Construction of interglycosidic N-O linkage via direct glycosylation of sugar oximes

Article abstract of DOI:10.1021/ol301863j

Direct glycosylation of sugar oximes and HONHFmoc has been realized for the first time by using glycosyl ortho-hexynylbenzoates as donors under the catalysis of PPh₃AuOTf, providing an effective approach to the synthesis of N-O linked saccharid

Full text of DOI:10.1021/ol301863j

ORGANIC
LETTERS
2012
Vol. 14, No. 15
4022–4025
Construction of Interglycosidic NÀO
Linkage via Direct Glycosylation of Sugar
Oximes
Jun Yu,† Jiansong Sun,*,‡ and Biao Yu*,‡
Department of Chemistry, University of Science and Technology of China, 96 Jinzhai
Road, Hefei, Anhui 230026, China, and State Key Laboratory of Bio-organic
and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
jssun@mail.sioc.ac.cn; byu@mail.sioc.ac.cn
Received July 6, 2012
ABSTRACT
Direct glycosylation of sugar oximes and HONHFmoc has been realized for the first time by using glycosyl ortho-hexynylbenzoates as donors under the
catalysis of PPh3AuOTf, providing an effective approach to the synthesis of NÀO linked saccharides, which are of great biological interest.
The peculiar three-bond glycosidic ÀNÀOÀ linkage is a
prominent structural feature of calicheamicin-esperamicin
antibiotics,1,2 providing a conformational control element
that allows selective binding of the antibiotics to specific
DNA sequences.3,4 Heroic efforts toward the synthesis of
this type of saccharide and the intact antibiotics have led to
three alternatives for the construction of this important
glycosidic linkage (Scheme 1).5À7 The first approach em-
ploys condensation of glycosyloxyamine A with sugar
ketone B to provide oxime disaccharide C which is then
subjected to reduction to afford the target disaccharide F.5
The second one applies SN2 displacement of a sugar
trifluoromethanesulfonate E with the sodium salt of gly-
cosyl urethane D, and a removal of the N-COOEt group, to
furnish disaccharide F.6 The third alternative employs
glycosylation of sugar nitrone H with a glycosyl bromide
or trichloroacetimidate G and subsequent removal of the
resulting N,O-benzylidene group to provide disaccharide
F.7 However, an obvious approach to the construction of
the interglycosidic NÀO linkage would be via the direct
glycosylation of sugar oximes (i.e., 2a).
† University of Science and Technology of China.
‡ Chinese Academy of Sciences.
(1) (a) Lee, M. D.; Dunne, T. S.; Siegel, M. M.; Chang, C. C.;
Morton, G. O.; Borders, D. B. J. Am. Chem. Soc. 1987, 109, 3464. (b)
Lee, M. D.; Dunne, T. S.; Chang, C. C.; Ellestad, G. A.; Siegel, M. M.;
Morton, G. O.; McGahren, W. J.; Borders, D. B. J. Am. Chem. Soc.
1987, 109, 3466.
(2) (a) Golik, J.; Clardy, J.; Dubay, G.; Groenewold, G.; Kawaguchi,
H.; Konishi, M.; Krishnan, B.; Ohkuma, H.; Saitoh, K.; Doyle, T. W. J.
Am. Chem. Soc. 1987, 109, 3461. (b) Golik, J.; Dubay, G.; Groenewold,
G.; Kawaguchi, H.; Konishi, M.; Krishnan, B.; Ohkuma, H.; Saitoh, K.;
Doyle, T. W. J. Am. Chem. Soc. 1987, 109, 3462.
(3) Walker, S.; Cange, D.; Gupta, V.; Kahne, D. J. Am. Chem. Soc.
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(4) For example, see: (a) Zein, N.; Sinha, A. M.; McGahren, W. J.;
Ellestad, G. A. Science 1988, 240, 1198. (b) Zein, N.; Poncin, M.;
Nilakantan, R.; Ellestad, G. A. Science 1989, 244, 697. (c) Zein, N.;
McGahren, W. J.; Morton, G. O.; Ashcroft, J.; Ellestad, G. A. J. Am.
Chem. Soc. 1989, 111, 6888. (d) Walker, S.; Landovitz, R.; Ding, W. D.;
Ellestad, G. A.; Kahne, D. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 4608.
(5) (a) Nicolaou, K. C.; Groneberg, R. D. J. Am. Chem. Soc. 1990,
112, 4085. (b) Groneberg, R. D.; Miyazaki, T.; Stylianides, N. A.;
Schulze, T. J.; Stahl, W.; Schreiner, E. P.; Suzuki, T.; Iwabuchi, Y.;
Smith, A. L.; Nicolaou, K. C. J. Am. Chem. Soc. 1993, 115, 7593. (c)
Nicolaou, K. C.; Hummel, C. W.; Nakada, M.; Shibayama, K.; Pitsinos,
E. N.; Saimoto, H.; Mizuno, Y.; Baldenius, K.-U.; Smith, A. L. J. Am.
Chem. Soc. 1993, 115, 7625.
(6) (a) Yang, D.; Kim, S.-H.; Kahne, D. J. Am. Chem. Soc. 1991, 113,
4715. (b) Halcomb, R. L.; Wittman, M. D.; Olson, S. H.; Danishefsky,
S. J.; Golik, J.; Wong, H.; Vyas, D. J. Am. Chem. Soc. 1991, 113, 5080.
(7) (a) Bamhaoud, T.; Lancelin, J.-M.; Beau, J.-M. J. Chem. Soc.,
Chem. Commun. 1992, 1494. (b) Da Silva, E.; Prandi, J.; Beau, J.-M. J.
Chem. Soc., Chem. Commun. 1994, 2127. (c) Moutel, S.; Prandi, J. J.
Chem. Soc., Perkin Trans. 1 2001, 305.
(8) Glycosylation of isatine 3-oximes with R-D-glucosaminyl chloride
peracetate under phase transfer conditions was reported; see: Kuryanov,
V. O.; Chupakhina, T. A.; Shapovalova, A. A.; Katsev, A. M.; Chirva,
V. Ya. Russ. J. Bioorg. Chem. 2011, 37, 231.
r
10.1021/ol301863j
Published on Web 07/25/2012
2012 American Chemical Society

Scheme 1. Known Approaches to the Synthesis of the NÀO
Scheme 2. Direct Glycosylation of Sugar Oximes (2aÀc) with
Glycosyl ortho-Hexynylbenzoates (1aÀe)
Linked Saccharides
To date, this approach has never been accomplished,7a,8
due to the lability of the oximes toward the Lewis acids
required for the glycosylation reaction. In this regard, the
newly developed glycosylation protocol with glycosyl
ortho-alkynylbenzoates as donors, and a gold(I) complex
as the catalyst, which performs under neutral conditions
might solve this problem.9,10
The glycosylation of 6-deoxy-glucopyranoside 4-oxime 2a
was first examined, which failed to be glycosylated pre-
viously,7a with perbenzoyl glucopyranosyl ortho-hexynyl-
benzoate 1a9 (1.2 equiv) under standard conditions (0.2 equiv
˚
of PPh3AuOTf, 5 A MS, CH2Cl2, rt) (Scheme 2). The
reaction led to the desired disaccharide 3(E) in 27% yield
as a single isomer, with the major product being the corre-
sponding orthoester. Thus, more reactive glucopyranosyl
ortho-hexynylbenzoate 1b, which is equipped with a super-
armed protecting pattern,11 was used as a glycosyl donor to
couple with 2a. Under identical conditions, disaccharide 4
was obtained in a high 90% yield as a pair of the Z/E isomers
(Z/E = 1:5.4). Similarly, the 6-deoxy perbenzoyl pyranose
donors, L-rhamnosyl and L-talosyl ortho-hexynylbenzoates
1c and 1d, coupled with 2a to provide the corresponding
disaccharides 5 (96%, Z/E = 1:9.7) and 6 (93%, Z/E =
1:6.8) in excellent yields in favor of the Eisomers. In addition,
perbenzoyl D-ribosyl ortho-hexynylbenzoate 1e, a furanose
donor, was also shown to be suitable for direct glycosylation
of 2a, providing disaccharide 7 cleanly (92%, Z/E = 1:6.4).
The reaction scope was further investigated with 1,2;5,6-
di-O-isopropylidene glucofuranoside 3-oxime 2b12 and
1,2;3,4-di-O-isopropylidene galactopyranoside 2c13 as
(9) (a) Li, Y.; Yang, Y.; Yu, B. Tetrahedron Lett. 2008, 49, 3604. (b)
Li, Y.; Yang, X. Y.; Liu, Y. P.; Zhu, C. S.; Yang, Y.; Yu, B. Chem.;Eur.
J. 2010, 16, 1871. (c) Zhu, Y.; Yu, B. Angew. Chem., Int. Ed. 2011, 50,
8329.
(10) For glycosylation of acid labile substrates with ortho-alkynyl-
benzoates, see: (a) Yang, W.; Sun, J.; Lu, W.; Li, Y.; Shan, L.; Han, W.;
Zhang, W.-D.; Yu, B. J. Org. Chem. 2010, 75, 6879. (b) Li, Y.; Sun, J.;
Yu, B. Org. Lett. 2011, 13, 5508. (c) Zhang, Q.; Sun, J.; Zhu, Y.; Zhang,
F.; Yu, B. Angew. Chem., Int. Ed. 2011, 50, 4933.
(11) Mydock, L. K.; Demchenko, A. V. Org. Lett. 2008, 10, 2107.
(12) (a) Tronchet, J. M. J.; Habashi, F.; Fasel, J.-P.; Zosimo-Landolfo,
G.; Barbalat-Rey, F.; Moret, G. Helv. Chim. Acta 1986, 69, 1132. (b) Hall,
A.; Bailey, P. D.; Rees, D. C.; Rosair, G. M.; Wightman, R. H. J. Chem.
Soc., Perkin Trans. 1 2000, 329.
acceptors. The glycosylation of furanose oxime 2b with
donors 1bÀ1e proceeded smoothly under standard condi-
tions, affording the desired disaccharides 8À11 in excellent
yields (85%À97%). In contrast to the previous reaction
with oxime 2a asthe acceptor, the coupling with 2bfavored
the formation of the Z isomer (Z/E = 2.1:1 to 5.0:1). Under
(13) Mishra, R. C.; Tewari, N.; Verma, S. S.; Tripathi, R. P.; Kumar,
M.; Shukla, P. K. J. Carbohydr. Chem. 2004, 23, 353.
Org. Lett., Vol. 14, No. 15, 2012
4023

Table 1. Stereoselective Reduction of Oxime Disaccharides 4À7
Scheme 3. Deprotection of the Benzyl and Benzoyl Groups in
the Presence of the Interglycosidic NÀO Linkage
accordance with the determination of the Z/E isomer of
acceptor 2b (Z/E = 4.5:1, H4 of the Z isomer: δ 4.70 ppm;
H4 of the E isomer: δ 5.19 ppm, in CDCl3)12b and is further
corroborated by the X-ray diffraction of compound 8E. The
Z/E isomers of disaccharides 12À15 were discriminated by
the imino H6 signals. The H6 signal in an E isomer appears
at >δ7.0 ppm with a J-value > 6.0 Hz, while the H6 in the Z
counterpart is < δ 7.0 ppm with J-value < 5.0 Hz. Such an
assignment has been applied in the determination of the
Z/E isomer of acceptor 2c (Z/E = 1.2:1).13
The interglycosidic oxime CdN bond has been reduced
with borane complexes (e.g, BH3 Et3N)5a,14 or NaBH3CN,5b,c
3
and the stereoselectivity of the reduction is largely depen-
dent on the oxime sugar unit.5,14 The reduction of dis-
accharides 4À7 bearing a methyl 2,3-di-O-benzyl-6-deoxy-
R-D-gluco/galactopyranoside 4-oxime unit with NaBH3CN/
BF3 Et2O (CH2Cl2, À40 to 0 °C) was examined, and the
3
results are shown in Table 1. Thus, reduction of oxime
disaccharide 4 led to the NÀO linked galactose derivative
16a (70%) and glucose derivative 16b (22%) in an excellent
overall yield (entry 1). The configurations of the resulting
C4-amino group in 16a and 16b were easily identified by
the H4 NMR signal (H4 in 16a: δ 3.97 ppm, dd, J3,4 = 5.2
Hz; H4 in 16b: δ 4.12 ppm, dd, J3,4 = 10.0 Hz; in CDCl3).
Reduction of oximes 5E and 5Z afforded the galactose
derivative 17 in 93% and 86% yield, respectively, without
detection of the corresponding glucose diastereoisomer
(entries 2 and 3). Similar results were attained with the pair
6E and 6Z as the substrates (entries 4 and 5); the galactose
diastereoisomer 18 was isolated in high yield (90% and 85%,
respectively). Treatment of oxime disaccharide 7(Z/E=1:6.4)
under similar conditions also afforded only the galactose
derivative 19 in 90% yield (entry 6). These results demon-
strate clearly that the stereoselectivity of the present re-
duction is independent of the geometry of the oxime and its
O-substituted sugar residue.
similar conditions, the glycosylation of aldehyde oxime 2c led
to disaccharides 12À15 in slightly lower yields (73%À95%)
in favor of the Z isomer (Z/E = 2.0:1 to 6.9:1). Clearly, the
Z/E outcome of the present reaction is mainly determined by
the structure of the coupling oximes. Interconversion be-
tween the coupled disaccharide Z/E isomers was not found
during purification, structure analysis, and storage.
The Z/E geometries of the oxime disaccharides (i.e.,
3À7) derived from 2a were determined by the diagnostic
quartet H5 signals of the acceptor residue.14 The H5 signal
in a Z isomer appears at δ 4.60À4.70 ppm (in CDCl3),
while in the E counterpart it appears evidently downfield
(δ ∼5.0 ppm) due to the shielding of the proximal donor
residue. This conclusion is validated by the X-ray diffrac-
tion of 6Z, whose H5 signal appears at δ 4.65À4.70 ppm.
The Z/E geometries of the oxime disaccharides 8À11 were
assigned according to the chemical shift of H4 in the
acceptor (2b) residue. The H4 signal appeared at δ
4.7À4.9 ppm (in CDCl3) for the Z isomer, while it appears
above δ 4.9 ppm for the E counterpart due to the shielding
effect of the donor residue. This assignment is in good
An additional concern was the feasibility of removal
of the benzyl and benzoyl groups in the presence of the
interglycosidic NÀO linkage. Although there is a pre-
cedent,15 subjection of 17 or 18 to hydrogenolysis (over
Pd/C, Pd(OH)2/C, or Raney Ni) led unavoidably to cleav-
age of the NÀO linkage. Fortunately, the benzyl groups in
17/18 could be removed selectively with EtSH/BF3 OEt2
3
ꢀ
ꢀ
(15) Hornyak, M.; Sztaricskai, F.; Pelyvas, I. F.; Batta, G. Carbo-
(14) Renaudet, O.; Dumy, P. Tetrahedron 2002, 58, 2127.
hydr. Res. 2003, 338, 1787.
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Org. Lett., Vol. 14, No. 15, 2012

The preparation of glycosyloxyamines has employed glyco-
sylation of N-hydroxy-succinimide,19 HONPhth,5,20 and
N-pentenoyl hydroxamate18c under a variety of the glyco-
sylation reactions, followed by removal of the N-protecting
groups. Considering the mild glycosylation conditions in the
present oxime glycosylation, we envisioned the use of N-
Fmoc-hydroxylamine 2421 as the coupling acceptor to en-
sure a mild and selective removal of the N-Fmoc group
afterward to liberate the glycosyloxyamines. Expectedly,
subjection of 24 to glycosylation with glycosyl ortho-hexy-
nylbenzoates 1aÀd (1.2 equiv) (0.1 equiv of PPh3AuOTf,
good 62À88% yields (Table 2).17 Subsequent removal of the
N-Fmoc group in 25À28 with piperidine (DMF, rt) met
with no difficulty, affording the desired glycosyloxyamines
29À32 in high yield (78%À88%),17 with the anomeric
configuration unchanged.
Table 2. Efficient Preparation of Glycosyloxyamines
˚
5 A MS, CH2Cl2, rt) led to the desired glycosides 25À28 in
In summary, direct glycosylation of sugar oximes has
been realized for the first time by using glycosyl ortho-
hexynylbenzoates as donors under catalysis by PPh3AuOTf.
Reduction of the resulting oxime with NaBH3CN/BF3 Et2O
3
leads to the NÀO linked saccharides stereoselectively.
Glycosylation of HONHFmoc has also been achieved
under similar conditions, providing glycosyloxyamines
conveniently after an easy removal of the N-Fmoc group.
These results shall facilitate greatly the synthesis of NÀO
linked saccharides, which are of considerable interest in
biomedical studies.
Acknowledgment. This work was financially supported
by the Ministry of Science and Technology of China
(2012ZX09502-002) and the National Natural Science
Foundation of China (20932009 and 20921091).
(CH2Cl2, rt, overnight, 61% and 65%; Scheme 3).16,17 The
remaining benzoyl groups were then cleaved cleanly with
K2CO3 in MeOH/THF (rt, 100%).
As mentioned, glycosyloxyamines (A) are key precur-
sors in the previous syntheses of glycosidic NÀO linkages
(Scheme 1). Inaddition, glycosyloxyamineshavebeenused
effectively for attaching glycans onto proteins/lipids bearing
a ketone/aldehyde group under bioorthogonal conditions.18
Supporting Information Available. Experimental de-
tails, characterization data, and NMR spectra for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(16) Daly, S. M.; Armstrong, R. W. Tetrahedron Lett. 1989, 30, 5713.
(17) See Supporting Information. The crystallographic data for
compounds 6Z and 8E (CCDC 875774 and 876961) can be obtained
free of charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(18) For example, see: (a) Rodriguez, E. C.; Winans, K. A.; King,
D. S.; Bertozzi, C. R. J. Am. Chem. Soc. 1997, 119, 9905. (b) Rodriguez,
E. C.; Marcaurelle, L. A.; Bertozzi, C. R. J. Org. Chem. 1998, 63, 7134.
(c) Hudak, J. E.; Yu, H. H.; Bertozzi, C. R. J. Am. Chem. Soc. 2011, 133,
16127. (d) Chen, W.; Xia, C.; Cai, L.; Wang, P. G. Bioorg. Med. Chem.
Lett. 2010, 20, 3859.
(19) Andersson, M.; Oscarson, S. Glycoconjugate J. 1992, 9, 122. (b)
Cao, S.; Tropper, F. D.; Roy, R. Tetrahedron 1995, 51, 6679. (c)
Andreana, P. R.; Xie, W.; Cheng, H. N.; Qiao, L.; Murphy, D. J.; Gu,
Q.-M.; Wang, P. G. Org. Lett. 2002, 4, 1863.
(20) (a) Grochowski, E.; Jurczak, J. Carbohydr. Res. 1976, 50, C15.
(b) Renaudet, O.; Dumy, P. Tetrahedron Lett. 2001, 42, 7575.
(21) Mellor, S. L.; McGuire, C.; Chan, W. C. Tetrahedron Lett. 1997,
38, 3311.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 15, 2012
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