Total synthesis of N-butyl-1-deoxynojirimycin

Article abstract of DOI:10.1080/07328303.2017.1330415

N-Butyl-1-deoxynojirimycin (NB-DNJ) derived from imino sugar deoxynojirimycin (DNJ) has been approved for the treatment of Gaucher’s disease. Herein, a facile and efficient synthetic procedure for NB-DNJ has been described. Comparing to the methods reported previously,methanesulfonyl group was used as a leaving group for easy displacement upon attack by the imine in the sugar ring, leading to a high yield during the introduction of the n-butyl group. Thismethod can serve as an excellent protocol for the synthesis of DNJ derivatives with a variety of N-alkyl substituents and for large-scale production.

Full text of DOI:10.1080/07328303.2017.1330415

Journal of Carbohydrate Chemistry
ISSN: 0732-8303 (Print) 1532-2327 (Online) Journal homepage: http://www.tandfonline.com/loi/lcar20
Total synthesis of N-butyl-1-deoxynojirimycin
Jiajia Wang, Yunyan Zhao, Wei Zhao, Peng Wang & Jing Li
To cite this article: Jiajia Wang, Yunyan Zhao, Wei Zhao, Peng Wang & Jing Li (2017):
Total synthesis of N-butyl-1-deoxynojirimycin, Journal of Carbohydrate Chemistry, DOI:
10.1080/07328303.2017.1330415
To link to this article: http://dx.doi.org/10.1080/07328303.2017.1330415
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Date: 09 July 2017, At: 22:54

JOURNAL OF CARBOHYDRATE CHEMISTRY
, VOL. , NO. , –
https://doi.org/./..
Total synthesis of N-butyl--deoxynojirimycin
Jiajia Wanga,b, Yunyan Zhaob, Wei Zhaob, Peng Wangb, and Jing Lib
aHenan University Joint National Laboratory for Antibody Drug Engineering; School of Medicine, Henan
University, Kaifeng, P. R. China; bState Key Laboratory of Medicinal Chemical Biology, College of Pharmacy
and Tianjin Key Laboratory of Molecular Drug, Nankai University, Tianjin, P. R. China
ABSTRACT
ARTICLE HISTORY
Received  April 
Accepted  May 
N-Butyl-1-deoxynojirimycin (NB-DNJ) derived from imino sugar
deoxynojirimycin (DNJ) has been approved for the treatment of
Gaucher’s disease. Herein, a facile and efficient synthetic proce-
dure for NB-DNJ has been described. Comparing to the methods
reportedpreviously, methanesulfonylgroupwasusedasaleaving
groupforeasydisplacement uponattackbytheimineinthesugar
ring, leading to a high yield during the introduction of the n-butyl
group. This method can serve as an excellent protocol for the syn-
thesis of DNJ derivatives with a variety of N-alkyl substituents and
for large-scale production.
KEYWORDS
DNJ; Gaucher disease;
NB-DNJ; total synthesis
GRAPHICAL ABSTRACT
Introduction
Iminosugars are a class of sugar mimics in which the endocyclic oxygen atom
of monosaccharides is substituted with a nitrogen atom.[1] 1-Deoxynojirimycin
(DNJ, 1, Fig. 1), one of the most common representatives of iminosugars, is a nat-
urally occurring piperidine 1-deoxyglucose mimic from the mulberry tree, which
exhibits potent α- and β-glucosidase inhibition activities.[2] Based on its high ther-
apeutic potential, two iminosugar medicines, Zavesca (NB-DNJ, miglustat, 2) and
®
Miglitol (3), have been developed and approved for the treatment of Gaucher’s dis-
®
ease (GD) and type II diabetes, respectively.[3,4] GD is a progressive lysosomal stor-
age disorder caused by the insufficient activity of the β-glucocerebrosidase (GCase,
acid β-glucosidase, EC 3.2.1.45) that is responsible for the hydrolysis of glucosyl-
ceramides (GCs) in lysosome. Mutant GCase with low catalytic activity results in
the accumulation of undegraded substrates, which ultimately leads to bone lesions,
CONTACT Jing Li
jinglink@nankai.edu.cn
State Key Laboratory of Medicinal Chemical Biology, College of
Pharmacy and Tianjin Key Laboratory of Molecular Drug, Nankai University, Haihe Education Park,  Tongyan Road,
Tianjin, P. R. China.
©  Taylor & Francis Group, LLC

2
J. WANG ET AL.
Figure . Structures of DNJ and representative derivatives.
hepatosplenomegaly, and other diseases. Two primary therapeutic approaches
for GD patients are enzyme replacement therapy (ERT) and substrate reduction
therapy (SRT). In 2000, NB-DNJ, known as an inhibitor of α-glucosidases I, II, and
ER-localized enzymes,[5,6] was approved for the treatment of type I GD ascribed to
the inhibition on the glucosylceramide synthase and reducing GC biosynthesis,[7]
and it has been widely used for the therapy of GC in Israel, USA, and Europe.[8]
Recently, pharmacological chaperones therapy (PCT) for GD has attracted
much attention. It is assumed that certain small molecules can selectively bind
and facilitate the correct folding of the mutant enzyme in ER, and the repaired
enzyme will be then transported into the lysosome to process the catalytic func-
tion. Iminosugars are the first class of compounds exploited as pharmacological
chaperones (PCs) for the treatment of GD. N-nonyl-DNJ (NN-DNJ, 4), one of the
site-directed GCase inhibitors, which can lead to a 2-fold increase in the cellular
activity of N370S GCase mutant at sub-inhibitory concentration. Thereafter, several
derivatives with incorporated functional groups at the endocyclic nitrogen of DNJ
have been screened as potential therapeutics for GD. These modifications include
amide or a sulfur atom (5, 6) in the alkyl chain, and extended modifications via
the popular copper-catalyzed azide-alkyne cycloaddition (CuAAC) (7) strategy
was also employed to make the substrate diversity.[9,10] As a part of our continuous
efforts in the development of PCs for the treatment of GD, we have prepared a series
of C2-subsituted 3,3-dimethyl-N-phenyl-4-amide-1-butyl glucoimidazole[11] and
O-(D-glucopyranosylidene) amino-Z-N-dodecylcarbamate,[12] which showed 2.1-
and 1.9-fold increases, respectively, in activity against N370S GCase mutant cell line.
Various synthetic methods have been developed to obtain 1-deoxynojirimycin
1 and its derivatives, some of which started with natural materials, such as nojir-
imycin, L-sorbofuranose, aldohexoses, ketohexoses, etc.[13–17] In addition, various
biochemical, microbiological, and immunochemical methods have been employed
to help explore new synthetic strategies.[18] One of the classic synthetic methods
was reported by Matos and co-workers,[19] which utilized 2,3,4,6-tetra-O-benzyl-
α-glucopyranose as the starting material. First, the hemiketal group was reduced
with lithium aluminum hydride in THF, and then Pftizner-Moffat oxidation of

JOURNAL OF CARBOHYDRATE CHEMISTRY
3
1,5-diol afforded unstable 1,5-dicarbonyl intermediate, which was cyclized in
the presence of ammonium formate and sodium cyanoborohydride. Thereafter,
cleavage of the protected group by lithium in ammonia treatment furnished the
desired compound. However, this multistep chemical procedure was only limited to
the laboratorial synthesis due to the unstable 1,5-dicarbonyl intermediate and the
deprotected conditions. Additionally, Zhang reported a practical and facile method
termed as “double inversion mechanism” to confirm the stereo-configuration at C5
position of 2.[20] Recently, another novel approach was developed for the synthesis
of N-butyl-1-deoxynojirmycin 2. In this case, 2,3,4,6-tetra-O-benzyl-D-glucono-
δ-lactam was derived first from 2,3,4,6-tetra-O-benzyl-α-D-glucopyranose after
four steps of reaction, followed by N-alkylation in the presence of n-butyl bromide
and base. However, the yield for each of the conversions in this procedure was
modest.[21,22] Here, we report an efficient synthetic method to generate N-butyl-1-
deoxynojirimycin with a high yield.
Results and discussion
The successful and efficient synthetic strategy of N-butyl-1-deoxynojirimycin devel-
oped in this work is outlined in Scheme 1. At the beginning, n-butanol was modified
with methylsulfonyl chloride to generate the reactive n-butyl methanesulfonate 9,
which was utilized later on. Commercially available methyl α-D-glucopyranoside
Scheme . The improved synthetic route of N-butyl--deoxynojirimycin.

4
J. WANG ET AL.
Scheme . Preparation of 20 from intermediate 16.
10 was subjected to BnBr and NaH treatment to form the per-benzylation prod-
uct 11, followed by hydrolysis of the anomeric methyl group in the presence of
AcOH/H2SO4. Then, the anomeric hydroxyl group in 12 was oxidized via Swern
oxidation to generate lactone intermediate 13. Treatment of 13 with methanolic
ammonia provided 14 in a high yield, which was subsequently subjected to Swern
oxidation again to furnish the corresponding keto amide 15. Then, 15 was sub-
jected to cyclization under the reducing conditions using formic acid and sodium
cyanoborohydride to afford lactam 16, in which the carbonyl group was eventu-
ally reduced with LiAlH4 to yield 2,3,4,6-tetra-O-benzyl-1-deoxynojirimycin 17.
The imine group in 17, which has relatively high nucleophilicity, was alkylated with
methanesulfonate 9 in the presence of K2CO3 to afford the benzyl protected NB-
DNJ 18 in a high yield (92%). Treatment of 18 with BCl3 removed smoothly the
benzyl protecting groups to provide the desired compound NB-DNJ 19.
The synthetic method described herein was significantly improved as compared
to reported ones.[21,22] For instance, during the introduction of n-butyl group, Zhang
utilized n-butyl bromide to react with 2,3,4,6-tetra-O-benzyl-1-deoxynojirimycin to
afford the 2,3,4,6-tetra-O-benzyl-N-butyl-1-deoxynojirimycin after carbonyl group
reduction in a low yield (39%), and the substitution reaction needed 4 d to give a
combined yield of only 24.5%.[21] Moreover, Qin incorporated the n-butyl group to
the iminosugar prior to the reduction of carbonyl group in the presence of stronger
base K2CO3, and the combined yield of these two steps was increased to 53%, which
was 2-fold higher than the former.[22] Clearly, compared to reported procedures, our
method could effectively prompt the yield by employing methylsulfonyl intermedi-
ate, which contained a better leaving group for the coupling with the iminosugar
and gave a high yield without the formation of any byproducts. The combined
yield of these two steps was 70.8%. In addition, 16 was also attempted to directly
react with N-butyl methanesulfonate 9 to furnish 2,3,4,6-tetra-O-benzyl-N-butyl-
gluconolactam 20 (Sch. 2), but the conversion rate was a little bit low, which can be
concluded that the nucleophilicity of nitrogen was increased after the reduction of
the carbonyl group.
Experimental
General
All reagents were purchased from commercially sources and were used without fur-
ther purification. Reactions were monitored by Thin-Layer Chromatography (TLC),
which were visualized under 254 nm UV light and/or stained the TLC plate with a

JOURNAL OF CARBOHYDRATE CHEMISTRY
5
solution of 10% phosphomolybdic acid in ethanol. Flash column chromatography
was performed by silica gel (100–200 mesh) with petroleum ether and ethyl acetate
or dichloromethane and methanol as eluent. 1H NMR and 13C NMR experiments
were recorded with Bruker AV 400 spectrometer at 400 MHz (1H NMR), 100 MHz
(13C NMR) using CDCl3 or D2O as solvents. The chemical shifts were recorded in
part per million (ppm) relative to TMS and the coupling constants J were reported
in hertz (Hz). High-resolution mass spectra (HRMS) were obtained on a Varian
QFT-ESI mass spectrometer.
Butyl methanesulfonate (9)
To a solution of butanol (500 mg, 6.7 mmol) in dry CH2Cl2 (10 mL) pyridine
(0.82 mL, 10.1 mmol) and MsCl (0.78 mL, 10.1 mmol) were added in sequence.
The reaction was stirred at 0°C and allowed to warm to temperature. After 6 h,
the mixture was quenched with MeOH and concentrated, then diluted with ethyl
acetate (50 mL), washed with 1M HCl (10 mL), saturated NaHCO3 (10 mL) and
saturated brine (10 mL), the organic layer was dried over anhydrous Na2SO4 and
concentrated. The resulting residue was purified by silica gel column chromatog-
1
raphy to afford compound 2 as colorless oil (0.94 g, 92%). H NMR (400 MHz,
CDCl3) δ 4.24 (t, J = 13.2, 6.4 Hz, 2H), 3.01 (s, 3H), 1.76–1.72 (m, 2H), 1.48–
1.42 (m, 2H), 0.96 (t, J = 12.8, 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 69.99,
37.30, 31.05, 18.67, 13.48. HRMS (ESI) calcd for [C5H12SO3 + Na]+ 175.0405, found
175.0401.
Methyl 2,3,4,6-Tetra-O-benzyl-α-D-glucopyranoside (11)
To a solution of methyl α-D-glucopyranoside 10 (10.0 g, 51.5 mmol) in anhydrous
DMF (30 mL) and the reaction mixture was cooled to 0°C, then sodium hydride
(12.4 g, 0.31 mol) and benzyl bromide (36.7 mL, 0.31 mol) were added successively.
The mixture was then allowed to warm to room temperature. After 8 h, the reaction
was analyzed by TLC (petroleum ether/ethyl acetate = 5:1) which indicating that
the starting material was consumed and conversed to a major product. The reac-
tion mixture was quenched with methanol, diluted with ethyl acetate (350 mL), the
organic layer washed with water (100 mL), NaHCO3 (100 mL) and saturated brine
(100 mL) in sequence, then collected the organic layer and dried over anhydrous
Na2SO4, the solvent was removed in vacuo and the residue was purified by flash
1
column chromatography to give 11 (23.2 g, 81.4%). H NMR (400 MHz, CDCl3)
δ 7.46–7.18 (m, 18H), 7.14–7.12 (m, 2H), 4.97 (d, J = 10.8 Hz, 1H), 4.84–4.77 (m,
3H), 4.67–4.58 (m, 3H), 4.47 (d, J = 11.6 Hz, 2H), 3.98 (t, J = 9.2 Hz, 1H), 3.75–3.69
(m, 2H), 3.63 (d, J = 9.2 Hz, 2H), 3.56 (dd, J = 9.6, 3.6 Hz, 2H), 3.37 (s, 3H); 13
C
NMR (100 MHz, CDCl3) δ 138.86, 138.32, 138.22, 137.98, 128.48, 128.39, 128.17,
128.00, 127.93, 127.87, 127.71, 127.61, 98.25, 82.17, 79.91, 77.73, 75.78, 75.05, 73.52,
73.42, 70.11, 68.55, 55.20. HRMS (ESI) calcd for [C35H38O6 + Na]+ 577.2566, found
577.2563.

6
J. WANG ET AL.
2,3,4,6-Tetra-O-benzyl-D-glucopyranoside (12)
Methyl 2,3,4,6-tetra-O-benzyl-α-D-glucopyranoside 11 (15.2 g, 27.4 mmol) was
dissolved in 80% AcOH (300 mL) and H2SO4 (75 mL), the solution was refluxed
overnight and cooled to the warm temperature. The white solid was filtered and
washed with 3 × 100 mL water, the white slide was dried by oil pump and afford
1
the pure 12 as white solid (7.1 g, 48%). H NMR (400 MHz, CDCl3) δ 7.42–
7.21 (m, 18H), 7.13 (m, 2H), 5.21 (d, J = 3.6 Hz, 1H), 4.93 (t, J = 11.2 Hz, 1H),
4.84–4.81 (m, 2H), 4.76–4.65 (m, 2H), 4.59–4.44 (m, 3H), 3.99 (t, J = 9.2 Hz,
1H), 3.69–3.41 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 138.74, 138.23, 137.94,
137.85, 128.56, 128.48, 128.45, 128.12, 128.05, 128.02, 127.95, 127.78, 127.70, 91.31,
81.81, 80.00, 77.80, 75.80, 75.09, 73.51, 73.24, 70.24, 68.63. HRMS (ESI) calcd for
[C34H36O6 + Na]+ 563.2410, found 563.2412.
2,3,4,6-Tetra-O-benzyl-D-gluconolactone (13)
To a solution of 2,3,4,6-tetra-O-benzyl-D-glucopyranoside 12 (7.1 g, 13.1 mmol) in
anhydrous DMSO was dropwise added acetic anhydride (26.8 mL, 0.26 mol), the
mixture was stirred at room temperature overnight. The reaction was analyzed and
showed the starting material was completely converted to a major product. The mix-
ture was diluted with diethyl ether (300 mL) and washed with water (8 × 100 mL),
saturated brine (100 mL). The organic layer was collected and dried over anhydrous
Na2SO4, after removing solvent, the crude product was purified by silica gel col-
umn chromatography and get 2,3,4,6-Tetra-O-benzyl-D-gluconolactone 13 as col-
1
orless oil (6.4 g, 92%). H NMR (400 MHz, DMSO) δ 7.36–7.22 (m, 20H), 4.87
(d, J = 11.5 Hz, 1H), 4.72–4.60 (m, 5H), 4.56–4.44 (dd, J = 20.8, 11.6 Hz, 3H),
4.37 (d, J = 6.4 Hz, 1H), 4.02 (t, J = 11.6, 5.6 Hz, 1H), 3.89 (t, J = 13.2, 6.6 Hz, 1H),
3.73–3.67 (m, 2H); 13C NMR (100 MHz, DMSO) δ 169.08, 137.86, 137.82, 137.61,
137.50, 128.25, 127.87, 127.80, 127.75, 127.72, 127.67, 127.58, 79.61, 77.58, 77.39,
75.30, 72.74, 72.38, 72.30, 68.30. HRMS (ESI) calcd for [C34H34O6 + Na]+ 561.2253,
found 561.2254.
2,3,4,6-Tetra-O-benzyl-D-gluconamide (14)
2,3,4,6-tetra-O-benzyl-D-gluconolactone 13 (6.4 g, 10 mmol) was dissolved in sat-
urated methanolic ammonia and the reaction was stirred at 0°C for 3 h. TLC anal-
ysis indicated that the starting material was completely consumed. The solvent
was removed in vacuo and the crude product was purified by column chromatog-
raphy (petroleum ether/ ethyl acetate = 5:1), affording 2,3,4,6-Tetra-O-benzyl-
1
D-gluconamide 14 as colorless oil (6.4 g, 96%). H NMR (400 MHz, DMSO) δ
7.50 (d, J = 7.0 Hz, 2H), 7.41 (d, J = 6.7 Hz, 2H), 7.37–7.19 (m, 16H), 5.09
(d, J = 5.6 Hz, 1H), 4.72–4.64 (m, 4H), 4.50–4.45 (m, 4H), 4.09–4.05 (m, 2H), 3.70–
3.63 (m, 2H), 3.53 (dd, J = 10.0, 5.6 Hz, 1H); 13C NMR (100 MHz, DMSO) δ 172.56,
138.91, 138.88, 138.48, 137.87, 128.22, 128.18, 128.06, 128.01, 127.83, 127.66, 127.60,

JOURNAL OF CARBOHYDRATE CHEMISTRY
7
127.38, 127.31, 127.25, 81.83, 80.36, 79.66, 73.57, 72.40, 71.72, 69.84. HRMS (ESI)
calcd for [C34H37NO6 + Na]+ 578.2519, found 578.2518.
2,3,4,6-Tetra-O-benzyl-D-gluconolactam (16)
To the solution of Compound 14 (6.4 g, 11.5 mmol) in anhydrous DMSO was added
acetic anhydride (21.7 mL, 0.23 mol), the solution was stirred at room temperature
for 6 h and analyzed by TLC which indicating that the starting material was com-
pletely consumed. The mixture was diluted with diethyl ether (300 mL) and washed
with water (6 × 100 mL), saturated brine (100 mL). The organic layer was dried over
anhydrous Na2SO4 and concentrated in vacuo, the crude product 15 was directly
used for next step without further purification.
A solution of compound 15 (11.5 mmol) and NaCNBH3 (1.4 g, 23.0 mmol)
in CH3CN was dropwise added formic acid (25.8 mL, 0.68 mol), the reaction
was refluxed for 3 h and allowed to cool to room temperature. The reaction was
quenched with 100 mL saturated NaHCO3 and continuously stirred for 15 min.
The aqueous was extracted with ethyl acetate (150 mL) and the organic layer was
washed with saturated brine (100 mL). The organic layer was dried over anhy-
drous Na2SO4, concentrated under reduced pressure. Purification by flash chro-
matography to afford compound 16 as white solid (2.96 g, two steps 48%). 1H NMR
(400 MHz, CDCl3) δ 7.45–7.38 (m, 2H), 7.35–7.24 (m, 16H), 7.18 (m, 2H), 5.97
(s, 1H), 5.18 (d, J = 11.2 Hz, 1H), 4.84 (dd, J = 11.2, 7.6 Hz, 1H), 4.75 (dd, J = 17.2,
11.2 Hz, 1H), 4.52–4.33 (m, 3H), 4.00 (d, J = 8.0 Hz, 1H), 3.91 (t, J = 8.0 Hz, 1H),
3.55 (m, 3H), 3.26 (t, J = 16.8, 8.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 170.61,
138.13, 137.95, 137.67, 137.37, 128.68, 128.60, 128.54, 128.50, 128.27, 128.14, 128.01,
127.93, 82.45, 78.93, 77.22, 74.88, 74.76, 73.46, 70.15, 53.89. HRMS (ESI) calcd for
[C34H35NO5 + Na]+ 560.2413, found 560.2406.
2,3,4,6-Tetra-O-benzyl-1-deoxynojirimycin (17)
To a solution of 16 (2.96 g, 5.5 mmol) in 100 mL anhydrous THF was slowly added
LiAlH4 (314 mg, 8.2 mmol) and the mixture was refluxed for 3 h. TLC analysis
showed that starting material was consumed completely (Petroleum ether/ ethyl
acetate = 5:1, Rf = 0.30), after cooling to room temperature, the mixture was poured
into diethyl ether/ water (V/V = 1/1, 500 mL) and continuously stirred for 15 min.
The aqueous was filtered and extracted with diethyl ether 300 mL, the organic layer
was washed with water (100 mL) and saturated brine (100 mL), dried over anhy-
drous Na2SO4 and concentrated, the resulting residue was purified by silica gel col-
umn chromatography to afford 17 as white solid (2.2 g, 77%). 1H NMR (400 MHz,
CDCl3) δ 7.37–7.25 (m, 18H), 7.19 (m, 2H), 4.98 (d, J = 10.8 Hz, 1H), 4.85
(t, J = 10.4 Hz, 2H), 4.68 (dd, J = 16.0, 11.6 Hz, 1H), 4.51–4.40 (m, 3H), 3.66 (dd,
J = 9.2, 2.8 Hz, 1H), 3.59–3.45 (m, 3H), 3.35 (t, J = 9.2 Hz, 1H), 3.24 (dd, J = 12.4,
5.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 138.94, 138.53, 138.42, 138.02, 128.48,
128.45, 128.09, 128.02, 127.93, 127.85, 127.82, 127.74, 127.60, 87.39, 80.71, 80.14,

8
J. WANG ET AL.
75.75, 75.26, 73.44, 72.84, 70.33, 59.78, 48.19. HRMS (ESI) calcd for [C34H37NO4 +
Na]+ 546.2620, found 546.2621.
2,3,4,6-Tetra-O-benzyl-N-butyl-1-deoxynojirimycin (18)
To a solution of 17 (500 mg, 0.95 mmol) and 4-methylsulfonybutane 9 (218 mg,
1.43 mmol) in CH3CN (5 mL) was added potassium carbonate (262.2 mg,
1.9 mmol). The reaction mixture was refluxed for 24 h under an argon atmo-
sphere then cooled. Most of the solvent was evaporated under reduced pressure.
The residue was diluted with CH2Cl2 (50 mL) and washed with water (25 mL), sat-
urated brine (25 mL) in sequence. The combined organic extracts were dried over
Na2SO4 and concentrated under reduced pressure. The residue was purified by flash
chromatography over silica gel to afford 18 as a white solid (506 mg, 92%). 1H NMR
(400 MHz, CDCl3) δ 7.27–7.16 (m, 18H), 7.06–7.04 (m, 2H), 4.88 (d, J = 11.2 Hz,
1H), 4.77 (dd, J = 23.6, 10.8 Hz, 12H), 4.60 (d, J = 5.4 Hz, 2H), 4.40 (dd, J = 15.2,
12.4 Hz, 2H), 4.33 (d, J = 10.8 Hz, 1H),3.62–3.42 (m, 1H), 3.38 (t, J = 9.1 Hz, 1H),
3.02 (m, 1H), 2.61–2.51 (m, 2H), 2.23–2.13 (m, 2H), 1.15 (m, 4H), 0.79 (t, J = 14.4,
7.2 Hz, 3H); 13C NMR (400 MHz, CDCl3) δ 139.06, 138.59, 137.82, 128.50, 128.41,
128.36, 128.03, 127.90, 127.78, 127.67, 127.57, 127.47, 87.42, 78.61, 75.35, 75.23,
73.50, 72.79, 65.21, 63.69, 54.49, 52.13, 25.61, 20.70, 14.05. HRMS (ESI) calcd for
[C38H45NO4 + H]+ 580.3427, found 580.3420.
N-butyl-1-deoxynojirimycin (19)
A solution of BCl3 (1 M in hexane) (5 mL) was added slowly to a stirred solution
of 18 (200 mg, 0.34 mmol) in dry CH2Cl2 (10 mL). The reaction was stirred at
−78°C overnight and then quenched by addition of MeOH (5 mL). The solvent was
removed and the residue was purified by flash chromatography to afford the target
compound N-butyl-1-deoxynojirimycin 19 as white solid (62.8 mg, 83%). 1H NMR
(400 MHz, D2O) δ 4.05 (d, J = 13.2, 1H), 3.92 (t, J = 13.2, 2.8 Hz, 1H), 3.73–3.67
(m, 1H), 3.59 (t, J = 10.0 Hz, 1H), 3.53 (dd, J = 12.4, 4.8 Hz, 1H), 3.44 (t, J = 9.2 Hz,
1H), 3.03–2.97 (m, 1H), 3.16 (dd, J = 12.0, 5.6 Hz, 1H), 3.11 (dd, J = 9.8, 2.4 Hz, 1H),
3.02 (t, J = 11.6 Hz, 1H), 1.65–1.63 (m, 1H), 1.32–1.29 (m, 1H), 0.82 (t, J = 7.6 Hz,
1H); 13C NMR (100 MHz, D2O) δ 75.82, 67.12, 66.13, 65.25, 53.07, 53.04, 24.29,
19.25, 12.75. HRMS (ESI) calcd for [C10H21NO4 + H]+ 220.1549, found 220.1544.
2,3,4,6-tetra-O-benzyl-N-butyl-gluconolactam (20)
Compound 16 (60 mg, 0.11 mmol) and potassium carbonate (30.8 mg, 0.22 mmol)
were dissolved in CH3CN (5 mL). 4-methylsulfonybutane 9 (25.8 mg, 0.17 mmol)
was added and the reaction mixture was refluxed overnight under an argon atmo-
sphere. After cooled to room temperature, remove the solvent under reduced pres-
sure. The residue was diluted with CH2Cl2 (25 mL) and washed with water (10 mL),
saturated brine (10 mL) in sequence. The combined organic extracts were dried

JOURNAL OF CARBOHYDRATE CHEMISTRY
9
over Na2SO4 and concentrated under reduced pressure. The residue was purified
by flash chromatography over silica gel to afford 20 as a white solid (34 mg, 52%).
1H NMR (400 MHz, CDCl3) δ 7.33–7.24 (m, 20H), 4.69 (m, J = 12.0 Hz, 2H),
4.62–4.48 (m, 6H), 4.27 (d, J = 2.5 Hz, 1H), 4.08 (dd, J = 5.1, 2.6 Hz, 1H), 3.93–
3.87 (m, 2H), 3.66–3.60 (m, 2H), 3.32–3.24 (m, 1 H), 3.15–3.07 (m, 1H), 1.37
(dd, J = 14.0, 6.8 Hz, 2H), 1.27 (dd, J = 14.2, 7.0 Hz, 2H), 0.87 (t, J = 7.2 Hz, 3H); 13C
NMR (400 MHz, CDCl3) δ 170.80, 138.19, 138.15, 137.87, 136.79, 128.70, 128.46,
128.42, 128.36, 128.31, 128.22, 128.06, 127.90, 127.80, 127.71, 80.75, 80.13, 77.53,
75.17, 74.12, 73.97, 73.44, 71.49, 71.11, 38.90, 31.55, 20.12, 13.73; HRMS (ESI) calcd
for [C38H43NO5 + Na]+ 616.3039, found 616.3042.
Funding
This work was supported by grants from the Natural Science Foundation of China
(NO. 31000371, NO. 21372130) and Natural Science Foundation of Tianjin (15JCYBJC29000).
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