A Short and Efficient Route from myo- to neo-Inositol

Abstract

An efficient route from myo- to neo-inositol is described. The key steps of the sequence are oxidation of the hydroxy group at C-5 to the corresponding ketone, followed by a highly (dr = 7.8:1) stereoselective reduction. The route includes nine steps with an overall yield of 51% and is therefore superior to all hitherto reported methods for the preparation of neo-inositol.

Key words

inositols - cyclitols - carbocycles - stereoselective synthesis - regioselectivity

References and Notes

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27

Ketone 9 was obtained as an oil, which was partly decomposed upon flash column chromatography on silica gel.

28

Alcohol 4 (20.18 g, 43.63 mmol) was dissolved in anhyd CH₂Cl₂ (500 mL) and Dess-Martin periodinane (20.59 g, 48.55 mmol, 1.1 equiv) was added. The resulting mixture was stirred at r.t. until complete conversion of 4 was monitored by TLC. The organic layer was washed several times with an aq solution of Na₂S₂O₃/NaHCO₃, dried, and evaporated. Ketone 9 was obtained as an oil (19.85 g, 43.10 mmol, 99%) and can be used without further purification; R _f  = 0.7 (hexanes-EtOAc, 2:1). ^¹H NMR (500 MHz, CDCl₃): δ = 3.95-3.97 (m, 2 H), 4.51 (d, ^² J = 11.6 Hz, 2 H), 4.52-4.54 (m, 2 H), 4.64 (d, ^² J = 4.8 Hz, 1 H), 4.67 (d, ^² J = 11.6 Hz, 2 H), 4.73 (s, 2 H), 4.76 (t, ^³ J = 1.3 Hz, 1 H), 5.52 (d, ^³ J = 4.8 Hz, 1 H), 7.24-7.41 (m, 15 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 69.8 (CH), 71.1 (CH₂), 72.2 (CH), 72.3 (CH₂), 81.6 (CH), 85.5 (CH₂), 127.8 (CH), 127.9 (CH), 127.9 (CH), 128.3 (CH), 128.4 (CH), 136.8 (C), 137.3 (C), 202.7 (C). HRMS: m/z [M + H]⁺ calcd for C₂₈H₂₈O₆ + H: 461.1964; found: 461.1986.

29

Ketone 9 (19.84 g, 43.08 mmol) was dissolved in anhyd MeOH (800 mL) and NaBH₄ (1.98 g, 52.39 mmol, 1.2 equiv) was added. The reaction mixture was stirred about 20 min until gas and heat evolution ceased. This mixture was directly used in the next step. To obtain spectroscopic data a small sample (2 mL) was taken from the mixture, and the solvent was evaporated. The resulting residue was treated with 0.1 M aq HCl solution and extracted thrice with Et₂O. The combined organic layers were dried and evaporated giving a pale yellow oil (49 mg, 0.10 mmol, 98%) with a ratio of 8 (neo) to 4 (myo) of 7.8:1 (determined by ^¹H NMR); R _f (8) = 0.46 (hexanes-EtOAc, 2:1); R _f (4) = 0.44 (hexanes-EtOAc, 2:1). ^¹H NMR (8): δ = 2.74 (br s, 1 H), 3.91-3.96 (m, 2 H), 4.30-4.32 (m, 1 H), 4.34-4.37 (m, 2 H), 4.43-4.47 (m, 1 H), 4.52 (s, 2 H), 4.59 (d, ^² J = 11.9 Hz, 2 H), 4.63 (d, ^² J = 4.5 Hz, 1 H), 4.67 (d, ^² J = 11.9 Hz, 2 H), 5.52 (d, ^² J = 4.5 Hz, 1 H), 7.25-7.39 (m, 15 H). ^¹H NMR (4): matches with literature.^²4

30

The reaction mixture of the previous step, containing 8 + 4, was treated with concd HCl (60 mL) and refluxed for 3 h. The solvents were evaporated, and the resulting residue was treated with H₂O and extracted thrice with CH₂Cl₂. The combined organic layers were dried, evaporated, and the resulting residue purified by flash chromatography (silica, CHCl₃ → CHCl₃-EtOAc, 1:2) giving 10 as colorless crystals (14.96 g, 33.21 mmol, 77%); mp 97-98 ˚C; R _f  = 0.26 (CHCl₃-EtOAc, 1:2).