Stereoselective rearrangement of trichloroacetimidates: application to the synthesis of α-glycosyl ureas

Article abstract of DOI:10.1021/ol900670a

A new method for the stereoselective synthesis of r-glycosyl ureas, via nickel-catalyzed [1,3]-rearrangement of glycosyl trichloroacetimidates, has been developed. The r-stereoselectivity at the anomeric carbon of the resulting trichloroacetamides depends

Full text of DOI:10.1021/ol900670a

ORGANIC
LETTERS
2009
Vol. 11, No. 11
2433-2436
Stereoselective Rearrangement of
Trichloroacetimidates: Application to
the Synthesis of r-Glycosyl Ureas
Nathaniel H. Park and Hien M. Nguyen*
Department of Chemistry and Biochemistry, Montana State UniVersity,
Bozeman, Montana 59717
hmnguyen@chemistry.montana.edu
Received March 31, 2009
ABSTRACT
A new method for the stereoselective synthesis of r-glycosyl ureas, via nickel-catalyzed [1,3]-rearrangement of glycosyl trichloroace-
timidates, has been developed. The r-stereoselectivity at the anomeric carbon of the resulting trichloroacetamides depends on the
nature of the cationic nickel catalyst. This method is applicable to a number of trichloroacetimidate substrates. The r-glycosyl
trichloroacetamides can be directly converted into r-glycosyl ureas in the presence of amines. In all cases, the stereochemical integrity
at the urea linkages remains intact.
Aminoglycosides are clinically important antibiotics with
a broad antibacterial spectrum.1 They are used predomi-
nantly in the treatment of Gram-negative bacterial infec-
tions. However, bacterial resistance against aminoglyco-
side antibiotics has been increasing at an alarming rate.2
In response to this medical concern, the search for new
classes of antibiotic has intensified.3 Research in the area
of glycosyl ureas, in which the O- and N-glycosidic bonds
are replaced with the urea linkage, has emerged due to
their potential application in the field of aminoglycosides.4
Methods for synthesizing glycosyl ureas require many
steps.5 In particular, general methods for the stereoselec-
tive synthesis of R-glycosyl ureas are still unavailable.6
A recent method developed in our group utilized Pd(II)-
ligand complexes for the stereoselective [3,3]-sigmatropic
rearrangement of glycal imidates to the corresponding R-
and ꢀ-2,3-unsaturated trichloroacetamides, which are then
converted into the glycosyl ureas.7 While this method is
(1) (a) Chow, C. S.; Bogdan, F. M. Chem. ReV. 1997, 97, 1489–1513.
(b) Busscher, G. F.; Rutjes, P. J. T.; van Delft, F. L. Chem. ReV. 2005,
105, 775–791. (c) Arya, D. P. Top. Curr. Chem. 2005, 253, 149–178. (d)
Hainrichson, M.; Nudelman, I.; Baasov, T. Org. Biomol. Chem. 2008, 6,
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2006, 128, 3934–3938. (e) Ichikawa, Y.; Matsukawa, Y.; Tamura, M.;
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Ichikawa, Y.; Matsukawa, Y.; Isobe, M. Synlett 2004, 6, 1019–1022. (i)
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64, 8780–8788.
(2) Magnet, S.; Blanchard, J. S. Chem. ReV. 2005, 105, 477–497.
(3) Payne, D. J.; Wallis, N. G.; Gentry, D. R.; Rosenberg, M. Curr.
Opin. Drug. DiscoVery DeV. 2003, 3, 177–190. (b) Haddad, J.; Kotra, L. P.;
Llano-Sotelo, B.; Kim, C.; Azucena, E. F.; Lui, M.; Vakulenko, S. B.; Chow,
C. S.; Mobashery, S J. Am. Chem. Soc. 2002, 124, 3229–3237. (c) Francois,
B.; Szuchowski, J.; Adhikari, S. S.; Pachamuthu, K.; Swayze, E. E.; Griffey,
R. H.; Migawa, M. T.; Westhof, E.; Hanessian, S. Angew. Chem., Int. Ed
2004, 43, 6735–6738. (d) Blout, K. F.; Zhao, F.; Hermann, T.; Tor, Y.
J. Am. Chem. Soc. 2005, 127, 9818–9829. (e) Kling, D.; Hesek, D.; Shi,
Q.; Mobashery, S. J. Org. Chem. 2007, 72, 5450–5453.
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1438–1446.
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4234. (b) Mercer, G. J.; Yang, J.; McKay, M. J.; Nguyen, H. M. J. Am.
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10.1021/ol900670a CCC: $40.75
Published on Web 04/30/2009
 2009 American Chemical Society

highly diastereoselective, its main drawbacks include the use
of toxic OsO4 to convert the resulting 2,3-unsaturated
trichloroacetamides into the diol prior to transforming them
into glycosyl ureas, the limited substrate scope (mannose
residue only), and the overall moderate yields. In this paper,
we report a practical method for the stereoselective synthesis
of R-glycosyl ureas that is applicable to an array of
carbohydrate substrates. The method utilizes a cationic
nickel(II) catalyst to rearrange glycosyl trichloroacetimidate
1 to R- trichloroacetamide 2 (Scheme 1). The resulting
glycosyl trichloroacetamide 5 in 86% yield with excellent
R-selectivity (entry 2). Lowering the catalyst loading from
5 to 2 mol % still maintained the yield and anomeric
selectivity (entry 3). Our interest in nickel catalysis led
us to consider Ni(PhCN)4(OTf)2, which was generated in
situ from Ni(PhCN)4Cl2 and AgOTf (entry 4). Employing
Ni(dppe)(OTf)2 led to an improvement of the yield and
maintained the R-selectivity (entry 7). Overall, with use
of either palladium or nickel catalyst, the rearrangement
proceeded smoothly within 1 h. In contrast, it took 14 h
for the reaction to go to completion with use of 6 mol %
of AgOTf, and trichloroacetamide 5 was isolated in 72%
yield with R/ꢀ ) 5:1 (entry 8). Employing BF3·OEt2
yielded 5 in 65% yield with R/ꢀ ) 4:1 (entry 9).
Scheme 1. Strategy for the Synthesis of R-Glycosyl Ureas
With the optimal conditions at hand, we set out to define
the substrate scope of this rearrangement. The cationic
nickel-catalyzed reaction is effective for a variety of
trichloroacetimidate substrates (Figure 1). Specifically,
product 2 is then directly converted to glycosyl urea 3,
eliminating the need for using OsO4.
In light of our previous success utilizing commercially
available cationic palladium(II), Pd(CH3CN)4(BF4)2, for
the [3,3]-sigmatropic rearrangement of glycal imidates,7
we chose this catalyst system for our preliminary studies
of the [1,3]-rearrangement of perbenzylated D-glucopy-
ranosyl trichloroacetimidate 4 (Table 1).8 The reaction did
Table 1. Optimization of Nickel-Catalyzed Rearrangement of
Glycosyl Trichloroacetimidate 4a
Figure 1. Cationic nickel-catalyzed 1,3-rearrangement of glycosyl
trichloroacetimidate substrates: (a) compound 10 was peformed
with 4 mol % of Ni(dppe)Cl2 and 8 mol % of AgOTf; (b) isolated
yield; (c) H NMR ratio.
loading time yieldb
1
entry
catalyst
(mol %)
(h)
(%)
R:ꢀc
1
2
3
4
5
6
7
8
9
Pd(CH3CN)4(BF4)2
Pd(PhCN)2(OTf)2
Pd(PhCN)2(OTf)2
Ni(PhCN)4(OTf)2
Ni(p-FPhCN)4(OTf)2
Ni(p-MeOPhCN)4(OTf)2
Ni(dppe)(OTf)2
AgOTf
5
5
2
2
2
2
2
6
4
5
NR
86
85
84
88
90
94
72
65
1
10:1
10:1
11:1
10:1
10:1
11:1
5:1
D-glucose trichloroacetimidates with allyl and TIPS groups
incorporated at the C(2)-positions afforded excellent yields
and R-selectivity of glycosyl trichloroacetamides 6 and
7. Substrates such as D-xylose and D-quinovose that lacked
the protected C(6)-hydroxyl functionality also provided
the corresponding trichloroacetamides 8 and 9, respec-
tively, in good yields and almost exclusively as R-rear-
rangement isomers. Furthermore, both D-mannose and
D-galactose substrates were viable trichloroacetimidates
for providing the desired products 10 and 11, respectively,
with excellent R-selectivity.
We have established that the trichloroacetamide proton of a
diol intermediate such as 13 can be deprotonated with Cs2CO3
to generate in situ an isocyanate 14, which participates in
glycosyl urea formation in the presence of a nucleophilic
nitrogen (Scheme 2).7 This approach requires three steps
(dihydroxylation, coupling, and acylation) starting from 2,3-
unsaturated trichloroacetamide 12.
1
1
1
1
1
14
6
BF3·OEt2
4:1
a The reactions were performed with Pd(CH3CN)4(BF4)2 or
Pd(PhCN)2(OTf)2 or LnNi(OTf)2, generated in situ from Pd(PhCN)2Cl2
or LnNiCl2 and AgOTf. b Isolated yield. 1H NMR ratio.
c
not proceed even with 5 mol % of Pd(CH3CN)4(BF4)2
(entry 1). Changing to the more reactive cationic palla-
dium(II) catalyst, Pd(PhCN)2(OTf)2,9 provided the desired
(8) (a) Schmidt, R. R.; Michel, J. Angew. Chem., Int. Ed. 1980, 19, 731–
732. (b) Schmidt, R. R.; Hoffmann, M. Angew. Chem. 1983, 95, 417–418.
(c) Schmidt, R. R.; Stumpp, M. Liebigs Ann. Chem. 1983, 7, 1249–1256.
(d) Schmidt, R. R.; Michel, J. Tetrahedron Lett. 1984, 25, 821–824.
(9) Mensah, E. A.; Azzarelli, J. M.; Nguyen, H. M. J. Org. Chem. 2009,
74, 1650–1657.
2434
Org. Lett., Vol. 11, No. 11, 2009

Carbohydrates linked to the amino acid backbone of
protein have received considerable attention due to their
involvement in a variety of biochemical processes.10
Although the synthesis of ꢀ-urea-linked glycopeptides has
been documented,11 there is no method available for the
stereoselective preparation of R-urea-linked glycopeptides.
To determine if both D- and L-amino acids are viable
nucleophiles, R-glycosyl trichloroacetamides 5 and 10
were coupled with four different amino acids. It was found
that R-urea-linked glycopeptides 23-26 were formed in
good yield (Table 3).
Scheme 2
.
Transformation of R-Glycal Trichloroacetamides into
R-Glycosyl Ureas
In this new strategy, the R-glycosyl ureas can be directly
obtained from the resulting R-trichloroacetamides in a
single step with much higher yields (Table 2). Our
Table 3. Coupling of Both D- and L-Amino Acids with
R-Trichloroacetamidesa
Table 2. Coupling of Amines with R-Trichloroacetamidesa
a The reactions were performed with 3 equiv of Cs2CO3 and 2 equiv of
amine in DMF (0.2 M) at 25 °C. b Isolated yield.
In summary, a novel method for the stereoselective
synthesis of R-glycosyl ureas, via cationic nickel-catalyzed
1,3-rearrangement of glycosyl trichloroacetimidates, has
been developed. The R-selectivity at the anomeric carbon
of the resulting glycosyl trichloroacetamides depends on
the nature of the nickel catalyst. This new method is
applicable to a number of glycosyl trichloroacetimidate
substrates which cannot be easily accessed by our previous
method. The R-glycosyl trichloroacetamides are then
directly converted into the corresponding R-glycosyl ureas
a The reactions were performed with 3-4 equiv of Cs2CO3 and 2-3
equiv of amine in DMF (0.2 M) at 25 °C. b Isolated yield.
previous work has shown that both primary and secondary
nitrogen nucleophiles gave the desired R-glycosyl ureas
in overall 51-61% yield.7 Our new method, however,
provided the corresponding R-glycosyl ureas 17-21 in
75-94% yield (entries 1-5). Similarly, the urea-linked
disaccharide 22 was also obtained in higher yield (entry
6).
(10) (a) Dwek, R. A. Chem. ReV. 1996, 96, 683–720. (b) Varki, A.
Glycobiology 1993, 3, 97–130.
(11) (a) Ichikawa, Y.; Ohara, F.; Kotsuki, H.; Nakano, K. Org. Lett.
2006, 8, 5009–5012. (b) Christiansen-Brams, I.; Meldal, M.; Bock, K.
J. Chem. Soc., Perkin Trans. 1 1993, 1461–1471. (c) van Ameijde, J.;
Albada, H. B.; Liskamp, R. M. J. J. Chem. Soc., Perkin Trans. 1 1994,
1042–1049.
Org. Lett., Vol. 11, No. 11, 2009
2435

in the presence of amine nucleophiles. In all cases, the
stereochemical integrity at the C(1)-carbon of the newly
formed glycosyl ureas remains intact.
Supporting Information Available: Experimental pro-
cedure and compound characterization data. This material
is available free of charge via the Iinternet at http://pubs.acs.
org.
Acknowledgment. We thank Montana State University
for finanical support. NHP was the 2008 recipient of Geer-
Howard-Callis Undergraduate Research Award.
OL900670A
2436
Org. Lett., Vol. 11, No. 11, 2009