Suzuki–Miyaura Coupling Based Enantioselective Synthesis of (+)-epi- Clausenamide and the Enantiomer of Its 3-Deoxy Analogue

Abstract

The first enantioselective synthesis of two biologically interesting close analogues of clausenamide, namely (+)-epi-clausenamide and (–)-3-deoxy-epi-clausenamide, was reported. Key steps of the synthesis included construction of the chiral pyrrolinone intermediates from d- and l-serine derivatives, introduction of the C4-phenyl by Suzuki–Miyaura coupling and establishment of the C6 configuration by a threo-selective Grignard reaction. Optimization of the key Suzuki–Miyaura coupling reaction was described in detail.

Key words

(+)-epi-clausenamide - (–)-3-deoxy-epi-clausenamide - nootropics - osteoporosis - Suzuki–Miyaura coupling

• References and Notes

• 1 Yang MH, Cao YH, Li WX, Yang YQ, Chen YY, Huang L. Acta Pharm. Sin. 1987; 22: 33
• 2a Liu Y, Shi CZ, Zhag JT. Acta Pharm. Sin. 1991; 26: 166
• 2b Duan WZ, Zhang JT. Acta Pharm. Sin. 1997; 32: 259
• 2c Duan WZ, Zhang JT. Chin. Med. J. 1998; 111: 1035
• 2d Tang K, Zhang JT. Life Sci. 2004; 74: 1427
• 2e Hu JF, Chu SF, Ning N, Yuan YH, Xue W, Chen NH, Zhang JT. Neurosci. Lett. 2010; 483: 78
• 3 Feng ZQ, Li XZ, Zheng GJ, Huang L. Bioorg. Med. Chem. Lett. 2009; 19: 2112
• 4a Cook JH, Barzya J, Brennan C, Lowe D, Wang Y, Redman A, Scott WJ, Wood JE. Tetrahedron Lett. 2005; 46: 1525
• 4b Gunn D, Akuche C, Baryza J, Blue ML, Brennan C, Campbell AM, Choi S, Cook J, Conrad P, Dixon B, Dumas J, Ehrlich P, Gane T, Joe T, Johnson J, Jordan J, Kramss R, Liu P, Levy J, Lowe D, McAlexander I, Natero R, Redman AM, Scott W, Seng T, Sibley R, Wang M, Wang Y, Wood J, Zhang Z. Bioorg. 2005; 15: 3053
• 5 Hartwig W, Born L. J. Org. Chem. 1987; 52: 4352
• 6a Rao EC, Hong H, Cheng JC, Yang GZ, Lin HS, Huag L. Chin. Chem. Lett. 1994; 5: 267
• 6b Rao EC, Cheng JC, Yang GZ, Yang MH, Huag L. Acta Pharm. Sin. 1994; 29: 502
• 7a Wang JQ, Tian WS. J. Chem. Soc., Perkin Trans. 1 1995; 209
• 7b Zhong C, Gautam LN. S, Petersen JL, Akhmedov NG, Shi XD. Chem.–Eur. J. 2010; 16: 8605
• 7c Cappi MW, Chen WP, Flood RW, Liao YW, Roberts SM, Skidmore JS, Smith JA, Williamson NM. Chem. Commun. 1998; 1159
• 8 Xue JJ, Zhou YM, Yu XM. Chin. Chem. Lett. 2011; 22: 1261
• 9 Ma DW, Ma JY, Ding WL, Dai LX. Tetrahedron: Asymmetry 1996; 7: 2365
• 10a Yoon-Miller SJ. P, Opalka SM, Pelkey ET. Tetrahedron Lett. 2007; 48: 827
• 10b Yoon-Miller SJ. P, Dorward KM, White KP, Pelkey ET. J. Heterocycl. Chem. 2009; 46: 447
• 11 Chemler SR, Trauner D, Danishefsky SJ. Angew. Chem. Int. Ed. 2001; 40: 4544
• 12 Typical Procedure for Suzuki–Miyaura Coupling: Compound (+)-8 (100 mg, 0.2 mmol, 1.0 equiv), phenylboronic acid (37 mg, 0.3 mmol, 1.5 equiv), PdCl₂ (3.6 mg, 0.02 mmol, 0.1 equiv), and DPPP (8.3 mg, 0.02 mmol, 0.1 equiv) were placed in a three-necked flask with a magnetic stirring bar and a condenser. The reactor was evacuated with an oil pump and then flushed with argon. After this process was repeated for three times, benzene (2.0 mL) was added through a syringe. Upon a clear solution was formed under stirring, CsF (91 mg, 3.0 equiv in H₂O, 0.4 mL) was added through a syringe. The reaction mixture was stirred at r.t. for 1 h and then heated to reflux (about 12 h). After cooling to r.t., the reaction mixture was washed with a sat. aq solution of NaHCO₃ (2.0 mL), brine (2.0 mL), and dried over Na₂SO₄. Removal of the solvent in vacuo and chromatography (PE–EtOAc, 10:1) gave (+)-9 (59 mg) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ = 7.455 (5 H, s, ArH), 6.297 (1 H, s, C3-H), 5.090 (1 H, s, C5-H), 4.231 (1 H, dd, J = 2.4, 10.4 Hz, C6-H), 3.808 (1 H, d, J = 10.4 Hz, C6-H), 1.590 (9 H, s, BocH), 0.731 (9 H, s, t-BuSi), –0.158 (3 H, s, CH₃Si), –0.228 (3 H, s, CH₃Si). ¹³C NMR (125 MHz, CDCl₃): δ = 169.063, 159.630, 149.756, 131.365, 130.571, 128.968, 127.122, 121.505, 82.754, 63.401, 60.440, 28.206, 25.581, 17.996, –5.875. ESI-HRMS: m/z calcd for [C₂₂H₃₃NO₄Si + Na]⁺: 426.2071; found: 426.2060. [α]_D ²⁰ +55.0 (c 0.64, CHCl₃)
• 13 (2R,3R)-tert-Butyl-2-[(tert-butyldimethylsilyloxy)-methyl]-5-oxo-3-phenylpyrrolidine-1-carboxylate [(-)-11]: To a solution of (+)-9 (400 mg, 1.0 mmol) in MeOH (20 mL), 10% Pd/C (40 mg) was slowly added. The mixture was hydrogenated (3.45 bar) for 12 h. After removal of the solid material, the filtrate was evaporated to dryness. Chromatograph of the residue (PE–EtOAc, 20:1) gave (–)-11 (345 mg, 85%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃): δ = 7.388 (5 H, m, ArH), 4.311 (1 H, d, J = 7.8 Hz, C6-H), 3.942 (1 H, d, J = 10.8 Hz, C6-H), 3.786 (1 H, m, C5-H), 3.289 (2 H, m, C3-H, C4-H), 2.642 (1 H, dd, J = 8.7, 16.5 Hz, C3-H), 1.613 (9 H, s, BocH), 0.911 (9 H, s, t-BuSi), –0.001 (3 H, s, CH₃Si), –0.021 (3 H, s, CH₃Si). ¹³C NMR (100 MHz, CDCl₃): δ = 173.975, 149.991, 136.679, 128.440, 128.127, 127.350, 82.768, 62.704, 60.348, 41.252, 37.340, 28.068, 25.731, 18.034, –5.884, –5.923. ESI-HRMS: m/z calcd for [C₂₂H₃₅NO₄Si + Na]⁺: 428.2228; found: 426. 2207. [α]_D ²⁰ –3.0 (c 0.99, CHCl₃)
• 14 (4R,5R)-5-[(tert-Butyldimethylsilyloxy)methyl]-1-methyl-4-phenylpyrrolidin-2-one [(–)-12]: To a stirred solution of (–)-11 (1.0 g, 2.5 mmol) in CH₂Cl₂ (17.0 mL) was added TFA (0.48 mL, 2.0 equiv in CH₂Cl₂ (4.8 mL)] through a syringe at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h and then diluted with EtOAc (20.0 mL). A sat. aq solution of NaHCO₃ (ca. 1.0 mL) was added dropwise to adjust the pH to 7. The organic phase was then washed with H₂O (40.0 mL) and brine (40.0 mL) and dried over Na₂SO₄. Evaporation of the solvent in vacuo afforded a white solid (860 mg). The solid was dissolved in DMF (10.5 mL) and cooled to 0 °C. NaH (147 mg, 1.3 mmol) was carefully added to the solution under argon. The mixture was stirred until the evolution of gas had ceased. MeI (0.31 mL, 1.3 equiv) was added through a syringe, and the reaction was stirred at r.t. until TLC showed complete conversion. A sat. aq NH₄Cl solution (ca. 5.0 mL) was added dropwise until pH 6. After the most amount of DMF was removed by evaporation under reduced pressure, the reaction mixture was diluted with EtOAc (10.0 mL) and washed with H₂O (10 mL). The aqueous phase was then extracted with EtOAc (5 × 10 mL). The organic layers were combined and washed with brine (50.0 mL) and dried over Na₂SO₄. Removal of the solvent in vacuo and chromato-graphy (PE–EtOAc, 4:1) gave (–)-12 (635 mg, 80% in 2 steps). ¹H NMR (400 MHz, CDCl₃): δ = 7.358–7.274 (5 H, m, PhH), 3.760 (1 H, m, C4-H), 3.692 (1 H, m, C5-H), 3.562 (1 H, d, J = 11.2 Hz, C6-H), 3.251 (1 H, d, J = 10.8 Hz, C6-H), 2.977 (1 H, m, C3-H), 2.920 (3 H, s, NMe), 2.535 (1 H, dd, J = 8.4, 15.6 Hz, C3-H), 0.842 (9 H, s, t-BuSi), –0.091 (3 H, s, CH₃Si), –0.121 (3 H, s, CH₃Si). ¹³C NMR (75 MHz, CDCl₃): δ = 174.718, 137.498, 128.493, 128.051, 127.803, 127.624, 126.755, 64.983, 59.452, 41.419, 35.213, 28.091, 25.404, 17.630, –6.151, –6.292. ESI-HRMS: m/z calcd for [C₁₈H₂₉NO₂Si + H]⁺: 320.2040; found: 320.2038. [α]_D ²⁰ –21.3 (c 1.11, CHCl₃)
• 15 Data for (–)-3: ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.29 (3 H, s, NCH₃), 2.278 (1 H, d, J = 8.4 Hz, C3-H), 3.057 (1 H, t, J = 13.6 Hz, C3-H), 3.814 (1 H, dd, J = 8.4, 19.2 Hz, C4-H), 4.161 (1 H, s, C6-H), 5.348 (1 H, d, J = 4.0 Hz, OH), 7.458–7.185 (10 H, m, PhH). ¹³C NMR (75 MHz, CDCl₃): δ = 175.351, 141.957, 137.607, 128.297, 127.930, 127.686, 126.862, 126.832, 124.725, 71.307, 70.025, 43.026, 34.586, 30.602. ESI-HRMS: m/z calcd for [C₁₈H₁₉NO₂ + H]⁺: 282.14920; found: 282.14966. [α]_D ²⁰ –139.2 (c 0.50, MeOH)
• 16 Data for (+)-2: ¹H NMR (400 MHz, CDCl₃): δ = 7.623–7.375 (10 H, m, PhH), 5.366 (1 H, d, J = 10.4 Hz, C6-H), 4.639 (1 H, s, C5-H), 4.116 (1 H, d, J = 8.0 Hz, C3-H), 3.845 (1 H, t, J = 9.2 Hz, C4-H), 2.489 (3 H, s, NMe). ¹³C NMR (100 MHz, CDCl₃): δ = 141.913, 136.126, 128.936, 128.497, 128.127, 127.476, 125.047, 109.630, 70.550, 70.382, 68.319, 52.414, 31.534. ESI-HRMS: m/z calcd for [C₁₈H₁₉NO₃ + H]⁺: 298.14432; found: 298.14426. [α]_D ²⁰ +205.3 (c 0.48, MeOH); lit.³ [α]_D ²⁰ +201 (c 0.25, MeOH)
• 17 Both (+)- and (–)-3 gave a single diastereomer when converted into their respective ester form with (S)-O-acetylmandelic acid, as indicated by ¹HNMR (see Supporting Information). Both esters were then hydrolyzed, and the recovered samples of (+)- and (–)-3 showed literally identical optical rotation on comparison to that of the original samples {(+)-3: [α]_D ²⁰ +137.0 (c 0.23, MeOH) vs. [α]_D ²⁰ +138.9 (c 0.62, MeOH); (–)-3: [α]_D ²⁰ –138.0 (c 0.45, MeOH) vs. [α]_D ²⁰ –139.2 (c 0.50, MeOH)}. Therefore, the possibility of epimerization during the process of synthesis, particularly the steps to (–)- and (+)-8, was precluded