Synthesis of C-aryl-Δ2,3-glycopyranosides via uncatalyzed addition of triarylindium reagents to glycals

Article abstract of DOI:10.1016/j.tetlet.2004.05.046

2,3-Unsaturated-C-aryl glycopyranosides are important intermediates in the synthesis of medicinally important C-aryl glycosides. Treatment of glycal acetates with triarylindiums in ether at room temperature gives good yields of C-aryl-Δ^2,3-glyc

Full text of DOI:10.1016/j.tetlet.2004.05.046

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5197–5201
Synthesis of C-aryl-D2,3-glycopyranosides via uncatalyzed
addition of triarylindium reagents to glycalsq
Sarah Price, Stephen Edwards, Tiffany Wu and Thomas Minehan*
Department of Chemistry, Harvey Mudd College, 301 E. Twelfth Street, Claremont, CA91711, USA
Received 25 January 2004; revised 6 May 2004; accepted 11 May 2004
Abstract—2,3-Unsaturated-C-aryl glycopyranosides are important intermediates in the synthesis of medicinally important C-aryl
glycosides. Treatment of glycal acetates with triarylindiums in ether at room temperature gives good yields of C-aryl-D2;3-glycosides
of predominantly a-configuration. The mechanism of this reaction likely involves the formation of an oxocarbenium ion inter-
mediate via indium(III) Lewis acid-assisted ionization of the glycal C.3 acetate. Coupling of trivinyl- and tris(alkynyl)indiums with
glycals similarly led to C-vinyl- and C-alkynyl-D2;3-glycosides in good yield.
Ó 2004Elsevier Ltd. All rights reserved.
The great current interest in C-aryl glycosides stems
from their occurrence in natural products, which possess
important medicinal and therapeutic properties.1 C-aryl
glycopyranosides with a double bond in the 2,3-position
are useful synthetic intermediates, since this unsatura-
tion can be further functionalized to produce an array of
complex carbohydrates.2 Several synthetic methods
allow access to such compounds, many relying on the
addition of organometallic reagents to hex-2-enopyr-
anosides.3–5 Although these approaches give good yields
of the desired glycosides, air- or moisture-sensitive,
toxic, and/or pyrophoric reagents are frequently
employed, and expensive transition metal catalysts are
often required. Furthermore, strongly basic or acidic
reaction conditions limit the functionality that can be
employed in either the aryl or carbohydrate coupling
partner. As an alternative, we sought to use easily pre-
pared arylindiums as nucleophiles for the construction
of C-aryl glycosides. These reagents are attractive be-
cause of their low toxicity, air- and moisture stability,
wide functional group tolerance, and atom efficiency.6;7
zincs, we hoped that the Lewis-acidic character of the
organoindium reagent6 might assist the reaction through
an SN1 manifold. Indeed, stirring tri-O-acetyl-D-glucal 1
in ether with 1 equiv of triphenylindium 2a at room
temperature for 24h furnished the desired glycoside 3a
in 95% yield with 5:1 a=b selectivity (Table 1).
Table 1. Uncatalyzed addition of Ph3In 2a to tri-O-acetyl-D
-glucal 1a
OAc
OAc
2a
O
3
Ph
5'
O
RT
AcO
AcO
OAc
3a
Yield 3a
1
Eq. 2a
Entry
Solvent
Time
a:b
1
1.0
Et2O
Et2O
Et2O
24h
48 h
48 h
24h
24h
24h
24h
24h
48 h
95
90
40
90
93
86
92
<5
20
5:1
5:1
5:1
6:1
6:1
6:1
6:1
––
2
0.50
0.33
1.0
3
4b
5b
6b
7b
8
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
THF
0.50
0.33
1.0
The uncatalyzed addition of arylzinc species to glycal
acetates has recently been reported.8 Although triaryl-
indiums are expected to be less reactive than organo-
1.0
1.0
9b
CH3CN
––
a Reactions were run at a concentration of 0.1 M glycal in the solvent
listed.
b Reactions in CH2Cl2, toluene, and CH3CN were performed by
evaporating ether or THF from the indium reagent and redissolving
the residue in the appropriate solvent, followed by addition of the
carbohydrate.
Keywords: Glycals; Triorganoindiums; C-glycosidation.
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2004.05.046
* Corresponding author. Tel.: +1-909-607-9701; fax: +1-909-607-7577;
e-mail: tom_minehan@hmc.edu
0040-4039/$ - see front matter Ó 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.046

5198
S. Price et al. / Tetrahedron Letters 45 (2004) 5197–5201
Nonpolar solvents such as ether, dichloromethane, and
toluene proved to be the media of choice, with reactions
performed in dichloromethane and toluene giving
slightly better stereoselectivities than those run in ether
(Table 1, entries 1, 4and 7). Reactions performed in
either THF or acetonitrile gave negligible quantities of
glycoside 3a, even after 48 stirring at room temperature
(entries 8 and 9).
could be prepared efficiently (entries 5, 10, and 12). The
a-configured11 C-aryl-D2;3-glycoside is obtained pre-
dominantly in most instances, with electron poor
arylindiums (entries 2, 3, and 8) generally giving better
a-selectivities than electron rich (entries 6 and 11), an
observation not unprecedented in Lewis-acid mediated
C-glycosidation chemistry.12 Furthermore, the solvent
effect on stereoselectivity is more pronounced when
electron-rich arylindiums are employed in the glycosyl-
ation (Table 2, compare entries 3 and 6 and Table
footnotes c and d), implying the possible intermediacy of
a carbohydrate-derived carbocation (vide infra).13 The
consistently high a-selectivity observed for products 7a,
7c, 7d derived from glycosidation of 6 (entries 13–16)
reflects the steric influence of the galactal axial C.4
acetate on the course of the addition reaction.14 Product
stereochemistries were confirmed by direct comparison
with literature data and spectra2 and also by 13C NMR
spectroscopy (as has been noted previously, the carbon
chemical shift of C50 is diagnostic of the stereochemistry
at the anomeric position15).
Since the atom efficiency of organoindium reagents in
cross-coupling reactions has been well documented,9 we
attempted the coupling reaction described above with
substoichiometric amounts of arylindium reagent (Table
1, entries 1–3 and 4–6). High yields were obtained after
24h for reactions performed in dichloromethane
employing either 0.50 or 0.33 equiv of 2a; in ether, a
longer reaction time (48 h) was required to obtain
moderate to high yields of 3a employing 0.33 or
0.50 equiv of 2a, respectively.10 These data suggest that
all three aryl groups on indium are indeed capable of
participating in the carbon–carbon bond-forming pro-
cess.
To further probe the mechanism of this reaction, we
The scope of the reaction was assessed by coupling a
variety of arylindiums with glucal (1), rhamnal (4) and
galactal (6) acetates (Table 2). Yields were good in the
majority of cases, and even sterically hindered glycosides
prepared tri-O-acetyl-D-allal 8, the C.3 epimer of glucal,
according to the protocol of Danishefsky.16 This com-
pound was subjected to 1 equiv of triphenylindium 2a in
ether at room temperature for 24h (Scheme 1).
Table 2. Triarylindium additions to glycals 1, 4, and 6 in ethera
OAc
O
OAc
O
O
4
AcO
AcO
AcO
OAc
OAc
OAc
1
4
6
OAc
OAc
Ar
Ar
Ar
O
O
O
1'
5'
AcO
AcO
AcO
3
5
7
Entry
Glycal
2 Ar3In
Ar
Product
a:b
Yield
1
1
2a
2b
2c
2d
2e
2f
Ph
3-F-Ph
3a
3b
3c
3d
3e
3f
5:1
6:1
95
45
89
68
55
75
60
70
95
70
55
67
50
50
80
2
1
3c
4b
5b
6d
7
1
4-Cl-Ph
4-Me-Ph
2-Me-Ph
4-OMePh
Ph
6:1
6:1
1
1
4:1
1
1:1.5
5:1
42a
42c
42d
42e
42f
42g
6
5a
5c
5d
5e
5f
8
4-Cl-Ph
4-Me-Ph
2-Me-Ph
4-OMePh
5:1
3:1
9
10b
11
12b
13
14
16
4.5:1
1:1
2-Napththyl
Ph
5g
7a
7c
7d
3:1
2a
2c
2d
10:1
10:1
10:1
6
4-Cl-Ph
4-Me-Ph
6
a All reactions were run at a concentration of 0.1 M glycal and organo-indium in ether at room temperature for 24or 48 h.
b The reaction took 48 h to reach completion.
c The reaction in CH2Cl2 gave 6:1 a:b 3c in 92% yield.
d The reaction in CH2Cl2 gave 4:1 a:b 3f in 90% yield.

S. Price et al. / Tetrahedron Letters 45 (2004) 5197–5201
5199
OAc
OAc
1.0 eq. 2a
OAc
1.0 eq. 2a
O
O
Et2O, (0.1M)
Et2O, (0.1M)
Ph
O
RT, 24h
RT, 24h
AcO
AcO
AcO
OAc
OAc
8
3a
5:1 :β
1
(ref. 15)
Scheme 1. Reactions of allal 8 and glucal 1 with Ph3In.
OAc
O
OAc
OAc
OAc
Ph
O
O
O
In Ph
Ph
AcO
O
AcO
AcO
A
O
O
InPh3
InPh3
OAc
Ph
O
AcO
Scheme 2. Mechanistic proposal.
The coupling reaction gave the same stereoisomeric
ratio of products (5:1 a:b) and approximately the same
yield (95%) of 3a as the analogous reaction of glucal 1
with 2a. This result lends support to the proposal that
the reaction proceeds through a common cationic
intermediate, such as that represented by structure A
(Scheme 2).
for very electron-rich nucleophiles, which can effectively
compete with the counterion/solvent to occupy the ste-
rically less-demanding b-face of the oxocarbenium ion.13
Finally, we studied the coupling reactions of alkenyl,
alkynyl, and alkylindiums with glucal (Scheme 3).
Reaction of 1 molar equivalent of tris(2-methylprop-
enyl)indium 9 with 1 in ether for 24h gave a ꢀ1:1 mix-
ture of a:b C-vinyl-D2;3-glycosides 12 in 75% yield. In
contrast, reaction of tris(phenylethynyl)indium 10 with
1 gave an 11:1 mixture of a:b C-alkynyl-D2;3-glycosides
1319 in 55% yield. Tributylindium 11 gave no addition
products when combined with 1 in ether for 24–48 h,
instead producing polar compounds likely resulting
from acetate cleavage/hydrolysis.
The triarylindium reagent acts as a Lewis acid in coor-
dinating a lone pair on the C.3 acetate ester, thus
facilitating an SN1 ionization process (assisted by lone-
pair donation from the pyranyl oxygen) that leads to A.
The nucleophilic indate species17 formed transfers a
phenyl ligand preferentially to the more electrophilic C.1
carbon of the carbohydrate, furnishing the observed
products. The resulting diorganoindium species can
enter another reaction cycle with 1 (or 8) in which it can
again act as a Lewis acid and transfer another phenyl
ligand to A.18 Kinetically preferred axial addition of the
carbon nucleophile is observed in most cases,12c except
The 2,3-unsaturated C-glycoside products of these
reactions can be stereoselectively transformed into C-
aryl glycosides20 by dihydroxylation with OsO4. For
example, applying the UpJohn protocol21 for catalytic
OAc
OAc
OAc
Ph
9
10
O
Ph
In
3 In
O
O
3
Ether (0.1M)
R.T., 24 h
Ether (0.1M)
R.T., 24 h
AcO
AcO
AcO
OAc
12
~1:1 :β
13
>10:1 :β
1
OAc
O
Bu3In 11
Decomposition
AcO
Ether (0.1M)
R.T., 24 h
OAc
1
Scheme 3. Reaction of organoindiums 9, 10, and 11 with 1.

5200
S. Price et al. / Tetrahedron Letters 45 (2004) 5197–5201
4. (a) Moineau, C.; Bolitt, V.; Sinou, D. J. Org. Chem. 1998,
OAc
OAc
1. cat. OsO4, NMO
8:1 acetone/H2O
63, 582–597; (b) Brakta, M.; Lhoste, P.; Sinou, D. J. Org.
Chem. 1989, 54, 1890–1896.
Ph
Ph
O
O
5. (a) Dunkerton, L. V.; Serino, A. J. J. Org. Chem. 1982, 47,
2812–2815; (b) Dunkerton, L. V.; Euske, J. M.; Serino, A.
J. Carbohydr. Res. 1987, 171, 89–91.
2. Ac2O, Py, DMAP
OAc
AcO
AcO
OAc
3a
6. Perez, I.; Sestelo, J. P.; Sarandeses, L. A. J. Am. Chem.
Soc. 2001, 123, 4155–4160.
14
Scheme 4. Preparation of C-aryl glycoside 14 via dihydroxylation.
7. Perez, I.; Sestelo, J. P.; Sarandeses, L. A. Org. Lett. 1999,
1, 1267–1269.
osmylation to a-C-phenyl-D2;3–glycoside 3a, followed by
acylation (Ac2O, pyridine, cat. DMAP) gives exclusively
a-phenyl-mannoside 1422 in 85% overall yield, in which
the hydroxyl groups have been introduced from the face
of the carbohydrate opposite the aromatic moiety
(Scheme 4). Although numerous C-glycosyl flavonoids
that have been isolated possess a b-C-glycosidic link-
age,23 there are notable and important exceptions.24
Since only a few procedures currently exist that provide
access to a-C-aryl glycosides,25 this mild, stereoselective
sequence should prove of great utility in the synthesis of
this class of compounds.
8. Steinhuebel, D. P.; Fleming, J. F.; DuBois, J. Org. Lett.
2002, 4, 293–295.
9. For the initial report, see: Nomura, R.; Miyazaki, S.-I.;
Matsuda, H. J. Am. Chem. Soc. 1992, 114, 2738–2741.
10. Interestingly, whereas reactions carried out in CH2Cl2
were completely homogenous, reactions performed in
ether or toluene had visible white precipitates that did
not dissolve throughout the course of the reaction.
11. For C-glycosides 5 derived from di-O-acetyl-L-rhamnal 4,
the ‘a-configuration’ corresponds to a trans relationship
between the substituents at C10 and C50 (Table 2).
12. (a) Stewart, A. O.; Williams, R. M. J. Am. Chem. Soc.
1985, 107, 4289–4296; (b) Minehan, T. G.; Kishi, Y.
Tetrahedron Lett. 1997, 38, 6815–6818; (c) Nicotra, F.
Topics Curr. Chem. 1997, 187, 55–83.
13. In ether, a ‘cation-solvating’ solvent, only electron-rich
arylindiums can effectively compete with the solvent for
addition to both sides of the oxonium ion; in the less polar
CH2Cl2, a tight ion pair (with AcOꢁ or Clꢁ) prevents the
addition of nucleophiles to the less-hindered b-face of the
oxonium ion. See Ref. 12a for a discussion of solvent
effects on the stereochemistry of glycosidation.
In summary, triorganoindiums are mild, atom-efficient
and environmentally friendly reagents that can be em-
ployed in the preparation of a diverse array of 2,3-
unsaturated C-glycosides.
Supplementary material
14. Ferrier, R. J. Topics Curr. Chem. 2001, 215, 153–175.
15. The gauche effect predicts that C10 and C50 of a-glycopyr-
anoside anomers will be shielded with respect to the
corresponding carbons of the b-anomers: (a) Brakta, M.;
Farr, R. N.; Chaguir, B.; Massiot, G.; Lavaud, C.;
Anderson, W. R.; Sinou, D.; Daves, G. D. J. Org. Chem.
1993, 58, 2992–2998; (b) Stothers, J. B. Carbon-13 NMR
Spectroscopy; Academic: New York, 1973; Chapter 3; (c)
Kalinowski, H. O.; Berger, S.; Braun, S. Carbon-13 NMR
Spectroscopy; Academic: New York, 1988; Chapter 3.
16. Wittman, M. D.; Halcomb, R. L.; Danishefsky, S. J.;
Golik, J.; Vyas, D. J. Org. Chem. 1990, 55, 1979–1981.
17. (a) Lee, P. H.; Lee, S. W.; Saemoon, D. Org. Lett. 2003, 5,
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Y. Chem. Commun. 1991, 824–825.
Complete experimental details and spectroscopic data
for all compounds prepared in Table 2 and Schemes 4
and 6.
Acknowledgements
We are grateful for the generous financial support of this
work by the National Science Foundation (under Grant
No. 0097262) and the ACS Petroleum Research Fund
(PRF # 38271-GB1).
18. The weakness of the indium-carbon bond (ꢀ40 kcal/mol)
has been cited as a possible reason for the atom efficiency
of indium reagents in transferring their organic ligands
(replacing them preferentially with more electronegative
substitutents, such as halides); see Refs. 9 and 6.
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