HETEROCYCLES

Paper | Special issue | Vol. 86, No. 2, 2012, pp. 1401-1417
Received, 13th July, 2012, Accepted, 28th August, 2012, Published online, 4th September, 2012.
DOI: 10.3987/COM-12-S(N)99

■ ASYMMETRIC SYNTHESIS OF 1-ALKYL-2-DEOXYIMINOFURANOSES VIA THE IRIDIUM-CATALYZED INTRAMOLECULAR CYCLIZATION OF AN ALLYLIC CARBONATE

Yoshihiro Natori, Shunsuke Kikuchi, Yuichi Yoshimura, Atsushi Kato, Isao Adachi, and Hiroki Takahata*

Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan

Abstract

An asymmetric synthesis of 1-alkyl-2-deoxyiminofuranoses was achieved in which the Ir-catalyzed intramolecular cyclization was the key step. The diastereoselective cyclization converted an allylic carbonate into pyrrolidine derivatives. The α-glucosidase inhibitory activities of the prepared 2-deoxyiminofuranoses were also investigated.

INTRODUCTION
Sugar mimics are very interesting compounds because of their ability to interact with carbohydrate-processing enzymes, where they act as competitive inhibitors of glycosidases and/or glycosyltransferases.1 Therefore, sugar mimics have the potential for use as anti-diabetic, antiobesity, antiviral, and therapeutic agents for certain types of genetic disorders. Sugar mimic type drugs, such as acarbose (Glucobay™), voglibose (Basen™), and miglitol (Glyset™) are already in use for the treatment of type 2 diabetes and miglustat (Zavesca™) is used as a therapeutic agent for the treatment of type 1 Gaucher disease (Figure 1).2

Iminosugars as transition state analogues are of particular interest in terms of the design of inhibitors. Accordingly, in recent years, extensive efforts have been directed to developing methodologies for the asymmetric syntheses of iminosugars.3 In general, a few systematic studies of the biological properties of the L-enantiomers of iminosugars have been reported. Therefore, our attention was focused on the synthesis and biological evaluation of both enantiomers of several iminosugars.4 We recently reported on the asymmetric synthesis of both enantiomers of 1-C-alkyl-arabinoiminofuranose derivatives, and their inhibitory activities with respect to α-glucosidase.5 Surprisingly, the inhibitory activities of the L-forms showed quite superior and potent inhibitory activities toward rat intestinal maltase and sucrase. Among the compounds investigated, 1-n-butyl-L-aravinoiminofuranose 1c showed a greater inhibition against rat intestinal sucrase activity relative to the above commercial drugs that are used for the treatment of type 2 diabetes. This prompted us to investigate the structure–activity relationships of 1-alkyl-L-arabinoiminofuranose. Herein, we wish to report on the synthesis of 2-deoxy type 1-C-alkyl-arabinoiminofuranoses αand systematic studies of their α-glycosidase inhibitory activities based on an iridium-catalyzed intramolecular allylic amination reaction.

RESULTS AND DISCUSSION
Over the last decade, iridium-catalyzed allylic cyclization has been developed into a powerful tool in the field of organic synthesis, that allows construction of heterocyclic compounds.6 In 2009, Helmchen and co-workers reported on some Ir-catalyzed allylic cyclizations using chiral ligands to prepare 2,6-disubstituted piperidines, which allow each of the two possible diastereomeric cyclization products to be prepared with a very high degree of diastereoselectivtiy (Scheme 1). The intramolecular cyclizaion of (E)-3 was carried out by using catalytic amount of [Ir(cod)Cl]2, chiral phosphoramidite Ligands and TBD in THF.7 They reported that piperidine derivatives 4a and 4b were produced in good yield with high diastereoselectivity (up to 98.5:1.5). We attempted to apply this concept to the construction of a pyrrolidine ring.

To accomplish this, we used the Ir-catalyzed intramolecular asymmetric allylic amination as a key step for producing 2-deoxy type 1-C-alkyl-L-arabinoiminofuranoses. Our synthetic plan is shown in Scheme 2. The desired 2-deoxyiminofuranoses 2 can be prepared from 7 through a series of manipulations. The pyrrolidine 7, with several long side chains at the C1 position, can be obtained by the olefin cross metathesis of a terminal vinyl group of 8. Pyrrolidine ring of 8 could be constructed by Ir-catalyzed cyclization as a key step from the cyclization precursors 9, which could be produced from the L-serine-derived Garner aldehyde (10).

Our synthesis starts from the allylboration of (S)-Garner aldehyde (10), as shown in Scheme 3. Using know, established procedures, the homoallylic alcohol 11 [[α]D21 –17.9 (c 3.4, CHCl3), reported 11 [α]D20 –17.6 (c 3.4, CHCl3)] was obtained as a single isomer in good yield.8 The olefin cross metathesis (Grubbs II catalyst) of 11 and (Z)-but-2-ene-1,4-diyl dimethyl dicarbonate (14) (5 equiv) afforded the allylic carbonate 12 in 96% yield as a ca. 9:1 mixture (1H NMR spectroscopy) of E and Z isomers. Deprotection of the Boc and hemiaminal groups under acidic conditions gave the diol 13. Protection of two hydroxy groups of 13 with a TBS group gave the cyclization precursor 9a in good yield.

With the cyclization precursors 9a in hand, the diastereoselective cyclization of allylic carbonate 9a was examined (Table 1). First, under standard conditions, no reaction occurred and the starting material 9a was recovered (entry 1). When the reaction was conducted using a larger (two fold) quantity of reagents at 40 °C, pyrrolidine derivatives were produced, but the diastereoselectivity was low (ca. 3.5:1 = 8a:15a). (entry 2). When the reaction was carried out at 50 °C, unfortunately, both the yield and diastereoselectivity were lower. (entry 3). Because, the diastereoselectivity of the cyclization of 9a was unsatisfactory, cyclization of an N-protected allylic carbonate such as N-nosyl 9b was performed (entries 4 and 5). When the cyclization of 9b was attempted under the same conditions at 40 °C, the reaction was incomplete. The cyclization was completed when reagents were added (entry 4). Therefore, we examined the simultaneous use of [Ir(cod)Cl]2 (8 mol %), Ligand 1 (16 mol %) and TBD (32 mol %) (entry 5). The reaction was carried out at 40 °C, and the desired cyclic compound 8b was obtained in 88% yield with a high diastereoselectivity (ca. 10:1 = 8b:15b).

The absolute configuration of new tertiary carbon of 8b was established as R by transforming 8b into the known compound 18 as shown in Scheme 4. An olefin cross metathesis between 8b and 1-tridecene (19) provided alkene 16. Deprotection of the Ns group was carried out under standard conditions using thiophenol in the presence of K2CO3. Hydrogenation of the unsaturated bond unit with H2 gas and PtO2 (20 wt%) gave 18 [[α]D23 –12.5 (c. 1.06, CHCl3)], the optical rotation of which was negative, as reported for 18.9

Olefin cross metathesis reactions between vinylpyrrolidine derivative 8b and Z-alkenes were carried out using the Grubbs II catalyst to introduce the alkyl chains (Scheme 5). When (Z)-hex-3-ene (22) was used as the alkene, the reaction product 20 and starting material 8b were obtained as an inseparable mixture. Therefore, the olefin metathesis reaction of the mixture was extended to finally afford 20. An olefin cross metathesis reaction using (Z)-oct-4-ene (23) provided a mixture of the corresponding alkene 21 and 8b, which were readily separated.

The three types of prepared alkenylpyrrolidine derivatives 8b, 20 and 21 were converted into the corresponding 1-alkyl-2-deoxyiminofuranoses 2a-c (Scheme 6). Deprotection of the Ns group followed by hydrogenation of the alkene unit gave 25a-c according to a similar method to that shown in Scheme 4. The TBS groups of 25a-c were deprotected by treatment with 3 N HCl aq. to provide desired iminofuranoses 2a-c in quantitative yield.

Having prepared the 1-alkyl-2-deoxyiminofuranoses 2a-c, their abilities to serve as inhibitors of rat intestinal α-glucosidase were compared with previous reported data for 1-alkyl L-arabinoiminofuranoses 1a, 1c and 1d and commercially available drugs such as acarbose, voglibose and miglitol (Table 2).10 We were disappointed to find that the prepared 1-alkyl-2-deoxyiminofuranoses 2 showed no effective inhibitory activity toward maltase, with a less than 50% inhibition at 1000 μM. On the other hand, the compound was a weak inhibitor of sucrase. Compound 2c, having n-pentyl chain at the C1 position, showed the most potent inhibitory activity among the prepared 2-deoxyiminofuranoses 2. 1-Alkyl L-arabinoiminofuranoses have been reported to show inhibitory activities toward α-glucosidases that are as strong as commercially available drugs. The data reported herein indicate that a hydroxy group at the C2 position is necessary for potent inhibitory activity toward α-glucosidase.

In conclusion, we report on the stereoselective synthesis of 1-alkyl-2-deoxyiminofuranoses 2 using Ir-catalyzed allylic cyclization as a key step. The overall yields are 24~30% and the synthesis involves 10 or 11 steps starting from the known compound 11. Further applications of this Ir-catalyzed intramolecular cyclization for the synthesis of other pyrrolidine alkaloid derivatives is currently in progress.

EXPERIMENTAL
Infrared (IR) spectra were recorded on a Perkin–Elmer 1600 series FT-IR spectrometer. Mass spectra (MS) were recorded on a JEOL JMN-DX 303/JMA-DA 5000 spectrometer. Microanalyses were performed on a Perkin–Elmer CHN 2400 Elemental Analyzer. Optical rotations were measured with a JASCO DIP-360 or JASCO P-1020 digital polarimeter. Proton nuclear magnetic resonance (1H NMR) spectra were recorded on JEOL JNM-EX 270 (270 MHz) or 300 MHz on a Varian Gemini-300 or JEOL JNM-AL 400 (400 MHz) 500 MHz on a Varian Unity-500 or JNM-LA (600 MHz) spectrometer, using tetramethylsilane as an internal standard. The following abbreviations are used: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet) Column chromatography was carried out on Merck Silica Gel 60 (230–400 mesh) or KANTO Silica Gel 60N (40–50 μm) for flash chromatography. Purification of products via ion-exchange resin chromatography was performed with Dowex 1_2 OH_ form, using water as eluent. All non-aqueous reactions were carried out under argon atmosphere. 1-Alkyl-L-arabinoiminofuranoses were available with the reported procedure. Additionally, allylic alcohol 11 was prepared from Garner aldehyde according to known method as a single diastereomer.8

(S)-tert-Butyl 4-[(R)-1-hydroxy-5-{(methoxycarbonyl)oxy}pent-3-en-1-yl]-2,2-dimethyloxazolidine-3-carboxylate (12)
To a solution of allylic alcohol 11 (490 mg, 1.81 mmol) and (Z)-but-2-ene-1,4-diyl dimethyl dicarbonate (14) (1.84 g, 9.03 mmol) in dry CH2Cl2 (36 mL) was added tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-yl-idene][benzylidine]-ruthenium(IV) dichloride (2nd Grubbs catalyst, 76.7 mg, 90.3 μmol). After the mixture was stirred for 2 h at room temperature, the solvents were removed under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/EtOAc = 5:1 → 3:1) to give 12 (623 mg, 96%) as a brown oil.
[α]D20 –15.7 (c 1.71, CHCl3). 1H-NMR (400 MHz, CDCl3) (mixture of E/Z isomers) E isomer δ 1.49 (9H, s), 1.58 (6H, s), 2.17-2.33 (2H, m), 3.59-4.13 (7H, m), 4.59 (2H, d, J = 6.3 Hz), 5.67 (1H, dt, J = 6.3, 15.5 Hz), 5.93 (1H, m); Z isomer δ 1.49 (9H, s), 1.58 (6H, s), 2.17-2.33 (2H, m), 3.59-4.13 (7H, m), 4.70 (2H, d, J = 5.8 Hz), 5.67 (1H, dt, J = 6.3, 15.5 Hz), 5.93 (1H, m). 13C-NMR (100 MHz, CDCl3) (mixture of E/Z isomers) δ 14.0, 20.8, 24.0, 26.4, 26.5, 28.1, 36.0, 54.5, 60.1, 61.7, 64.2, 64.5, 68.1, 72.1, 80.9, 94.1, 125.7, 132.6, 133.3, 155.4. IR (neat) cm–1: 3483, 2979, 1750, 1698, 1445, 1367, 1268. EI-MS (m/z): 359 (M+). HRMS Calcd for C17H29O7: 359.1944, Found: 359.1939.

(5R,6S)-6-Amino-5,7-bis{(tert-butyldimethylsilyl)oxy}hept-2-en-1-yl methyl carbonate (9a)
To a solution of 12 (315 mg, 0.876 mmol) in dry CH2Cl2 (8 mL) was added TFA (8 mL) at 0 °C. After the mixture was stirred for 2 h at room temperature, the solvents were removed under reduced pressure. Traces of TFA were removed from a mixture by azeotropic distillations with MeOH (2 × 5 mL) and toluene (2 × 5 mL) under reduced pressure at room temperature.
The residue was dissolved in CH2Cl2 (8 mL). Imidazole (895 mg, 13.1 mmol) and TBSCl (528 mg, 3.5 mmol) were added to this solution at 0 °C. After the reaction was stirred at room temperature overnight, the reaction was quenched with water (10 mL). The whole was extracted with CH2Cl2 (2 × 30 mL) and the combined organic layer was dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/EtOAc = 5:1→ 2:1) to give 9a (324 mg, 83%) as a colorless oil.
[α]D24 –10.7 (c 0.95, CHCl3). 1H-NMR (400 MHz, CDCl3) (mixture of E/Z isomers) E isomer δ 0.05 (12H, s), 0.89 (18H, s), 2.24-2.39 (2H, m), 2.83-2.88 (1H, m), 3.43-3.48 (1H, dd, J = 7.2, 9.6 Hz), 3.66-3.73 (2H, m), 3.78 (3H, s), 4.58 (2H, d, J = 6.8 Hz), 5.62 (1H, dt, J = 6.3, 15.5 Hz), 5.83 (1H, m); Z isomer δ 0.05 (12H, s), 0.89 (18H, s), 2.24-2.39 (2H, m), 2.83-2.88 (1H, m), 3.43-3.48 (1H, dd, J = 7.2, 9.6 Hz), 3.66-3.73 (2H, m), 3.78 (3H, s), 4.69 (2H, J = 6.8 Hz), 5.62 (1H, dt, J = 6.3, 15.5 Hz), 5.83 (1H, m). 13C-NMR (100 MHz, CDCl3) (mixture of E/Z isomers) δ –5.4, –5.3, –4.7, –4.6, –4.3, 18.0, 18.3, 25.8, 25.9, 26.0, 35.8, 54.7, 56.5, 63.8, 64.8, 65.2, 68.3, 68.4, 73.1, 125.7, 125.8, 131.9, 133.0, 133.3, 155.7. IR (neat) cm–1: 2956, 2858, 1751, 1472, 1259. EI-MS (m/z): 447 (M+). HRMS Calcd for C21H45NO5Si2: 447.2836, Found: 447.2845.

(5R,6S)-5,7-Bis{(tert-butyldimethylsilyl)oxy}-6-(2-nitrophenylsulfonamido)hept-2-en-1-yl methyl carbonate (9b)
To a mixture of amine 9a (2.03 g, 4.52 mmol), Et3N (1.1 mL, 8.14 mmol) and N,N-dimethylaminopyridine (133 mg, 1.08 mmol) in dry CH2Cl2 (45 mL) was added 2-nitrobenzenesulfonyl chloride (1.20 g, 5.42 mmol) at 0 °C. The mixture was stirred at room temperature overnight. After evaporation, the residue was diluted with EtOAc (50 mL). The whole mixture was transferred to a separatory funnel. The organic layer was washed with brine (15 mL), 5% KHSO4 aq. (15 mL) and brine (15 mL), and dried over anhydrous Na2SO4. Filtration and evaporation in vacuo furnished the crude product, which was purified by silica gel column chromatography (n-hexane/EtOAc = 10:1 →8:1) to afford 9b (5.20 g, 84%) as a pale yellow oil.
[α]D20 +52.7 (c 0.88, CHCl3). 1H-NMR (400 MHz, CDCl3) (mixture of E/Z isomers) E isomer δ –0.17 (3H, s), –0.09 (3H, s), 0.04 (6H, s), 0.78 (9H, s), 0.83 (9H, s), 2.33 (2H, dd, J = 6.3, 6.8 Hz), 3.45-3.51 (1H, m), 3.52 (1H, dd, J = 4.8, 10.1 Hz), 3.70 (1H, dd, J = 4.8, 10.1 Hz), 3.79 (3H, s), 3.98 (1H, m), 4.58 (2H, d, J = 6.3 Hz), 5.58 (1H, dt, J = 6.3, 15.4 Hz), 5.69 (1H, d, J = 7.2 Hz), 5.79 (1H, dt, J = 6.8, 15.4 Hz), 7.68 (3H, m), 7.86 (1H, d, J = 5.8 Hz), 8.10 (1H, d, J = 5.8 Hz). 13C-NMR (100 MHz, CDCl3) (mixture of E/Z isomers) δ –5.7, –5.4, –4.4, –4.1, 0.1, 18.2, 18.3, 25.9, 26.0, 36.7, 54.9, 59.8, 61.2, 68.4, 71.7, 125.5, 126.8, 130.6, 131.9, 133.1, 133.4, 135.3, 155.8; IR (neat) cm–1: 3349, 2956, 2858, 1749, 1543, 1443, 1361, 1260. FAB-MS (m/z): 633 (M+1)+. HRMS Calcd for C27H49N2O9SSi2: 633.2697, Found: 633.2708.

(2S,3R,5R)-3-{(tert-Butyldimethylsilyl)oxy}-2-[{(tert-butyldimethylsilyl)oxy}methyl]-5-vinylpyrrolidine (8a)
(2S,3R,5S)-3-{(tert-Butyldimethylsilyl)oxy}-2-[{(tert-butyldimethylsilyl)oxy}methyl]-5-vinylpyrrolidine (15a)
To a solution of [Ir(cod)Cl]2 (3.2 mg, 0.0048 mmol, 4 mol %) and (S,S,S)-(+)-(3,5-dioxa-4-phosphacyclohepta[2,1-a:3,4-a’]dinaphthalen-4-yl)bis(1-phenylethyl)amine (Ligand 1) (5.2 mg, 0.0096 mmol, 8 mol %) in THF (0.3 mL) was added 1,5,7-triazabicyclo[4.4.0]dec-5-ene (2.7 mg, 0.0192 mmol, 16 mol %). After the mixture was stirred for 1 h at room temperature, a solution of allylic carbonate 9a (54.0 mg, 0.12 mmol) in THF (0.8 mL) was added to the reaction mixture. After stirring for 40 h at 40 °C, and the mixture was concentrated and the residue purified by silica gel column chromatography (n-hexane/EtOAc = 10:1) to give 8a (27.8 mg, 62%) as a pale yellow oil and 15a (7.9 mg, 18%) as a pale yellow oil.
8a; [α]D24 –14.8 (c 1.60, CHCl3). 1H-NMR (400 MHz, CDCl3) δ 0.05 (12H, s), 0.88 (9H, s), 0.90 (9H, s), 1.56 (1H, dt, J = 6.8, 6.8, 13.1 Hz), 2.17 (1H, m), 3.02 (1H, dt, J = 4.8, 4.9 Hz), 3.58 (2H, d, J = 4.8 Hz), 3.64 (1H, dt, J = 7.3, 7.4 Hz), 4.11 (1H, dt, J = 5.8, 6.3 Hz), 4.95 (1H, d, J = 10.1 Hz), 5.06 (1H, d, J = 16.9 Hz), 5.89, (1H, m). 13C-NMR (100 MHz, CDCl3) δ –5.48, –5.44, –4.83, –4.60, 17.96, 18.25, 25.78, 25.89, 41.36, 59.17, 62.92, 67.03, 73.57, 113.67, 142.25. IR (neat) cm–1: 3431, 2928, 2856, 1643, 1463, 1256, 1115; EI-MS (m/z): 371 (M+). HRMS Calcd for C19H41NO2Si2: 371.2676, Found: 371.2665.
15a; 1H-NMR (400 MHz, CDCl3) δ 0.05 (12H, s), 0.89 (18H, s), 1.67 (1H, m), 1.87 (1H, m), 3.22 (1H, m), 3.60 (2H, m), 3.86 (1H, q, J = 7.7 Hz), 4.37 (1H, m), 4.98 (1H, d, J = 9.2 Hz), 5.10 (1H, d, J = 16.9 Hz), 5.77 (1H, m).

(2S,3R,5R)-3-{(tert-Butyldimethylsilyl)oxy}-2-[{(tert-butyldimethylsilyl)oxy}methyl]-1-{(2-nitrophenyl)sulfonyl}-5-vinylpyrrolidine (8b)
(2S,3R,5S)-3-{(tert-Butyldimethylsilyl)oxy}-2-[{(tert-butyldimethylsilyl)oxy}methyl]-1-{(2-nitrophenyl)sulfonyl}-5-vinylpyrrolidine (15b)
To a solution of [Ir(cod)Cl]2 (8.7 mg, 8 mol %) and (S,S,S)-(+)-(3,5-dioxa-4-phosphacyclohepta[2,1-a:3,4-a’]dinaphthalen-4-yl)bis(1-phenylethyl)amine (Ligand 1) (13.9 mg, 16 mol %) in THF (0.45 mL) was added 1,5,7-triazabicyclo[4.4.0]dec-5-ene (7.2 mg, 0.052 mmol). The mixture was stirred for 1 h at room temperature, a solution of allylic carbonate 9b (102 mg, 0.161 mmol) in THF (1 mL) was added to the reaction mixture. After stirring for 15 h at 40 °C, and the mixture was concentrated and the residue purified by silica gel column chromatography (n-hexane/EtOAc = 15:1) to give 8b as a white solid (78.7 mg, 88%) and 15b (7.9 mg 9%) as a white solid.
8b; mp 100-102 °C. [α]D20 +142.4 (c 1.03, CHCl3). 1H-NMR (400 MHz, CDCl3) δ 0.04 (6H, s), 0.05 (6H, s), 0.81 (9H, s), 0.86 (9H, s), 1.65 (1H, d, J = 13.5 Hz), 2.47-2.54 (1H, m), 3.45 (1H, dd, J = 8.2, 10.1 Hz), 3.92 (1H, dd, J = 3.4, 10.0 Hz), 4.04-4.09 (1H, m), 4.40-4.46 (1H, m), 4.75 (1H, d, J = 10.1 Hz), 5.01 (1H, d, J = 16.9 Hz), 5.68-5.78 (1H, m), 7.51-7.60 (3H, m), 8.09-8.11 (1H, m). 13C-NMR (100 MHz, CDCl3) δ –5.5, –5.4, –5.0, –4.9, 17.9, 18.2, 25.7, 25.9, 39.6, 64.0, 64.3, 71.9, 74.7, 117.4, 123.7, 130.5, 131.0, 132.8, 135.8, 138.3. IR (KBr) cm–1: 3097, 2953, 2931, 2886, 2858, 1584, 1546, 1472, 1352. FAB-MS (m/z): 557 (M+1)+. HRMS Calcd for C25H45N2O6SSi2: 557.2537, Found: 557.2545.
15b; 1H-NMR (400 MHz, CDCl3) δ 0.05 (6H,s), 0.07 (6H, s), 0.88 (9H, s), 0.91 (9H, s), 1.29 (1H, d, J = 13.5 Hz), 3.49 (1H, m), 3.81 (1H, dd, J = 4.8, 10.5 Hz), 3.92 (2H, m), 4.13 (1H, m), 4.26 (1H, m), 4.97 (1H, d, J = 10.1 Hz), 5.05 (1H, d, J = 16.9 Hz), 5.89 (1H, m), 7.59 (3H, m), 8.08 (1H, m).

(2S,3R,5R)-3-{(tert-Butyldimethylsilyl)oxy}-2-[{(tert-butyldimethylsilyl)oxy}methyl]-1-{(2-nitro- phenyl)sulfonyl}-5-(tridec-1-en-1-yl)pyrrolidine (16)
To a solution of 8b (50.9 mg, 0.091 mmol) and 1-tridecene (19) (0.22 mL, 0.91 mmol) in dry CH2Cl2 (1.0 mL) was added tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene][benzylidine]ruthenium (IV) dichloride (2nd Grubbs catalyst) (7.8 mg, 0.0091 mmol). After the mixture was stirred for 24 h at 40 °C, 2nd Grubbs catalyst (7.8 mg, 0.0091 mmol) was added to the reaction mixture. After the mixture was stirred for 24 h at 40 °C, the solvents were removed under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/EtOAc = 30:1 → 5:1) to give 16 (31.5 mg, 48%) as a colorless oil.
[α]D24 +129.4 (c 0.70, CHCl3). 1H-NMR (400 MHz, CDCl3) (mixture of E/Z isomers) E isomer δ 0.05-0.13 (15H, m), 0.89 (18H, s), 1.25 (18H, m), 1.57 (3H, m), 2.47 (1H, m), 3.45 (1H, dd, J = 1.4, 10.1 Hz), 3.98 (1H, dd, J = 3.9, 10.2 Hz), 4.08 (1H, m), 4.42 (2H, m), 5.29 (1H, dd, J = 10.1, 15.4 Hz), 5.48 (1H, dt, J = 6.3, 15.0 Hz), 7.51 (3H, m), 8.13 (1H, d, J = 7.7 Hz); Z isomer δ 0.05-0.13 (15H, m), 0.89 (18H, s), 1.25 (18H, m), 1.57 (3H, m), 2.47 (1H, m), 3.45 (1H, dd, J = 1.4, 10.1 Hz), 3.98 (1H, dd, J = 3.9, 10.2 Hz), 4.08 (1H, m), 4.42 (2H, m), 4.83 (1H, m), 5.09 (1H, m), 7.51 (3H, m), 8.13 (1H, d, J = 7.7 Hz). 13C-NMR (100 MHz, CDCl3) (mixture of E/Z isomers) δ -5.4, -5.3, -4.8, -4.7, 14.3, 18.1, 18.3, 22.8, 25.8, 25.9, 26.0, 28.5, 29.3, 29.5, 29.6, 29.7, 29.8, 30.0, 31.9, 32.1, 39.7, 63.7, 64.4, 72.3, 74.9, 76.8, 123.8, 129.9, 130.5, 130.9, 132.6, 134.6, 136.6, 148.6. IR (neat) cm–1: 3420, 2929, 2857, 1638, 1548, 1471, 1359. FAB-MS (m/z): 711 (M+1)+. HRMS Calcd for C36H67N2O6SSi2: 711.4258, Found: 711.4252.

(2S,3R,5R)-3-{(tert-Butyldimethylsilyl)oxy}-2-[{(tert-butyldimethylsilyl)oxy}methyl]-5-(tridec-1-en-1-yl)pyrrolidine (17)
To a suspension of 16 (81.5 mg, 0.044 mmol) and K2CO3 (30.5 mg, 0.221 mmol) in MeCN (1.1 mL) was added PhSH (13.7 μL, 0.133 mmol). The reaction mixture was stirred overnight at 40 °C. After filtration, the filtrate was concentrated under reduced pressure. The residue was diluted with CH2Cl2 (15 mL). The whole mixture was transferred to a separatory funnel. The organic layer was washed with 10% Na2S2O3 aq. (5 mL) and brine (5 mL), and dried over anhydrous Na2SO4.The residue was purified by silica gel column chromatography (n-hexane/EtOAc = 20:1) to give amine 17 (21.3 mg, 91%) as a colorless oil.
[α]D24 –16.8 (c 1.24, CHCl3). 1H-NMR (400 MHz, CDCl3) (mixture of E/Z isomers) E isomer δ 0.05 (12H, s), 0.85 (21H, m), 1.25 (18H, m), 1.50 (1H, m), 1.94 (2H, m), 2.13 (1H, m), 3.01 (1H, dd, J = 4.8, 10.1 Hz), 3.55 (3H, m), 4.08 (1H, m), 5.45 (2H, m); Z isomer δ 0.05 (12H, s), 0.85 (21H, m), 1.25 (18H, m), 1.50 (1H, m), 1.94 (2H, m), 2.13 (1H, m), 3.01 (1H, dd, J = 4.8, 10.1 Hz), 3.55 (3H, m), 4.08 (1H, m), 5.34 (2H, m). 13C-NMR (100 MHz, CDCl3) (mixture of E/Z isomers) δ –5.47, –5.42, –4.82, –4.59, 14.10, 17.97, 18.27, 22.67, 25.80, 25.92, 29.19, 29.26, 29.34, 29.50, 29.55, 29.64, 29.68, 31.91, 32.18, 41.79, 58.56, 63.14, 67.09, 73,72, 130.51, 133.92. IR (neat) cm–1: 3422, 2956, 2928, 2857, 1639, 1472, 1464, 1256, 1116. EI-MS (m/z): 525 (M+). HRMS Calcd for C30H63NO2Si2: 525.4397, Found: 525.4387.

(2S,3R,5S)-3-{(tert-Butyldimethylsilyl)oxy}-2-[{(tert-butyldimethylsilyl)oxy}methyl]-5-tridecylpyrrolidine (18)
To a solution of 17 (21.5 mg, 0.0405 mmol) in EtOAc (0.5 mL) was added PtO2 (4.2 mg, 20 wt%), and the resulting mixture was stirred under hydrogen at atmospheric pressure at room temperature overnight. The reaction mixture was then filtered through a plug of Celite, and the Celite filter cake was washed with EtOAc. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (n-hexane/EtOAc = 20:1) to afford 18 (11.8 mg, 63%) as a colorless oil.
[α]D23 –12.5 (c 1.06, CHCl3). 1H-NMR (400 MHz, CDCl3) δ 0.05 (12H, s), 0.86 (21H, m), 1.25 (25H, m), 2.10 (2H, m), 2.97 (1H, m), 3.09 (1H, m), 3.60 (2H, d, J = 4.3 Hz), 4.09 (1H, ddd, J = 5.8, 6.3, 6.8 Hz). 13C-NMR (100 MHz, CDCl3) δ –5.31, –5.28, –4.7, –4.4, 14.3, 18.1, 18.4, 22.8, 26.0, 27.2, 29.5, 29.78, 29.8, 32.1, 37.7, 41.4, 56.6, 62.2, 66.7, 73.5. IR (neat) cm–1 : 3424, 2956, 2929, 2856, 1638, 1468, 1254, 1081. EI-MS (m/z): 528 (M+); HRMS Calcd for C30H65NO2Si2: 527.4554, Found: 527.4556.

(2S,3R,5R)-5-(But-1-en-1-yl)-3-{(tert-butyldimethylsilyl)oxy}-2-[{(tert-butyldimethylsilyl)oxy}methyl]-1-{(2-nitrophenyl)sulfonyl}-pyrrolidine (20)
To a solution of 8b (116 mg, 0.209 mmol) and (Z)-hex-3-ene (22) (0.26 mL, 2.09 mmol) in dry CH2Cl2 (2.1 mL) was added tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-yl-idene][benzylidine]ruthenium (IV) dichloride (2nd Grubbs catalyst) (17.7 mg, 0.0209 mmol). After the mixture was stirred for 24 h at 40 °C, 2nd Grubbs catalyst (17.7 mg, 0.0209 mmol) was added to the reaction mixture. After the mixture was stirred for 24 h at 40 °C, the solvents were removed under reduced pressure. The residue was dissolved in CH2Cl2 (2.1 mL), and 2nd Grubbs catalyst (17.7 mg, 0.0209 mmol) was added to the solution. The mixture was stirred for 24 h at 40 °C, to the reaction mixture was added 2nd Grubbs catalyst (8.9 mg, 0.0105 mmol). After stirring for 24 h at 40 °C, the solvents were removed under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/EtOAc = 10:1 → 5:1) to give 20 (99.3 mg, 81%) as a brown oil.
[α]D24 +137.1 (c 1.54, CHCl3). 1H-NMR (400 MHz, CDCl3) E isomer δ 0.08 (12H, s), 0.62 (3H, t, J = 7.3 Hz), 0.87 (18H, s), 1.58 (3H, m), 2.48 (1H, m), 3.46 (1H, m), 3.99 (1H, dd, J = 3.4, 6.8 Hz), 4.10 (1H, m), 4.43 (1H, t, J = 9.3 Hz), 4.50 (1H, d, J = 3.4 Hz), 5.28 (1H, m), 5.48 (1H, m), 7.52 (3H, m), 8.13 (1H, d, J = 7.8 Hz); Z isomer δ 0.08 (12H, s), 0.71 (3H, t, J = 7.3 Hz), 0.87 (18H, s), 1.58 (3H, m), 2.48 (1H, m), 3.46 (1H, m), 3.99 (1H, dd, J = 3.4, 6.8 Hz), 4.10 (1H, m), 4.43 (1H, t, J = 9.3 Hz), 4.50 (1H, d, J = 3.4 Hz) 4.83 (1H, m), 5.09 (1H, m), 7.52 (3H, m), 8.13 (1H, d, J = 7.8 Hz). 13C-NMR (100 MHz, CDCl3) (mixture of E/Z isomers) δ –5.5, –5.4, –4.9, –4.9, 12.2, 13.6, 14.0, 17.9, 18.2, 20.1, 21.5, 24.5, 25.7, 25.8, 29.7, 33.8, 39.5, 39.6, 39.9, 57.3, 63.45, 63.5, 64.1, 64.2, 72.0, 72.2, 74.7, 123.6, 123.7, 128.8, 129.1, 130.1, 130.3, 130.4, 130.7, 130.8, 130.9, 132.4, 132.5, 132.6, 134.1, 136.7, 148.4. IR (neat) cm–1 2929.5, 2857.2, 1547.1, 1471.7, 1354.2, 1256.2. FAB-MS (m/z): 585 (M+1)+. HRMS Calcd for C27H49N2O6SSi2: 585.2850, Found: 585.2843.

(2S,3R,5R)-3-{(tert-Butyldimethylsilyl)oxy}-2-[{(tert-butyldimethylsilyl)oxy}methyl]-1-{(2-nitrophenyl)sulfonyl}-5-(pent-1-en-1-yl)pyrrolidine (21)
To a solution of 8b (131 mg, 0.236 mmol) and (Z)-oct-4-ene (23) (0.37 mL, 2.36 mmol) in dry CH2Cl2 (4.7 mL) was added tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-yl-idene][benzylidine]ruthenium (IV) dichloride (2nd Grubbs catalyst) (20.0 mg, 0.0236 mmol). After the mixture was stirred for 24 h at 40 °C, 2nd Grubbs catalyst (20.0 mg, 0.0236 mmol) was added to the reaction mixture. After stirring for 24 h at 40 °C, the solvents were removed under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/EtOAc = 20:1) to give 21 (114.5 mg, 81%) as a brown oil.
[α]D24 +152.6 (c 1.07, CHCl3). 1H-NMR (400 MHz, CDCl3) (mixture of E/Z isomers) E isomer δ 0.08 (12H, s), 0.70 (3H, t, J = 7.3 Hz), 0.86 (18H, s), 1.02 (2H, m), 1.60 (3H, m), 2.48 (1H, m), 3.45 (1H, m), 3.98 (1H, dd, J = 3.8, 10.6 Hz), 4.08 (1H, dd, J = 3.8, 10.4 Hz), 4.42 (1H, t, J = 9.2 Hz), 4.50 (1H, d, J = 3.9 Hz), 5.30 (1H, dd, J = 9.7, 15.4 Hz), 5.46 (1H, m), 7.52 (3H, m), 8.13 (1H, d, J = 7.8 Hz). Z isomer δ 0.08 (12H, s), 0.70 (3H, t, J = 7.3 Hz), 0.86 (18H, s), 1.02 (2H, m), 1.60 (3H, m), 2.48 (1H, m), 3.45 (1H, m), 3.98 (1H, dd, J = 3.8, 10.6 Hz), 4.08 (1H, dd, J = 3.8, 10.4 Hz), 4.42 (1H, t, J = 9.2 Hz), 4.50 (1H, d, J = 3.9 Hz), 4.83 (1H, m), 5.09 (1H, m), 7.52 (3H, m), 8.13 (1H, d, J = 7.8 Hz); 13C-NMR (100 MHz, CDCl3) (mixture of E/Z isomers) δ -5.5, -5.4, -5.0, -4.9, 13.6, 17.9, 18.2, 21.5, 25.6, 25.9, 33.8, 39.6, 63.5, 64.2, 72.1, 74.7, 123.6, 130.0, 130.18, 130.22, 130.8, 132.5, 134.1, 136.39, 136.44, 148.39. IR (neat) cm–1: 2930, 2858, 1547, 1472, 1440, 1355, 1256. FAB-MS (m/z): 599 (M+1)+. HRMS Calcd for C28H51N2O6SSi2: 599.3006, Found: 599.3002.

(2S,3R,5R)-5-(But-1-en-1-yl)-3-{(tert-butyldimethylsilyl)oxy}-2-[{(tert-butyldimethylsilyl)oxy}methyl]pyrrolidine (24b)
To a suspension of 20 (60.5 mg, 0.103 mmol) and K2CO3 (71.5 mg, 0.515 mmol) in MeCN (2.4 mL) was added PhSH (31.9 μL, 0.309 mmol). The reaction mixture was stirred overnight at 40 °C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/EtOAc = 10:1 → 3:1) to give 24b (41.2 mg, 99%) as a pale yellow oil.
[α]D26 –15.9 (c 1.22, CHCl3). 1H-NMR (400 MHz, CDCl3) (mixture of E/Z isomers) E isomer δ 0.05 (12H, s), 0.89 (18H, s), 0.96 (3H, t, J = 7.3 Hz), 1.50 (1H, m), 1.64 (1H, d, J = 5.4 Hz), 1.97 (1H, m), 2.13 (1H, m), 3.01 (1H, m), 3.55 (3H, m), 4.08 (1H, m), 5.46 (2H, m); Z isomer δ 0.05 (12H, s), 0.89 (18H, s), 0.96 (3H, t, J = 7.3 Hz), 1.50 (1H, m), 1.64 (1H, d, J = 5.4 Hz), 1.97 (1H, m), 2.13 (1H, m), 3.01 (1H, m), 3.55 (3H, m), 4.08 (1H, m), 5.33 (1H, m). 13C-NMR (100 MHz, CDCl3) (mixture of E/Z isomers) δ –5.47, –5.42, –4.82, –4.59, 13.46, 13.68, 17.97, 18.27, 22.35, 25.78, 25.91, 34.26, 41.37, 58.56, 62.89, 66.98, 73.58, 132.28, 132.64. IR (neat) cm–1: 3401, 2956, 2930, 2858, 1633, 1588, 1472, 1463, 1256, 1117. EI-MS (m/z): 399 (M+). HRMS Calcd for C21H45NO2Si2: 399.2989, Found: 399.2990.

(2S,3R,5R)-3-{(tert-Butyldimethylsilyl)oxy}-2-[{(tert-butyldimethylsilyl)oxy}methyl]-5-(pent-1-en-1-yl)pyrrolidine (24c)
To a suspension of 21 (30.9 mg, 0.052 mmol) and K2CO3 (35.7 mg, 0.258 mmol) in MeCN (1.2 mL) was added PhSH (15.9 μL, 0.155 mmol). The reaction mixture was stirred overnight at 40 °C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/EtOAc = 30:1 → 5:1) to give 24c (17.2 mg, 81%) as a pale yellow oil.
[α]D24 –20.5 (c 1.46, CHCl3). 1H-NMR (400 MHz, CDCl3) (mixture of E/Z isomers) E isomer δ 0.05 (12H, s), 0.84 (21H, m), 1.25 (3H,m), 1.48 (1H, m), 1.93 (1H, m), 2.12 (1H, m), 3.01(1H,m), 3.55 (3H, m), 4.09 (1H, m), 5.43 (2H, m); Z isomer δ 0.05 (12H, s), 0.84 (21H, m), 1.25 (3H,m), 1.48 (1H, m), 1.93 (1H, m), 2.12 (1H, m), 3.01(1H,m), 3.55 (3H, m), 4.09 (1H, m), 5.29 (1H, m). 13C-NMR (100 MHz, CDCl3) (mixture of E/Z isomers) δ –5.45, –5.41, –4.80, –4.57, 13.67, 17.99, 18.28, 22.38, 25.81, 25.85, 25.92, 34.27, 41.84, 58.57, 63.17, 67.12, 73.75, 130.25, 134.15. IR (neat) cm–1: 3368, 2957, 2930, 2897, 2858, 1652, 1472, 1464, 1256, 1116. EI-MS (m/z): 413 (M+). HRMS Calcd for C22H47NO2Si2: 413.3145, Found: 413.3150.

(2S,3R,5S)-3-{(tert-Butyldimethylsilyl)oxy}-2-[{(tert-butyldimethylsilyl)oxy}methyl]-5-ethylpyrrolidine (25a)
To a solution of 8a (48.3 mg, 0.130 mmol) in MeOH (2.2 mL) was added PtO2 (9.7 mg, 20 wt%), and the resulting mixture was stirred under hydrogen at atmospheric pressure at room temperature overnight. The reaction mixture was then filtered through a plug of Celite, and the Celite filter cake was washed with MeOH. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (n-hexane/EtOAc = 10:1 → 3:1) to afford 25a (25.2 mg, 52%) as a pale yellow oil.
[α]D24 –24.3 (c 1.26, CHCl3). 1H-NMR (400 MHz, CDCl3) δ 0.04 (12H, s), 0.87 (21H, m), 1.36 (3H, m), 2.10 (1H, m), 2.94 (2H,m), 3.59 (2H, d, J = 4.3 Hz), 4.07 (1H, m). 13C-NMR (100 MHz, CDCl3) δ –5.47, –5.42, –4.80, –4.55, 11.32, 17.99, 18.26, 25.82, 25.91, 30.59, 40.91, 58.01, 62.27, 66.76, 73.47. IR (neat) cm–1: 3429, 2957, 2930, 2858, 2103, 1644, 1471, 1463, 1256, 1114. EI-MS (m/z): 373 (M+). HRMS Calcd for C19H43NO2Si2: 373.2832, Found: 373.2823.

(2S,3R,5S)-5-Butyl-3-{(tert-butyldimethylsilyl)oxy}-2-[{(tert-butyldimethylsilyl)oxy}methyl]pyrrolidine (25b)
To a solution of 24b (41.2 mg, 0.103 mmol) in MeOH (1.7 mL) was added PtO2 (8.2 mg, 20 wt%), and the resulting mixture was stirred under hydrogen at atmospheric pressure at room temperature overnight. The reaction mixture was then filtered through a plug of Celite, and the Celite filter cake was washed with MeOH. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (CHCl3 only → CHCl3/MeOH = 20:1) to afford 25b (29.6 mg, 72%) as a pale yellow oil.
[α]D24 –22.9 (c 0.96, CHCl3). 1H-NMR (400 MHz, CDCl3) δ 0.04 (12H, s), 0.89 (21H, m), 1.25 (7H, m), 2.10 (1H, m), 2.96 (1H, m), 3.06 (1H, m), 3.60 (2H, d, J = 4.3 Hz), 4.08 (1H, m). 13C-NMR (100 MHz, CDCl3) δ –5.48, –5.43, –4.82, –4.56, 14.06, 17.97, 18.25, 22.77, 25.80, 25.90, 29.26, 37.62, 41.32, 56.36, 62.27, 66.72, 73.47. IR (neat) cm–1: 3401, 2957, 2930, 2859, 1639, 1472, 1256, 1114. EI-MS (m/z): 401 (M+). HRMS Calcd for C21H47NO2Si2: 401.3145, Found: 401.3152.

(2S,3R,5S)-3-{(tert-Butyldimethylsilyl)oxy}-2-[{(tert-butyldimethylsilyl)oxy}methyl]-5-pentylpyrrolidine (25c)
To a solution of 24c (18.5 mg, 0.045 mmol) in MeOH (1.0 mL) was added PtO2 (3.7 mg, 20 wt%), and the resulting mixture was stirred under hydrogen at atmospheric pressure at room temperature overnight. The reaction mixture was then filtered through a plug of Celite, and the Celite filter cake was washed with MeOH. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (CHCl3 only → CHCl3/MeOH = 20:1) to afford 25c (11.8 mg, 63%) as a pale yellow oil.
[α]D24 –18.2 (c 1.45, CHCl3). 1H-NMR (400 MHz, CDCl3) δ 0.04 (12H, s), 0.86 (21H, m), 1.25 (9H, m), 2.10 (1H, ddd, J = 6.8, 6.8, 13.1 Hz), 2.96 (1H, dd, J = 4.3, 10.1 Hz), 3.06 (1H, m), 3.60 (2H, d, J = 4.3 Hz), 4.08 (1H, m). 13C-NMR (100 MHz, CDCl3) δ –5.47, –5.44, –4.81, –4.55, 14.04, 17.97, 18.26, 22.61, 25.80, 25.91, 26.70, 31.88, 37.42, 41.17, 56.57, 62.11, 66.64, 73.34. IR (neat) cm–1: 3401, 2956, 2930, 2858, 1639, 1472, 1256, 1116. EI-MS (m/z): 415 (M+). HRMS Calcd for C22H49NO2Si2: 415.3302, Found: 415.3311.

(1S,3R,4S)-1-Ethyl-2-deoxy-L-iminofuranose (2a)
Compound 25a (14.1 mg, 0.038 mmol) was dissolved in 3 N HCl aq. (0.6 mL), and the mixture was stirred for 1 h at 100 °C. The reaction mixture was concentrated in vacuo, and the residue was washed with Et2O (2 × 5 mL) and purified by silica gel column chromatography (CH2Cl2 : MeOH : 25% NH4OH aq.= 50 : 50 : 1 → MeOH : 25% NH4OH aq. = 100 : 1) to give 2a (5.5 mg, quant) as a colorless oil.
[α]D24 –16.6 (c 0.81, MeOH). 1H-NMR (400 MHz, CD3OD) δ 0.91 (3H, t, J = 7.2 Hz), 1.37 (3H, m), 2.22 (1H, ddd, J = 6.6, 6.8, 12.9 Hz), 2.98 (1H, m), 3.51 (1H, dd, J = 5.8, 11.1 Hz), 3.58 (1H, dd, J = 4.8, 11.0 Hz), 4.02 (1H, m). 13C-NMR (100 MHz, CD3OD) δ 11.61, 30.37, 41.37, 59.18, 62.81, 67.57, 73.95. IR (neat) cm–1: 3428, 2930, 2127, 1645, 1463, 1422, 1088. EI-MS (m/z): 145 (M+). HRMS Calcd for C7H15NO2: 145.1103, Found: 145.1096.

(1S,3R,4S)-1-n-Butyl-2-deoxy-L-iminofuranose (2b)
Compound 25b (22.6 mg, 0.0563 mmol) was dissolved in 3 N HCl aq. (0.9 mL), and the mixture was stirred for 1 h at 100 °C. The reaction mixture was concentrated in vacuo, and the residue was washed with Et2O (2 × 5 mL) and purified by silica gel column chromatography (CH2Cl2 : MeOH : 25% NH4OH aq. = 100 : 50 : 1.5 → MeOH : 25% NH4OH aq. = 100 : 1) to give 2b (9.8 mg, quant) as a colorless oil.
[α]D24 –36.7 (c 0.16, MeOH). 1H-NMR (400 MHz, CD3OD) δ 0.86 (3H, t, J = 7.3 Hz), 1.19 (7H, m), 2.19 (1H, m), 3.00 (1H, m), 3.12 (1H, m), 3.46 (1H, dd, J = 6.3, 11.6 Hz), 3.55 (1H, dd, J = 6.8, 11.4 Hz), 4.00 (1H, m). 13C-NMR (100 MHz, CD3OD) δ 14.33, 23.76, 30.30, 37.11, 41.67, 57.78, 62.62, 67.65, 73.85. IR (neat) cm–1: 3401, 2958, 2928, 2858, 1651, 1463, 1417, 1120, 1089, 1041. EI-MS (m/z): 173 (M+). HRMS Calcd for C9H19NO2: 173.1416, Found: 173.1411.

(1S,3R,4S)-2-Deoxy-1-n-pentyl-L-iminofuranose (2c)
Compound 25c (16.1 mg 0.0387 mmol) was dissolved in 3 N HCl aq. (0.6 mL), and the mixture was stirred for 1 h at 100 °C. The reaction mixture was concentrated in vacuo, and the residue was washed with Et2O (2 × 5 mL) and purified by silica gel column chromatography (CH2Cl2 : MeOH : 25% NH4OH = 100 : 50 : 1.5 → MeOH : 25% NH4OH = 100 : 1) to give 2c (7.2 mg, quant) as a colorless oil.
[α]D24 –13.0 (c 0.61, MeOH). 1H-NMR (400 MHz, CD3OD) δ 0.90 (3H, m), 1.29 (9H, m), 2.22 (1H, m), 2.97 (1H, m), 3.07 (1H, m), 3.51 (1H, dd, J = 5.8, 11.1 Hz), 3.58 (1H, dd, J = 5.3, 11.1 Hz), 4.02 (1H, m). 13C-NMR (100 MHz, CD3OD) δ 14.3, 23.7, 27.8, 33.0, 37.5, 41.7, 57.7, 62.7, 67.6, 72.9. EI-MS (m/z): 187 (M+). HRMS Calcd for C10H21NO2: 187.1572, Found: 187.1579.

ACKNOWLEDGEMENTS
This study was financially supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS).

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10. Experimental procedure: Male Wistar rats with body weight of 130 g were obtained from Japan SLC, Inc. (Hamamatsu, Japan). Brush border membranes were prepared from the rat small intestine according to the method of Kessler et al.,11 and were assayed at pH 5.8 for rat intestinal maltase, isomaltase, sucrase, cellobiase, and lactase using the appropriate disaccharides as substrates. The reaction mixture contained 25 mM substrate and the appropriate amount of enzyme, and the incubations were performed for 30 min at 37 °C. The reaction was stopped by heating at 100 °C for 3 min. After centrifugation (600 g; 10 min), the resulting reaction mixture were added to the Glucose CII-test Wako (Wako Pure Chemical Ind., Osaka, Japan). The absorbance at 505 nm was measured to determine the amount of the released D-glucose.
11. M. Kessler, O. Acuto, C. Strelli, H. Murer, and G. A. Semenza, Biochem. Biophys. Acta, 1978, 506, 136. CrossRef