Glycosylation using unprotected alkynyl donors

Article abstract of DOI:10.1021/jo901857x

(Chemical Equation Presented) Gold(III) activation of unprotected propargyl glycosyl donors has been shown to be effective for the synthesis of saccharides. Terminal propargyl glycosides of glucose, galactose, and mannose required heating at reflux in ace

Full text of DOI:10.1021/jo901857x

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Glycosylation Using Unprotected Alkynyl Donors
Sreeman K. Mamidyala* and M.G. Finn*
Department of Chemistry and The Skaggs Institute for
Chemical Biology, The Scripps Research Institute, 10550 N.
Torrey Pines Rd., La Jolla, California 92037
sreeman@scripps.edu; mgfinn@scripps.edu
Received September 8, 2009
FIGURE 1. Synthesis of glycosides by the activation of propargyl
donors 1-3 with AuCl3.
TABLE 1. Effect of Various Reaction Parameters for Au(III)-Cata-
lyzed Glycosylation Reactionsa
temp
(°C)
time
(h)
yield
(%)c
entry donor acceptorb solvent
R:β
Gold(III) activation of unprotected propargyl glycosyl
donors has been shown to be effective for the synthesis of
saccharides. Terminal propargyl glycosides of glucose,
galactose, and mannose required heating at reflux in
acetonitrile with 5% AuCl3 for reaction with various
primary alcohol acceptors, the latter used in 10-fold
molar excess relative to donor. Donors containing the
2-butynyl group were more reactive, giving good yields of
glycoside products at lower temperatures. Secondary
alcohols could also be used but with diminished effi-
ciency. The propargylic family of donors is especially
convenient because they can be easily prepared on large
scale by Fischer glycosylation and stored indefinitely
before chemoselective activation by the catalyst.
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
1
4
4
4
4
4
4
4
4
MeCN
MeCN
MeCN
MeNO2
DMF
THF
rt
60
82
82
82
82
82
82
24
12
4
0
0
60
25
0
32
35
15
1.5:1
2.3:1
4
24
1.5d
2d
4
3.0:1
3.0:1
2.3:1
neat
MeCN
(2 equiv)
aIn all cases AuCl3 was used at 5 mol % with respect to donor. bUnless
otherwise specified, 10 equiv was used with respect to donor. cIsolated
yields of chromatographically purified products. dHeating for longer
periods gave the same or lower yields.
Among recent developments have been the discovery of
novel glycosyl donors,10 adding to the repertoire of more
established reagents such as trichloroacetamidates,11 halides,12
sulfoxides,13 glycols,14 phosphates,15 phosphites,16 n-pentenyl
glycosides,17 and thioglycosides.18-20 A significant difficulty
with many popular reagents is the need for protection and
Carbohydrates are important components of glycolipids and
glycoproteins, playing key roles in cell-cell communication,
cell adhesion, development, differentiation, and immune re-
sponse and in disease processes such as inflammation, tumor
metastasis, and pathogen infection.1-5 Thus the synthesis of
carbohydrates and their analogues may provide novel thera-
peutic agents and diagnostic tools.6-9Although revolutionary
advances have been made in carbohydrate synthesis in recent
years, oligosaccharide synthesis remains far more difficult than
the modular assembly of oligopeptides and oligonucleotides as
a result of the extraordinary complexity of glycan structures.
(10) For reviews on glycoside synthesis, see: (a) Smoot, J. T.; Demchenko,
A. V. Adv. Carbohydr. Chem. Biochem. 2009, 62, 161–250. (b) Zhu, X.;
Schmidt, R. R. Angew. Chem., Int. Ed. 2009, 48, 1900–1934. (c) Demchenko,
A. V., Handbook of Chemical Glycosylation, Wiley-VCH, Weinheim, 2008;
(d) Galonic, D. P.; Gin, D. Y. Nature 2007, 446, 1000–1007. (e) Toshima, K.
Carbohydr. Res. 2006, 341, 1282–1297. (f) Demchenko, A. V. Synlett 2003,
1225–1240. (g) Jensen, K. J. J. Chem. Soc. Perkin Trans. 1 2002, 2219–2233.
(h) Davis, B. G. J. Chem. Soc. Perkin Trans. 1 2000, 2137–2160.
(11) Schmidt, R. R.; Kinzy, W. Adv. Carbohyd. Chem. Biochem. 1994, 50,
21–123.
(12) Shimizu, M.; Togo, H.; Yokoyama, M. Synthesis 1998, 799–822.
(13) Kahne, D.; Walker, S.; Cheng, Y.; van Engen, D. J. Am. Chem. Soc.
1989, 111, 6881–6882.
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DOI: 10.1021/jo901857x
r
Published on Web 10/14/2009
J. Org. Chem. 2009, 74, 8417–8420 8417
2009 American Chemical Society

Mamidyala and Finn
JOCNote
TABLE 2. Au(III)-Catalyzed Glycosylation with Various Propargyl Glycan Donors and Acceptors; All Reactions Performed As Shown in Figure 1
deprotection steps in order to achieve stereo-, chemo-, and
regioselectivity. The use of glycosylation reactions with un-
protected building blocks has certainly been explored,21 but is
less well developed. Among the most successful of these
strategies is the use of 3-methoxy-2-pyridyloxy glycosyl donors
based on a remote activation concept.21
In order to be useful as an unprotected glycosyl donor, the
molecule should be stable, easily synthesized, and chemose-
lectively activated for assembly of the desired glycoconju-
gate. Toward this end, we became enamored of reports that
alkyne-containing glycosyl donors could be selectively
activated by alkynophilic metals such as Au(III),22-26
Hg(II),27 and Au(I).28 Of these, the Au(III) method of Hotha
and co-workers using propargyl glycosides of benzyl-pro-
tected glycan donors is particularly attractive.24,26 This
method seemed to be well suited to the use of unprotected
glycosyl donors, since Au(III) is not strongly oxophilic and
functions well in protic solvents.
We therefore explored the reactions of unprotected galac-
tosyl, glucosyl, and mannosyl donors 1-3,29-31 using AuCl3
to activate the propargyl unit (Figure 1). A survey of reaction
conditions using allyl alcohol (4) as the glycosyl acceptor
revealed the following trends: (1) Acetonitrile provided
significantly better yields than reactions performed in
(21) Hanessian, S. Chem. Rev. 2000, 100, 4443–4463.
(22) Arcadi, A. Chem. Rev. 2008, 108, 3266–3325.
(23) Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239–3265.
(24) Hotha, S.; Kashyap, S. J. Am. Chem. Soc. 2006, 128, 9620–9621.
(25) Kashyap, S.; Hotha, S. Tetrahedron Lett. 2006, 47, 2021–2023.
(26) Sureshkumar, G.; Hotha, S. Tetrahedron Lett. 2007, 48, 6564–6568.
(27) Imagawa, H.; Kinoshita, A.; Fukuyama, T.; Yamamoto, H.;
Nishizawa, M. Tetrahedron Lett. 2006, 48, 4729–4731.
(28) Li, Y.; Yang, Y.; Yu, B. Tetrahedron Lett. 2008, 49, 3604–3608.
(29) Mereyala, H.; Gurrala, S. R. Carbohydr. Res. 1998, 307, 351–354.
(30) Blinkovsky, A. M.; Dordick, J. S. Tetrahedron: Asymmetry 1993, 4,
1221–1228.
(31) Hasegawa, T.; Numata, M.; Okumura, S.; Kimura, T.; Sakurai, K.;
Shinkai, S. Org. Biomol. Chem. 2007, 5, 2404–2412.
8418 J. Org. Chem. Vol. 74, No. 21, 2009

Mamidyala and Finn
JOCNote
nitromethane, DMF, THF, or without solvent (Table 1,
entries 3-7), suggesting that coordination of ligands to the
metal may be an important factor. (2) Heating to reflux was
required to achieve complete reactions within a few hours,
which proved to be much better than reactions at 60 °C for
propargyl donors such as 1 (Table 1, entries 1-3). (3) A large
excess (10 equiv) of the aglycon acceptor was required for
acceptable yields (Table 1, entry 8 vs 3). This common
limitation21 arises from the fact that unprotected donors
can also act as acceptors if not swamped by the desired
reaction partner.
29 provided excellent yields at lower temperatures as well, of
course allowing the use of lower concentrations of glycosyl
acceptor because of its protected nature (entries 11-13).
Lastly, unprotected 28 was found to couple to other glycosyl
acceptors in straightforward fashion in refluxing acetonitrile
(entries 7-10). When conducted at lower temperatures,
substantial glycosylation was observed, but product purifi-
cation was more difficult.
TABLE 3. Glycosylation Reactions Using 2-Butynyl Donors
The optimized glycosylation reaction conditions were
used to test the reaction with donors 2-propynyl-O-β-
D-glucopyranoside (2)29 and 2-propynyl-O-R-D-mannopyra-
noside (3),31 and acceptors 4-9, shown in Figure 1, to afford
glycosides 11-25 (Table 2). While the primary alcohol
galactose diacetonide 7 afforded the expected disaccharides
(entries 4, 10, and 16), diacetone-D-glucose (8), a secondary
alcohol, did not. Instead, cleavage of the 5,6-isopropylidene
group occurred to give the corresponding 1,2-O-isopropyli-
dene-R-D-glucofuranose32 as the major product, with
little or no disaccharide formation detected. This presum-
ably reflects steric hindrance of the capture of the
activated donor. Adducts of a smaller secondary alcohol,
cyclohexanol (9), were obtained from each of the three
donors in modest yield (entries 6, 12, and 18). All of the
reactions described here were quite clean when analyzed by
thin-layer chromatography, with complete conversion of
donor to the desired product and oligomeric material, the
latter appearing at the bottom of the TLC plate and
often adhering to the flask, making purification convenient.
We presume that such oligomerization is responsible
for the moderate yields obtained, and efforts are under-
way to optimize these procedures to boost yields and
stereoselectivities.
entry reactants temp (°C) time (h) product yield (%)
R:β
1
2
3
4
5
6
7
8
9
10
11
12
13
27 þ 5
27 þ 5
27 þ 5
28 þ 5
28 þ 5
28 þ 5
28 þ 4
28 þ 6
28 þ 7
28 þ 9
29 þ 5a
29 þ 5a
29 þ 5a
RT
60
82
24
60
82
82
82
82
82
0
no rxn
no rxn
no rxn
35
52
61
61
64
47
36
24
12
3
7
6
11
11
11
10
12
13
14
30
30
30
1:1
1.5:1
1:1.4
1:1.2
1.3:1
3
7
1:1.6
3:1
no rxn
85
88
24
60
12
4
1:1
1:1
a1.5-2 equiv of acceptor 5 was used.
Alkynophilic activation by Au(III) has been shown here to
be practical for unprotected sugars, as long as the capturing
nucleophile is used in excess and is not too sterically hin-
dered. The propargylic ethers can be easily prepared by
Fisher glycosylation and are stable toward hydrolysis. The
greater reactivity provided by the 2-butynyl group does not
provide definitive mechanistic information, as either of the
steps of the Au-mediated activation process (π-complexa-
tion and oxocarbenium ion formation by cyclization of
the anomeric oxygen on the Au-complexed alkyne) could
be assisted by methylation at the terminal alkyne posi-
tion. It does, however, provide encouragement for the
further development of this process and for the use of Au-
catalyzed activation for glycan synthesis under very mild
conditions.
The formation of a 1,6-linked trisaccharide was accom-
plished without difficulty, as shown in eq 1. Propargylated
lactosyl donor 25 and diacetone-D-galactose (7) provided an
equimolar mixture of the R- and β-adducts 26 (1:1) in 47%
yield under standard conditions, suggesting that complex
oligosaccharides may be accessible with limited protection/
deprotection steps.
Experimental Section
The likely mechanism of Au(III) glycosylation catalysis
begins with the formation of a π-complex between the alkyne
and the metal.24 Since σ-acetylide intermediates are presum-
ably not involved, we reasoned that an internal alkyne,
rather than a terminal propargyl group, might be beneficial.
Accordingly, the protected and unprotected 2-butynyl ga-
lactosyl donors 27-29 were prepared. As expected,24 the
acetylated donor 27 was not activated by catalytic Au(III)
(Table 3, entries 1-3). Donor 28 proved to be more reactive
than its propargyl analogue, giving substantial yields of 11 at
room temperature and 60 °C (entries 4 and 5), whereas
heating to reflux was required for donor 1. Perbenzylated
General Procedure. To a solution of glycosyl donor (0.1 mmol)
and aglycone (1.0 mmol; 0.2 mmol for donor 29) in anhydrous
CH3CN (10 mL) was added a solution of 5 mol % of AuCl3 in
anhydrous acetonitrile (2 mL) under argon atmosphere at room
temperature. The resulting mixture was heated to reflux, and the
progress of the reaction was monitored by TLC. After comple-
tion, the reaction mixture was concentrated under vacuum to
obtain a crude residue that was purified by conventional silica
gel column chromatography using mixtures of MeOH and
CH2Cl2 as mobile phase. All adducts are known compounds,
and their identities were confirmed by comparison to published
spectra.
Compound 28 was prepared by standard BF3-mediated
glycosylation of 2-butyn-1-ol, as described in Supporting In-
formation, and was isolated as a hygroscopic white solid (1.25 g,
(32) Vic, G.; Crout, D. H. G. Carbohydr. Res. 1995, 279, 315–319.
J. Org. Chem. Vol. 74, No. 21, 2009 8419

Mamidyala and Finn
JOCNote
90%). Mp 154 °C. 1H NMR (300 MHz, CDCl3): δ 1.83 (t, 3H,
J = 3.0, 6.0 Hz), 3.45-3.60 (m, 3H), 3.72-3.82 (m, 2H), 4.30 (2d,
Acknowledgment. We are grateful to The Skaggs Institute
for Chemical Biology and Pfizer, Inc. for financial support.
1H, J = 3.0 Hz), 4.35-4.40 (m, 2H) 4.42 (d, 1H, J = 9.0 Hz). 13
C
Supporting Information Available: Experimental details and
representative HPLC and MALDI mass spectrometry data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
NMR (75 MHz, CDCl3): δ 53.9 (CH3), 59.3 (C-3), 67.1 (C-2),
69.1 (C-60), 71.7 (C-50), 72.3 (C-30), 73.5 (C-40), 80.2 (C-20), 99.4
(C-10). Anal. (after drying under vacuum) Calcd for C10H16O6: C,
51.72; H, 6.95; N, 0.00. Found: C, 51.82; H, 6.84; N, 0.00.
8420 J. Org. Chem. Vol. 74, No. 21, 2009