Synthesis of C-Aryl and C-Alkyl Glycosides Using Glycosyl Phosphates

Article abstract of DOI:10.1021/ol0158462

matrix presented Mannosyl and glucosyl phosphate donors were successfully used in constructing C-aryl linkages common to many natural products via a Lewis acid induced Fries-like rearrangement. The rearrangement was stereo- and regiospecific, yielding onl

Full text of DOI:10.1021/ol0158462

ORGANIC
LETTERS
2001
Vol. 3, No. 10
1547-1550
Synthesis of C-Aryl and C-Alkyl
Glycosides Using Glycosyl Phosphates
Emma R. Palmacci and Peter H. Seeberger*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
seeberg@mit.edu
Received March 14, 2001
ABSTRACT
Mannosyl and glucosyl phosphate donors were successfully used in constructing C-aryl linkages common to many natural products via a
Lewis acid induced Fries-like rearrangement. The rearrangement was stereo- and regiospecific, yielding only one C-glycoside product. C-Alkyl
glycoside carbohydrate mimetics were generated by using silicon-derived C-nucleophiles and glycosyl phosphates.
C-Glycoside natural products such as bergenin and muscarine
exhibit medicinally interesting properties, including antifun-
gal and antitumorigenic responses.1 Furthermore, C-glycoside
analogues of biologically active carbohydrates are attractive
pharmaceutical targets since they are not enzymatically
degraded in ViVo. Replacement of the exocyclic carbon-
oxygen bond at the anomeric center with a carbon-carbon
bond creates a hydrolytically stable carbohydrate mimetic
with many possible biological applications.2 For instance,
examination of carbohydrate-protein interactions and cell-
surface carbohydrate signaling is possible by conjugation of
oligosaccharides to molecular probes through a C-alkyl
glycoside tether.3
common method for C-glycoside construction exploits the
electrophilicity of the anomeric carbon by coupling nucleo-
philes to a glycosyl donor. Various leaving groups have been
used as glycosyl donors in the electrophilic approach to
preparing C-glycosides including anomeric acetates, tri-
chloroacetimidates, thioglycosides, halides, and methyl gly-
cosides.1 Of interest to the work described here, anomeric
phosphites were coupled to aromatic C-nucleophiles to yield
C-aryl glycosides5 and glycosyl phosphates were activated
by SmI2 to generate anomeric anions that were coupled with
various electrophilic species.6 Other approaches to C-
glycoside formation involve the use of transition metal
anomeric complexes, anomeric anions, sigmatropic rear-
rangements, and palladium-mediated couplings. Still, cur-
rently employed methodologies are often limited by long
reaction times, poor stereoselectivity, the necessity for a large
excess of activator, and low yields.
High-yielding and stereospecific methods for the prepara-
tion of C-glycosides have enabled the synthesis of many
natural products and the construction of specific enzyme
substrates. Several different approaches for the synthesis of
C-glycosides have been explored previously.1,4 The most
An indirect route to fashion C-aryl glycosidic linkages
(1) For a review, see: Levy, D. E.; Tang, C. The Chemistry of
C-Glycosides; Pergamon: 1995; Vol. 13. Postema, M. H. D. C-Glycoside
Synthesis; CRC Press: London, UK, 1995.
(2) Weatherman, R. V.; Mortell, K. H.; Chervenak, M.; Kiessling, L.
L.; Toone, E. J. Biochemistry 1996, 35, 3619-3624.
(3) Bertozzi, C. R.; Bednarski, M. D. J. Org. Chem. 1991, 56, 4326-
4329.
(4) Toshima, K.; Matsuo, G.; Ishizuka, T.; Ushiki, Y.; Nakata, M.;
Matsumura, S. J. Org. Chem. 1998, 63, 2307-2313.
(5) Lin, C.-C.; Shimazaki, M.; Heck, M.-P.; Aoki, S.; Wang, R.; Kimura,
T.; Ritzen, H.; Takayama, S.; Wu, S.-H.; Weitz-Schmidt, G.; Wong, C.-H.
J. Am. Chem. Soc. 1996, 118, 6826-6840.
(6) Hung, S.-C.; Wong, C.-H. Angew. Chem., Int. Ed. Engl. 1996, 35,
2671-2674.
10.1021/ol0158462 CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/12/2001

involves the initial installation of an O-glycosidic linkage
followed by a Fries-like O-to-C rearrangement (Scheme 1).
Scheme 1. O-to-C Rearrangement with Glycosyl Phosphates
Figure 1. Glycosyl phosphates 1 and 2.
synthesis of C-aryl mannosides, phosphate 16 (Figure 1) was
prepared. Donor 1 was activated with trimethylsilyl tri-
fluoromethanesulfonate (TMSOTf) at 0 °C in the presence
of electron-rich phenolic acceptors. Coupling of phosphate
1 with 3,4,5-trimethoxyphenol afforded exclusively the R-C-
linked glycoside 3 in just 30 min (Table 1). The rearrange-
Table 1. O-to-C Rearrangement with Phosphate 1a
A glycosyl donor is activated to generate an electrophilic
anomeric species that couples to an aromatic phenol to afford
an O-glycoside. The initial O-glycoside then rearranges to
the C-aryl bond under Lewis acidic conditions. Various
aromatic systems, such as naphthol, methoxy phenol, and
resorcinol derivatives, have been used in this approach. This
rearrangement had been evaluated previously in the glucose
series with glycosyl trichloroacetimidates7 and fluorides.8 The
O-to-C conversion exclusively afforded the sterically favored
â-C-aryl glucoside product.
The construction of C-alkyl glycosides can be achieved
by the coupling of a carbon nucleophile, most commonly a
silicon-based nucleophile, and a glycosyl donor. The ano-
meric stereochemistry of these C-alkyl glycosides is strongly
dependent on the nature of the nucleophile. Generally,
formation of the thermodynamically more stable R-glycosides
predominates.
Here we present a new method for the synthesis of
C-glycosides using glycosyl phosphates as the anomeric
leaving group. We recently reported the one-pot synthesis
of glycosyl phosphates from glycals and demonstrated their
utility in the rapid and efficient formation of O- glycosidic
linkages in solution and on solid support.9,10 On the basis of
our previous success with phosphate donors in creating
O-glycosides, we sought to expand their use to the synthesis
of C-glycosidic linkages.
a Conditions: 1 equiv of phosphate, 1.2 equiv of acceptor, and 1.2 equiv
of TMSOTf in CH2Cl2 at 0 °C.
ment occurred even at low temperatures (-15 °C) and did
not allow for the isolation of any O-glycoside product. The
aromatic phenol was varied to explore the scope of the
O-to-C conversion with mannosyl phosphates. Using phos-
phate 1, the R-C-mannosides of 2-naphthol and 3-benzyl-
oxyphenol (4 and 5) were synthesized in excellent yield.
O-Mannosides were obtained exclusively with less nucleo-
philic aromatic systems, such as 3-acetoxy phenol.
Several natural products, including gilvocarcin M and
castacrenin B, contain a C-aryl glucosyl fragment. Given the
success with mannosyl phosphate 1, the construction of
C-aryl linkages via an O-to-C rearrangement with glucosyl
phosphate 211 (Figure 1) was investigated. Coupling of 3,4,5-
trimethoxyphenol and 2 afforded R-O-glycoside 6 (Figure
2) in 79% yield in 15 min. The rearrangement to the â-C-
aryl linkage (9, Table 2) required a longer (>3 h) reaction
time.
Mannosyl donors had not previously been employed in
the formation of aryl bonds via the O-to-C rearrangement
pathway; thus the effect of the axial C2 substituent on the
stereochemistry of this rearrangement had not been inves-
tigated. To evaluate the Fries-like rearrangement in the
(7) Mahling, J.-A.; Schmidt, R. R. Synthesis 1993, 325-328.
(8) Matsumoto, T.; Hosoya, T.; Suzuki, K. Synlett 1991, 709-711.
(9) Plante, O. J.; Andrade, R. B.; Seeberger, P. H. Org. Lett. 1999, 1,
211-214.
(10) Andrade, R. B.; Plante, O. J.; Melean, L. G.; Seeberger, P. H. Org.
Lett. 1999, 1, 1811-1814.
In expanding this methodology to other phenols, 2-naph-
thol and 3-benzyloxyresorcinol were used as aromatic
(11) Hashimoto, S.; Honda, T.; Ikegami, S. J. Chem. Soc., Chem.
Commun. 1989, 685-687.
1548
Org. Lett., Vol. 3, No. 10, 2001

ing a C2-ester (Scheme 2) was synthesized from the
corresponding glycal. Coupling of 12 to 3,4,5-trimethoxy-
phenol was accomplished in 12 h by TMSOTf activation to
afford C-glycoside 13 and O-glycoside 14 in 21% and 35%
yield, respectively. The conversion required extended reac-
tion times (12 h) to obtain the desired product in modest
yield. C-Glycoside 1312 provides access to bergenin-like
structures (Figure 3)13 since the difficult linkage to the
aromatic system is installed from readily available educts.
Figure 2. O-Glycosides.
nucleophiles. The O-glycoside products (7 and 8) were
isolated after 15 min at 0 °C, and C-glycosides (107 and 11)
Table 2. O-to-C Rearrangement with Phosphate 2a
Figure 3. 8,10-Di-O-methylbergenin.
C-Alkyl glycosides are useful carbohydrate mimetics,
commonly employed as enzyme inhibitors. The formation
of various C-alkyl glycosides was evaluated with phosphates
1 and 2 (Table 3). Mannosyl phosphate 1 was activated with
Table 3. Synthesis of C-Alkyl Glycosides from 1 and 2
a Conditions: 1 equiv of phosphate, 1.2 equiv of acceptor, and 1.2 equiv
of TMSOTf in CH2Cl2 at 0 °C f rt.
were obtained after longer reaction times. In all cases, the
rearrangement was completely stereospecific, yielding ex-
clusively the â-C-aryl linkage. Interestingly, O-glycoside
products were obtained in trace amounts even after extended
reaction times (>3 h), indicating that the O-to-C conversion
did not reach completion. Furthermore, O-glucosides could
be exclusively formed with less nucleophilic aromatic
systems, as was observed with mannosyl phosphate 1.
To investigate the effect of electron-withdrawing protecting
groups on the O-to-C rearrangement, phosphate 129 contain-
Scheme 2 O-to-C Rearrangement with Phosphate 12
TMSOTf and coupled to allyl trimethylsilane to provide
R-allyl glycoside 1614 in excellent yield (93%). Allyl
glycoside 16 has previously served as a handle for studying
mannose-binding lectins.4
Coupling of 1 to the cyclopentanone-derived trimethylsilyl
enol ether afforded 18 as a mixture of diastereomers in 84%
(12) Schmidt, R. R.; Effenberger, G. Carbohydr. Res. 1987, 171, 59-
79.
(13) Hay, J. E.; Haynes, L. J. J. Chem. Soc. 1958, 2231-2238.
(14) Hosomi, A.; Sakata, Y.; Sakurai, H. Carbohydr. Res. 1987, 171,
223-232.
Org. Lett., Vol. 3, No. 10, 2001
1549

yield. Other silyl enol ethers can be employed in a similar
fashion to construct different C-alkyl derivatives. Phosphate
2 was activated with TMSOTf at 0 °C in the presence of
allyltrimethylsilane to afford the R-allyl glycoside 17.15Donor
2 was coupled to the TMS enol ether, resulting in the
formation of 1915 as a mixture of diastereomers.
phosphate donors allowed for the generation of C-alkyl
glycosides containing a handle for conjugation to proteins
or molecular probes.
Acknowledgment. Financial support from Merck (Fel-
lowship for E.R.P.) and the MIT Chemistry Department is
gratefully acknowledged. Funding for the MIT-DCIF Inova
501 was provided by NSF (Grant CHE-9808061) and the
Bruker 400 provided by NIH (Grant 1S10RR13886-01).
In summary, we have demonstrated the use of glycosyl
phosphates in the efficient synthesis of various C-aryl and
C-alkyl glycosides. Mannosyl and glucosyl phosphates were
successfully employed in a Lewis acid induced Fries-like
rearrangement. Construction of C-aryl linkages present in
natural products was easily accomplished by this rearrange-
ment. Use of silicon-derived C-nucleophiles and glycosyl
Supporting Information Available: Detailed experi-
mental procedures and compound characterization data,
1
including H, 13C, and 31P NMR data for all described
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(15) Hoffman, M. G.; Schmidt, R. R. Liebigs. Ann. Chem. 1985, 2403-
2419.
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