Tandem Prins/pinacol reaction for the synthesis of oxaspiro[4.5]decan-1-one scaffolds

Article abstract of DOI:10.1039/c4ob01188k

A novel Lewis acid catalyzed Prins/pinacol cascade process has been developed for the synthesis of 7-substituted-8-oxaspiro[4.5]decan-1-ones in good yields with excellent selectivity. This is the first example of the synthesis of oxaspirocycles from aldehydes and 1-(4-hydroxybut-1-en-2-yl)cyclobutanol through a cascade of Prins/pinacol rearrangement. This method is applicable to a wide range of aldehydes such as aromatic, aliphatic, heteroaromatic, and α,β-unsaturated aldehydes. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob01188k

Organic &
Biomolecular Chemistry
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Tandem Prins/pinacol reaction for the synthesis of
oxaspiro[4.5]decan-1-one scaffolds†
Cite this: Org. Biomol. Chem., 2014,
2, 7257
1
a
a,b
a
b
B. V. Subba Reddy,* S. Gopal Reddy, M. Ramana Reddy, Manika Pal Bhadra and
c
A. V. S. Sarma
A novel Lewis acid catalyzed Prins/pinacol cascade process has been developed for the synthesis of
7-substituted-8-oxaspiro[4.5]decan-1-ones in good yields with excellent selectivity. This is the first
example of the synthesis of oxaspirocycles from aldehydes and 1-(4-hydroxybut-1-en-2-yl)cyclobutanol
through a cascade of Prins/pinacol rearrangement. This method is applicable to a wide range of alde-
hydes such as aromatic, aliphatic, heteroaromatic, and α,β-unsaturated aldehydes.
Received 9th June 2014,
Accepted 28th July 2014
DOI: 10.1039/c4ob01188k
www.rsc.org/obc
Cascade reactions are important transformations as they
provide structural complexity and diversity in a single step
1
process. ‘Prins cyclization’ is a very useful reaction for the
stereoselective construction of oxygen containing hetero-
2
cycles. In particular, Prins cascade reaction is a versatile
strategy for the synthesis of fused or bridged tetrahydropyran
3
scaffolds and it has been successfully employed in the total
4
synthesis of natural products. Recently, we reported the syn-
thesis of fused five- and six-membered oxacycles in high yields
with excellent diastereoselectivity through a tandem Prins
5
cyclization. On the other hand, the oxaspirocycles are fre-
quently found in various natural products and biologically
6
active molecules (Fig. 1). These complex structures possess a
well-defined three-dimensional spatial arrangement, which
exhibits specificity of action with enzymes and biological Fig. 1 Biologically active oxaspirocyclics.
7
receptors. Recently, a multi-component Prins cyclization
8
has been reported for the synthesis of dioxaspirodecanes.
However, to date, there are only a few reports on the synthesis
9
of spirocycles through a Prins/pinacol reaction.
1
0
Following our interest in Prins spirocyclization we herein
report a novel cascade reaction for the stereoselective synthesis
of oxaspirocycles through a Prins/pinacol sequence. The
required starting material was easily prepared from commer-
Scheme 1 Preparation of the starting material (1d).
a
Natural Product Chemistry, Indian Institute of Chemical Technology, Uppal Road,
Tarnaka, Hyderabad, 500607, India. E-mail: basireddy@iict.res.in;
Fax: (+)91 40 27160512
cially available homopropargylic alcohol as depicted in
Scheme 1.
b
Centre for Chemical Biology, Indian Institute of Chemical Technology, Uppal Road,
At first, we attempted the Prins/pinacol reaction of 1d with
4-bromobenzaldehyde in the presence of a Lewis acid. To opti-
mize the reaction conditions, several acid catalysts were
screened and the results are presented in Table 1. Of the
various acids tested, both BF ·OEt and TMSOTf were found to
3 2
be equally effective for this conversion (entries a and b,
Tarnaka, Hyderabad, 500607, India
c
Centre for Nuclear Magnetic Resonance, Indian Institute of Chemical Technology,
Uppal Road, Tarnaka, Hyderabad, 500607, India
†
Electronic supplementary information (ESI) available: Detailed procedures and
spectroscopy data for novel compounds, NOESY spectra of product 3m and
1
13
copies of H NMR and C NMR spectra of novel compounds. See DOI: 10.1039/
c4ob01188k
This journal is © The Royal Society of Chemistry 2014
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Organic & Biomolecular Chemistry
a
Table 1 Screening the catalysts in the formation of 3a
Table 2 Synthesis
scaffolds
of
7-substituted-8-oxaspiro[4.5]decan-1-one
a
b
Entry
A
Aldehydes
Product (3)
Time (min)
25
Yield (%)
85
78
86
80
86
82
b
Entry
Catalyst
mol%
Time (min)
Yield (%)
B
C
D
E
F
20
30
25
30
20
a
b
c
d
e
f
g
h
i
BF
TMSOTf
SnCl
Yb(OTf)
InCl
3
·OEt
2
10
10
10
10
10
10
10
10
10
25
30
40
50
30
50
50
45
50
85
83
65
20
50
10
30
55
40
4
3
3
Benzoic acid
CSA
InBr
Sc(OTf)
3
3
a
Reaction was performed on the 0.5 mmol scale with respect to olefin.
The yield of the pure product after column chromatography.
b
Table 1). In addition, 10 mol% SnCl also afforded the desired
product 3a in moderate yield (entry c, Table 1). Other Lewis
, InCl , Sc(OTf) , Yb(OTf) ) and Brønsted acids
3 3 3 3
CSA, benzoic acid) were found to be inferior for this reaction.
Next, we examined the effect of solvents such as tetrahydro-
furan, dichloromethane, and toluene. Of these, dichloro-
methane appeared to give the best results. Under optimized
conditions, the reaction of 1d with 4-bromobenzaldehyde
4
acids (InBr
(
3 2
in the presence of 10 mol% of BF ·OEt afforded the corres-
ponding oxaspirocycle 3a in 85% yield as
a
single
diastereomer.
G
35
30
78
85
Inspired by the above result, we extended this method to
other aromatic aldehydes such as 4-cyanobenzaldehyde,
4
-chlorobenzaldehyde, 4-nitrobenzaldehyde, 2,4-dichloro-
benzaldehyde, 2,4,5-trifluorobenzaldehyde, 4-tolualdehyde,
benzaldehyde and 4-isopropylbenzaldehyde (entries a–h and l,
Table 2). In all cases, the corresponding 7-aryl-8-oxaspirocycles
were obtained in good to excellent yields (Table 2). This
method works not only with aromatic aldehydes but also with
aliphatic aldehydes such as 3-methylbutanal and pivalalde-
hyde (entries i and n, Table 2). In the case of aliphatic
aldehydes, the corresponding 7-alkyl-8-oxaspirocycles were
obtained in slightly lower yield than the aromatic counterpart.
Furthermore, a sterically hindered pivalaldehyde also
reacted well with 1-(4-hydroxybut-1-en-2-yl)cyclobutanol (1d) to
furnish the respective oxaspirocycle in good yield (entry n,
Table 2). The efficacy of this approach was also tested by per-
forming the reaction with heteroaromatic aldehydes like
H
I
J
30
25
78
88
K
L
35
30
80
82
4
-bromo-thiophene-3-carboxaldehyde (entry k, Table 2). This
method is effective even with acid sensitive cinnamaldehyde to
provide the respective oxaspirocycle in good yield (entry m,
Table 2). Next the reaction was performed with substituted
cyclobutanol to produce the 2,4,6-trisubstituted tetra-
hydropyran derivative. Accordingly, treatment of 1-(4-hydroxy-
6
-phenylhex-1-en-2-yl)cyclobutanol (2d) with 2,4,5-trifluoro-
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Table 2 (Contd.)
a
b
Entry
M
Aldehydes
Product (3)
Time (min)
30
Yield (%)
78
N
30
75
Scheme 3 A possible reaction pathway.
a
All the products were characterized by NMR, IR and mass
b
spectroscopy. The yield of the pure product after chromatography.
In summary, we have developed a novel cascade process for
the stereoselective synthesis of 7-substituted-8-oxaspiro[4.5]-
decan-1-one derivatives through a Prins/pinacol reaction. This
method offers several advantages such as high yields, excellent
selectivity and compatibility with various aldehydes, which
make it attractive for the synthesis of oxaspirocycles.
Experimental
General
Scheme 2 Synthesis of 7,9-disubstituted-8-oxaspiro[4.5]decan-1-one.
All reactions were carried out under a nitrogen atmosphere.
Commercial reagents were used as received, unless otherwise
1
stated. H NMR spectra were recorded on a 300 MHz or
1
3
5
00 MHz spectrometer using CDCl3 as a solvent. C NMR
spectra were recorded on 75 MHz and 125 MHz spectrometers
using CDCl . TMS was used as an internal reference for
3
1
H NMR analysis. All the compounds were purified by column
chromatography on silica gel (60–120 mesh) using the hexane–
ethyl acetate mixture as the eluent. Mass analysis was carried
out using an APCI mass spectrometer.
Fig. 2 Characteristic nOe cross-correlations of 3m.
benzaldehyde under similar conditions gave the 7-phenethyl-
Acknowledgements
-(2,4,5-trifluorophenyl)-8-oxaspiro[4.5]decan-1-one (4) in 78%
9
yield (Scheme 2).
M.R.R. thanks CSIR, New Delhi, India, for the award of a fel-
lowship. S.G.R. thanks CSIR, New Delhi for financial support
as a part of XII five year plan under the title SMiLE.
The relative stereochemistry of 3m was established by exten-
sive NMR experiments including nuclear Overhauser effect
spectroscopy (NOESY). The assignments were made with the
help of NOESY experiments (Fig. 2). The nOe correlations
between H4e/H10, H4a/H10, H2a/H10, H1a/H
confirm the structure as shown in Fig. 2.
6 7 6
, H1a/H and H5e/H
Notes and references
A plausible mechanism for a Prins/pinacol cascade is pro-
posed in Scheme 2. The reaction is assumed to proceed
through the formation of an oxocarbenium ion that is gener-
ated in situ from the homoallylic diol (1d) and aldehyde under
acidic conditions. Thus formed oxocarbenium ion is attacked
by an internal olefin resulting in the formation of a carbo-
cation, which is simultaneously terminated by a pinacol
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,2-shift to give the desired oxaspirocycle 3 as depicted in
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Finally, the reaction was performed on a 1 gram scale using
the present reaction conditions. To our delight, the results are
consistent with the small scale reaction (0.5 mmol).
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