Convergent and stereoselective synthesis of iminosugar-containing Galf and UDP-Galf mimicks: Evaluation as inhibitors of UDP-Gal mutase

Article abstract of DOI:10.1021/jo8001134

(Chemical Equation Presented) The synthesis of a UDP-Galf analog incorporating a 1,4-dideoxy-1,4-imino-D-galactitol skeleton α-linked to UMP by a 3C-tether and of a series of related pyrrolidine galactofuranose mimicks is reported. These compounds were obtained by way of the highly stereoselective reaction of silylated nucleophiles with a N-Cbz glucofuranosylamine which afforded the corresponding open-chain product with a 1,2-syn stereochemistry, as predicted from pionneering studies from Kobayashi. Cyclization of these intermediates afforded α-C-glycosides of imino-galactofuranose carrying various functional groups in the aglycone. Further elaboration of the α-C-allyl substituted derivative by cross-metathesis with a uridin-5′-yl vinylphosphonate provided, after deprotection, the desired original UDP-Galf mimicks. Cleavage of the benzyl ether protecting groups in the iminosugar component using BCl₃ proved critical to the success of the synthetic plan. Several of the new 1,4-dideoxy-1,4-imino-D-galactitol derivatives were evaluated as inhibitors of UGM (UDP-galactopyranose mutase) from Escherichia coli; however, none of them exhibited less than mM activities toward this enzyme which catalyzes a crucial step of the biosynthesis of galactofuranose-containing bacterial cell-surface glycans.

Full text of DOI:10.1021/jo8001134

Convergent and Stereoselective Synthesis of Iminosugar-Containing
Galf and UDP-Galf Mimicks: Evaluation as Inhibitors of UDP-Gal
Mutase
Virginie Liautard,† Vale´rie Desvergnes,*,†,‡ Kenji Itoh,§ Hung-wen Liu,§ and
Olivier R. Martin*,†
Institut de Chimie Organique et Analytique, UniVersite´ d’Orle´ans, CNRS-UMR 6005, BP 6759, 45067
Orle´ans, France, and DiVision of Medicinal Chemistry, College of Pharmacy and Department of
Chemistry and Biochemistry, UniVersity of Texas at Austin, Austin, Texas 78712
oliVier.martin@uniV-orleans.fr; V.desVergnes@ism.u-bordeaux1.fr
ReceiVed January 17, 2008
The synthesis of a UDP-Galf analog incorporating a 1,4-dideoxy-1,4-imino-D-galactitol skeleton R-linked
to UMP by a 3C-tether and of a series of related pyrrolidine galactofuranose mimicks is reported. These
compounds were obtained by way of the highly stereoselective reaction of silylated nucleophiles with a
N-Cbz glucofuranosylamine which afforded the corresponding open-chain product with a 1,2-syn
stereochemistry, as predicted from pionneering studies from Kobayashi. Cyclization of these intermediates
afforded R-C-glycosides of imino-galactofuranose carrying various functional groups in the aglycone.
Further elaboration of the R-C-allyl substituted derivative by cross-metathesis with a uridin-5′-yl
vinylphosphonate provided, after deprotection, the desired original UDP-Galf mimicks. Cleavage of the
benzyl ether protecting groups in the iminosugar component using BCl3 proved critical to the success of
the synthetic plan. Several of the new 1,4-dideoxy-1,4-imino-D-galactitol derivatives were evaluated as
inhibitors of UGM (UDP-galactopyranose mutase) from Escherichia coli; however, none of them exhibited
less than mM activities toward this enzyme which catalyzes a crucial step of the biosynthesis of
galactofuranose-containing bacterial cell-surface glycans.
Introduction
and leprosy. In the context of the fight against such diseases,2
which is becoming even more critical as a result of the
appearance of drug-resistant strains,3 inhibition of the biosyn-
thetic pathway leading to galactofuranose-containing glycans
has been identified as a promising new therapeutic approach.4
Indeed, the key intermediate of this pathway, UDP-galactofura-
nose (Scheme 1), is absent from mammalians;5 it is formed from
UDP-galactopyranose by a ring contraction process catalyzed
by UDP-galactopyranose mutase (UPM)6 and in the next step,
The mycobacterial cell wall exhibits a lipidated polysaccha-
ridic structure unique in the prokaryote reign that is essential
for the microorganism growth and survival.1 This mycolyl-
arabinogalactan-peptidoglycan (mAGP) complex includes a
galactan biopolymer composed of D-galactofuranose units (Galf),
a ring-form of galactose that occurs much less frequently than
its pyranose form (Galp). Members of the genus Mycobacterium
are responsible for major health problems such as tuberculosis
(2) (a) O’Brien, R. J.; Nunn, P. P. Am. J. Respir. Crit. Care Med. 2001,
163, 1055-1058. (b) Zhang, Y.; Amzel, L. M. Curr. Drug Targets 2002,
3, 131-154. (c) Tripathi, R. P.; Tewari, N.; Dwivedi, N.; Tiwari, V. K.
Med. Res. ReV. 2005, 25, 93-131. (d) Agrawal, Y. K.; Bhatt, H. G.; Raval,
H. G.; Oza, P. M.; Vaidya, H. B.; Manna, K.; Gogoi, P. J. Sci. Ind. Res.
2007, 66, 191-208.
(3) See in particular the recent article in C&EN 2007, 39, 21-32.
(4) (a) Pedersen, L. L.; Turco, S. J. Cell. Mol. Life Sci. 2003, 60, 259-
266. (b) Brennan, P. J.; Crick, D. C. Curr. Top. Med. Chem. 2007, 7, 475-
488.
* To whom correspondence should be addressed. Tel: ++ 33 2 38 49 45
81. Fax: ++ 33 2 38 41 72 81 (O.R.M.); Tel: ++ 33 5 40 00 62 87 (V.D.).
† Universite´ d’Orle´ans.
‡ Present address : Institut des Sciences Mole´culaires, Universite´ de Bordeaux
1, CNRS-UMR 5255, 351 cours de la libe´ration, 33405 Talence, France.
§ University of Texas at Austin.
(1) (a) Rastogi, N.; Goh, K. S.; David, H. L. Antimicrob. Agents
Chemother. 1990, 34, 759-764. (b) Barry, C. E. Biochem. Pharmacol. 1997,
54, 1165-1172. (c) Pan, F.; Jackson, M.; Ma, Y.; McNeil, M. J. Bacteriol.
2001, 183, 3991-3998. (d) Brennan, P. J. Tuberculosis 2003, 83, 91-97.
10.1021/jo8001134 CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/22/2008
J. Org. Chem. 2008, 73, 3103-3115
3103

Liautard et al.
SCHEME 1. UDP-Galactofuranose and Galactan Biosynthesis
Galf residues are incorporated into the galactan structure via
alternating â-(1f5) and â-(1f6) linkage by a bifunctional
UDP-Galf transferase.7
enzyme inhibitors reported to date. More largely, iminosugars
behave as inhibitors of a wide range of enzymatic processes
and are under investigations as potential therapeutic agents for
a diversity of diseases.11
Despite elegant bioorganic studies,8 the mechanism of the
unprecedented ring contraction promoted by the mutase has not
yet been fully elucidated. According to most recent studies, it
appears that the reaction involves a displacement mechanism
in which a reduced flavin cofactor acts as a nucleophile, thus
substituting UDP from UDP-Galp and leading to a N-galacto-
sylated intermediate which allows equilibration between the
furanose and pyranose forms of galactose. As in other reactions
at the anomeric carbon of glycosyl donors, these displacements
are thought to occur by way of an oxocarbenium-like transition
state.9 Since iminosugars are known to be mimicks of such
positively charged states, we considered that pyrrolidine-
containing analogs of UDP-Galf might be of interest as potential
inhibitors of both the ring contraction and the glycosyl transfer
reactions. In support of this proposal, pyrrolidine-based nucleo-
side analogs have been conceived by Schramm and Tyler10 as
inhibitors of purine nucleoside phosphorylases and related
enzymes on the basis of a detailed study of transition state
structures carrying a partial positive charge at the reaction site;
some of these compounds turned out to be the most powerful
In the context of our studies on iminosugars of biological
interest,12 we engaged in a research program on novel UDP-
Galf mimicks containing a 1,4-dideoxy-1,4-imino-D-galactitol
entity. While syntheses of the parent 1,4-dideoxy-1,4-imino-D-
galactitol and of a homo-derivative have been reported,13 a single
example of such galacto-pyrrolidine linked to uridine has been
described so far.14 We reported recently the first synthesis of a
â-linked UDP-Galf mimicks based on a pyrrolidinol skeleton
by way of a 1,3-dipolar cycloaddition process onto a cyclic
nitrone.15 We describe in this article the full details of a synthetic
study of UDP-Galf mimicks in which a UMP fragment is
R-linked to 1,4-dideoxy-1,4-imino-D-galactitol by a 3-carbon
tether.16 The final, fully deprotected UDP-Galf analogs as well
as related compounds were then tested as inhibitors of UDP-
Gal mutase.
Synthetic Design. Our retrosynthetic analysis starts with
D-glucose and is based on reactions of the Z-protected gluco-
sylamine A as key intermediate (Scheme 2). The crucial step
of the strategy is the highly stereoselective Lewis-acid-catalyzed
nucleophilic addition of silylated nucleophiles onto the corre-
sponding N-acyl iminium ion, a process pionneered by Koba-
yashi et al.17 This process would thus lead to precursors of ‘R-
configured’ 1,4-iminogalactitol derivatives. Then, coupling with
UMP would be achieved by cross-metathesis between an R-1-
C-allyl-1,4-imino-D-galactitol B and a uridin-5′-yl vinylphos-
phonate to provide eventually compounds of type C.
(5) Galf is found in: Trypanosomatids: De Lederkremer, R. M.; Colli,
W. Glycobiology 1995, 5, 547-552; S. disenteriae: Dmitriev, B. A.; Lvov,
V. L.; Kochetkov, N. K. Carbohydr. Res. 1977, 56, 207-209; M.
tuberculosis: Besra, G. S.; Khoo, K. H.; McNeil, M. R.; Dell, A.; Morris,
H. R.; Brennan, P. J. Biochemistry 1995, 34, 4257-4266. Galf has also
been found recently in lower eukaryotes: (a) Bakker, H.; Kleczka, B.;
Gerardy-Schahn, R.; Routier, F. H. Biol. Chem. 2005, 7, 657-661. (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, 1147-1154.
(6) (a) Sanders, D. A. R.; Staines, A. G.; McMahon, S. A.; McNeil, M.
R.; Whitfield, C.; Naismith, J. H. Nat. Struct. Biol. 2001, 8, 858-863. (b)
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, 971-982.
(7) (a) Belanova, M.; Dianiskova, P.; Brennan, P. J.; Completo, G. C.;
Rose, N. L.; Lowary, T. L.; Mikusova, K. J. Bacteriol. 2008, 190, 1141-
1145. (b) Rose, N. L.; Completo, G. C.; Lin, S.-J.; McNeil, M.; Palcic, M.
M.; Lowary, T. L. J. Am. Chem. Soc. 2006, 128, 6721-6729. (c) Mikusova,
K.; Belanova, M.; Kordulakova, J.; Honda, K.; McNeil, M. R.; Mahapatra,
S.; Crick, D. C.; Brennan, P. J. J. Bacteriol. 2006, 188, 6592-6598. (d)
Mikusova, K.; Yagi, T.; Stern, R.; McNeil, M. R.; Besra, G. S.; Crick, D.
C.; Brennan, P. J. J. Biol. Chem. 2000, 275, 33890-33897. (e) Kremer,
L.; Dover, L. G.; Morehouse, C.; Hitchin, P.; Everett, M.; Morris, H. R.;
Dell, A.; Brennan, P. J.; McNeil, M. R.; Flaherty, C.; Duncan, K.; Besra,
G. S. J. Biol. Chem. 2001, 276, 26430-26440.
(11) (a) Stu¨tz, A. E. Iminosugars as Glycosidase Inhibitors: Nojirimycin
and Beyond; Wiley-VCH: Weinheim, 1999. (b) For a review of iminosugar-
based glycosyl transferase inhibitors, see: Compain, P.; Martin, O. R. Curr.
Top. Med. Chem. 2003, 3, 541-560. (c) Compain, P.; Martin, O. R.
Iminosugars: From Synthesis to Therapeutic Application; Wiley: Chich-
ester, 2007.
(12) Boucheron, C.; Desvergnes, V.; Compain, P.; Martin, O. R.; Lavi,
A.; Mackeen, M.; Dwek, R. A.; Wormald, M.; Butters, T. D. Tetrahedron
Asymmetry 2005, 16, 1747-1756.
(13) (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, 6733-6736. (b) Pham-Huu, D.-P.; Gizaw, Y.;
BeMiller, J. N.; Petrus, L. Tetrahedron 2003, 59, 9413-9417.
(14) Linkage by a diamide tether: Lee, R. E.; Smith, M. D.; Pickering,
L.; Fleet, G. W. J. Tetrahedron Lett. 1999, 40, 8689-8692.
(15) (a) Liautard, V.; Christina, A. E.; Desvergnes, V.; Martin, O. R. J.
Org. Chem. 2006, 71, 7337-7345. See also: (b) Desvergnes, S.; Des-
vergnes, V.; Martin, O. R.; Itoh, K.; Liu, H. W.; Py, S. Bioorg. Med. Chem.
2007, 15, 6443-6449.
(8) (a) Huang, Z.; Zhang, Q.; Liu, H. W. Bioorg. Chem. 2003, 31, 494-
502. (b) Soltero-Higgin, M.; Carlson, E. E.; Gruber, T. D.; Kiessling, L. L.
Nat. Struct. Mol. Biol. 2004, 11, 539-543. (c) Caravano, A.; Sinay¨, P.;
Vincent, S. P. Bioorg. Med. Chem. Lett. 2006, 16, 1123-1125. (d)
Mansoorabadi, S. O.; Thibodeaux, C. J.; Liu, H. W. J. Org. Chem. 2007,
72, 6329-6342. (e) Chad, J. M.; Sarathy, K. P.; Gruber, T. D.; Addala, E.;
Kiessling, L. L.; Sanders, D. A. Biochemistry 2007, 46, 6723-6732.
(9) Itoh, K.; Huang, Z.; Liu, H. W. Org. Lett. 2007, 9, 879-882.
(10) Schramm, V. L.; Tyler, P. C. Curr. Top. Med. Chem. 2003, 3, 525-
540. See also Chapter 8 in ref. 11c.
(16) For a preliminary communication, see: Liautard, V.; Desvergnes,
V.; Martin, O. R. Org. Lett. 2006, 8, 1299-1302.
(17) (a) Sugiura, M.; Kobayashi, S. Org. Lett. 2001, 3, 477-480. (b)
Sugiura, M.; Hagio, H.; Hirabayashi, R.; Kobayashi, S. Synlett 2001, 1225-
1228. (c) Sugiura, M.; Hagio, H.; Hirabayashi, R.; Kobayashi, S. J. Am.
Chem. Soc. 2001, 123, 12510-12517. (d) Sugiura, M.; Hirabayashi, R.;
Kobayashi, S. HelV. Chem. Acta 2002, 85, 3678-3691.
3104 J. Org. Chem., Vol. 73, No. 8, 2008

Galf and UDP-Galf Mimicks
TABLE 1. Allylation of 2 under Various Conditionsa
SCHEME 2. Synthetic Targets and Retrosynthesis
entry
lewis acid (equiv)
reaction time (h)
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
TMSOTf (0.1)
TMSOTf (0.5)
TMSOTf (1)
TMSOTf (1.25)
Bi(OTf)3 (0.1)
Bi(OTf)3 (0.5)
Bi(OTf)3 (1.25)
TIPSOTf (0.1)
TIPSOTf (1)
TIPSOTf (1.25)
HNTf2 (0.1)
HNTf2 (0.5)
HNTf2 (1.25)
Sc(OTf)3 (1.25)
BF3.Et2O (1.25)
48
65
48
72
48
64
48
48
64
48
48
48
48
48
48
61
74
83
86
52
80
81
72
80
80
36
75
53
0
8
a Seven equivalents of AllSiMe3 were used in MeCN at -40 °C.
SCHEME 3. Synthesis of the N-Z Glucosylamine 2
with the rather oxophilic BF3 etherate, disappointing results were
obtained, that could be linked to the numerous chelation sites
(OBn, CO2Bn) on the substrate, thereby decreasing the avail-
ability of the Lewis acid to form the N-acyl iminium ion (entry
15). Surprisingly, scandium triflate, which was expected to
behave like bismuth triflate, did not lead to the conversion of
the N-glucosylamine 2 whatever the reaction conditions used
(entry 14). HNTf2 is a very reactive acid but its air and moisture
sensitivity limited the reproducibility of the reactions.
SCHEME 4. Synthesis of the Allylamine 3a
As a consequence, TMSOTf was used to scale up the
synthesis of 3a and to perform the addition of a variety of other
silylated nucleophiles to N-glucofuranosylamine 2, thus extend-
ing the synthetic value of this reaction (Scheme 5 and Table
2). Several useful functionalities could thus be introduced: with
TMSCN, the reaction led to heptononitrile 3b in an unoptimized
63% yield (entry 2). With silyl enol ethers, various keto
functions were appended (entries 3, 4 and 5): a benzoylmethyl
group with the silyl enol ether of acetophenone, a 2-oxocyclo-
hexyl and a 2-oxocyclopentyl group with the silyl enol ethers
of cyclohexanone and cyclopentanone respectively. It is note-
worthy that a single stereoisomer was formed at the alkylation
site R to the carbonyl group in cyclohexanone derivative 3d
whereas a mixture of two stereoisomers (ratio 2:1) was isolated
for its cyclopentanone analog 3e. A similar result was obtained
using 2-(trimethylsiloxy)furan as the reagent: in this case, the
two epimers at the alkylation site Cγ, butenolides 3f and 3f′
(27:73), could be isolated and fully characterized. These
compounds are of particular interest as synthetic precursors of
disaccharide mimicks (entry 6). Despite a disappointing yield
(12%) and low stereoselectivity, it was possible to obtain the
protected R-amino phosphonate 3g by reaction with diethyl
trimethylsilyl phosphite (entry 7). Unsaturated aliphatic chains
could also be introduced as alkyne or allene moieties in moderate
yields using 3-trimethylsilyl-1,2-butadiene or propargyltrimeth-
ylsilane as reagents (entries 8 and 9). The reaction of 2 with
TMS isocyanate provided in one step the original cyclic
carbamate 3j resulting from the reaction of the free 4-hydroxyl
group with the isocyanate function introduced as nucleophile.
This stereochemically homogeneous structure incorporates an
unprecedented, stable aminal of D-glucose (entry 10).
Results and Discussion
1-O-Acetyl-2,3,5,6-tetra-O-benzyl-D-glucofuranose 1 was pre-
pared from D-glucose on a 20 g scale by a four-step procedure.15
Under the conditions reported by Kobayashi (Z-NH2, TMSOTf),
the corresponding N-Z glycosylamine was obtained as a single
product in 85% yield using 2 equiv of benzyl carbamate. When
only 1.5 equiv or less of the carbamate was used, 2 was obtained
as a mixture (from 96/4 to 84/16) with the byproduct 2′ (1,6-
anhydro-2,3,5-tri-O-benzyl-â-D-glucofuranose)18 arising from a
Lewis acid-assisted regioselective de-O-benzylation at O-6
(Scheme 3). It is noteworthy that the reaction also works directly
from 2,3,5,6-tetra-O-benzyl-D-glucofuranose. This reaction was
recently extended to other deactivated amines (e.g., TsNH2) and
other sugar hemiacetals.19
The glucofuranosylamine 2 (R,â mixture) was then submitted
to the Lewis acid-catalyzed reaction with allyltrimethylsilane
(Scheme 4). After extensive investigations on the nature of the
Lewis acid and on reaction conditions (Table 1), it was found
that TMSOTf was the best reagent. 1.25 equiv of TMSOTf and
7 equiv of allyltrimethylsilane (added in portions) were neces-
sary for the reaction to go to completion (entry 4). Compound
3a was then isolated in a good yield of 86% and as a single
syn-stereoisomer (see below).
Silylated Lewis acids and bismuth triflate, known to be
somewhat azaphilic,20 led to the best results. On the other hand,
With one exception, all addition reactions exhibited a high
degree of stereoselectivity: for the reactions leading to a single
new stereogenic center by formation of a C-C bond, only one
product was isolated (d.e. > 98%), which was shown, after
cyclization, to have a 1,2-syn relationship, as expected from a
(18) Ko¨ll, P.; John, H.-G.; Schulz, J. Liebigs Ann. Chem. 1982, 613-
625.
(19) Liautard, V.; Pillard, C.; Desvergnes, V.; Martin, O. R. Carbohydr.
Res. in press; doi 10.1016/j.carres.2007.11.022.
(20) Kobayashi, S.; Busujima, T.; Nagayama, S. Chem.-Eur. J. 2000,
6, 3491-3494.
J. Org. Chem, Vol. 73, No. 8, 2008 3105

Liautard et al.
SCHEME 5. Addition of Silylated Nucleophiles to Glycosylamine 2
a
TABLE 2. Reactions of 2 with Silylated Nucleophiles NuSiMe3
a All reactions were performed using 0.5 equiv of TMSOTf and 7 equiv of silylated nucleophile, in CH3CN at -40 °C.
favored Re-face addition on the intermediate iminium ion.14 The
addition of the P-nucleophile, (EtO)2POTMS, is the only
reaction that proceeded with poor diastereoselectivity.
Next, to achieve cyclization, a classical two-step sequence
involving mesylation of the free 4-OH group and subsequent
treatment of the mesylate with a base (t-BuOK) provided the
corresponding pyrrolidinol derivatives (series 5) in modest to
good yields (Scheme 6 and Table 3). In particular, the nitrile
5b was found to be sensitive to base and we experienced some
difficulties with the synthesis of this compound. Also, in most
cases, better yields could be reached if the two steps from 3
were performed without isolating and purifying the mesylated
3106 J. Org. Chem., Vol. 73, No. 8, 2008

Galf and UDP-Galf Mimicks
SCHEME 6. Synthesis of Pyrrolidinols 5
SCHEME 7. N-Deprotection of Compound 5a
intermediate 4. All new compounds 5a-j are original imino-C-
glycosyl mimicks of R-galactofuranosides. The functional
groups in the aglycone can be used to tether a UDP surrogate
by various synthetic approaches or to prepare analogs of other
Galf conjugates.
configuration of the pseudo-anomeric center was performed on
the N-deprotected pyrrolidine 6a (Scheme 7) and 6b.
Since the carbamate rotamers in compounds of series 5
complicated their analysis by NMR, the determination of
Vicinal coupling constants as well as clear NOESY connec-
tivities established unambiguously the 1,2-cis configuration of
TABLE 3. Synthesis of Pyrrolidinols 5
a Two-step sequence starting from 3. b Three-step sequence starting from 2. c Undetermined configuration at C*. d d.r. 67:33 at C*.
J. Org. Chem, Vol. 73, No. 8, 2008 3107

Liautard et al.
SCHEME 8. Cross-Metathesis Reactions of 5a and
Deprotections
FIGURE 1. NOE correlations in compounds 6a and 6b.
the 1-C-substituted iminogalactitol derivative 6a and 6b and
hence the 1,2-syn configuration of the addition product 3a
(Figure 1). By analogy and on the basis of similarities in NMR
spectra of compounds in the same series, the 1,2-cis configu-
ration was assigned to all pyrrolidinol derivatives 5 and the 1,2-
syn configuration to all addition products 3.
Further elaboration into UDP-Galf mimicks was performed
from the R-C-allylated pyrrolidinol 5a and functionalized
alkenes by cross-metathesis. This powerful coupling process is
relatively insensitive to the presence of heteroatoms in the
reaction partners, with the exception of amino groups.21 It has
already been used by our group22 and others23 to access
functionalized C-glycosyl compounds in iminosugars carrying
a deactivating protecting group at nitrogen. The coupling
procedure was first investigated using diethyl vinylphosphonate
24
(DEVP). Hoveyda-Grubbs II complex [Ru]-3 turned out to
be the most efficient catalyst and provided the cross-coupling
product 9 in good yield, as the (E)-stereoisomer only, together
with some homodimerization product 10 (10%). With Nolan’s
catalyst [Ru]-2,25 the reaction did not go to completion and,
surprisingly, no conversion was observed with Grubbs II
complex [Ru]-1 (Scheme 8 and Table 4).
Moreover, the latter compound (10) was obtained efficiently
(53% yield) via the homo-cross-coupling of 5a using 10 mol
% of [Ru]-3 as catalyst (Scheme 8). This compound is the
precursor of interesting structures mimicking fragments of
galactan. The coupling products 9 and 10 were N- and
O-deprotected efficiently without affecting the alkene function
using a large excess of BCl3, thus providing unsaturated
phosphonate 11 and the bis-imino-C-disaccharide 13 as hydro-
chlorides in 74% and 96% yield respectively. A further treatment
26
of 11 using BrSiMe3 led to the free phosphonic acid 12 (as
hydrobromide) and catalytic hydrogenation of 13 provided
compound 14. These new imino-C-glycosyl compounds are of
interest as potential inhibitors of various carbohydrate-processing
enzymes.
TABLE 4. Screening of Catalysts for Coupling of 5a with DEVP
[Ru] catalyst
5a
9
10
Grubbs II [Ru]-1
100%
9%
-
68%
75%
-
Nolan [Ru]-2
8%
(21) Compain, P. AdV. Synth. Catal. 2007, 349, 1829-1846.
(22) Godin, G.; Compain, P.; Martin, O. R. Org. Lett. 2003, 5, 3269-
3272.
Hoveyda-Grubbs II [Ru]-3
-
10%
(23) Dondoni, A.; Giovannini, P. P.; Perrone, D. J. Org. Chem. 2005,
70, 5508-5518.
Interestingly, the allyl group of 5a could be isomerized into
a 1-propenyl substituent to give compound 15 (69%) in the
presence of Hoveyda’s catalyst when the reaction was performed
in methanol at higher temperature, as shown recently by
Hanessian and co-workers.27 The same isomerization process
was also successful (in 61% yield) using Pd(MeCN)2Cl2 (10
mol % in toluene at 60 °C for 48 h).28 Cross-metathesis with
(24) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda, A.
H. J. Am. Chem. Soc. 1999, 121, 791-799. See also: Vehlow, K.;
Maechling, S.; Blechert, S. Organometallics 2006, 25, 25-28.
(25) (a) Huang, J.; Stevens, E. D.; Nolan, S. P.; Petersen, J. L. J. Am.
Chem. Soc. 1999, 121, 2674-2678. (b) Amblard, F.; Nolan, S. P.; Schinazi,
R. F.; Agrofoglio, L. A. Tetrahedron 2005, 61, 537-544. For an application
to a homodimerization process, see, e.g., Grellepois, F.; Crousse, B.; Bonnet-
Delpon, D.; Be´gue´, J. P. Org. Lett. 2005, 7, 5219-5222.
(26) For phosphonate deprotection using BrSiMe3, see, e.g.: (a) Vidil,
C.; More`re, A.; Garcia, M.; Barragan, V.; Hamdaoui, B.; Rochefort, H.;
Montero, J.-L. Eur. J. Org. Chem. 1999, 447-450. (b) Ladame, S.; Faure´,
R.; Denier, C.; Lakhdar-Ghazal, F.; Wilson, M. Org. Biomol. Chem. 2005,
3, 2070-2072.
(27) Hanessian, S.; Giroux, S.; Larsson, A. Org. Lett. 2006, 24, 5482-
5484.
(28) Chang, G. X.; Lowary, T. Tetrahedron Lett. 2006, 47, 4561-4564.
3108 J. Org. Chem., Vol. 73, No. 8, 2008

Galf and UDP-Galf Mimicks
TABLE 5. Inhibition of E. Coli UGM by Selected Compoundsa
SCHEME 9. Isomerization of Allyl Group in 5a
inhibitor
concentration
residual
activity
compound #
7a
8
25 mM
2.5 mM
2.5 mM
2.5 mM
2.5 mM
25 mM
2.5 mM
61%
52.1%
50%
36.9%
59.2%
52%
13
14
16
19
20
43%
a See experimental procedures in ref 15b.
SCHEME 10. Synthesis of UDP-Galf Mimick 20
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. To the best of our knowledge this
compound is the closest iminosugar-based analog of UDP-Galf
ever reported.
The inhibitory activity of compounds 7a, 8, 13, 14, 16, 19,
and 20 toward UGM from Escherichia coli was then evaluated
and the results are reported in Table 5. Inhibition assays on the
purified enzyme were conducted in the reverse direction in
which UDP-Galf is converted to UDP-Galp using an HPLC
method developped by Lee and co-workers29 under the same
conditions as previously reported.15b Residual activity is ex-
pressed in % of the activity in absence of inhibitor.
All derivatives tested were found to exhibit weak inhibition
of UGM. Residual activity is in the order of 50% for most
compounds at 2.5 mM inhibitor concentration. Noticably, the
presence of the UMP motif, which was anticipated to provide
significant binding, increased only to a very minor extent the
activity of the compounds carrying a simple 3-carbon substituent
at C-1. This is even more surprising in view of Kiessling’s recent
work on chemical probes for UGM which suggested that the
presence of an aromatic group mimicking uracil is essential for
better binding with the enzyme.30 Most of the recognition by
the enzyme appears to arise from the 1,4-iminogalactitol moiety,
and dimerization of this unit, as in 13 and 14, contributes to
enhance the inhibitory activity. Compound 14 is indeed the most
active inhibitor of the series.
In conclusion, we report in this article a convenient and highly
stereoselective methodology for the synthesis of a diversity of
R-1-C-substituted-1,4-dideoxy-1,4-imino-D-galactitols; such com-
pounds constitute novel, original galactofuranoside mimicks.
One of these compounds was converted into UDP-Galf analogs
(19, 20) in which UMP is linked to the galacto-pyrrolidinol by
a 3-C tether, thereby mimicking closely the structure of the
natural sugar nucleotide; carbon-linked disaccharide analogs (13,
14) were also generated from the same precursor. Whereas the
activity of compounds such as 19 and 20 as inhibitors of UGM
was found to be weak, these sugar nucleotide analogs remain
promising chemical probes of the Galf transfer process involved
in the biosynthesis of mycobacterial galactans. In addition the
1-C-substituted iminogalactitol derivatives and the corresponding
dimers are of interest as potential inhibitors of various glyco-
furanosidases. Further biological investigations on these com-
pounds are in progress and the results will be reported in due
course.
other alkenes however was unsuccessful from 15. Deprotection
of 15 by the action of excess BCl3 provided 16 (Scheme 9).
The same coupling approach was used to obtain the R-linked
UDP-Galf mimicks 20 using the ethyl uridin-5′-yl vinylphos-
phonate 1715 as cross-metathesis partner (Scheme 10). As with
the previous reagent, total conversion of compound 5a was
achieved using Hoveyda-Grubbs II complex [Ru]-3 as the
catalyst. The iminosugar-nucleotide conjugate 18 was thus
obtained as a mixture of non-separable P*-epimers in 61% yield
together with a small amount of compound 10 (13%). A two-
step deprotection sequence led to the fully deprotected target
compound 20 (42% overall). Treatment of 18 with BCl3 in
excess at 0 °C promoted the complete deprotection of the
ribofuranose and iminogalactitol moieties and led to the
phosphonic diester 19. The ethyl phosphonate could then be
cleaved selectively by reacting 19 with BrSiMe3 to provide
UDP-Galf analog 20. This compound incorporates an iminosugar
moiety that mimicks the putative galactofuranosyl cation
(29) Lee, R.; Monsey, D.; Weston, A.; Duncan, K.; Rithner, C.; McNeil,
M. Anal. Biochem. 1996, 242, 1-7.
(30) Carlsson, E. E.; May, J. F.; Kiessling, L. L. Chem. Biol. 2006, 13,
825-837.
J. Org. Chem, Vol. 73, No. 8, 2008 3109

Liautard et al.
mg, 81%) from 2 (208 mg, 0.31 mmol), using 0.5 equiv of
trimethylsilyl triflate and after a stirring time of 72 h. [R]25D -3 (c
Experimental Section
General Procedure A: Addition of Silylated Nucleophiles.
In a dry 10 mL flask, under Ar, the silylated nucleophile (NuSiMe3
in Table 2) (1.45 mmol, 7 equiv) was added to a solution of
N-benzyloxycarbonyl-2,3,5,6-tetra-O-benzyl-R,â-D-glucofuranosy-
lamine 2 (140 mg, 0.21 mmol)19 in anhydrous acetonitrile (2.1 mL).
The mixture was stirred at -40 °C during 15 min and trimethylsilyl
triflate (19 µL, 0.10 mmol, 0.5 equiv) was then added by portions
to the colorless solution. The mixture was stirred at -40 °C during
20-82 h, and the reaction was then quenched with saturated
aqueous NaHCO3 (1 mL). Ethyl acetate (20 mL) was added and
the organic layer was separated, washed with brine (20 mL) and
dried over sodium sulfate. The solvents were removed by evapora-
tion under vacuum to afford a brown oil which was purified by
flash chromatography (toluene/acetone 99:1 to 98:2 containing a
trace of Et3N unless otherwise indicated).
1
) 0.69, CHCl3); H NMR (500 MHz, CDCl3) δ 2.93 (d, 1H, J ≈
7.5 Hz, OH), 3.01-3.05 (m, 1H, CH2COPh), 3.19-3.26 (m, 1H,
CH2COPh), 3.73-3.79 (m, 2H, H2 + H6a), 3.92-3.95 (m, 4H,
H6b + H5 + H3 + H4), 4.33-4.49 (m, 5H, H1 + OCH2Ph), 4.55
(broad s, 2H, OCH2Ph), 4.70-4.77 (m, 2H, OCH2Ph), 5.02 (d, 1H,
J ≈ 12 Hz, OCH2Ph), 5.07 (d, 1H, J ≈ 12 Hz, OCH2Ph), 5.43-
5.47 (m, 1H, NH), 7.08-7.81 (m, 30H, HAr’s); 13C NMR (125 MHz,
CDCl3) δ 41.5 (CH2COPh), 48.3 (C1), 66.9 (OCH2Ph), 70.3 (C5),
71.2 (C6), 71.7, 73.6, 74.4, and 75.0 (OCH2Ph), 77.9 (C3 or C4),
78.3 (C2), 78.7 (C4 or C3), 127.5-128.6, 133.3, 136.5, 138.0,
138.3, 138.4, and 138.8 (CqAr), 155.9 (CdO), 198.4 (CdO); HRMS
(ESI) calcd for C50H51NNaO8: m/z ) 816.3512 [M + Na]+;
found: m/z ) 816.3506.
1(R)-2,3,5,6-Tetra-O-benzyl-1-benzyloxycarbonylamino-1-
deoxy-1-C-(2-oxocyclohexyl)-D-glucitol (3d). According to general
procedure A, compound 3d (107 mg, 68%) was obtained from
compound 2 (138.1 mg, 0.205 mmol) as a single product and as a
colorless oil after purification by flash chromatography (EP/AcOEt
4:1). [R]25D -19 (c ) 0.99, CHCl3); IR (NaCl, cm-1) 3435, 3063,
1
3031, 2935, 2863, 1718, 1702, 1498, 1454, 1210, 1072, 1028; H
NMR (250 MHz, CDCl3) δ 1.48-2.10 (m, 7H), 2.17-2.33 (m,
1H), 2.78-3.00 (m, 2H, OH and CHCO), 3.57-3.75 (m, 2H, H5
+ H6a), 3.77-3.90 (m, 2H, H3 + H6b), 3.92-4.06 (m, 2H, H2 +
H4), 4.08-4.18 (m, 1H, H1), 4.24 (d, 1H, J ≈ 11 Hz, OCH2Ph),
4.31 (d, 1H, J ≈ 11.5 Hz, OCH2Ph), 4.43-4.59 (m, 4H, OCH2-
Ph), 4.60-4.72 (m, 2H, OCH2Ph), 5.52 (d, 1H, J ≈ 10 Hz, NH),
7.06-7.40 (m, 25H, CHAr’s); 13C NMR (125 MHz, CDCl3) δ 24.4,
27.8, 31.3, 42.4, and 52.1 (cyclohexyl CH2 and CH), 53.5 (C1),
66.8 (OCH2Ph), 70.0 (C4), 71.0 (C6), 71.9, 73.6, 73.7, and 74.0
(OCH2Ph), 77.0 (C3), 77.3 (C2), 78.6 (C5), 127.5-128.8 (CHAr’s),
136.8, 138.0, 138.2, 138.3, and 138.7 (CqAr), 156.8 (CdO), 211.7
(CdO); (+) MS (ESI) : m/z ) 789.5 [M + NH4]+, 795.0 [M +
Na]+; HRMS (ESI) calcd for C48H53NNaO8: m/z ) 794.3669
[M + Na]+; found : m/z ) 794.3672.
1(R)-1-C-Allyl-2,3,5,6-tetra-O-benzyl-1-benzyloxycarbony-
lamino-1-deoxy-D-glucitol (3a). According to general procedure
A, compound 3a was obtained as a colorless oil (129 mg, 86%)
from 2 (140 mg, 0.21 mmol) after a stirring time of 72 h. [R]25
D
-6 (c ) 1.22, CHCl3); IR (NaCl, cm-1) 3436, 3029, 3013, 2927,
1
2866, 1716, 1498, 1454, 1333, 1216, 1097, 1060, 1027; H NMR
(500 MHz, CDCl3) δ 2.18-2.31 (m, 2H, CH2CHdCH2), 2.56 (d,
1H, J ≈ 9 Hz, OH), 3.55-3.59 (m, 1H, H4), 3.62-3.68 (m, 2H,
H5, H6a), 3.72 (d, 1H, J ≈ 8 Hz, H2), 3.81-3.91 (m, 3H, H1, H3,
H6b), 4.22 (d, 1H, J ≈ 11 Hz, OCH2Ph), 4.29 (d, 1H, J ≈ 11.5
Hz, OCH2Ph), 4.43-4.49 (m, 3H, OCH2Ph), 4.63 (d, 2H, J ≈ 11.5
Hz, OCH2Ph), 4.73 (d, 1H, J ≈ 11 Hz, OCH2Ph), 4.86-4.96 (m,
3H, OCH2Ph, CH2dCH), 5.04 (d, 1H, J ≈ 12.5 Hz, OCH2Ph) 5.13
(d, 1H, J ≈ 9.5 Hz, NH), 5.62-5.70 (m, 1H, CH)CH2), 7.08-
7.26 (m, 25H, CHAr’s); 13C NMR (125 MHz, CDCl3) δ 38.3 (CH2-
CHdCH2), 51.5 (C1), 66.8 (OCH2Ph), 70.9 (C5), 71.2 (C6), 71.7,
73.7, 74.7, and 75.2 (OCH2Ph), 78.2 (C3+C4), 79.7 (C2), 117.9
(CH2dCH), 127.5-128.6 (CHAr’s), 134.7 (CHdCH2), 136.7, 138.3,
138.4, and 138.6 (CqAr), 156.1 (CdO); (+) MS (ESI): m/z ) 733.5
[M + NH4]+, 738.5 [M + Na]+; HRMS (ESI): calcd for C45H49-
NNaO7: m/z ) 738.3407 [M + Na]+, found : m/z ) 738.3401.
Anal. Calcd. for C45H49NO7: C, 75.50; H, 6.90; N, 1.96. Found:
C, 75.72; H, 6.96; N, 1.84.
1(R)-2,3,5,6-Tetra-O-benzyl-1-benzyloxycarbonylamino-1-
deoxy-1-C-(2-oxocyclopentyl)-D-glucitol (3e). According to general
procedure A, compound 3e (367.5 mg, 70%) was obtained from
compound 2 (463 mg, 0.688 mmol) as a colorless oil (mixture of
diastereoisomers at cp-C2) after purification by flash chromatog-
raphy (EP/ AcOEt 5:2 to 2:1). IR (NaCl, cm-1) 3435, 3063, 3017,
1720, 1454, 1404, 1217, 1093, 1028; 1H NMR (400 MHz, CDCl3)
δ 1.22-2.42 (m, 7H), 2.71 (br s, 1H, OH), 3.59-4.05 (m, 6H),
4.20-4.95 (m, 8H, OCH2Ph and H2), 5.00-5.42 (m, 2H, OCH2-
Ph and NH), 7.11-7.42 (m, 25H, CHAr’s); 13C NMR (100 MHz,
CDCl3; d1 and d2 for diast. 1 and 2, respectively; cp for cyclopentyl)
δ 20.3 (d1, cp-C4), 20.5 (d2, cp-C4), 27.3 (d1, cp-C3), 27.7 (d2,
cp-C3), 38.7 (d1, cp-C5), 38.9 (d2, cp-C5), 50.2 (d2, cp-C2), 50.9
(d1, cp-C2), 51.2 (d1, C1), 52.3 (d2, C1), 67.0 (OCH2Ph), 70.3
(d1, C4), 70.7 (d2, C4), 71.0 (d2, C6), 71.5 (d1, C6), 71.7, 71.8,
73.58, 73.63, 74.2, 74.38, 74.44, and 74.8 (OCH2Ph), 77.4 (C3),
77.5 (C3), 77.9 (d1, C5), 78.1 (d2, C5), 78.3 (d1, C2), 78.5 (d2,
C2), 127.4-128.5 (CHAr’s), 136.6, 136.7, 137.9, 138.2, 138.3,
138.38, 138.40, 138.5, 138.6, and 138.9 (CqAr), 156.3 (CdO), 156.7
(CdO), 218.9 (cp-C1), 219.2 (cp-C1); (+) MS (ESI) : m/z ) 775.5
[M + NH4]+, 780.0 [M + Na]+; HRMS (ESI) calcd for C47H51-
NNaO8: m/z ) 780.3512 [M + Na]+; found : m/z ) 780.3513.
1(R)-2,3,5,6-Tetra-O-benzyl-1-benzyloxycarbonylamino-1-C-
but-2-ynyl-1-deoxy-D-glucitol (3h). According to general procedure
A, compound 3h (100 mg, 47%) was obtained from compound 2
(196 mg, 0.291 mmol) as a colorless oil after purification by flash
3,4,6,7-Tetra-O-benzyl-2-benzyloxycarbonylamino-2-deoxy-
D-glycero-D-ido-heptono-nitrile (3b). According to general pro-
cedure A, compound 3b was obtained as a colorless oil (35.1 mg,
63%) from 2 (53.4 mg, 0.079 mmol) using 0.5 equiv of trimeth-
ylsilyl triflate and after a stirring time of 56 h. [R]25 -4 (c )
D
0.45, CHCl3); IR (NaCl, cm-1) 3427, 3033, 2253, 1726, 1497, 1455,
1271, 1215, 1096, 1028; 1H NMR (500 MHz, CDCl3) δ 2.70 (broad
s, 1H, OH), 3.57-3.61 (m, 1H, H4), 3.65-3.73 (m, 1H, H6a),
3.78-3.82 (m, 2H, H6b + H5), 3.85 (d, 1H, J ≈ 7 Hz, H3), 4.03-
4.05 (m, 1H, H2), 4.28 (t, 2H, J ≈ 10.5 Hz, OCH2Ph), 4.50-4.65
(m, 4H, OCH2Ph), 4.71 (AB, 2H, J ≈ 11 Hz, OCH2Ph), 4.91-
4.93 (m, 1H, H-1), 5.02-5.12 (m, 2H, OCH2Ph), 5.67-5.69 (m,
1H, NH), 7.14-7.32 (m, 25H, CHAr’s); 13C NMR (125 MHz,
CDCl3) δ 43.8 (C1), 67.9 (OCH2Ph), 70.2 (C6, C5), 71.8, 73.7,
74.5, and 75.0 (OCH2Ph), 76.6 (C3), 77.6 (C4), 78.0 (C2), 118.2
(CN), 127.8-130.0 (CHAr’s), 135.8, 136.8, 137.7, 138.0, and 138.3
(CqAr), 155.4 (CdO); (+) MS (ESI) : m/z ) 719 [M + NH4]+;
HRMS (ESI) calcd for C43H44N2NaO7: m/z ) 723.3046 [M + Na]+,
found: m/z ) 723.3041.
chromatography (Toluene/ AcOEt 16:1). [R]25 -6 (c ) 0.71,
D
CHCl3); IR (NaCl, cm-1) 3429, 3063, 3032, 2919, 2866, 1718,
1
1498, 1454, 1334, 1266, 1216, 1095, 1062, 1027; H NMR (400
MHz, CDCl3) δ 1.71 (s, 3H, CH3), 2.30-2.57 (m, 2H, CH2), 2.66
(br s, 1H, OH), 3.56-3.71 (m, 1H, H5), 3.73-3.82 (m, 1H, H4),
3.85-3.94 (m, 3H, 2H6 and H3), 3.98-4.07 (m, 1H, H1), 4.09-
4.18 (m, 1H, H2), 4.23-4.42 (m, 2H, OCH2Ph), 4.49-5.00 (m,
4,5,7,8-Tetra-O-benzyl-3-benzyloxycarbonylamino-2,3-dideoxy-
1-C-phenyl-D-glycero-D-ido-1-octulose (3c). According to general
procedure A, compound 3c was obtained as a colorless oil (200
3110 J. Org. Chem., Vol. 73, No. 8, 2008

Galf and UDP-Galf Mimicks
7H, OCH2Ph), 5.07-5.17 (m, 1H, OCH2Ph), 5.24 (d, 1H, J ≈ 9.6
Hz, NH), 7.18-7.43 (m, 25H, CHAr’s); 13C NMR (100 MHz, CDCl3)
δ 3.6 (CH3), 23.6 (CH2), 51.2 (C1), 66.9 (OCH2Ph), 70.5 (C4),
71.2 (C6), 71.7, 73.6, and 74.5 (OCH2Ph), 75.36 (Calkyne-CH3), 75.41
(OCH2Ph), 76.8 (Calkyne-CH2), 77.9 (C3), 78.2 (C5), 78.9 (C2),
127.5-128.6 (CHAr’s), 136.6, 138.2, 138.3, and 138.7 (CqAr), 155.9
(CdO); (+) MS (ESI) : m/z ) 728 [M + H]+, 745.5 [M + NH4]+,
750.5 [M + Na]+; HRMS (ESI) calcd for C46H49NNaO7: m/z )
750.3407 [M + Na]+, found : m/z ) 750.3416.
providing a colorless oil which was purified by flash chromatog-
raphy (PE/AcOEt 7:1 containing a trace of Et3N).
1(R)-1-C-Allyl-2,3,5,6-tetra-O-benzyl-N-benzyloxycarbonyl-
1,4-dideoxy-1,4-imino-D-galactitol (5a). According to general
procedure B applied to 3a, compound 5a was obtained as a colorless
t
oil (70% yield, 2 steps), using 2.5 equiv BuOK. [R]25 + 7 (c )
D
0.73, CHCl3); IR (NaCl, cm-1) 3359, 3064, 3032, 2929, 2867, 1699,
1497, 1454, 1402, 1352, 1097, 1070, 1028; H NMR (500 MHz,
1
acetone-d6) δ 2.38-2.45 (m, 1H, CH2CHdCH2), 2.65 (broad s,
1H, CH2CH)CH2), 3.62-3.64 (m, 1H, H6a), 3.74-3.77 (m, 1H,
H6b), 3.97-4.01 (m, 1H, H5), 4.12 (dd, 1H, J ≈ 3 Hz, J ≈ 6.5
Hz, H2), 4.21-4.24 (m, 1H, H1), 4.26 (t, 1H, J ≈ 3 Hz, H3), 4.30-
4.32 (m, 1H, H4), 4.46 (d, 1H, J ≈ 12 Hz, OCH2Ph), 4.51 (d, 1H,
J ≈ 12 Hz, OCH2Ph), 4.53-4.74 (m, 6H, OCH2Ph), 4.94-4.96
(m, 1H, CH2dCH), 5.01-5.05 (m, 1H, OCH2Ph), 5.10 (d, 1H, J
≈ 12 Hz, OCH2Ph), 5.17 (d, 1H, J ≈ 12 Hz, OCH2Ph), 5.75-5.86
(m, 1H, CH)CH2), 7.27-7.42 (m, 25H, CHAr’s); 13C NMR (125
MHz, acetone-d6) δ 35.2 (CH2CHdCH2), 62.2-62.9 (C1), 66.2
(C4), 68.1 (OCH2Ph), 72.7 (C6), 73.3, 73.7, 74.3, and 74.5 (OCH2-
Ph), 79.6 (C5), 82.6 (C3), 83.9 (C2), 117.4 (CH)CH2), 128.8-
131.0 (CHAr’s), 134.6 (CqAr), 135.1 (CqAr), 137.7 (CHdCH2), 139.9,
139.8, 140.2, 140.4 and 140.7 (CqAr), 158.0 (CdO); (+) MS
(ESI): m/z ) 715.5 [M + NH4]+; HRMS (ESI) calcd for C45H47-
NNaO6: m/z ) 720.3301 [M + Na]+; found : m/z ) 720.3296.
Anal. Calcd. for C45H47NO6: C, 77.45; H, 6.79; N, 2.01. Found:
C, 77.80; H, 6.68; N, 2.09. Note: A sample of mesylate 4a was
purified (PE/AcOEt 85/15 containing a trace of Et3N); yield: 62%.
Then using the general cyclization procedure, compound 5a was
obtained in 55% yield.
1(R)-1-C-Allenyl-2,3,5,6-tetra-O-benzyl-1-benzyloxycarbony-
lamino-1-deoxy-D-glucitol (3i). According to general procedure
A, compound 3i (149 mg, 54%) was obtained from compound 2
(259 mg, 0.233 mmol) as a colorless oil after purification by flash
chromatography (PE/ AcOEt 7:1 to 6:1). [R]25 -1.6 (c ) 3.14,
D
CHCl3); IR (NaCl, cm-1) 3432, 3063, 3031, 2926, 2867, 1958,
1719, 1498, 1455, 1399, 1337, 1276, 1215, 1096, 1062, 1028, 854;
1H NMR (400 MHz, CDCl3) δ 2.67 (d, 1H, J ≈ 8.8 Hz, OH), 3.57-
3.97 (m, 6H), 4.31 (d, 1H, J ≈ 11.2 Hz, OCH2Ph), 4.35 (d, 1H, J
≈ 11.8 Hz, OCH2Ph), 4.47-4.65 (m, 4H, OCH2Ph and H1), 4.67-
4.84 (m, 5H, OCH2Ph and CH2)), 4.98 (d, 1H, J ≈ 12 Hz, OCH2-
Ph), 5.14 (d, 1H, J ≈ 12 Hz, OCH2Ph), 5.24 (q, 1H, J ≈ 5.9 Hz,
CH)), 5.38 (d, 1H, J ≈ 9.2 Hz, NH), 7.17-7.38 (m, 25H, CHAr’s);
13C NMR (100 MHz, CDCl3) δ 50.4 (C1), 66.9 (OCH2Ph), 70.9
(C6), 71.7, 73.6, 74.8, and 75.4 (OCH2Ph), 78.0 (CH), 78.6 (CH2)),
81.5 (CH), 91.8 (CH)), 127.5-128.6 (CHAr’s), 136.6, 138.19,
138.21, 138.4, and 138.6 (CqAr), 156.1 (CdO), 207.6 (dCd); (+)
MS (ESI) : m/z ) 714.5 [M + H]+, 731.5 [M + NH4]+, 736.5 [M
+ Na]+; HRMS (ESI) calcd for C45H47NNaO7: m/z ) 736.3250
[M + Na]+; found : m/z ) 736.3260.
2,3,5,6-Tetra-O-benzyl-D-glucose aminal NS-benzyl carbamate
NR,O-cyclic carbamate (3j). According to general procedure A,
compound 3j (96.5 mg, 58%) was obtained from compound 2 (157
mg, 0.233 mmol) as a colorless oil after purification by flash
3,4,6,7-Tetra-O-benzyl-N-benzyloxycarbonylamino-2,5-dideoxy-
2,5-imino-D-glycero-L-gluco-heptononitrile (5b). According to
general procedure A (using TMSCN) and B applied to 3b,
compound 5b was obtained as a colorless oil in 69% yield (3-step
yield). [R]25D +17 (c ) 0.66, CHCl3); IR (NaCl, cm-1) 3055, 2987,
chromatography (PE/AcOEt 3:1). [R]25 -26 (c )1.05, CHCl3);
D
IR (NaCl, cm-1) 3392, 3321, 3063, 3032, 2869, 1732, 1513, 1499,
2306, 1715, 1454, 1421, 1265, 1099, 1028; H NMR (500 MHz,
1
1
1455, 1266, 1309, 1227, 1102, 1028, 1046; H NMR (400 MHz,
acetone-d6) δ 3.65-3.67 (m, 1H, H6a), 3.71-3.73 (m, 1H, H6b),
4.05 (br s, 1H, H5), 4.30-4.31 (m, 2H, H3 + H4), 4.43-4.50 (m,
3, H2 + OCH2Ph), 4.52 (s, 2H, OCH2Ph), 4.63-4.78 (m, 3H,
OCH2Ph), 4.77 (d, 1H, J ≈ 11.8 Hz, OCH2Ph), 5.11 (very br s,
2H, OCH2Ph), 5.30 (br s, 1H, H1), 7.21-7.42 (m, 25H, CHAr’s);
13C NMR (125 MHz, acetone-d6) δ 53.9-54.2 (C1), 66.0 (C4),
69.0 (OCH2Ph), 72.3-72.6 (C6), 73.0 (OCH2Ph), 74.3 (OCH2Ph),
74.6 (OCH2Ph), 78.5 (C5), 82.7-82.9 (C2), 83.7-83.8 (C3), 117.8
(CN), 128.9-130.3 (CHAr’s), 138.2, 139.1, 139.7, 140.3, and 140.5
(CqAr); (+) MS (ESI) : m/z ) 700.5 [M + NH4]+; HRMS (ESI)
calcd for C43H42N2NaO6: m/z ) 705.2941 [M + Na]+; found :
m/z ) 705.2944.
Note: Stepwise process from compound 3b (75.9 mg, 0.108
mmol): mesylated intermediate 4b was obtained as a colorless oil
(74.5 mg, 88%) after purification by flash chromatography (PE/
AcOEt 3:1). Compound 5b was then obtained from 4b (173 mg,
0.222 mmol) as a colorless oil (100.7 mg, 67%) after purification
by flash chromatography (PE/AcOEt 85:15).
CDCl3) δ 3.64 (t, 1H, J ≈ 3.6 Hz, H2), 3.80 (dd, 1H, J ≈ 4.4 and
10.4 Hz, H6a), 3.88 (ddd, 1H, J ≈ 1.6, 4.4 and 9.6 Hz, H5), 3.99
(dd, 1H, J ≈ 1.6 and 10.4 Hz, H6b), 4.09 (d, 1H, J ≈ 3.6 Hz, H3),
4.25-4.39 (m, 3H, OCH2Ph), 4.45-4.65 (m, 5H, OCH2Ph and H4),
4.79 (d, 1H, J ≈ 11.6 Hz, OCH2Ph), 4.95-5.01 (m, 2H, OCH2Ph
and H1), 5.12 (d, 1H, J ≈ 12.4 Hz, OCH2Ph), 5.86 (d, 1H, J ≈ 6
Hz, NH), 6.99 (d, 1H, J ≈ 9.2 Hz, NH), 7.04-7.36 (m, 25H,
CHAr’s); 13C NMR (100 MHz, CDCl3) δ 61.0 (C1), 67.2 (OCH2-
Ph), 69.1 (C6), 71.0 (C2), 71.8, 72.0, 73.3, and 73.6 (OCH2Ph),
74.9 (C4), 75.6 (C5), 76.0 (C3), 127.6-128.7 (CHAr’s), 136.1, 136.7,
137.0, 138.3, and 138.4 (CqAr), 155.5 (CdO), 157.3 (CdO); (+)
MS (ESI) : m/z ) 717.5 [M + H]+, 734.5 [M + NH4]+, 739.5 [M
+ Na]+; HRMS (ESI) calcd for C43H44N2NaO8: m/z ) 739.2995
[M + Na]+; found : m/z ) 739.2980.
General Procedure B: Cyclization Procedure. In a dry flask
(10 mL), under Ar, methanesulfonyl chloride (8.2 µL, 0.11 mmol,
2.1 equiv) was added by portions to a solution of substrate 3 (38
mg, 0.053 mmol) in anhydrous dichloromethane (530 µL) contain-
ing triethylamine (16 µL, 0.12 mmol, 2.2 equiv). The yellow
mixture was stirred at room temperature for 5-12 h. After total
conversion (TLC monitoring), the reaction was quenched with
saturated aqueous NH4Cl (1 mL). Ethyl acetate (20 mL) was added,
the organic layer was separated, washed with brine (20 mL) and
dried over sodium sulfate. The solvents were then evaporated, thus
providing the corresponding methanesulfonate 4 as a yellow oil
which could be used in the next step without further purification.
Crude 4 (142 mg, 0.18 mmol) was dissolved in anhydrous THF
(1.8 mL) and t-BuOK (20.12 mg, 0.18 mmol) was added. The
mixture was stirred during 12-24 h at room temperature. After
total conversion (TLC monitoring), the reaction was quenched with
saturated aqueous NH4Cl (1 mL). Ethyl acetate (20 mL) was added,
the organic layer was separated, washed with brine (20 mL) and
dried over sodium sulfate. Then the solvents were evaporated, thus
4,5,7,8-Tetra-O-benzyl-N-benzyloxycarbonylamino-2,3,6-
trideoxy-3,6-imino-1-C-phenyl-D-glycero-L-gluco-1-octulose (5c).
Compound 5c was prepared from 3c according to general procedure
B; mesylation was immediately followed by the cyclization step
because intermediate 4c degrades rapidly. Compound 5c was
obtained as a colorless oil (40%, 2 steps). [R]25 -2 (c ) 0.73,
D
CHCl3); IR (NaCl, cm-1) 3400, 3063, 3032, 2927, 2867, 1699,
1
1685, 1453, 1408, 1351, 1317, 1266, 1094, 1071, 1027; H NMR
(500 MHz, acetone-d6) δ 3.31 (m, 1H, CH2COPh), 3.55 (m, 2H,
H6a + CH2COPh), 3.71 (br s, 1H, H6b), 3.91 (m, 1H, H5), 4.21-
4.28 (m, 3H, H3, H2 + OCH2Ph), 4.39-4.45 (m, 3H, OCH2Ph +
H4), 4.54-4.65 (m, 4H, OCH2Ph), 4.70-4.89 (m, 2H, OCH2Ph +
H1), 5.13 (br s, 2H, OCH2Ph), 6.87-7.58 (m, 30H, CHAr’s); 13C
NMR (125 MHz, acetone-d6) δ 39.9 (br, CH2COPh), 59.9-60.4
(C1), 66.5 (C4), 68.0 (OCH2Ph), 72.4-72.6 (C6), 73.85,73.93, 74.4,
and 79.3 (OCH2Ph), 82.3 (C3), 83.4-83.5 (C2), 127.5-131.2
J. Org. Chem, Vol. 73, No. 8, 2008 3111

Liautard et al.
(CHAr’s), 134.4-134.8 (CHAr’s), 138.7, 138.9, 139.3, 140.0, 140.2,
and 140.7 (CqAr), 157.6 (CdO), 199.9 (CdO); (+) MS (ESI) :
m/z ) 794.0 [M + NH4]+; HRMS (ESI) calcd for C50H49NNaO7:
m/z ) 798.3407 [M + Na]+; found : m/z ) 798.3410.
Note: A sample of mesylated intermediate 4c was purified by
flash chromatography (PE/AcOEt 4:1, 70% yield). Cyclization of
4c according to procedure B provided 5c in 21% yield.
(NaCl, cm-1) 3424, 2921, 2861, 1695, 1454, 1403, 1353, 1095,
1070, 1027; H NMR (400 MHz, CDCl3) δ 1.70 (s, 3H, CH3),
1
2.28-2.35 (m, 1H, CH2a), 2.53-2.91 (m, 1H, CH2b), 3.37-3.66
(m, 2H, H6), 3.85-3.97 (m, 1H, H5), 4.00-4.10 (m, 2H, H2, H3),
4.18-4.31 (m, 2H, H1, H4), 4.37-4.70 (m, 8H, OCH2Ph), 5.04-
5.20 (m, 2H, OCH2Ph), 7.10-7.34 (m, 25H, CHAr’s); 13C NMR
(100 MHz, CDCl3) δ 3.7 (CH3), 19.0-20.3 (CH2), 60.5-61.9 (C1),
65.1 (C4), 67.2 (OCH2Ph), 71.4 (OCH2Ph), 71.5-71.8 (C6), 73.1,
73.2, and 73.4 (OCH2Ph), 76.4 (Calkyne-CH3), 77.4 (Calkyne-CH2),
77.6 (C5), 80.8-81.0 (C2 or C3), 81.6-82.8 (C2 or C3), 127.6-
128.6 (CHAr’s), 136.9, 137.9, 138.1, 138.4, and 138.8 (CqAr), 156.8
(CdO); (+) MS (ESI) : m/z ) 712.5 [M + H]+; HRMS (ESI)
calcd for C46H47NNaO6: m/z ) 732.3301 [M + Na]+; found : m/z
) 732.3313.
1(R)-2,3,5,6-Tetra-O-benzyl-N-benzyloxycarbonyl-1,4-dideoxy-
1,4-imino-1-C-(2-oxocyclohexyl)-D-galactitol (5d). According to
general procedure B applied to compound 3d (649 mg, 0.841
mmol), mesylated intermediate 4d was isolated (223.1 mg, 32%)
as a colorless oil after purification by flash chromatography (PE/
AcOEt 4:1). Cyclization of intermediate 4d (184 mg, 0.228 mmol)
according to procedure B afforded compound 5d as a colorless oil
(61.5 mg, 36%) after purification by chromatography (PE/AcOEt
4:1). Alternatively, starting from crude 3d, compound 5d was
obtained in 36% yield after purification by flash chromatography,
without purification of intermediate 4d. Compound 5d: [R]25D +31
(c ) 0.94, CHCl3); IR (NaCl, cm-1) 3063, 3031, 2935, 2862, 1703,
1(R)-1-C-Allenyl-2,3,5,6-tetra-O-benzyl-N-benzyloxycarbonyl-
1,4-dideoxy-1,4-imino-D-galactitol (5i). According to general
procedure B applied to compound 3i (50 mg, 0.063 mmol),
compound 5i was obtained as a colorless oil (33.8 mg, 77%) after
purification by flash chromatography (PE/ AcOEt 9:1) by way of
1
mesylate 4i. Compound 5i: [R]25 +28 (c ) 0.61, CHCl3); IR
1453, 1402, 1351, 1307, 1213, 1093, 1027; H NMR (250 MHz,
D
(NaCl, cm-1) 3415, 2929, 2867, 1957, 1702, 1497, 1454, 1405,
DMSO-d6, 80 °C) δ 1.11-1.65 (m, 4H), 1.67-2.31 (m, 4H), 2.69-
2.81 (m, 1H, CHCO), 3.39-3.79 (m, 3H, 2H6 and H5), 4.02-
4.17 (m, 2H, H3 and H2), 4.28-4.39 (m, 2H, H4 and OCH2Ph),
4.39-4.56 (m, 6H, OCH2Ph), 4.60-4.74 (m, 2H, OCH2Ph and H1),
4.96-5.11 (m, 2H, OCH2Ph), 7.16-7.35 (m, 25H, CHAr’s); 13C
NMR (62.5 MHz, DMSO-d6, 80 °C) δ 24.1, 27.8, 31.3, 41.5, and
50.3 (cyclohexyl CH2 and CH), 58.6 (C1), 63.9 (C4), 66.0, 70.2,
70.6, 70.7, 71.9, 72.2, and 72.2 (OCH2Ph, C6), 77.8 (C5), 82.1
(C3 or C2), 82.6 (C3 or C2), 127.0-127.8 (CHAr’s), 136.4, 137.5,
137.7, 137.9, and 138.2 (CqAr), 156.3 (CdO), 210.5 (CdO); (+)
MS (ESI) : m/z ) 754.5 [M + H]+, 771.5 [M + NH4]+.
1
1353, 1267, 1097; H NMR (400 MHz, CDCl3) δ 3.54-3.75 (m,
2H, H6), 3.95-4.05 (m, 2H, H2 and H5), 4.07-4.20 (m, 2H, H3
and H4), 4.37-4.85 (m, 11H, OCH2Ph, CH2) and H1), 4.98-
5.28 (m, 3H, OCH2Ph and CH)), 7.18-7.35 (m, 25H, CHAr’s);
13C NMR (100 MHz, CDCl3) δ 60.0 (C1), 63.5 (C4), 67.4, 72.1,
72.2, 73.3, 73.4 (OCH2Ph, C6), 75.8-76.1 (CH2)), 77.7 (C5),
81.9-82.1 (C3), 82.9-83.1 (C2), 88.2 (CH)), 127.6-128.5
(CHAr’s), 136.6, 137.8, 138.2, 138.5, and 138.7 (CqAr), 156.1 (Cd
O), 209.3 (dCd); (+) MS (ESI) : m/z ) 696.5 [M + H]+, 714
[M + NH4]+; HRMS (ESI) calcd for C45H45NNaO6: m/z )
718.31446 [M + Na]+; found : m/z ) 718.3143.
1(R)-2,3,5,6-Tetra-O-benzyl-N-benzyloxycarbonyl-1,4-dideoxy-
1,4-imino-1-C-(2-oxocyclopentyl)-D-galactitol (5e). According to
general procedure B applied to compound 3e (127 mg, 0.186 mmol),
mesylated intermediate 4e was obtained as a colorless oil (103 mg,
73%) after purification by flash chromatography (PE/AcOEt 7:3).
Then compound 5e was obtained from intermediate 4e (83 mg,
0.1 mmol) as a colorless oil (18.3 mg, 25%, 67:33 mixture of
diastereoisomers at cp-C2) after purification by flash chromatog-
raphy (PE/AcOEt 4:1). IR (NaCl, cm-1) 3019, 2401, 1727, 1720,
General Procedure C: Carbamate Deprotection. Compound
5a or 5b (0.056 mmol) and triethylamine (2 µL) were dissolved in
ethanol (0.5 mL). The flask was submitted to 3 freeze-pump-
thaw cycles and palladium on charcoal (10% Pd on C, 0.1 equiv)
was added under argon. The mixture was then placed under
hydrogen. After a stirring time of 1.5-3 h at room temperature,
the solids were removed by filtration on celite and washed with
dichloromethane. Evaporation of the solvents provided a colorless
oily product which was homogeneous by NMR.
1
1701, 1454, 1406, 1353, 1216, 1093, 1071, 1028; H NMR (500
MHz, acetone-d6; d1 and d2 for diast. 1 and 2, respectively; cp for
cyclopentyl) δ 1.52-2.15 (m, 6H, cp-CH2), 2.32-2.40 (m, 1H,
cp-CH), 3.52 (dd, 0.76H, J ≈ 11 and 5.5 Hz, H6a, d1), 3.61 (dd,
0.34H, J ≈ 11 and 5 Hz, H6a, d2), 3.72 (dd, 0.76H, J ≈ 11 and 3
Hz, H6b, d1), 3.77 (dd, 0.34H, J ≈ 11 and 3 Hz, H6b, d2), 4.02-
4.06 (m, 1H, H5), 4.07 (d, 0.75H, J ≈ 6 Hz, H2, d1), 4.16-4.27
(m, 1.35H, H3 and H2, d2), 4.36-4.52 (m, 5H, OCH2Ph, H1 and
H4), 4.54-4.66 (m, 4H, OCH2Ph), 4.69-4.80 (m, 1H, OCH2Ph),
4.97 (d, 0.7H, J ≈ 13 Hz, OCH2Ph), 5.00-5.11 (m, 1.3H, OCH2-
Ph), 7.24-7.44 (m, 25H, CHAr’s); 13C NMR (125 MHz, acetone-
d6; d1 and d2 for diast. 1 and 2, respectively; cp for cyclopentyl)
δ 21.4 (d1, cp-C4), 21.5 (d2, cp-C4), 26.7 (d1, cp-C3), 28.4 (d2,
cp-C3), 37.5 (d1, cp-C5), 38.9 (d2, cp-C5), 49.0-49.2 (cp-C2),
62.0-62.3 (C1), 66.5 (C4), 67.3, 67.4, 71.5, 71.6, 71.68, 71.74,
72.8, 73.0, 73.3, 73.66, and 73.73 (OCH2Ph, C6), 79.1 (d2, C5),
79.2 (d1, C5), 80.3-80.5 (d1, C3), 80.58-80.63 (d2, C3), 84.2-
84.6 (C2), 128.0-129.2 (CHAr’s), 138.0, 138.4, 138.89, 138.90,
139.3, 139.6, and 140.3 (CqAr), 157.5 (CdO), cp-C1 hidden by
solvent CdO signal; (+) MS (ESI) : m/z ) 762.0 [M + Na]+;
HRMS (ESI) calcd for C47H49NNaO7: m/z ) 762.3407 [M + Na]+;
found : m/z ) 762.3416.
1(R)-2,3,5,6-Tetra-O-benzyl-1,4-dideoxy-1,4-imino-1-C-propyl-
D-galactitol (6a). This product was obtained from 5a (39 mg, 0.056
mmol) as a colorless oil (31.2 mg, 99%). [R]25 -33 (c ) 0.91,
D
CHCl3); IR (NaCl, cm-1) 3055, 2864, 1612, 1454, 1420, 1265,
1108; 1H NMR (500 MHz, acetone-d6) δ 0.91 (t, 3H, J ≈ 7.4 Hz,
CH3), 1.29-1.46 (m, 2H, CH2CH3), 1.50-1.57 (m, 1H) and 1.59-
1.67 (m, 1H) (CH2CH2CH3), 2.97 (dt, 1H, J ≈ 7 Hz, J ≈ 4 Hz,
H1), 3.14 (t, 1H, J ≈ 4 Hz, H4), 3.72-3.74 (m, 2H, 2H6), 3.81 (d,
1H, J ≈ 4 Hz, H2), 3.81-3.81 (m, 1H, H5), 3.92 (d, 1H, J ≈ 4.5
Hz, H3), 4.18-4.25 (m, 0.5H, NH), 4.45-4.55 (m, 5H, OCH2Ph),
4.60-4.66 (m, 2H, OCH2Ph), 4.76 (d, 1H, J ≈ 11.7 Hz, OCH2-
Ph), 7.21-7.37 (m, 20H, HAr); 13C NMR (125 MHz, acetone-d6) δ
15.7 (CH3), 22.1 (CH2CH3), 32.7 (CH2CH2CH3), 63.9 (C1), 68.8
(C4), 72.3, 73.3, and 74.1 (CH2OPh), 74.5 (C6), 74.7 (CH2OPh),
79.7 (C5), 86.4 (C2), 86.9 (C3), 129.1-130.6 (CHAr’s), 130.6
(CHAr), 133.0 (CHAr), 140.76, 140.80, 140.8, and 141.0 (CqAr); (+)
MS (ESI) : m/z ) 566.5 [M + H]+; HRMS (ESI) calcd for C37H43-
NO4: m/z ) 566.3270 [M + H]+; found : m/z ) 566.3266.
3,4,6,7-Tetra-O-benzyl-2,5-dideoxy-2,5-imino-D-glycero-L-gluco-
heptononitrile (6b). Deprotection of 5b (12 mg, 0.018 mmol)
according to general procedure C afforded 6b as colorless oil (9.5
1(R)-2,3,5,6-Tetra-O-benzyl-N-benzyloxycarbonyl-1-C-but-2-
ynyl-1,4-dideoxy-1,4-imino-D-galactitol (5h). According to general
procedure B applied to compound 3h (30.1 mg, 0.037 mmol),
compound 5h was obtained as a colorless oil (16.2 mg, 63%) after
purification by flash chromatography (PE/AcOEt 9:1) by way of
mg, 99%). [R]25 -7 (c ) 0.81, CHCl3); IR (NaCl, cm-1) 3019,
D
1
2927, CtN not visible, 1602, 1455, 1215, 1096; H NMR (500
MHz, CDCl3) δ 3.09 (t, 1H, J ≈ 5.3 Hz, H4), 3.54-3.61 (m, 2H,
H6), 3.68 (dd, 1H, J ≈ 10 Hz, J ≈ 5 Hz, H5), 3.81 (dd, 1H, J ≈
5 Hz, J ≈ 3.2 Hz, H3), 3.90 (d, 1H, J ≈ 5.2 Hz, H1), 4.00 (dd, 1H,
mesylate 4h. Compound 5h: [R]25 +1.5 (c ) 1.42, CHCl3); IR
D
3112 J. Org. Chem., Vol. 73, No. 8, 2008

Galf and UDP-Galf Mimicks
J ≈ 3.1 Hz, J ≈ 5.2 Hz, H2), 4.21 (d, 1H, J ≈ 11.7 Hz, OCH2Ph),
4.33 (d, 1H, J ≈ 11.7 Hz, OCH2Ph), 4.40 (s, 2H, OCH2Ph), 4.43
(d, 1H, J ≈ 11.7 Hz, OCH2Ph), 4.50 (d, 1H, J ≈ 11.8 Hz, OCH2-
Ph), 4.57 (d, 1H, J ≈ 11.8 Hz, OCH2Ph), 4.66 (d, 1H, J ≈ 11.5
Hz, OCH2Ph), 7.10-7.31 (m, 20H, CHAr’s); 13C NMR (125 MHz,
CDCl3) δ 51.4 (C1), 65.0 (C4), 71.1 (C6), 72.3, 72.6, 73.1, and
73.6 (OCH2Ph), 77.3 (C5), 83.4 (C2), 83.9 (C3), 118.0 (CN),
127.8-128.7 (CHAr’s), 137.1, 137.7, 138.1, and 138.3 (CqAr); (+)
MS (ESI): m/z ) 550.0 [M + H]+; HRMS (ESI) calcd for
C35H36N2NaO4: m/z ) 571.2573 [M + Na]+; found : m/z )
571.2572.
General Procedure D: O-Debenzylation. To a 0.01 M solution
of benzylated compound (1 equiv) in dry CH2Cl2 was added at
0 °C a fresh 1 M solution of BCl3 in hexane (11.5 equiv). The
mixture was stirred overnight at 0 °C, and then the solids formed
were dissolved by addition of MeOH (20 mL) and a few drops of
water. The reaction mixture was then concentrated under reduced
pressure. In some cases, it was found necessary to repeat the reaction
with 3 equiv of BCl3 overnight. In general, purification of the crude
final product was performed by flash chromatography on C18-
reverse phase silica gel (H2O/MeOH 1:0 to 4:1), thus providing
the debenzylated compound as its hydrochloride salt.
1(R)-1-C-Allyl-1,4-dideoxy-1,4-imino-D-galactitol (7a). Ac-
cording to general procedure D, compound 7a was prepared from
5a (134 mg, 0.19 mmol). MeOH and water (5 mL, 20:1) were added
to the mixture at the end of the reaction and the solution was quickly
filtered through ion-exchange resin (Dowex 1 × 8, OH- form)
which was then washed with MeOH (2 × 20 mL) and water (10
mL). Purification of the crude product by flash chromatography
on silica gel (CH2Cl2/MeOH 7:3 to 3:2) provided compound 7a
(12.7 mg, 33%) as a brown product. [R]25D -30 (c ) 1.21, MeOH);
1H NMR (CD3OD, 500 MHz) δ 2.48-2.54 (m, 1H) and 2.60-
2.66 (m, 1H)(allyl-CH2), 3.37 (dd, 1H, J ≈ 8 Hz, J ≈ 2.5 Hz, H4),
3.57 (td, 1H, J ≈ 3 and 7.5 Hz, H1), 3.65 (dd, 1H, J ≈ 5 and 11.5
Hz, H6a), 3.72 (dd, 1H, J ≈ 4.5 and 11.5 Hz, H6b), 3.85-3.90
(m, 1H, H5), 3.98 (dd, 1H, J ≈ 1 and 3 Hz, H2), 4.08 (dd, 1H, J
≈ 1 and 2.5 Hz, H3), 5.18 (dd, 1H, J ≈ 1.5 and 10 Hz, )CHaHb),
5.27 (dd, 1H, J ≈ 1.5 and 17 Hz, )CHaHb), 5.89 (m, 1H, )CH);
13C NMR (CD3OD, 125 MHz) δ 31.5 (CH2CH)), 63.1 (C1), 64.8
(C6), 70.3 (C4), 71.7 (C5), 77.0 (C2), 78.8 (C3), 119.0 ()CH2),
134.5 ()CH); (+) MS (ESI) : m/z ) 204.0 [M + H]+; HRMS
(ESI) calcd for C9H18NO4 : m/z ) 204.1236 [M + H]+, found :
m/z ) 204.1239.
1(R)-2,3,5,6-Tetra-O-benzyl-N-benzyloxycarbonyl-1,4-dideoxy-
1-C-(3-diethylphosphono-2-propen-1-yl)-1,4-imino-D-galactitol
(9). To a solution of 5a (172.4 mg, 0.248 mmol) in dry CH2Cl2
(4.1 mL) was added dropwise commercial diethyl vinylphosphonate
(76.8 µL, 0.495 mmol, 2 equiv). The flask was submitted to 3
freeze-pump-thaw cycles and placed under Ar. Then Hoveyda-
Grubbs catalyst (7.8 mg, 5%) was added and the 3 freeze-pump-
thaw-argon cycles were repeated. The reaction mixture was stirred
for 12 h at 40 °C, then another addition of Hoveyda-Grubbs catalyst
(7.8 mg, 5%) was made. After an additional stirring time of 12 h
at 40 °C, the reaction mixture was concentrated under reduced
pressure. Excess diethyl vinylphosphonate was removed from the
brown residue by coevaporation with toluene. Purification by flash
chromatography (CH2Cl2/MeOH 99:1) afforded compound 9 (154.9
mg, 75%) as a brown oily product. IR (NaCl, cm-1) 3063, 3031,
2981, 2867, 1701, 1454, 1402, 1353, 1267, 1247, 1216, 1099, 1059,
1027; 1H NMR (400 MHz, DMSO-d6, 80 °C; JH,H coupling
constants were measured on a 31P-decoupled spectrum) δ 1.22 (t,
6H, J ≈ 7 Hz, CH3), 2.48-2.53 (m, 1H) and 2.58-2.66 (m, 1H)
(CH2CHdCH), 3.57 (dd, 1H, J ≈ 5.9 Hz, J ≈ 10.9 Hz, H6a), 3.70
(dd, 1H, J ≈ 2.8 Hz, J ≈ 10.9 Hz, H6b), 3.87 (m, 1H, H5), 3.92
(quint, 4H, J ≈ 7.1 Hz, CH2CH3), 4.09-4.13 (m, 1H, H2), 4.16-
4.19 (m, 2H, H3, H4), 4.29 (q, 1H, J ≈ 7.2 Hz, H1), 4.43-4.68
(m, 8H, OCH2Ph), 5.09 (broad s, 2H, OCH2Ph), 5.61-5.70 (dd,
1H, J ≈ 17 Hz, JH-P∼21.3 Hz, PCH)CH), 6.58-6.71 (ddt, 1H, J
≈ 6.6 Hz, J ≈ 17 Hz, JH-P∼21.8 Hz, PCHdCH), 7.28-7.37 (m,
25H, CHAr’s); 13C NMR (125 MHz, DMSO-d6, 80 °C) δ 16.5 (d,
CH3), 34.2 (d, J ≈ 21.6 Hz, CH2CHdCHP), 59.8 (C1), 61.4 (d,
CH3CH2O), 64.4 (C2), 66.9 (OCH2Ph), 71.4 (OCH2Ph), 71.8 (C6),
72.4 (OCH2Ph), 72.9 (OCH2Ph), 73.1 (OCH2Ph), 78.2 (C5), 81.9
(C3 or C4), 82.5 (C3 or C4), 118.8 (PCHdCH2 JC,P∼186 Hz,
measured in CDCl3), 127.7-128.7 (CHAr’s), 137.8-138.2 (CqAr),
150.0 (CH2CHdCH), 156.4 (CdO); 31P NMR (202 MHz, CDCl3)
δ 18.25; (+) MS (ESI): m/z ) 835 [M + H]+, 856 [M + Na]+;
HRMS (ESI) calcd for C49H56NNaO9P : m/z ) 856.3590 [M +
Na]+, found : m/z ) 856.3583. Anal. Calcd. for C49H56NO9P: C,
70.57; H, 6.77; N, 1.68. Found: C, 70.15; H, 6.70; N, 1.71.
1,4-Bis-[1(R)-2,3,5,6-tetra-O-benzyl-N-benzyloxycarbonyl-1,4-
dideoxy-1,4-imino-D-galactit-1-yl)-2-butene (10). A solution of
5a (209 mg, 0.3 mmol) in dry CH2Cl2 (3.5 mL) was submitted to
3 freeze-pump-thaw cycles and placed under Ar. Then Hoveyda-
Grubbs catalyst (9.4 mg, 5%) was added and the 3 freeze-pump-
thaw-argon cycles were repeated. The green reaction medium was
stirred overnight at 40 °C and then the brown mixture was
concentrated under reduced pressure. Purification by flash chro-
matography (PE/AcOEt 85:15) provided compound 10 (108.1 mg,
53%) as a green oily product. IR (NaCl, cm-1) 3442, 3052, 3031,
1695, 1454, 1403, 1265, 1096, 1069; 1H NMR (400 MHz, CDCl3)
δ 2.17-2.31 (m, 2H, CH2CH)), 2.37-2.77 (m, 2H, CH2CH)),
3.39-3.68 (m, 4H, H6), 3.84-3.96 (m, 4H, H5, H2), 3.99-4.14
(m, 4H, H1, H3), 4.20 (dd, 2H, J ≈ 2.4 and 6.8 Hz, H4), 4.28-
4.56 (m, 14H, OCH2Ph), 4.58-4.70 (m, 2H, OCH2Ph), 4.97-5.13
(m, 4H, OCH2Ph), 5.39-5.50 (m, 2H, CH)), 7.16-7.29 (m, 50H,
CHAr’s); 13C NMR (62.5 MHz, CDCl3) δ 27.7 (CH2CH)), 32.4,
(CH2CH)), 60.6-61.6 (C1), 64.1 (C4), 64.4 (C4), 67.06 (C6),
67.10 (C6), 71.5, 71.6, 72.0-72.1, 72.4, 73.15, 73.21, and 73.3
(OCH2Ph), 77.4 (C5), 77.9 (C5), 80.8 (C3), 81.12-81.15 (C3),
82.3-82.8 (C2), 127.5-128.5 (CHAr’s), 129.1 (CH2CH)), 129.2
(CH2CH)), 136.82, 136.84, 137.8, 138.1, 138.2, 138.4, 138.7, and
138.8 (CqAr), 156.8 (CdO); (+) MS (ESI) : m/z ) 1385.0 [M +
NH4]+; HRMS (ESI) calcd for C88H90N2O12Na: m/z ) 1389.63915
[M + Na]+; found : m/z ) 1389.6389. Anal. Calcd. for
C88H90N2O12: C, 77.28; H, 6.63; N, 2.05. Found: C, 77.06; H,
6.65; N, 1.98.
1(R)-1,4-Dideoxy-1-C-(3-diethylphosphono-2-propen-1-yl)-
1,4-imino-D-galactitol (11). Compound 11 was obtained according
to procedure D, starting from compound 9 (220 mg, 0.263 mmol).
Purification by C18-reverse phase silica gel chromatography (H2O/
MeOH 1:0 to 9:1) afforded the hydrochloride salt of 11 (98.8 mg,
74%) as a colorless foamy product. [R]25D -20 (c ) 1.46, MeOH);
1H NMR (500 MHz, CD3OD) δ 1.33 (t, 6H, J ≈ 7 Hz, CH3), 2.74-
2.80 (m, 1H) and 2.85-2.91 (m, 1H)(CH2CHdCH), 3.44-3.48
(m, 1H, H4), 3.66 (dd, 1H, J ≈ 4.5 Hz, J ≈ 11.5 Hz, H6a), 3.71-
3.77 (m, 2H, H1 and H6b), 3.86-3.90 (m, 1H, H5), 4.01 (d, 1H,
J ≈ 2.5 Hz, H2), 4.06-4.13 (m, 5H, H3 and CH2CH3), 6.02 (dd,
1H, J ≈ 17 Hz, JH-P∼20.8 Hz, PCH)CH), 6.75 (ddt, 1H, J ≈ 7
Hz, J ≈ 17 Hz, JH-P∼21.5 Hz, PCHdCH); 13C NMR (125 MHz,
CD3OD) δ 16.6 (CH3), 16.7 (CH3), 31.4 (d, J ≈ 23.7 Hz, CH2-
CHdCHP), 62.1 (C1), 63.5 (CH3CH2O), 63.6 (CH3CH2O), 64.7
(C6), 70.9 (C4), 71.5 (C5), 76.9 (C2), 78.1 (C3), 121.8 (d, J ≈
186.5 Hz, PCHdCH2), 148.9 (d, J ≈ 5.3 Hz, CH2CHdCH); 31P
NMR (202 MHz, CD3OD) δ 17.84 (s); (+) MS (ESI): m/z ) 340.5
[M + H]+, 362.5 [M + Na]+; HRMS (ESI) calcd for C13H26-
NNaO7P: m/z ) 362.13446 [M + Na]+; found : m/z ) 362.1340.
Anal. Calcd. for C13H27ClNO7P+2H2O: C, 39.65; H, 7.42; N, 3.56;
Cl, 9.00. Found: C, 39.75; H, 6.94; N, 3.4; Cl, 9.66.
General Procedure E: Preparation of Free Phosphonic Acids.
To a 0.1 M solution of ethyl phosphonate (11 or 19) (1 equiv) in
dry MeCN was added BrSiMe3 (10 eq) at room temperature. The
mixture was stirred for the indicated time. The mixture was then
diluted with MeOH (15 mL) and concentrated under reduced
pressure. The dilution and evaporation process was repeated twice.
The residue was then taken up with water and the mixture extracted
with CH2Cl2 to remove traces of less polar organic compounds.
The aqueous phase was concentrated under reduced pressure.
J. Org. Chem, Vol. 73, No. 8, 2008 3113

Liautard et al.
Chromatography of the crude product on C18-reversed phase silica
gel (H2O/MeOH 1:0 to 4:1) provided free phosphonic acids.
(1R)-1,4-Dideoxy-1-C-(3-phosphono-2-propen-1-yl)-1,4-imino-
D-galactitol (12). Compound 12 was obtained as a brownish foam
(10.7 mg, 59%) from 11 (20 mg, 0.05 mmol) according to general
d2), 136.4 (PCH)CH2), 141.8, 141.9 (C6, d1 and d2), 150.13,
150.15 (C2, d1 and d2), 163.7 (C4); 31P NMR (202 MHz, CDCl3)
δ 17.83 (s), 18.0 (s); (+) MS (ESI) : m/z ) 420.0 [M + NH4]+;
HRMS (ESI) : calcd for C16H23N2NaO8P: m/z ) 425.1090 [M +
Na]+; found : m/z ) 425.1092.
1
procedure E (reaction time: 64 h). H NMR (400 MHz, CD3OD)
1(R)-2,3,5,6-Tetra-O-benzyl-N-benzyloxycarbonyl-1,4-dideoxy-
1-C-{3-[(ethyl)(2′,3′-O-isopropylideneuridin-5′-yl)phosphono]-
2-propen-1-yl}-1,4-imino-D-galactitol (18). To a solution of
compound 5a (115 mg, 0.165 mmol) in dry CH2Cl2 (2.75 mL) was
added compound 17 (133 mg, 0.33 mmol, 2 equiv). The flask was
then submitted to 3 freeze-pump-thaw cycles and placed under
Ar. Then Hoveyda-Grubbs catalyst (5.2 mg, 5%) was added and
the 3 freeze-pump-thaw-argon cycles were repeated. The reaction
medium was stirred for 24 h at 40 °C, then a second addition of
Hoveyda-Grubbs catalyst (5.2 mg, 5%) was performed. After 20 h
stirring time at 40 °C, the reaction mixture was concentrated under
reduced pressure. The brownish residue was dried by coevaporation
with toluene. Purification by flash chromatography (CH2Cl2/MeOH
99:1 to 98:2) provided compound 18 (107.5 mg, 61%) as a brown
oily product (1:1 mixture of P-stereoisomers, d1 and d2). IR (NaCl,
cm-1) 3032, 2988, 2935, 2249, 1695, 1455, 1266, 1215, 1158, 1095,
1068, 1028; 1H NMR (500 MHz, DMSO-d6, 80 °C) δ 1.22 (t, 3H,
J ≈ 6.3 Hz, OCH2CH3, d1), 1.24 (t, 3H, J ≈ 6.3 Hz, OCH2CH3
d2), 1.34 (s, 3H) and 1.54 (s, 3H, CH3 isopropylidene), 2.48-2.53
(m, 1H, CHaCHdCHP), 2.61-2.68 (m, 1H, CHbCHdCHP), 3.58
(dd, J ≈ 5.8 Hz, J ≈ 10.9 Hz, 1H, H6a), 3.69 (dd, J ≈ 3.24 Hz, J
≈ 10.9 Hz, 1H, H6b), 3.88-3.94 (m, 1H, H5), 3.93-4.00 (m, 2H,
OCH2CH3), 4.08-4.13 (m, 2H, H3 + H5′), 4.18 (m, 2H, H2 +
H4), 4.22 (q, 1H, J ≈ 5.2 Hz, H4′), 4.27-4.33 (m, 1H, H1), 4.46
(d, 1H, J ≈ 5.1 Hz, OCH2Ph), 4.50-4.59 (m, 6H, OCH2Ph), 4.66
(d, 1H, J ≈ 11.6 Hz, OCH2Ph), 4.82 (dd, 1H, J ≈ 4 Hz, J ≈ 6.4
Hz, H3′), 5.02 (m, 1H, H2′), 5.10 (broad s, 2H, OCH2Ph), 5.61 (d,
1H, J ≈ 8 Hz, H5”), 5.66-5.74 (m, 1H, CHdCHP), 5.86-5.87
(m, 1H, H1′), 6.62-6.76 (m, 1H, CH)CHP), 7.27-7.39 (m, 25H,
CHAr’s), 7.64 (dd, 1H, J ≈ 8 Hz, H6”); 13C NMR (125 MHz,
DMSO-d6, 80 °C) δ 16.28 (CH3), 16.32 (CH3), 25.6 and 27.3 (2
CH3 isopropylidene), 34.1 (d, JC-P∼22.1 Hz, CH2CHdCHP), 59.66,
59.71 (C-1, d1 and d2), 61.66, 61.71 (OCH2CH3, d1 and d2), 64.26,
64.31 (C2, d1 and d2), 64.96, 65.00 (C5′, d1 and d2), 66.8 (OCH2-
Ph), 71.2, 71.5, 72.3, 72.7, 72.9 (C6 + 4 OCH2Ph), 78.0 (C5), 81.1
(C3′), 81.8 (C4), 82.3 (C-3), 83.9 (C2′), 85.2 (m, C4′), 92.65, 92.68
(C-1′, d1 and d2), 102.3 (C5”), 113.8 (Cq isopropylidene), 118.5
(d, JC-P∼185.6 Hz, CH)CHP d1), 118.7 (d, JC-P∼185.6 Hz,
CH)CHP d2), 127.5-128.5 (CHAr’s), 137.1, 138.0, 138.5, 138.7,
and 138.9 (CqAr), 142.4 (C-6”), 150.6 (d, JC-P∼21.6 Hz, CHd
CHP), 156.2 (CdO), 163.2 (CdO); 31P NMR (202 MHz, CDCl3)
δ 17.94 (s), 18.01 (s); (+) MS (ESI) : m/z ) 1095.5 [M + Na]+;
HRMS (ESI) calcd for C59H66N3NaO14P: m/z ) 1094.4180 [M +
Na]+; found : m/z ) 1094.4175. Anal. Calcd. for C59H66N3O14P:
C, 66.09; H, 6.20; N, 3.92. Found: C, 66.07; H, 6.20; N, 3.79.
δ 2.70-2.77 (m, 1H) and 2.81-2.89 (m, 1H) (CH2CHdCH), 3.47
(dd, 1H, J ≈ 2.4 and 8.8 Hz, H4), 3.67 (dd, 1H, J ≈ 8 Hz, J ≈
11.6 Hz, H6a), 3.70-3.77 (m, 2H, H1 and H6b), 3.88-3.92 (m,
1H, H5), 4.02-4.07 (m, 1H, H2), 4.13 (m, 1H, J ≈ 2.4 Hz, H3),
6.01-6.11 (m, 1H, PCH)CH), 6.54-6.70 (m, 1H, PCHdCH); 13
C
NMR (100 MHz, CD3OD) δ 31.1 (d, J ≈ 23 Hz, CH2CHdCHP),
62.3 (C1), 64.6 (C6), 70.7 (C4), 71.5 (C5), 76.7 (C2), 78.1 (C3),
117.5 (PCHdCH2), 144.7 (CH2CHdCH); 31P NMR (162 MHz,
CD3OD) δ 14.54 (s); HRMS (ESI) calcd for C13H26NNaO7P: m/z
) 362.13446 [M + Na]+; found : m/z ) 362.1340.
1,4-Bis-[1(R)-1,4-dideoxy-1,4-imino-D-galactit-1-yl]-2-
butene (13). Compound 13 was prepared by the debenzylation
procedure D, starting from compound 10 (196 mg, 0.143 mmol).
Compound 13 was obtained as a colorless foam, as its hydrochloride
salt (62 mg, 96%) and as a mixture of Z/E isomers (1:2). 1H NMR
(250 MHz, CD3OD) δ 2.48-2.83 (m, 4H, CH2CH)), 3.40-3.53
(m, 2H, H4), 3.57-3.81 (m, 6H, H1, 2H6), 3.86-3.94 (m, 2H,
H5), 3.98-4.07 (m, 2H, H2), 4.07-4.18 (m, 2H, H3), 5.63-5.69
(m, 0.7H, CH), Z-isomer), 5.71-5.80 (m, 1.3H, CH), E-isomer);
13C NMR (62.5 MHz, CD3OD) δ 24.9 (CH2CH), Z), 29.9 (CH2-
CH), E), 63.25 (C1, Z), 63.30 (C1, E), 64.6 (C6), 70.56 (C4, E),
70.60 (C4, Z), 71.45 (C5, Z), 71.49 (C5, E), 76.6 (C2, Z), 76.7
(C2, E), 78.2 (C3, E), 78.3 (C3, Z), 128.5 (CH), Z), 130.0 (CH),
E); (+) MS (ESI) : m/z ) 379.5 [M + H]+; HRMS (ESI) calcd
for C16H30N2NaO8: m/z ) 401.18999 [M + Na]+, found : m/z )
401.1898
Ethyl (2′,3′-O-isopropylideneuridin-5′-yl) vinylphosphonate
(17). To a solution of diethyl vinylphosphonate (377 µL, 2.44 mmol)
in dry CH2Cl2 (10 mL) was added oxalyl chloride (230 µL, 2.68
mmol, 1.1 equiv) under Ar. After stirring overnight at room
temperature, the mixture was stirred at 35 °C for 24 h and then
concentrated under reduced pressure. Ethyl vinylphosphonyl chlo-
ride was thus obtained with a conversion of 94% (1H NMR
integration) as a colorless oily product. This reagent was used
without further purification because it was air and moisture
sensitive. To a solution of ethyl vinylphosphonyl chloride (340 mg,
2.2 mmol) in dry CH2Cl2 (11 mL) under Ar were added 2′,3′-O-
isopropylideneuridine (940 mg, 3.30 mmol, 1.5 equiv) and Et3N
(618 µL, 4.39 mmol, 2 equiv). The purple mixture was stirred for
36 h at 35 °C, then the reaction was quenched by adding water (2
mL). Compound 17 was extracted with CH2Cl2 (3×), the organic
layers were combined and dried over Na2SO4, and the solvent was
evaporated under reduced pressure. The pink foam thus obtained
was purified by flash chromatography (CH2Cl2/MeOH 99:1 to 96:
4). Compound 17 was obtained as a white foam (540 mg, 61%
from commercial diethyl vinylphosphonate) and as a 1:1 mixture
of P-stereoisomers (d1 and d2). IR (NaCl, cm-1) 3466, 3169, 3057,
2989, 2940, 1694, 1633, 1457, 1383, 1271, 1235, 1159, 1067, 1019;
1H NMR (250 MHz, CDCl3) δ 1.21-1.27 (m, 6H, CH3 isopropy-
lidene + CH3CH2O), 1.48 (s, 3H, CH3 isopropylidene), 3.98-4.11
(dquint, 2H, J ≈ 7.5 Hz, CH3CH2O d1 and d2), 4.24-4.29 (m,
2H, H5′), 4.32-4.40 (m, 1H, H4′), 4.77-4.80 (m, 1H, H3′), 4.86
(dd, 1H, J ≈ 6.25 Hz, H2′ d1 and d2), 5.64 (d, 1H, J ≈ 8 Hz, H5),
5.73 (dd, 1H, J ≈ 4.75 Hz, H1′ d1 and d2), 5.87-6.39 (m, 3H,
CH2dCHP + CH2dCHP d1 and d2), 7.39 (t, 1H, J ≈ 8.25 Hz,
H6 d1 and d2), 10.44 (broad s, 1H, NH); 13C NMR (62.5 MHz,
CDCl3) δ 16.0, 16.1 (CH3, d1 and d2), 26.0 and 26.9 (CH3,
isopropylidene), 62.2, 62.3 (CH3CH2O d1 and d2), 64.9-65.0 (m,
C5′ d1 and d2), 80.5, 80.6 (C3′ d1 and d2), 84.2, 84.3 (C2′ d1 and
d2), 85.3 (d, JC-P ∼11.3 Hz, C4′ d1), 85.5 (d, JC-P ∼11.3 Hz, C4′
d2), 93.4, 93.7 (C1′ d1 and d2), 102.2, 102.3 (C5, d1 and d2),
114.15, 114.18 (Cq isopropylidene, d1 and d2), 124.8 (d, JC-P
∼183 Hz, PCHdCH2 d1), 124.9 (d, JC-P ∼183 Hz, PCHdCH2
1(R)-1,4-Dideoxy-1-C-{3-[(ethyl)(uridin-5′-yl)phosphono]-2-
propen-1-yl}-1,4-imino-D-galactitol (19). To a solution of 18 (79
mg, 0.073 mmol) in dry CH2Cl2 (2.5 mL) was added BCl3 (862
µL, 735 mmol, 100 equiv) at 0 °C under argon. The reaction mixture
was stirred overnight at 0 °C, then it was diluted by the addition of
CH2Cl2 (2.5 mL) and the solids formed during the reaction were
dissolved by the addition of MeOH (15 mL) and a few drops of
water. The reaction mixture was then concentrated under reduced
pressure. MeOH and water (5 mL, 20:1) were added and the
solution was quickly filtered through ion-exchange resin (Dowex
1 × 8, OH- form) which was then washed with MeOH (2 × 20
mL) and water (10 mL). Purification of the crude product by flash
chromatography on C18-reversed phase silica gel (H2O/i-PrOH 1:0
to 7:3) provided compound 19 (20.2 mg, 52%) as a white foam
1
(1:1 mixture of P-stereoisomers). H NMR (500 MHz, CD3OD,
d1 and d2 for P-epimers) δ 1.35 (t, 3H, J ≈ 6.3 Hz, OCH2CH3,
d1), 1.36 (t, 3H, J ≈ 6.3 Hz, OCH2CH3, d2), 2.70-2.78 (m, 1H)
and 2.83-2.88 (m, 1H)(CH2CHdCHP), 3.40 (m, 1H, H4), 3.63-
3114 J. Org. Chem., Vol. 73, No. 8, 2008

Galf and UDP-Galf Mimicks
3.74 (m, 3H, H1, 2H6), 3.85-3.88 (m, 1H, H5), 3.99-4.00 (m,
1H, H2), 4.09 (brs, 1H, H3), 4.12-4.18 (m, 4H, OCH2CH3 + H2′),
4.19-4.21 (m, 1H, H4′), 4.22-4.26 (m, 1H, H5′a), 4.30-4.34 (m,
1H, H5′b), 5.71 (d, 1H, J ≈ 8 Hz, H5”), 5.83 (dd, 1H, J ≈ 3.9 Hz,
J ≈ 6.1 Hz, H1′), 6.01-6.09 (m, 1H, CHdCHP), 6.68-6.77 (m,
1H, CH)CHP), 7.72 (dd, 1H, J ≈ 8 Hz, H6” d1 and d2); 13C NMR
(125 MHz, CD3OD) δ 16.65, 16.70 (CH3, d1 and d2), 32.0 (d,
JC-P∼22.1 Hz, CH2CHdCHP), 61.8 (C1), 63.9, 64.0 (OCH2CH3,
d1 and d2), 64.8 (C2), 66.2-66.3 (m, C5′), 70.5 (C4), 70.9 (C3′),
71.7 (C5), 74.99, 75.02 (C2′, d1 and d2), 77.1 (C3), 78.6, 78.7
(C2, d1 and d2), 83.55, 83.60 (C4′, d1 and d2), 91.8, 91.9 (C1′, d1
and d2), 102.9 (C5′′), 120.7 (d, JC-P∼187.3 Hz, CH)CHP), 120.8
(d, JC-P∼187.1 Hz, CH)CHP), 142.49, 142.54 (C-6′′, d1 and d2),
150.5 (m, CHdCHP), 152.2 (CdO), 166.0 (CdO); 31P NMR (202
MHz, CD3OD) δ 18.35 (s), 18.53 (s); (+) MS (ESI) : m/z ) 538.5
[M + H]+; HRMS (ESI) calcd for C20H33N3O12P: m/z ) 538.1802
[M + H]+; found : m/z ) 538.1800. Calcd for C20H32N3NaO12P:
m/z ) 560.1621 [M + Na]+; found : m/z ) 560.1622.
CHdCHP), 3.42 (dd, 1H, J ≈ 2.4 Hz, J ≈ 8.4 Hz, H4), 3.62-3.77
(m, 3H, H1 and 2H6), 3.85-3.90 (m, 1H, H5), 3.98-4.12 (m, 5H),
4.19-4.23 (m, 2H), 5.79 (d, 1H, J ≈ 8 Hz, H5′′), 5.89-6.01 (m,
2H, H1 and CHdCHP), 6.36-6.50 (m, 1H, CH)CHP), 8.01 (d,
1H, J ≈ 8 Hz, H6′′); 13C NMR (100 MHz, CD3OD) δ 31.4 (d,
JC-P∼21.6 Hz, CH2CHdCHP), 62.8 (C1), 64.5 (d, JC-P∼4.6 Hz,
C5′), 64.7 (m, C6), 70.7 (C4), 71.5 (C3′ or C2′), 71.7 (C5), 75.6
(C2′ or C3′), 77.0 (C2), 78.3 (C3), 85.1 (d, JC-P∼8.2 Hz, C4′),
90.0 (C1′), 103.0 (C5”), 128.4 (d, JC-P∼175 Hz, CH)CHP), 142.1
(CHdCHP), 142.6 (C6”), 152.6 (CdO), 166.2 (CdO); 31P NMR
(162 MHz, CD3OD) δ 12.05 (s); (+) MS (ESI): m/z ) 532.5 [M
+ Na]+; HRMS (ESI) calcd for C18H28N3NaO12P: m/z ) 532.13083
[M + Na]+; found : m/z ) 538.1306.
Inhibition Assay. Inhibition assays of UGM by the new
compounds were performed as previously described.15b
Acknowledgment. Funding of this research by CNRS and
by the French Ministry of Research and Higher Education is
gratefully acknowledged.
Procedure for 19‚HCl. Debenzylation of phosphonate 18 (149
mg, 0.139 mmol) according to general procedure D afforded
compound 19 as its hydrochloride salt (62.6 mg, 78%). Anal. Calcd.
for C20H33ClN3O12P+2H2O: C, 39.38; H, 6.11; N, 6.89; Cl, 5.81.
Found: C, 39.27; H, 6.29; N, 6.53; Cl, 5.80.
Supporting Information Available: Experimental procedures
and characterization data for compounds 2, 2′, 3f, 3f′, 3g, 8, 14,
15, 16, and copies of NMR spectra of all new compounds. This
material is available free of charge via the Internet at http://pubs.
acs.org.
1(R)-1,4-Dideoxy-1-C-{3-[(uridin-5′-yl)phosphono]-2-propen-
1-yl}-1,4-imino-D-galactitol (20). Compound 20 (8 mg, 36%) was
obtained as a white foam from 19 (21.9 mg, 0.038 mmol) according
to general procedure E (stirring time: 3 d). [R]25 -2 (c ) 0.49,
D
MeOH); 1H NMR (400 MHz, CD3OD) δ 2.58-2.80 (m, 2H, CH2-
JO8001134
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