Synthesis of 3-substituted isoxazolidin-4-ols using hydroboration–oxidation reactions of 4,5-unsubstituted 2,3-dihydroisoxazoles

Isoxazolidines represent a very important class of N/O-containing heterocycles used as the key intermediates in the synthesis of more complex cyclic and acyclic compounds, including various biologically active molecules. Here, we present a fast and highly stereoselective approach towards both C-3/4-cis and C-3/4-trans isomers of 3-substituted isoxazolidin-4-ols. The strategy relies on a highly regio- and trans-stereoselective hydroboration–oxidation reaction of the 4,5-unsubstituted 2,3-dihydroisoxazoles with basic hydrogen peroxide. The consecutive oxidation/reduction route, sequentially employing Dess–Martin periodinane and ʟ-selectride, is used for the inversion of the C-3/4-trans relative configuration of the isoxazolidine ring. The significance of the method lies in its variability and applicability to a concise synthesis of various 4-hydroxyisoxazolidines, starting from the readily available C-alkyl/aryl-nitrones. The resemblance to 3-hydroxypyrrolidines certainly makes the 4-hydroxyisoxazolidines important and valuable structural fragments in drug discovery.


Experimental cection General
Flash column chromatography (FCC) was carried out with a Büchi system  and Fraction Collector C-660) using Normasil 60 silica gel (0.040-0.063 mm; VWR). Thin-layer chromatography (TLC) analysis was carried out using TLC silica gel 60 F254 (aluminium sheets, Merck), and plates were visualized with UV light or by treatment with permanganate solution followed by heating. Optical rotations were measured with a JASCO P-2000 digital polarimeter with a Na-D lamp (10 cm cell length). Concentrations (c) are given in gram per 100 mL. Infrared (IR) spectra were recorded as neat samples with a Nicolet 5700 FTIR spectrometer with an ATR Smart Orbit Diamond adapter (Thermo Electron Corporation). NMR spectra were recorded with a Varian INOVA-300 spectrometer ( 1 H,299.95 MHz,and 13 C,75.42 MHz) and a Varian VNMRS-600 instrument ( 1 H,599.75 MHz,and 13 C,150.81 MHz) in CDCl3 using tetramethylsilane as the internal standard. Data are presented as follows: chemical shift (in ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, ddd = doublet of doublet of doublets, td = triplet of doublets, dt = doublet of triplets, m =multiplet, bs = broad singlet), coupling constants (J/Hz) and integration. HRMS analysis was carried out with an Orbitrap Velos Pro spectrometer (Thermo Fisher Scientific). All solvents used were dried and distilled according to conventional methods. 2,3-Dihydroisoxazoles 5a, 5b and benzoylated isoxazolidine-4,5-diols 6a, 6b were prepared using already published procedures [1,2].

(±)-2-Benzyl-3-isopropylisoxazolidin-4-yl benzoate (7b)
A round-bottom reaction flask was charged with isoxazolidinyl dibenzoate 6b (360 mg, 0.81 mmol), sealed with a rubber septum, evacuated, and filled with argon. Anhydrous CH2Cl2 was added (0.8 mL) followed by Et3SiH (390 µL, 2.44 mmol), and the resulting solution was cooled in an ice-water bath (0 °C). TMSOTf (290 µL, 1.60 mmol) was added dropwise to the stirred solution. After stirring at 0 °C for 5 min, the cooling bath was removed, and the mixture was further stirred at room temperature for 2 h. After this time, TLC showed that the reaction was complete (hexanes/ethyl acetate, 4:1). The reaction mixture was cooled in an ice-water bath and the reaction was quenched by addition of saturated aqueous solution of NaHCO3 (5 mL). Afterwards, the mixture was diluted with water (5 mL) and extracted with CH2Cl2 (2 × 5 mL). The combined organic layers were washed with water (10 mL), dried with MgSO4 and evaporated in vacuo. The product was isolated by FCC (hexanes/EtOAc, 9:1) to give the isoxazolidine 7b (210 mg, 0.65 mmol, 80%) as a colourless oil. Rf
The reaction mixture was stirred at rt overnight. After the reaction was complete (TLC; hexanes/EtOAc, 7:3), above mixture was diluted with water (15 mL) and repeatedly extracted with CH2Cl2 (3 × 15 mL). The combined organic layers were dried over MgSO4 and the solvent was removed by rotary evaporation. The product was isolated by FCC (CH2Cl2) to give the isoxazolidine 7b (320 mg, 0.98 mmol, 80%) as a colourless oil; Rf = 0.18 (CH2Cl2). All analytical data were consistent with those described above.

(±)-2-Benzyl-3-phenylisoxazolidin-4-one (9a)
A Schlenk flask was charged with isoxazolidinol 8a (450 mg, 1.76 mmol), evacuated and filled with argon. The starting material was dissolved in anhydrous CH2Cl2 (18 mL), the reaction mixture was cooled to 0 °C and solid Dess-Martin periodinane (1.5 g, 3.54 mmol) was slowly added under stream of argon. The reaction was stirred at 0 °C for 12 h and after complete conversion of the starting material (TLC, hexanes/EtOAc, 1:1), a sat. aq NaHCO3 solution (20 mL) and a sat. aq Na2S2O3•5H2O solution (20 mL) were added. The mixture was stirred for 15 min at 0 °C, and then the solution was allowed to warm to rt. The organic layer was separated and washed with water (2 × 20 mL), dried over MgSO4 and evaporated in vacuo. The residue was purified by FCC (hexanes/EtOAc, 9:1) to give isoxazolidin-4-one 9a (305 mg, 1.20 mmol, 68%) as a yellowish waxy solid that gradually
The combined organic layers were washed with water (50 mL), dried over MgSO4