A Formal Total Synthesis of Deoxynojirimycin from D-Glucitol

Descrevemos a síntese formal da desoxinojirimicina usando D-glucitol como material de partida economicamente atraente. Através de uma seqüência de reações de proteção e desproteção seletivas e reações de substituição nucleofílica obtivemos diversos intermediários isopropilidênicos. A formação de um epóxido intermediário e sua subseqüente abertura, através de uma reação nucleofílica intramolecular, levou à obtenção do heterociclo 1,5-didesoxi-1,5-diamino-2,3-O-isopropilideno-6silila-D-glucitol, que é um precursor da desoxinojirimicina (DNJ).


Introduction
3][4][5] Because of the potential chemotherapeutic applications of such compounds, there is a continuing interest on the synthesis of imino sugars.7][8] Its importance is disclosed by the large number of publications devoted to its preparation.
After Paulsen et al. 9 have obtained 1-deoxynojirimycin and disclosed its potent glucosidase inhibitor effects, it has been synthesized by a variety of methods.Kinast et al. 10 obtained 1-deoxynojirimycin in four steps from D-glucose through an enzymatic oxidation.Behling et al. 11 described a synthesis of DNJ (1) from L-sorbose that requires the isolation of only two intermediates and the use of only one protection/deprotection protocol.Setoi et al. [12][13][14] described a synthesis of DNJ (1) from D-mannose by a multi-step approach with protecting/deprotecting group manipulation.][17][18] This report deals with the formal total synthesis of DNJ (1) using D-glucitol, an inexpensive starting material, through a sequence of several selective protection/ deprotection and nucleophilic substitution reactions. 19
The 4-O-acetyl-1-azido-1-deoxy-2,3:5,6-di-Oisopropylidene-D-glucitol (7) was obtained from 3 in 37% overall yield by the sequence of sulfonylation, acetylation and azidation (3 → 5a → 6 → 7).Selective cleavage of the terminal acetonide group was accomplished using p-toluenesulfonic acid in methanol at 0 o C for 5 h.The resulting mixture of acetonides 7 (51%) and 8a (34%) was purified by flash column chromatography.Under the applied conditions, acyl group migration from C-4 to C-6 was observed.Acyl group migration in non-acidic aqueous media or in dichloromethane containing triethylamine was also observed by Kilonda et al. 6 When this reaction is carried out using pyridinium 4-toluenesulfonate as catalyst, acyl group migration is not observed.This migration protects the primary group at C-6 from tosylation during the next step.The azide epoxide 10 was obtained after sulfonation of 8a and treatment with K 2 CO 3 , followed by basic treatment to promote deacetylation.The trans stereochemistry of the resulting epoxide 10 is confirmed by the coupling constant (J 2.2 Hz) between H4 and H5. 20,21he intermediate 11 is obtained by protection with TBDMSCl.Treatment of the epoxide azide 11 with NaBH 4 in boiling methanol gave 13 a protected form of DNJ (1).The intermediate epoxide amine 12 could not be isolated (Scheme 1) and this reaction afforded a single piperidine heterocycle.In summary, 13 was obtained in 9 steps and 0.4% overall yield from D-glucitol.
1 H NMR, 13 C NMR, 2D proton-proton homocorrelated and C-H heterocorrelated spectra and comparation with literature data confirmed the structure of intermediates. 21heme 1.

General procedures
Thin-layer chromatography (TLC) was carried out on plates precoated with silica gel F 254 (E.Merck).Detection was by UV at 254 nm, followed by charring with a solution of ammoniun molybdate or Dragendorff reagent. 22Column chromatography was carried out on silica gel (230-400 mesh) and, unless otherwise stated, mixtures of heptane-EtOAc or CH 2 Cl 2 -MeOH were used as eluent.All reactions were conducted under an argon atmosphere.Anhydrous Na 2 SO 4 was used to dry organic solution and the removal of the solvent was done under vacuum with a rotary evaporator.Solvents were dried and purified using standard methods. 23IR spectra were recorded with a Bomen FTIR spectrometer using KBr pellets or NaCl cells.Elemental analyses were performed on a model 2400 CHN-Perkin Elmer instrument.Nuclear magnetic resonance spectra were obtained using Varian 300 MHz or Bruker AC-300 MHz spectrometers in CDCl 3 solutions with (CH 3 ) 4 Si as internal reference (300 MHz for 1 H and 75 MHz for 13 C).The assignments were confirmed by proton-proton homocorrelated and carbon-proton heterocorrelated spectra.HREIMS (70 eV, direct probe) experiment was performed using a VG Auto Spec-Fisions Instrument using electron ionisation at 70 eV (linked scan from 8 keV collisions with helium).Optical rotations were measured with a Jasco model J-720 digital polarimeter.

1,5-dideoxy-1,5-imino-2,3-O-isopropylidene-D-glucitol (13)
To a solution of 0.02 g of epoxide 11 (0.057 mmol) in 5.0 cm 3 of EtOH, NaBH 4 was added (0.002 g).The reaction was stirred at room temperature for 12 h.As no reaction was observed, the mixture was heated to 40 °C.After 24 h of reaction, more NaBH 4 (0.003 g) was added and the solution was stirred at 40 °C for next 12 h.CH 2 Cl 2 was added to the mixture, which was then washed with aqueous NaCl, dried over anhydrous Na 2 SO 4 and the solvent was removed under reduced pressure.