Download PDF
Synlett 2008(5): 671-674  
DOI: 10.1055/s-2008-1042801
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthetic Studies Directed toward Kaitocephalin: A Highly Stereocontrolled Route to the Right-Hand Pyrrolidine Core

Keisuke Takahashi, Natsumi Haraguchi, Jun Ishihara, Susumi Hatakeyama*
Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
Fax: +81(95)8192426; e-Mail: susumi@nagasaki-u.ac.jp;
Further Information

Publication History

Received 14 December 2007
Publication Date:
26 February 2008 (online)

    Permissions and Reprints All articles of this category

Abstract

A highly stereocontrolled method for the construction of the right-hand segment of kaitocephalin, an antagonist of AMPA/KA and NMDA glutamate receptors, has been developed employing palladium-catalyzed cyclization of an oxiranylacrylate at the quaternary center as the key step.

Key words

kaitocephalin - natural products - pyrrolidines - Tsuji-Trost reaction - ring closure

    References and Notes

  • 1a Shin-ya K. Kim J.-S. Furihata K. Hayakawa Y. Seto H. Tetrahedron Lett.  1997,  38:  7079 
    CrossrefGoogle Scholar
  • 1b Kobayashi H. Shin-ya K. Furihata K. Hayakawa Y. Seto H. Tetrahedron Lett.  2001,  42:  4021 
    CrossrefGoogle Scholar
  • 1c Shin-ya K. Biosci. Biotechnol. Biochem.  2005,  69:  867 
    CrossrefGoogle Scholar
  • 2a Sheardown MJ. Nielsen EP. Hansen AJ. Jacobsen P. Honore T. Science  1990,  247:  571 
    CrossrefGoogle Scholar
  • 2b Bleakman D. Lodge D. Neuropharmacology  1998,  37:  1187 ; and references therein
    CrossrefGoogle Scholar
  • 3a Loh T.-P. Chok Y.-K. Yin Z. Tetrahedron Lett.  2001,  42:  7893 
    CrossrefGoogle Scholar
  • 3b The synthesis of the 2S-isomer of kaitocephalin: Ma D. Yang J. J. Am. Chem. Soc.  2001,  123:  9706 
    CrossrefGoogle Scholar
  • 3c The structure revision of kaitocephalin: Okue M. Kobayashi H. Shin-ya K. Furiata K. Hayakawa Y. Seto H. Watanabe H. Kitahara T. Tetrahedron Lett.  2002,  43:  857 
    CrossrefGoogle Scholar
  • 4a Watanabe H. Okue M. Kobayashi H. Kitahara T. Tetrahedron Lett.  2002,  43:  861 
    CrossrefPubMedGoogle Scholar
  • 4b Kawasaki M. Shinada T. Hamada M. Ohfune Y. Org Lett.  2005,  7:  4165 
    CrossrefPubMedGoogle Scholar
  • 5 Very recently, Watanabe et al. presented an efficient synthesis of kaitocephalin. See: Doi F. Watanabe H. In 49th Symposium on the Chemistry of Natural Products   Symposium Papers:  Sapporo; Japan: 2007.  p.533 
    Google Scholar
  • 6 For a representative review, see: Tsuji J. In Handbook of Organopalladium Chemistry for Organic Synthesis   Vol. 2:  Negishi E. Wiley and Sons; New York: 2002.  p.1669-1687  
    Google Scholar
  • 7 For a similar palladium-catalyzed cyclization forming a pyrrolidine, see: Noguchi Y. Uchiro H. Yamada T. Kobayashi S. Tetrahedron Lett.  2001,  42:  5253 
    CrossrefGoogle Scholar
  • 8 Takano S. Iwabuchi Y. Ogasawara K. J. Chem. Soc., Chem. Commun.  1988,  1294 
    CrossrefGoogle Scholar
  • 9 Luche JL. J. Am. Chem. Soc.  1978,  100:  2226 
    CrossrefGoogle Scholar
  • 10 For a leading review, see: Gololobov YG. Kasukhin LF. Tetrahedron  1992,  48:  1353 
    CrossrefGoogle Scholar
  • 11 Gao Y. Hanson RM. Klunder JM. Ko SY. Masamune H. Sharpless KB. J. Am. Chem. Soc.  1987,  109:  5765 
    CrossrefGoogle Scholar
  • 16 The authentic samples were prepared from the known aldehyde (Scheme 5), see: Bittermann H. Gmeiner P. J. Org. Chem.  2006,  71:  97 
    CrossrefPubMedGoogle Scholar
  • 17a Hirai Y. Watanabe J. Nozaki T. Yokoyama T. Yamaguchi S. J. Org. Chem.  1997,  62:  776 
    CrossrefGoogle Scholar
  • 17b Masaki H. Maeyama J. Kameda K. Esumi T. Iwabuchi Y. Hatakeyama S. J. Am. Chem. Soc.  2000,  122:  5216 
    CrossrefGoogle Scholar
  • 19 Ishizuka T. Kunieda T. Tetrahedron Lett.  1987,  28:  4185 
    CrossrefGoogle Scholar
  • 21a Murray RW. Iyanar K. J. Org. Chem.  1996,  61:  8099 
    CrossrefGoogle Scholar
  • 21b Goti A. Nannelli L. Tetrahedron Lett.  1996,  37:  6025 
    CrossrefGoogle Scholar
12

Since the aldehyde derived from 12b existed as the corresponding aminal, Wittig reaction using Ph3P=CHCO2Et did not give 13b.

13

The ee values of 14a (entry 2) and 14b (entries 7, 9, 11) were determined by HPLC analysis [Daicel Chiralcell OJ-H, hexane-i-PrOH (20:1)] of 26 and 27, respectively (Scheme [4] ).

Scheme 4

14

Reaction of 13a Giving 14a (Entry 2)To a solution of 13a (51 mg, 0.17 mmol) in THF (3.3 mL) was added (Ph3P)4Pd (10 mg, 0.0583 mmol) under an argon atmosphere, and the mixture was refluxed for 1 h. The reaction mixture was diluted with EtOAc, washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography twice [SiO2 5 g, hexane-EtOAc (3:1); SiO2 5 g, PhH-EtOAc (10:1)] to give 14a as a colorless oil (35 mg, 68%, 76% ee): [α]D 24 +56.5 (c 0.66, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.00 (d, J = 15.9 Hz, 1 H), 5.73 (d, J = 15.9 Hz, 1 H), 5.43 (d, J = 10.2 Hz, 1 H), 4.20 (q, J = 7.0 Hz, 2 H), 3.89 (t, J = 10.5 H, 1 H), 3.76 (d, J = 10.5 Hz, 1 H), 3.56 (br s, 1 H), 3.41 (br s, 1 H), 1.75 (m, 4 H), 1.58 (s, 9 H), 1.29 (t, J = 7.0 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 166.1, 155.8, 148.3, 121.0, 80.8, 69.6, 68.8, 60.5, 48.9, 36.0, 28.3, 20.9, 14.2. FT-IR (neat): 3400, 1702, 1545, 1395, 1170 cm-1. HRMS (EI): m/z calcd for C11H25NO5 [M+]: 299.1733; found: 299.1717.

15

Reaction of 13b Giving 14b (Entry 11)To a solution of 13b (8.8 g, 27.6 mmol) and Et3N (3.87 ml, 27.6 mmol) in DMF (276 mL) was added (Ph3P)4Pd (1.6 g, 1.38 mmol) under an argon atmosphere, and the mixture was stirred for 0.5 h at 70 °C. The reaction mixture was diluted with Et2O, washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography [SiO2 600 g, hexane-EtOAc (2:1)] to give 14b as a colorless oil (7.6 g, 86%, 91% ee): [α]D 26 +47.2 (c 0.96, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.32 (s, 5 H), 7.02 (d, J = 15.9 Hz, 1 H), 5.76 (d, J = 15.9 Hz, 1 H), 5.20 (s, 2 H), 4.96 (d, J = 10.8 Hz, 1 H), 3.98-3.77 (m, 2 H), 3.74 (s, 3 H), 3.67-3.44 (m, 2 H), 1.87-1.78 (m, 4 H). 13C NMR (75 MHz, CDCl3): δ = 166.3, 155.9, 148.1,136.2, 128.8, 128.7, 128.5, 128.1, 127.8, 120.8, 70.5, 68.2, 67.4, 51.6, 48.7, 35.6, 20.9. FT-IR (neat): 3419, 1691, 1412, 1350,1309 cm-1. HRMS (EI): m/z calcd for C17H21NO5 [M+]: 319.1421; found: 319.1420.

18

Compound 20: [α]D 27 +103.6 (c 0.87, CHCl3). 1H NMR (500 MHz, CDCl3, ca 2:3 mixture of rotamers): δ = 7.99 (d, J = 7.0 Hz, 2 H), 7.92 (d, J = 7.0 Hz, 2 H), 7.65 (m, 1 H), 7.38 (m, 5 H), 5.65 (d, J = 7.0 Hz, 0.6 H), 5.24 (d, J = 7.5 Hz, 0.4 H), 5.14 (s, 1 H), 5.14 (d, J = 11.0 Hz, 0.4 H), 4.96 (d, J = 11.0 Hz, 0.6 H), 4.81 (dd, J = 8.0 Hz, 0.6 H), 4.73 (dd, J = 8.0 Hz, 0.6 H), 4.46 (dd, J = 8.0 Hz, 0.4 H), 4.43 (m, 0.6 H), 4.30 (m, 0.4 H), 4.10 (m, 0.4 H), 3.73 (m, 1 H), 3.67 (m, 1 H), 2.75 (m, 1 H), 2.17 (m, 3 H). 13C NMR (75 MHz, CDCl3): δ = 180.0, 167.2, 154.4, 148.8, 135.8, 134.2, 131.2, 129.6, 129.1, 129.0, 128.9, 128.8, 128.5, 128.2, 128.0, 78.1, 71.3, 68.7, 67.6, 58.6, 47.7, 31.1, 24.5. FT-IR (film): 1835, 1738, 1565 cm-1. HRMS (EI): m/z calcd for C24H22N2O7 [M+]: 450.1425; found: 450.1427.

20

Compound 22: [α]D 23 +32.0 (c 1.14, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 4.18-4.12 (m, 1 H), 4.06 (d, J = 3.9 Hz, 1 H), 3.75 (dd, J = 10.4, 2.0 Hz, 1 H), 3.68 (br s, 1 H), 3.22-3.16 (m, 1 H), 2.93-2.89 (m, 1 H), 2.22-2.17 (m, 1 H), 1.90-1.74 (m, 3 H), 1.53 (s, 9 H) 0.92-0.83 (m, 18 H), 0.07-0.01 (m, 12 H). 13C NMR (75 MHz, CDCl3): δ = 176.8, 150.2, 83.1, 73.1, 72.1, 64.7, 59.8, 47.0, 29.3, 28.0, 25.7, 25.6, 17.9, -4.8, -5.4; FT-IR (film): 1754, 1719, 1489 cm-1. HRMS (EI): m/z calcd for C25H50N2O5Si2 [M+]: 514.3260; found: 528.3258.

22

Oxidation of 22 to 23To a solution of urea·H2O2 (1.54 g, 16.4 mmol) in MeOH (5 mL) was added MeReO3 (47 mg, 0.16 mmol) under an argon atmosphere, and the mixture was stirred at r.t. for 10 min. A solution of 22 (449 mg, 0.82 mmol) in MeOH (8 mL) and SiO2 (1.35 g) were added and the mixture was stirred at r.t. for 1.5 h. The reaction was quenched with sat. Na2S2O3 and the reaction mixture was extracted with EtOAc. The extract was washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography [SiO2 20 g, hexane-EtOAc (3:2)] to give 23 (350 mg, 81%) as a colorless viscous oil. [α]D 23 +39.2 (c 1.01, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 7.17 (s, 1 H), 5.33 (d, J = 7.0 Hz, 1 H), 4.37 (d, J = 10.5 Hz, 1 H), 3.74 (d, J = 10.5 Hz, 1 H), 3.61 (m, 1 H), 2.87 (m, 1 H), 2.76-2.71 (m, 1 H), 2.64-2.59 (m, 1 H) 2.08 (t, J = 10.5 Hz, 1 H), 1.52 (s, 9 H), 0.84 (s, 18 H), 0.16-0.14 (m, 12 H). 13C NMR (75 MHz, CDCl3): δ = 168.5, 149.6, 136.0, 84.7, 83.9, 65.4, 63.3, 59.6, 28.2, 26.0, 25.7, 22.8, 17.4, 17.1, 4.0, -5.6. FT-IR (neat): 1764, 1725, 1304, 1254 cm-1. HRMS (EI): m/z calcd for C25H48N2O6Si2 [M+]: 528.3035; found: 528.3051.

23

Compound 24: [α]D 23 +19.2 (c 1.05, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 8.03 (d, J = 7.2 Hz, 2 H), 7.60 (t, J = 7.3 Hz, 1 H), 7.47 (t, J = 7.5 Hz, 2 H), 6.37 (br s, 1 H), 5.24 (d, J = 5.7 Hz, 1 H), 4.53 (dd, J = 11.6, 3.6 Hz, 1 H), 4.26 (dd, J = 12.0, 8.1 Hz, 1 H), 3.81 (m, 1 H), 3.79 (s, 3 H), 3.29-2.15 (m, 1 H), 3.10-2.92 (m, 1 H), 2.38-2.31 (m, 1 H), 1.92-1.79 (m, 3 H). 13C NMR (75 MHz, CDCl3): δ = 179.4, 165.6, 155.4, 133.6, 129.7, 129.1, 128.6, 77.6, 69.6, 68.1, 56.0, 55.1, 47.7, 29.9, 26.5. FT-IR (neat): 3240, 2262, 2875, 1720, 1448 cm-1. HRMS (EI): m/z calcd for C17H20N2O6 [M+]: 348.1306; found: 348.1321.

24

Oxidation of 24 to 25Compound 24 (139 mg, 0.40 mmol) was oxidized using urea·H2O2 (827 mg, 8.80 mmol), MeReO3 (11 mg, 0.044 mmol), and SiO2 (580 mg) in MeOH (5 mL) in the same manner as described in ref. 22. Purification of crude product by column chromatography [SiO2 7 g, MeOH-EtOAc (0:1 to 1:10)] gave 25 (92 mg, 64%) as a colorless viscous oil: [α]D 23 +65.9 (c 0.83, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 8.04 (d, J = 7.2 Hz, 2 H), 7.64 (t, J = 7.2 Hz, 1 H), 7.49 (t, J = 7.2 Hz, 2 H), 7.07 (s, 1 H), 6.95 (br s, 1 H), 5.99 (d, J = 3.9 Hz, 1 H), 4.79 (dd, J = 11.1, 4.8 Hz, 1 H), 4.48 (dd, J = 11.1, 4.8 Hz, 1 H), 4.04-3.96 (m, 1 H), 3.78 (s, 3 H), 2.97, 2.91 (m, 1 H), 2.69-2.61 (m, 1 H), 2.56-2.51 (m, 2 H). 13C NMR (75 MHz, CDCl3): δ = 170.4, 165.1, 155.2, 133.9, 129.8, 128.7, 128.5, 128.3, 82.8, 72.0, 68.4, 57.0, 55.1, 26.9, 23.7. FT-IR (neat): 3230, 2922, 1724, 1373, 1277,1176, 1109 cm-1. HRMS (EI): m/z calcd for C17H18N2O7 [M+]: 362.1104; found: 362.1114.

25

Coupling reactions of 2 (Ar = 4-benzyloxy-3,5-dichlorophenyl) with 23 and 25 were preliminarily examined following the procedure reported by Kitahara et al.,3c,4a but the desired coupling products were obtained in <10% yield, respectively. To improve the yield, these coupling reactions are now being examined under various conditions.