Synlett 2002(12): 2098-2100
DOI: 10.1055/s-2002-35584
LETTER
© Georg Thieme Verlag Stuttgart · New York

Asymmetric Synthesis of the Polyol Portion of the Polyene Macrolide Antibiotic RK-397

Christoph Schneider*, Frank Tolksdorf, Markus Rehfeuter
Institut für Organische Chemie, Georg-August-Universität Göttingen, Tammannstr. 2, 37077 Göttingen, Germany
Fax: +49(551)399660; e-Mail: cschnei1@gwdg.de;
Further Information

Publication History

Received 10 September 2002
Publication Date:
20 November 2002 (online)

Abstract

A highly convergent and asymmetric synthesis of a fully functionalized polyol portion of the new polyene macrolide antibiotic RK-397 has been achieved taking advantage of a novel polyol synthesis.

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Experimental Procedure: An amount of 149 mg (0.39 mmol) of methyl ketone 7 was dissolved in 4 mL diethyl ether and cooled to -78 °C. For enolization 0.59 mL (0.59 mmol) of a 1 M solution of dibutylboron triflate in dichloromethane were added and subsequently 92 µL (0.66 mmol) triethyl-amine and the resulting solution was stirred for 30 min at -78 °C and for 30 min at 0 °C. Then the solution was cooled to -100 °C and 122 mg (0.27 mmmol) of aldehyde 8, dissolved in 1 mL diethyl ether, were added with a syringe. Stirring was continued for 3 h at -100 °C and 3 h at -78 °C after which the reaction was quenched with pH 7 buffer. After separation of the phases the aq phase was repeatedly extracted with diethyl ether, the combined organic extracts were dried over MgSO4, filtered and evaporated in vacuo. Purification of the crude mixture through flash chromatography with diethyl ether/pentane (1:2) as eluent yielded 145 mg (65%) of the desired aldol product 9 as a colourless oil (84:16 mixture of stereo-isomers) along with 34 mg (27%) of unreacted aldehyde 8 and 44 mg (30%) of methyl ketone 7 both of which were used again in the aldol reaction. [α]D 20 +19.7 (c 0.58, CHCl3); IR(film): ν = 3471 (OH), 2992, 2949, 2857 (CH), 1741 (C=O), 1712 (C=O) cm-1; 1H NMR (300 MHz, CDCl3): δ = 0.05 (s, 6 H, SiMe2), 0.90 (s, 9 H, t-Bu), 1.07-1.33 (m, 2 H), 1.36, 1.40, 1.41 [3 s, 12 H, 2 × C(CH3)2], 1.50-1.97 (m, 10 H), 2.37 (dd, J = 15.5, 6.0 Hz, 1 H, 2-H), 2.43-2.65 (m, 4 H) 2.73 (dd, J = 15.5, 7.0 Hz, 1 H, 2-H), 3.68 (s, 3 H, OMe), 3.65-4.29 (m, 9 H), 4.45, 4.48, 4.55, 4.56 (4 × d, J = 11.5 Hz, 4 H, 2 × OBn), 7.25-7.36 (m, 10 H, 2 × Ph); 13C NMR (75 MHz, CDCl3): δ = -5.35, 18.30, 19.81, 19.84, 25.94, 30.11, 30.26, 36.86, 37.41, 39.45, 40.20, 40.47, 41.18, 42.39, 49.29, 50.81, 51.60, 58.77, 65.28, 65.48, 65.76, 65.87, 66.49, 70.36, 72.44, 71.93, 74.63, 98.36, 98.81, 127.70, 127.80, 128.00, 128.10, 128.40, 138.10, 138.30, 171.30, 209.40; MS (200 eV, DCI/NH3):
m/z (%) = 847(100) [M + NH4 +]; calcd for C46H72O11Si (829.15): C, 66.63; H, 8.75. Found: C, 66.82; H, 8.50.

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Spectroscopic Data of 2: [α]D 20 0 (c 0.2, CHCl3); IR(film): ν = 2990, 2938, 2857 (CH), 1745 (C=O) cm-1; 1H NMR (500 MHz, C6D6): δ = 0.06, 0.08 (2 × s, 6 H, SiMe2), 0.98 (s, 9 H, t-Bu), 1.10-1.60 (m, 14 H), 1.32, 1.37, 1.47, 1.49, 1.50, 1.54, 1.55 [7 s, 24 H, 8 × C(CH3)2], 1.67 (s, 3 H, OAc), 1.73-1.82 (m, 1 H), 2.06 (quint, J = 7.0 Hz, 1 H), 3.68 (dt, J = 10.0, 5.0 Hz, 1 H, CH2OTBS), 3.82 (ddd, J = 10.0, 8.5, 5.0 Hz, 1 H, CH2OTBS), 3.83-3.89 (m, 1 H), 3.96-4.34 (m, 9 H); 13C NMR (150 MHz, C6D6): δ = -5.38, 18.49, 19.82, 19.92, 19.97, 20.42, 24.86, 26.13, 30.39, 30.63, 30.67, 37.60, 37.80, 39.46, 40.16, 42.80, 43.08, 43.59, 59.20, 62.55, 62.69, 64.86, 65.34, 65.60, 65.71, 65.76, 67.38, 67.70, 98.54, 98.59, 98.80, 100.50, 170.10; MS (200 eV, EI): m/z (%) = 715(34) [M+ - CH3], 414(4), 380(5), 337(10), 256(18), 149(21), 57(100) [C4H9]; HRMS calcd for C38H70O11Si: for [M+ - CH3] 715.4453. Found: 715.4531.