First O-glycosylation of hydroxamic acids

Article abstract of DOI:10.1021/jo0701839

(Chemical Equation Presented) The first O-glycosylation of hydroxamic acids is reported. This process involves the use of glycosyl N-phenyl trifluoroacetimidates as glycosyl donors in the presence TMSOTf and 4 A molecular sieves in dichloromethane. Under

Full text of DOI:10.1021/jo0701839

SCHEME 1. Some Hydroxamic Acid-Containing Drugs
First O-Glycosylation of Hydroxamic Acids
Mickae¨l Thomas, Jean-Pierre Gesson, and Se´bastien Papot*
UMR 6514, Synthe`se et Re´actiVite´ des Substances Naturelles,
UniVersite´ de Poitiers et CNRS, 40, AV. du Recteur Pineau,
86022 Poitiers, France
sebastien.papot@uniV-poitiers.fr
ReceiVed January 30, 2007
SCHEME 2. Preparation of Glycosyl Hydroxamates by
Amidation of Carboxylic Acids with O-gLycosyl
Hydroxylamines
SCHEME 3. Glycosylation Attempts of Hydroxamic Acid 1
under Koenigs-Knorr Conditions
The first O-glycosylation of hydroxamic acids is reported.
This process involves the use of glycosyl N-phenyl trifluo-
roacetimidates as glycosyl donors in the presence TMSOTf
and 4 Å molecular sieves in dichloromethane. Under such
conditions, a wide range of new glycosyl donors including
glucosyl, galactosyl, mannosyl, glucuronyl, and ribosyl
hydroxamates were prepared in good to high yields. This
procedure appears to be an advantageous alternative for the
synthesis of glycosyl hydroxamates of biological interest.
Surprisingly, despite the rising interest in O-glycosyl hydrox-
amates, no direct method for the glycosylation of hydroxamic
acids has been reported in the literature. To date, the sole known
methodology for preparing such carbohydrate derivatives invol-
ves amidation of the corresponding carboxylic acids with O-
glycosyl hydroxylamines (Scheme 2).7-9 Therefore, the devel-
opment of an effective glycosylation method of hydroxamic
acids is particularly warranted. This paper reports our investiga-
tions in this area that led with success to the first stereoselective
and high-yielding O-glycosylation of hydroxamic acids.
Our initial efforts focused upon the coupling of commercially
available benzhydroxamic acid 1 to the well-known methyl
2,3,4-tri-O-acetyl-R-D-glucopyranosyluronate bromide 2a10 in
the presence of either Ag2O or Ag2CO3 (Scheme 3). In spite of
several attempts, using various amounts of glycosyl donor 2a
(ranging from 1 to 2.5 equiv), coupling between 1 and 2a always
failed and resulted in a complex mixture presumably due to
the instability of the hydroxamic acid toward silver salts. This
Over the past decade, hydroxamic acid-containing derivatives
have emerged as a class of compounds of great therapeutical
interest especially with respect to inhibition of histone deacety-
lases1 (HDACs) and matrix metalloproteases (MMPs).2 Some
of them, such as SAHA3 and Trocade,4 are currently undergoing
clinical trials for the indications of cancer and rheumatoid
arthritis, respectively (Scheme 1). More recently, the O-glycosyl
hydroxamate counterparts appeared as compounds of biological
relevance too. For example, Trichostatin D, the R-glucosyl
derivative of the potent HDAC inhibitor Trichostatin A (TSA),
is an inducer of phenotypic reversion in oncogene-transformed
cells and as a consequence is expected to be a selective
antitumor agent.5 The glucuronylated derivatives of SAHA and
Trocade are major metabolites of the corresponding drug
substances.6,7 In a recent study, the â-O-galactoside of SAHA
has been reported as a promising prodrug for selective cancer
chemotherapy.8
(6) Du, L.; Musson, D. G.; Wang, A. Q Abstracts of Papers, 229th
National Meeting of the American Chemical Society, San Diego, CA, March
13-17, 2005; ; American Chemical Society: Washington, DC, 2005.
(7) Mitchell, M. B.; Whitcombe, I. W. A. Tetrahedron Lett. 2000, 41,
8829-8834.
(1) For a review see: Monneret, C. Eur. J. Med. Chem. 2005, 40, 1-13.
(2) For a review see: Whittaker, M.; Floyd, C. D.; Brown, P.; Gearing,
A. J. H. Chem. ReV. 1999, 99, 2735-2776.
(3) Krug, L. M.; Curley, T.; Schwartz, L.; Richardson, S.; Marks, P.;
Chiao, J.; Kelly, W. K. Clin. Lung Cancer 2006, 7, 257.
(4) Hemmings, F. J.; Farhan, M.; Roland, J.; Banken, L.; Jain, R.
Rheumatology (Oxford) 2001, 40, 537-543.
(5) Hayakawa, Y.; Nakai, M.; Furihata, K.; Shin-ya, K.; Seto, H. J.
Antibiot. 2000, 53, 179-183.
(8) Thomas, M.; Rivault, F.; Tranoy-Opalinski, I.; Roche, J.; Gesson,
J.-P.; Papot, S. Bioorg. Med. Chem. Lett. 2007, 17, 983-986.
(9) Hosokawa, S.; Ogura, T.; Togashi, H.; Tatsuta, K. Tetrahedron Lett.
2005, 46, 333-337.
(10) Bollenback, G. N.; Long, J.; Benjamin, D. G.; Lindquist, J. A. J.
Am. Chem. Soc. 1955, 77, 3310-3315.
10.1021/jo0701839 CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/28/2007
4262
J. Org. Chem. 2007, 72, 4262-4264

TABLE 1. O-Glycosylation of Hydroxamic Acids with Glucosyl Imidates 8 and 9
entry
donor
acceptor
product 13
yield (%)
R:â
1
2
3
4
5
6
7
8
8
8
8
8
9
9
9
9
1
10
11
12
1
10
11
12
13a
13b
13c
13d
13a
13b
13c
13d
80
54
60
45
97
90
97
97
â only
â only
â only
â only
â only
â only
â only
â only
SCHEME 4. Glycosylation of Hydroxamic Acid 1 under
Phase Transfer Catalyzed Conditions
leading to the 2-O-deacetylated glucosyl hydroxamate 5 with
complete â-selectivity though only in moderate yield (31%).
Initially, the â-stereoselectivity of this glycosylation reaction
appeared surprising taking into account the absence of any
participating group at C-2 in the final product 5. However, a
careful analysis of the reaction mixture allowed the isolation
of the O-acetylated hydroxamic acid 7, which provided us an
interesting clue for explaining the formation of 5. Thus, it may
be postulated that the synthesis of the later proceeded via the
nucleophilic attack of benzhydroxamic acid 1 by the â-face of
the previously formed orthoester 6 followed by subsequent
elimination of 7 (Scheme 4).
Further attempts with lower amounts of 1 were undertaken
under the PTC conditions described above. However, since all
these experiments afforded 5 in lower yields, we decided to
turn our attention to other procedures such as imidate-mediated
glycosylations.
Glycosyl trichloroacetimidates, introduced by Schmidt and
co-worker in 1980,14 are among the most widely used glycosyl
donors.15 Such derivatives are easily accessible from the
corresponding 1-hydroxy sugars by treatment with trichloroac-
etonitrile in the presence of a suitable base and require mild
activation conditions, using in most cases TMSOTf or BF3.Et2O
as promoters.
Thus, to examine coupling reactions between these glycosyl
donors and hydroxamic acids, we first prepared R-glucosyl
trichloroacetimidate 8 from â-D-glucose pentaacetate in two
steps according to literature procedures.16 Various substituted
commercially available hydroxamic acids 1, 11, and 12 as well
as the HDAC inhibitor SAHA 10 were chosen for this study.
As depicted in Table 1, glycosylation reactions were conducted
with 1.5 equiv of each hydroxamic acid in the presence of an
equimolar amount of TMSOTf and 4 Å MS at -20 °C in
dichloromethane. In all cases, glycosylations provided the
corresponding O-glucosyl hydroxamates 13 exclusively as the
hypothesis was supported by TLC analysis that indicated total
consumption of 1 under all tested Koenigs-Knorr conditions
whereas 2a appeared to be mostly unreactive. Thus, to confirm
such a hypothesis, hydroxamic acid 1 was dissolved in CH3CN
in the presence of Ag2O. In this case, rapid degradation of 1
was observed leading mainly to the formation of N,O-diacyl-
hydroxylamine 311 together with several unidentified products.
On the other hand, no degradation was detected without silver
salts. Thus, since further attempts with the more reactive12
bromoglucoside 2b afforded similar results, we considered it
preferable to employ glycosylation methods avoiding the use
of silver salts as activating reagents.
We next investigated glycosylation of benzhydroxamic acid
1 under phase transfer catalysis (PTC) conditions. This method
has been used successfully with a wide number of nucleophiles
employing bromo sugars as glycosyl donors.13 Glycosylation
was performed with glucosyl bromide 2b and 5 equiv of 1 with
methylene chloride as the organic phase and 1 M Na2CO3 as
the aqueous phase in the presence of tetrabutylammonium
hydrogen sulfate (TBAHS) as catalyst (Scheme 4). After 4 h at
room temperature, acetobromoglucose 2b was totally consumed
(11) Schraml, J.; Sykora, J.; Fiedler, P.; Roithova, J.; Mindl, J.; Blechta,
V.; Cisarova, I.; Exner, O. Org. Biomol. Chem. 2004, 2, 2311-2314.
(12) Mu¨ller, T.; Schneider, R.; Schmidt, R. R. Tetrahedron Lett. 1994,
35, 4763-4766.
(13) For a review see: Roy, R. In Phase transfer catalysis in carbohy-
drate chemistry; Sasson, Y., Neumann, R., Eds.; Handbook of Phase
Transfer Catalysis; Chapman and Hall: Glascow, UK, 1997; Chapter 7, pp
244-272.
(14) Schmidt, R. R.; Michel, J. Angew. Chem., Int. Ed. Engl. 1986, 19,
731-732.
(15) For a review see: Schmidt, R. R.; Jung, K.-H. In PreparatiVe
carbohydrate chemistry; Hanessian, S., Ed.; Marcel Dekker: New York,
1997.
(16) Cook, B. N.; Bhakta, S.; Biegel, T.; Bowman, K. G.; Armstrong, J.
I.; Hemmerich, S.; Bertozzi, C. R. J. Am. Chem. Soc. 2000, 122, 8612-
8622.
J. Org. Chem, Vol. 72, No. 11, 2007 4263

TABLE 2. Synthesis of Glycosyl N-Phenyl Trifluoroacetimidates
9a-e
TABLE 3. O-Glycosylation of Hydroxamic Acids with Glucosyl
Imidates 9a-e
entry
sugar
D-glucose
D-galactose
D-mannose
D-glucuronic acid
D-ribose
product 9
yield (%)
1
2
3
4
5
9a
9b
9c
9d
9e
99
93
80
95
87
donor
yield
entry
sugar
D-glucose
9
acceptor product (%)
R:â
1
2
3
4
5
6
7
8
9
10
9a
9a
9b
9b
9c
9c
9d
9d
9e
9e
1
10
1
13a
13b
14a
14b
15a
15b
16a
16b
17a
17b
97
90
80
69
92
84
80
78
81
69
â only
â only
â only
â only
R only
R only
â only
â only
â only
â only
D-glucose
D-galactose
D-galactose
D-mannose
D-mannose
D-glucuronic acid
D-glucuronic acid
D-ribose
â-anomers in good yields after purification by flash column
chromatography (entries 1-4).
10
1
10
1
At this stage, we considered it worthwhile to pursue our
investigations in this direction by studying other imidate
types as glycosyl donors. Within this framework, glycosyl
trifluoroacetimidates17 have been recently introduced as val-
uable alternatives to their trichloroacetimidate analogues
and used advantageously in sialylation18 and glycosylation of
amides.19 Therefore, to examine the glycosylation of hy-
droxamic acids with such donors we first synthesized the
novel glucosyl N-phenyl trifluoroacetimidate 9a in quantita-
tive yield from 2,3,4,6-tetra-O-acetyl-D-glucose and N-phenyl
trifluoroacetimidoyl chloride20 employing the procedure de-
scribed by Yu et al. (Table 2).17 As illustrated in Table 1, use
of donor 9a afforded â-glucosyl hydroxamates 13 in drama-
tically increased yields (>90%, entries 5-8) compared to
those obtained with trichloroacetimidate 8 (45-80%, entries
1-4).
In light of these results, we next investigated O-glycosylation
of hydroxamic acids 1 and 10 with a range of glycosyl imidates
9 previously prepared in nearly quantitative yields following
the procedure mentioned above (Table 2).17 It is worth noting
that most glycosyl trifluoroacetimidates 9 were not stable for
long periods and consequently were used rapidly after flash
column chromatography purification.
As shown in Table 3, all glycosylation reactions gave good
to excellent yields (69-97%) of the expected coupling products,
including the two glycosylated SAHA derivatives 14b and 16b
recently introduced as compounds of biological relevance
(entries 4 and 8, 69% and 78%, respectively).6,8 It should be
mentioned that this new glycosylation method brings a real
improvement for the preparation of such SAHA derivatives with
regard to yields, number of steps, and the accompanying
decrease in loss of material, compared to the synthesis recently
reported in the literature.8
10
1
10
D-ribose
In conclusion, we have demonstrated the first efficient
O-glycosylation of hydroxamic acids with glycosyl N-phenyl
trifluoroacetimidates as sugar donors and TMSOTf as promoter
in dichloromethane. This method appears to be general and
appropriate to the preparation of a wide range of glycosyl
hydroxamates. Additionally, since this glycosylation reaction
has been applied with success to the synthesis of glycosyl
derivatives of SAHA, this finding may open a new door for
the investigation of biological properties of this family of
carbohydrate derivatives. Indeed, we believe this glycosylation
method should be very useful for the preparation of glycosyl
of hydroxamic acid-containing drugs.
Experimental Section
General Procedure for the O-Glycosylation of Hydroxamic
Acids. A mixture of glycosyl donor 9 (1.0 equiv), hydroxamic acid
(1.5 equiv), and freshly activated 4 Å molecular sieves (4 g/mmol)
in anhydrous dichloromethane (10 mL/mmol) was stirred at room
temperature for 1 h under N2 to remove traces of water, and then
cooled to -20 °C. TMSOTf (1.0 equiv) was added. The mixture
was then allowed to warm to room temperature. After being stirred
for 3 h, the reaction mixture was quenched by the addition of Et3N
(1 mL/mmol). The resulting mixture was filtered through Celite
and MgSO4. The filtrate was concentrated under reduced pressure
and then subjected to flash column chromatography.
Acknowledgment. The authors thank CNRS, La Ligue
Nationale contre le Cancer, and the Re´gion Poitou-Charentes
for financial support of this study.
Supporting Information Available: General experimental
information, spectroscopic data (1H NMR, 13C NMR, and HRMS)
and copies of 1H NMR and 13C NMR spectra for all new glycosyl
trifluoroacetimidate donors 9 and new glycosyl hydroxamates 13-
17. This material is available free of charge via the Internet at
http://pubs.acs.org.
(17) (a) Yu, B.; Tao, H. Tetrahedron Lett. 2001, 42, 2405-2407. (b)
Yu, B.; Tao, H. J. J. Org. Chem. 2002, 67, 9099-9102.
(18) Cai, S.; Yu, B. Org. Lett. 2003, 5, 3827-3830.
(19) Tanaka, H.; Iwata, Y.; Takahashi, D.; Adachi, M.; Takahashi, T. J.
Am. Chem. Soc. 2005, 127, 1630-1631.
(20) Tamura, K.; Mizukami, H.; Maeda, K.; Watanabe, H.; Uneyama,
K. J. Org. Chem. 1993, 58, 32-35.
JO0701839
4264 J. Org. Chem., Vol. 72, No. 11, 2007