Convenient Synthesis of 1,4-Dideoxy-1,4-imino-D-ribitol from D-Ribose

This paper describes a convenient synthesis of 1,4-dideoxy-1,4-imino-D-ribitol (DRB) from D-ribose. L-Lyxonolactone, a key intermediate in this synthesis, was prepared by base-promoted hydrolysis of a 5-chlorinated D-ribonolactone derivative with inversion of configuration at the C-4 position. Cyclization of the generated dimesylated L-lyxitol with benzylamine proceeded with another configurational inversion at C-4 to afford the D-ribo-configured pyrrolidine system, which upon deprotection gave DRB.


Introduction
1,4-Dideoxy-1,4-imino-D-ribitol (DRB, 1) is a polyhydroxylated pyrrolidine alkaloid isolated from the roots of mulberry trees (Morus alba) [1] and from the bark and pods of leguminous plants (Angylocalyx pynaertii) [2,3].Owing to its structural [4-aza]ribofuranose feature, DRB and its derivatives have attracted considerable attention as enzyme inhibitors that mimic glycoside and nucleoside substrates.In fact, DRB was found to be a potent inhibitor of lysosomal -mannosidase [3] and eukaryotic DNA polymerases [4] and was also employed as a synthetic precursor of some enzyme inhibitors containing the [4-aza]ribosyl group [5][6][7][8].Therefore, there is a need to develop a simple method for the preparation of DRB derivatives.
Two major approaches have been used to construct the DRB framework.One is the stereoselective dihydroxylation of optically active 2-substituted 3-pyrroline derivatives, in which the oxidation is usually carried out using a highly toxic osmium catalyst [9][10][11][12][13]; the other is a sugar-based approach.The D-and L-forms of 1,4-dideoxy-1,4-iminoribitol were prepared from D-gulonolactone (29% overall yield over 9 steps) and D-mannose (28% overall yield over 9 steps), respectively [14][15][16].From the viewpoint of atom economy, pentose as a starting material is more favorable.Recently, a related study was reported by Mercer and coworkers [17], in which both enantiomers of 1,4-dideoxy-1,4-iminolyxitol were efficiently synthesized from D-and L-ribonolactone.Since the process involves configurational inversion at the C-4 position, a straightforward precursor to DRB is considered to be L-lyxose, which is an expensive unnatural pentose.Herein, we describe a convenient synthesis of DRB starting from Dribose via L-lyxonolactone , in which the D-ribo-configured pyrrolidine ring is constructed with overall retention of the stereochemistry at C-4 by a double inversion.

Results and Discussion
The synthetic route to DRB is illustrated in Scheme 1. 2,3-O-Isopropylidene-D-ribono-1,4-lactone (2) is easily obtained from inexpensive D-ribose using a well-established procedure [18,19] or is commercially available.At the beginning of the synthesis, we examined the conversion of D-ribonolactone 2 to L-lyxonolactone 4 with inversion of stereochemistry at C-4.A production-scale synthesis of 4 from 2 via a 5-O-methanesulfonyl derivative was reported (59% yield at a 200 kg scale) [18]; however, we experienced variable yields at a laboratory scale.In this study, therefore, we adopted an alternative route via the corresponding chloride 3.
Chlorination of the hydroxyl group at C-5 of 2 was performed using a Vilsmeier reagent prepared in situ from DMF and oxalyl chloride to afford 5-chloro-5-deoxy derivative 3 in 97% yield [20]. Treatment of chloride 3 with an aqueous KOH solution followed by acidification gave 2,3-O-isopropylidene-L-lyxono-1,4-lactone (4) in quantitative yield.It is believed that configurational inversion at the C-4 position occurred as reported for the mesylate reaction [21].Namely, a base-promoted ring opening of the chlorinated ribonolactone 3 followed by intramolecular  N 2 reaction gave epoxide 10 (Scheme 2).Subsequent 5-exo-tet [22] ring closure between the carboxylate and epoxide proceeded with inversion of configuration at C-4 to furnish the lactone, which was then hydrolyzed to the open-chain derivative 11 under strongly basic conditions.Upon acidification, carboxylate 11 immediately cyclized to lyxonolactone 4.
After protection of the primary hydroxyl group of 4 as a tert-butyldimethylsilyl (TBS) ether in 91% yield, the fully protected lactone 5 was subjected to reductive ring opening by NaBH 4 in MeOH to afford partially protected L-lyxitol derivative 6 in 95% yield.Diol 6 was then treated with methanesulfonyl chloride in pyridine to give the corresponding dimesylate 7 in 85% yield.Cyclization of 7 with benzylamine involving inversion at C-4 was performed in refluxing toluene for 3 days to give fully protected DRB 8 in 86% yield.Acidic hydrolysis of both the acetonide and TBS protective groups in 1 M HCl gave N-benzyl DRB derivative 9 in quantitative yield.Finally, DRB was quantitatively obtained as its hydrochloride salt by catalytic hydrogenolysis of the N-benzyl group.Comparison of the physical and spectral data of DRB with the literature data completely confirmed its identity.
In conclusion, we have achieved a convenient synthesis of DRB in 61% overall yield from D-ribonolactone 2 over eight steps.The D-ribo-configured pyrrolidine system was constructed with overall retention of the stereochemistry at C-4 by a double  N 2 inversion.All reagents and solvents were of commercial grade and used according to supplier instructions unless otherwise mentioned.[20,23].DMF was added (117 L, 110 mg, 1.51 mmol) to a solution of oxalyl chloride (129 L, 194 mg, 1.52 mmol) in CH 2 Cl 2 (4 mL) at 0 ∘ C, and the mixture was stirred for 12 min.To the resultant cloudy suspension, a solution of compound 2 (188 mg, 0.999 mmol) in CH 2 Cl 2 (2 mL) was added dropwise at the same temperature, and the mixture was refluxed for 90 min.The cooled reaction mixture was diluted with CHCl 3 , washed with brine, and dried over MgSO 4 .After removal of the solvent, the residue was chromatographed on SiO 2 .Elution with a mixture of hexane and AcOEt (7/3) gave compound 3 (200 mg, 0.968 mmol, 97%) as a white solid.An analytical sample was obtained by recrystallization from a mixture of EtOH and acetone.Colorless powder, mp 97.5-98.4) [18].Compound 3 (207 mg, 1.00 mmol) was added to a 2.5 M aqueous solution of KOH (1.00 mL, 2.50 mmol), and the resulting mixture was stirred at room temperature overnight.

2,3-O-Isopropylidene-L-lyxono-1,4-lactone (
The solution was acidified with 3 M HCl to pH 3 and concentrated.The residue was triturated with acetone (6 mL) and heated to reflux.After removal of the insoluble materials by filtration, the filtrate was dried over MgSO 4 and concentrated under reduced pressure to give compound 4 (193 mg) in quantitative yield as a white solid, mp 94-95 ∘ C (lit [18], mp 98-99 ∘ C).

N-Benzyl
A mixture of compound 7 (695 mg, 1.50 mol) and benzylamine (891 L, 874 mg, 8.16 mmol) in toluene (8 mL) was heated to reflux for 3 days.The reaction mixture was then diluted with CHCl 3 , successively washed with water and saturated aqueous NaHCO 3 , and dried over MgSO 4 .After removal of the solvent, the residue was chromatographed on SiO 2 .Elution with a mixture of hexane and AcOEt (9/1) gave compound 8 (487 mg, 1.29 mmol, 86%) as a colorless oil.

Scheme 2 :
Scheme 2: Plausible reaction pathway for the configurational inversion at C-4 by base-promoted hydrolysis of lactone 3.
Melting points were determined using a Yamato MP-21 melting point apparatus in open capillaries and are uncorrected. 1H and 13 C-nuclear magnetic resonance (NMR) spectra were measured on a Varian Mercury plus 400 spectrometer at 400 and 100 MHz, respectively.All chemical shifts are reported as  values (ppm) relative to residual chloroform ( H 7.26), HDO ( H 4.79), the central peak of deuteriochloroform ( C 77.0), or dioxane ( C 67.2); J values are expressed in Hz.Optical rotations were measured on a HORIBA SEPA-200 polarimeter.Elemental analyses were performed using a PerkinElmer 2400 Series II analyzer. 3.1.General.