS: m/z [M⁺ + H] calcd for C₂₅H₄₂NO₅Si: 464.2833; found: 464.2835. IR: 3443, 2930, 2892, 2859, 1732, 1468, 1409, 1357, 1297, 1255, 1169, 1104, 1036, 840, 777 cm^–1. ¹H  (400 MHz, CDCl₃): δ (major epimer 4) = 0.04 (s, 3 H, SiCH₃), 0.05 (s, 3 H, SiCH₃), 0.88 [s, 9 H, SiC(CH₃)₃], 1.50–2.05 (m, 6 H, 3 × CH₂), 2.22 (br. s, 1 H, OH), 2.37 (m, 1 H, 2′-H), 2.57 (m, 1 H, 4-CH), 3.36 (s, 3 H, OCH₃), 3.57 (dd, J = 6.0, 9.5 Hz, 1 H, 3′-H), 3.63 (dd, J = 6.0, 9.5 Hz, 1 H, 3′-H), 3.66 (s, 2 H, 4-CH₂), 3.85–3.94 (m, 2 H, 1′-H₂), 4.17 (d, J = 15.8 Hz, 1 H, PhHCH), 4.48 (d, J = 6.0 Hz, 1 H, 5-H), 4.66 (d, J = 15.8 Hz, 1 H, PhHCH), 7.24–7.40 (m, 5 H, ArH); δ (minor epimer 25) = 0.03 (s, 3 H, SiCH₃), 0.05 (s, 3 H, SiCH₃), 0.87 [s, 9 H, SiC(CH₃)₃], 2.83 (br. t, J = 5.5 Hz, 1 H, OH), 3.36 (s, 3 H, OCH₃), 3.72 (dd, J = 9.5, 3.5 Hz, 1 H, 3′-H), 3.79 (dd, J = 9.5, 5.5 Hz, 1 H, 3′-H′), 4.55 (d, J = 7.8 Hz, 1 H, 5-H), 4.70 (d, J = 15.7 Hz, 1 H, PhHCH). ¹³C (100 MHz, CDCl₃): δ (major epimer 4) = –5.9, –5.8, 17.2, 17.9, 23.1, 23.3, 25.7, 38.7, 40.8, 45.8, 59.1, 61.2, 62.3, 68.5, 73.3, 77.4, 127.3, 127.6, 128.5, 138.4, 159.1; δ (minor epimer 25) = –5.8, 17.1, 17.9, 23.1, 23.4, 25.6, 38.7, 40.3, 45.8, 59.3, 60.8, 64.4, 68.8, 73.6, 75.4, 127.2, 127.6, 128.4, 138.5, 159.5. MS (CI+): m/z (%) = 464 (1) [M⁺ + 1], 90 (100)
• 10 (1RS,6SR)-4,7-Bis-benzyl-6-cyclobutyl-2-methoxymethyl-4,7-diaza-9-oxabicyclo[4.3.0]nonan-8-ones (30) and (31): Freshly distilled methane sulfonyl chloride (0.112 mL, 1.42 mmol, 3 equiv) and Et₃N (0.20 mL, 1.42 mmol, 3 equiv) were added successively to a mixture of diols 27 and 28 (166 mg, 0.475 mmol) in CH₂Cl₂ (5 mL) at 0 °C. The reaction mixture was allowed to warm to r.t. and stirred for 1 h before the addition of Et₂O (5 mL) and sat. aq NH₄Cl (10 mL). The aqueous phase was extracted with Et₂O (3 × 10 mL) and the organic extracts were dried (MgSO₄) and concentrated under reduced pressure to give a mixture of bis-mesylates 29 (228 mg), which was used without purification. Bis-mesylates 29 (228 mg) were dissolved in benzylamine (15 mL) and the solution was heated at 80 °C for 18 h. After cooling to r.t., the benzylamine was removed by distillation under reduced pressure. Chromatography (EtOAc–light petroleum, 1:20 to 1:10) of the residue achieved partial separation of piperidines 30 and 31 to give the title compound 30 (72 mg, 36%); R_f = 0.28 (EtOAc–light petroleum, 1:2). HRMS: m/z [M]⁺ calcd for C₂₆H₃₂N₂O₃: 420.2413; found: 420.2410. IR: 3083, 3060, 3029, 2924, 2872, 2811, 1744, 1494, 1453, 1405, 1349, 1294, 1201, 1168, 1117, 1090, 1060, 1028, 978, 818, 746 cm^–1. ¹H (400 MHz, CDCl₃): δ = 1.40–1.78 (m, 5 H, cyclobutyl H), 2.00 (m, 1 H, cyclobutyl H), 2.10 (d, J = 12.5 Hz, 1 H, 5-H), 2.22 (m, 1 H, 2-H), 2.36 (t, J = 10.5 Hz, 1 H, 3-H), 2.41 (d, J = 12.5 Hz, 1 H, 5-H′), 2.49 (pent, J = 8.7 Hz, 1 H, 6-CH), 2.58 (dd, J = 7.25, 10.5 Hz, 1 H, 3-H′), 3.32–3.37 (m, 6 H, 2-CH, OCH₃, PhCH₂), 3.57 (t, J = 8.5 Hz, 1 H, 2-CH′), 3.91 (d, J = 16.0 Hz, 1 H, PhHCH), 4.28 (d, J = 16.0 Hz, 1 H, PhHCH), 4.51 (d, J = 2.5 Hz, 1 H, 1-H), 7.21–7.34 (m, 10 H, ArH). ¹³C (100 MHz, CDCl₃): δ = 17.6, 22.9, 23.3, 36.7, 39.2, 44.7, 50.6, 53.0, 59.1, 61.9, 64.4, 72.0, 74.3, 127.2, 127.3, 127.9, 128.3(2), 128.9, 138.0, 138.3, 159.1; MS (EI): m/z (%) = 420 (1) [M⁺], 91 (100). The second fraction was a mixture of the title compounds 30 and 31 (53 mg, 26%); 30/31 ratio 55:45; R_f = 0.28–0.22 (EtOAc–light petroleum, 1:2). HRMS: m/z [M]⁺ calcd for C₂₆H₃₂N₂O₃: 420.2413; found: 420.2412. IR: 3083, 3061, 3029, 2927, 2869, 2823, 1746, 1495, 1453, 1436, 1403, 1355, 1334, 1193, 1170, 1106, 1053, 1027, 996, 923, 809, 743 cm^–1. ¹H (400 MHz, CDCl₃): δ (minor epimer 31) = 2.75–2.85 (m, 2 H, 3-H, 5-H), 3.24 (d, J = 12.8 Hz, 1 H, PhHCH), 3.47 (dd, J = 3.0, 9.5 Hz, 1 H, 2-CH), 3.53 (dd, J = 5.25, 9.5 Hz, 1 H, 2-CH′), 4.02 (d, J = 15.5 Hz, 1 H, PhHCH), 4.40 (d, J = 8.7 Hz, 1 H, 1-H), 4.45 (d, J = 15.5 Hz, 1 H, PhHCH). ¹³C (100 MHz, CDCl₃): δ (minor epimer 31) = 16.9, 23.3, 23.7, 41.2, 41.6, 44.4, 53.3(2), 59.1, 62.4, 63.6, 71.8, 73.8, 127.4(2), 128.0, 128.3, 128.4, 129.3, 137.9, 138.1, 158.4. MS (CI+): m/z (%) = 421 (100) [M⁺ + 1].
• 11 (1RS,2SR,6SR)-7-Benzyl-6-cyclobutyl-2-methoxymethyl-4,7-diaza-9-oxabicyclo[4.3.0]nonan-8-one (3) A solution of formic acid (93 μL, 0.025 mmol, 0.4 equiv) in MeOH (1 mL) was added to N-benzylpiperidine 30 (26 mg, 0.062 mmol) and 10% Pd/C (41 mg) under N₂, and the reaction mixture was stirred at r.t. for 20 min. K₂CO₃ (50 mg) was added, the reaction mixture was filtered through Celite, and the residue was washed with Et₂O. After concentration under reduced pressure, chromatography (MeOH–Et₂O, 1:50, saturated in ammonia) of the residue gave the title compound 3 (14 mg, 71%); R_f = 0.38 (MeOH–Et₂O, 1:10 saturated in ammonia). HRMS: m/z [M]⁺ calcd for C₁₉H₂₆N₂O₃: 330.1943; found: 330.1941. IR: 3343, 3086, 3062, 3029, 2935, 2871, 2832, 2815, 1742, 1672, 1496, 1454, 1432, 1409, 1345, 1199, 1167, 1146, 1112, 1090, 1071, 984, 759, 707 cm^–1. ¹H (400 MHz, CDCl₃): δ = 1.54–2.00 (m, 7 H, 3 × CH₂, 6-CH), 2.12 (m, 1 H, 2-H), 2.37 (d, J = 14.2 Hz, 1 H, 5-H), 2.57 (t, J = 12.0 Hz, 1 H, 3-H), 2.61 (d, J = 14.2 Hz, 1 H, 5-H′), 2.91 (dd, J = 6.5, 12.0 Hz, 1 H, 3-H′), 3.31 (dd, J = 6.0, 9.0 Hz, 1 H, 2-CH), 3.36 (s, 3 H, CH₃), 3.52 (t, J = 9.0 Hz, 1 H, 2-CH′), 4.22 (d, J = 15.7 Hz, 1 H, PhHCH), 4.43 (d, J = 15.7 Hz, 1 H, PhHCH), 4.71 (d, 1 H, J = 2.7 Hz, 1-H), 7.24–7.39 (m, 5 H, ArH). ¹³C (100 MHz, CDCl₃): δ = 17.5, 22.2, 22.8, 35.8, 38.5, 40.7, 44.6, 45.0, 59.0, 63.4, 71.4, 73.6, 127.8(2), 128.7, 138.1, 158.7. MS (CI+): m/z (%) = 331 (60) [M⁺ + 1], 91 (100).