InBr3-catalyzed stereoselective synthesis of 3,4-disubstituted hexahydro-1H-furo[3,4-c]pyran derivatives

Article abstract of DOI:10.1016/j.tetlet.2014.05.121

An γ,δ-unsaturated alcohol tethered with a hydroxyl group, that is, (E)-2-styrylbutane-1,4-diol (1) undergoes a smooth bicyclization with various aldehydes in the presence of 10 mol % InBr₃ and at 0 °C to afford a novel series of hexahydro-1H-furo[3,4-c]pyran derivatives in good yields with high diastereoselectivity.

Full text of DOI:10.1016/j.tetlet.2014.05.121

Accepted Manuscript
InBr3-catalyzed stereoselective synthesis of 3,4- disubstituted hexahydro-1H-
furo[3,4-c]pyran derivatives
B.V. Subba Reddy, M. Ramana Reddy, B. Sridhar, C. Suresh Reddy
PII:
S0040-4039(14)00954-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.05.121
TETL 44712
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
29 March 2014
28 May 2014
29 May 2014
Please cite this article as: Subba Reddy, B.V., Ramana Reddy, M., Sridhar, B., Suresh Reddy, C., InBr3-catalyzed
stereoselective synthesis of 3,4- disubstituted hexahydro-1H-furo[3,4-c]pyran derivatives, Tetrahedron Letters
(2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.05.121
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Graphical Abstract
InBr3-catalyzed stereoselective synthesis of
3,4-disubstituted hexahydro-1H-furo[3,4-
c]pyran derivatives
Leave this area blank for abstract info.
B. V. Subba Reddy*, M. Ramana Reddy, B. Sridhar and C.
Suresh Reddy

1
Tetrahedron Letters
jo u rn al h ome p ag e : w ww .e lse vie r .c om
InBr3-catalyzed stereoselective synthesis of 3,4- disubstituted hexahydro-1H-
furo[3,4-c]pyran derivatives
B. V. Subba Reddya∗, M. Ramana Reddya, B. Sridharb and C. Suresh Reddyc
aNatural Product Chemistry, bLaboratory of X-ray Crystallography, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India. cDepartment of
Chemistry, Sri Venkateswara University, Tirupathi, 517 502, India. E-mail: basireddy@iict.res.in, Fax: 91-40-27160512.
ARTICLE INFO
ABSTRACT
Article history:
Received
An ϒ,δ-unsaturated alcohol tethered with a hydroxyl group, i.e. (E)-2-
styrylbutane-1,4-diol (1) undergoes a smooth bicyclization with various aldehydes
in the presence of 10 mol% InBr3 and at 0 oC to afford a novel series of
hexahydro-1H-furo[3,4-c]pyran derivatives in good yields with high
diastereoselectivity.
Received in revised form
Accepted
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Prins bicyclisation
C-O, C-C bond formation
Aldehydes
2-Styrylbutane-1,4-diol
Heck coupilng
Prins cyclization is one of the useful methods for the
synthesis of a broad range of substituted tetrahydropyran
derivatives (THP).1,2 In particular, an intramolecular Prins
cyclization is a versatile strategy for the stereoselective
synthesis of fused heterocycles.3 Recently, we reported an
intramolecular version of Prins cyclization by trapping the
carbenium ion with tethered nucleophiles like hydroxyl, N-
tosylamide and aryl group to generate the corresponding
heterobicycles.4 To the best of our knowledge, there are no
reports on the synthesis of 3,4-disubstituted hexahydro-1H-
furo[3,4-c]pyrans from the easily accessible aldehydes and a
hydroxyl tethered ϒ,δ-unsaturated alcohol. Furthermore,
hexahydrofuropyran motif is a core structure of many natural
products such as triFA15 and rubioncolin B.6 Rubioncolin B
belongs to a class of naphthohydroquinone family isolated
from the roots of Rubia oncotricha and R. cordifolia7a and is
used in the Chinese traditional medicine (Figure 1).7b
OMe
H
HO
O
O
HO2C
HO
O
O
H
HOOC
O
O
H
H
HO2C
rubioncolin B
O
OH
H
OMe
OH
OMe
triFA1
Figure 1. Biologically active furopyranone derivatives
In continuation of our research on Prins type
cyclizations,8 we herein report a novel Prins bicyclization for
the stereoselective synthesis of trans-fused 3,4-disubstituted
hexahydro-1H-furo[3,4-c]pyran derivatives. The starting
material (1) was prepared from the allylic alcohol (1a)
through a Johnson–Claisen rearrangement. Reduction of the
ester (1b) with LAH, followed by silyl deprotection afforded
the desired alcohol (1) in good yield (Scheme 1).
———
∗B. V. Subba Reddy. Tel.: +91-40-27191642; fax: +91-40-27160512; e-mail: basireddy@iict.res.in

2
Tetrahedron
Yb(OTf)3) and Brønsted acids (TsOH, CSA, benzoic acid)
TBSO
were found to be ineffective (Table 1).
OH
CH3C(OEt)3
OTBS
Table 1. Screening of catalysts in the formation of 2aa
Cat. EtCO2H
80%
EtO
O
1a
1b
HO
1. LiAlH ,
4 THF,90%
2. TBAF,
THF, 85%
HO
1
Scheme 1. Preparation of the starting material (1)
In a model reaction, we treated (E)-2-styrylbutane-1,4-
diol (1) with 3,4,5-trimethoxybenzaldehyde in the presence of
10 mol InBr3 in dichloromethane. The reaction proceeded
smoothly at 0 °C affording the corresponding product 2a in
90% yield with a high trans-selectivity (95:5, Scheme 2, entry
b, Table 1). The ratio of trans/cis-isomers was determined by
1H NMR spectrum of a crude mixture. The diastereomers
could easily be separated by silica gel column
chromatography.
Next, we examined the effect of solvents such as toluene,
benzene,
dichloroethane,
chloroform,
acetonitrile,
H
H
O
O
HO
CHO
OMe
tetrahydrofuran and dichloromethane (Table 2, supporting
information). Among them, dichloromethane gave the best
results.
10 mol% InBr3
DCM , 0 o
H
H
O
O
+
C
MeO
OMe
MeO
MeO
2a (major)
MeO
MeO
3a (minor)
HO
1
OMe
OMe
Inspired by the above results, we extended this method to
other aromatic aldehydes such as 4-bromo-, 4-chloro-, 2-
chloro-, 4-fluoro-, 2,4-dichloro-, 3,4-dimethoxy-, 4-nitro-, 4-
cyano-, and 2,3,4,5,6-pentafluorobenzaldehydes. In all cases,
the corresponding trans-fused furo[3,4-c]pyran derivatives
were obtained in good to excellent yields with high selectivity
(Table 3). This method works not only with aromatic
aldehydes but also with aliphatic aldehydes. The efficacy of
this approach was also tested by performing the reaction with
heteroaromatic aldehyde like furan-2-carboxaldehyde (Table
3).
Scheme 2. Synthesis of furo[3,4-c]pyran derivatives 2a/3a
The structure and stereochemistry of 3-phenyl-4-(3,4,5-
trimethoxyphenyl)hexahydro-1H-furo[3,4-c]pyran 2a were
established by X-ray crystallography (Figure 2).9
Table 3. Synthesis of 3,4-substituted hexahydro-1H-furo[3,4-
c]pyran derivativesa,b
Figure 2. ORTEP diagram of product 2a
The efficiency of various other Lewis and Brønsted acids was
tested for this conversion, and the results are presented in
Table 1. Of various acids tested, 10 mol% of Sc(OTf)3 was
found to be equally effective to InBr3 for this conversion to
furnish the product 2a in 80% yield (entry c, Table 1).
Furthermore, 10 mol% of In(OTf)3 also afforded the product
2a in 75% yield (entry a, Table 1). Other Lewis acids (B(Ph)3,

3
H
3). The structure and stereochemistry of a minor isomer 3o
were established by X-ray crystallography (Figure 4).9
H
HO
O
O
O
10mol% InBr3
DCM , 0 oC
H
+
H
O
O
R
H
R
R
HO
(minor)
H
(major)
3
1
2
H
H
O
O
O
H
O
H
H
H
O
O
O
H
O
MeO
MeO
Br
Cl
OMe
(dr 95:5)
H
(dr 88:12)
H
(dr 90:10)
H
(dr 92:8)
2a 90%
2b 87%
2c 85%
2d 86%
H
O
O
O
O
H
H
H
O
O
O
H
O
MeO
MeO
Cl
Cl
F
Cl
2h 90% (dr 94:6)
(dr 92:8)
H
(dr 98:2)
H
2g 80% (dr 92:8)
2e 82%
2f 80%
O
H
O
H
O
O
H
H
H
O
O
H
Figure 4. ORTEP diagram of product 3o
O
7
O
O
3
The reaction is expected to proceed via the formation of an
oxocarbenium ion which is formed in situ from the aldehyde
and ϒ,δ-unsaturated alcohol, likely after activation with InBr3.
The E-oxocarbenium ion is trapped with an internal olefin
resulting in the formation of benzylic carbocation, which is
simultaneously trapped by a tethered hydroxyl group leading
to the formation of furopyrans as depicted in Scheme 3.10
O2N
75% (dr 94:6)
(dr 93:7)
H
(dr 97:3)
2l 78%
2j
2k 77%
(dr 96:4)
H
2i 82%
H
O
O
O
H
O
H
O
H
O
F
F
F
F
Cl
NC
2o, 78%, (dr 89:11)
F
Cl
(dr 96:4)
(dr 98:2)
2n 80%
2m 75%
aReaction was performed at 0.5 mmol scale with respect to olefin.bCombined yield of trans- and
cis-fused products after column chromatography.
HO
..
OH
Ph
Ph
OH
The structure and stereochemistry of
a
minor
R
HO
R
..
diastereomer, i.e. cis-fused hexahydro-1H-furo[3,4-c]pyran 3c
were confirmed by X-ray crystallography (Figure 3).9
+
O
O
Br3In
R
O
H
Ph
O
R
O
2
Scheme 3. A plausible reaction pathway
To demonstrate the synthetic utility, we applied this
method to generate allocolchicine analogues. Accordingly, the
product 2p was transformed into polycyclic compound 4 via
aryl-aryl bond formation11 using Pd(OAc)2 (10 mol%),
triphenylphosphine (10 mol%) and K2CO3 (2 equiv) in DMA
o
at 130 C. The desired product 4 was obtained in 75% yield
(Scheme 4). The 6-7-6 carbocyclic framework is a common
structural core of allocolchicine (A) and N-acetyl colchinol-O-
methyl ether (NCME) (B). The allocolchicines are seven-
membered biaryl derivatives of naturally occurring
colchicines, which are potent tubulin inhibitors.12
Figure 3. ORTEP diagram of product 3c
The above results provided a gateway to extend this process
to other substrates such as (E)-2-(4-chlorostyryl)butane-1,4-
diol (5). Accordingly, the coupling of (E)-2-(4-
chlorostyryl)butane-1,4-diol (5) with 4-chlorobenzaldehyde
under similar conditions afforded the corresponding product
as a mixture of 2o and 3o in 78% yield with 89:11 ratio Table

4
Tetrahedron
H. Choi, M. H. Chang, Org. Lett. 2002, 4, 2025; (e)
Z.-H. Chen, Y.-Q. Tu, S.-Y. Zhang, F.-M. Zhang,
Org. Lett. 2011, 13, 724.
H
O
HO
CHO
4. (a) Yadav, J. S.; Borkar, P.; Chakravarthy, P. P.;
Reddy, B. V. S.; Sarma, A. V. S.; Sridhar, B.; Grée,
R. J. Org. Chem. 2010, 75, 2081; (b) Reddy, B. V.
S.; Borkar, P.; Yadav, J. S.; Sridhar, B.; Grée, R. J.
Org. Chem. 2011, 76, 7677; (c) Reddy, B. V. S.;
Borkar, P.; Yadav, J. S.; Reddy, P. P.; Kunwar, A.
C.; Sridhar, B.; Grée, R. Org. Biomol. Chem. 2012,
10, 1349.
10mol% InBr3
Br
+
H
O
DCM , 0 0
C
Br
HO
2p
95% (dr 94:6)
1
H
O
H
MeO
MeO
NHAc
R
Pd(OAc)2
O
K2CO3, PPh3
DMA
OMe
R=CO2Me (
5. Liu, H. L.; Kong, L. Y.; Takaya, Y.; Niwa, M. Chem.
Pharm. Bull. 2005, 53, 816.
A
)
4
B
R=OMe (
)
6. Trauner, D.; Lumb, J. P.; Choong, K. C. J. Am.
Chem. Soc. 2008, 130, 9230.
Scheme 4. Synthesis of seven-membered biaryl derivative 4
7. (a) Itokawa, H.; Ibraheim, Z. Z.; Qiao, Y. F.; Takeya,
K. Chem. Pharm. Bull. 1993, 41, 1869 and
references cited therein; (b) Singh, R.; Geetanjali.;
Chauhan, S. M. S. Chem. Biodiversity 2004, 1, 1241.
8. (a) Reddy, B. V. S.; Jalal, S.; Borkar, P.; Yadav, J.
S.; Reddy, P. P.; Kunwar, A. C.; Sridhar, B. Org.
Biomol. Chem. 2012, 10, 6562; (b) Reddy, B. V. S.;
Venkateswarlu, A.; Borkar, P.; Yadav, J. S.;
Kanakaraju, M.; Kunwar, A. C.; Sridhar, B. J. Org.
Chem. 2013, 78, 6303; (c) Reddy, B. V. S.; Prasad,
D. P.; Sridhar, B.; Kumar, S. K. J. Org. Chem. 2013,
78, 8161.
In conclusion, a novel Prins bicyclization strategy has been
developed for the synthesis of hexahydro-1H-furo[3,4-c]pyran
derivatives. This is the first report on the synthesis of
furopyrans via tandem Prins cyclization.13 This approach
generates two heterocyclic rings with four new stereogenic
centers in a one pot operation.
Acknowledgments
M.R.R thanks CSIR, New Delhi and for the award of a
fellowship. B.V.S thanks CSIR, New Delhi for the financial
support as a part of XII five year plan program under title
ORIGIN (CSC-0108).
9. CCDC 958083, CCDC 958084, CCDC 958085 ,
CCDC
958086
contain
supplementary
Supplementary data
crystallographic data for compound 2n, 3c, 30 and
2a respectively. These data can be obtained free of
charge from the Cambridge Crystallographic Data
1
Experimental details, characterization data, copies of H and
13C NMR spectrum of products can be found, in the online
version, at http:// dx.doi.org/
Centre via www.ccdc.cam.ac.uk/data_request/cif.
10. Bunt, A. J.; Bailey, C. D.; Cons, B. D.; Edwards, S.
J.; Elsworth, J. D.; Pheko, T.; Willis, C. L. Angew.
Chem. Int. Ed. 2012, 51, 3901.
References and notes
1. Reviews on Prins cyclization see (a) Olier, C.;
Kaafarani, M.; Gastaldi, S. S.; Bertrand, M. P.
Tetrahedron 2010, 66, 413; (b) Adams, D. R.;
Bhatnagar, S. R. Synthesis 1977, 661; (c) Arundale,
E.; Mikeska, L. A. Chem. Rev. 1952, 51, 505; (d)
Pastor, I. M.; Yus, M. Curr. Org. Chem. 2007, 11,
925; (e) Crane, E. A.; Scheidt, K. A. Angew. Chem.,
Int. Ed. 2010, 49, 8316; (f) Overman, L. E.;
Pennington, L. D. J. Org. Chem. 2003, 68, 7143.
2. (a) Epstein, O. L.; Rovis, T. J. Am. Chem. Soc. 2006,
128, 16480; (b) Overman, L. E.; Velthuisen, E. J. J.
Org. Chem. 2006, 71, 1581; (c) Yadav, J. S.; Reddy,
B. V. S.; Maity, T.; Kumar, G. G. K. S. N.
Tetrahedron Lett. 2007, 48, 7155; (d) Rychnovsky,
S. D.; Thomas, C. R. Org. Lett. 2000, 2, 1217.
11. Campeau, L. C.; Fagnou, K. Chem. Commun. 2006,
1253.
12. (a) Bergemann, S.; Brecht, R.; Buttner, F.; Guenard,
D.; Gust, R.; Seitz, G.; Stubbs, M. T.; Thoret, S.
Bioorg. Med. Chem. 2003, 11, 1269; (b) Brecht, R.;
Seitz, G.; Guenard, D.; Thoret, S. Bioorg. Med.
Chem. 2000, 8, 557; (c) Roesner, M.; Capraro, H. G.;
Jacobson, A. E.; Atwell, L.; Brossi, A.; Iorio, M. A.;
Williams, T. H.; Sik, R. H.; Chignell, C. F. J. Med.
Chem. 1981, 24, 257.
13. General procedure: To a stirred solution of ϒ,δ-
unsaturated alcohol (1, 0.5 mmol) and aldehyde (0.6
o
mmol) in dry dichloromethane (5 mL) at 0 C was
added 10 mol% InBr3. The resulting mixture was
stirred at the same temperature under nitrogen
atmosphere. After completion of the reaction as
indicated by TLC, the mixture was quenched with
saturated NaHCO3 solution (1 mL) and extracted
with dichloromethane (2x5 mL). The combined
3. (a) Elsworth, J. D.; Willis, C. L. Chem. Commun.
2008, 1587; (b) Suginome, M.; Ohmori, Y.; Ito, Y.
Chem. Commun. 2001, 1090; (c) Yang, X.-F.; Wang,
M.; Zhang, Y.; Li, C.-J. Synlett 2005, 1912; (d) Y. S.
Cho, H. Y. Kim, J. H. Cha, A. N. Pae, H. Y. Koh, J.

5
organic layers were washed with brine (5 mL), dried
over anhydrous Na2SO4, and concentrated in vacuo.
The resulting crude product was purified by silica gel
column chromatography with ethyl acetate/hexane as
eluent to afford the pure product (2 and 3).