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Synlett 2012; 23(8): 1217-1220
DOI: 10.1055/s-0031-1290804
letter
© Georg Thieme Verlag Stuttgart · New York

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

Lu Zhang
State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Beijing Key Laboratory of Active Substance Discovery and Drugability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, P. R. of China, Fax: +86(10)63017757   eMail: mingxyu@imm.ac.cn
,
Yumei Zhou
State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Beijing Key Laboratory of Active Substance Discovery and Drugability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, P. R. of China, Fax: +86(10)63017757   eMail: mingxyu@imm.ac.cn
,
Xiaoming Yu*
State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Beijing Key Laboratory of Active Substance Discovery and Drugability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, P. R. of China, Fax: +86(10)63017757   eMail: mingxyu@imm.ac.cn
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Publikationsverlauf

Received: 13. Januar 2012

Accepted after revision: 16. März 2012

Publikationsdatum:
26. April 2012 (online)

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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

Supporting Information

    for this article is available online at http://www.thieme-connect.com/ejournals/toc/synlett.
  • Supporting Information
 

  • References and Notes

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  • 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