A highly expeditious synthesis of a bicyclic iminosugar using the novel key step of [NMM]+[HSO4]- promoted conjugate addition and Mitsunobu reaction

Article abstract of DOI:10.1039/c3ra23467c

A simple and highly facile protocol has been developed for the stereoselective synthesis of 1-deoxy-norcastanospermine from readily available d-glucose. N-Methylmorpholinium hydrogen sulphate was seen for the first time as a suitable catalyst for the faci

Full text of DOI:10.1039/c3ra23467c

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A highly expeditious synthesis of a bicyclic iminosugar
using the novel key step of [NMM]+[HSO4]2 promoted
conjugate addition and Mitsunobu reaction3
Cite this: RSC Advances, 2013, 3, 5794
Received 25th December 2012,
Accepted 28th January 2013
Virendra Prasad, Dhananjay Kumar and Vinod K. Tiwari*
DOI: 10.1039/c3ra23467c
www.rsc.org/advances
A simple and highly facile protocol has been developed for the
stereoselective synthesis of 1-deoxy-norcastanospermine from
readily available D-glucose. N-Methylmorpholinium hydrogen
sulphate was seen for the first time as a suitable catalyst for the
facile conjugate addition of an amine to a glycosyl olefinic ester.
Furthermore, the key step of this strategy is the internal reductive
amination of glycosyl azetidine, obtained from glycosyl b-amino
alcohol under Mitsunobu reaction conditions.
the construction of these molecules for the study of their
biological activities against various diseases. Although tremendous
efforts have been directed towards the development of synthetic
routes for iminosugars,12 these deceptively simple looking
molecules are not easy to synthesize, mainly due to the difficulty
associated with the introduction of an aminomethyl group next to
a stereocenter of suitably substituted carbohydrate molecules.
Thus, the development of a general synthetic strategy for these
iminosugars has remained sparse. Herein we report a highly
convergent stereoselective synthetic route for a novel bicyclic
iminosugar analogue from D-glucose.
During the course of our synthesis, we envisaged 2-(3-O-benzyl-
1,2-O-isopropylidene-b-L-ido-furanose)-1-benzyl azetidine 7 as a
suitable scaffold for the stereoselective synthesis of target bicyclic
iminosugar 1-deoxy-norcastanospermine (Scheme 1). Glycosyl
azetidine 7 can be hydrogenated to give the target molecule 8.
The required compound 7 can in turn be synthesized by the 1,2-
isopropylidene deprotection of 6, which may be achieved from the
corresponding amino alcohol, 5, prepared from cheap and readily
available D-glucose (Scheme 2).
Iminosugars, where the ring oxygen is replaced by nitrogen, form
undoubtedly the most fascinating and attractive class of
carbohydrate mimics known so far.1 In recent years, bicyclic
iminosugar ring skeletons, present in numerous alkaloids as
important structural subunits, have aroused a burgeoning interest
in the area of glycobiology.1–3 Due to the well-known glucosidase2
and the inhibitory activity of glycosyltransferase,3 these molecules
offer both new tools for studying the biological functions of
oligosaccharides and a new generation of emerging carbohydrate-
based therapeutics for the control of a wide range of diseases,
including diabetes,4 HIV,5 hepatitis,6 cancer,5–7 Gaucher’s disease8
and viral infections.9 The unravelling of the potential of
nojirimycin and deoxynojirimycin as strong a and b-glucosidase
inhibitors triggered an intensive research impetus dealing with the
synthesis and evaluation of their potential to inhibit enzyme
systems, which revealed castanospermine and swainsonine as
potent inhibitors of glucosidase enzymes and golgi a-mannosidase
II, respectively, and culminated in the approval of miglustat and
miglitol for the treatment of, respectively, type-1 Gaucher’s disease
and type-2 diabetes mellitus (Fig. 1).10
Our synthetic strategy commenced with glycosyl olefinic ester
(1R,2R,3S,4R)-ethyl-(3-O-benzyl-1,2-O-isopropylidine-1,4-pentofura-
nose-4-yl)-hept-5-enoate, 3, prepared from readily available D-
glucose.13,14 The 1,4-conjugate addition of benzyl amine to 3 led to
Since iminosugars equipped with hydrophobic substituents are
known for their increased enzyme inhibition and enhanced
bioavailability,11 the routes available for the ready installation of
hydrophobic moieties are of high value. The paucity of natural
materials has made total synthesis the only available avenue for
Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi-
221005, India. E-mail: tiwari_chem@yahoo.co.in; vtiwari@ucdavis.edu;
Fax: 91-542-2368174; Tel: 91-542-6702466
Electronic supplementary information (ESI) available: 1H and 13C NMR spectra of
3
Fig. 1 Bioactive iminosugars.
all new compounds. See DOI: 10.1039/c3ra23467c
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Table 1 Optimization of the 1,4-conjugate addition of benzyl amine to glycosyl
olefinic ester 3
Yieldb Diastereomer ratio
Entry Catalyst used
Timea (%)
(major/minor)c
Scheme 1 Retrosynthetic analysis of 1-deoxy-norcastanospermine.
1
2
3
4
5
6
7
8
9
—
40 h
12 h
20 h
20 h
30 h
18 h
85
90
85
85
70
91
85
78 : 22
75 : 25
74 : 26
77 : 23
76 : 24
80 : 20
77 : 23
80 : 20
80 : 20
InCl3 (5 mmol%)
DBU
DABCO
Starch
Y(NO3)3?6H2O
(1R,2R,3S,4R)-ethyl-(3-O-benzyl-5-benzylamino-5,6-dideoxy-1,2-
O-isopropylidene)-a-D-gluco- and b-L-ido-heptofuranuronate (4a
and 4b) as a diastereomeric mixture in good yield. A variety of
promising catalysts such as InCl3, 1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), starch,
Y(NO3)3?6H2O15 and ionic liquids16 were screened to identify a
suitable activator for a high diastereoselective addition with a
reduced reaction span (Table 1). Unfortunately, InCl3, DBU,
DABCO, starch and Y(NO3)3?6H2O failed to bring a significant
improvement to the diastereoselectivity of the conjugate addition
as well as to shorten the reaction time. However, the conjugate
addition carried out in the presence of an ionic liquid, e.g. N-
methylmorpholinium hydrogen sulphate, [NMM]+[HSO4]2, and
N-methylmorpholinium methyl sulphonate, [NMM]+[CH3SO3]2, is
notable as the reaction time is now reduced to 15–20 min. The
predominant diastereoselectivity observed in this addition was
merely because of the alkene–arene p stacking effect as previously
elaborated on the basis of the Felkin–Anh like transition state
model.13 The configuration at the newly formed stereogenic centre
C-5 in compound 4 was determined after the lithium aluminium
hydride reduction of the individual major/minor isomers to the
corresponding alcohols, where J = 8.7 Hz (threo-) was calculated for
alcohols reduced from major isomers, while J = 5.7 Hz (erythro-)
from minor isomers and thus the relative configurations were
assigned as ‘S’ and ‘R’ for the major (4a) and minor isomers (4b),
respectively.14e The reduction of glycosyl b-amino ester 4a with
Y(NO3)3?6H2O, solvent free 25 h
[NMM]+[CH3SO3]2
[NMM]+[HSO4]2
20 min 95
15 min 95
a
b
c
Time required. Isolated yield. Determined by 1HNMR.
LiAlH4 in anhydrous THF resulted in glycosyl b-amino alcohol 5a
in 96% quantitative yield.
Access to esters and their related compounds by the reaction of
alcohols and carboxylic acids through Mitsunobu reaction
conditions is well known. Following a similar chemistry, the
DEAD–PPh3 induced intramolecular cyclization of 5 was carried
out in anhydrous THF to afford 2-(3-O-benzyl-1,2-O-isopropylidene-
b-L-ido-furanose)-1-benzyl azetidine 6. Diethyl azodicarboxylate
(DEAD) is known to be toxic, shock sensitive and thermally
unstable, thus the exploration of another azo reagent such as
diisopropyl azodicarboxylate (DIAD) may be a more feasible
approach because it is less expensive, easy to handle and has
previously been proved to allow a wider range of nucleophiles.17
DIAD–PPh3 mediated intramolecular cyclization of compound
5a was very effective but required an excess amount of reagent to
afford the product in a significantly high yield. Developing a
strategy which could reduce the quantity of DIAD required in the
reaction would be of vital importance to expedite the overall
synthetic protocol for the scale-up synthesis. Employing diacetox-
yiodobenzene (DIB) to oxidize 1,2-dicarbisopropoxyhydrazine back
to DIAD during the intramolecular cyclization of 5a was studied, as
DIB has emerged as an efficient oxidant for metal free oxidations
in organic transformations.18 To test the feasibility of this strategy,
the intramolecular cyclization reaction of glycosyl b-amino alcohol
5a was performed under various conditions. The desired azetidine
6 was formed in good yield using the initial conditions of 0.2
equiv. of DIAD in combination with 1.5 equiv. of DIB and PPh3
each. Eventually, the optimal conditions were determined to be 1.0
equiv. of 5a and 1.2 and 1.5 equiv. of both DIB and PPh3,
respectively, after conducting a set of reactions (Table 2, entry 6).
Since the involved alcohol is of a primary nature, the inversion of
configuration under Mitsunobu reaction conditions using PPh3–
DIAD is feasible, hence intramolecular cyclization afforded
Scheme 2 Synthesis of 1-deoxy-norcastanospermine. Reaction conditions: (a)
benzyl amine, EtOH, [NMM]+[HSO4]2, rt., 15 min, 95% (ratio 80 : 20), major isomer
(4a) isolated in pure form using flash column chromatography; (b) LiAlH4, THF, rt., 3
h, 96%; (c) PPh3, DIAD, PhI(OAc)2, THF, rt., 10 h, 72%; (d) PPh3 and DIAD (each 1.5
equiv.), THF, rt., 12 h, 70% (e) TFA–H2O (3 : 2), rt., 12 h, 90%; (f) 10% Pd/C, H2, 80
psi, MeOH, 12 h, 60%.
glycosyl azetidine
deprotection of glycosyl azetidine 6 was carried out using TFA–
6 in good yield. The 1,2-isopropylidene
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Table 2 Cycle of catalytic intramolecular cyclization of glycosyl b-amino alcohol 5a
Entry
Amino alcohol (equiv.)
Ph3P (equiv.)
DEAD (equiv.)
DIAD (equiv.)
DIB
Yield (%)
1
2
3
4
5
6
1.0
1.0
1.0
1.0
1.0
1.0
1.2
1.5
1.5
1.2
1.5
1.2
1.2
1.5
0.1
—
—
—
—
—
—
1.2
1.5
0.2
—
—
2.0
—
—
68
70
72
70
73
72
1.5
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H2O (3 : 2) at room temperature and the diol 7 thus obtained was
subjected to debenzylation by treatment with 10% palladium on
charcoal under a hydrogen atmosphere in methanol. The resultant
product after removal of the benzyl groups was found to be
unstable and quickly slipped into intramolecular cyclization after
in situ formation to deliver the desired final bicyclic iminosugar
1-deoxy-norcastanospermine 8 in 60% yield (Scheme 2). All the
synthesized molecules, such as the glycosyl amino esters, glycosyl
b-amino alcohol, glycosyl azetidine and 1-deoxy-norcastanosper-
mine, were purified by flash column chromatography (SiO2) and
characterized by spectroscopic techniques (IR, 1H NMR, 13C NMR)
and elemental analysis.
In conclusion, a novel, simple and facile protocol has been
developed for the stereoselective synthesis of the bicyclic
iminosugar analogue 1-deoxy-norcastanospermine from readily
available D-glucose. The key step of our strategy is the internal
reductive amination of novel glycosyl azetidine, achieved from
glycosyl b-amino alcohol under Mitsunobu reaction conditions
with the aid of a modified reduction and recycling of DIAD
through a hypervalent iodine reagent. In addition, this method
reports other attractive features like the development of an ionic
liquid catalyzed and highly facile conjugate addition to reduce the
reaction time. This protocol may be useful to develop other
bicyclic iminosugars with potential chemotherapeutic properties.
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Acknowledgements
Authors thank CISC and BHU for providing the spectroscopic
and analytical data of the synthesized compounds, Prof. Dilip
D. Dhavle for his useful discussions and CSIR, India for the
funding.
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