Toward Fluorinated Aminoglycosides: Structural Studies of Phenylhydrazine Condensation with Carbohydrate Derivatives

Abstract

The reaction of phenylhydrazine with a sugar dialdehyde in water, as a key step for the synthesis of the 3-amino-3-deoxy-d-glucose moiety contained in kanamycin, has been revisited. Structural studies (IR and NMR as well as a simple theoretical model based on energy-minimization calculations and MD calculations) reported herein support the observed stereo- and regioselectivity. Efforts to improve the reproducibility and viability of the process as part of a convenient approach towards fluorinated kanamycin are also now presented.

Key words

carbohydrates - condensation - phenylhydrazine - stereo- and regioselectivity - green chemistry

• References and Notes

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• 6 Synthesis of Compound 2 (Method B) NaIO₄ (7.7 g, 36 mmol) was dissolved in H₂O (95 mL). After cooling at 5 °C, a solution of methyl 4,6-O-benzylidene-α-d-glucopyranoside (5 g, 17.73 mmol) in MeOH (95 mL) was added. The mixture was stirred in the dark for 20 h at r.t. EtOH was added to precipitate iodates, and the filtered solution was evaporated under vacuum and dried to obtain dialdehyde 2 (98% yield). ¹³C NMR (125.7 MHz, D₂O): δ = 196.8 (CHO), 135.5–126.4 (Ph), 101.2 (CHPh), 96.6 (C-1), 75.9 (C-4), 71.3 (C-6), 64.6 (C-5), 48.9 (OCH₃) ppm. HRMS (CI): m/z calcd for C₁₃H₁₅O₅ [M–CHO]: 251.0919; found: 251.0913; and m/z calcd for C₁₃H₁₃O₅ [M–OMe]: 249.0763; found 249.0766.
• 7 Preparation and Most Relevant Data of Compound 4
  Conditions A⁵ Phenylhydrazine (250 μL, 2.59 mmol) was added to a solution of compound 2 (0.5 g, 1.79 mmol) in H₂O (125 mL) at 85 °C. On shaking the yellow mixture rapidly with ice-water, a yellow solid precipitated. This crude product was filtered off and purified by recrystallization from a small volume of butan-1-ol to give a yellow solid, identified as a mixture of 4 (95.2 mg, 15%) and 4a (27.7 mg, 7%). Attempted column chromatography on silica gel resulted in rapid decomposition. Conditions E A solution of compound 2 (0.33 g, 1.18 mmol) in H₂O (100 mL) was heated at 92 °C, under argon in darkness. The solution was cooled, then NaOAc (0.39 g, 4.73 mmol) was added followed by slow addition of phenylhydrazine hydrochloride (0.34 g, 2.36 mmol). After rapid cooling to –15 °C and shaking of the mixture, a yellow solid precipitated. This product was filtered off, washed with cool H₂O, recrystallized from butan-1-ol and dried under vacuum to give a yellow solid which was identified as pure methyl 4,6-O-benzylidene-3-deoxy-3-phenylazo-α-d-glucopyranoside (4, 68.6 mg, 16%). R_f = 0.88 (CH₂Cl₂–acetone = 49:1). ¹H NMR (300 MHz, CDCl₃): δ = 7.74–7.29 (m, 10 H, Ph), 5.77 (s, 1 H, H-7), 5.48 (t, 1 H, H-3, J _3,4 = J _3,2 = 10.2 Hz), 4.75 (dd, 1 H, H-2, J _2,1 = 4.5, J _2,3 = 10.6 Hz), 4.72 (br s, 1 H, H-1), 4.46 (dd, 1 H, J _6ec,5 = 4.6 Hz, J _6ec,6ax = 10.2 Hz, H-6_eq), 3.32 (m, 2 H, H-5 and H-6_ax), 4.10 (t, 1 H, H-4, J _4,3 = J _4,5 = 10.0 Hz), 3.50 (s, 3H, OCH₃) ppm. HRMS (CI): m/z calcd for C₂₀H₂₂N₂O₅: 370.1529; found: 370.1522.
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• 15 Preparation of Compound 12 A solution of compound 10 (109 mg, 0.355 mmol) in dry MeCN (6.5 mL) was treated with DAST (236 μL, 1.785 mmol) at 0 °C under argon. After several minutes, the cooling bath was removed, and the mixture was heated to reflux for 6 h, monitoring the reaction by TLC. On completion, after evaporation of the solvent, the residue was treated with CH₂Cl₂ (20 mL) and cold sat. aq NaHCO₃ (50 mL). The aqueous layer was extracted with CH₂Cl₂ (3 × 20 mL), and the combined organic layers were washed with sat. aq NaCl (50 mL), dried (Na₂SO₄), filtered, and concentrated. The residue was purified by column chromatography on silica gel (1:5 to 1:3 gradient hexane–Et₂O with 1% Et₃N) to give unreacted 10 (9%), compound 12 (25 mg, corresponding to 25% yield from converted substrate) and the epimeric mixture 13/14 [63% yield, characterized by transformation into the corresponding (1R and 1S)-2,5-anhydro-3-azido-6-O-tert-butyl-diphenylsilyl-3,4-dideoxy-1,4-difluoro-1-O-methyl-d-talitols.⁴] Selected Analytical Data Compound 12: solid; mp 56–60 °C; R_f = 0.44 (Et₂O–hexane = 1:3). ¹H NMR (300 MHz, CD₃COCD₃): δ = 7.49–7.36 (m, 5 H, Ph), 5.81 (s, 1 H, CHPh), 4.91 (dd, 1 H, ³ J _1,F = 7.8 Hz, J _1,2 = 1.7 Hz, H-1), 4.78 (ddd, 1 H, ² J _2,F = 48.2 Hz, J _2,3 = 2.3 Hz, H-2), 4.27 (dd, 1 H, J _6,6′ = 11.7 Hz, J _5,6 = 1.7 Hz, H-6), 4.12 (ddd, 1 H, J _3,4 = 10.6 Hz, J _4,5 = 9.0 Hz, ⁴ J _4,F = 1.6 Hz, H-4), 3.92 (ddd, ³ J _3,F = 29.0 Hz, H-3), 3.89–3.83 (m, 2 H, H-5 and H-6′), 3.44 (s, 3 H, OCH₃) ppm. ¹³C NMR (75.8 MHz, CD₃COCD₃): δ = 138.8–127.2 (Ph), 102.5 (CHPh), 99.5 (d, ² J _C1,F = 31.0 Hz, C-1), 89.8 (d, ¹ J _C2,F =180.0 Hz, C-2), 74.6 (C-4), 69.2 (C-6), 64.9 (C-5), 59.7 (d, ² J _C3,F = 16.6 Hz), 55.7 (OCH₃) ppm. HRMS (CI): m/z calcd for C₁₄H₁₆FN₃O₄ + H: 310.1203; found: 310.1207.
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