Sc(OTf)3-catalyzed sugar based tandem ene-Prins cyclization: A novel synthesis of hexahydro-2H-furo[3,2-b]pyranopyran scaffolds

Article abstract of DOI:10.1016/j.tetlet.2011.04.077

Ttandem ene-Prins cyclization between an aldehyde and an olefin tethered sugar aldehyde has been achieved using a catalytic amount of scandium triflate (10 mol %) at ambient temperature to give a novel series of sugar annulated pyranopyran derivatives in

Full text of DOI:10.1016/j.tetlet.2011.04.077

Tetrahedron Letters 52 (2011) 3342–3344
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Tetrahedron Letters
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Sc(OTf)3-catalyzed sugar based tandem ene-Prins cyclization: a novel
synthesis of hexahydro-2H-furo[3,2-b]pyranopyran scaffolds
⇑
B. V. Subba Reddy , A. V. Ganesh, A. Siva Krishna, G. G. K. S. Narayana Kumar, J. S. Yadav
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Ttandem ene-Prins cyclization between an aldehyde and an olefin tethered sugar aldehyde has been
achieved using a catalytic amount of scandium triflate (10 mol %) at ambient temperature to give a novel
series of sugar annulated pyranopyran derivatives in good yields with high selectivity. This is the first
report on sugar based ene-Prins cyclization between an aldehyde and O-prenyl derivative of a sugar
aldehyde.
Received 28 November 2010
Revised 17 April 2011
Accepted 19 April 2011
Available online 27 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
D-Glucose
ene-Prins cyclization
Sugar annulated heterocycles
Metal triflate
The development of new synthetic strategies to construct the
fused ring systems continues to be an attractive target in organic
synthesis.1 In this context, ‘tandem’ reactions, in which multiple
reactions are combined into single operation in a convergent
way, have been reported for the synthesis of a wide range of organ-
ic molecules.2 The advantages of tandem reactions are the forma-
tion of several bonds with high degree of selectivity, efficiency,
and atom-economy by a single catalyst in one-pot operation. The
Lewis acid-catalyzed intramolecular carbonyl-ene reaction is one
of the most attractive methods for ring closure, leading to the for-
mation of two contiguous stereocentres with high degree of stere-
oselectivity.3 The Prins cyclization is one of the elegant methods
for the construction of tetrahydropyran ring system.4 Generally,
Lewis acids and Brønsted acids are known to catalyze the Prins
cyclization to produce a wide range of tetrahydropyran scaffolds
under mild conditions.5–7 However, to the best of our knowledge,
there are no reports on tandem ene-Prins cyclization between an
aldehyde and O-prenyl tethered sugar aldehyde derived from
O
O
H
O
O
O
H
H
H
O
10 mol% Sc(OTf)3
CH2Cl2 , 0 °C-rt
O
O
H
+
O
O
O
1
3a
2
Scheme 1. ene-Prins cyclization of prenyl tethered sugar aldehyde
2 with
benzaldehyde.
..
O
Sc(OTf)3
H
O
OH
OHC
O
O
Carbonyl ene
R
H
O
O
O
O
H
-OH
O
R
R
D-glucose.
H
H
O
O
In continuation of our interest on Prins-cyclization,8 we herein
O
O
O
O
report a novel method for the synthesis of sugar fused pyranopyran
derivatives by means of Prins cyclization of aldehydes with homo-
allyl alcohol generated in situ from olefin tethered sugar aldehyde
via an intramolecular ene reaction. Initially, we have attempted the
coupling of benzaldehyde (1) with O-prenyl tethered sugar alde-
hyde (2) in the presence of 10 mol % of scandium triflate in dichlo-
romethane. The reaction proceeded smoothly at room temperature
O
H
O
H
O
O
R
H
H
O
H
H
H
O
O
O
O
H H
⇑
Corresponding author. Tel.: +91 40 27193535; fax: +91 40 27160512.
E-mail address: basireddy@iict.res.in (B.V.S. Reddy).
Scheme 2. A plausible reaction mechanism.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.077

B.V.S. Reddy et al. / Tetrahedron Letters 52 (2011) 3342–3344
3343
Table 1
Sc(OTf)3-catalyzed ene-Prins cyclization with glucose-aldehyde (1) and various aldehydes
Entry
Aldehyde(2)
Alkene (3)a
Time (h)
10.0
Yieldb (%)
O
O
O
H
H
H
H
O
O
H
a
88
86
O
O
O
H
O
O
H
O
b
10.5
O
H
Me
O
Me
Cl
O
H
H
O
O
O
c
d
e
f
10.5
11.0
10.0
12.0
13.0
14.0
10.5
83
82
84
78
76
70
90
H
O
H
H
Cl
O
H
O
O
O
H
H
O
O
O
O
O
O
H
H
Br
O
H
Br
O
H
MeO
O
MeO
O2N
N
O
H
H
O
O
O
H
O
H
O2N
O
O
H
H
O
O
O
g
h
i
H
O
H
H
O
O
O
N
H
H
O
O
O
O
H
H
O
O
O
O
O
H
O
H
O
H
H
O
H
H
O
O
O
j
10.0
11.0
10.0
12.0
90
88
86
80
O
H
O
O
O
O
H
H
H
O
O
O
k
l
H
H
H
H
O
O
O
O
O
H
H
O
O
O
H
H
O
O
H
m
a
All products were characterized by 1H NMR, IR, and mass spectroscopy.
Yield refers to pure products after chromatography.
b
O
O
Br
CHO
Br
O
O
OHC
H
H
H
O
10 mol% Sc(OTf)3
O
+
O
CH2Cl2 , 0 °C-rt
11 h, 87%
O
O
5
4
Scheme 3. ene-Prins cyclization of cyclohexylidene protected sugar with p-bromobenzaldehyde.

3344
B.V.S. Reddy et al. / Tetrahedron Letters 52 (2011) 3342–3344
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and the corresponding product 3a was obtained in 88% yield with
high selectivity (Scheme 1).
The stereochemistry of the product was confirmed by NOE
studies.9 This result provided the incentive for further study of
reactions with various aromatic aldehydes, such as 2-naphthalde-
hyde, p-tolualdehyde, p-chlorobenzaldehyde, p-bromobenzalde-
hyde, p-anisaldehde and p-nitrobenzaldehyde.
3. (a) Snider, B. B. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
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Funk, R. L. J. Am. Chem. Soc. 2004, 126, 12216; (d) Chan, K.-P.; Ling, Y. H.; Loh, T.-
P. Chem. Commun. 2007, 939; (e) Wender, P. A.; DeChristopher, B. A.; Schrier, A.
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Kumar, G. G. K. S. N. Tetrahedron Lett. 2007, 48, 7155; (d) Yadav, J. S.; Reddy, B.
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The aromatic aldehydes underwent smooth coupling with a
homoallyl alcohol generated in situ via an intramolecular ene
reaction of 2 to furnish a variety of aryl substituted furopyranopy-
ran derivatives (Table 1, entries b–g). Like aromatic aldehydes,
pyridin-2-carboxaldehyde also participated well in this reaction
(Table 1, entry h). Furthermore, aliphatic substrates, such as hydro-
cinnamaldehyde, hexanaldehyde, cyclohexanecarboxaldehyde and
isovelaraldehyde also gave the desired products in good yields (Ta-
ble 1, entries i–l). Notably, acid sensitive trans-cinnamaldehyde
also participated effectively in this cyclization (Table 1, entry m).
In the absence of a catalyst, no reaction was observed under similar
conditions. As solvent, dichloromethane was found to give the best
results. All the products were characterized and confirmed by
NMR, IR, and mass spectrometry. Probably, the reaction proceeds
via an intramolecular ene reaction of O-prenyl derivative of a sugar
aldehyde to generate a homoallyl alcohol. Thus in situ formed
homoallylic alcohol may undergo Prins cyclization with an alde-
hyde to afford the desired product (Scheme 2).
The scope and generality of this process is illustrated with re-
spect to various aldehydes and the results are presented in Table
1.10 Eventually, we attempted the coupling of p-bromobezalde-
hyde with cyclohexylidene protected O-prenyl tethered sugar alde-
hyde. The reaction was also successful with cyclohexylidene
protected sugar derivative to furnish the corresponding cyclized
product 5 in 87% yield under similar conditions (Scheme 3).
In summary, we have demonstrated a novel approach for the
synthesis of sugar annulated pyranopyran derivatives via a tandem
ene-Prins cyclization using a catalytic amount of Sc(OTf)3. In situ
generated homoallyl alcohol, by means of intramolecular ene cycli-
zation of O-prenyl derivative of a sugar aldehyde was successfully
coupled with various aldehydes to produce a novel class of sugar
fused pyranopyran derivatives.
10. General procedure: To
a solution of O-prenyl tethered sugar aldehyde
(5.0 mmol), in dichloromethane (10 mL) was added scandium triflate
(0.5 mmol) at rt. After completion of the ene reaction (1.5 h) as indicated by
TLC, aldehyde (5.0 mmol) in dichloromethane (6 mL) was added to the reaction
mixture at the same temperature. The reaction mixture was stirred at room
temperature for a specified amount of time (Table 1). After completion of the
reaction as indicated by TLC, the reaction mixture was extracted with
dichloromethane (2 ꢀ 10 mL). The combined organic layers were dried over
anhydrous Na2SO4. Removal of the solvent followed by purification on silica gel
(Merck, 60–120 mesh, ethyl acetate–hexane, 1.0–9.0) gave the pure products.
Acknowledgments
AVG thanks the CSIR, New Delhi for the award of a fellowship.
Supplementary data
3a: ½a 2D5
ꢁ
+47.6 (C 1.00, CHCl3); IR (KBr): mmax 3066, 2932, 2858, 1636, 1608,
1542, 1329, 1290, 1164, 1089, 964, 821, 738 cmꢂ1
.
1H NMR (500 MHz, CDCl3):
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.04.077.
d 7.39–7.19 (m, 5H), 5.82 (d, J = 3.8 Hz, 1H), 4.99 (s, 1H), 4.89 (s, 1H), 4.44–4.40
(m, 1H), 4.39 (dd, J = 2.9, 11.6 Hz, 1H), 4.15–4.09 (m, 1H), 4.08–4.05 (m, 1H),
4.01–3.96 (m, 1H), 3.84 (t, J = 11.6 Hz, 1H), 3.49–3.44 (m, 1H), 2.76–2.67 (m,
1H), 2.40–2.25 (m, 2H), 1.46 (s, 3H), 1.29 (s, 3H). 13C NMR (75 MHz, CDCl3): d
142.4, 141.6, 128.4, 127.8, 125.6, 112.8, 111.7, 104.7, 83.7, 80.5, 76.4, 75.9,
72.5, 64.6, 40.0, 39.8, 26.6, 26.1. LCMS: m/z: 367 (M+Na). HRMS Calcd for
References and notes
½ ꢁ +19.8 (C 1.00,
a 2D5
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Liao, J.-H. Tetrahedron Lett. 2009, 50, 704; (d) Schreiber, S. L. Science 2000, 287,
1964.
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Reactions; Wiley-Interscience: New York, 1992; (c) Hall, N. Science 1994, 266,
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Subburaj, K.; Montgomery, J. J. Am. Chem. Soc. 2003, 125, 11210; (j) Guo, H. C.;
C
20H24O5Na (M+Na): 367.1521. Found: 367.1526. 3l:
CHCl3); IR (KBr): mmax 2962, 2916, 2850, 1638, 1606, 1440, 1364, 1316, 1243,
1134, 1076, 1018, 960, 886 cmꢂ1 1H NMR (300 MHz, CDCl3):
5.81 (d,
.
d
J = 3.4 Hz, 1H), 4.88 (s, 1H), 4.80 (s, 1H), 4.44–4.34 (m, 1H), 4.06–3.91 (m, 2H),
3.80–3.73 (m, 1H), 3.71–3.61 (m, 1H), 3.43–3.29 (m, 2H), 2.64–2.52 (m, 1H),
2.13–1.97 (m, 1H), 1.88–1.72 (m, 1H), 1.62–1.52 (m, 1H), 1.49 (s, 3H), 1.29 (s,
3H), 1.34–1.14(m, 2H), 0.92 (d, J = 6.2 Hz), 0.89 (d, J = 6.2 Hz). 13C NMR
(75 MHz, CDCl3): d 143.0, 112.0, 111.5, 104.5, 83.7, 77.0, 76.2, 76.0, 71.9, 64.3,
45.1, 40.2, 38.0, 26.5, 25.9, 24.1, 23.0, 22.2. LCMS: m/z: 347 (M+Na). HRMS
Calcd for C18H28O5Na(M+Na):347.1834. Found:347.1836.