Synthesis of α- and β-glycosyl isothiocyanates via oxazoline intermediates

Article abstract of DOI:10.1021/jo062419z

(Chemical Equation Presented) A practical synthesis of acylated glycosyl isothiocyanates from sugar oxazolines, by reaction with thiophosgene, is reported. In the absence of any additive, the reaction is governed by the reverse anomeric effect, leading to

Full text of DOI:10.1021/jo062419z

and oligosaccharides are currently at hand. Most of them rely on
either the isothiocyanation reaction of a glycosylamine1,6 (e.g.,
1) or the nucleophilic displacement of an anomeric leaving group,
commonly from a glycosyl halide (e.g., 2 or 4) by isothiocyanate
anion.1,7 The first approach leads to the corresponding â-glycosyl
isothiocyanate (e.g., 3â) by virtue of the reverse anomeric effect
(Scheme 1, a).8 The second method yields the 1,2-trans
compound (e.g, the 3â in the case of a D-glucopyranosyl
derivative) or a mixture of the R and â anomers (e.g, the 5R
and 5â) depending on the participating (Scheme 1, b) or
nonparticipating character of the neighboring group (Scheme
1, c). In the frame of a project aiming at developing thiourea-
linked glycooligomers for the specific binding of oligonucle-
otides,9 we were interested in accessing glycosyl isothiocyanates
having the R-configuration in the D-gluco and D-galacto series.
The corresponding per-O-benzyl ether protected derivatives have
previously been obtained from the corresponding glycosyl
halides.7c However, separation from the â-anomer was rather
troublesome, and moreover, further hydrogenolysis of the benzyl
groups in the presence of thiocarbonyl functionalities became
exceedingly problematic. Using instead ester protection would
imply the axial orientation of the NCS groups and a cis-relative
disposition with respect to the vicinal O-acyl group, a problem
that is outside the scope of the above methodologies.10
Synthesis of r- and â-Glycosyl Isothiocyanates
via Oxazoline Intermediates
Jose´ L. Jime´nez Blanco,† Balla Sylla,†
Carmen Ortiz Mellet,*,† and Jose´ M. Garc´ıa Ferna´ndez*,‡
Departamento de Qu´ımica Orga´nica, Facultad de Qu´ımica,
UniVersidad de SeVilla, Apartado 553, E-41071 SeVilla, Spain,
and Instituto de InVestigaciones Qu´ımicas, CSIC, Ame´rico
Vespucio 49, Isla de la Cartuja, E-41092 SeVilla, Spain
mellet@us.es; jogarcia@iiq.csic.es
ReceiVed NoVember 24, 2006
A practical synthesis of acylated glycosyl isothiocyanates from
sugar oxazolines, by reaction with thiophosgene, is reported.
In the absence of any additive, the reaction is governed by
the reverse anomeric effect, leading to the equatorially
oriented isothiocyanate. However, in the presence of copper-
(II) chloride, the reaction proceeds preferentially with
retention of the configuration at the anomeric center,
providing the axial anomer as the major product. Noteworthy,
this strategy allows accessing per-O-acetylated glycopyra-
nosyl isothiocyanates with 1,2-cis relative configuration (e.g.,
the R-anomer in the D-gluco and D-galacto series), a problem
that was outside the scope of previous methodologies.
Here, we report a general method for the synthesis of glycosyl
isothiocyanates based on the ring-opening reaction of glycosyl-
amine-derived oxazoline precursors (e.g., 6) with thiophosgene
(Scheme 1, c). The transformation proceeds to give the target iso-
thiocyanate while regenerating an acetoxy group at the vicinal car-
bon atom. The stereochemical outcome of the reaction depends
on the nature of the starting sugar template, but it can be tuned to
(3) (a) Seitz, O. ChemBioChem 2000, 1, 215-246. (b) Taylor, C. M.
Tetrahedron 1998, 54, 11317-11362. (c) Gunther, W.; Kunz, H. Angew.
Chem., Int. Ed. 1990, 29, 1050-1051. (d) Khorlin, A. Y.; Zurabyan, S. E.;
Macharadze, R. G. Carbohydr. Res. 1980, 85, 201-208.
Sugar isothiocyanates rank among the most versatile synthetic
intermediates in carbohydrate chemistry. The isothiocyanate
group plays a pivotal role in the preparation of a broad series
of functional groups such as amide, isonitrile, carbodiimide, and
N-thiocarbonyl derivatives allowing, simultaneously, the cova-
lent attachment of a quite unrestricted variety of structures to
the saccharide moiety.1 Thus, glycosyl isothiocyanates have been
profusely used to construct a battery of N-nucleoside and
glycosylaminoheterocycles,1,2 the N-glycopeptide linkage present
in natural N-glycoproteins,1,3 the cyclic isourea group of
trehazoloid glycosidase inhibitors,1,4 or the thiourea bridge in
multivalent glycoconjugates,1,5 to cite just a few examples.
Several efficient general methods for the introduction of the
isothiocyanate functionality at the anomeric position of mono-
(4) (a) Chiara, J. L.; de Gracia, I. S.; Garc´ıa, A.; Bastida, A.; Bobo, S.;
Mart´ın-Ortega, M. D. ChemBioChem 2005, 6, 186-191. (b) Garc´ıa-Moreno,
Rodr´ıguez-Lucena, D.; Ortiz Mellet, C.; Garc´ıa Ferna´ndez, J. M. J. Org.
Chem. 2004, 69, 3578-3581. (c) Garc´ıa-Moreno, M. I.; D´ıaz-Pe´rez, P.;
Ortiz, Mellet, C.; Garc´ıa Ferna´ndez, J. M. J. Org. Chem. 2003, 68, 8890-
8901. (d) Kobayashi, Y. Carbohydr. Res. 1999, 315, 3-15. (e) de Gracia,
I. S.; Bobo, S.; Martin-Ortega, M. D.; Chiara, J. L. Org. Lett. 1999, 1,
1705-1708.
(5) (a) Rodr´ıguez-Lucena, D.; Benito, J.; Ortiz Mellet, C.; Garc´ıa
Ferna´ndez, J. M. Chem. Commun. 2007, 831-833. (b) Walter, M.;
Lindhorst, T. K. Synthesis 2006, 952-958. (c) Walter, M.; Wiegand, M.;
Lindhorst, T. K. Eur. J. Org. Chem. 2006, 719-728. (d) Go´mez-Garc´ıa,
M.; Benito, J. M.; Rodr´ıguez-Lucena, D.; Yu, J.-X.; Chmur-
ski, K.; Ortiz Mellet, C.; Gutie´rrez-Gallego, R.; Maestre, A.; Defaye, J.;
Garc´ıa Ferna´ndez, J. M. J. Am. Chem. Soc. 2005, 127, 7970-7971. (e)
Oshovsky, G. V.; Verboom, W.; Fokkens, R. H.; Reinhoudt, D. N. Chem.
Eur. J. 2004, 10, 2739-2748. (f) Kohn, M.; Benito, J. M.; Ortiz, Mellet, C.;
Lindhorst, T. K.; Garc´ıa, Ferna´ndez, J. M. ChemBioChem 2004, 5, 771-777.
(6) (a) Ortiz Mellet, C.; Jime´nez Blanco, J. L.; Garc´ıa Ferna´ndez, J. M.;
Fuentes, J. J. Carbohydr. Chem. 1993, 12, 487-505. (b) Babiano, R.;
Fuentes Mota, J.; Galbis Pe´rez, J. A. Carbohydr. Res. 1986, 154, 280-288.
(7) (a) Ku¨hne, M; Gyo¨rgydea´k, Z.; Lindhorst, T. K. Synthesis 2006, 949-
951. (b) Lindhorst, T. K.; Kieburg, C. Synthesis 1995, 1228-1230. (c)
Camarasa, M. J.; Ferna´ndez-Resa, P.; Garc´ıa-Lo´pez, M. T.; de las Heras,
F. G.; Me´ndez-Castrillo´n, P. P.; San Fe´lix, A. Synthesis 1984, 509-510.
(8) Tvarosˇka, I.; Bleha, T. AdV. Carbohydr. Chem. Biochem. 1989, 47,
45-123.
† Universidad de Sevilla.
‡ Instituto de Investigaciones Qu´ımicas, CSIC - Universidad de Sevilla.
(1) (a) Garc´ıa Ferna´ndez, J. M.; Ortiz Mellet, C. AdV. Carbohydr. Chem.
Biochem. 2000, 55, 35-135. (b) Garc´ıa Ferna´ndez, J. M.; Ortiz Mellet, C.
Sulfur Rep. 1996, 19, 61-169. (c) Witczak, Z. J. AdV. Carbohydr. Chem.
Biochem. 1986, 44, 91-145.
(2) (a) Khodair, A. I. A.; El Ashrid, E. S. H.; Al-Masoudi, N. A. L.
Monatsh. Chem. 2004, 135, 1061-1079. (b) Al-Masoudi, N. A. L; Al-
Soud, Y. A.; Al-Masoudi, W. A. Nucleos. Nucleot. Nucleic Acids 2004,
23, 1739-1749. (c) Pearson, M. S. M.; Robin, A.; Bourgougnon, N.; Meslin,
J. C.; Deniaud, D. J. Org. Chem. 2003, 68, 8583-8587. (d) Gasch, C.;
Salameh, B. A. B.; Pradera, M. A.; Fuentes, J. Tetrahedron Lett. 2001, 42,
9615-8617.
(9) Jime´nez Blanco, J. L.; Bootello, P.; Benito, J. M.; Ortiz Mellet, C.;
Garc´ıa Ferna´ndez, J. M. J. Org. Chem. 2006, 71, 5136-5143. (b) Jime´nez
Blanco, J. L.; Bootello, P.; Ortiz Mellet, C.; Garc´ıa Ferna´ndez, J. M. Eur.
J. Org. Chem. 2006, 183-196. (b) Jime´nez Blanco, J. L.; Bootello, P.;
Ortiz Mellet, C.; Garc´ıa Ferna´ndez, J. M. Chem. Commun. 2004, 92-93.
10.1021/jo062419z CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/11/2007
J. Org. Chem. 2007, 72, 4547-4550
4547

SCHEME 1. Synthetic Routes to Glycosyl Isothiocyanates
SCHEME 3. Possible Routes Involved in the Transformation
of Glycooxazolines into Glycosyl Isothiocyanates
SCHEME 2. Synthetic Strategies for the Preparation of
Glycooxazolines
with retention of the configuration to give a transient N-
chlorothioformyl oxazolinium cation (7) that, after hydrolysis,
would lead to an N-glycosylchlorothioformamide (8R). Further
elimination of hydrogen chloride would provide the target
glycosyl isothiocyanate with 1,2-cis relative configuration (3R;
Scheme 3, route a). Two parallel processes may, however,
compete with the above reaction sequence. First, glycooxazo-
lines are relatively moisture sensitive and can undergo hydrolysis
to a kinetic axial glycosylamine (9R) that experiences fast
isomerization to the equatorial anomer (9â; Scheme 3, route
b).15 Second, the transient chlorothioformamide is also suscep-
tible of undergoing anomerization (f 8â; Scheme 3, route c).16
In both cases, the final reaction product would be the 1,2-trans
glycosyl isothiocyanate (3â). In order to assess the relative
prevalence of these three possible concomitant pathways and
determine the optimum reaction conditions, preliminary studies
on the D-glucopyranosyloxazoline derivative 6 were undertaken.
In dry dichloromethane, the reaction of 6 with thiophosgene
led to a complex mixture of highly polar compounds arising,
probably, from oligomerization reactions of the highly reactive
N-chlorothioformyloxazolinium intermediate 7 (Table 1, entry
1). When the reaction was carried out in a heterogeneous mixture
of dichloromethane-water-calcium carbonate, a fast conversion
into the peracetylated â-D-glucopyranosyl isothiocyanate 3â was
achieved (Table 1, entry 2). The transformation is much faster
than oxazoline hydrolysis, suggesting that epimerization of the
N-glucopyranosylthioamide intermediate is the main reaction
pathway. To confirm this point, an experiment using thiocar-
bonyldiimidazole (TCI) instead of thiophosgene as the isothio-
cyanation reagent was performed. TLC monitoring of the
favor the elusive axial-equatorial cis-relative disposition of the
isothiocyanateandacyloxygroups(e.g.,3R).Noteworthy,theacyl-
ated glycosyl isothiocyanate anomers can be readily separated
by column chromatography, which is an important difference of
practical importance as compared with per-O-benzyl derivatives.
There have been numerous reports on the synthesis and
reactivity of glycooxazolines having the oxygen atom linked
to the anomeric carbon atom (C-1 in aldoses).11 In sharp contrast,
the synthetic potential of the N-glycosyl positional isomers has
been much less explored. Recently, several approaches for the
synthesis of this type of sugar derivatives from readily available
starting materials, such as glycosyl azides, acetal-protected
monosaccharides, or glycals, have been reported, involving
intramolecular condensation of glycosylphosphinimes with
vicinal ester groups (Scheme 2, a),12 Ritter-like reaction of
transient glycosyl isonitriles (Scheme 2, b)13 and intramolecular
nucleophilic displacement in 2-deoxy-2-iodoaldosylamides,
respectively (Scheme 2, c).14 We have chosen the first two
methodologies for accessing aldopyranose- (6, 13-16) and
aldofuranose- (17) or ketose-derived oxazolines (18, 19),
respectively (see the Supporting Information).
(11) (a) Rising, T. W. D. F.; Claridge, T. D. W.; Davies, N.; Gamblin,
D. P.; Moir, J. W. P.; Fairbanks, A. J. Carbohydr. Res. 2006, 341, 1574-1596.
(b) Crasto, C. F.; Jones, G. B. Tetrahedron Lett. 2004, 45, 4891-4894. (c)
Donohoe, T. J.; Logan, J. G.; Laffan, D. D. P. Org. Lett. 2003, 5, 4995-
4998. (d) Banoub, J.; Boullanger, P.; Lafont, D. Chem. ReV. 1992, 92, 1167-
1195.(e)Rollin,P.;Sinay¨,P.J.Chem.Soc.,PerkinTrans.11977,2513-2517.
(12) Damkaci, F.; DeShong, P. J. Am. Chem. Soc. 2003, 125, 4408-4409.
(13) Jime´nez Blanco, J. L. Rubio, E. M., Ortiz Mellet, C.; Garc´ıa
Ferna´ndez, J. M. Synlett 2004, 2230-2232.
(14) (a) De Castro, M.; Marzabadi, C. H. J. Carbohydr. Chem. 2005,
24, 179-185. (b) De Castro, M.; Marzabadi, C. H. Tetrahedron Lett. 2004,
45, 6501-6504.
(15) Gordon,D.M.;Danishefsky,S.J. J.Org.Chem.1991,56,3713-3715.
(16) The propensity of N-thiocarbonylglycosylamine derivatives to
undergo anomerization processes has already been demonstrated. See:
Benito, J. M.; Ortiz Mellet, C.; Sadalapure, K., Lindhorst, T. K.; Defaye,
J.; Garc´ıa Ferna´ndez, J. M. Carbohydr. Res. 1999, 320, 37-48.
In all cases, the formation of cis-fused heterocycles is
thermodynamically favored, therefore placing the key nitrogen
and oxygen atoms in the desired cis-orientation. We reasoned
that further reaction with thiophosgene would initially occur
(10) Alternative approaches for the synthesis of glycosyl isothiocyanates
have been reported on the basis of the addition of iodoisothiocyanate to
glycals and on the phosphine imide type reaction of glycosyl azides with
triphenylphosphine and carbon disulfide, yet none of these approaches allows
accessing the target relative stereochemistry either. See: (a) Santoyo-
Gonza´lez, F.; Garc´ıa-Calvo-Flores, F.; Isac-Garc´ıa, J.; Herna´ndez-Mateo, F.;
Garc´ıa-Mendoza, P.; Robles-D´ıaz, R. Tetrahedron 1994, 50, 2877-2894.
(b) Menuel, S.; Porwanski, S., Marsura, A. New J. Chem. 2006, 30, 603-608.
4548 J. Org. Chem., Vol. 72, No. 12, 2007

CHART 1. Structures of Glycooxazolines 13-19a and
Glycosyl Isothiocyanates 20-26b
TABLE 1. Synthesis of Glucopyranosyl Isothiocyanates from
Glucooxazoline 6
T (°C)
reaction time
producta
(%)
R/â
entry reagent/base
solvent
CH2Cl2
ratio
1
2
3
4
5
CSCl2/Et3N
0-25/1 h
mixture
3â (75)
3â (65)
3R:3â (60) 29:71
3R:3â (83) 60:40
CSCl2/CaCO3 CH2Cl2-H2O 25/10 min
0:100
0:100
TCI
CH2Cl2
0/6 h
0/2 h
CSCl2/CaCO3 acetone
CSCl2-CuCl2/ CH2Cl2-H2O 25/2 h
CaCO3
a Isolated yields. When mixtures of anomers are formed, the total yield
matches the sum of the individual isolated yields.
SCHEME 4. Copper(II)-Mediated Synthesis of 3r
reaction mixture in dry dichloromethane revealed total con-
sumption of the starting compound 6 after 5 h. No formation
of glycosyl isothiocyanate 3â was detected at this stage,
however, which discards participation of the reactive glycosy-
lamine 9â and suggests that the reactions stops at the initial
N-thiocarbonyl oxazolinium adduct 7. During the aqueous
workup, transformation into 3â occurred (Table 1, entry 3),
which strongly supports an anomerization step at the level of
the N-glucosylthioamide intermediate 8R.
From the above results, it was inferred that decreasing the
anomerization/elimination ratio was critical in order to shift the
reaction toward the target 1,2-cis diastereomer 3R. Using wet
acetone as the solvent, therefore increasing the solvent polarity,
afforded a 1:2.5 mixture of 3R and 3â, although in lower yield
(Table 1, entry 3). Alternatively, the use of copper(II) chloride
as an additive was attempted. We hypothesized that the highly
thiophilic copper(II) cation would coordinate to the thiocarbonyl
sulfur atom in the transient thioformamide (8R). Formation of
this complex should slow the anomerization process (f 8â)
through the open-chain form 11 and facilitate chloride anion
departure (Scheme 4). Accordingly, under these conditions the
3R/3â ratio rose up to 1.5:1 (83% yield; Table 1, entry 5). The
pure 1,2-cis compound 3R was further transformed into the
corresponding N-benzyl-N′-(2,3,4,6-tetra-O-acetyl-R-D-glucopy-
ranosyl)thiourea 12R with total steroselectivity by reaction with
benzylamine, thus confirming its suitability to access R-con-
figured thiourea-linked neoglycoconjugates.
The generality of the methodology was further demonstrated
by the transformation of a series of mono- and disaccharide
oxazoline derivatives into the corresponding glycosyl isothio-
cyanates (Chart 1 and Table 2).
The reactivity of the mono- and disaccharide aldopyranosy-
loxazolines derived from D-galactose, cellobiose, maltose, and
lactose 13-16, respectively, was first examined (Table 2, entries
1-8). In all cases, the reaction with thiophosgene in the absence
of copper(II) led to corresponding â-glycopyranosyl isothiocy-
anate (20â-23â) as the only reaction product, while a binary
mixture of the R and â anomers was obtained in the presence
a Compound 14 was obtained as an inseparable mixture of the R- and â-
anomers that was directly used for its transformation into the corresponding
cellobiosyl isothiocyanate 21. bThe individual anomers for the aldosyl deriv-
atives20-24couldseparatedinallcases. Theyarereferredtointhetextbythe
corresponding number followed by the stereochemical notation R or â.
TABLE 2. Synthesis of Glycosyl Isothiocyanates from
Glycooxazoline Precursors
oxazoline
entry precursor reagent/base
T (°C)
reactn time
producta R/â
(%) ratio
solvent
1
2
13
13
CSCl2/CaCO3 CH2Cl2-H2O
CSCl2-CuCl2/ CH2Cl2-H2O
CaCO3
25/1
25/2
20â (83) 0:100
20R/20â 77:23
(86)
3
4
14
14
CSCl2/CaCO3 CH2Cl2-H2O
CSCl2-CuCl2/ CH2Cl2-H2O
CaCO3
25/1
25/2
21â (78) 0:100
21R/21â 71:29
(74)
5
6
15
15
CSCl2/CaCO3 CH2Cl2-H2O
CSCl2-CuCl2/ CH2Cl2-H2O
CaCO3
25/1
25/2
22â (80) 0:100
22R/22â 91:9
(86)
7
8
16
16
CSCl2/CaCO3 CH2Cl2-H2O
CSCl2-CuCl2/ CH2Cl2-H2O
CaCO
25/1
25/2
23â (65) 0:100
23R/23â 37:63
(63)
9
17
17
CSCl2/CaCO3 CH2Cl2-H2O
25/3
25/3
24R/24â 57:43
(71)
10
CSCl2-CuCl2/ CH2Cl2-H2O
CaCO
CSCl2/CaCO3 CH2Cl2-H2O
CSCl2/CaCO3 CH2Cl2-H2O
24R/24â 67:33
(71)
25 (97) 0:100
26 (22) 0:100
11
12
18
19
25/1b
25/16
a Isolated yields. When mixtures of anomers are formed, the total yield
matches the sum of the individual isolated yields. b Longer reaction times
resulted in lower yields due to concomitant hydrolysis of the isopropylidene
group under the reaction conditions.
of copper(II) chloride. The relative proportion of the anomers
was strongly sensitive upon the orientation and the nature of
the substituent at C-4, going from 1:1.7 in the case of lactose
J. Org. Chem, Vol. 72, No. 12, 2007 4549

up to 10.3:1 for maltose, which probably reflects differences in
anomerization rates of the transient chlorothioformamides.
Experimental Section
General Procedure for the Preparation of Glycosyl Isothio-
cyanates 3 and 20-26 from Glycooxazolines. To a heterogeneous
mixture of the corresponding oxazoline derivative 6 and 13-19
(see refs 12 and 13 and the Supporting Information) in CH2Cl2-
H2O (1:1, 5 mL per 100 mg of reacting oxazoline) were added
CaCO3 (3 equiv), CuCl2‚2H2O (1.5 equiv), and CSCl2 (1.5 equiv).
The mixture was vigorously stirred for the indicated time (Tables
1 and 2) in a round-bottomed flask provided with a system for
evacuation of gases and then filtered (CAUTION: use a well-
ventilated hood). The organic layer was separated, washed with
water, dried (MgSO4), and concentrated to dryness. The resulting
residue was purified by column chromatography using the eluent
indicated in each case.
The above copper(II)-mediated reversion of the anomeric
stereoselectivity is remarkable. For the D-galactopyranosyl
isothiocyanate 20, a R/â ratio ranging from 1:9 to 1:8 has been
previously reported from the reaction of the corresponding
peracetylated glycosyl bromide with potassium thiocyanate or
trimethylsilyl isothiocyanate.7a,b The 3.3:1 ratio obtained from
galactooxazoline 13 implies a 25-30-fold increase in the
R-selectivity. In the case of the D-gluco derivative 3 and the
disaccharide isothiocyanates 21-23, the R-anomers had not been
detected before. Interestingly, the isothiocyanation step can be
effected on the crude oxazoline precursor (see the Supporting
Information), thereby avoiding yield losses due to hydrolysis
during column chromatography purification. Globally, this
methodology allows the one-pot transformation of a per-O-
acetyl-â-glycopyranosyl azide into the corresponding â- or
R-glycopyranosyl isothiocyanate.
In order to expand the repertoire of the approach, the
transformations of the D-glucofuranose (17) and D-fructopyra-
nose oxazolines (18 and 19) into glycosyl isothiocyanates were
next examined (Table 2, entries 9-12). Compound 17 afforded
a mixture of the R- and â-D-glucofuranosyl isothiocyanates 24R
and 24â upon reaction with thiophosgene, the R/â relative
proportion increasing from 1.3:1 to 2:1 in the presence of
copper(II) chloride. For the fructose derivatives 18 and 19 the
isothiocyanation reaction proceeded with retention of the
anomeric configuration, independently of the presence or
absence of the copper(II) additive, to give the corresponding
â-fructopyranosyl isothiocyanates 25 or 26. In both cases, the
vicinal coupling constants around the pyranoid ring were
consistent with the 2C5 conformation, which is consistent with
that reported in the literature for â-D-fructopyronsyl derivatives
bearing nitrogen substituents.17 The absence of NOE contacts
between the H-1 and H-6axial protons further supports the axial
orientation of the NCS group.
The relatively high proportion of 24R in the reaction mixture
of 17 with thiophosgene is consistent with the expected weaker
contribution of the reverse anomeric effect in the transient
furanoid chlorothioformamide as compared with pyranoid
derivatives. On the other hand, anomerization processes are
faster for five-membered rings, which is probably responsible
for the lower increase in the 24R/24â ratio in he presence of
copper(II). In the fructose series, the R-configuration would
imply either the axial orientation of the bulky carbon substituent
(C-1) or the inversion of the chair conformation, both being
unfavorable arrangements.
In conclusion, a robust and flexible methodology for the prepa-
ration of acylated glycosyl isothiocyanates from N-glycooxazo-
line precursors is reported. The preference for the R- or
â-configuration in the final compounds can be tuned, to some
extent, by using copper(II) chloride as an additive. Noteworthy,
the strategy allows the global transformation of â-glycopyra-
nosyl azides into a-glycopyranosyl isothiocyanates with axial-
equatorial 1,2-cis dispositions. Further endeavors will include
reactivity experiments and neoglycoconjugate synthesis.
In the absence of CuCl2, the above procedure afforded exclu-
sively the â-anomer, except for the glucofuranosyl oxazoline
derivative 17, which led to a 57:43 24R/24â mixture (Table 2).
2,3,4,6-Tetra-O-acetyl-R-D-glucopyranosyl Isothiocyanate (3R).
Compound 3R (92 mg, 49%) was obtained, together with 3â (61
mg, 34%), by isothiocyanation of 6 (160 mg, 0.49 mmol) in the
presence of CuCl2 after column chromatography using 1:2 EtOAc-
petroleum ether: Rf (3R) ) 0.55 (1:1 EtOAc-petroleum ether); Rf
(3â) ) 0.46 (1:1 EtOAc-petroleum ether). The spectroscopic and
physicochemical data of 3â were identical to those reported in the
literature.1 The R-anomer 3R, isolated as an amorphous solid, had
[R]D ) +125 (c 1.0, CH2Cl2). IR (KBr): νmax 2956, 2014, 1755,
1433, 911 cm-1. 1H NMR (300 MHz, CDCl3): δ (ppm) 5.81 (d, 1
H, J1,2 ) 4.5 Hz, H-1), 5.39 (t, 1 H, J2,3 ) J3,4 ) 9.6 Hz, H-3),
5.10 (t, 1 H, J4,5 ) 9.6 Hz, H-4), 5.01 (dd, 1 H, H-2), 4.24 (dd, 1
H, J6a,6b ) 12.9 Hz, J5,6a ) 4.8 Hz, H-6a), 4.10 (dd, 1 H, J5,6b
)
2.4 Hz, H-6b), 4.09 (ddd, 1 H, H-5), 2.09, 2.07, 2.06, 2.05 (4 s, 12
H, 4 MeCO). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 169.8-170.5
(4 CO), 144.7 (NCS), 81.9 (C-1), 70.5 (C-3, C-5), 69.8 (C-2), 67.5
(C-4), 61.2 (C-6), 20.6 (MeCO). ESIMS: m/z ) 428 ([M + K]+),
412 ([M + Na]+). Anal. Calcd for C15H19NO9S: C, 46.27; H, 4.92;
N, 3.60. Found: C, 46.08; H, 4.87; N, 3.65.
N-Benzyl-N′-(2,3,4,6-tetra-O-acetyl-R-D-glucopyranosyl)thio-
urea (12R). A solution of 3R (115 mg, 0.295 mmol), benzylamine
hydrochloride (47.2 mg, 1.1 equiv), and DIPEA (37 µL, 1.1 equiv)
in CH2Cl2 (3.5 mL) was stirred at room temperature for 3 h. Solvent
was removed, and the resulting residue was purified by column
chromatography (1:2 EtOAc-petroleum ether) to give 12R (93 mg,
72%) as an amorphous solid. Rf ) 0.27 (1:1 EtOAc-petroleum
ether). [R]D: +135 (c 1.0, CH2Cl2). UV (CH2Cl2): λmax 256 nm,
(ꢀmm ) 8.5). IR (KBr): νmax 3367, 1749, 1536, 1223, 1036 cm-1
.
1HNMR(500MHz, CDCl3, 313K):δ(ppm)7.34-7.26(m, 5H, Ph),
7.05 (bt, 1 H, JNH,H ) 5.5 Hz, N′H), 6.43 (bs, 1 H, NH), 5.45 (bt,
1H, H-1), 5.29(t, 1H, J2,3 )J3,4 )10.0Hz, H-3), 5.01(dd, 1H, J1,2
)
5.0 Hz, H-2), 4.97 (t, 1H, J4,5 ) 11.5 Hz, H-4), 4.81 (dd, 1 H,
2JH,H ) 15.0 Hz, CHPh), 4.73 (dd, 1 H, CHPh), 4.07 (dd, 1 H, J5,6a
) 5.5, J6a,6b ) 12.5 Hz, H-6a), 4.03 (ddd, 1 H, H-5), 3.89 (dd, 1
H, J5,6b ) 2.0 Hz, H-6b), 2.11, 2.02, 1.97, 1.96 (4 s, 12 H, 4 MeCO).
13CNMR(125.7MHz,CDCl3,323K): δ(ppm)184.8(CS),170.1-169.0
(4CO),137.0-127.6(Ph),78.8(C-1),69.8(C-2),68.6(C-3),68.1(C-4,5),
61.7 (C-6), 49.8 (CH2), 20.4-20.2 (MeCO). ESIMS: m/z ) 535
([M + Na]+), 497 ([M + H]+). Anal. Calcd for C22H28N2O9S: C,
53.22; H, 5.68; N, 5.64. Found: C, 53.21; H, 5.55; N, 5.52.
Acknowledgment. We thank the Spanish Ministerio de
Educacio´n y Ciencia for financial support (contract nos.
CTQ2006-15515-C02-01/BQU and CTQ2004-05854/BQU) and
the Erasmus program for a fellowship (to B.S.).
Supporting Information Available: Experimental procedures,
compound characterization data, and copies of the 1H and 13C NMR
spectra for the new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
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