Palladium-catalyzed glycal imidate rearrangement: Formation of α- and β-N-glycosyl trichloroacetamides

Article abstract of DOI:10.1021/ol701778z

A novel palladium(ll)-catalyzed stereoselective synthesis of α- aα (v-glycosyl trichloroacetamldes has been developed. The α - and β-selectivity at the anomeric carbon depends on the nature of the palladium-ligand catalyst. While the cationic palladium(ll

Full text of DOI:10.1021/ol701778z

ORGANIC
LETTERS
2007
Vol. 9, No. 21
4231-4234
Palladium-Catalyzed Glycal Imidate
Rearrangement: Formation of - and
-N-Glycosyl Trichloroacetamides
r
â
Jaemoon Yang, Gregory J. Mercer, and Hien M. Nguyen*
Department of Chemistry and Biochemistry, Montana State UniVersity,
Bozeman, Montana 59717
hmnguyen@chemistry.montana.edu
Received July 25, 2007
ABSTRACT
A novel palladium(II)-catalyzed stereoselective synthesis of
at the anomeric carbon depends on the nature of the palladium
neutral palladium(II) favors the -selectivity.
r
- and
â
-N-glycosyl trichloroacetamides has been developed. The
r
- and
â-selectivity
−ligand catalyst. While the cationic palladium(II) promotes the
r-selectivity, the
â
The stereoselective synthesis of R- or â-N-glycosyl amides
has recently received considerable attention since the rec-
ognition of glycoproteins is important in a variety of
biochemical processes such as cell-cell recognition, cellular
transport, adhesion for the binding of pathogens to cells, and
metastasis.1 Early work on the synthesis of glycosyl amides
employed the reaction of glycosyl amines with activated
carboxylic acid derivatives.2 Although this method is still
frequently used, drawbacks of this methodology include
hydrolysis of the starting glycosyl amines as well as
anomerization of the protected glycosyl azides upon reduc-
tion.3 In an alternative strategy, the glycosyl amides can be
produced by treatment of isothiocyanates with the appropriate
acids.4 In recent years, glycosyl amides have also been made
via Staudinger reduction of glycosyl azides.5 Although this
approach gives the desired glycosyl amides in good yields,
the R/â-selectivity at the anomeric carbon is poor. DeShong
and several research groups, who recognized the challenge
of this approach, developed a stereoselective synthesis of
R-N-glycosyl amides from glycosyl azides using isoxazoline
intermediates.6 We report herein a novel method for the
stereoselective synthesis of R- and â-N-glycosyl amides
involving Pd(II)-catalyzed glycal imidate rearrangement. In
our approach, the nature of the palladium-ligand complex
(1) (a) Kobata, A. Acc. Chem. Res. 1993, 26, 319-323. (b) Varki, A.
Glycobiology 1993, 3, 97-130. (c) Bill, R. M.; Flitch, S. L. Chem. Biol.
1996, 3, 145-149. (d) Arsequell, G.; Valenciak, G. Tetrahedron: Asym-
metry 1998, 10, 3045-3094. (e) Roberge, J. Y.; Beebe, S. J.; Danishefsky,
J. J. Am. Chem. Soc. 1998, 120, 3915-3917.
(2) (a) Lockhoff, O. Angew. Chem., Int. Ed. 1991, 30, 1639-1647. (b)
Gordon, D. M.; Danishefsky, S. J. Org. Chem. 1991, 56, 3713-3715. (c)
Timmer, C. M.; Turner, J. J.; Ward, C. M.; van der Marel, G. A.; Kouwijzer,
M. L. C. E.; Grootenhuis, P. D. J.; Boom, J. H. Chem.-Eur. J. 1997, 3,
920-930. (d) Avalos, M.; Babiano, R.; Carratero, M. J.; Cintas, P.; Higes,
F. J.; Jimenez, J. L.; Palacios, J. C. Tetrahedron 1998, 54, 615-628. (e)
Rottman, H.; Synstad, B.; Eijsink, V.; Peter, M. G. J. Org. Chem. 1999,
64, 2293-2297.
(3) Takeda, T.; Utsuno, A.; Okamoto, N.; Ogihara, Y. Carbohydr. Res.
1990, 207, 71-79.
(4) (a) Khorlin, A. Y.; Zhurabyan, S. E.; Macharadze, R. E. Carbohydr.
Res. 1980, 85, 201-208. (b) Gunther, W.; Kunz, H. Angew. Chem., Int.
Ed. 1990, 29, 1050-1051. (c) Kassab, R.; Felix, C.; Parrot-Lopez, H.;
Bonaly, R. Tetrahedron Lett. 1997, 38, 7555-7558.
(5) (a) Teshima, T.; Nakajima, K.; Takahashi, M.; Shiba, T. Tetrahedron
Lett. 1992, 33, 363-366. (b) Takeda, T.; Kojima, K.; Ogihara, Y.
Carbohydr. Res. 1993, 243, 79-89. (c) Shalev, D. E.; Chiacchiera, S. M.;
Radkovsky, A. E.; Kosower, E. M. J. Org. Chem. 1996, 61, 1689-1701.
(d) Ariza, X.; Urpi, F.; Vildomat, C.; Vilarrasa, J. Tetrahedron Lett. 1998,
39, 9101-9102. (e) Malkinson, J. P.; Falconer, R. A.; Toth, I. J. Org. Chem.
2000, 65, 5249-5252.
10.1021/ol701778z CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/19/2007

Scheme 1
Table 1. Pd(II)-Catalyzed Formation of â-N-Glycosyl
Trichloroacetamidea
controls the anomeric selectivity (Scheme 1). The cationic
Pd(II), which promotes ionization of the glycal imidate 1
by coordinating to the imidate nitrogen,7 results in the
formation of R-N-glycosyl trichloroacetamide 2. In contrast,
use of neutral Pd(II) promotes a concerted-type mechanism
to provide â-N-glycosyl trichloroacetamide 3.8 Although the
allylic imidate rearrangement is pioneered by Overman,9
there is no report on utilizing this method in carbohydrate
synthesis to control the R- and â-selectivity of the glycosyl
amide at the anomeric carbon.
phosphine
entry
ligand
none
Ph3P
additive
time yieldb R:âc
2 h 60% 1:1
16 h 83% 1:2
16 h 77% 1:3
25 h 73% 1:4
16 h 89% 1:7
1
2
3
4
5
6
7
8
none
none
RUPHOS none
DTTBP
TTMPP
DTTBP
TTMPP
none
none
none
10 mol % of salicylaldehyde 4 h
10 mol % of salicylaldehyde 4 h
10 mol % of salicylaldehyde 1 h
70% 1:7
86% 1:9
71% 1:2
Treatment of glucal imidate 4 with 2.5 mol % of
Pd(PhCN)2Cl2 in CH2Cl2 at 25 °C for 2 h provided a 1:1
mixture of R- and â-N-glycosyl trichloroacetamide 5 in 60%
yield (Table 1, entry 1). It was anticipated that the anomeric
selectivity would depend on the ligand on palladium.
Accordingly, glucal imidate 4 was treated with a preformed
solution of Pd(PhCN)2Cl2 and Ph3P, and 5 was isolated in
83% yield with R:â ) 1:2 (entry 2). With the use of
RUPHOS and DTTBP as the phosphine ligands,10 the
anomeric selectivity was slightly improved, favoring the
â-anomer (entries 3 and 4). Employing TTMPP as the
phosphine ligand led to an improvement of both the yield
and the â-selectivity (entry 5). However, it took 16 h for
the reaction to go to completion. Gratifyingly, it was found
that addition of 10 mol % of salicylaldehyde significantly
shortened the reaction time to 4 h (entries 6 and 7), and the
desired N-glycosyl trichloroacetamide 5 was obtained in good
yield with excellent â-selectivity. Thus, the combination of
the bulky phosphine ligand and salicylaldehyde increased
both the yield and the â-selectivity as well as shortened the
reaction time. We also examined whether temperature
affected the selectivity; increasing or decreasing the reaction
temperature only decreased the â-selectivity. This is the first
example wherein a bulky phosphine ligand is employed to
control the stereoselectivity at the anomeric carbon in the
allylic imidate rearrangement.
a
All reactions were carried out in CH2Cl2 (0.2 M) with 2.5 mol % of
Pd(II)/ phosphine ligand. Isolated yield. c 1H NMR ratio.
b
When cationic palladium,11 Pd(CH3CN)4(BF4)2, was em-
ployed in the reaction, the desired R-N-glycosyl trichloro-
acetamide 5 was obtained in 73% yield as the major anomer
(Table 2, entry 1). Addition of 10 mol % of salicylaldehyde
Table 2. Pd(II)-Catalyzed Formation of R-N-Glycosyl
Trichloroacetamidea
entry palladium salicylaldehyde
time
yieldb
R:âc
1
2
3
4
2.5 mol %
2.5 mol %
0.1 mol %
0.5 mol %
none
45 min
1 h
2 h
73%
80%
78%
82%
9:1
14:1
9:1
10 mol %
0.4 mol %
2 mol %
1 h
13:1
(6) (a) Damkaci, F.; DeShong, P. J. Am. Chem. Soc. 2003, 125, 4408-
4409. (b) He, Y.; Hinklin, R. J.; Chang, J.; Kiessling, L. L. Org. Lett. 2004,
6, 4479-4482. (c) Grandjean, C.; Boutonnier, A.; Guerreiro, C.; Fournier,
J.-M.; Mulard, L. A. J. Org. Chem. 2005, 70, 7123-7132. (d) Bianchi, A.;
Bernardi, A. J. Org. Chem. 2006, 71, 4565-4577. (e) Temelkoff, D. P.;
Smith, C. R.; Kibler, D. A.; McKee, S.; Duncan, S. J.; Zeller, M.; Hunsen,
M.; Norris, P. Carbohydr. Res. 2006, 341, 1645-1656.
(7) (a) Calter, M.; Hollis, T. K.; Overman, L. E.; Ziller, J.; Zipp, G. G.
J. Org. Chem. 1997, 62, 1449. (b) Lappert, M. F.; Singh, A.; Atwood, J.
L.; Hunter, W. E.; Zhang, H.-M. J. Chem. Soc., Chem. Commun. 1983,
68-69
a
All reactions were carried out in CH2Cl2 with Pd(CH3CN)4(BF4)2 and
salicylaldehyde (1:4) except for entry 1. Isolated yield. c 1H NMR ratio.
b
significantly increased the R-selectivity (entry 2).12 Decreas-
ing the catalyst loading still maintained the yield and the
selectivity (entries 3 and 4). Thus, switching to the cationic
palladium reverses the anomeric selectivity, favoring the
R-anomer.13
(8) Waltson, M.; Overman, L. E.; Bergman, R. G. J. Am. Chem. Soc.
2007, 129, 5031-5044.
(9) (a) Overman, L. E. J. Am. Chem. Soc. 1974, 96, 597-598. (b) For
a comprehensive review, see: Overman, L. E.; Carpenter, N. E. In Organic
Reactions; Overman, L. E., Ed.; WILEY-VCH: Weinheim, 2005; Vol. 66,
pp 1-107.
(10) Barder, T. E.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 5096-
5101.
(11) Mikami, K.; Hatano, M.; Akiyama, K. Top. Organomet. Chem. 2005,
14, 279-321 and references therein.
(12) Miller, K. J.; Baag, J. H.; Abu-Omar, M. M. Inorg. Chem. 1999,
38, 4510-4514.
4232
Org. Lett., Vol. 9, No. 21, 2007

To assess the feasibility of this palladium reaction for the
synthesis of â-N-glycosyl trichloroacetamides, glycal imi-
dates incorporating cyclic ketal protecting groups were
investigated (Figure 1). The desired products 6-10 were
Figure 2. Stereoselective formation of R-N-glycosyl trichloro-
acetamides. All reactions were performed with 0.5 mol % of
Pd(CH3CN)4(BF4)2 and 2 mol % of salicylaldehyde. b Isolated yield.
c 1H NMR ratio.
Figure 1. Stereoselective formation of â-N-glycosyl trichloro-
acetamides. All reactions were performed with 2.5 mol % of
Pd(PhCN)2Cl2/TTMPP and 10 mol % of salicylaldehyde. b Isolated
yield. c 1H NMR ratio.
provides R-anomer 5.7b In contrast, use of the Pd(PhCN)2Cl2-
TTMPP-salicylaldehyde complex promotes a cyclization-
induced rearrangement.8 In this pathway, the palladium
catalyst coordinates to the double bond of 4 to form
π-complex 16, which is activated toward nucleophilic attack
by the imidate nitrogen. Subsequent cyclization of 16
provides σ-complex 17. Grob-like fragmentation followed
by dissociation releases â-anomer 5.
The glycosyl urea is found in nature as a structural unit
of glycocinnamoylspermidine antibiotics.15 There are sev-
eral methods reported for the construction of glycosyl urea.16
To demonstrate the utility of the 2,3-unsaturated glycosyl
obtained with good â-selectivity. The deactivating effect of
4,6-acetal protecting groups on these glycal imidates restricts
them in the tag conformations, thus limiting ionization to
favor â-anomers.14 In contrast, glycal imidates incorporating
acyclic protecting groups gave a mixture of R- and â-N-
glycosyl trichloroacetamides such as 11 and 12.
In the formation of R-N-glycosyl trichloroacetamides, a
number of glycal imidates incorporating a variety of cyclic
and acyclic protecting groups were examined (Figure 2). The
desired glycosyl amides 6-13 were obtained with excellent
R-selectivity. These results suggest that the cationic pal-
ladium-salicylaldehyde complex was responsible for the
observed R-selectivity at the anomeric center and the
protecting groups on the glycal imidates had little effect on
the selectivity.
The proposed mechanism for Pd(II)-catalyzed forma-
tion of R- and â-N-glycosyl trichloroacetamides is out-
lined in Figure 3. In the case of the cationic palladium, the
Pd(CH3CN)4(BF4)2-salicylaldehyde complex coordinates to
the imidate nitrogen of 4 to form 14 which subsequently
undergoes ionization to generate allylic cation 15. Regiose-
lective addition of trichloroamide to the R-face of 15
followed by displacement of the amide from palladium
(13) We also investigated whether the glycal imidate rearrangement could
be catalyzed by a Lewis acid. Accordingly, treatment of 4 with 0.5 mol %
of TMSOTf in CH2Cl2 at 0 °C only resulted in decomposition.
(14) (a) Jensen, H. H.; Nordstrøm, L. U.; Bols, M. J. Am. Chem. Soc.
2004, 126, 9205-9213. (b) Crich, D.; Chandrasekera, N. S. Angew. Chem.,
Int. Ed. 2004, 43, 5386-5389.
Figure 3. Proposed mechanism for the R-/â-selectivity.
Org. Lett., Vol. 9, No. 21, 2007
4233

acetamides and subsequent treatment with Cs2CO3 and
amines in DMF (Scheme 2).17 The diol and triol intermedi-
ates of certain glycosyl ureas were acylated to ease the
purification process.
Scheme 2
In summary, a novel method for palladium(II)-catalyzed
stereoselective formation of R- and â-N-glycosyl trichloro-
acetamides has been developed. The R- and â-selectivity at
the anomeric carbon depends on the nature of the palladium-
ligand catalyst. While the cationic palladium-salicylaldehyde
complex promotes the R-selectivity, the neutral palladium-
ligand catalyst favors the â-selectivity. Because of its
substrate tolerance and mild conditions, this palladium
method is applicable to a wide range of glycal imidates. The
resulting N-glycosyl trichloroacetamides were further trans-
formed into glycosyl ureas.
Acknowledgment. We thank Montana State University
and NSF EPSCoR for financial support.
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL701778Z
(15) (a) Ellestad, G. A.; Cosulich, D. B.; Broschard, R. W.; Martin, J.
H.; Kunstmann, M. P.; Morton, G. O.; Lancaster, J. E.; Fulmor, W.; Lovell,
F. M. J. Am. Chem. Soc. 1978, 100, 2515-2524. (b) Dobashi, K.; Nagaoka,
K.; Wantanabe, Y.; Nishida, M.; Hamada, M.; Naganawa, H.; Takita, T.;
Takeuchi, T.; Umezawa, H. J. Antibiot. 1985, 38, 1166-1170.
(16) (a) Benn, M. H.; Jones, A. S. J. Chem. Soc. 1960, 3837-3841. (b)
Garc´ıa-Ferna´ndez, J. M.; Ortiz-Mellet, C.; D´ıaz-Pe´rez, V. M.; Fuentes, J.;
Kova´c, J.; Pinte´r, I. Tetrahedron Lett. 1997, 38, 4161-4164. (c) Garc´ıa-
Moreno, M. I.; Benito, J. M.; Ortiz-Mellet, C.; Garc´ıa-Ferna´ndez, J. M.
Tetrahedron: Asymmetry 2000, 11, 1331-1341. (d) Ichikawa, Y.; Nish-
iyama, T.; Isobe, M. Synlett 2000, 1253-1256. (e) Ichikawa, Y.; Ohara,
F.; Kotsuki, H.; Nakano, K. Org. Lett. 2006, 8, 5009-5012. (f) Ichikawa,
Y.; Matsukawa, Y.; Isobe, M. J. Am. Chem. Soc. 2006, 128, 3934-3938.
(17) Urabe, D.; Sugino, K.; Nishikawa, T.; Isobe, M. Tetrahedron Lett.
2004, 45, 9405-9407.
amide products, both the R- and â-N-glycosyl trichloro-
acetamides were transformed into the corresponding glycosyl
ureas 18-23 by dihydroxylation of N-glycosyl trichloro-
4234
Org. Lett., Vol. 9, No. 21, 2007