Model Studies towards the Total Synthesis of GKK1032s, Novel Antibiotic Anti-Tumor Agents: Enantioselective Synthesis of the Alkyl Aryl Ether Portion of GKK1032s

Moriteru Asano; Munenori Inoue; Tadashi Katoh

doi:10.1055/s-2005-917112

LETTER

Model Studies towards the Total Synthesis of GKK1032s, Novel Antibiotic Anti-Tumor Agents: Enantioselective Synthesis of the Alkyl Aryl Ether Portion of GKK1032s

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 enantioselective synthesis of an alkyl aryl ether portion of GKK1032s, novel antibiotic anti-tumor agents, was achieved via Mitsunobu reaction between a sterically congested indenol derivative and a p-substituted phenol derivative. The indenol derivative, the key substrate for the Mitsunobu reaction, was efficiently synthesized starting from the known indanone derivative through regio- and stereoselective methylation, Saegusa oxidation, and carbonyl transposition as the pivotal steps.

Key words

GKK1032s - antibiotic - anti-tumor agent - natural products synthesis - Mitsunobu reaction - Saegusa oxidation

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References

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13 Data for 8. Colorless viscous oil, [α]_D ²⁰ -52.2 (c 0.70 CHCl₃). IR (neat): 644, 808, 993, 1039, 1049, 1140, 1205, 1377, 1439, 1456, 2839, 2868, 2906, 2949, 3317 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 0.51-0.61 (m, 1 H), 0.83 (s, 3 H), 0.85-0.94 (m, 1 H), 0.89 (d, J = 6.5 Hz, 3 H), 1.05 (d, J = 6.6 Hz, 3 H), 1.00-1.08 (m, 1 H), 1.23 (d, J = 7.4 Hz, 1 H), 1.55-1.62 (m, 1 H), 1.65 (t, J = 1.8 Hz, 3 H), 1.68-1.75 (m, 1 H), 1.76-1.89 (m, 2 H), 4.47-4.54 (m, 1 H), 5.27 (t, J = 1.5 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 12.3, 19.4, 20.7, 22.8, 28.3, 29.5, 43.3, 45.8, 48.0, 66.5, 77.7, 127.8, 152.6. HRMS (EI): m/z calcd for C₁₃H₂₂O [M⁺]: 192.0786; found: 192.0790

14

This remarkable stereoselectivity can be rationalized by the consideration that the hydride attack occurred exclusively from α-face of the carbonyl group under an influence of stereoelectronic effect, which may involve the so-called ‘product development control’.

15

Since separation of 13α-form and 13β-form was very difficult, the ratio was estimated by ¹H NMR (500 MHz) spectroscopy.

16 Degenhardt CR. J. Org. Chem. 1980, 45: 2763

17

Data for 9.
White solid, mp 101-104 °C. IR (KBr): 652, 677, 818, 843, 972, 985, 1171, 1186, 1223, 1516, 1743, 3342 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 1.89-1.99 (m, 1 H), 2.21-2.30 (m, 1 H), 2.31-2.40 (m, 1 H), 2.41-2.51 (m, 1 H), 2.89 (dd, J = 14.2, 5.9 Hz, 1 H), 2.97 (dd, J = 14.2, 6.0 Hz, 1 H), 4.67-4.75 (m, 1 H), 5.05 (s, 1 H), 6.78 (d, J = 8.5 Hz, 2 H), 7.09 (d, J = 8.5 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 26.9, 28.7, 40.4, 81.1, 115.5 (2 C), 127.7, 130.7 (2 C), 154.8, 177.5. HRMS (EI): m/z calcd for C₁₁H₁₂O₃ [M⁺]: 194.1671; found: 194.1667.

18

Data for 6.
Colorless viscous oil, [α]_D ²⁰ +129.5 (c 0.16 CHCl₃). IR (neat): 607, 634, 806, 937, 1005, 1045, 1173, 1227, 1240, 1373, 1508, 1736, 1774, 2910, 2949 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 0.54-0.65 (m, 1 H), 0.82 (t, J = 12.0 Hz, 1 H), 0.90 (d, J = 6.4 Hz, 3 H), 0.92 (d, J = 6.5 Hz, 3 H), 1.18 (s, 3 H), 1.30 (dd, J = 11.6, 5.1 Hz, 1 H), 1.63 (dd, J = 11.6, 4.1 Hz, 1 H), 1.71 (s, 3 H), 1.80-1.88 (m, 1 H), 1.88-2.07 (m, 3 H), 2.18-2.27 (m, 1 H), 2.30-2.50 (m, 2 H), 2.85 (dd, J = 14.1, 6.4 Hz, 1 H), 2.99 (dd, J = 14.1, 5.8 Hz, 1 H), 4.64-4.73 (m, 1 H), 4.82-4.87 (m, 1 H), 5.67 (s, 1 H), 6.85 (d, J = 8.5 Hz, 2 H), 7.09 (d, J = 8.5 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 12.8, 19.4, 22.0, 22.9, 26.7, 27.0, 28.1, 28.7, 40.40 (1/2 C), 40.39 (1/2 C), 43.1, 45.6, 48.2, 60.4, 78.896 (1/2 C), 78.868 (1/2 C), 81.1, 115.695 (1/2 C × 2), 115.703 (1/2 C × 2), 121.883 (1/2 C), 121.892 (1/2 C), 127.104 (1/2 C), 127.111 (1/2 C), 130.3 (2 C), 157.840 (1/2 C), 157.831 (1/2 C), 159.6, 177.155 (1/2 C), 177.172 (1/2 C). HRMS-FAB: m/z calcd for C₂₄H₃₃O₃ [M + H]⁺: 369.2430; found: 369.2465.