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

Keisuke Takahashi; Natsumi Haraguchi; Jun Ishihara; Susumi Hatakeyama

doi:10.1055/s-2008-1042801

LETTER

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;

Abstract

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

Full Text

References

References and Notes

<A NAME="RU12407ST-1A">1a</A> Shin-ya K. Kim J.-S. Furihata K. Hayakawa Y. Seto H. Tetrahedron Lett. 1997, 38: 7079

<A NAME="RU12407ST-1B">1b</A> Kobayashi H. Shin-ya K. Furihata K. Hayakawa Y. Seto H. Tetrahedron Lett. 2001, 42: 4021

<A NAME="RU12407ST-1C">1c</A> Shin-ya K. Biosci. Biotechnol. Biochem. 2005, 69: 867

<A NAME="RU12407ST-2A">2a</A> Sheardown MJ. Nielsen EP. Hansen AJ. Jacobsen P. Honore T. Science 1990, 247: 571

<A NAME="RU12407ST-2B">2b</A> Bleakman D. Lodge D. Neuropharmacology 1998, 37: 1187 ; and references therein

<A NAME="RU12407ST-3A">3a</A> Loh T.-P. Chok Y.-K. Yin Z. Tetrahedron Lett. 2001, 42: 7893

<A NAME="RU12407ST-3B">3b</A> The synthesis of the 2S-isomer of kaitocephalin: Ma D. Yang J. J. Am. Chem. Soc. 2001, 123: 9706

<A NAME="RU12407ST-3C">3c</A> 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

<A NAME="RU12407ST-4A">4a</A> Watanabe H. Okue M. Kobayashi H. Kitahara T. Tetrahedron Lett. 2002, 43: 861

<A NAME="RU12407ST-4B">4b</A> Kawasaki M. Shinada T. Hamada M. Ohfune Y. Org Lett. 2005, 7: 4165

<A NAME="RU12407ST-5">5</A> 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

<A NAME="RU12407ST-6">6</A> 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

<A NAME="RU12407ST-7">7</A> For a similar palladium-catalyzed cyclization forming a pyrrolidine, see: Noguchi Y. Uchiro H. Yamada T. Kobayashi S. Tetrahedron Lett. 2001, 42: 5253

<A NAME="RU12407ST-8">8</A> Takano S. Iwabuchi Y. Ogasawara K. J. Chem. Soc., Chem. Commun. 1988, 1294

<A NAME="RU12407ST-9">9</A> Luche JL. J. Am. Chem. Soc. 1978, 100: 2226

<A NAME="RU12407ST-10">10</A> For a leading review, see: Gololobov YG. Kasukhin LF. Tetrahedron 1992, 48: 1353

<A NAME="RU12407ST-11">11</A> Gao Y. Hanson RM. Klunder JM. Ko SY. Masamune H. Sharpless KB. J. Am. Chem. Soc. 1987, 109: 5765

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

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

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.

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.

<A NAME="RU12407ST-16">16</A> The authentic samples were prepared from the known aldehyde (Scheme 5), see: Bittermann H. Gmeiner P. J. Org. Chem. 2006, 71: 97

<A NAME="RU12407ST-17A">17a</A> Hirai Y. Watanabe J. Nozaki T. Yokoyama T. Yamaguchi S. J. Org. Chem. 1997, 62: 776

<A NAME="RU12407ST-17B">17b</A> Masaki H. Maeyama J. Kameda K. Esumi T. Iwabuchi Y. Hatakeyama S. J. Am. Chem. Soc. 2000, 122: 5216

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.

<A NAME="RU12407ST-19">19</A> Ishizuka T. Kunieda T. Tetrahedron Lett. 1987, 28: 4185

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.

<A NAME="RU12407ST-21A">21a</A> Murray RW. Iyanar K. J. Org. Chem. 1996, 61: 8099

<A NAME="RU12407ST-21B">21b</A> Goti A. Nannelli L. Tetrahedron Lett. 1996, 37: 6025

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.

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.

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.

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.