A Stereoselective Approach to the Core Structure of the Polyoxin and Nikkomycin Antibiotics

Abstract

A stereoselective synthesis of the core structure of the polyoxin and nikkomycin antibiotics is described. Notable elements of the synthesis include the use of an IBX-based oxidation protocol in the high-yielding production of ribosyl aldehydes, and the use of a diastereoselective zinc-mediated acetylide addition for the generation of the C-5 stereocenter. The synthesis only requires three chromatographic purifications and should be amenable to the large-scale preparation of numerous polyoxin analogs.

Key words

antifungal agents - amino acids - carbohydrates - diastereoselectivity - stereoselective synthesis

References

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• 5a

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8

Attempted use of the zinc acetylide addition with a uridine-derived aldehyde was thwarted by a complete lack of reactivity with a variety of alkynes.

11

Other methods of oxidation investigated (e.g. PCC, Swern, CrO₃/pyridine, TPAP, IBX/DMSO, Dess-Martin) proved to be much less reliable for this transformation, being difficult to reproduce and providing aldehyde of lower purity than with IBX.

12

Experimental Details for the Synthesis of Compound 4: The alcohol 2 (6.2 g, 30.18 mmol, 1.0 equiv) was dissolved in 250 mL CH₃CN and IBX (16.9 g, 60.35 mmol, 2.0 equiv) was added. The flask was fitted with a reflux condenser and the suspension was immersed in an oil bath heated to 80 °C with vigorous stirring. After 75 min, an aliquot was removed and analyzed by ¹H NMR, which indicated consumption of starting material and clean conversion to product. The reaction was stopped, cooled to room temperature and filtered, washing the flask and filter thoroughly with EtOAc. The combined filtrate and washings were combined and concentrated to yield a white, glassy semi-solid, which was used without further purification in the next step. ¹H NMR (400 MHz, CDCl₃) δ 9.56 (s, 1 H), 5.08 (s, 1 H), 5.04 (d,
1 H, J = 8 Hz), 4.48 (d, 1 H, J = 8 Hz), 4.46 (s, 1 H), 3.44 (s, 3 H), 1.48 (s, 3 H), 1.32 (s, 3 H). An oven-dried 1 L round bottom flask was cooled under N₂, then charged with (-)-N-methyl ephedrine (11.9 g, 66.39 mmol, 2.2 equiv) and Zn(OTf)₂ (23.0 g, 63.37 mmol, 2.1 equiv), and purged with N₂. Freshly distilled NEt₃ (8.9 mL, 63.37 mmol, 2.1 equiv) was added via syringe, followed by 250 mL anhydrous toluene via cannula. The heterogeneous mixture was stirred vigorously for 2 h, and phenyl acetylene (6.6 mL, 60.35 mmol, 2.0 equiv) was added via syringe. After stirring for an additional 30 min, the aldehyde 3 (azeotropically dried twice with benzene) was added in 80 mL toluene via cannula. The reaction was stirred overnight (approx. 18 h), at which time TLC analysis showed formation of a new, UV-active spot (R_f 0.24, 30% ethyl acetate in hexanes). The reaction was stopped, diluted with 300 mL EtOAc, and poured into a separatory funnel containing 700 mL 0.1 M sodium EDTA. The aqueous layer was removed and extracted twice with EtOAc (approx 300 mL each). The combined organics were washed twice with 0.1 M sodium EDTA (500 mL total), 3 times with 1.0 M HCl (to remove and recycle N-methyl ephedrine), and brine, then dried over Na₂SO₄, filtered and concentrated to afford pure 4 as a brown semi-solid (8.05 g, 26.5 mmol, 87.6% over 2 steps). R_f = 0.24 (20% in EtOAc /hexanes); ¹H NMR (400 MHz, CDCl₃) δ 7.46-7.48 (m, 2 H), 7.30-7.32 (m, 3 H), 5.08 (d, 1 H, J = 6 Hz), 5.03 (s, 1 H), 4.71 (br s, 1 H), 4.63 (d, 1 H, 6 Hz), 4.55 (d, 1 H, J = 2 Hz), 3.99 (br s, 1 H), 3.48 (s, 3 H), 1.50 (s, 3 H), 1.35 (s, 3 H); ¹³C NMR (125 MHz, CDCl₃) δ 131.7, 128.5, 128.1, 122.1, 112.2, 110.7, 91.0, 86.5, 85.6, 85.5, 80.8, 64.4, 55.9, 26.4, 24.8; FTIR (thin film; NaCl) 3415, 2986, 2943, 1492, 1375, 1212, 1095, 1037, 868, 763 cm^-1; HRMS (DCI) m/z: (M + NH₄ ⁺) calc. for C₁₇H₂₄O₅N 322.1654, found 322.1657.