One pot oxidative dehydration - oxidation of polyhydroxyhexanal oxime to polyhydroxy oxohexanenitrile: A versatile methodology for the facile access of azasugar alkaloids

Article abstract of DOI:10.1016/j.carres.2016.09.003

A unique oxidative dehydration-oxidation of polyhydroxy-oxime (7) to the corresponding ketonitrile (8) in one pot is reported for the first time in carbohydrate literature. Key ketonitrile intermediate (8) upon palladium hydroxide mediated cascade reaction afforded 1-deoxynojirimycin (DNJ) 1b in moderate diastereoselectivity. The cascade reaction involves the conversion of nitrile to amine, heteroannulation, reduction of the imine and subsequent debenzylation to furnish the azasugars. This oxidative dehydration-oxidation and reductive heteroannulation methodology is successfully utilized for the total synthesis of 1-deoxynojirimycin (1b), miglitol (2) and miglustat (3).

Full text of DOI:10.1016/j.carres.2016.09.003

Carbohydrate Research 435 (2016) 1e6
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
One pot oxidative dehydration - oxidation of polyhydroxyhexanal
oxime to polyhydroxy oxohexanenitrile: A versatile methodology for
*
the facile access of azasugar alkaloids
a
,
b
a
a
a
Sandip R. Khobare , Vikas Gajare , E. Vishnuvardhan Reddy , Rajender Datrika ,
a
b
c
a
Malavika Banda , Vidavalur Siddaiah , Sharad S. Pachore , Upadhya Timanna ,
c
c, *
Vilas H. Dahanukar , U.K. Syam Kumar
a
Technology Development Center, Custom Pharmaceutical Services, Dr. Reddy's Laboratories Ltd., Miyapur, Hyderabad 500049, India
Department of Organic Chemistry, Andhra University, Visakhapatanum 530003, India
Integrated Product Development, Innovation Plaza, Dr. Reddy's Laboratories Ltd., Bachupalli, Qutubullapur, R. R. Dist., 500072, Andhra Pradesh, India
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 July 2016
Received in revised form
A unique oxidative dehydration-oxidation of polyhydroxy-oxime (7) to the corresponding ketonitrile (8)
in one pot is reported for the first time in carbohydrate literature. Key ketonitrile intermediate (8) upon
palladium hydroxide mediated cascade reaction afforded 1-deoxynojirimycin (DNJ) 1b in moderate
diastereoselectivity. The cascade reaction involves the conversion of nitrile to amine, heteroannulation,
reduction of the imine and subsequent debenzylation to furnish the azasugars. This oxidative dehy-
dration-oxidation and reductive heteroannulation methodology is successfully utilized for the total
synthesis of 1-deoxynojirimycin (1b), miglitol (2) and miglustat (3).
5
September 2016
Accepted 6 September 2016
Available online 14 September 2016
Keywords:
Deoxynojirimycin
Miglitol
©
2016 Elsevier Ltd. All rights reserved.
Miglustat
Alcohol oxidation & oxime dehydration
Cascade reaction
Reductive aminative cyclization
1
. Introduction
dependent) diabetes. Deoxynojirimycin analog Miglustat (3, N-
butyldeoxynojirimycin) is also an azasugar based drug invented by
Acetlion and it is prescribed for the treatment of progressive
neurological manifestations in adults and pediatric patients with
NiemannePick type C disease [6]. Other prominent bioactive
members of this azasugar groups are manno-DNJ (4) [7] and gal-
Polyhydroxylated heterocycles possessing an endocyclic nitro-
gen atom (azasugars or iminosugars) have long been attractive
targets due to their unique biological properties, especially, for the
inhibition of a variety of sugar processing enzymes [1]. Minor
structural or functional modifications on these carbohydrate mi-
metics can have remarkable changes in their potency and speci-
ficity of inhibition [2]. Inouye et al. [3a] and latter Yagi et al. [3b]
isolated azasugar based alkaloids nojirimycin 1a and deoxynojir-
imycin (DNJ) 1b in 1966 and 1976 respectively.
DNJ congeners (Fig. 1) attached with pharmacophoric groups
are potentially bioactive compounds [4,5]. Miglitol (2, N-hydrox-
yethyldeoxynojirimycin), an azasugar based drug developed by
Bayer AG, is approved for the treatment of type II (non-insulin
acto-DNJ (5). Manno-DNJ (4) inhibits
a-L-fucosidase, a-D-man-
nosidase and -D-glucosidase activities [8] whereas Galacto-DNJ (5,
a
AT1001) is currently under phase B clinical trials for the treatment
of Fabry's disease [9].
Several elegantly designed synthetic protocols have been
demonstrated in literature for the synthesis of DNJ (1b) and its
analogs [10]. These syntheses employ stereoselective introduction
of amino functionality during the endo-heterocyclization reaction
with double nucleophilic displacement as key step. Intramolecular
amination using azide functionality is also reported for the syn-
thesis of DNJ (1b) in higher yield and good diastereoselectivity [11].
Overkleeft and co-workers developed transamination based highly
stereocontrolled cascade synthesis of DNJ using enantiomerically
*
Dedicated to Prof. H. Junjappa on the occasion of his 80th Birthday.
*
Corresponding author.
E-mail address: syam_kmr@yahoo.com (U.K. Syam Kumar).
http://dx.doi.org/10.1016/j.carres.2016.09.003
008-6215/© 2016 Elsevier Ltd. All rights reserved.
0

2
S.R. Khobare et al. / Carbohydrate Research 435 (2016) 1e6
ꢁ ꢁ
2 2 5
OH.HCl, Pyridine, 25 C, 15e18 h (b) DMSO, P O ,18e20 C or DMSO,
Scheme 2. (a) NH
oxalyl chloride, Et
N, CH
2
Cl
2
, ꢀ65 to ꢀ70 ꢁC, 45 min.
3
in excellent yields as reported in literature [15]. The O-protected
glucose derivatives (6a-c) were subsequently converted to the
corresponding hydroxyoximes (7a-c) in moderate to good yields by
reacting them with hydroxyl amine hydrochloride in the presence
of pyridine at ambient temperature. Oximes 7b and 7c were iso-
lated after column chromatographic purification, whereas 7a
directly precipitated during the concentration of organic layer after
aqueous extractive work up.
Fig. 1. Azasugar based alkaloids and their analogs.
pure cyanohydrin [12]. The ring contraction of polyhydroxy imi-
nosugars obtained by the chemo and diastereoselective oxidation
of unsaturated cyclic amines is a noteworthy approach for the
synthesis of DNJ [13]. Development of new and efficient method-
ologies for the synthesis of DNJ and its analogs are in high demand
due to their varied therapeutic properties and limited availability.
As a part of our effort to develop biologically active natural and
unnatural products [14], here in we describe a unique oxidative
dehydration of hydroxyoxime (7) to ketonitrile (8) for the first time
in carbohydrate literature and its application in the development of
concise synthesis of DNJ (1b), miglitol (2) and miglustat (3) under
cascade reaction conditions.
Synthesis of ketonitrile 8a from hydroxy-oxime 7a was origi-
nally planned in a sequential fashion with the oxidation of hydroxyl
group to keto functionality as the first step followed by the dehy-
dration of oxime to nitrile. Thus, oxidation of 7a was attempted
with different reagents and conditions as described in Table 1. The
exposure of hydroxy oxime 7a under Swern oxidation conditions
ꢁ
(2.2 equiv. of DMSO, 1.1 equiv. of oxalyl chloride, ꢀ70 C) provided
hydroxynitrile 10a as major product along with 1e2% of ketonitrile
8a. No traces of expected keto oxime 9a were observed in the re-
action. Based on this observation, it was planned to further explore
this unique oxidative dehydration of oxime and oxidation of sec-
ondary alcohol strategy to improve the yield of ketonitrile 8a in a
single pot operation. Considering that water liberated during the
conversion of oxime to nitrile may retard further oxidation of hy-
droxyl group to ketone, we decided to increase the mole equiva-
lents of DMSO and oxalyl chloride to maximize the yield of 8a. Thus
when oxidative dehydration was carried out with higher equiva-
lents of DMSO and oxalyl chloride, the expected ketonitrile 8a was
isolated as the major product in 52% yield. Interestingly, nearly 5%
of O-alkylated oxime 11a was also observed in the reaction. For-
mation of 11a is possibly due to the reaction of Pummerer adduct
[16] with hydroxyl oxime 7a (Fig. 2).
The retrosynthetic strategy employed for the synthesis of DNJ
1b), miglitol (2) and miglustat (3) is described in Scheme 1. N-
(
Alkylation of DNJ (1b) with bromoethanol or n-butyl bromide un-
der base assisted alkylation conditions provides miglitol (2) and
miglustat (3), respectively. DNJ (1b) in turn could be obtained from
ketonitrile 8 by a cascade reaction involving reduction of nitrile and
subsequent intramolecular endo-heterocyclization under reductive
amination condition. Oxidation and dehydration of hydroxy-oxime
7
, obtained from O-protected D-glucose (6) by reaction with hy-
droxylamine, provides ketonitrile 8. The hydroxy-oxime 7 could be
obtained from O-protected D-glucose
6 by reaction with
hydroxylamine.
2
. Results and discussion
Synthesis of miglitol (2) was initiated with protected D-glucose
To further optimize the conversion of 7a to ketonitrile 8a,
oxidation was performed under AlbrighteOnodera oxidation
(
(
6) as shown in Scheme 2. D-Glucose was subjected to tetrabenzyl
6a), pentapivaloyl (6b) and benzylidene triacetate (6c) protection
(DMSO/P
2
O
5
) [17] and Parikh Doering (DMSO-Py.SO
3
) [18] condi-
tions (Table 1). The oxidation of 7a with DMSO/P O (excess mol.
2 5
Table 1
Oxidative dehydration-oxidation of hydroxy oxime 7a-c.
S.
Oxidation
Reactant Ketonitrile
Hydroxy
Alkylated
No. condition
(8)
nitrile (10) product (11)
1
2
3
4
5
6
7
8
DMSO/COCl
2
7a
7b
7c
7a
7b
7c
7a
7b
52
45
e
e
5
6
Complex mixture
e
DMSO/P
DMSO/
2
O
5
73
e
e
40
e
e
65
e
e
48
10
Pyridine.SO
3
complex mixture
Scheme 1. Retrosynthetic approach.
*Mentioned yields are isolated yields after chromatographic purification.

S.R. Khobare et al. / Carbohydrate Research 435 (2016) 1e6
3
dimethyl formamide at elevated temperature, as described in
Scheme 4. The obtained crude miglitol (2) was then purified by
®
using Indion 225H acidic resin followed by trituration with
methanol to afford the desired product 2 in 80% yield with 99%
HPLC purity. In a similar way, miglustat (3) was also synthesized by
reacting 1-deoxynojirimycin (1b) with n-bromobutane under basic
conditions, followed by purification on acidic resin.
In conclusion, a novel one pot oxidative dehydration of hydroxyl
oxime to ketonitrile was developed for the first time in carbohy-
drate chemistry. Further application of this finding was explored
towards synthesis of deoxynojirimycin (1b) and its analogs in
moderate to good yields. The synthetic route described herein for
the synthesis of imino sugars utilizes fairly inexpensive reagents
and it is easy to carry out. This strategy opens a new way for the
short synthesis of imino sugars and it highlights the utility of chiral
ketonitriles in asymmetric synthesis. Further applications of this
novel methodology for the synthesis of other biologically relevant
natural products are under progress.
Fig. 2. Unexpected impurity-plausibly via Pummerer Rearrangement.
ꢁ
equiv.) conditions at 18e22 C mostly yielded 10a, however, when
ꢁ
the temperature of the reaction was increased to 45e50 C,
decomposition of 10a to a complex mixture of products was
observed. Oxidation of 7a with TEMPO/NaOCl [19] as well as Dess
Martin conditions [20] was also not successful. To further study the
substrate scope of this transformation, tetrapivaloyl oxime 7b was
subjected to Swern conditions to furnish the expected ketonitrile
8
b in 45% yield. However, benzylidene acetate derivative 7c under
Swern and Parikh-Doering oxidation conditions resulted in
uncharacterisable complex mixture of products.
3. Experimental section
The cascade reaction involving the reduction of nitrile to pri-
mary amine followed by in situ endo-heterocyclization via reduc-
tive amination to 1-deoxynojirimycin (1b) was attempted with
ketonitriles 8a and 8b as described in Scheme 3. The reduction of
ketonitrile 8a was carried out with Raney-Ni. The cascade reaction
afforded tetra-O-benzyl DNJ (12) and its C5 epimer 13 with 1:1.5
diastereoselectivity in 95% yield. The diastereomers thus obtained
were separated by column chromatography and major diastereo-
isomer was identified as epi-DNJ (13) [21,22]. In order to improve
the diastereoselectivity during reductive amination reaction,
different catalysts and conditions were screened. The superior
result was obtained when the hydrogenation was carried out with
3
.1. General
All reagents were used as received from commercial sources
without further purification or prepared as described in the liter-
ature. Reactions were stirred using Teflon-coated magnetic stirring
bars. TLC plates were visualized by ultraviolet light or by treatment
with a spray of Pancaldi reagent, anisaldehyde, ninhydrine, etc.
Chromatographic purification of products was carried out by flash
column chromatography on silica gel (60e120 mesh,
100e200 mesh, and 230e400 mesh). Melting points were deter-
mined using a differential scanning calorimeter (DSC, Q-2000, TA)
apparatus. Infrared spectra were recorded on a Perkin-Elmer 1650
Fourier transform spectrometer. NMR spectra were measured in
Pd(OH)
2
/C in methanol-tBuOH under hydrogen pressure of
ꢁ
150e170 psi at 25e30 C. The desired 1-deoxynojirimycin (1b) and
its epimer (1b’) were obtained in 1.2:1 ratio (by HPLC). The crude
CDCl
3 2 6
, D O, DMSO-d (all with TMS as internal standard) on a
product was then recrystallized from methanol to get pure DNJ (1b)
Varian Gemini 400 MHz FT NMR spectrometer. Chemical shifts (
d
)
ꢁ
with 99% de (m.p. 199
C
[23], specific optical rotation
are reported in ppm and coupling constants (J) are in Hz. The
following abbreviations were used to explain the multiplicities:
s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, m ¼ multiplet.
HRMS spectra were recorded on Micromass LCT Premier mass
spectrometer equipped with an ESI Lockspray source for accurate
mass values. Specific optical rotations were recorded on Jasco P-
2
5
ꢁ
25
D
ꢁ
{½
aꢂ
¼ þ41.64 (c 0.2, H
2
O); lit. [24] ½
aꢂ
¼ þ40.3 (c 1.47, H
2
O).
D
The spectral data of our synthetic DNJ (1b) was found to be in
accordance with the reported literature values [25]. The ketonitrile
8
b was also subjected to reduction under the same reaction con-
ditions, however, 12b and 13b were observed only in 5e10% yields.
Our subsequent efforts to improve the yields under hydrogenation
conditions were not successful due to the unstable nature of the
substrate under the hydrogenation condition.
Further, DNJ (1b) was converted to miglitol (2) by reacting 1b
with bromoethanol in the presence of potassium carbonate in
2
000 Polarimeter.
3
3
.2. General procedure for synthesis of 7a-c
.2.1. (2S,3R,4R,5R)-2,3,4,6-tetrakis(benzyloxy)-5-hydroxyhexanal
oxime (7a)
Hydroxylamine hydrochloride (22.2 g, 320 mmol) was added to
a stirred solution of pyridine (108 mL) and 2, 3, 4, 6-tetra-O-benzyl-
D-glucopyranoside (6a) (21.62 g, 40 mmol) and stirred for 15e18 h
at ambient temperature. After completion of reaction, (monitored
by TLC) the reaction mass was concentrated completely, added
CH
2
Cl
2
(105 mL) and filtered to remove pyridine hydrochloride salt.
Scheme 3. (a) Raney-Ni, MeOH, H
2
, RT; (b) Pd(OH)
2
/C, MeOH-tBuOH, MeOH.HCl, H
2
.
Scheme 4. N-Alkylation of DNJ.

4
S.R. Khobare et al. / Carbohydrate Research 435 (2016) 1e6
Filtrate was washed with 1N hydrochloric acid (2 ꢃ 100 mL),
concentrated and co-distilled with toluene. Hexane (60 mL) was
added to residue, stirred for 30 min and obtained solid was sepa-
rated by filtration to afford title compound 7a after drying (21.8 g,
3.4. General procedure for oxidation of 7a-c with DMSO-Py.SO
3
To a solution of 7a (0.5 g, 0.9 mmol) in CH
2
Cl
2
(5.0 mL) was
ꢁ
added N, N-diisopropylamine (1.09 mL, 6.0 mmol) at 0e5 C under
nitrogen atmosphere. The solution of pyridine sulphur trioxide
(0.57 g, 3.0 mmol) in DMSO (1.5 mL) was slowly added to the re-
ꢁ
ꢀ1
9
2
8.0%); White solid; M.P 74.4 C; IR (cm ): 3355, 3196, 3063, 3030,
880, 1454, 1399, 1391, 1113, 1093, 1064, 920, 734, 695. H NMR
1
ꢁ
(
400 MHz, DMSO-d
6
):
d
11.13 (s, 1H, NOH), 7.38 (d, J ¼ 7.8 Hz, 1H),
action mass at 0e5 C and stirred for 60e90 min at the same
7
1
1
.15e7.4 (m, 20H, ArH), 5.02 (d, J ¼ 6.3 Hz, 1H), 4.72 (d, J ¼ 10.8 Hz,
temperature. After completion of reaction (monitored by TLC), re-
action mixture was concentrated under vacuum. Water (50 mL)
was added to the residue and extracted with MTBE (2 ꢃ 50 mL).
Combined organic layer was washed with 1N HCl followed by brine
solution and concentrated under vacuum to afford crude ketonitrile
which was purified by flash chromatography to yield 8a (0.22 g,
H), 4.42e4.62 (m, 8H), 4.30 (t, J ¼ 7.8, 1H), 3.99 (dd, J ¼ 2.4, 7.8 Hz,
13
H), 3.82 (m, 1H), 3.52e3.66 (m, 3H); C NMR (100 MHz, DMSO-
): 147.7, 138.7, 138.4, 138.0, 128.2, 128.09, 128.07, 127.8, 127.7,
d
6
d
1
7
5
27.6, 127.40, 127.38, 127.33, 79.4, 78.7, 77.5, 74.3, 72.9, 72.3, 71.6,
þ
[MþH]þ
0.1, 69.3. HRMS (ESI ) m/z calculated for C34
H38NO
6
ꢀ
1
56.2699, found 556.2679.
45.0% yield); Colorless liquid; IR (film) cm : 3030, 2925, 1735,
1
1
455, 1217, 1091, 698 (No sharp peak for nitrile observed) [26]; H
NMR (400 MHz, CDCl ):
7.17e7.37 (m, 20 ArH), 4.78 (d, J ¼ 11.2 Hz,
H, PhCH ), 4.54 (d, J ¼ 9.8 Hz, 1H,
), 4.61 (d, J ¼ 11.2 Hz, 2H, PhCH
PhCH
), 4.49e4.52 (m, 3H), 4.39 (d, J ¼ 3.4 Hz, 1H), 4.37 (d,
J ¼ 4.0 Hz, 1H), 4.36 (d, J ¼ 3.4 Hz, 1H), 4.1e4.23 (m, 3H); C NMR
100 MHz, CDCl ): 206.8, 137.0, 136.6, 136.2, 135.2, 128.7, 128.6,
28.57, 128.48, 128.3, 127.95, 127.93, 116.3, 82.1, 79.0, 77.3, 77.0, 76.7,
3
d
3.2.2. (2R,3R,4R,5S)-2-hydroxy-6-(hydroxyimino)hexane-1,3,4,5-
1
2
2
tetrayl tetrakis(2,2-dimethylpropanoate) (7b)
Prepared using the similar procedure as described above and
crude compound was purified by silica gel chromatography
2
13
(
3
1
(
Yield ¼ 57.0%); White solid; H NMR (400 MHz, CDCl
3
, E isomer
7.62 (d, J ¼ 11.8 Hz, 1H,
O), 7.35 (d, J ¼ 5.8 Hz, 1H), 5.48e5.65
1
7
C
with mixture of rotamers ratio (57:43)):
NOH, exchangeable with D
d
þ
5.1, 74.8, 74.4, 73.3, 73.1, 68.3; HRMS (ESI ) m/z calculated for
H34NO
34 5
2
[MþH]þ 536.2437, found 536.2427.
(
1
2
m, 2H), 5.13 & 5.35 (dd, J ¼ 2.4, 8.8 Hz, 1H), 4.13 & 4.73 (dd, J ¼ 2.4,
2.2 Hz, 1H), 3.69e4.0 (m, 1H), 3.4 & 3.64 (dd, J ¼ 2.9, 13.2 Hz, 1H),
2 5
3.5. General procedure for DMSO/P O oxidation of 7a-c
1
3
.64 & 3.14 (m,1H, exchangeable with D
2
O),1.18e1.28 (m, 36H);
C
NMR (100 MHz, CDCl
3
): 178.6, 178.5, 178.4, 177.2, 176.9, 145.6,
d
Phosphorous pentoxide (0.8 g, 5.64 mmol) was added in three
lots to dry DMSO (2.5 mL) at 18e22 C under nitrogen atmosphere
145.4, 70.3, 70.2, 69.6, 69.5, 69.0, 68.5, 68.3, 64.4, 59.9, 39.2, 39.15,
ꢁ
3
8.98, 38.95, 38.86, 27.2, 27.12, 27.07, 27.05, 27.04, 26.95; HRMS
and stirred for 20 min. A solution of 7b (0.5 g, 0.94 mmol) in DMSO
þ
46NO10 [MþH]þ 532.3122, found
(
ESI ) m/z calculated for C26
H
ꢁ
(
2.0 mL) was added to the reaction mixture at 25e30 C and stirring
5
32.3109.
was maintained until TLC showed no unreacted starting material
left out. Reaction mixture was quenched with ice water (50 mL) and
extracted with MTBE (2 ꢃ 50 mL). Combined organic layers were
washed with brine solution and concentrated under vacuum to get
crude product which was purified by column chromatography to
3.2.3. (1R,2S)-1-((4R,5R)-5-hydroxy-2-phenyl-1,3-dioxan-4-yl)-3-
(
hydroxyimino)propane-2-diyl diacetate (7c)
Prepared using the similar procedure as described above and
ꢀ1
yield 8b (0.19 g, 40.0%); Solid; IR (film) cm : 2979, 1744, 1483,
crude compound was purified by silica gel chromatography
1
1
1123, 1034; H NMR (400 MHz, CDCl
3
): d 5.66e5.72 (m, 2H), 5.6 (d,
(
Yield ¼ 62.0%); H NMR (400 MHz, CDCl
3
,E/Z 3:1): d 8.44 (s, 0.25H,
J ¼ 2.9 Hz,1H), 4.69 (dd, J ¼ 17.1, 9.3 Hz, 2H), 1.33 (s, 9H), 1.25 (s, 9H),
NOH), 8.13 (s, 0.75H, NOH), 7.46 (m, 2H, AreH), 7.35 (m, 3H,
13
1
1
2
[
3
.22 (s, 9H), 1.21 (s, 9H); C NMR (100 MHz, CDCl ): 196.8, 177.3.
AreH þ 0.75He C ), 6.74 (d, J ¼ 5.9 Hz, 0.25HeC1), 6.32 (t,
1
77.1,176.5,175.7,113.9, 73.4, 68.1, 66.3, 59.1, 39.0, 38.92, 38.88, 38.7,
J ¼ 5.9 Hz, 0.25HeC2), 5.81 (dd, J ¼ 5.3, 5.9 Hz, 0.75HeC2), 5.63 (dd,
J ¼ 1.5 & 5.9 Hz, 0.25HeC4), 5.5 (dd, J ¼ 1.9 & 7.8 Hz, 0.75HeC4), 5.4
þ
7.1, 26.95, 26.87, 26.8. HRMS (ESI ) m/z calculated for C26
H42NO
9
þ
MþH] 512.2860, found 512.2853.
(
3
s, 0.25HeC7), 5.39 (s, 0.75HeC7), 4.28 (dd, J ¼ 4.8, 13.7 Hz, 1H, 6a),
.79 (m, 1H, 6b), 3.61 (t, J ¼ 10.2 Hz, 1HeC5), 3.55 (m, 1HeC3), 3.2
13
3.6. General procedure for synthesis of tetrabenzyl DNJ (12)
(
(
1
m, 1H, OH), 2.19 (s, 3H), 1.99 (s, 2H), 1.87 (s, 1H); C NMR
100 MHz, CDCl ): E-isomer: 172.2, 169.9, 145.8,136.9, 129.0, 128.2,
26.2, 126.0, 101.0, 80.0, 70.2, 69.4, 66.4, 60.9, 20.7, 20.6; Z-isomer:
3
d
To a solution of ketonitrile 8a (1.0 g, 1.9 mmol) in MeOH (20 mL)
was added Raney Nickel (0.5 g, wet) and the mixture was hydro-
genated at 150e170 psi hydrogen pressure at ambient temperature
for 24 h. The suspension was filtered through celite and washed
with methanol. The filtrate was concentrated under vacuum to
afford crude tetrabenzyl DNJ (12) and its C5 epimer (13) in 4:6 ratio
and 95% yield. Both isomers were separated by column chroma-
tography to afford 12 (0.29 g, 30%) and its C5 epimer 13 (0.39 g,
1
72.4, 170.0, 146.5, 137.1, 101.3, 80.6, 70.5, 69.1, 61.1, 20.5; HRMS
þ
[MþH]þ 368.1345, found
(
ESI ) m/z calculated for C17H22NO
8
3
68.1355.
3.3. General procedure for oxidation of 7a-c with DMSO/Oxalyl
chloride
40%).
To a solution of freshly distilled oxalyl chloride (9.26 mL,
Compound 12: Colorless liquid; 1H NMR (400 MHz, CDCl
3
):
0
.1029 mol) in dry CH
2
Cl
2
(130.0 mL) was added dry DMSO
d
7.18e7.37 (m, 20H, AreH), 4.9 (d, J ¼ 11.3 Hz, 1H), 4.8 (t,
ꢁ
(
14.6 mL, 0.205 mol) under nitrogen atmosphere at e65 to e70 C
J ¼ 10.3 Hz, 2H), 4.64 (dd, J ¼ 4.9 & 11.8 Hz, 2H), 4.4 (m, 3H), 3.65
(dd, J ¼ 2.5 & 6.3 Hz, 1H), 3.3e3.57 (m, 3H), 3.22 (dd, J ¼ 4.7, 12.2 Hz,
2H), 2.7 (ddd, J ¼ 2.9, 6.3, 9.2 Hz, 1H), 2.47 (dd, J ¼ 10.3, 12.2 Hz, 1H);
and stirred for 30 min. Solution of 7a (13.0 g, 0.023 mol) in CH
65.0 mL) was added over 30e45 min and stirred for 45 min at
same temperature. Triethylamine (42.4 mL, 0.30 mol) was added
2 2
Cl
(
13
3
C NMR (100 MHz, CDCl ): d 138.8, 138.4, 138.3, 137.9, 128.35,
ꢁ
ꢁ
drop wise over 30e40 min at ꢀ65 C to ꢀ70 C. The turbid mixture
128.32, 128.30, 127.96, 127.89, 127.81, 127.7, 127.6, 127.5, 87.3, 80.5,
80.0, 75.6, 75.1, 73.3, 72.7, 70.2, 59.7, 48.0. HRMS (CI) calcd for
C
ꢁ
was slowly warmed to 0 C and diluted with water (130 mL).
þ
Organic layer was separated and distilled under vacuum to get
crude compound which was purified by column chromatography to
afford 8a (6.5 g, 52% yield) as yellow to colorless oil.
34
H
38NO
4
(MþH) 524.2801, found 524.2794.
Compound 13 (C5 epimer of tetrabenzylated DNJ):
H NMR (400 MHz, CDCl ) d 7.2e7.36 (m, 20H, AreH), 4.51e4.64
3
1

S.R. Khobare et al. / Carbohydrate Research 435 (2016) 1e6
5
(
m, 8H, 4 ꢃ CH
2
, Bn), 3.54e3.71 (m, 4H), 3.39e3.48 (m, 2H), 3.0 (dd,
Acknowledgments
J ¼ 3.9, 13.2 Hz, 1H), 2.9 (m, 1H).
The authors would like to thank analytical department, Dr.
Reddy's Laboratories Ltd. for providing the analytical support.
3.7. General procedure for synthesis of DNJ (1b)
(IPDO-DRL IPM No.:00433)
A solution of 8a (2.0 g, 3.73 mmol) in MeOH: t-BuOH (4:1)
(
4
40 mL) was treated with Pd(OH)
00 mg) and the mixture was hydrogenated at ambient tempera-
2
(20 wt % Pd, dry basis on carbon,
Appendix A. Supplementary data
ture for 6e8 h at 150e170 psi hydrogen pressure. The suspension
was filtered through celite, washed with methanol and the filtrate
was concentrated under vacuum. Methanolic HCl was added to the
residue, stirred for 30 min and concentrated under vacuum and
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.carres.2016.09.003.
References
again hydrogenated for 48e72 h at 90e100 psi using Pd(OH)
2
/C
(
20 wt % Pd dry basis on carbon, 400 mg) and methanol (40 mL).
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D
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1
1
cm : 3349, 2894, 2699, 1408, 1373, 1105, 992, 838, 625; H NMR
(
(
b) J.L. Dunne, P.V. Murphy, Curr. Org. Synth. 3 (2006) 403;
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(
400 MHz D
2
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d
3.82 (dd, J ¼ 1.9 Hz,1.8 Hz,1H-6a), 3.61 (dd, J ¼ 6.2,
1
3
1.6 Hz,1H-6b), 3.46 (dt, J ¼ 5.2, 9.8 Hz,1H-2), 3.3 (t, J ¼ 9.0 Hz,1H-3),
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13
J ¼ 3.0, 6.4, 9.3 Hz,1H-5), 2.44 (dd, J ¼ 10.8,12.2 Hz,1H-1b); C NMR
þ
(
100 MHz, D
2
O):
d
81.1, 74.3, 73.7, 64.1, 63.3, 51.4, HRMS (ESI ) m/z
calculated for C
6
H
14NO
4
[MþH]þ 164.0923, found 164.0918.
12550.
3.8. Procedure for synthesis of miglitol (2)
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(
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bonate (0.34 g, 2.4 mmol) in DMF (1.0 mL) was added bromoe-
ꢁ
thanol (0.30 g, 2.4 mmol) and stirred at 90e100 C for 4e5 h. After
(
completion of the reaction, reaction mass pH was adjusted to acidic
pH ~5) using acetic acid. Reaction mass was next passed through
(
8
(
acidic resin and subsequently treated with 1e5% aqueous ammonia
solution. Aqueous ammonical solution was concentrated
completely to get crude miglitol (2) which was re-crystallized using
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[
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2
0
ꢁ
ꢁ
White solid; ½
a
ꢂ
: ꢀ7.95 (c 0.56, H
2
O); M.P. ¼ 145.17 C. IR (thin
D
ꢀ
1
1
film) cm : 3365, 3280, 2922, 1545, 1429, 1304, 1075, 1033; H NMR
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(
1
1
400 MHz, D
2
O):
d
3.9 (dd, J ¼ 2.5,13.5 Hz, 1H), 3.79 (dd, J ¼ 3.4,
(
(
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J ¼ 6.8, 14.2 Hz, 1H), 2.68 (dt, J ¼ 6.8, 14.2 Hz, 1H), 2.29 (m, 2H);
C
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8
H18NO
5
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3
.9. Procedure for synthesis of miglustat (3)
(
To a suspension of 1b (0.1 g, 0.61 mmol) and potassium car-
1
(
bonate (0.34 g, 2.4 mmol) in DMF (1.0 mL) was added 1-bromo-
butane (0.2 g, 2.4 mmol) and stirred at 80e90 C for 24 h. Reaction
mass pH was adjusted to acidic side with acetic acid and subse-
quently passed through acidic resin followed by treatment with
1
concentrated completely to get miglustat (3) (0.108 g, 76%);
NMR (400 MHz, D O):
9
ꢁ
J. Wiltenburg, M. Wolberg, J. Aerts, H. Overkleeft, Org. Process Res. Dev. 12
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H
2
d
3.95 (d, J ¼ 2.2 Hz, 2H), 3.64 (dd, J ¼ 3.8,
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m, 2H), 0.91 (t, J ¼ 7.3 Hz, 3H); C NMR (100 MHz, D
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4
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[
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