Green synthesis of 1,5-dideoxy-1,5-imino-ribitol and 1,5-dideoxy-1,5-imino-dl-arabinitol from natural d-sugars over Au/Al2O3 and SO42−/Al2O3 catalysts

A green synthetic route for the synthesis of some potential enzyme active hydroxypiperidine iminosugars including 1,5-dideoxy-1,5-imino-ribitol and 1,5-dideoxy-1,5-imino-dl-arabinitol, starting from commercially available d-ribose and d-lyxose was tested out. Heterogeneous catalysts including Au/Al2O3, SO42−/Al2O3 as well as environmentally friendly reagents were employed into several critical reaction of the route. The synthetic route resulted in good overall yields of 1,5-dideoxy-1,5-imino-ribitol of 54%, 1,5-dideoxy-1,5-imino-d-arabinitol of 48% and 1,5-dideoxy-1,5-imino-l-arabinitol of 46%. The Au/Al2O3 catalyst can be easily recovered from the reaction mixture and reused with no loss of activity.


Preparation and characterization of catalysts
The Au/C with 3 wt.% gold loading and commercial Pd (10 wt.%)/C were purchased from Haruta Gold Incorporated and Degussa, respectively. 10 wt.% Pd-Bi/C was prepared according to the method we reported previously [1]. Au/Al2O3 catalyst was synthesized with solid grinding method [2]: γ-Al2O3 (3.0 g), [Me2Au(acac)] (acac=acetylacetonate) (50 mg), and acetone (13 ml) were ground by ball milling (350 rpm) at room temperature for 1 h. The resulting mixture was calcined in air at 300 o C for 4 h. Prior to use, the catalysts were reduced under H2 flow for 2 h at 150 o C. SO4 2-/Al2O3 was synthesized by incipient wetness method [3]: γ-Al2O3 were impregnated with different concentration of aqueous H2SO4 solutions (15 mL solution/g γ-Al2O3 powder). The surface wt.% of SO4 2-/Al2O3 was analyzed by XRF. For example, to prepare 3 wt.% SO4 2-/Al2O3, 1 g of γ-Al2O3 powder was suspended in 1 M aqueous H2SO4 solution for 12 hour with continuous stirring at room temperature. Then the precipitate was dried at 60 o C for 24 h, followed by further drying at 100 o C for 24 h. Finally, the resulting solid was calcined in a stream of dry air at 500 o C for 24 h.
The recycle procedure for used SO4 2-/Al2O3 catalyst is: after reaction, the mixture was cooled to room temperature and filtered. The resulting solid was calcined in a stream of dry air at 500 o C for 24 h.
The re-generation procedure for used SO4 2-/Al2O3 catalyst is: after reaction, the mixture was cooled to room temperature and filtered. The resulting solid was calcined in a stream of dry air at 500 o C for 24 h. The recycled sample was then suspended in 0.5 M aqueous H2SO4 solution for 12 hour with continuous stirring at room temperature, followed by drying at 60 o C for 24 h and further drying at 100 o C for 24 h. Finally, the resulting solid was calcined in a stream of dry air at 500 o C for 24 h. Figure S1 shows NH3-TPD curves of fresh, recycled and re-generated 3 wt.% SO4 2-/Al2O3 catalysts. Figure S1. NH3-TPD curves of fresh, recycled and re-generated 3 wt.% SO4 2-/Al2O3 catalysts The nitrogen adsorption/desorption isotherms of the Au/Al2O3 samples were measured with a Micromeritics Tristar 3000. Before the measurement, the sample was degassed at 100 o C for 6 h to remove physisorbed water. The surface area was determined using the Brunauer-Emmett-Teller (BET) method. The pore size distribution was calculated from the desorption branch of the isotherm using the Barrett-Joyner-Halenda (BJH) equation. The total pore volume of the sample was taken from the volume of nitrogen adsorbed at the P/P o of 0.99. The crystal structure and phase of the samples were determined with a Siemens D5005 powder x-ray diffractometer equipped with a Cu anode and variable primary and secondary beam slits. The diffractograms were measured from 2 theta of 5 o to 120 o , using a step size of 0.02 o and a dwell time of 1 s/step. X-ray photoelectron spectroscopy (XPS) was used to determine the surface elemental composition. The measurements were made with a VG Escalab MkII using monochromated Al Kα radiation (1486.6 eV, 15 kV) under a vacuum of 3 × 10 −8 Pa. The binding energies are referenced to the carbon 1 s peak of CH at 284.6 eV. The peak areas were determined after peak fitting and normalized with the manufacturer's atomic sensitivity factors for the different elements. Au particle size on Al2O3 support was analyzed with scanning transmission electron microscopy (STEM, JEOL 2200FS), The samples for this analysis were prepared by ultrasound dispersion in isopropanol and a drop of the solution was put on a carbon grid. The average size of Au particles and its distributions was estimated by counting about 300 Au particles. Inductively coupled plasma optical emission spectrometer (ICP-OES, Varian 720-ES instrument) was utilized to determine the Au content.
The XRF analysis was applied to identify the elements ratio of S/Al for the SO4 2-/Al2O3 catalysts and was set at 30 kV and 0.120 mA with a live time of 110 sec. The acidity of the SO4 2-/Al2O3 catalyst was examined with the ammonia temperature programmed desorption technique (NH3-TPD). Firstly, the catalyst powder was placed in a quartz reactor and pretreated at 400 °C under helium (He) flow (30mL/min) for 0.5 h to remove any impurities. Then, the catalyst was cooled to 60 °C and equilibrated with NH3. Thirdly, the catalyst was purged by He for 1 h to remove physically and gas-phase adsorbed NH3. Once a stable baseline of NH3 was acquired, the temperature was increased to 800 °C at the speed of 10 °C/min in He flow (30 mL/min) to allow the desorption of NH3. The temperature was maintained at 800 °C for 40 min, and the amount of desorbed NH3 was recorded by using the Balzers Prisma quadrupole mass spectrometer. The Brønsted to Lewis acid sites of SO4 2-/Al2O3 catalyst was detected through pyridine-adsorption infrared spectroscopy. In general, two peaks at around 1450 and 1540 cm -1 are attributed to Lewis and Brønsted acid sites respectively, while the peak at 1490 cm -1 is assigned to both sites. This measurement was conducted with a Nicolet IS-10 spectrometer (100 scans, 4 cm -1 resolution, Thermofish, America) on thin wafers (10 mg/cm 2 ) prepared under 7 × 10 3 kPa pressure and pretreated in-situ in the IR cell. The IR spectrum was obtained at 25 °C after the pretreatment period and pyridine thermo-desorption in vacuum at increasing temperatures up to 150 °C.

Identification of products
Melting points were determined with a Buchi 535 melting point apparatus and were uncorrected.
Proton and 13C NMR spectra were measured at 300 MHz with a Bruker Avance 300 NMR spectrometer using tetramethylsilane (TMS) as the internal standard. Chemical shifts were reported in ppm downfield from TMS. Mass spectrometry (MS) and high resolution-mass spectrometry electron ionization (HR-MS EI ) were taken with a Finnigan MAT95XL-T and Micromass VG7035 double focusing mass spectrometer of high resolution, respectively. Optical rotations were measured by a Perkin Elmer 341 polarimeter in a 1 dm cell. Analytical and preparative thin layer chromatography (TLC) were conducted on precoated TLC plates (silica gel 60 F254, Merck).

Al2O3 catalyst
A 20 mL pressure reactor was charged with 36 mg of 1 wt.% Au/Al2O3 catalyst, 0.15 g of D-ribose and 10 mL deionized water. The system was first vacuumed with a pump and then fed with oxygen (1 MPa). The reaction system was heated to 100 °C and kept for 2 h. After reaction, the reactor was rapidly immersed in a water bath to cool, and oxygen was released at the same time to stop the reaction. Afterward, the reaction mixtures were immediately syringed out, filtered and analyzed by high-performance liquid chromatography HPLC (Shimadzu SPD-10AV equipped with a UVvisible detector, 200 nm). A Jordi Gel DVB organic acid column (250 mm length x 10 mm diameter) was used with 0.05 M H2SO4 as the eluent (flow rate 1.5 ml min -1 ). Figure S2 shows a representative HPLC spectrum of the reaction. In the recycle tests, the catalysts were recovered after reaction by

General procedure for conversion of D-ribonolactone 2 to mesylate 3
The crude D-ribonolactone (1.5 g, obtained from oxidation of 1.5 g D-ribose) was dissolved in acetone (40 mL) and 3 wt.% SO4 2-/Al2O3 (0.5 g) was added to the resulting solution. After stirred and refluxed for 2 h, the mixture was cooled to room temperature and filtered. The precipitate was washed with hot acetone (10 mL). The filtrate together with the washing was rotary evaporated to give white solid. The white solid was dissolved in ethyl acetate (20 mL) and washed with deionized water (2 x 10 mL). The organic phase was rotary evaporated to dryness to afford 1.52 g of white crystals (2,3-O-isopropylidene-D-ribonolactone, 81 % overall yield from D-ribose, the characterization info of this pure product could be found in [4]). Then, the white crystals were dissolved in an ice-cooled pyridine (5 mL) and methanesulfonyl chloride (0.7 mL, 9 mmol) was added dropwise to the solution. The mixture was kept for 2 h at 0 °C. The reaction was quenched with water (5 mL) and CH2C12 (15 mL) was added. The mixture was washed successively with 10 % aq HC1 (3 mL) until the extract became acidic and then with an additional portion of 10 % aq HC1 (3 mL) followed by aq NaHCO3 (3 mL [4] http://www.rsc.org/suppdata/ob/c1/c1ob06116j/c1ob06116j.pdf

General procedure for conversion of mesylate 3 to 1,5-dideoxy-1,5-imino-ribitol 4
Mesylate 3 (1.0 g, 3.80 mmol) was dissolved in aq NH3 (5 mL, 25%) and allowed to stand for 18 h at room temperature in a sealed flask. Concentration and co-concentration twice with EtOAc gave a residue which was extracted with boiling EtOAc (2 x 15 mL). The combined organic phases were treated with activated carbon, dried with Na2SO4, filtered. The filtrate was concentrated in vacuo to 0.6 g colorless crystals. The crystals were then dissolved in methanol (15 mL) and the resulting solution was cooled to -20 °C and NaBH4 (0.26 g, 6.5 mmol) was slowly added over 1 h. After stirring for 4 h, the solution was adjusted to pH 5-6 with 1 M HCl solution. Concentration in vacuo afforded a white solid. The white solid was suspended in CH2Cl2 (20 mL) and the suspension was heated to boiling. The hot suspension was filtered and the solids were rinsed with hot CH2Cl2 (10 mL). The filtrate was concentrated in vacuo to give a 0.48 g syrup. The syrup was dissolved in water (20 ml) and Amberlite IR-120H (3.0 g) was added to the solution. The mixture was kept at room temperature and stirred overnight. After filtering out the ion exchange resin, the resin was eluted with 5-15% aqueous NH3. The resulting eluent was concentrated under reduced pressure.1,5dideoxy-1,5-imino-D-ribitol 4 was isolated as the HCl salt (0.49 g, 2.88mmol, 76 % overall yield from Mesylate 3).

General procedure for conversion of mesylate 3 to mesylate 5
To mesylate 3 (2.12g, 8 mmol) was added a solution of KOH (1.3 g, 23.2 mmol, 2.9 equiv) in water (10 mL), keeping the temperature at 25 o C. After stirring for 6 h, the pH was adjusted to 2.5-3.0 by adding 1 M HCl. The acidic solution was concentrated in vacuo to afford a solid mass. The solid mass was triturated with acetone (15 mL) and heated to reflux for 15 min. The acetone was decanted and the procedure was repeated. The combined acetone was dried over Na2SO4, and filtered. The clear filtrate was concentrated in vacuo below 35 °C to afford white crystals. Then, the white crystals were dissolved in an ice-cooled pyridine (5 mL) and methanesulfonyl chloride (0.7 mL, 9 mmol) was added dropwise to the solution. The mixture was kept for 2 h at 0 °C. The reaction was quenched with water (5 mL) and CH2C12 (15 mL) was added. The mixture was washed successively with 10% aq HC1 (3 mL) until the extract became acidic and then with an additional portion of 10% aq HC1 (3 mL) followed by aq NaHCO3 (3 mL). The organic phase was dried with