Multicomponent cascade transformation of d -glucal to furan-appended triazole glycoconjugates

Article abstract of DOI:10.1021/jo100475e

Novel one-pot three- and four-component transformations of d-glucal to furan-based hydroxy triazole glycoconjugates have been achieved by sequential addition of reagents in the presence of Cu(OTf)₂-Cu powder as catalysts. In general the carbohy

Full text of DOI:10.1021/jo100475e

pubs.acs.org/joc
SCHEME 1. One-Pot Synthesis of Furan-Based Hydroxy
Triazole from D-Glucal
Multicomponent Cascade Transformation of
D-Glucal to Furan-Appended Triazole
Glycoconjugates
Syed Khalid Yousuf, Subhash Chandra Taneja, and
Debaraj Mukherjee*
Bio-organic Chemistry Division, Indian Institute of
Integrative Medicine (CSIR), Canal Road, Jammu,
India-180001
synthetic compounds with significant biological activities.2
In addition, these products can be converted to β-adrenergic
receptor blocker analogues with furan-based hydroxy tria-
zole moiety by employing click chemistry,3 i.e., copper(I)-
catalyzed azide-alkyne [3þ2] cycloaddition.4 Since hydro-
xytriazoles have become increasingly useful and important in
drugs and pharmaceuticals,5a,b the development of improved
methods for their synthesis with structural diversity is highly
desirable. Although there are reports on the synthesis of
hydroxy triazoles from epoxides5a via click reaction, the
synthesis of furan-based hydroxy triazoles still remains a
challenge.
dmukherjee@iiim.res.in.
Received September 14, 2009
Multicomponent reactions6 (MCRs), which combine two
or more distinct reactions into a single transformation,
present significant advantages over conventional linear step
synthesis by reducing reaction time period and saving money,
energy, and raw materials, thus resulting in both economical
and environmental benefits. One-pot MC sequential syn-
thetic methods, in which a number of synthetic steps invol-
ving two or more reactants are carried out in the same flask
without the isolation of any intermediate, feature a high
degree of reaction mass efficiency and are especially suitable
in diversity oriented synthetic programs.
Novel one-pot three- and four-component transforma-
tions of D-glucal to furan-based hydroxy triazole glyco-
conjugates have been achieved by sequential addition of
reagents in the presence of Cu(OTf)2-Cu powder as
catalysts. In general the carbohydrate-derived products
were formed with high diastereomeric purity.
Traditionally, methods based on MC reactions have
proved quite efficient for the construction of different arrays
of heterocyclic compounds. One-pot MC reactions involving
Knoevenagel condensation,7a Diels-Alder cycloaddition,7b
Povarov reaction,7c Biginelli reaction,7d Passerini 3-component
reaction,7e Ugi-4 condensation,7f Ritter-Prins reaction,7g
and Cu(I)-catalyzed alkyne-azide7h coupling have been
particularly explored. Despite these advances, there is a need
to broaden the scope of carbohydrate-based one-pot MC
reactions in combination with click chemistry. Since carbo-
hydrates have secured their place in pharmaceutical chemistry,
At the interface between chemistry and biology, where so
much new scientific insight, discovery, and development is
being witnessed, the heterocyclic motifs dominate in more
than 90% of the new drugs. The essential science upon which
these advances are based is the synthesis of designed hetero-
cyclic compounds which make it possible to probe sensitively
the key events in biology in partnership with structural
biology. The range of easily accessible and diversely functio-
nalized heterocyclic building blocks is, however, surprisingly
limited and there is still a need for novel and improved
methodologies for constructing the molecular materials.
Substituted furans represent a popular class of heterocycles
with a number of pharmacological activities. Also these
motifs exhibit their presence in innumerable natural and
synthetic materials such as industrial intermediates, insecti-
cides, flavors, and fragrances. In addition, they are widely
used as precursors in synthetic chemistry.1 Especially β-hydroxy
R-furfuryl azide derivatives serve as important synthetic
precursors in the preparation of numerous natural and
(3) (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed.
2001, 40, 2004.
(4) Ankati, H.; Yang, Y.; Zhu, D.; Biehl, E. R.; Hua, L. J. Org. Chem.
2008, 73, 6433.
(5) (a) Yadav, J. S.; Reddy, B. V. S.; Reddy, G. M.; Chary, D. N.
Tetrahedron Lett. 2007, 48, 8773. (b) Lee, T.; Cho, M.; Ko, S.-Y.; Youn,
H.-J.; Baek, D. J.; Cho, W.-J.; Kang, C.-Y.; Kim, S. J. Med. Chem. 2007,
50, 585.
(6) Shindoh, N.; Tokuyama, H.; Takemoto, Y.; Takasu, K. J. Org. Chem.
2008, 73, 7451.
(7) (a) Taha, N.; Sasson, Y.; Chidambaram, M. Appl. Catal., A 2008, 350,
217. (b) Powell, D. A.; Batey, R. A. Tetrahedron Lett. 2003, 44, 7569.
(c) Kudale, A, A.; Kendall, J.; Miller, D. O.; Collins, J. L.; Bodwell, G. J.
J. Org. Chem. 2008, 73, 8437. (d) Suzuki, I.; Iwata, Y.; Takeda, K. Tetra-
hedron Lett. 2008, 49, 238. (e) Fan, L.; Adams, A. M.; Ganem, B. Tetrahedron
Lett. 2008, 49, 5983. (f) Thompson, M. J.; Chen, B. Tetrahedron Lett. 2008,
49, 5324. (g) Shao, L. X.; Qui, M.; Minshi, H. Tetrahedron Lett. 2008, 49, 165.
(h) Jackson, D.; Megiatto, J.; Schuster, D. I. J. Am. Chem. Soc. 2008,
130, 8898.
(1) For importance and synthesis of substituted furans, see: Saquib,M.;
Husain, I.; Kumar B.; Shaw, A, K. Chem.;Eur. J. 2009, 15, 6041 and
refrences cited therein
(2) Mukherjee, D.; Yousuf, S. K.; Taneja, S. C. Org. Lett. 2008, 10, 4831
and refrences cited therein.
DOI: 10.1021/jo100475e
r
Published on Web 04/09/2010
J. Org. Chem. 2010, 75, 3097–3100 3097
2010 American Chemical Society

Yousuf et al.
JOCNote
TABLE 1. Synthesis of R-Substituted Furan Derivatives from D-Glucal and Nucleophilesc
aCharacterized from 1H and 13C NMR. bIsolated yield. cIn the last column (Yield): (/) dr = 90:10, (//) dr = 92:8 as determined from LCMS.
in biopharmaceuticals as well as in “small molecule” chem-
istry, they are more attractive substrates for the pressing
demand in the present diversity oriented synthesis programs
in combination with MC reactions. In carbohydrate chem-
istry Dondoni and co-workers have made significant con-
tributions toward MCR.8
The screening process for new active principles critically
depends on the availability of versatile compound libraries.
MCRs are well suited to prepare libraries by variation of the
individual components. Aiming at hydroxyl triazole com-
pounds, we departed from activated carbohydrate compo-
nents and explored new MCRs.
With our recent success in the development of one-pot
tandem methodology in carbohydrate chemistry,2,9 we envi-
sioned that transformation of the easily available D-glucal (1)
to racemic substituted furyl triazole derivatives can be
completed in one pot without isolation of any intermediate.
Further, by careful choice of the Lewis acid, an efficient
cascade of several reactions can be performed in one pot,
providing a high degree of atom-economy and complexity.
Earlier we have achieved direct conversion of D-glucal into R-
azido furfuryl alcohol catalyzed by In(OTf)3.2 Gratifyingly,
we observed that Cu(OTf)2 can catalyze the same reaction as
In(OTf)3, which prompted us to design a one-pot synthetic
strategy. To obtain evidence in favor of our hypothesis, a
solution of D-glucal and TMSN3 in acetonitrile was treated in
a preliminary study with catalytic Cu(OTf)2 and allowed to
stir for 20 min. Then methyl propiolate and Cu powder were
added successively to the same reaction mixture, which was
stirred for 7.5 h (Scheme 1). The completion of the reaction
was indicated by complete consumption of D-glucal. The
presence of peaks at δ 8.14 (triazole), 7.4, 6.52, 6.4 (furan),
1
and 3.8 (-OMe) in H NMR, and 161.0, 147.6, 143.5, and
127.7 in 13C NMR confirmed the formation of R-1,2,3-
triazole-substituted furan moiety.
Gratifyingly, the degree of conversion was found to be the
same when compared to the traditional sequential metho-
dology. After getting positive results from the one-pot multi-
component transformation, the scope and generality of the
reaction was expanded by varying the alkyne partner. Thus
different sets of aromatic (electron rich as well as electron
deficient), alicyclic, aliphatic O-/C-/N-substituted alkynes
including sugar-derived ones (Table 1) were allowed to react
with D-glucal and TMSN3 under optimized conditions. In
(8) Dondoni, A.; Massi, A. Acc. Chem. Res. 2006, 39, 451.
(9) (a) Mukherjee, D.; Shah, B. A.; Gupta, P.; Taneja, S. C. J. Org. Chem.
2007, 72, 8965. (b) Thota, N.; Mukherjee, D.; Reddy, M. V.; Yousuf, S. K.;
Koul, S.; Taneja, S. C. Org. Biomol. Chem. 2009, 7, 1280.
3098 J. Org. Chem. Vol. 75, No. 9, 2010

Yousuf et al.
JOCNote
SCHEME 2. Reaction of D-Mannose, Propargyl Alcohol,
D-Glucal, and TMSN3
TABLE 2. Copper-Mediated Synthesis of Furan-Based Glycocongugates
general the reaction rate of aromatic C-alkynes is compar-
able to that of their aliphatic counterparts (Table1, entries
1 and 2 vs entries 3, 4, and 5). In all the reactions including
N- (entry 6, Table1) and O-derived alkynes, the yields were
very good (>80%); the electronic nature of the alkyne had
negligible effect on the rate as well as the regioselectivity of
the reaction.
Triazole-O-glycosides have long been used as fluores-
cence10 probes and anticancer agents.11 However, synthesis
of this class of glycoconjugates involves Lewis acid-catalyzed
glycosylation of glycosyl donors to obtain R/β-anomeric
mixtures, which are further subjected to copper-mediated
azide alkyne cycloaddition to generate glycoconjugate liber-
aries. With the modified 3-component one-pot procedure in
hand, we then explored the possibility of extending the
“tandem” process further by sequential addition of reagents
that could become active under Cu(OTf)2 catalysis to gen-
erate biologically important furan-appended triazole glyco-
conjugates. We envisioned that by fine-tuning the reaction
conditions, both sugar-alkyne and azide partners can be
generated in situ, which thereafter may undergo Huisgen’s
cycloaddition4 under the same Lewis acidic condition to
make it practically a four-component reaction. To obtain
practical evidence in favor of our notion, a solution of
pentaacetylated D-mannose and propargyl alcohol in acet-
onitrile was subjected to O-glycosylation under Cu(OTf)2
activation, followed by sequential addition of D-glucal,
TMSN3, and finally copper powder to afford the triazole
3c (Scheme 2) as the major product in good yield (84%) along
with furan diol (4) as the side product (5%).
aProducts obtained with use of glycosyl donor (1 equiv), propargyl
alcohol (1.2 equiv), D-glucal (1 equiv), and TMSN3 (1.5 equiv). bIsolated
yield after column chromatography. dr values have been determined
c
from LCMS.
Other glycosyl donors also reacted in the similar fashion to
yield structurally diverse glycocongugates in moderate yield
(Table 2, entries 2, 3, 4, and 5). Further, taking advantage of
Cu(OTf)2-mediated Ferrier transformation,12 rapid one-pot
synthesis of triazole-linked glycocongugates has also been
accomplished from readily available glycal derivatives
(Table 2, entries 6 and 7). The structure of newly formed
furan-based hydroxy triazolyl glycoconjugate was deter-
mined from 1H-1H COSY, HMBC, and HSQC experi-
ments. The observed HMBC correlations H1/C10, H10/C30,
H600/C200, H100/C30, and H100/C300 are in complete accord
with the proposed structure (Figure 1).
FIGURE 1. Determination of furan-based hydroxy triazolyl gly-
coconjugate structure by 2D NMR.
formation of four diastereomers. Simple silica gel column
chromatographic purification failed to separate the diaster-
eomers. However, after several attempts we could separate
the diastereomers using LCMS-reverse phase chromatogra-
phy. With anomeric selectivity of all the derivatives almost
To our surprise we obtained the products with high
distereoselective control, though there is a possibility of
1
∼100% (as observed from H NMR given in Supporting
Information), it was apparent that the formation of the new
stereogenic center at the R-position of the furan ring led to
the formation of two diastereomers with one in preponder-
ance. Similar results were obtained in 3-component reactions
where sugar templates have been used as alkyne partners
(Table 1 entries 10 and 11) The high diastereoselectivity of
(10) Sawa, M.; Hsu, T.-L.; Itoh, T.; Sugiyama, M.; Hanson, S. R.; Vogt,
P. K.; Wong, C.-H. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 12371.
(11) Wilkinson, B. L.; Bornaghi, L. F.; Houston, T. A.; Innocenti, A.;
Vullo, D.; Supuran, C. T.; Poulsen, S. A. J. Med. Chem. 2007, 50, 1651.
(12) Mukherjee, D.; Yousuf, S. K.; Taneja, S. C. Tetrahedron Lett. 2008,
49, 4944.
J. Org. Chem. Vol. 75, No. 9, 2010 3099

Yousuf et al.
JOCNote
SCHEME 3. Determination of Absolute Configuration at the
r-Position of the Furan Ring
besides azide formation, thus making this cascade reaction
atom economic.
In summary, we have developed a novel Cu(OTf)2/Cu
powder-mediated one-pot reaction for synthesizing highly
substituted hydroxy triazoles from the easily available
D-glucal. To the best of our knowledge this is the first report
of synthesizing furan-based hydroxy triazoles. The study has
led to the development of a Lewis acid-catalyzed multi-
component reaction culminating in one-pot construction of
highly functionalized motifs from carbohydrate precursors
as represented in diversity oriented synthesis. Future work
will address the exploration of this principle in the construc-
tion of other highly substituted heterocyclic natural product
skeletons.
the products may be attributed to the presence of the sugar
template, which may direct the formation of a particular
diastereomer predominantly. Though sugar residue is far
away from the chiral center, there is ample evidence that the
sugar residue is involved in a high level of remote asymmetric
inductions.13
To assign14 the stereochemistry at the newly derived furan-
substituted stereogenic center of the major diastereomer,
enantiomerically pure (S)-2-(tert-butyldiphenylsilyloxy)-
1-(2-furyl)ethyl azide has been synthesized following the
literature procedure.15 Deprotection of the TBDPS group
resulted in enantiomerically pure 4 having S-configuration
(ee, 98%), which was further reacted with anomerically
pure sugar alkynes to obtain diastereomerically pure furan-
appended triazole glycoconjugates (3a-h). The specific rota-
tion values as well as LCMS profiles of resulting products
were compared with those of the compounds synthesized by
using the current MCR methodology (see the Supporting
Information) and accordingly the newly developed stere-
ogenic center in all the compounds was assigned the S-
configuration (Scheme 3).
Experimental Section
A typical procedure for four component reactions follows:
Propargyl alcohol (0.307 mmol, 17 mg) and Cu(OTf)2 (10 mol %)
were added to a stirred solution of R-D-mannose pentaacetate
(100 mg, 0.256 mmol) in acetonitrile (5 mL). The reaction
mixture was allowed to stir for 2.5 h. D-Glucal (37 mg, 0.256 mmol)
and TMSN3 (0.384 mmol) were added successively followed by
the addition of 10 mol % of Cu powder. The reaction mixture
was stirred for the specified time (Table 2) at room temper-
ature. The completion of reaction was confirmed through TLC
(complete consumption of D-mannose pentaacetate). The reac-
tion mixture was passed through Celite, concentrated, and
subjected to column chromatography (hexane:ethyl acetate,
20:80) over silica gel (60-120 mesh size) to afford the product
3c (84%): 1H NMR (500 MHz, CDCl3) δ 7.7 (s, 1H, H-30), 7.4 (s,
1H, H-60), 6.39 (dd, J= 3.2, 2.0 Hz, 1H, H-400), 6.51-6.49 (m,
1H, H-500), 5.87(dd, J= 7.0, 4.7 Hz, 1H, H-100), 5.29(d, J=1.33Hz,
H-2), 5.28 (d, J= 2.2 Hz, 1H, H-4), 5.20 (m, 1H, H-3), 4.94 (dd,
J= 1.36, 4.21 Hz, 1H, H-1), 4.78 (dd, J= 4.5, 12.4 Hz, 1H, H-
2a), 4.65 (m, 1H, H-2a00), 4.45-4.39 (m, 1H, H-6b), 4.28-4.24
(m, 2H, H-6a, H-1a0), 4.08-4.05 (m, 2H, H-5, H-1b0), 2.13 (s,
3H, COCH3), 2.08 (s, 3H, COCH3), 2.04 (s, 3H, COCH3), 1.97
(s, 3H, COCH3); 13C NMR (50 MHz, CDCl3) δ 170.8, 170.7,
170.1, 169.5 (4 ꢀ -CO), 148.5 (C-300), 143.8 (C-20), 143.2 (C-600),
123.1 (C-30), 110.6 (C-500), 109.6 (C-400), 96.9 (C-1), 69.4 (C-3),
68.9 (C-2), 68.0 (C-5), 65.9 (C-4), 62.9 (C-6), 62.1 (C-10), 60.9
(C-200), 60.2 (C-100), 20.6, 20.5, 20.4, 20.3 (4 ꢀ COCH3); ESI MS
(m/z) 562 [M þ Na]þ. Anal. Calcd for C23H29N3O12: C, 51.21;
H, 5.42; N, 7.79. Found C, 51.06; H, 5.23; N, 7.56.
In the present multicomponent reaction, it needs to be
emphasized that use of both Cu(OTf)2 and Cu powder is
necessary as we failed to obtain the desired products in the
absence of either of the two.
On the basis of our earlier experimental studies,2 the one-
pot formation of hydroxy triazole can be explained by the
Cu(OTf)2-mediated in situ generation of racemic furfuryl
azide from D-glucal followed by the Cu(I) (generated in situ
by the redox reaction Cu2þ þ Cu0 f Cu1þ) catalyzed 1,3
dipolar alkyne-azide cycloaddition. In the case of four-
component reactions, Cu(OTf)2 is also catalyzing glycosylation,
(13) (a) Dondoni, A.; Massi, A.; Sabbatini, S. Tetrahedron Lett. 2002, 43,
5913. (b) Togo, H.; Ishigami, S.; Fujii, M.; Ikuma, T.; Yokoyama, M.
J. Chem. Soc., Perkin Trans. 1 1994, 1931. (c) Huber, R.; Vasella, A.
Tetrahedron 1990, 46, 33. (d) Kishida, M.; Eguchi, T.; Kakinuma, K.
Tetrahedron Lett. 1996, 37, 2061. (e) Ewing, D. F.; Len, C.; Mackenzie, G.;
Ronco, G.; Villa, P. Tetrahedron: Asymmetry 2000, 11, 4995.
(14) Assignment of the stereochemistry has been carried out as suggested
by one of the reviewers.
(15) Koulocheri, S. D.; Haroutounian, S. A. Synthesis 1999, 11, 1889.
Acknowledgment. This work is supported by CSIR, India.
Supporting Information Available: Compound characteri-
zation data, including copies of 1H and 13C 2D NMR spectra.
This material is available free of charge via the Internet at http://
pubs.acs.org.
3100 J. Org. Chem. Vol. 75, No. 9, 2010