InBr3-catalyzed stereoselective synthesis of trans-2,6-disubstituted 3,6-dihydro-2H-pyrans

Article abstract of DOI:10.1016/j.tetlet.2007.11.177

A new method for the stereoselective synthesis of trans-2,6-disubstituted 3,6-dihydro-2H-pyrans with a variety of substitution patterns is described, involving Lewis acid induced tandem allylation or cyanation of δ-hydroxy-α,β-unsaturated aldehydes to pro

Full text of DOI:10.1016/j.tetlet.2007.11.177

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 855–857
InBr3-catalyzed stereoselective synthesis of trans-2,6-disubstituted
3,6-dihydro-2H-pyrans
J. S. Yadav *, V. Sunitha, B. V. Subba Reddy, P. P. Das, E. Gyanchander
Division of Organic Chemistry-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 21 September 2007; revised 19 November 2007; accepted 28 November 2007
Available online 4 December 2007
Abstract
A new method for the stereoselective synthesis of trans-2,6-disubstituted 3,6-dihydro-2H-pyrans with a variety of substitution
patterns is described, involving Lewis acid induced tandem allylation or cyanation of d-hydroxy-a,b-unsaturated aldehydes to produce
dihydropyrans in good yields and with trans-selectivity. This method is very useful for the synthesis of trans-2,6-disubstituted dihydro-
pyran ring-containing natural products such as laulimalide, scytophycin C and many others.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Dihydropyrans; d-Hydroxy-a,b-unsaturated aldehydes; Allylation; Cyanation
The 2,6-disubstituted dihydropyran ring system is fre-
quently found in various natural products, examples
include swinholide,1,2 scytophycin C3,4 and laulimalide
(Fig. 1).5
H
O
HO
H
H
O
OH
O
O
2,6-Disubstituted dihydropyrans are also synthetically
useful intermediates in the preparation of polysubstituted
tetrahydropyran ring systems, such as those found in the
pseudomonic acids.6 As a result, several approaches7–13
have been reported for the preparation of dihydropyrans,
and some of the more varied methodologies include
electrophile-initiated alkylation of glycals,14 hetero-
Diels–Alder cycloadditions,15–18 olefin metathesis,19 Prins-
cyclizations of cyclopropyl carbinols,20 or homoallylic
alcohols,21 and an intramolecular silyl-modified Sakurai
reaction (ISMS).22,23 Many of these reactions have limita-
tions, such as the need for strictly anhydrous conditions,
stoichiometric quantities of a Lewis acid initiator, or deliv-
ery of a strong Lewis acid at a low temperature. Recently,
indium tribromide has received increasing attention as a
water-tolerant, green Lewis acid catalyst for organic syn-
thesis demonstrating highly chemo-, regio- and stereoselec-
H
O
Laulimalide
OMe
O
O
OMeOMe
N
H
O
OH
O
OMe
Me
OH
O
Scytophycin C
Fig. 1. Structures of laulimalide and scytophycin C.
tive results.24,25 Compared to conventional Lewis acids, it
has advantages of water stability, recyclability, operational
simplicity, strong tolerance to oxygen and nitrogen-con-
taining substrates and functional groups, and it can often
be used in catalytic amounts.26–28 In continuation of our
interest in the synthesis of scytophycin C,29 we disclose
*
Corresponding author. Tel.: +91 40 27193535; fax: +91 40 27160512.
E-mail address: yadavpub@iict.res.in (J. S. Yadav).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.177

856
J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 855–857
Table 1
herein a novel protocol for the construction of trans-2,6-
disubstituted dihydropyrans.
InBr3-catalyzed synthesis of trans-2,6-disubstituted 3,6-dihdro-2H-pyrans
Entry Substrate 1
Producta 3
Time Yieldb
Following our interest in the catalytic uses of indium tri-
bromide,30–36 we describe an efficient method for the prep-
aration of trans-2,6-disubstituted dihydropyrans through a
tandem allylation/cyanation of d-hydroxy-a,b-unsaturated
aldehydes. To the best of our knowledge, no synthesis
of C6-(allyl)- or C6-(cyano)-3, 6-dihydropyrans from d-
hydroxy-a,b-unsaturated aldehydes has been reported. In
a model reaction, d-hydroxy-enal 1 was treated with allyl-
trimethylsilane 2 using 5 mol % of indium(III) bromide as
(h)
(%)
OH
BnO
BnO
O
O
1.0
CHO
CHO
a
82
BnO
BnO
b
0.5
0.5
0.5
2.0
2.0
1.5
1.0
1.5
2.0
1.0
1.0
85
88
70
85
70
85
75
70
70
82
72
OH
OAc
O
O
AcO
c
d
e
f
AcO
AcO
CHO
AcO
OH
OAc
a
catalyst. Interestingly, product 6-allyl-2-[2-(benzyl-
CN
AcO
AcO
CHO
oxy)ethyl]-3,6-dihydro-2H-pyran 3a was isolated in 82%
yield with trans-selectivity (Scheme 1).
OH
OH
The structure of product 3a was established using
NMR, the proton assignment was achieved with a QCOSY
experiment. The presence of NOE’s between the C-2 pro-
ton and the C-7 protons suggests that the stereochemistry
at C-6 is R (a single enantiomer) and that the protons at
C-2 and C-6 are trans to each other (Fig. 2).
O
CHO
O
OH
CHO
O
OH
BnO
g
h
i
BnO
CHO
1
No cis-diastereoisomer was observed in the H NMR
spectrum of the crude products obtained from the C-allyl-
ation of d-hydroxy-enals. This result provided the incentive
for a further study of reactions with various d-hydroxy-
enals. Interestingly, a diverse range of hydroxy-enals
participated well in this reaction to afford the correspond-
ing trans-2,6-disubstituted dihydropyrans in good yields
(Table 1). Enantiomerically pure aldehydes gave optically
pure products (Table 1, entries a–d). Trimethylsilyl cyanide
also participated effectively in this reaction (Scheme 2).
However, ortho-hydroxy trans-cinnamaldehyde and all-
ylsilane did not give the desired product under similar reac-
tion conditions. Furthermore, a,b-unsaturated aldehydes
without a d-hydroxyl group failed to give the expected
products, although, homoallylic alcohols were obtained
in good yields. A possible reaction mechanism is illustrated
in Scheme 3. The reaction proceeds with activation of alde-
hyde by indium(III) bromide and subsequent formation of
an oxonium intermediate in which stereoelectronic and/or
steric factors dictate the direction of the incoming
nucleophile.
OH
PMBO
O
CHO
PMBO
OH
CHO
O
OH
O
j
CHO
OH
OH
BnO
BnO
O
O
k
l
CHO
BnO
CN
CHO
BnO
a
The products were characterized 1H NMR, IR and mass spectrometry.
Yield refers to pure products after chromatography.
b
OH
InBr3
O
CN
Ph
O
( )2
Ph
O
( )2
TMSCN
+
CHO
CH2Cl2, r.t.
Scheme 2. A tandem cyanation.
The scope and generality of this process is illustrated in
Table 1.
Various indium(III) reagents such as InBr3, InCl3,
In(OTf)3 and In(ClO4)3 were screened for this transforma-
tion. Of these catalysts, indium tribromide was found to be
Ph
O
OH
InBr3
Ph
O
O
Si
+
CHO
CH2Cl2, r.t.
1
2
3a
Scheme 1. A tandem allylation.
R
..
O
OH
H
OH
R
InBr3
R
+
O
-
In(III)
O
+ -
In(III)
O
H
H
H
H
H
H
10
9
R
Ph
O
O
R
..
O
7
H
O
2
6
8
11
12
+
R
O
Si
In(III)
+
H
3
O
5
+
4
H
Fig. 2. Characteristic NOE’s of product 3a.
Scheme 3. A plausible reaction mechanism.

J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 855–857
857
most effective in terms of conversion and selectivity. For
example, treatment of aldehyde 1a with allyltrimethylsilane
in the presence of 5 mol % of InBr3 and 5 mol % of InCl3
for 1 h afforded 3a in 82% and 70% yields, respectively.
In addition, this method is useful for the direct synthesis
of 2,3-dideoxy C-glycoside analogues (Table 1, entries c
and d). This method facilitates the introduction of an allyl
or cyano functionality on the pyran ring system in one-pot,
making it an efficient pathway for producing 6-allyl- or 6-
cyano-3,6-dihydro-2H-pyrans, which can be further modi-
fied to give biologically important natural products.
In summary, we have demonstrated an efficient protocol
for the synthesis of trans-2,6-disubstituted dihydropyrans
from d-hydroxy-a,b-unsaturated aldehydes and allyltri-
methylsilane in a highly regio- and stereoselective manner.
We believe that this new method will find applications in
the synthesis of biologically active natural products that
contain a dihydropyran ring system.
General procedure: A mixture of the d-hydroxy-a,b-
unsaturated aldehyde (1 mmol), allyltrimethylsilane or tri-
methylsilyl cyanide (1.2 mmol) and indium tribromide
(5 mol %) in dichloromethane (10 mL) was stirred at room
temperature. After complete conversion, as indicated by
TLC, the reaction mixture was diluted with water
(10 mL) and extracted with dichloromethane (2 Â 15 mL).
The combined organic layers were dried over anhydrous
Na2SO4 and purified by column chromatography on silica
gel (Merck, 100–200 mesh, ethyl acetate–hexane, 1:9) to
afford pure dihydropyran.
NMR (75 MHz, CDCl3) d 30.8, 32.2, 37.3, 39.1, 67.4,
72.4, 117.0, 124.4, 125.9, 128.5, 128.6, 129.4, 135.3, 142.5.
IR (KBr) Neat: mmax: 3446, 2925, 2855, 1637, 1457, 1216,
1082, 761 cmÀ1. ESI-HRMS [M+Na] found 251.1411,
C16H20ONa requires 251.1402.
Acknowledgement
V.S. thanks the CSIR, New Delhi, for the award of
fellowship.
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1
Compound 3e: H NMR (300 MHz, CDCl3): d 7.40–7.12
(m, 5H, Ar-H), 6.01–5.68 (m, 3H), 5.26–4.97 (m, 2H),
4.26 (m, 1H), 3.71 (tt, J = 4.0, 8.5 Hz, 1H), 2.88 (ddd,
J = 5.2, 9.5, 13.7 Hz, 1H), 2.67 (ddd, J = 7.0, 9.5,
13.7 Hz, 1H), 2.46 (m, 1H), 2.35–2.21 (m, 1H), 2.12–1.95
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