Direct C-glycosylation of organotrifluoroborates with glycosyl fluorides and its application to the total synthesis of (+)-varitriol

Article abstract of DOI:10.1021/ol102473k

A mild, stereoselective, and quick approach to accessing alkynyl and alkenyl C-glycosides via BF₃?Et₂O promoted coupling of organotrifluoroborates and glycosyl fluorides is reported. The application of this method was further demonstrated by the concise and efficient total synthesis of (+)-varitriol in only seven steps.

Full text of DOI:10.1021/ol102473k

ORGANIC
LETTERS
2011
Vol. 13, No. 1
42-45
Direct C-Glycosylation of
Organotrifluoroborates with Glycosyl
Fluorides and Its Application to the
Total Synthesis of (+)-Varitriol
Jing Zeng, Seenuvasan Vedachalam, Shaohua Xiang, and Xue-Wei Liu*
DiVision of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological UniVersity, Singapore 637371
xuewei@ntu.edu.sg
Received October 12, 2010
ABSTRACT
A mild, stereoselective, and quick approach to accessing alkynyl and alkenyl C-glycosides via BF3·Et2O promoted coupling of organotrifluo-
roborates and glycosyl fluorides is reported. The application of this method was further demonstrated by the concise and efficient total
synthesis of (+)-varitriol in only seven steps.
Glycosylation reactions play a pivotal role in carbohydrate
chemistry.1 O-Glycosidic compounds are the most abundant
and important among all types of glycosides, whereas
C-glycosides have attracted considerable interest in carbo-
hydrate, enzymatic, and metabolic chemistry over the past
decades for their interesting structures and higher stability
toward glycosidases and hydrolytic conditions.2 Furthermore,
C-glycosides are also widely found in natural products and
synthetic pharmaceuticals such as (+)-varitriol (1),3 (-)-
aspergillide C (2),4 C-mannosyltryptophan (C-man-trp, 3),5
and chaetiacandin (4) (Figure 1).6 In addition, C-glycosides
are useful chiral building blocks for the syntheses of natural
products and pharmaceuticals.7 Undoubtedly, these features
have stimulated the development of successful strategies for
the stereoselective construction of C-glycosides, and a
plethora of methods have been reported over the past years.8
Among the contemporary methods, direct attachment of
carbon nucleophiles to sugar anomeric carbon presents
significant achievements, especially the methods of capturing
(5) Nishikawa, T.; Koide, Y.; Kajii, S.; Wada, K.; Ishikawa, M.; Isobe,
M. Org. Biomol. Chem 2005, 3, 687.
(1) For reviews, see: (a) Varki, A. Glycobiology 1993, 3, 97. (b) Dwek,
R. A. Chem. ReV. 1996, 96, 683. (c) Bertozzi, C. R.; Kiessling, L. L. Science
2001, 291, 2357. (d) Toshima, K.; Tatsuta, K. Chem. ReV. 1993, 93, 1503.
(e) Davis, B. G. J. Chem. Soc., Perkin Trans. 1 2000, 2137.
(2) For reviews, see: (a) Hultin, P. G. Curr. Top. Med. Chem. 2005, 5,
1299. (b) Zhou, W. Curr. Top. Med. Chem. 2005, 5, 1363. (c) Compain,
P.; Martin, O. R. Biorg. Med. Chem. 2001, 9, 3077. (d) Yang, G.; Schmieg,
J.; Tsuji, M.; Franck, R. W. Angew. Chem., Int. Ed. 2004, 43, 3818. (e)
Levy, D. E.; Tang, C. The Chemistry of C-Glycosides; Pergamon: Tarrytown,
NY, 1995.
(6) (a) Komori, T.; Itoh, Y. J. Antibiot. 1985, 38, 544. (b) Komori, T.;
Yamashita, M.; Tsurumi, Y.; Kohsaka, M. J. Antibiot. 1985, 38, 455.
(7) For recent reports, see: (a) Isobe, M.; Nishizawa, R.; Hosokawa, S.;
Nishikawa, T. Chem. Commun. 1998, 2665. (b) Nagasawa, T.; Kuwahara,
S. Org. Lett. 2009, 11, 761. (c) Larrosa, I.; Romea, P.; Urpi, F. Org. Lett.
2006, 8, 527. (d) de Vicente, J.; Betzemeier, B.; Rychnovsky, S. D. Org.
Lett. 2005, 7, 1853. (e) Reddy, C. R.; Madhavi, P. P.; Chandrasekhar, S.
Synthesis 2008, 2939. (f) Yeager, A. R.; Min, G. K.; Porco, J. A.; Schaus,
S. E. Org. Lett. 2006, 8, 5065. (g) Nishikawa, T.; Koide, Y.; Kanakubo,
A.; Yoshimura, H.; Isobe, M. Org. Biomol. Chem. 2006, 4, 1268.
(8) For reviews, see: (a) Somsak, L. Chem. ReV. 2001, 101, 81. (b) Du,
Y.; Linhardt, R. J.; Vlahov, I. R. Tetrahedron 1998, 54, 9913. (c) Postema,
M. H. D. Tetrahedron 1992, 48, 8545.
(3) Malmstrom, J.; Christophersen, C.; Barrero, A. F.; Oltra, J. E.;
Justicia, J.; Rosales, A. J. Nat. Prod. 2002, 65, 364.
(4) Kito, K.; Ookura, R.; Yoshida, S.; Namikoshi, M.; Ooi, T.; Kusumi,
T. Org. Lett. 2007, 10, 225.
10.1021/ol102473k  2011 American Chemical Society
Published on Web 11/29/2010

Table 1. Optimization of Direct C-Glycosylation of Potassium
Phenylethynyltrifluoroborate
promoter
X
(equiv)
temp(°C) solvent time(h) yield(%)
1
OMe
OAc
OAc
OAc
OAc
OAc
STol
BF3·OEt2 (2)
BF3·OEt2 (2)
TiCl4 (1.2)
80
rt
rt
rt
0
rt
rt
rt
rt
rt
rt
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DCM
24
14
12
14
2
16
4
1
-
2
61
11
20
43
-
3
4
SnCl4 (1.2)
TMSOTf (1.2)
SiCl4 (1.2)
5
6
Figure 1. Naturally occurring C-glycosides.
7
BF3·OEt2 (2)
65
81
94
71
51
8
OCNCl3 BF3·OEt2 (2)
9
F
F
F
BF3·OEt2 (1.3)
BF3·OEt2 (1.3)
BF3·OEt2 (1.3)
0.3
0.5
2
10
11
the electrophilic oxocarbenium ion (which was generated by
activation of the anomeric center with a Lewis acid or
Brønsted acid) with a carbon nucleophile.8a,9
toluene
R-selectivity, which simplifies the isolation and characteriza-
tion of the product. In addition, mannosylation also attracted
significant interest in biological and medicinal chemistry.13
Initially, methyl mannoside was subjected to the glycosyla-
tion reaction with BF3·Et2O as a Lewis acid (entry 1).
However, no product was formed even under refluxing
conditions due to the poor reactivity of an anomeric methoxy
group. To our delight, the reaction with mannosyl acetate
gave R-mannoside in 61% yield (entry 2). Further screening
of Lewis acids such as TiCl4, SnCl4, SiCl4, and TMSOTf
revealed that BF3·Et2O produced the best result whereas
TMSOTf gave moderate yields (entries 3-6). Furthermore,
the efficiency of anomeric leaving groups was examined in
the presence of BF3·Et2O (entries 7-9). Good leaving groups
such as STol and trichloroacetimidate afforded better results
than that of the acetate group; the reaction of mannosyl
fluoride completed in the shortest reaction time with the
highest yield (entry 9). Use of solvent other than MeCN gave
diminished results (entries 10, 11).
With these optimal reaction conditions in hand, we
continued to investigate the scope of the C-glycosylation
coupling reaction. First, a series of potassium organotrifluo-
roborates were tested toward C-mannosylation (Figure 2).
Among them, alkynyl-trifluoroborates possessing either
aromatic or aliphatic substituents provided the desired
products in good yields; even aliphatic alkynyltrifluoroborates
with long chains gave the mannosylation product in good
yields (7aa-7ad). Alkenyltrifluoroborates gave lower yields
due to the reduced reactivity of the sp2-hybridized bonds
(7ae, 7af). Unfortunately, preliminary efforts attempted to
employ potassium alkyl- and aryl-trifluoroborates failed, in
which the anomeric position was intramolecularly arylated
by 2-OBn group instead.14
Organoboron compounds exhibit wide-ranging utilities in
synthetic chemistry. As one of the most stable organoboron
reagents, potassium organotrifluoroborates offer various
advantages such as an easier preparation procedure and
higher nucleophilicity, compared to relevant boronic acids
and boronic esters. Based on their synthetic utility, they have
become increasingly popular for C-C bond formation.10
Recently, Stefani9b and Bode11 have demonstrated the
efficiency of nucleophilic addition reactions of potassium
organotrifluoroborates with oxocarbenium ions. In connection
with our continuous research interest in carbohydrate chem-
istry,12 herein, we report a direct C-glycosylation method
by coupling of potassium organotrifluoroborates with sugar
oxocarbonium ions.
Our investigation began with the optimization of direct
C-glycosylation of potassium phenylethynyltrifluoroborate
(Table 1). To this end, benzylated mannose derivatives were
chosen as glycosyl donors, because mannosylation without
neighboring group participation usually exhibits excellent
(9) For selected examples, see: (a) Ferrier, R. J.; Overend, W. G.; Ryan,
A. E. T. J. Chem. Soc. Abstracts 1962, 3667. (b) Vieira, A. S.; Fiorante,
P. F.; Hough, T. L. S.; Ferreira, F. P.; Lu¨dtke, D. S.; Stefani, H. A. Org.
Lett. 2008, 10, 5215. (c) Larrosa, L.; Romea, P.; Urp´ı, F.; Balsells, D.;
Vilarrasa, J.; Font-Bardia, M.; Solans, X. Org. Lett. 2002, 4, 4651. (d)
Steinhuebel, D. P.; Fleming, J. J.; Du Bois, J. Org. Lett. 2001, 4, 293. (e)
Cook, M. J.; Fletcher, M. J. E.; Gray, D.; Lovell, P. J.; Gallagher, T.
Tetrahedron 2004, 60, 5085. (f) Lubin-Germain, N.; Baltaze, J.-P.; Coste,
A.; Hallonet, A.; Laureano, H.; Legrave, G.; Uziel, J.; Auge, J. Org. Lett.
2008, 10, 725. (g) Lee, D. Y. W.; He, M. S. Curr. Top. Med. Chem. 2005,
5, 1333
.
(10) For review, see: (a) Darses, S.; Genet, J.-P. Chem. ReV. 2007, 108,
288. (b) Stefani, H. A.; Cella, R.; Vieira, A. S. Tetrahedron 2007, 63, 3623.
(c) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275.
(11) Mitchell, T. A.; Bode, J. W. J. Am. Chem. Soc. 2009, 131, 18057.
(12) (a) Lorpitthaya, R.; Xie, Z. Z.; Sophy, K. B.; Luo, J. L.; Liu, X.-
W. Chem.sEur. J. 2010, 16, 588. (b) Gorityala, B. K.; Lorpitthaya, R.;
Bai, Y.; Liu, X.-W. Tetrahedron 2009, 65, 5844. (c) Yang, R. Y.; Pasunooti,
K. K.; Li, F.; Liu, X.-W.; Liu, C.-F. J. Am. Chem. Soc. 2009, 131, 13592.
(d) Gorityala, B. K.; Cai, S. T.; Lorpitthaya, Ma, J. M.; Pasunooti, K. K.;
Liu, X.-W. Tetrahedron Lett. 2009, 50, 676. (e) Liu, X.-W.; Le, T. N.; Lu,
Y. P.; Xiao, Y. J.; Ma, J. M.; Li, X. Org. Biomol. Chem. 2008, 6, 3997. (f)
Lorpitthaya, R.; Xie, Z. Z.; Kuo, J. L.; Liu, X.-W. Chem.sEur. J. 2008,
14, 1561. (g) Lorpitthaya, R.; Sophy, K. B.; Luo, J. L.; Liu, X.-W. Org.
Biomol. Chem. 2009, 7, 1284.
The versatility of the BF3·OEt2 promoted C-glycosylation
protocol for other sugar fluorides was studied using potas-
(13) (a) Asano, N. Glycobiology 2003, 13, 93R. (b) Asano, N.; Nash,
R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11,
1645.
(14) See details in Supporting Information.
Org. Lett., Vol. 13, No. 1, 2011
43

Figure 2. Direct C-glycosylation of organotrifluoroborates with glycosyl fluorides. (a) For the entire figure, unless otherwise noted, the
reactions were carried out according to Procedure A. (b) Unless otherwise noted, only one anomer was observed as drawn; for those
depicting an R,ꢀ ratio, the stereochemistry of the major isomer was shown as drawn. (c) Isolated yields are recorded above. Unless otherwise
1
noted, R,ꢀ ratio was deternmined by HNMR. (d) Only E alkene was observed. (e) The R,ꢀ ratio was determined by HPLC. (f) Reaction
was carried out according to Procedure B. (g) Unstable and decomposed quickly. (h) Reaction was carried out according to Procedure C.
Procedure A: To a solution of glycosyl fluoride (0.2 mmol) and organo trifluoroborate (1.2 equiv) in acetonitrile (1 mL) was added
BF3·OEt2 (1.3 equiv) at rt. The reaction was carried out at rt for 20 min. Procedure B: To a solution of glycosyl fluoride (0.2 mmol) and
organo trifluoroborate (2.0 equiv) in acetonitrile (1 mL) was added BF3·OEt2 (2.2 equiv) at -40 °C. The reaction was carried out at -40
°C for 6 h. Procedure C: Premixing of BF3·OEt2 (2.2 equiv) and organo trifluoroborate (2.0 equiv) in acetonitrile (1 mL) followed by
addition of glycosyl fluoride (0.2 mmol). The reaction was carried out at -40 °C for 6 h.
sium phenylacetylene trifluoroborate as the coupling partners.
D-Galactosyl fluoride 6c gave the desired product 7c in good
yield with high selectivity under the optimized conditions.
2-Deoxyglucosyl fluoride 6d was also tolerated in this
condition and gave the R-isomer 7d in 92% yield as a single
product. Extending the glycosylation method to furanose was
also pursued. Unlike D-mannofuranosyl fluoride 6f and
D-arabinosyl fluoride 6g which were able to generate the
corresponding alkynyl sugar in good yields with exclusive
R-selectivities (7f, 7g), D-ribofuranosyl fluoride 6e and
L-furanosyl fluoride 6h were considerably more ꢀ-selective
(7e, 7h). The diastereoselectivities for both furanose and
pyranose have no correlation with their anomeric fluoride
configuration, but rather, they depend on the conformation
of the oxonium intermediates.15
however, the yield diminished. The product was obtained in
63% yield with good R-selectivity (5.3:1 R:ꢀ) at -40 °C.
Interestingly, we found that a reversed sequence of reagent
addition (premixed excess potassium organotrifluoroborate
and BF3·OEt2 in MeCN prior to addition of the fluoride)
slightly increased the yield (67%) and selectivity (6.9:1)
(7ba). The reaction between 6b and 5b also gave the
corresponding glucoside in good selectivity under the current
conditions (7bb). Interestingly, only the R-product was
observed while 5d was employed as the coupling partner
(7bd).
We further examined the applicability of this methodol-
ogy to natural product synthesis. (+)-Varitriol (1) exhibits
significant cytotoxic activity toward renal, central nervous
system, and breast cancer cell lines. It was first isolated
from a marine-derived strain of the fungus Emericella
Variecolor in 2002.3 Several total syntheses of (+)- and
(-)-varitriol have been reported recently.16 Based on our
methodology, we envisaged that the coupling reaction of
glycosyl fluoride 6h with organotrifluoroborate 9 would
be implemented as the key step in the synthesis of (+)-
varitriol (1) (Scheme 1). Our synthesis commenced with
a fluorination reaction of known compound 817 to afford
Extending the C-glycosylation method to C-glucosylation
was further studied. The reaction of glucosyl fluoride 6b and
trifluoroborate 5a produced 7ba in good yields with a slight
preference for R-selectivity (2.6:1 R:ꢀ). Gratifyingly, further
lowering of the reaction temperature increased the selectivity;
(15) (a) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Smith, D. M.;
Woerpel, K. A. J. Am. Chem. Soc. 2005, 127, 10879. (b) Lucero, C. G.;
Woerpel, K. A. J. Org. Chem. 2006, 71, 2641.
44
Org. Lett., Vol. 13, No. 1, 2011

trifluoriborate 9c, the reaction proceeded smoothly which
gave 10 in 65% yield for two steps from 8. A subsequent
Sonogashira cross-coupling reaction provided internal
alkyne 12 in 91% yield. Reduction of the ester group of
12 and selective protection of the generated phenol group
with iodomethane and K2CO3 furnished 13 in 83% yield.
The chemoselective reduction of the triple bond was
conducted by Red-Al which produced alkene 14 in 89%
yield with an E:Z ratio of 2.8:1. Interestingly, after
removal of the protecting group of 14 with 1 M HCl
followed by flash chromatography on silica gel, all of the
Z-isomer was exclusively transformed to the E-isomer
which furnished the target molecule 1 in 93% yield. Thus,
we succeeded in the synthesis of (+)-varitiol (1) from
known compound 8 in only seven steps and 41% overall
yield, including the C-glycosylation reaction as a key step.
In conclusion, we have identified a versatile and facile
method for the synthesis of C-glycosides Via cross-coupling
of potassium organotrifluoroborates and glycosyl fluorides.
This approach furnishes C-glycosides in a relatively short
time with good to excellent yields and high diastereoselec-
tivity. Furthermore, this strategy enabled the concise and
efficient synthesis of naturally occurring C-glycoside (+)-
varitriol (1) in the shortest route and highest overall yield
so far as we know.
Scheme 1. Total Synthesis of (+)-Varitriol 1
Acknowledgment. Financial support from Nanyang Tech-
nological University (RG50/08) and the Ministry of Educa-
tion, Singapore (MOE 2009-T2-1-030) are gratefully ac-
knowledged.
fluoride 7h. Unfortunately, the coupling reaction of 7h
with alkenyl trifluoroborate 9a18 or 9b could not give the
desired products. While replacing 9a or 9b with ethynyl-
Supporting Information Available: Experimental pro-
cedures and compound characterization data of glycosyl
fluorides and C-glycosylation products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(16) (a) Senthilmurugan, A.; Aidhen, I. S. Eur. J. Org. Chem. 2010,
555. (b) Palik, M.; Karlubikova, O.; Lackovicova, D.; Lasikova, A.; Gracza,
T. Tetrahedron 2010, 66, 5244. (c) Palik, M.; Karlubikova, O.; Lasikova,
A.; Kozisek, J.; Gracza, T. Eur. J. Org. Chem. 2009, 709. (d) Nagarapu,
L.; Paparaju, V.; Satyender, A. Bioorg. Med. Chem. Lett. 2008, 18, 2351.
(e) McAllister, G. D.; Robinson, J. E.; Taylor, R. J. K. Tetrahedron 2007,
63, 12123. (f) Kumar, V.; Shaw, A. K. J. Org. Chem. 2008, 73, 7526. (g)
Ghosh, S.; Pradhan, T. K. J. Org. Chem. 2010, 75, 2107. (h) Clemens,
R. T.; Jennings, M. P. Chem. Commum. 2006, 2720. (i) Brichacek, M.;
Batory, L. A.; McGrath, N. A.; Njardarson, J. T. Tetrahedron 2010, 66,
4832.
OL102473K
(17) Srihari, P.; Prem Kumar, B.; Subbarayudu, K.; Yadav, J. S.
Tetrahedron Lett. 2007, 48, 6977.
(18) Molander, G. A.; Dehmel, F. J. Am. Chem. Soc. 2004, 126, 10313.
Org. Lett., Vol. 13, No. 1, 2011
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