New access to 1-deoxynojirimycin derivatives via azide-alkene cycloaddition

Article abstract of DOI:10.1021/ol8014495

(Chemical Equation Presented) The synthesis of 1-deoxynojirimycin (DNJ) derivatives is described from D-glucono-δ-lactone. The DNJ derivatives were obtained via a sequence that included a stereoselective intramolecular Huisgen reaction, decomposition to an aziridine, and its subsequent reaction with a nucleophile. Minimization of allylic strain in the transition state accounts for the stereoselectivity of the cycloaddition reaction.

Full text of DOI:10.1021/ol8014495

ORGANIC
LETTERS
2008
Vol. 10, No. 17
3777-3780
New Access to 1-Deoxynojirimycin
Derivatives via Azide-Alkene
Cycloaddition
Ying Zhou and Paul V. Murphy*
UCD School of Chemistry and Chemical Biology and Centre for Synthesis and
Chemical Biology, UniVersity College Dublin, Belfield, Dublin 4, Ireland
paul.V.murphy@ucd.ie
Received June 26, 2008
ABSTRACT
The synthesis of 1-deoxynojirimycin (DNJ) derivatives is described from D-glucono-δ-lactone. The DNJ derivatives were obtained via a sequence
that included a stereoselective intramolecular Huisgen reaction, decomposition to an aziridine, and its subsequent reaction with a nucleophile.
Minimization of allylic strain in the transition state accounts for the stereoselectivity of the cycloaddition reaction.
1-Deoxynojirimycin (DNJ, 1) is a naturally occurring inhibi-
tor of glucosidases.1 Its derivatives have found clinical
application and have potential in the therapy of HIV and
hepatitis C infection.2 DNJ derivatives also inhibit gluco-
sylceramide,3 and the glycosidase inhibitor 3 is a bifunctional
inhibitor of angiogenesis in vitro.4 Moreover, DNJ has
potential as a scaffold in peptidomimetic research.5 In this
regard, a novel ligand for somatostatin receptors was obtained
when Lys and Trp side chains were grafted to DNJ to give
2.6 Thus, novel synthetic strategies to DNJ7 provide access
to novel inhibitors of glycoprocessing and peptidomimetics.
Herein, we describe a novel approach to DNJ derivatives
from D-glucono-δ-lactone.
(1) (a) Lillelund, V. H.; Jensen, H. H.; Liang, X.; Bols, M. Chem. ReV.
2002, 102, 515–553. (b) Asano, N.; Nash, R. J.; Molyneaux, R. J.; Fleet,
G. W. J. Tetrahedron: Asymmetry 2000, 11, 1645–80. (c) Greimel, P.;
Spreitz, J.; Stutz, A. E.; Wrodnigg, T. M. Curr. Top. Med. Chem. 2003, 3,
513–523.
(5) (a) Le Merrer, Y.; Poitout, L.; Depezay, J.-C.; Dosbaa, I.; Geoffroy,
S.; Foglietti, M.-J. Bioorg. Med. Chem. Lett. 1997, 6, 1667. (b) Chery, F.;
Cronin, L.; O′ Brien, J. L.; Murphy, P. V. Tetrahedron 2004, 60, 6597. (c)
Tsukida, T.; Moriyama, H.; Inoue, Y.; Kondo, H.; Yoshino, K.; Nishimura,
S. Bioorg. Med. Chem. Lett. 2004, 14, 1569–72. (d) Timmer, M. S. M.;
Verhelst, S. H. L.; Grotenbreg, G. M.; Overhand, M.; Overkleeft, H. S.
Pure Appl. Chem. 2005, 77, 1173–81. (e) Gouin, S. G.; Murphy, P. V. J.
Org. Chem. 2005, 70, 8527–32. (f) Chery, F.; Murphy, P. V. Tetrahedron
Lett. 2004, 45, 2067–69.
(2) (a) Hughes, A. B.; Rudge, A. J. Nat. Prod. Rep. 1994, 135. (b)
Winchester, B.; Fleet, G. W. J. Glycobiology 1992, 2, 199.
(3) Wennekes, T.; Van den Berg, R. J. B. H. N.; Donker, W.; van der
Marel, G. A.; Strijland, A.; Aerts, J. M. F. G.; Overkleeft, H. S. J. Org.
Chem. 2007, 72, 1088–1097.
(4) (a) Zhou, Y.; Zhao, Y.; O’Boyle, K. M.; Murphy, P. V. Bioorg.
Med. Chem. Lett. 2008, 18, 954–8. (b) Zhou, Y.; Zhao, Y.; O’Boyle, K. M.;
Murphy, P. V. Bioorg. Med. Chem. 2008, 16, 6333–7.
(6) Chagnault, V.; Lalot, J.; Murphy, P. V. ChemMedChem 2008, 3,
1071–6.
10.1021/ol8014495 CCC: $40.75
Published on Web 08/02/2008
2008 American Chemical Society

workers.9 Regioselective mesylation of the primary hydroxyl
group of 8, followed by exchange of the mesyl group for an
azide, benzylation, and the subsequent regioselective acetal
cleavage, gave 9. Oxidative cleavage of 9 using NaIO4 gave
aldehyde 10, which overall was obtained in 49% yield from
7. The alkene 11 was prepared from aldehyde 10 by a Wittig
reaction (67%) using the reagent obtained after treatment of
methyl triphenylphosphonium iodide with base.
The thermally promoted intramolecular cycloaddition10 of
organic azide11 11 was investigated next. The heating of 11
at reflux in toluene gave, in a stereoselective manner, the
stable 1,2,3-triazoline 12 (Scheme 3). Although the complete
Figure 1. Structures of 1-3.
Scheme 3
The retrosynthetic analysis of DNJ derivatives 4 from
D-glucono-δ-lactone 7 is shown in Scheme 1. We envisaged
Scheme 1. Retrosynthetic Analysis
that 6 could be prepared from 7 and that intramolecular
Huisgen 1,3-dipolar cycloaddition8 and subsequent loss of
nitrogen would provide access to the aziridine 5. Subsequent
reaction of 5 with nucleophiles would provide access to 4.
The synthesis (Scheme 2) began from 8, which was
prepared from 7 as described previously by Fleet and co-
conversion of 11 was observed by TLC, the isolated yield
of 12 was 50-60% from a number of experiments. The
stereoselectivity observed in this reaction can be rationalized
by comparing the relative energy of two transition states 11A
and 11B depicted in Scheme 3. Hence, allylic strain
destabilizes conformer 11B compared with 11A and progres-
sion of the reaction through 11A gives 12 with an identical
configuration to DNJ. A fraction containing the aziridine 13
was obtained after treatment of 12 with silica gel, suggesting
Scheme 2
(7) For selected recent syntheses of DNJ, see: (a) Afarinkia, K.; Bahar,
A. Tetrahedron: Asymmetry 2005, 16, 1239–1287. (b) Yokoyama, H.;
Kobayashi, H.; Miyazawa, M.; Yamaguchi, S.; Hirai, Y. Heterocycles 2007,
74, 283–292. (c) Roy, A.; Achari, B.; Mandal, S. B. Synthesis 2006, 6,
1035–1039. Kim, I. S.; Lee, H. Y.; Jung, Y. H. Heterocycles 2007, 71,
1787–1800. (d) Danieli, E.; Lalot, J.; Murphy, P. V. Tetrahedron 2007,
63, 6827–34. (e) Boucheron, C.; Compain, P.; Martin, O. R. Tetrahedron
Lett. 2006, 47, 3081–4. (f) McDonnell, C.; Cronin, L.; O’Brien, J. L.;
Murphy, P. V. J. Org. Chem. 2004, 69, 3565–8.
(8) Huisgen, R. J. Org. Chem. 1968, 33, 2291.
(9) Long, D. D.; Smith, M. D.; Martin, A.; Wheatley, J. R.; Watkin,
D. G.; Mu¨ller, M.; Fleet, G. W. J. J. Chem. Soc., Perkin Trans. 1 2002,
1982.
(10) For reviews on intramolecular 1,3-dipolar cycloaddition in targeted
synthesis, see: (a) Nair, V.; Suja, T. D. Tetrahedron 2007, 63, 12247–75.
(b) Padwa, A. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed;
Wiley-Interscience: New York, 1984; Vol. 2, p 316.
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Org. Lett., Vol. 10, No. 17, 2008

that the acidic nature of the gel promoted loss of nitrogen.
The isolation of 1312 was supported by mass spectrometry.13
The fraction containing the aziridine 13 was treated with
hydrogen in the presence of 10% Pd-C in ethyl acetate as
solvent and this gave an inseparable mixture of DNJ
derivatives 14 and 15 (78%). The formation of 14 was
expected from this reduction reaction whereas the formation
of 15 is explained by hydrolysis of 13 in the presence of
adventitious water. These results support the proposal that
13 is formed from 12.14
methylene carbon atom of 20 and acid-catalyzed hydrolysis
of the acetal. It would appear that the acetal group is more
stable in the azepane 16 when compared with the piperidine
15. When this reaction was carried out at higher temperature
(70 °C) a complex mixture was obtained.
The one-pot conversion of 11 with a variety of nucleo-
philes was next investigated, and the results are summarized
in Table 1.
The possibility to carry out a one-pot conversion of 11 to
DNJ derivatives was next investigated.The decomposition
of the triazoline 12 and subsequent reactions of the resulting
aziridine 13 were expected to be promoted in acidic
conditions.The reaction of 11 in aqueous acetic acid over-
night at room temperature gave a mixture of 13 (15%),
azepane 16 (33%), and DNJ derivative 17 (14%) (Scheme
4). That azepane15 16 is obtained as the major product from
Table 1. One-Pot Conversion of 11 to DNJ Derivatives
entry
1
reagents and conditions
product (yield, %)
NaN3 (5.0 equiv), AcOH
(1.5 equiv), toluene, 110 °C
MeOH, 60 °C, 1 ha
21 (R ) N3, 35%)
Scheme 4
2
3
4
22 (R ) OMe, 20%),
13 (31%)
23 (R ) OAc, 45%)
AcOH (5.0 equiv), toluene,
110 °C, 1 h
PhSH, 15 ha
24 (R ) SPh, 57%)
a Toluene removed before addition of reagents.
Accordingly, 11 was first heated to reflux in toluene for
1 h, and then reagents (entries 1 and 3) were added and
heating continued. Reaction of 11 with sodium azide and
acetic acid in toluene by this protocol gave 21 (35%),
whereas reaction with acetic acid in toluene gave 23 (45%).
Interestingly, only the piperidines, and not azepane products,
were isolated under these conditions, contrasting with the
behavior shown in Scheme 4. This may be due to the use of
the nonpolar solvent which would favor an SN2 pathway and
reaction of the nucleophile at the least hindered carbon,
disfavoring the formation of 19. An alternative explanation
is that the reaction is under steric control and that C-N bond
breaking in 20 has not occurred to a great extent when the
transition state is reached under these conditions, favoring
nucleophilic attack at the least hindered carbon of the
aziridine 20.
The second protocol involved the initial formation of the
triazoline 12 in toluene, evaporation of the toluene and
subsequent addition of the nucleophile. Thus, conversion of
11 to 22 (20%) and 24 (57%) was achieved by this procedure
using methanol and thiophenol as nucleophiles, respectively.
For the reaction with methanol the aziridine 13 was also
isolated (31%).
this reaction where water is the nucleophile suggests that
carbocation 19 is generated under these conditions.16 An
alternative explanation is that the reaction is under electronic
control and C-N bond breaking in 20 is more complete when
the transition state (of its reaction with water) is reached
under these conditions, favoring azepane formation. The
formation of 17 is explained by the reaction of water at the
(11) For a review on applications of organic azides including alkene-azide
cycloadditions, see: Bra¨se, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew.
Chem., Int. Ed. 2005, 44, 5188–240.
(12) Kim, S.; Lee, Y. M.; Lee, J.; Lee, T.; Fu, Y.; Song, Y.; Cho, J.;
Kim, D. J. Org. Chem. 2007, 72, 4886–91.
(13) We could not obtain satisfactory NMR data as the aziridine 13
decomposed in standard deuterated solvents.
(14) Decomposition of 1,2,3-triazolines to aziridines and imines is
known. For a recent example, see: Kim, S.; Lee, Y. M.; Lee, J.; Lee, T.;
Fu, Y.; Song, Y.; Cho, J.; Kim, D. J. Org. Chem. 2007, 72, 4886–91.
(15) Le Merrer, Y.; Poitout, L.; Depezay, J.-C.; Dosbaa, I.; Geoffroy,
S.; Foglietti, M.-J. Bioorg, Med. Chem. 1997, 5, 519–33.
(16) For an example of Markovnikov addition of water to an aziridine
and proposal of a carbocation intermediate, see: Hanaoka, M.; Kim, S.;
Inoue, M.; Nagami, K.; Shimada, Y.; Yasuda, S. Chem. Pharm. Bull. 1985,
33, 1434–43.
In summary, the synthesis of a range of novel DNJ
derivatives has been achieved from D-glucono-δ-lactone. The
sequence has included a Huisgen cycloaddition reaction of
alkene and azide in a key step. The resulting triazoline can
be promoted to give an aziridine, which can be converted to
DNJ derivatives in the presence of nucleophiles and DNJ
Org. Lett., Vol. 10, No. 17, 2008
3779

itself can also be obtained by debenzylation of 17. Although
the yields from the one pot reactions are modest, 11 can,
after removal of protecting groups, provide entry to a variety
of DNJ derivatives for biological evaluation. Also the DNJ
derivatives obtained have potential to be further exploited.For
instance, “click chemistry”17 of 21 will be possible, and 24
or a protected derivative could be oxidized to a sulfone and
used to generate alkenes by Julia olefination.18 The approach
described herein will lend itself strategies to give novel
compounds of interest to medicinal chemists.
Acknowledgment. We are grateful to the School’s NMR
and MS Centres. The research was funded by Science
Foundation Ireland (PI/IN1/B966, 03/IBN/B352).
Supporting Information Available: Experimental pro-
cedures; 1H and 13C NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL8014495
(18) (a) Julia, M.; Paris, J. M. Tetrahedron Lett. 1973, 4833. (b)
Dumeunier, R.; Marko, I. E. In Modern Carbonyl Olefination; Takeda, T.,
Ed.; Wiley-VCH: Germany, 2004; p 104-150.
(17) Van der Eycken, E.; Sharpless, K. B. QSAR Comb. Sci 2007, 26,
1115.
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