Enantioselective Synthesis of the Tricyclic Core of GKK1032, Novel Antibiotic Anti-Tumor Agents, by Employing an Intramolecular Diels-Alder Cycloaddition Strategy

Moriteru Asano; Munenori Inoue; Tadashi Katoh

doi:10.1055/s-2005-869843

LETTER

Enantioselective Synthesis of the Tricyclic Core of GKK1032, Novel Antibiotic Anti-Tumor Agents, by Employing an Intramolecular Diels-Alder Cycloaddition Strategy

Moriteru Asano^a, Munenori Inoue*^a,b, Tadashi Katoh*^c
^a Department of Electronic Chemistry, Tokyo Institute of Technology, Nagatsuta, Yokohama 226-8502, Japan
^b Sagami Chemical Research Center, 2743-1 Hayakawa, Ayase, Kanagawa 252-1193, Japan
^c Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
Fax: +81(22)2752013; e-Mail: katoh@tohoku-pharm.ac.jp;

Abstract

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Abstract

An efficient and enantioselective synthesis of a decahydrofluorene nucleus, the tricyclic core (ABC-ring system) of GKK1032s, novel antimicrobial and anti-tumor agents, was achieved using a highly diastereoselective intramolecular Diels-Alder (IMDA) reaction. The substrate for the IMDA reaction was synthesized through intermolecular Diels-Alder reaction of Kitahara-Danishefsky’s diene and an enone derived from enulose to construct the functionalized C-ring. CuCl-promoted Stille coupling of a vinyl iodide and a vinylstannane installed the requisite triene side chain.

Key words

Diels-Alder reaction - Stille coupling - natural product synthesis - GKK1032s - antimicrobial agents - anti-tumor agents

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Referenzen

References

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Quite recently, three other synthetic studies of GKK1032s and pyrrocidines were independently presented by Kuwajima’s group, Tadano’s group, and Uchiro’s group:

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5b Kurosaka J. Sinkawa T. Miyazaki Y. Munakata R. Takao K. Tadano K. The 85th Annual Spring Meeting of the Chemical Society of Japan, Yokohama Japan 2005, Abstract 2: 874

5c Hasegawa D. Sakuma Y. Takagi Y. Uchiro T. The 125th Annual Meeting of the Pharmaceutical Society of Japan, Tokyo Japan 2005, Abstract 4: 71

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8

Data for 13: Pale yellow oil [α]_D ²⁰ -55.7 (c 0.24, CHCl₃). IR (neat): 631, 733, 787, 852, 906, 920, 968, 1057, 1084, 1211, 1242, 1358, 1371, 1419, 1456, 1680, 1709, 1736, 2937, 2985 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 1.30 (s, 3 H), 1.36 (s, 3 H), 1.38 (s, 3 H), 2.25 (s, 3 H), 2.49 (dd, J = 4.5, 17.1 Hz, 1 H), 2.60 (dd, J = 11.1, 17.1 Hz, 1 H), 2.71 (ddd, J = 2.7, 4.5, 11.1 Hz, 1 H), 3.36 (dd, J = 7.6, 8.2 Hz, 1 H), 4.01 (dd, J = 6.7, 8.2 Hz, 1 H), 4.07-4.15 (m, 1 H), 6.07 (d, J = 10.2 Hz, 1 H), 6.66 (d, J = 10.2 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 17.6, 25.0, 25.8, 26.2, 34.3, 40.1, 53.4, 67.6, 74.3, 109.4, 129.0, 150.1, 198.0, 208.1. HR-FABMS: m/z calcd for C₁₄H₂₁O₄ [(M + H)⁺]: 253.1440; found: 253.1448.

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17

Detailed discussions on this IMDA reaction will be presented in a full account.

The vinylstannane 9 was prepared from the known compound i:

18a Scarlato GR. DeMattei JA. Chong LS. Ogawa AK. Lin MR. Armstrong RW. J. Org. Chem. 1996, 61: 6139

18b Baker R. Castro JL. J. Chem. Soc., Perkin Trans. 1 1990, 47 ; via a two-step sequence of reactions as shown in Scheme 6

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Data for 7: Colorless viscous oil, [α]_D ²⁰ +18.2 (c 0.23, CHCl₃). IR (neat): 607, 648, 731, 779, 897, 908, 985, 1043, 1097, 1167, 1194, 1240, 1273, 1373, 1435, 1655, 1722, 2860, 2933, 2947, 2979, 3463 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 1.31 (s, 3 H), 1.41-1.48 (m, 1 H), 1.50 (d, J = 4.8 Hz, 1 H), 1.83-2.04 (m, 4 H), 1.87 (d, J = 1.0 Hz, 3 H), 1.92 (d, J = 1.0 Hz, 3 H), 2.06-2.19 (m, 3 H), 2.24-2.30 (m, 1 H), 2.61-2.76 (m, 2 H), 2.81-2.98 (m, 2 H), 3.74 (s, 3 H), 4.59-4.65 (m, 1 H), 5.03 (d, J = 10.7 Hz, 1 H), 5.17 (d, J = 17.4 Hz, 1 H), 5.26 (br s, 1 H), 5.88 (br s, 1 H), 6.04 (dd, J = 1.9, 15.6 Hz, 1 H), 6.37 (dd, J = 10.7, 17.4 Hz, 1 H), 6.94 (dd, J = 4.1, 15.6 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 13.3, 18.7, 21.0, 25.8, 26.0, 26.3, 32.0, 33.6, 34.6, 40.0, 44.5, 50.2, 51.7, 71.4, 112.2, 119.8, 133.1, 133.6, 137.7, 140.2, 142.0, 151.2, 166.8. HR-EIMS: m/z calcd for C₂₃H₃₄O₃S₂ (M⁺): 422.1949; found: 422.1954.

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Data for 6: White solid, mp 161-166 °C, [α]_D ²⁰ +65.7 (c 0.45, CHCl₃). IR (neat): 607, 621, 688, 783, 804, 852, 908, 995, 1047, 1159, 1223, 1259, 1331, 1375, 1435, 1716, 2875, 2931, 3500 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 0.79 (s, 3 H), 1.28 (s, 3 H), 1.42-1.53 (m, 1 H), 1.69-1.83 (m, 3 H), 1.75 (s, 3 H), 1.89-2.00 (m, 3 H), 2.00-2.10 (m, 2 H), 2.11-2.18 (m, 1 H), 2.33 (dt, J = 8.3, 12.0 Hz, 1 H), 2.52 (dt, J = 13.4, 2.2 Hz, 1 H), 2.61 (d, J = 12.0 Hz, 1 H), 2.65-2.75 (m, 1 H), 2.77-2.87 (m, 2 H), 2.95-3.03 (m, 1 H), 3.68 (s, 3 H), 3.93-3.99 (m, 1 H), 4.85 (s, 1 H), 4.98 (dd, J = 1.5, 17.2 Hz, 1 H), 5.05, (dd, J = 1.5, 10.4 Hz, 1 H), 5.69 (dd, J = 10.4, 17.2 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 13.3, 21.2, 25.9, 26.1, 26.4, 26.7, 34.5, 35.0, 35.3, 41.3, 42.4, 44.0, 50.3, 51.3, 52.3, 54.4, 55.5, 72.7, 114.5, 131.3, 135.4, 142.8, 174.8. HR-EIMS: m/z calcd for C₂₃H₃₄O₃S₂ (M⁺): 422.1949; found 422.1950.

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In this IMDA reaction, a small amount (<10% yield) of unidentified products was generated along with the desired decahydrofluorene 6.