General access to iminosugar C-glycoside building blocks by means of cross-metathesis: A gateway to glycoconjugate mimetics

Article abstract of DOI:10.1021/ol035117h

Cross-metathesis reactions of α-1-C-allyl-1-deoxynojirimycin derivatives 7a,b and various functionalized alkenes mediated by Grubbs's catalyst 3 are reported. The reactions showed reasonable to very good yields and excellent E/Z selectivity. This methodol

Full text of DOI:10.1021/ol035117h

ORGANIC
LETTERS
2003
Vol. 5, No. 18
3269-3272
General Access to Iminosugar
C-Glycoside Building Blocks by Means
of Cross-Metathesis: A Gateway to
Glycoconjugate Mimetics
Guillaume Godin, Philippe Compain,* and Olivier R. Martin*
Institut de Chimie Organique et Analytique, UMR-CNRS 6005, UniVersite´ d’Orle´ans,
rue de Chartres, BP 6759, 45067 Orle´ans Cedex 2, France
philippe.compain@uniV-orleans.fr; oliVier.martin@uniV-orleans.fr
Received June 18, 2003
ABSTRACT
Cross-metathesis reactions of r-1-C-allyl-1-deoxynojirimycin derivatives 7a,b and various functionalized alkenes mediated by Grubbs’s catalyst
3 are reported. The reactions showed reasonable to very good yields and excellent E/Z selectivity. This methodology allows the efficient and
convergent synthesis of iminosugar C-glycosides with a great degree of structural diversity in the aglycone, opening the way to a variety of
new glycoconjugate mimetics of biological interest.
Iminosugars form probably the most fascinating class of
carbohydrate mimetics reported so far. Historically, they are
best known for their role as powerful glycosidase inhibitors,1
but more recently, the scope of their biological activities has
been extended to the inhibition of various carbohydrate-
processing enzymes such as glycosyltransferases2 and nu-
cleoside phosphorylases.3 Since these enzymes are involved
in a number of fundamental biological processes, iminosugars
have recently entered the clinical field for assessment of their
therapeutic potential in a wide range of diseases,4 including
viral infection, tumor metastasis, and lysosomal storage
disorders. First successes are being recorded: N-butyl-1-
deoxynojirimycin has recently been approved by the EMEA
(European Agency for the Evaluation of Medicinal Products)
for the treatment of type 1 Gaucher disease, a severe
lysosomal disorder.5 New exciting applications are being
uncovered. For example, N-alkyliminosugars have been
found to reversibly induce infertility in male mice, opening
the way to a nonhormonal approach to male contraception.6
Considering the high potential of “azasugars” for drug
discovery, general and efficient approaches to stable deriva-
tives such as iminosugars C-glycosides are still needed to
facilitate the exploration of new biological targets and the
(1) Stu¨tz, A. E. Iminosugars as Glycosidase Inhibitors: Nojirimycin and
Beyond; Wiley-VCH: Weinheim, 1999.
(4) Iminosugars: Recent Insights Into Their Bioactivity and Potential
As Therapeutic Agents. In Current Topics in Medicinal Chemistry; Martin,
O. R., Compain, P., Eds.; Bentham: Hilversum, The Netherlands, 2003;
Vol. 3, Issue 5.
(5) Butters, T. D.; Dwek, R. A.; Platt, F. M. Curr. Top. Med. Chem.
2003, 3, 561.
(6) Van der Spoel, A. C.; Jeyakumar, M.; Butters, T. D.; Charlton, H.
M.; Moore, H. D.; Dwek, R. A.; Platt, F. M. Proc. Natl. Acad. Sci. U.S.A.
2002, 99, 17173
(2) (a) Compain, P.; Martin, O. R. Bioorg. Med. Chem. 2001, 9, 3077.
(b) Compain, P.; Martin, O. R. Curr. Top. Med. Chem. 2003, 3, 541. (c)
Sears, P.; Wong, C.-H. Angew. Chem., Int. Ed. 1999, 38, 2300.
(3) (a) Fedorov, A.; Shi, W.; Kicska, G.; Fedorov, E.; Tyler, P. C.;
Furneaux, R. H.; Hanson, J. C.; Gainsford, G. J.; Larese, J. Z.; Schramm,
V. L.; Almo, S. C. Biochemistry 2001, 40, 853. (b) Miles, R. W.; Tyler, P.
C.; Furneaux, R. H.; Bagdassarian, C.; Schramm, V. L. Biochemistry 1998,
37, 8615.
10.1021/ol035117h CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/02/2003

finding of more selective/potent inhibitors. Recently, we
reported a general strategy for the practical synthesis of
nojirimycin C-glycosides and analogues bearing an olefinic
group at C-1 (Scheme 1).7 Starting from these advanced
using 4 equiv of CAN in a two-phase system (THF/H2O)12
in 35-50% yield to furnish the iminosugar 2a (Scheme 1).
This unsatisfactory process prompted us to find a new
protective group for the endocyclic amine that could be
selectively removed in the presence of benzyloxy groups and
that would be resistant to the strongly acidic conditions
needed for the cleavage of the acetal function.13 To achieve
this aim, we applied successfully our initial synthetic
strategy7 to the 2-naphthalenemethyl (NAP)14 protected imine
obtained from 4 instead of the corresponding N-benzyl
derivative (Scheme 2). Condensation of aldehyde 4, obtained
Scheme 1
Scheme 2a
intermediates, we investigated olefin cross-metathesis8 as a
powerful methodology to a wide range of functionalized
iminosugar-based building blocks. These extended glyco-
mimetics can be further transformed into neoglycoconjugates
mimicking glycoproteins, glycolipids, and sugar nucleotides,
as well as into dendrimers.
Although ruthenium-carbene catalysts have been widely
used in carbohydrate chemistry for ring-closing metathesis,9
there are relatively few examples of selective cross-meta-
thesis.10 Taking into account the concomitant self-metathesis
reactions, the number of unproductive catalytic pathways,
and the reversibility of all reactions involved, selective cross-
metathesis of two complex alkene derivatives containing
various functional groups represents a great challenge in
organic synthesis. In the case of iminosugars, an additional
issue is the presence of the endocyclic amino function that
could potentially chelate the metal center and thus form
unproductive complexes. First attempts to perform cross-
metathesis reactions with Grubbs catalyst (3) using 1 or its
hydrochloride salts11 failed under various experimental
conditions. The replacement of the endocyclic amine by a
less coordinating function required finding experimental
conditions for the selective and efficient deprotection of the
endocyclic tertiary amine. After various attempts, it was
found that the N-benzyl group in 1 could be removed by
a Reagents and conditions: (a) NAPNH2 (1.05 equiv), CH2Cl2,
molecular sieves, 4 °C, 2 h. (b) AllMgBr or vinylMgBr (3 equiv),
ether, 0 to 20 °C, 24 h. (c) TFA/H2O (9/1), 30 h. (d) NaBH3CN (4
equiv), AcOH (1 equiv), MeOH, 30 h. (e) Ac2O (6 equiv), Py, 5 h.
(f) DDQ (3 equiv), CH2Cl2/MeOH, 1 h. (g) HCOONa (2.5 equiv),
PivCl (2.5 equiv), CH2Cl2, 8 h. (h) TrocCl (1.5 equiv), Py, 2 h.
in seven steps and 64% yield from L-sorbose,7a with
2-naphthalenemethylamine afforded the corresponding imine,
which was reacted with allyl- or vinylmagnesium bromide
to give the diastereomerically pure amines 5 after purification
by flash chromatography. The three-step sequence of depro-
tection of the acetal function, intramolecular reductive
amination, and acylation of the resulting piperidinols afforded
the expected protected nojirimycine C-glycosides 6 in good
(7) (a) Godin, G.; Compain, P.; Masson, G.; Martin, O. R. J. Org. Chem.
2002, 67, 6960. (b) Masson, G. Compain, P.; Martin, O. R. Org. Lett. 2000,
2, 2971.
(8) For a recent review about olefin cross-metathesis see: Connon, S.
J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42, 1900.
(9) (a) Roy, R.; Das, S. K. Chem. Commun. 2000, 519. (b) Jorgensen,
M.; Hadwiger, P.; Madsen, R.; Stu¨tz, A. E.; Wrodnigg, T. M. Curr. Org.
Chem. 2000, 4, 565.
(10) See for example: (a) Roy, R.; Dominique, R.; Das, S. J. Org. Chem.
1999, 64, 5408. (b) Blackwell, H. E.; O’Leary, D. J.; Chatterjee, A. K.;
Washenfelder, R. A.; Bussmann, D. A.; Grubbs, R. H. J. Am. Chem. Soc.
2000, 122, 58. (c) Plettenburg, O.; Mui, C.; Bodmer-Narkevitch, V.; Wong,
C.-H. AdV. Synth. Catal. 2002, 344, 622. (d) Dondoni, A.; Giovanni, P. P.;
Marra, A. J. Chem. Soc., Perkin Trans. 1 2001, 2380. (e) Biswas, K.; Coltart,
D. N.; Danishefsky, S. J. Tetrahedron Lett. 2002, 43, 6107.
(11) Rambaud, L.; Compain, P.; Martin, O. R. Tetrahedron: Asymmetry
2001, 12, 1807 and references cited therein.
(12) Cipolla, L.; Palma, A.; La Ferla, B.; Nicotra, F. J. Chem. Soc., Perkin
Trans. 1 2002, 2161.
(13) In our case, N-allyl or N-PMB groups were found to be partially or
totally cleaved during the deprotection of the acetal function in aqueous
TFA.
(14) Gaunt, M. J.; Yu, J.; Spencer, J. B. J. Org. Chem. 1998, 63, 4172.
3270
Org. Lett., Vol. 5, No. 18, 2003

yields and high diastereoselectivities. The N-naphthalene-
methyl protective group was selectively and efficiently
removed in the presence of 3 equiv of DDQ,15 and the
resulting secondary amines 2a,b were formylated16 or
protected with a Troc group to provide iminosugars 7 in 77-
82% yield for the two steps.
Table 1. Ruthenium-Catalyzed Cross-Metathesis of
Imino-C-glycoside 7 with Olefin 8 Using 10 Mol % 3
Starting from R-1-C-allyl-1-deoxynojirimycin analogues
7a,b, the cross-metathesis reaction was first investigated with
R,â-unsaturated ester, sulfone and phosphonate 8a-c (Table
1, entries 1-4). These alkenes were chosen because of the
utility of their functions as reagents or chemical intermedi-
ates. For example, δ-amino esters 9a,b may be regarded as
sugar amino acid (SAA) mimics: such compounds are useful
building blocks for the assembly of oligosaccharide- or
peptide-mimetic libraries;17 phosphonate 9d is an advanced
precursor of sugar nucleotide analogues. In a typical experi-
mental procedure, a solution of 7 (0.06 M in dichlo-
romethane) was refluxed in the presence of 2-3 equiv of 8
and 5-10 mol % Grubbs catalyst (3) for 20 h. Under these
conditions, the expected iminosugars C-glycosides 9a-d
were obtained in 50-96% yield and with excellent stereo-
selectivity, as the (E)-stereoisomer was the only product
detected by NMR spectroscopy. The lower yields obtained
for compounds 9c and 9d were due to homodimerization of
7b (9e was isolated in around 25% yield in both cases).
Iminosugar 7b was independently homodimerized to give
efficiently the pseudodisaccharide 9e in 85% yield (entry
5). The cross-metathesis reaction was also performed with
aromatic olefins 8d,e. The reaction of 7b with 3 equiv of
4-bromostyrene 8d led to the formation of the expected
product 9f in 45% yield together with 52% yield of
homodimer 9e. Dimerization of the iminosugar moiety could
be suppressed successfully by using 5 equiv of the aromatic
olefin as was shown with 2-vinylnaphthalene (Table 1, entry
7). Another powerful application of this methodology is to
provide C-linked pseudoglycolipids or glycopeptides18 that
can be used for the synthesis of biorelevant glycoconjugate
mimetics or as building blocks in combinatorial synthesis.19
The metathesis reaction between 7b and enantiopure
protected diol 8f or oxazolidine 8g led to the formation of
the expected iminosugar C-glycosides 9h,i in high yields
(entries 8 and 9). The N-Troc protecting group of iminosugar
9b was selectively removed using Zn in AcOH/ether20 to
yield the secondary endocyclic amine 10 that could be further
functionalized to obtain potential glycosyltransferase inhibi-
tors on the basis of a bisubstrate concept2 (Table 1, entry
2).
To further explore the scope and generality of this method,
the cross-metathesis reaction was performed with the â-1-
C-vinyl-1-deoxynojirimycin derivative 15 and its R-epimer
a E/Z > 20/1. b Isolated yield. c Performed with 5 mol % catalyst 3
relative to 7a. d Dimer 9e (25%) was also isolated. e Dimer 9e (52%) was
also isolated. f Performed with 20 mol % catalyst 3 relative to 7b. g Zn (30
equiv), Et2O/AcOH (2/1), 3 h, 90%.
(15) (a) Xia, J.; Abbas, S. A.; Locke, R. D.; Piskorz, C. F.; Alderfer, J.
L.; Matta, K. L. Tetrahedron Lett. 2000, 41, 169. (b) Wright, J. A.; Yu, J.;
Spencer, J. B. Tetrahedron Lett. 2001, 42, 4033.
(16) Bringmann, G.; Ochse, M.; Michel, M. Tetrahedron 2000, 56, 581.
(17) Gruner, S. A. W.; Locardi, E.; Lohof, E.; Kessler, H. Chem. ReV.
2002, 102, 491.
(18) Dondoni, A.; Marra, A. Chem. ReV. 2000, 100, 4395.
(19) Schweizer, F. Angew. Chem., Int. Ed. 2002, 41, 230.
(20) Endo, A.; Yanagisawa, A.; Abe, M.; Tohma, S.; Kan, T.; Fukuyama,
T. J. Am. Chem. Soc. 2002, 124, 6552.
analogue 7c. The fully protected â-configured iminosugar
15 was synthesized in seven steps and 30% overall yield
from aldehyde 4 (Scheme 3). Previous studies in our group
Org. Lett., Vol. 5, No. 18, 2003
3271

hydrolysis of the isopropylidene group provided the diaste-
reomerically pure pseudo-â-D-gluco product 14. N-For-
mylation of the endocyclic amine followed by acylation of
the hydroxyl groups at C-2 and C-4 afforded the protected
â-1-C-vinyl-1-deoxynojirimycin analogues 15.
Scheme 3a
In sharp contrast with findings for R-1-C-allyl-1-deoxy-
nojirimycin analogues 7a,b, exposure of â-1-C-vinyl deriva-
tive 15 to various olefins (8a,c,d,g) using 5-20 mol %
Grubbs catalyst (3) led to almost complete recovery of the
1
starting material (less than 5% conversion according to H
NMR and mass spectroscopy). In addition, attempts to
perform ruthenium-catalyzed cross-metathesis of R-1-C-vinyl
derivative 7c with ethyl acrylate (8a) or its self-metathesis
reaction proved to be unsuccessful. These results may be
reasonably explained by greater Ru-O chelation possibili-
ties8 and increased steric hindrance due to close proximity
of the reacting alkene and the bulky iminosugar moiety.22
In conclusion, we have reported the first example of cross-
metathesis reactions with iminosugar C-glycosides. The
results obtained from R-1-C-allyl-1-deoxynojirimycin ana-
logues 7a,b demonstrated the simplicity and the power of
cross-metathesis reaction to rapidly generate iminosugar
C-glycosides with a great degree of structural diversity in
the aglycon moieties. This practical and selective methodol-
ogy provides new avenues for the synthesis of glycoconjugate
mimetics of biological interest. Efforts toward this aim are
currently in progress in our laboratory.
a Reagents and conditions: (a) AllylNH2 (1.1 equiv), CH2Cl2,
molecular sieves, 4 °C, 2 h. (b) VinylMgBr (3 equiv), ether, 0 to
20 °C, 24 h. (c) Pd(PPh3)4, NDMBA (2.1 equiv), CH2Cl2, 35 °C,
3 h. (d) TFA/H2O (9/1), 36 h. (e) NaBH3CN (4 equiv), AcOH (1
equiv), MeOH, 24 h. (f) HCOONa (2.5 equiv), PivCl (2.5 equiv),
CH2Cl2, 8 h. (g) Ac2O (6 equiv), Py, 16 h.
indicated that the amine function of the sorbofuranose 12
had to be deprotected before the reductive amination step to
obtain high stereocontrol at C-5. Allylamine was used as a
temporary nitrogen protecting group. Diastereoselective chain
extension of N-allylimine 11 with vinylmagnesium bromide
afforded the expected primary amine 13 after deprotection
under classical conditions.21 Intramolecular reductive ami-
nation of the aminosorbose hemiketal liberated upon acidic
Acknowledgment. Financial support of this study by
grants from CNRS and the association “Vaincre les Maladies
Lysosomales” is gratefully acknowledged. G.G. thanks the
council of Re´gion Centre and the CNRS for a fellowship.
Supporting Information Available: 1H and 13C NMR
spectra data for selected compounds (2a, 2b, 5b, 6a, 7b, 9b,
9d, 9f, 9h, 9i, 10, and 12-14) and selected experimental
procedures. This material is available free of charge via the
Internet at http://pubs.acs.org.
(21) Garro-Helion, F.; Merzouk, A.; Guibe, F. J. Org. Chem. 1993, 58,
6109.
(22) For related examples with 1-C-vinyl glycoside, see: (a) Roy, R.;
Das, S. K.; Dominique, R.; Trono, M. C.; Hernandez-Mateo, F.; Santoyo-
Gonzalez, F. Pure Appl. Chem. 1999, 71, 565. (b) Nolen, E. G.; Kurish, A.
J.; Wong, K. A.; Orlando, M. D. Tetrahedron Lett. 2003, 44, 2449.
OL035117H
3272
Org. Lett., Vol. 5, No. 18, 2003