Stereoselective synthesis of α-C-substituted 1,4-dideoxy-1,4-imino-D- galactitols. Toward original UDP-Galf mimics via cross-metathesis

Article abstract of DOI:10.1021/ol053078z

Various α-C-substituted 1,4-dideoxy-1,4-imino-D-galactitols were prepared efficiently from 1-O-acetyl-2,3,5,6-tetra-O-benzyl-D-glucofuranose by a four-step sequence involving as the key step the highly syn-selective TMSOTf-catalyzed addition of silylated

Full text of DOI:10.1021/ol053078z

ORGANIC
LETTERS
2006
Vol. 8, No. 7
1299-1302
Stereoselective Synthesis of
-C-Substituted
1,4-Dideoxy-1,4-imino-
r
D
-galactitols.
Toward Original UDP-Galf Mimics via
Cross-Metathesis
Virginie Liautard, Vale´rie Desvergnes,* and Olivier R. Martin*
Institut de Chimie Organique et Analytique, UMR 6005, UniVersite´ d’Orle´ans-CNRS
Rue de Chartres, BP 6759, F-45067 Orle´ans Cedex 2, France
oliVier.martin@uniV-orleans.fr; Valerie.desVergnes@uniV-orleans.fr
Received December 20, 2005
ABSTRACT
Various
a four-step sequence involving as the key step the highly syn-selective TMSOTf-catalyzed addition of silylated nucleophiles to a glycofurano-
sylamine. Cross-metathesis of the -C-allylated iminogalactofuranose derivative with an original uridin-5 -yl vinylphosphonate led to novel
UDP-galactofuranose mimics. Such compounds are of interest as potential inhibitors of the mycobacterial galactan biosynthesis pathway.
r-C-substituted 1,4-dideoxy-1,4-imino-D-galactitols were prepared efficiently from 1-O-acetyl-2,3,5,6-tetra-O-benzyl-D-glucofuranose by
r
′
Mycobacterial viability is dependent upon the ability of the
organism to produce an intact cell wall. Therefore, com-
pounds that interfere with the biosynthesis of the cell wall
complex glycans have the potential to become new drugs
for the treatment of mycobacterial infections.1 The oligosac-
charide galactan is one of the major structural components
of the outer wall of the microorganism. It is constituted of
roughly 30 galactofuranose (Galf) residues linked alterna-
tively by â-1,5 and â-1,6 linkages; this form of galactose is
present in several pathogenic prokaryotes, but it is not found
in mammals.2 The use of gene knockout techniques has
demonstrated that Galf is essential for cell growth and
survival,3 and therefore, its biosynthesis constitutes a new
drug target.4 The biosynthetic process involves several
enzymes having uridine-diphosphogalactofuranose (UDP-
Galf) as the substrate: uridine 5′-diphospho-(UDP)-galac-
topyranose mutase which catalyzes the interconversion of
UDP-galactopyranose into UDP-galactofuranose, as well as
Galf transferases. As the mechanism5 of the mutase inter-
conversion is still unclear, we are seeking and designing
molecules that could be mechanistic probes and/or inhibitors.
Our initial objective was the synthesis of original UDP-Galf
mimics based on an iminosugar skeleton linked to UMP by
structurally diverse tethers. During the past decade, interest
(3) Pan, F.; Jackson, M.; Ma, Y.; McNeil, M. R. J. Bacteriol. 2001, 183,
3991.
(4) Pedersen, L. L.; Turco, S. J. Cell. Mol. Life Sci. 2003, 60, 259.
(5) (a) Barlow, J. N.; Blanchard, J. S.; Girvin, M. E. J. Am. Chem. Soc.
1999, 121, 6968. (b) Zhang, Q.; Liu, H.-w J. Am. Chem. Soc. 2000, 122,
9065. (c) Barlow, J. N.; Blanchard, J. S. Carbohydr. Res. 2000, 328, 473.
(d) Zhang, Q.; Liu, H.-w J. Am. Chem. Soc. 2001, 123, 6756. (e) Sanders,
D. A. R.; Staines, A. G.; McMahon, S. A.; McNeil, M. R.; Whitfield, C.;
Naismith, J. H. Nature Struct. Biol. 2001, 8, 858 and references cited therein.
(f) Fullerton, S. W. B.; Daff, S.; Sanders, D. A. R.; Ingledew, W. J.;
Whitfield, C.; Chapman, S. K.; Naismith, J. H. Biochemistry 2003, 42 ,
2104. (g) Beis, K.; Srikannathasan, V.; Liu, H.; Fullerton, S. W.; Bamford,
V. A.; Sanders, D. A.; Whitfield, C.; McNeil, M. R.; Naismith, J. H. J.
Mol. Biol. 2005, 4, 971.
(1) Lowary, T. L. Mini ReV. Med. Chem. 2003, 3, 689.
(2) (a) Galf has been found recently in lower eukaryotes: Bakker, H.;
Kleczka, B.; Gerardy-Schahn, R.; Routier, F. H. Biol. Chem. 2005, 7, 657.
(b) Beverley, S. M.; Owens, K. L.; Showalter, M.; Griffith, C. L.; Doering,
T. L.; Jones, V. C.; McNeil, M. R. Eukaryotic Cell 2005, 6, 1147.
10.1021/ol053078z CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/03/2006

in so-called iminosugars has widely increased. Indeed, these
nitrogen-containing sugar analogues constitute leads for the
development of new therapeutic agents in a range of diseases
(viral infections, diabetes, lysosomal diseases).6 1,4-Dideoxy-
1,4-imino-D-galactitol 1 is the first known inhibitor of E.
coli K12 UDP-Galp mutase and of mycobacterial galactan
biosynthesis, although the inhibitory effect was rather weak.7
It was also shown that analogue 2 with a short aglycone,
such as a R-hydroxymethyl group, was somewhat more
active (Figure 1). Analogues of galactofuranose in the 1-N-
Scheme 1. Glucofuranosylamine Synthesis
excellent substrates for Lewis acid (LA)-catalyzed ring
opening with silylated nucleophiles leading to syn addition
product, as required for the eventual formation of a pseudo-
R-configuration of the galactofuranose mimic. We report the
first application of this methodology to a hexofuranose sugar
derivative and the conversion of the addition product to a
UDP-Galf mimic.
The starting material, namely 1-O-acetyl-2,3,5,6-tetra-O-
benzyl-D-glucofuranose 3, was prepared in four steps from
D-glucose: the procedure described by Ferrie`res et al.11
required optimization12 and provided 3 in an average of 41%
yield for the four steps (30 g scale).
The formation of the corresponding N-Z-glycosylamine
was then investigated: under the conditions reported by
Kobayashi (Z-NH2, TMSOTf),10 we obtained the desired
product 4 as well as the byproduct 5 (1,6-anhydro-2,3,5-tri-
O-benzyl-â-D-glucofuranose)13 (Scheme 1 and Table 1, entry
Figure 1.
iminosugar series have also been reported as moderate
inhibitors of galactan biosynthesis.8
We wish to report in this paper, the efficient and
stereoselective synthesis of R-C-substituted 1,4-imino-ga-
lactitol derivatives and their conversion by cross-metathesis
into a novel type of UDP-Galf mimics in which UMP is
linked to the iminogalactitol by a C3-tether.
Since glucofuranose derivatives are readily available, the
formation of a glucofuranosylamine followed by the addition
of an organometallic species to the corresponding open-chain
imine and ring closure with inversion of configuration
appeared to be a most useful approach to the desired R-C-
substituted 1,4-iminogalactitol derivatives.9 Kobayashi et al.10
have recently reported a method for the direct synthesis of
Z-protected glycosylamines from simple glycosyl donors and
carbamates in the presence of trimethylsilyl trifluoromethane-
sulfonate (TMSOTf). In addition, these glycosylamines are
Table 1a
yield of 4
reaction
time
entry Lewis acid
(%)
4/5
solvent
1
2
3
4
5
6
7
8
9
TMSOTf
TMSOTf
TMSOTf
TMSOTfb
TMSOTf
BF3‚Et2O
SnCl4
58
59
15
85
68
45
7
84/16 CH2Cl2
30 min
3h20
7 days
1h
96/4
100/0
100/0
100/0
83/17 CH2Cl2
30/70 CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN 30 min
84 h
15 min
30 min
20 min
20 min
20 min
c
Sc(OTf)3
c
ZnCl2
TiCl4
CH2Cl2
CH2Cl2
d
10
11
6
43
Bi(OTf)3
90/10 CH2Cl2
a All reactions were performed using 1.1 equiv of NH2CO2Bn except
for entries 2 (1.5 equiv), 4, and 5 (2 equiv) and using 1 equiv of Lewis
acid except for entries 3 (0.1 equiv) and 6 (2 equiv). b Reaction performed
on a 3 g scale. c No reaction occurred; the starting material was recovered.
d Only traces of compounds 4 and 5 and starting material 3 were detected
(NMR). Degradation products were observed on TLC and NMR spectra.
(6) Iminosugars: Recent Insights Into Their Bioactivity and Potential
As Therapeutic Agents. In Current Topics in Medicinal Chemistry; Martin,
O. R., Compain, P., Eds.; Bentham: The Netherlands, 2003; Vol. 3, issue
5.
(7) (a) Lee, R. E.; Smith, M. D.; Nash, R. J.; Griffiths, R. C.; McNeil,
M.; Grewal, R. K.; Yan, W.; Besra, G. S.; Brennan, P. J.; Fleet, G. W. J.
Tetrahedron Lett. 1997, 38, 6733. (b) Pham-Huu, D.-P.; Gizaw, Y.;
BeMiller, J. N.; Petrus, L. Tetrahedron 2003, 59, 9413. (c) Lee, R. E.;
Smith, M. D.; Pickering, L.; Fleet, G. W. J. Tetrahedron Lett. 1999, 40,
8689.
(8) (a) Cren, S.; Gurcha, S. S.; Blake, A. J.; Besra, G. S.; Thomas, N. R.
Org. Biomol. Chem. 2004, 2, 2418. (b) Cren, S.; Wilson, C.; Thomas, N.
R. Org. Lett. 2005, 7, 3521.
1). This side product 5 arose from the participation of the
benzyloxy group at C-6 as a nucleophile trapping the
intermediate oxocarbenium ion and undergoing subsequent
O-debenzylation of the resulting benzyloxonium ion. Such
Lewis acid mediated regioselective de-O-benzylations in the
presence of Lewis acids were previously reported on other
(9) A similar strategy has been used to prepare imino-C-glycosyl
compounds in the piperidine series: Cipolla, L.; Lay, L.; Nicotra, F.;
Pangrazio, C.; Panza, L. Tetrahedron 1995, 51, 4679.
(10) (a) Sugiura, M.; Kobayashi, S. Org. Lett. 2001, 3, 477. (b) Sugiura,
M.; Hagio, H.; Hirabayashi, R.; Kobayashi, S. Synlett 2001, 1225. (c)
Sugiura, M.; Hagio, H.; Hirabayashi, R.; Kobayashi, S. J. Am. Chem. Soc.
2001, 123, 12510. (d) Sugiura, M.; Hirabayashi, R.; Kobayashi, S. HelV.
Chim. Acta 2002, 85, 3678.
(11) Ferrie`res, V.; Bertho, J. N.; Plusquellec, D. Carbohydr. Res. 1998,
311, 25.
(12) Experimental details are provided in the Supporting Information.
(13) Ko¨ll, P.; John, H.-G.; Schulz, J. Liebigs Ann. Chem. 1982, 613.
1300
Org. Lett., Vol. 8, No. 7, 2006

With 1-phenyl-1-trimethylsilyloxyethylene, the reaction
gave compound 6c in good yield (entry 8). The reactions
with vinyloxytrimethylsilane and TMS-thiazole, the latter
being well-known to perform nucleophilic attack onto
aldehydes,15 were unsuccessful (entries 5 and 7).
Scheme 2. Lewis Acid-Assisted Nucleophilic Addition to 4
The most remarkable feature of these addition reactions
is their diastereoselectivity. Indeed, in each case, only one
diastereoismer was observed, which was anticipated to be
the Re face addition product leading to a syn stereochem-
istry.10 The configurational assignment of the products 6a,b
could, however, be made only after conversion to pyrrolidine
derivatives 9a,b.
A two-step sequence with inversion at C-4 provided
original imino-R-C-galactofuranosyl compounds 8a-c: me-
sylation of the free hydroxyl group of compounds 6a-c
followed by treatment of the resulting sulfonate 7a-c with
potassium tert-butoxide gave the corresponding pyrrolidine
having a D-galacto configuration by internal nucleophilic
displacement.
Because of the presence of rotamers, it was impossible to
determine directly the configuration of compounds 8a-c by
NOE-NMR analysis, even at 80 °C. Compounds 8a,b were
therefore N-deprotected by mild hydrogenolysis to provide
quantitatively pyrrolidines 9a,b (Scheme 3). The connec-
sugar substrates.14 A wide range of conditions and Lewis
acids were explored in order to minimize the formation of 5
(Table 1). It was found eventually that, using an excess of
benzyl carbamate in CH2Cl2 or MeCN (2.0 equiv, entries 4
and 5), the formation of byproduct 5 could be eliminated. It
is important to note that, when TMSOTf was used, the
conversion of the starting material was complete and
provided good quality 1H NMR spectra of the crude product.
On a small scale, the reactions gave lower yields because of
some degradation of the glycosylamine 4 during purification
on silica gel.
The glucofuranosylamine 4 (R,â mixture) was then
subjected to the TMSOTf-catalyzed reaction with various
silylated nucleophiles (Scheme 2, Table 2). Using allyltri-
Scheme 3. Pyrrolidine Synthesis
Table 2 a
yield
LA
of 6
reaction
entry
NuSiMe3
equiv (equiv) (%)
de time (h)
1
2
3
4
5
6
7
8
CH2dCHCH2SiMe3
CH2dCHCH2SiMe3
CH2dCHCH2SiMe3
CH2dCHCH2SiMe3
2
6
7
7
6
7
7
7
0.2
1
35 >98
44
62
65
72
39
15
92
22
b
b
b
56 >98
74 >98
86 >98
0.5
1.25
0.25
0.5
0.5
0.5
c
CH2dCHOSiMe3
TMSCNd
63 >98
TMS-thiazolec
CH2dC(Ph)OSiMe3
b
62 >98
tivities determined by NOESY experiments as well as the
magnitude of the vicinal coupling constants supported a 1,2-
cis configuration in the 1,4-iminoalditol,16 thus establishing
the formation of syn products 6a-c as unique diastereoiso-
mers in the addition reaction. In addition, comparison with
similar pyrrolidine structures17 having an unambiguous
pseudo-â-configuration obtained in our laboratory confirmed
the stereochemistry of 8a-c.
With the original imino-R-C-galactofuranoside derivatives
8a-c in hand, we envisaged their transformation into
neoglycoconjugates mimicking UDP-galactofuranose by
various coupling processes. In particular, we decided to
investigate the coupling of the R-1-C-allyl derivatives with
a All reactions were performed in dried CH3CN at -40 °C and under
Ar. b 4 equiv of NuSiMe3 and 0.5 equiv of LA were first introduced in the
flask, and then an additional 1 equiv of NuSiMe3 and 0.25 equiv of LA
were added every 2 h (3×). c No reaction occurred; the starting material 4
was recovered. d 100% conversion, but 6c degraded during purification on
silica gel.
methylsilane, it was found after extensive investigation that
1.25 equiv of LA and 7 equiv of reagent (added in portions)
were necessary for the reaction to go to completion (entry
4). Compound 6a was isolated in a good yield of 86%. With
TMSCN, the reaction led to product 6b in a unoptimized
yield of 63% (entry 6). Compound 6b was used without any
purification in subsequent synthetic sequences.
(15) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini, P. J.
Org. Chem. 1988, 53, 1748.
(14) Hori, H.; Nishida, Y.; Ohrui, H.; Meguro, H. J. Org. Chem. 1989,
54, 1346.
(16) Serianni, A. S.; Barker, R. J. Org. Chem. 1984, 49, 3292.
(17) Christina, A.; Desvergnes, V.; Martin, O. R. Unpublished results.
Org. Lett., Vol. 8, No. 7, 2006
1301

unsaturated UMP derivatives by cross-metathesis. While
ring-closing metathesis has been widely used in glycochem-
istry,18 there are few applications of selective cross-metathesis
processes. In particular, our group has recently exploited this
reaction for a general access to iminosugar C-glycosides,19
and more recently, Dondoni et al.20 reported the synthesis
of imino-C-glycosyl R-amino acids using this powerful
procedure.
Scheme 5. Synthesis of UDP-Galf Mimic 16
Surprisingly, initial investigations on the cross-metathesis
reaction between 8a and vinylphosphonates using second-
generation Grubbs catalyst failed under various experimental
conditions. On the other hand, the expected cross-coupling
products could be obtained using 5-10 mol % of Nolan’s
catalyst.21 The reaction was performed first with diethyl
vinylphosphonate 12 to set up the conditions. The imino-
phosphonate 10 was obtained in a moderate 68% yield and
with excellent stereoselectivity as the (E)-stereoisomer.22
Some homodimerization product 11 and unreacted 8a were
also isolated (total yield 17%) (Scheme 4).
Scheme 4. CM Reaction of Phosphonate 12
at 40 °C, the iminosugar nucleotide conjugate 15 was isolated
in a unoptimized yield of 51% as a mixture of nonseparable
P-stereoisomers. A small amount of homodimerization
product 11 (8%) was also obtained, and unreacted 8a (9%)
was recovered. Compound 15 was deprotected efficiently
with an excess of BCl3 in CH2Cl2 to give compound 16, a
significant UDP-galactofuranose analogue. In this compound,
the iminosugar moiety mimicks a putative galactofuranosyl
cation involved in the reactions catalyzed by UDP-Gal
mutase and/or UDP-Galf transferases, and the three-carbon
linker places the nucleotide fragment at an appropriate
distance with respect to the pseudosugar moiety.
In conclusion, we report herein the first stereoselective
synthesis of R-C-substituted 1,4-iminogalactitols by way of
an expedient and versatile strategy. The R-1-C-allylated
derivative was used as the starting material for the preparation
of a new UDP-Galf analogue via a cross-metathesis
coupling process. Compounds such as 16 are potential
inhibitors of the enzymes involved in mycobacterial galactan
biosynthesis. The elaboration of the double bond in 15 as
well as the utilization of compounds 6b and 6c for the
preparation of further new UDP-Galf mimics are now in
progress, and results will be reported in due course.
To apply this methodology to a uridine-monophosphate
derivative, we developed a simple two-step synthesis of ethyl
uridin-5′-yl vinylphosphonate 14 (Scheme 5). First, diethyl
vinylphosphonate was directly chlorinated using oxalyl
chloride.23 The resulting crude phosphochloridate 13 was then
converted into the mixed diester 14 using 2′,3′-O-isopropyl-
ideneuridine in the presence of triethylamine in 61% overall
yield. Cross-metathesis reaction between 8a and 14 was
performed using 10 mol % of Nolan’s catalyst. After 44 h
(18) (a) Pandit, U. K.; Overkleeft, H. S.; Borer, B. C.; Biera¨ugel, H.
Eur. J. Org. Chem. 1999, 959. (b) Philips, A. J.; Abell, A. D. Aldrichim.
Acta 1999, 32, 75. (c) Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104,
2199. (d) Roy, R.; Das, S. K. Chem. Commun. 2000, 519. (e) Jorgensen,
M.; Hadwiger, P.; Madsen, R.; Stu¨tz, A. E.; Wrodnigg T. M. Curr. Org.
Chem. 2000, 4, 565. (f) Cardona, F.; Moreno, G.; Guarna, F.; Vogel, P.;
Schuetz, C.; Merino, P.; Goti, A. J. Org. Chem. 2005, 70, 6552. (g) Cooper,
T. S.; Larigo, A. S.; Laurent, P.; Moody, C. J.; Takle, A. K. Org. Biomol.
Chem. 2005, 3, 1252.
(19) Godin, G.; Compain, P.; Martin, O. R. Org. Lett. 2004, 5, 3269.
(20) Dondoni, A.; Giovanni, P. P.; Perrone, D. J. Org. Chem. 2005, 70,
5508.
(21) Huang, J.; Stevens, E. D.; Nolan, S. P.; Petersen, J. L. J. Am. Chem.
Soc. 1999, 121, 2674.
Acknowledgment. Steve Nolan is warmly thanked for
providing us with a sample of his catalyst. V.L. thanks the
“Ministe`re de la Recherche et de la Technologie” for a Ph.D.
fellowship. Partial funding of this research by CNRS is also
gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures for the following compounds are provided (3-5,
6a-c, 8a-c, 9a,b, 10, and 13-16). 1H and 13C NMR spectral
data for selected compounds are reported. This material is
available free of charge via the Internet at http://pubs.acs.org.
(22) The (Z)-stereoisomer was not detected by NMR spectrometry.
(23) Lapeyre, C.; Bedos-Belval, F.; Duran, H.; Baltas, M.; Gorrichon,
L. Tetrahedron Lett. 2003, 44, 2445.
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Org. Lett., Vol. 8, No. 7, 2006