The Application of tert-Butanesulfinamide in the Asymmetric Synthesis of the Core Structure of Polyoxin and Nikkomycin Antibiotics

Abstract

A stereoselective approach to the core structure of polyoxin and nikkomycin antibiotics has been developed. The key steps of this approach include diastereoselective nucleophilic addition of 2-lithiofuran to tert-butanesulfinyl imine derived from (S)-tert-­butanesulfinamide and ribosyl aldehyde for the generation of C-5 stereocenter, and the use of triflic acid to remove tert-butylsulfonyl group. Significantly, the synthesis provides a method for large-scale preparation of polyoxin and nikkomycin analogues because of simple operation, excellent yield and high stereoselectivity.

polyoxin - nikkomycin - (S)-tert-butanesulfinamide - ­ribose - asymmetric synthesis

References and Notes

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Procedure for the Synthesis of Compound 4: To a solution of n-BuLi (2.164 M in hexane, 1.39 mL, 3.0 mmol) at -78 ˚C was added a solution of furan (245 mg, 3.6 mmol) in THF (5 mL), and the mixture was stirred at r.t. for 3 h. The mixture was then cooled to -78 ˚C, and a solution of tert-butanesulfinyl imine 2 (0.5 M in THF, 4.0 mL, 2.0 mmol) was added via syringe over 10 min. The reaction mixture was stirred at -78 ˚C for 3 h and quenched with a sat. NH₄Cl solution (2 mL). The solvent was evaporated under reduced pressure and the residue was treated with H₂O (10 mL). The mixture was extracted with EtOAc, dried over anhyd Na₂SO₄ and concentrated. Flash chromatography of the residue (petroleum ether-EtOAc, 6:1) afforded compound 4 (96%) as a white solid; mp 81-82 ˚C; [α]_D ^²0 +3 (c = 0.5, CH₂Cl₂). IR (KBr): 3235, 2935, 1462, 1377, 1210, 1157, 1092 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.42 (d, J = 0.8 Hz, 1 H), 6.37 (d, J = 2.8 Hz, 1 H), 6.34 (dd, J = 2.0, 3.2 Hz, 1 H), 4.95 (d, J = 6.0 Hz, 1 H), 4.93 (s, 1 H), 4.63 (d, J = 6.0 Hz, 1 H), 4.43 (s, 1 H), 4.42 (d, J = 3.6 Hz, 1 H), 3.71 (dd,
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Crystal data for 4 has been deposited at the Cambridge Crystallographic Data Centre with the deposition number 701981. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.com.

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Spectroscopic Data of Compound 14: [α]_D ^²0 +16 (c = 0.98, CHCl₃). IR (KBr): 3299, 3065, 1750, 1696, 1239 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 9.09 (br s, 1 H), 7.30 (m, 5 H), 7.05 (s, 1 H), 5.94 (d, J = 5.2 Hz, 1 H), 5.93 (d, J = 8.8 Hz, 1 H), 5.53 (t, J = 5.6 Hz, 1 H), 5.28 (t, J = 6.0 Hz, 1 H), 5.10 (d, J = 4.0 Hz, 2 H), 4.84 (d, J = 3.9 Hz, 1 H), 4.38 (t, J = 4.4 Hz, 1 H), 3.80 (s, 3 H), 2.09 (s, 6 H), 1.88 (s, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 169.6, 169.5, 169.3, 163.3, 156.0, 135.8, 135.5, 128.5, 128.3, 128.1, 112.0, 87.5, 81.9, 77.2, 72.3, 69.7, 67.4, 60.3, 55.1, 52.9, 20.3, 12.4. HRMS: m/z [M + NH₄ ⁺] calcd for C₂₄H₃₁N₄O₁₁: 551.1989; found: 551.1984.

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