Access to L-and D-iminosugar C-glycosides from a D-gluco-derived 6-azidolactol exploiting a ring isomerization/alkylation strategy

Article abstract of DOI:10.1021/ol203385w

A flexible synthetic access to six-membered l- and d-iminosugar C-glycosides is reported starting from the easily available 6-azido-6-deoxy-2,3, 4-tri-O-benzyl-d-glucopyranose precursor. This methodology involves a highly diastereoselective tandem ring enlargement/alkylation and a stereocontrolled ring contraction. It allows an efficient synthesis of iminosugar C-glycosides displaying structural diversity at both C-1 and C-6.

Full text of DOI:10.1021/ol203385w

ORGANIC
LETTERS
2012
Vol. 14, No. 3
870–873
Access to L- and D-Iminosugar
C-Glycosides from a D-gluco-Derived
6-Azidolactol Exploiting a Ring
Isomerization/Alkylation Strategy
†
Martine Mondon, Nathalie Fontelle, Jerome Desire, Frederic Lecornue,
†
ꢀ ^
Jerome Guillard, Jerome Marrot, and Yves Bleriot*
ꢀ
ꢀ
ꢀ † ꢀ ꢀ
ꢀ †
†
‡
,†
ꢀ ^
ꢀ ^
ꢀ
Institut de Chimie des Milieux et des Materiaux de Poitiers (IC2MP),
UMR CNRS 7285, Universite de Poitiers, Equipe “Chimie Organique,
ꢀ
ꢀ
Bioorganique et Supramoleculaire” 4 avenue Michel Brunet, 86022 Poitiers cedex,
France, and Institut Lavoisier de Versailles, UMR CNRS 8180, Universite de Versailles,
ꢀ
45 avenue des Etats-Unis, 78035 Versailles cedex, France
yves.bleriot@univ-poitiers.fr
Received December 20, 2011
ABSTRACT
A flexible synthetic access to six-membered L- and D-iminosugar C-glycosides is reported starting from the easily available 6-azido-6-deoxy-2,3,4-
tri-O-benzyl-D-glucopyranose precursor. This methodology involves a highly diastereoselective tandem ring enlargement/alkylation and a
stereocontrolled ring contraction. It allows an efficient synthesis of iminosugar C-glycosides displaying structural diversity at both C-1 and C-6.
Iminosugars, sugar analogs in which the endocyclic
oxygen has been replaced by nitrogen, constitute a major
class of sugar mimetics.1 Their promising therapeutic
potential2 is illustrated by the approval of Glyset3 and
Zavesca4 (Figure 1) for the treatment of type II diabetes
and Gaucher disease respectively. Moving the alkyl chain
from the endocyclic nitrogen to the pseudoanomeric carbon
leads to another class of important iminosugars, the imino-
sugar C-glycosides which can be seen as glycoconjugates
with a stable substituent at the C-1 position (Figure 1).
Iminosugar C-glycosides are usually more potent and
selective compared to the more synthetically accessible
iminoalditols, an improved efficacy which can be attributed
in part to a better location of the alkyl chain.5 The main
challenge associated with iminosugar C-glycosides is cur-
rently the design of efficient and general routes enabling
introduction of structural diversity from advanced synthons
to accelerate the discovery of biologically relevant mole-
cules. Ideally such routes would require introduction of
additional substituents on a late stage intermediate. Most of
†
ꢀ
ꢀ
Universite de Poitiers.
‡
Universite de Versailles.
(1) Martin, O. R.; Compain, P. Iminosugars: From synthesis to
(5) (a) Wennekes, T.; Van den Berg, R. J. B. H. N.; Boltje, T. J.;
Donker-Koopman, W. E.; Kuijper, B.; van der Marel, G. A.; Strijland,
A.; Verhagen, C. P.; Aerts, J. M. F. G.; Overkleeft, H. S. Eur. J. Org.
therapeutic applications; Wiley-VCH: Weinheim, 2007.
(2) (a) Horne, G.; Wilson, F. X. Prog. Med. Chem. 2011, 50, 135–176.
(b) Horne, G.; Wilson, F. X.; Tinsley, J.; Williams, D. H.; Storer, R.
Drug Discov. Today 2011, 16, 107–118.
(3) Jacob, G. S. Curr. Opin. Struct. Biol. 1995, 5, 605–611.
(4) McCormack, P. L.; Goa, K. L. Drugs 2003, 63, 2427–2434.
€
Chem. 2010, 1258–1283. (b) Schonemann, W.; Galienne, E.; Compain,
P.; Ikeda, K.; Asano, N.; Martin, O. R. Bioorg. Med. Chem. 2010, 18,
2645–2650. (c) Weber, K. T.; Hammache, D.; Fantini, J.; Ganem, B.
Bioorg. Med. Chem. Lett. 2000, 10, 1011–1014.
r
10.1021/ol203385w
Published on Web 01/20/2012
2012 American Chemical Society

the reported synthetic strategies are based either on the
formation of the C1ÀN or C5ÀN bond through intramo-
lecular reductive amination or on the late formation of the
C1ÀCH2R bond through the use of an electrophilic imino-
sugar donor (Figure 1).6
aspects to develop a new powerful strategy toward piper-
idine iminosugar C-glycosides based on the alkylation
of a seven-membered electrophilic iminosugar and its
subsequent ring isomerization. This approach should al-
low tuning of the substituents at C-1 and C-6. We have
previously disclosed the synthesis of seven-membered imi-
nosugar homologues of glycosidase inhibitor noeuromycin
starting from a sugar-based azidolactol 1 and exploiting a
Staudinger/aza-Wittig ring expansion.15 Since this transfor-
mation proceeds by a two-step reduction, trapping of the
intermediate seven-membered imine by an organometallic
species instead of hydride should allow selective functiona-
lization at the C-7 position. Subsequent azepane ring iso-
merization through 3-OH group activation should provide
the corresponding six-membered iminosugar C-glycosides
displaying structural diversity at C-6 (Scheme 1).
Figure 1. Structures of Glyset and Zavesca and general strate-
gies to access iminosugar C-glycosides.
The intermolecular approach, inspired from the syn-
thetic strategies developed in the field of C-glycosides,
appears as the best strategy for late stage diversification.
It has been less explored due to the difficult generation of
stable electrophilic iminosugars. Piperidinose donors have
been developed by Johnson,7 Vasella,8 and Schmidt,9 and
nucleophilic addition to the endocyclic CdN bond of a six-
membered iminosugar-derived cyclic imine or nitrone has
been reported by Davis10 and Vasella11 respectively. These
elegant routes focus on introduction of various substitu-
ents at C-1 but usually do not allow decoration at other
positions of the piperidine ring. Such modification could
be of interest to increase their biological potency and/or
selectivity. One exception is the SAWU strategy developed
by Overkleeft which enables the synthesis of a library of
iminosugar C-glycosides displaying diversity both at C-1
and at the endocyclic nitrogen.12 Introduction ofstructural
diversity at both C-1 and C-6 has not been developed
despite the fact that it should give rise to novel sugar
mimetics with enhanced potency through hydrophobic
interaction with protein residue side chains. Our interest
in the synthesis13 and skeletal rearrangement14 of seven-
membered iminosugars prompted us to combine both
Scheme 1. New Strategy Developed Herein to Access Iminosu-
gar C-Glycosides
Initial attempts using triphenylphosphine and starting
from azidolactol 1, easily available from methyl
glucopyranoside,16 failed to furnish the pure imine 2 in
good yield. More encouraging results were obtained by
switching tothepolymer-bound triphenylphosphine. After
optimization of the reaction conditions, a major product
was isolated in 62% yield and assigned to the bicyclic N,O-
acetal 317 by NMR (signals at 5.06 and 88.7 ppm in the 1H
and 13C NMR spectra respectively for the hemiaminal
moiety). It results from the trapping of the transient seven-
membered imine 2 by the free 3-OH group (Scheme 2).
This electrophilic bicycle can be seen as a stable form of
2 allowing introduction of hydrophobic groups at C-7
through organometallic addition. The reactivity of N,O-
acetals with organometallics is well-documented18 but has
(6) Compain, P.; Chaignault, V.; Martin, O. R. Tetrahedron: Asym-
metry 2009, 20, 672–711.
(7) Johnson, C. R.; Golebiowski, A.; Sundram, H.; Miller, M. W.;
Dwaihy, R. L. Tetrahedron Lett. 1995, 36, 653–654.
(8) Granier, T.; Vasella, A. Helv. Chim. Acta 1998, 81, 865–880.
(9) Fuchss, T.; Streicher, H.; Schmidt, R. R. Liebigs Ann. Recl. 1997,
1315–1321.
(10) (a) Maughan, M. A. T.; Davies, I. G.; Claridge, T. D. W.;
Courtney, S.; Hay, P.; Davis, B. G. Angew. Chem., Int. Ed. 2003, 42,
3788–3792. (b) Davis, B. G.; Maughan, M. A. T.; Chapman, T. M.;
Villard, R.; Courtney, S. Org. Lett. 2002, 4, 103–106.
(11) Peer, A.; Vasella, A. Helv. Chim. Acta 1999, 82, 1044–1065.
(12) Timmer, M. S. M.; Risseeuw, M. D. P.; Verdoes, M.; Filippov,
D. V.; Plaisier, J. R.; Van der Marel, G. A.; Overkleeft, H. S.; Van Boom,
J. H. Tetrahedron: Asymmetry 2005, 16, 177–185.
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Commun. 2007, 183–185.
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Chem. 1996, 61, 1894–1897. (b) Chakraborty, T. K.; Ghosh, S.;
Jayaprakash, S.; Sharma, J. A. R. P.; Ravikanth, V.; Diwan, P. V.;
Nagaraj, R.; Kunwar, A. C. J. Org. Chem. 2000, 65, 6441–6457.
(17) Similar bicyclic [5,6] N,O-acetals derived from sugars have been
reported: (a) Lafont, D.; Wollny, A.; Boullanger, P. Carbohydr. Res.
1998, 310, 9–16. (b) Beacham, A. R.; Smelt, K. H.; Biggadike, K.;
Britten, C. J.; Hackett, L.; Winchester, B. G.; Nash, R. J.; Griffiths,
R. C.; Fleet, G. W. J. Tetrahedron Lett. 1998, 39, 151–154. (c) Fuentes, J.;
Gasch, C.; Olano, D.; Pradera, M. A.; Repetto, G.; Sayago, F. J.
Tetrahedron: Asymmetry 2002, 13, 1743–1753.
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(13) (a) Marcelo, F.; He, Y.; Yuzwa, S. A.; Nieto, L.; Jimenez-
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Barbero, J.; Sollogoub, M.; Vocadlo, D. J.; Davies, G. J.; Bleriot, Y.
J. Am. Chem. Soc. 2009, 131, 5390–5392. (b) Li, H.; Liu, T.; Zhang, Y.;
Favre, S.; Bello, C.; Vogel, P.; Butters, T. D.; Oikonomakos, N. G.;
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Marrot, J.; Bleriot, Y. ChemBioChem 2008, 9, 253–260. (c) Li, H.;
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Bleriot, Y.; Chantereau, C.; Mallet, J.-M.; Sollogoub, M.; Zhang, Y.;
Rodriguez-Garcia, E.; Vogel, P.; Jimenez-Barbero, J.; Sinay, P. Org.
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(18) (a) Bloch, R. Chem. Rev. 1998, 98, 1407–1438. (b) Enders, D.;
Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895–1946. (c) Steinig,
A. G.; Spero, D. M. Org. Prep. Proc. Int. 2000, 32, 205–234.
Biomol. Chem. 2004, 2, 1492–1499.
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Org. Lett., Vol. 14, No. 3, 2012
871

been unexplored with [5,6] bicyclic systems.19 The one-pot
Staudinger/aza-Wittig/alkylation of 1 was thus studied
screening various conditions and organometallics to gen-
erate the corresponding C-7 alkyl azepanes 4 (Scheme 2).
constant J6,7 close to 0 Hz indicative of a 6,7 cis relative
configuration and an R configuration for the C-7 carbon,
the phenyl and allyl derivatives 4a and 4e displayed a large
J6,7 (8.5 and 9.5 Hz respectively) in agreement with a
6,7 trans relative configuration and a S configuration for
C-7.21 The 6,7 cis relative configuration for 4bÀd could be
explained by a mechanism involving an intramolecular
delivery of the nucleophile in an early transition state
(Scheme 2). The rationale for the 3,7 trans configura-
tion of 4a and 4e remains unclear. One notable aspect
of this strategy is that it allows a fast access to 7-C-alkyl-
3,4,5,6-tetrahydroxyazepanes, which have been scarcely
reported,22 and could display potent glycosidase inhibition
and a pharmacological chaperone profile.23 Polyhydroxy-
lated azepanes are useful synthons for generating polysub-
stituted piperidines through ring isomerization.24 This
process is triggered by activation of the free 3-OH group
and displacement bythe endocyclicnitrogenwhich leads to
a transient fused piperidine-aziridinium intermediate. Its
regioselective opening by the released nucleophile at the
methylene carbon leads to a six-membered azacycle, while
attack at the methine carbon gives the corresponding
azepane with retention of configuration at C-3. Applied
to the C-alkyl azepanes, this transformation, which re-
quires an electron-rich nitrogen, should furnish the six-
membered iminosugar C-glycosides displaying structural
diversity at C-6 brought by the incoming nucleophile.
Azepane 4a was chosen as a representative model of the
C-alkyl azepanes synthesized. Its N-benzylation under
mild basic conditions afforded hydroxyazepane 5 (53%
yield over 3 steps from azidolactol 1) which was then
submitted to different OH group activation conditions
(Scheme 3) to introduce several functionalities at C-6
during the ring isomerization process. Mesylation (MsCl,
Et3N, CH2Cl2) of 5 furnished the chlorinated six-mem-
bered iminosugar-C-glycoside 6a (72%). Mitsunobu con-
ditions (PPh3, DEAD, pNO2PhCOOH) applied to 5
yielded the corresponding piperidine 6b in satisfactory
yield (67%) along with some azepane 7b (21%).25 Piper-
idine 6a displays a typical J5,6 value (5.7 Hz) for a cis
relative configuration between H-5 and H-6 which is in
agreement with a double displacement mechanism during
the skeletal rearrangement. Furthermore, the observed J2,3
value (9.7 Hz) confirms the trans relative configuration for
Scheme 2. Synthesis of C-7 Alkyl Azepanes 4aÀ4e
Initial experiments, to optimize the reaction conditions,
were performed using allylmagnesium bromide as a nu-
cleophile as it gave the best yield for this transformation.
In a typical procedure, 1 was treated with solid-supported
PPh3 at 40 °C in THF overnight and the solution was
filtered through a Celite plug. The crude solution was
concentrated and engaged in the next alkylation step
involving organomagnesium reagents. Reverse addition
of a crude solution of 3 in THF into an excess of Grignard
reagent (10 equiv) in THF, and running the reaction at rt,
gave the best conversion.20Allyl azepane 4a was obtained
in 58% yield and as a single diastereomer after SiO2 flash
column chromatography. Its structure was ascertained by
typical NMR data. The 13C NMR spectrum in CDCl3
displayed five CH signals at 85.5, 82.4, 78.6, 70.0, and 60.5
ppm (C-7), one CHd signal at 135.8 ppm and one CH2d
1
signal at 117.9 ppm. The H NMR spectrum in CDCl3
showed a signal at 2.93 ppm for the C-7 proton. Other
Grignard reagents, namely, methyl, ethyl, vinyl, and phe-
nyl magnesium halides, were also reacted leading to the
corresponding C-7 alkyl azepanes 4bÀ4e in moderate
yields (35À49% yield over two steps) and excellent dia-
stereoselectivities (>95%) except for the vinyl derivative
(34%). The configuration of the C-7 stereogenic center for
each new azepane was determined by NMR. While the
methyl, ethyl, vinyl azepanes 4bÀd displayed a coupling
(21) Configuration of the C-7 carbon of azepane 4a was further
confirmed after its ring contraction leading to classical coupling con-
stants associated with a piperidine motif. It allowed deduction of the C-7
configuration of azepanes 4bÀe.
ꢀ
ꢀ
(22) (a) Otero, J. M.; Estevez, A. M.; Soengas, R. Q.; Estevez, J. C.;
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Nash, R. J.; Fleet, G. W. J.; Estevez, R. J. Tetrahedron: Asymmetry 2008,
19, 2443–2446. (b) Tite, T.; Tsimilaza, A.; Lallemand, M.-C.; Tillequin,
F.; Leproux, P.; Libot, F.; Husson, H.-P. Eur. J. Org. Chem. 2006, 863–
868.
(23) Orwig, S. D.; Tan, Y. L.; Grimster, N. P.; Yu, Z.; Powers, E. T.;
Kelly, J. W.; Lieberman, R. L. Biochemistry 2011, 50, 10647–10657.
(24) (a) Poitout, L.; Le Merrer, Y.; Depezay, J.-C. Tetrahedron Lett.
1996, 37, 1613–1616. (b) Bagal, S. K.; Davies, S. G.; Lee, J. A.; Roberts,
P. M.; Russell, A. J.; Scott, P. M.; Thompson, J. E. Org. Lett. 2010, 12,
136–139.
(25) In all cases azepanes 7aÀd proved to be less polar than the
corresponding piperidines 6aÀ6d and were isolated first by column
chromatography. Their structures were unambiguously established
through extensive NMR analysis.
(19) Addition of organomagnesium reagents to a related [5,6] bicyclic
aminal has been disclosed in a tandem ring enlargement/alkylation
strategy to afford 3-aminoazepane derivatives: Cutri, S.; Bonin, M.;
Micouin, L.; Husson, H.-P.; Chiaroni, A. J. Org. Chem. 2003, 68,
2645–2651.
(20) Organomagnesium halide normal addition or use of diethyl
ether as solvent gave a lower yield and diastereomeric excess.
872
Org. Lett., Vol. 14, No. 3, 2012

the C-6/C-7 carbons of azepane 4a. Introduction of the
more biologically relevant fluorine atom which has been
considered as an isostere of an OH group26 was then
investigated. Skeletal rearrangement of cyclic β-aminoal-
cohols with concomitant introduction of fluorine has been
extensively explored to rapidly access fluorinated piper-
idines and pyrrolidines of interest.27 Among the various
fluorinating agents, N,N-diethylaminosulfur trifluoride
(DAST) appears as the most effective reagent to perform
such reactions. When reacted with hydroxyazepane 5, the
expected fluoropiperidine 6c (63%) was obtained as the
major product with some minor azepane 7c (17%). Final-
ly, introduction ofanazido group wasinvestigatedasitcan
rapidly generate compound libraries through click chemis-
try or reductive amination/peptide coupling starting from
the corresponding amine. Treatment of 5with diphenylpho-
sphoryl azide (dppa)28 yielded the expected azidopiperidine
6d in modest yield (32%) along with some azidoazepane 7d
(16%). Piperidine 6d was alternatively obtained (52%) from
6a by azide displacement of the chlorine atom (Scheme 3).
precursor 5. Accordingly, inversion of the 3-OH group in
azepane 4 should pave the way to D-iminosugar C-glyco-
sides via the same sequence. It requires preliminary deac-
tivation of the endocyclic nitrogen to avoid its anchimeric
assistance and the subsequent ring isomerization. To this
end, 1 was converted into the N-Boc hydroxyazepane 8
(48% over 3 steps). Uneventful inversion of the free OH
group under Mitsunobu conditions (PPh3, DEAD,
pNO2PhCOOH) to afford azepane 9 followed by ester
hydrolysis yielded the diastereomeric and crystalline hy-
droxyazepane 10 (86% yield over two steps) whose crystal
structure was solved (see Supporting Information) firmly
confirming the 3-OH group inversion and the C-7 allyl
group configuration. Removal of the Boc protecting group
with TFA followed by N-benzylation under mild basic
conditions furnished the N-benzyl azepane 11 (82% yield
over two steps) which upon treatment under Mitsunobu
conditions (pNO2PhCOOH, DEAD, PPh3) yielded the
protected piperidine D-iminosugar C-glycoside 12 (77% yield)
along with some azepane 13 (10%) (Scheme 4).
Scheme 3. Ring Isomerization of Azepane 5
Scheme 4. Synthesis of D-Iminosugar C-Glycoside 12
In conclusion, we have developed a flexible strategy
to access both L- and D-iminosugar-C-glycosides from
a common and easily available precursor, the 6-azido-6-
deoxy-2,3,4-tri-O-benzyl-D-glucopyranose 1. Our approach
is based on the generation of an electrophilic [5,6] bicyclic N,
O-acetal 3 and exploits the ability of β-hydroxyazepanes
to undergo skeletal rearrangement. This methodology is
powerful as it allows introduction of additional structural
diversity at C-6 leading to fluoro-, chloro-, and azidopi-
peridines. This work highlights the synthetic potential of
polyhydroxylated azepanes. Such an approach appears
general and should, in principle, be applicable to other
glycosides. Work in this direction is in progress.
L-Iminosugars are attracting increased interest from the
synthetic community because, while being usually less
potent glycosidase inhibitors than their D-counterparts,
they demonstrate unexpected biological activities includ-
ingpharmacologicalchaperonebehavior.29 Inthiscontext,
6aÀd constitute valuable precursors of new L-iminosugar
C-glycosides. It can be arguedthat the approach developed
herein is only limited to L-iminosugar C-glycosides and
misses the most studied D-iminosugar C-glycosides. Dur-
ing the skeletal rearrangement which operates with overall
retention of configuration, the L-identity of the six-
membered iminosugar C-glycosides 6aÀd is imposed by the
R configuration of the free 3-OH group in the azepane
ꢀ
Acknowledgment. N.F. thanks the CNRS and Region
Poitou-Charentes for a PhD grant.
(26) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308–319.
(27) (a) Deschamps, I.; Gomez Pardo, D.; Cossy, J. Synlett 2007,
263–267. (b) Ferret, H.; Deschamps, I.; Gomez Pardo, D.; Van Hijfte,
L.; Cossy, J. ARKIVOC 2010, 8, 126–159.
(28) Lal, B.; Pramanik, B. N.; Manhas, M. S.; Bose, A. K. Tetra-
hedron Lett. 1977, 18, 1977–1980.
(29) (a) D’Alonzo, D.; Guaragna, A.; Palumbo, G. Curr. Med. Chem.
2009, 16, 473–505. (b) Jenkinson, S. F.; Fleet, G. W. J.; Nash, R. J.;
Koike, Y.; Adachi, I.; Yoshihara, A.; Morimoto, K.; Izumori, K.; Kato,
A. Org. Lett. 2011, 13, 4064–4067.
Supporting Information Available. Experimental pro-
cedures, characterization data, copies of 1H and 13C
NMR spectra, and crystallographic information file (for
structure CCDC 857995). This material is available free
of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
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