An Efficient One-Pot Synthesis of ω-Hydroxy Ketones from Lactones

Abstract

An efficient and convenient one-pot strategy was developed for the synthesis of 1-hydroxydodecan-6-one, an important precursor for total synthesis of sphingofungin F. A series of ω-hydroxy ketones were prepared from readily available lactones using this one-pot reaction.

Weinreb ketone synthesis - one-pot reaction - ω-hydroxy ketones - lactones

References and Notes

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10

It is worth to note that when phenylmagnesium bromide was used, an unexpected small amount byproduct was obtained. Its structure was identified as 1,4-dihydroxy-1-phenyl-butane. The reaction detail is being studied.

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General Procedure for the Synthesis of ω-Hydroxy Ketones from Lactones
A slurry of lactone (1.0 mmol), HN(OMe)Me˙HCl (116 mg, 1.2 mmol), and NaOMe (14 mg, 0.25 mmol) in THF (20 mL) was cooled with an ice-salt bath under nitrogen. A solution of Grignard reagent in THF (16 mL, 0.5 M, 8.0 mmol) was added slowly. After 2 h in an ice-salt bath the reaction mixture was allowed to warm to r.t. and stirred for 8 h. The reaction was quenched with 1 N HCl solution (10 mL). The mixture was stirred for another 2 h, and THF was evaporated. The residue was treated with H₂O (20 mL) and then extracted with CH₂Cl₂. The organic extract was dried over MgSO₄ and concentrated. The residue was purified by flash column chromatography on silica gel (EtOAc-PE) to give the desired hydroxy ketone.

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Spectral Data for Compound 7 Mp 45-47 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 0.82-0.87 (m, 3 H, CH₃), 1.24-1.37 (m, 8 H, 4 CH₂), 1.50-1.59 (m, 6 H, 3 CH₂), 1.94 (s, 1 H, OH), 2.37 (dd, J = 8.4, 15.9 Hz, 4 H, 2 CH₂), 3.60 (t, J = 6.3 Hz, 2 H, CH₂). ^¹³C NMR (75 MHz, CDCl₃): δ = 13.92, 22.38, 23.34, 23.76, 25.26, 28.81, 31.49, 32.31, 42.52, 42.78, 62.38, 211.67. MS (EI): m/z (%) = 200 (0.8) [M⁺], 183 (0.3), 141 (1.3).