Grob-type fragmentation of 5-oxabicyclo[2.1.1]hexane system: A strategy for synthesis of annulated and 2,2,5-trisubstituted tetrahydrofurans

Article abstract of DOI:10.1016/j.tet.2013.07.005

Acid mediated, efficient Grob-type fragmentation reaction facilitated by vicinal ketal and ester moieties in variety of 5-oxabicyclo[2.1.1]hexanes leading to the corresponding annulated and 2,2,5-trisubstituted tetrahydrofurans is reported. Among the Br?nsted and Lewis acids tested, BF ₃·OEt₂ appears to give the best results, furnishing near quantitative yield (>99%) of tetrahydrofuran tricarboxylate derivatives under mild reaction condition. In case of unsymmetrical monosubstituted 5-oxabicyclo[2.1.1]hexanes two regioisomeric products are obtained. A strategy to transform one of the ester groups of the title compounds to protected hydroxymethyl moiety was evolved, which allows access to differentially protected 2-hydroxymethyl THF derivatives upon fragmentation. Employing TiCl₄/R or S-BINOL as chiral Lewis acid, an enantioselective fragmentation (up to 66% ee) was described for the meso bis-furan derivative.

Full text of DOI:10.1016/j.tet.2013.07.005

Tetrahedron 69 (2013) 8494e8504
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Grob-type fragmentation of 5-oxabicyclo[2.1.1]hexane system:
a strategy for synthesis of annulated and 2,2,5-trisubstituted
tetrahydrofurans
,
Surendra H. Mahadevegowda b, Faiz Ahmed Khan a
*
a Department of Chemistry, Indian Institute of Technology Hyderabad, Ordnance Factory Estate, Yeddumailaram 502205, India
b Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208016, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Acid mediated, efficient Grob-type fragmentation reaction facilitated by vicinal ketal and ester moieties in
variety of 5-oxabicyclo[2.1.1]hexanes leading to the corresponding annulated and 2,2,5-trisubstituted
tetrahydrofurans is reported. Among the Brønsted and Lewis acids tested, BF3$OEt2 appears to give the
best results, furnishing near quantitative yield (>99%) of tetrahydrofuran tricarboxylate derivatives under
mild reaction condition. In case of unsymmetrical monosubstituted 5-oxabicyclo[2.1.1]hexanes two re-
gioisomeric products are obtained. A strategy to transform one of the ester groups of the title compounds
to protected hydroxymethyl moiety was evolved, which allows access to differentially protected 2-
hydroxymethyl THF derivatives upon fragmentation. Employing TiCl4/R or S-BINOL as chiral Lewis acid,
an enantioselective fragmentation (up to 66% ee) was described for the meso bis-furan derivative.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 23 April 2013
Received in revised form 10 June 2013
Accepted 2 July 2013
Available online 6 July 2013
Keywords:
Grob-type fragmentation
5-Oxabicyclo[2.1.1]hexane
Tetrahydrofurans
Lewis acid
1. Introduction
dimethoxybicyclo[2.2.1]hept-5-en-2-one (R¼alkyl or aryl) 1 to
obtain trihalo phenols 2 is represented in Scheme 1.6a In continu-
Grob fragmentations are heterolytic sigma bond cleavage re-
actions involving a five-atom system. These fragmentation re-
actions have been widely explored since their study was started 60
years ago.1 The selectivity and high efficiency makes them more
attractive to synthetic chemists. This reaction was extensively uti-
lized to construct variety of organic frameworks,2a,b and served as
the key step in numerous multistep syntheses of complex natural
products.2c,d Among these heterolytic fragmentations, base or nu-
cleophile induced fragmentations in molecules containing groups
ation of this work we also reported recently, Grob-fragmentation of
symmetrically and asymmetrically substituted 1,4-dihalo-7,7-
dimethoxybicyclo[2.2.1]heptane-2,3-diones
3
(R1, R2¼H, alkyl,
aryl or ring substituents etc.) to form six membered a
-keto enol 4.6a
A variety of trihalo phenol derivatives and substituted aromatic
derived from 1,3-diol,2e,f
b
-hydroxy ketone2g are most common.
Although Barluenga et al.3a and others3b,c,4 reported, Lewis acid-
mediated or catalyzed Grob fragmentation reactions are not
much known in the literature due to their lack of selectivity in
polyfunctional molecules. However, the routine Grob fragmenta-
tions culminate with the formation of carbonecarbon multiple
bonds and such examples are abound.1 Recently, Charette and
Lemonnier reported a Tf2O-mediated Grob-fragmentation of aza-
bicyclo[2.2.2]octane leading to substituted piperidines via a re-
active dihydropyridinium intermediate.5
Our previous works on acid-mediated Grob fragmenta-
tionearomatization
reactions
of
1,4,5,6-tetrahalo-7,7-
* Corresponding author. Tel.: þ91 40 23016084; e-mail addresses: faiz@iith.ac.in,
Scheme 1. Our previous work on acid-mediated Grob-fragmentation.
fakhankanpur@gmail.com (F.A. Khan).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.07.005

S.H. Mahadevegowda, F.A. Khan / Tetrahedron 69 (2013) 8494e8504
8495
compounds were efficiently synthesized by successful utilization of
fragmentation protocol. In addition to this, our group has recently
reported the utility of afore-mentioned reaction (1 to 2) for the
synthesis of marine originated brominated alkaloids.6b
Development of new stereoselective strategy for synthesis of
heterocyclic molecules having many stereocenters is one of the
challenging, as well as attractive area of research. Among these,
2,2,5-trisubstituted tetrahydrofurans,7a,b hexahydroisobenzofur-
ans
(2-oxabicyclo[4.3.0]nonane),7c,d
2,5-di-
and
2,2,5-
trisubstituted 3,4-dihydroxy-tetrahydrofurans7eeg having impor-
tance, because of their presence as structural motifs in various
biologically active natural products. This saturated heterocycles
could be routinely made from cyclization of unsaturated8aee or
epoxy alcohols.8f,g Plumet et al.9a reported ring-opening cross-
metathesis of 2-substituted 7-oxabicyclo[2.2.1]-5-heptenes lead-
ing to 2,3,5-trisubstituted tetrahydrofurans. Recently, Martin and
Benjamin reported similar strategy leading to 2,2,5-tri and
2,2,5,5-tetrasubstituted tetrahydrofurans starting from [4þ2] cy-
cloaddition of substituted furan with chiral vinyl sulphoxide.9b
However, these methods are not elaborated to 3,4-substituted or
annulated tetrahydrofurans because of less or moderate diaster-
eoselectivity in cycloaddition step.9c In this paper we describes
the new stereoselective route to access highly substituted tetra-
hydrofurans from oxa-bridged compounds, which are readily
and easily preparable from commercial reagents via diaster-
eoselective DielseAlder reaction. Some naturally occurring
annulated and 2,2,5-trisubstituted tetrahydrofurans are shown in
Fig. 1.10
Scheme 2. Our stereoselective two step strategy for the synthesis of highly substituted
tetrahydrofurans from norbornyl a-diketones.
2. Result and discussion
During our study on oxa-bridged compounds,13 we subjected
compound 5a for deprotection of ketal with MeSO3H (2.5 equiv).
Instead of expected ketone 6c we found the fragmented bicyclic
tetrahydrofuran tricarboxylate 6a, albeit, in low (38%) yield.
This observation prompted us to study and explore the fragmen-
tation reaction due to potentially wide synthetic applications of
the substituted tetrahydrofuran building blocks thus formed
(Scheme 3).
(a) MeSO3H, 1,2-DCE, 0 °C, 4 h.
Scheme 3. Initial observation of Grob-type fragmentation reaction.
We have chosen the compound 5a as a reference starting ma-
terial for the optimization purpose and treated it with various
Brønsted and Lewis acids, the obtained results are summarized in
Table 1. Due to our interest in PTSA-mediated Grob fragmentation
reactions,6a we first carried out fragmentation of 5a with PTSA in
refluxing toluene. Under these conditions, the fragmented products
6a,b were obtained in 83% yield and the two isomers were found to
be in 71:29 ratio, respectively. When MeSO3H (4 equiv) and TFA
(6 equiv) were used, complete conversion of starting material was
not observed (Table 1, entries 2 and 3). Next, we turned our at-
tention to see the efficiency of fragmentation reaction with Lewis
acids. Compound 5a was treated with BF3$OEt2, TiCl4, In(OTf)3, and
Cu(OTf)2 and the results are shown in Table 1 (entries 4e10).
Among the Lewis acids tested, BF3$OEt2 appeared to be good in
terms of yield while TiCl4 with regard to selectivity.
This straightforward route to access substituted bicyclic tetra-
hydrofurans via an interesting Grob-type fragmentation reaction
inspired us to elaborate the fragmentation protocol for various oxa-
bridged derivatives. The result of BF3$OEt2-mediated Grob-type
fragmentation reactions for various symmetric tricyclic oxa-
bridged compounds is depicted in Table 2. The annulated and
2,2,5-tricarboxylate tetrahydrofurans 6a,b to 11a,b were obtained
nearly quantitative yield (>99%) through Grob-type fragmentation
Fig. 1. Some naturally occurring annulated and 2,2,5-trisubstituted tetrahydrofurans.
In continuation of our journey on exploring the chemistry of
norbornyl
a
-diketones11a for the synthesis of various organic
templates11bed and natural products,11e,f we previously reported
synthesis of novel constrained oxa-bridged molecules, such as 5.12
Herein, we wish to report an efficient Lewis acid-mediated Grob-
type fragmentation reaction involving ester as a nucleofuge group
and dimethoxy as an electrofuge group of constrained oxa-bridged
molecules to access annulated and 2,2,5-trisubstituted tetrahy-
drofuran building blocks. The oxa-bridged bicyclo[2.1.1]hexane
systems with a variety of substituents could be obtained expedi-
tiously as shown in Scheme 2.

8496
S.H. Mahadevegowda, F.A. Khan / Tetrahedron 69 (2013) 8494e8504
Table 1
experiments for compound 11a (see S59eS60 in Supplementary
data), which clearly suggest cis relative stereochemistry of C4 and
C5 protons as similar to previous cases (6a,be10a,b).
Screening of Grob-type fragmentation reaction of compound 5a with Brønsted and
Lewis acids
Due to the presence of two competing nucleofuge groups for
fragmentation reaction, we were interested to investigate
regioselectivity of this transformation. With this consideration,
we extended the fragmentation protocol to monosubstituted
oxa-bridged derivatives. BF3$OEt2-mediated Grob-type frag-
mentation reaction of these compounds is depicted in Scheme 4.
The ratios of regioisomers were determined by the integration of
1H NMR for H-5 proton of the tetrahydrofurans (13a,b and 15a,b).
For the sensitive ethoxy substituted compound 14, moderate
yield of 59% was obtained. These experiments demonstrate that
there is little or no regioselectivity in case of monosubstituted
derivatives.
Entry
Acid (equiv)
Reaction condition
Time (h)
Yield (%)a (6a/6b)b
1c
p-TsOH (2)
MeSO3H (4)
TFA (6)
BF3$OEt2 (4)
BF3$OEt2 (6)
TiCl4 (1.3)
Reflux
0e5 ꢀC
Reflux
3
4
8
8
8
3
3
8
6
2
83 (71:29)
82 (85:15)
47 (83:17)
94 (77:23)
>99 (75:25)
92 (94:06)
94 (94:06)
94 (67:33)
97 (71:29)
92 (74:26)
2d
3d
4d
5
0
0
0
0
ꢀC to rt
ꢀC to rt
ꢀC
6d,e
7d,e
8d
9
TiCl4 (1.4)
ꢀC
In(OTf)3 (1.5)
In(OTf)3 (2)
Cu(OTf)2 (1.5)
rt
rt
70 ꢀC
10
a
Isolated yields.
b
The ratios of epimers (6a and 6b) were determined by 1H NMR analysis of the
crude reaction mixtures.
c
Dry toluene is used as a solvent.
Complete consumption of starting material was not observed and the amount of
d
minor isomers were determined from 1H NMR.
e
Freshly prepared 0.05 M solution of TiCl4 in 1,2-DCE was used for fragmentation.
Table 2
BF3$OEt2-mediated fragmentation of various tricyclic oxa-bridged compounds
BF3.OEt2
(6.0 equiv)
MeO
OMe
CO2Me
MeO2C
CO2MeMeO2C
MeO2C
CO2Me
H
Scheme 4. BF3$OEt2-mediated fragmentation of bicyclic monosubstituted oxa-bridged
compounds.
O
5
O
2
MeO2C
MeO2C
3
4
O
H
H
H
H
H
1,2-DCE,
0
oC to rt
X
6a-11a
X
6b-11b
X
5a-f
7 to 8 h.
The presence of highly substituted oxygenated tetrahydrofuran
natural products,7e,10d and also to further demonstrate the practical
utility of our methodology, we elaborated the fragmentation re-
action to highly oxygenated 5-oxabicyclo[2.1.1]hexane systems 17,
20, and 22. The details for the synthesis of compounds 17, 20, and
X = (CH2)n, O, CHMe
n = 1-4
Entrya
Substrate [5aef]
Products
Yieldb (%)
6ae11a/6be11b
[ratio of epimers]c
22 from symmetric norbornyl
Scheme 5. One pot transformation of
oxa-bridged compound 17 was accomplished by oxidative cleavage
of -diketone with alkaline 30% H2O2, followed by refluxing with
a-diketone 16 are depicted in
1
2
3
4
5
6
5a, X¼e(CH2)2e
5b, X¼e(CH2)e
5c, X¼e(CH2)3e
5d, X¼e(CH2)4e
5e, X¼eOe
6a,b
7a,b
8a,b
9a,b
10a,b
11a,b
>99
>99
>99
>99
>99
>99
75:25
95:05
88:12
84:16
86:14
84:16
a
-diketone 16 to symmetric
a
30 equiv of NaOH and esterification of resultant dicarboxylic acids
with CH2N2 in Et2O/MeOH at 0 ꢀC afforded compound 17 in 93%
yield. At this stage, we were interested to synthesize oxa-bridged
monoester derivative of compound 17, by focusing our attention
to our previously reported synthesis of oxa-bridged compounds via
bridge-head lactone in two step protocol. The synthesis involves
5f, X¼eCHMee
a
All fragmentation reactions (entries 1e6) were performed by treating oxa-
bridged compounds [5aef] with 6.0 equiv of BF3$OEt2 at 0 ꢀC to rt in dry 1,2-DCE
solvent under argon atmosphere.
b
Isolated yields.
The ratios of epimers were determined by 1H NMR of crude reaction mixture.
c
conversion of a-diketone 16 to bridged-lactone 18 in 98% yield. The
chemoselective reduction of bridge-head ester with NaBH4 in di-
oxane at reflux condition afforded alcohol 19a in 97% yield and
subsequent protection of alcohol as benzyl ether gave 19b in 78%
yield. Then bridged-lactone 19b was successfully converted into
oxa-bridged monoester 20 by refluxing with 30 equiv of NaOH in
MeOH, followed by CH2N2 treatment of resultant mono carboxylic
acid in Et2O/MeOH at 0 ꢀC in 95% yield. The meso diester 17 was
subjected to partial reduction14 with NaBH4 in THF/EtOH (1:1) us-
ing LiCl to afford a monoalcohol 21 in 86% yield. Subsequently, the
resultant monoalcohol 21 was protected with TBDPS group with
95% yield gave oxa-bridged monoester derivative 22 in two steps
from compound 17.
Having di and monoester derivatives (17, 20, and 22) of 5-
oxabicyclo[2.1.1]hexane system in hand, we focused our attention
to see the efficiency of these substrates to form tetrahydrofurans
via fragmentation reaction. The presence of sensitive cyclo-
hexylidene protection on constrained bicyclic core would be
of the corresponding symmetric oxa-bridged derivatives 5aef. The
1H and 13C NMR spectra of the products (6a,b to 11a,b), obtained
simply after a short filtration through a SiO2 column, showed
that the samples are fairly clean and do not require extensive
chromatographic purification. A detailed analysis of 1H NMR of
the bicyclic tetrahydrofurans (6a,be10a,b), revealed shielding
(0.03e0.27 ppm) of C5 proton of the minor isomer. This observation
is consistent with the assigned structure wherein C5 proton is syn
to C3 and C4 ring substituents. To rule out any ambiguity, NOE (for
6a and 6b, for details, see S56eS59 in Supplementary data) and
single crystal X-ray analysis (for 6a) experiments were carried out
to confirm the relative stereochemistry of C5 proton. In addition to
this, in case of compounds 11a,b, contrary to other cases, C5 proton
of the major isomer is observed at slightly high field (0.04 ppm),
because due to presence of cis methyl substituent at annulated
cyclopentane ring. Further evidence was obtained by NOE

S.H. Mahadevegowda, F.A. Khan / Tetrahedron 69 (2013) 8494e8504
8497
Scheme 5. Synthesis of highly oxygenated 5-oxabicyclo[2.1.1]hexane systems 17, 20, and 22 from norbornyl a-diketone 16.
additional factor of curiosity for these substrates selectively un-
dergo fragmentation reaction. The details of fragmentations of
compounds 17, 20, and 22 are summarized in Table 3. Treatment of
compound 17 with 3.0 equiv of BF3$OEt2 for 9 h forms tetrahy-
drofurans 23a,b with 97% yield (ratio of epimers 88:12). On the
other hand, In(OTf)3 gave moderate yield for the fragmentation of
compounds 17 and 20, despite of products (epimers) selectivity in
case of monoesters (compounds 20 and 22). The chemoselectivity
in the presence of an acid sensitive cyclohexylidene group is the
consequence of non-nucleophilic reaction conditions and efficiency
of the system to undergo fragmentation.
Debenzylation of compound 24a with H2, 10% PdeC afford an
alcohol 24c in 99% yield. Access to 24c having oxaquaternary ster-
eocenter, which is attractive from the view point of being a poten-
tial precursor in natural product synthesis, could not have been
possible via a direct chemoselective reduction of one of the three
ester groups of 23. When 3.0 equiv of TMSOTf was employed,
compound 17 underwent chemoselective fragmentation to furnish
two epimers 23a,b (ratio 97:03) in 72% yield. The reaction was
found to be relatively faster compared to BF3$OEt2 and In(OTf)3-
mediated fragmentations.
Table 3
Chemoselective Grob-type fragmentation of compounds 17, 20, and 22
Due to the reverse in Rf values of major isomer (23a) in com-
parison with major isomer (6a) in TLC we anticipated, the relative
stereochemistry of C4 and C5 proton might be reverse in former
case (23a). By keeping this in mind, single crystal X-ray analysis was
carried out for the compound 23a, the X-ray pictures of compounds
6a and 23a are shown in Fig. 2.16 The structure shows that C4 and
C5 protons having trans relationship in case of compound 23a. The
inversion of stereochemistry at C5 stereocenter for the compound
23a might be due to overlaying chair conformation of cyclo-
hexylidene protection on tetrahydrofuran ring affect the enolate
intermediate to form 4,5-trans substituted tetrahydrofuran 23a
(major isomer).
We thought of exploring the possibility of enantioselective
Grob-type fragmentation of symmetric oxa-bridged compounds by
using cheap chiral auxiliaries (R or S-BINOL). Literature survey15
reveals that, 1:1 of BINOL and Ti-Lewis acid have more acidity to
bind with substrate. Our initial effort for enantioselective frag-
mentation of 5a with TiCl4/R-BINOL (1:1) resulted in 12.9% ee. Next,
our attention was turned on tricyclic bis-furan substrate for the
study of asymmetric Grob-type fragmentation reaction. The results
of enantioselective fragmentation of meso substrate 5e with TiCl4/R
or S-BINOL in various reaction conditions are depicted in Table 4.
After treating the compound 5e with in situ generated chiral Lewis
acid, 3.0 equiv of TiCl4 were generally used as a promoter for
Lewis acida (equiv) Substrate Condition Time (h) Yield %b (ratio of epimers)c
BF3$OEt2 (3.0)
BF3$OEt2 (3.0)
In(OTf)3 (2.0)
In(OTf)3 (2.0)
BF3$OEt2 (3.0)
TMSOTf (3.0)
17
20
17
20
22
17
0
0
rt
rt
0
ꢀC to rt
ꢀC to rt
9
4
7
4
5
2
97 (23a/23b¼88:12)
86 (24a/24b¼57:43)
66 (23a/23b¼82:18)
71 (24a/24b¼55:45)
94 (25a/25b¼46:54)
72 (23a/23b¼97:03)
ꢀC to rt
ꢀC
0
a
All the reactions were carried out in dry 1,2-DCE solvent under argon
atmosphere.
b
c
Isolated yields.
The ratios of epimers were determined by analyzing 1H NMR of the crude re-
action mixture.

8498
S.H. Mahadevegowda, F.A. Khan / Tetrahedron 69 (2013) 8494e8504
Fig. 2. X-ray crystal structures of compound 6a and 23a depicting cis relationship of C4eC5 protons in case of 6a and trans relationship of C4eC5 protons in case of 23a. Dis-
placement ellipsoids are shown at the 30% probability level.
Table 4
Enantioselective Grob-type fragmentation reaction of bis-furan (5e) with TiCl4/R or S-BINOL
Entrya
TiCl4/ligand [ratios]
Condition
ꢀC to rt
Timeb
Promoter (equiv)
Timec (h)
Yieldd (%)
10a/10be
eef for 10a
1
2
3
4
TiCl4/R-BINOL (1:1)
TiCl4/R-BINOL (1.5:1)
TiCl4/R-BINOL (1:1)
TiCl4/R-BINOL (1:1)
TiCl4/R-BINOL (1:1)
TiCl4/R-BINOL (1:1)
TiCl4/R-BINOL (1:1)
TiCl4/S-BINOL (1:1)
TiCl4/S-BINOL (1:1)
0
1 h
0.5 h
1 h
0.5 h
0.5 h
0.5 h
15 min
0.5 h
0.5 h
TiCl4 (3.0)
TiCl4 (3.0)
TiCl4 (2.0)
TiCl4 (3.0)
TiCl4 (3.0)
TiCl4 (3.0)
TiCl4 (3.0)
TiCl4 (3.0)
TiCl4 (3.0)
2
3
2.5
2
3
2
2
2
4
97
96
95
97
71
67
95
97
70
87:13
88:12
90:10
90:10
88:12
89:11
89:11
88:12
91:09
20
37
45
55
57
66
64
34
66
ꢁ5 ꢀC
ꢁ5 ꢀC
ꢁ5 ꢀC
ꢁ20 ꢀC
ꢁ20 ꢀC
ꢁ5 ꢀC
5g,h
6g,h,i
7j
8
0
ꢀC
9g,h
ꢁ20 ꢀC
a
Unless otherwise specified, all reactions were carried out using 2 equiv of freshly prepared 0.1 M TiCl4 in dry 1,2-DCE and 2 equiv R or S-BINOL in 1,2-DCE solvent.
Time of reaction carried with TiCl4 and R or S-BINOL chiral Lewis acid.
b
c
d
e
f
Time of reaction carried after addition of 3.0 equiv of TiCl4 (promoter).
Isolated yields.
Ratios of 10a and 10b were determined from analysis of 1H NMR of crude reaction mixtures.
ee was determined by preparative HPLC equipped with JAIGEL-OA4100 column at detector wave length 230 nm.
Yield was determined from 1H NMR due to incomplete conversion of starting material.
0.1 M TiCl4 in CH2Cl2 and CH2Cl2 used as a solvent.
g
h
i
3.0 equiv of 0.1 M TiCl4 in CH2Cl2 and R-BINOL is used.
3.0 equiv of 0.1 M TiCl4 in 1,2-DCE and R-BINOL is used.
j
fragmentation reaction. When compound 5e was treated with 1:1
A plausible mechanism is depicted in Scheme 6. The Grob-
type fragmentation can take place by cleavage of either bond
a or b of compound 5a. The fragmentation reaction is initiated
from activation of carbonyl functionality of ester (5a) by
Lewis acid and rapture of CaeCb bond to generate ester enolate
oxonium intermediate (26). In the case of p-TsOH, protonation
of carbonyl of one of the ester groups followed by cleavage
of CaeCb leads to enol 27. Tautomerization of enol 27 to ester
28 and subsequent departure of methyl cation as 4-
TiCl4/R or S-BINOL as chiral Lewis acid at ꢁ20 ꢀC in CH2Cl2 gave up
to 66% ee. The reason for higher ee (up to 66% ee) in the case of
compound 5e compared to 5a might be due to the presence of
a hetero atom in the attached ring, which provides additional
binding site for the chiral Lewis acid. Though moderate, but to the
best of our knowledge this is the first enantioselective Grob-type
fragmentation reaction reported so far and further exploration of
this reaction is under way in our group.

S.H. Mahadevegowda, F.A. Khan / Tetrahedron 69 (2013) 8494e8504
8499
methylbenzenesulfonate (29) gives tetrahydrofuran tricarbox-
ylate 6a. The byproduct 4-methylbenzenesulfonate (29),
which supports the mechanistic proposal, was isolated and
characterized.
carried to determine the relative stereochemistry of the THF com-
pounds. The IR spectra were recorded as KBr pellets (solids) or as
thin films (liquids). The mass spectrometry analysis was done
ESI, EI or APCI mode. The CHN analysis was carried using CE-440
Scheme 6. Mechanism of BF3$OEt2 and PTSA-mediated Grob-type fragmentation reaction of compound 5a.
3. Conclusion
Elemental Analyzer of Exeter analytical Inc (at IITK). Melting
points are uncorrected. The crystal structures of compounds 6a and
23a were solved using SIR-92 and refined using SHELXL-97.17
In conclusion, a straightforward stereoselective strategy for the
synthesis of annulated and 2,2,5-trisubstituted tetrahydrofurans
via an efficient Grob-type fragmentation of abundantly available 5-
oxabicyclo[2.1.1]hexane derivatives is developed. A useful meth-
odology for the conversion of one of the ester groups of the title
compounds to protected hydroxymethyl moiety was evolved,
which allows access to differently protected 2-hydroxymethyl THF
derivatives. In case of bis-furan derivative, an enantioselectivity
(upto 66% ee) during Grob-type fragmentation is observed using
chiral auxiliaries (R or S-BINOL) by in situ generated chiral Lewis
acid with TiCl4.
4.2. General procedure 1 for BF3$OEt2-mediated Grob-type
fragmentation reaction of oxa-bridged compounds
To a stirred solution of oxa-bridged compounds (1 mmol) in dry
1,2-DCE (5 mL) was added BF3$OEt2 (6.0 mmol) at 0 ꢀC, then the
reaction mixture was slowly brought to rt. After completion of re-
action (monitored by TLC), the reaction mixture was quenched with
aqueous saturated NaHCO3 solution (3 mL) at 0 ꢀC and 1,2-DCE was
evaporated under reduced pressure. To the obtained residue was
added H2O (3 mL), aqueous part was extracted with EtOAc
(3ꢂ20 mL), the combined organic layers were washed once with
brine solution (6 mL), organic layer was separated, dried over
Na2SO4, and concentrated under reduced pressure. The silica gel
column chromatography purification of the crude reaction mixture
(EtOAc/Hexane solvent system as eluent) afforded the analytically
pure tetrahydrofuran derivatives.
4. Experimental section
4.1. General methods
1H and proton decoupled 13C NMR spectra were recorded in 400
and 100 MHz, respectively, unless at field strength of 500 (1H NMR)
and 125 MHz (13C NMR). The samples for NMR were made by
dissolving in CDCl3 and TMS is used as an internal standard, the
4.3. Experimental procedure for TiCl4 promoted Grob-type
fragmentation reaction of oxa-bridged compound 5a
d
value for the peaks in 1H NMR were reported in terms of parts per
million with reference to TMS (0 ppm) peak and the coupling
constants were reported in hertz. The multiplicity are reported as
follows br¼broad, s¼singlet, d¼doublet, t¼triplet, q¼quartet,
m¼multiplet. The chemical shift in 13C NMR is assigned by fixing
middle peak of CDCl3 at 77.00 ppm. The NOE experiments were
To a solution of oxa-bridged compound 5a (62 mg, 0.197 mmol)
in dry 1,2-DCE (6 mL) was added drop wise freshly prepared 0.05 M
TiCl4 (5.52 mL, 0.276 mmol, 1.4 equiv) in 1,2-DCE at 0 ꢀC. After 3 h,
the reaction mixture was quenched by addition of H2O (2 mL) and

8500
S.H. Mahadevegowda, F.A. Khan / Tetrahedron 69 (2013) 8494e8504
then 1,2-DCE was evaporated on rotary evaporator, the aqueous
part was extracted with EtOAc (2ꢂ20 mL), the combined organic
layers were washed once with brine solution (6 mL), then organic
layer was separated, dried over anhydrous Na2SO4, and concen-
trated under reduced pressure. Then the residue was purified by
silica gel column chromatography (20e30% EtOAc in Hexane elu-
ent, v/v) afforded 6a,b, yield 94%, ratio of epimers 94:06.
1032 cmꢁ1. HRMS (ESI): m/z calcd for C14H20O7Na [MþNa]þ
323.1101; found 323.1101.
4.5.3. (ꢃ)-(3R,3aS,6aR)-Trimethyl
ran-1,1,3(3H,3aH)-tricarboxylate (7a). The general procedure
mentioned above was followed when compound 5b (52 mg,
0.173 mmol) was treated with BF3$OEt2 (129 L, 1.04 mmol) for 7 h
tetrahydro-1H-cyclopenta[c]fu-
1
m
to afford 7a,b, yield >99% (49.3 mg, 0.172 mmol), colorless liquid,
ratio of epimers 95:05, Rf¼0.5 (30% EtOAc in Hexane, silica gel TLC);
4.4. Experimental procedure for enantioselective Grob-type
fragmentation of compound 5e with TiCl4/R-BINOL
major isomer (7a), 1H NMR (400 MHz, CDCl3);
d 4.42 (d, 1H,
J¼7.8 Hz), 3.75 (s, 3H), 3.71 (s, 3H), 3.70 (s, 3H), 3.38 (q, 1H,
J¼8.5 Hz), 2.99e3.07 (m, 1H), 1.61e1.84 (m, 3H), 1.18e1.39 (m, 3H);
To a stirred solution of 0.1 M TiCl4 (1.72 mL, 32.6 mg, 0.172
mmol) in 1,2-DCE (1 mL) was added R-BINOL (49.2 mg, 0.172 mmol)
at ꢁ5 ꢀC, after 5 min, compound 5e (26 mg, 0.086 mmol) in 1,2-DCE
(1.5 mL) was added to reaction mixture via cannula. After additional
stirring of reaction mixture for 30 min at same temperature, was
added TiCl4 (49 mg, 0.258 mmol) drop wise. After 2 h, the reaction
mixture was quenched with H2O (2 mL) and concentrated to
remove 1,2-DCE, aqueous layer was extracted with EtOAc
(2ꢂ20 mL), washed with brine (4 mL), dried over Na2SO4, and
concentrated. Chromatography of the crude residue on silica gel
13C NMR (100 MHz, CDCl3)
d 169.4, 168.7, 167.1, 89.8, 80.1, 53.1, 52.6,
51.9, 49.0, 46.0, 30.1, 29.6, 27.1; IR nmax (neat) 1957, 2873, 1741, 1438,
1286, 1237, 1114 cmꢁ1. Anal. Calcd for C13H18O7: C, 54.54; H, 6.34.
Found: C, 54.47; H, 6.22.
4.5.4. (ꢃ)-(3R,3aS,8aR)-Trimethyl
ran-1,1,3(3H,3aH)-tricarboxylate (8a). The general procedure
mentioned above was followed when compound 5c (80 mg,
0.243 mmol) was treated with BF3$OEt2 (181 L, 1.46 mmol) for
hexahydro-1H-cyclohepta[c]fu-
1
m
7 h to afford 8a,b, yield >99% (75.9 mg, 0.241 mmol), colorless
liquid, ratio of epimers 88:12, Rf¼0.6 (30% EtOAc in Hexane, silica
[30e60% EtOAc in Hexane, v/v] afforded 10a,b. Yield 97% (24.0 mg,
25
0.083 mmol), 10a/10b¼90:10, [
a
]
þ17.7 (c 0.27, CHCl3), for 10a
D
gel TLC); major isomer (8a), 1H NMR (400 MHz, CDCl3);
d 4.58 (d,
55% ee.
1H, J¼7.8 Hz), 3.81 (s, 3H), 3.77e3.78 (br s 6H), 3.20e3.27 (m,
1H), 2.78e2.83(m, 1H), 1.76e1.86 (m, 4H), 1.54e1.57 (m, 1H),
4.5. Trapping of methyl cation during PTSA-mediated frag-
mentation reaction of compound 5a
1.18e1.46 (m, 5H); 13C NMR (100 MHz, CDCl3)
d 169.9, 169.6,
168.0, 90.8, 82.0, 53.0, 52.6, 51.8, 49.0, 46.5, 31.0, 28.7, 28.0, 27.2,
26.1; IR nmax (neat): 2929, 2856, 1742, 1438, 1276, 1231,
1120 cmꢁ1; Anal. Calcd for C15H22O7: C, 57.32; H, 7.05. Found: C,
57.19; H, 6.90.
p-TsOH$H2O (68 mg, 0.356 mmol) in anhydrous toluene (2 mL)
was refluxed for 10 min, then solution of compound 5a (56 mg,
0.178 mmol) in toluene (2 mL) was added drop wise to reaction
mixture at reflux condition. After 2 h, the reaction mixture was
cooled to 0 ꢀC, quenched with aqueous saturated NaHCO3 solution
(2 mL) and solvent was evaporated under reduced pressure. To the
obtained residue was added H2O (2 mL) and the aqueous layer was
extracted with EtOAc (3ꢂ15 mL), the combined organic layers were
washed once with brine solution (3 mL), finally dried over Na2SO4,
and concentrated. The SiO2 column chromatography for the ob-
tained crude afforded the analytically pure tetrahydrofuran de-
rivatives 6a,b, yield 79% (42.2 mg, 0.140 mmol) and methyl 4-
methylbenzenesulfonate (29), yield 80% (21 mg, 0.112 mmol,
based on 6a,b).
4.5.5. (ꢃ)-(3R,3aS,9aR)-Trimethyl
octahydrocycloocta[c]furan-
1,1,3(3H)-tricarboxylate (9a). The general procedure 1 mentioned
above was followed when compound 5d (80 mg, 0.233 mmol) was
treated with BF3$OEt2 (173 mL, 1.40 mmol) for 7 h to afford 9a,b,
yield >99% (76.0 mg, 0.231 mmol), colorless liquid, ratio of epi-
mers 84:16, Rf¼0.5 (30% EtOAc in Hexane, silica gel TLC); major
isomer (9a), 1H NMR (400 MHz, CDCl3);
d
4.57 (d, 1H, J¼7.3 Hz),
3.74 (s, 3H), 3.71 (s, 6H), 2.93e2.96 (br t, 1H), 2.60e2.65 (br q, 1H),
1.56e1.63 (m, 4H), 1.18e1.52 (m, 8H); 13C NMR (100 MHz, CDCl3)
d
170.2, 169.2, 168.3, 89.1, 80.1, 53.1, 52.7, 51.9, 48.4, 45.0, 28.9,
28.5, 25.4, 25.2, 23.6, 23.6; IR nmax (neat) 2928, 2854, 1743, 1439,
1278, 1105, 1035 cmꢁ1. HRMS (ESI): m/z calcd for C16H25O7
[MþH]þ 329.1600; found 329.1602.
4.5.1. (ꢃ)-(3R,3aS,7aR)-Trimethyl hexahydroisobenzofuran-1,1,3(3H)-
tricarboxylate (6a). The general procedure 1 mentioned above was
followed, when compound 5a (67 mg, 0.213 mmol) was treated
4.5.6. (ꢃ)-(3R,3aR,6aS)-Trimethyl tetrahydrofuro[3,4-c]furan-1,1,3(3H)-
tricarboxylate (10a). The general procedure 1 mentioned above
was followed when compound 5e (60 mg, 0.198 mmol), was
with BF3$OEt2 (158 mL, 1.28 mmol) for 8 h to afford 6a,b, yield >99%
(55.4 mg, 0.212 mmol), ratio of epimers 75:25, major isomer (6a),
colorless liquid (solidified after cooling, Mp 62e64 ꢀC), Rf¼0.45
(30% EtOAc in Hexane, silica gel TLC); 1H NMR (400 MHz, CDCl3);
treated with BF3$OEt2 (147 mL, 1.19 mmol) for 7 h to afford 10a,b,
yield >99% (56.8 mg, 0.197 mmol), colorless liquid, ratio of epi-
mers 86:14, Rf¼0.5 (40% EtOAc in Hexane, silica gel TLC); major
d
4.60 (d,1H, J¼8.3 Hz), 3.83 (s, 3H), 3.78 (s, 3H), 3.77 (s, 3H), 3.06 (q,
1H, J¼6.7 Hz), 2.72e2.77 (m, 1H), 1.51e1.75 (m, 4H), 1.20e1.34 (br
m, 4H); 13C NMR (100 MHz, CDCl3)
170.8, 169.2, 168.3, 89.1, 80.1,
isomer (10a), 1H NMR (400 MHz, CDCl3);
d
4.72 (d, 1H, J¼7.8 Hz),
d
3.79e4.05 (m, 2H), 3.84 (s, 3H), 3.80 (s, 6H), 3.63e3.68 (m, 1H),
53.1, 52.7, 52.0, 43.2, 40.5, 22.6, 22.2, 22.0, 21.8; IR nmax (neat) 2950,
2870, 1744, 1473, 1283, 1217, 1101, 1088 cmꢁ1. HRMS (ESI): m/z calcd
for C14H21O7 [MþH]þ 301.1287; found 301.1280.
3.46e3.55 (m, 2H), 3.27e3.43 (m, 1H); 13C NMR (100 MHz, CDCl3)
d
168.9, 168.2, 166.6, 88.9, 79.3, 70.5, 70.4, 53.4, 53.0, 52.3, 50.0,
46.9; IR nmax (neat): 2957, 2860, 1744, 1438, 1267, 1240, 1108 cmꢁ1
;
Anal. Calcd for C12H16O8: C, 50.00; H, 5.59. Found: C, 50.16; H,
5.68.
4.5.2. (ꢃ)-(3S,3aS,7aR)-Trimethyl hexahydroisobenzofuran-1,1,3(3H)-
tricarboxylate (6b). Minor isomer, colorless liquid (solidified after
cooling, Mp 66e68 ꢀC); Rf¼0.5 (30% EtOAc in Hexane, silica gel TLC);
4.5.7. (ꢃ)-(3R,3aS,5S,6aR)-Trimethyl 5-methyltetrahydro-1H-cyclo-
penta[c]furan-1,1,3(3H,3aH)-tricarboxylate (11a). The general pro-
cedure 1 mentioned above was followed when compound 5f
1H NMR (400 MHz, CDCl3);
d
4.57 (d, 1H, J¼10.2 Hz), 3.81 (s, 3H),
3.78 (s, 3H), 3.72 (s, 3H), 2.92e2.97 (m, 1H), 2.67e2.71 (m, 1H),
1.49e1.87 (m, 5H), 1.22e1.41 (m, 3H); 13C NMR (100 MHz, CDCl3)
(75 mg, 0.238 mmol) was treated with BF3$OEt2 (177 mL,1.43 mmol)
d
172.3, 168.8, 167.9, 91.0, 79.5, 53.0, 52.6, 52.2, 43.3, 42.0, 23.8, 23.4,
for 8 h to afford 11a,b, yield >99% (70.8 mg, 0.236 mmol), ratio of
epimers 84:16, major isomer (11a), colorless liquid, Rf¼0.5 (30%
22.9, 20.7; IR nmax (neat) 2935, 2861, 1745, 1436, 1240, 1202, 1088,

S.H. Mahadevegowda, F.A. Khan / Tetrahedron 69 (2013) 8494e8504
8501
EtOAc in Hexane, silica gel TLC); 1H NMR (500 MHz, CDCl3);
d
4.46
HRMS (ESI): m/z calcd for C12H19O8 [MþH]þ 291.1080; found
(d, 1H, J¼7.9 Hz), 3.82 (s, 3H), 3.78 (s, 3H), 3.77 (s, 3H), 3.44e3.49
291.1085.
(m, 1H), 3.08e3.15 (m, 1H), 1.81e1.95 (m, 3H), 0.97 (d, 3H, J¼6.1 Hz),
0.83e0.92 (m, 2H); 13C NMR (125 MHz, CDCl3)
d
169.4, 168.7, 167.1,
4.5.12. Cyclohexylidene protection of endo diol (1,4,5,6-tetrachloro-
89.3, 79.7, 53.2, 52.7, 52.0, 49.1, 46.0, 38.3, 37.8, 36.3, 18.1; IR nmax
(neat): 2955, 2871,1741, 1437,1233,1117,1055 cmꢁ1. HRMS (ESI): m/
z calcd for C14H21O7 [MþH]þ 301.1287, found 301.1281.
7,7-dimethoxybicyclo[2.2.1]hept-5-ene-2,3-diol). To a solution of
endo diol (4.37 g, 13.488 mmol) in dry benzene (90 mL) were added
cyclohexanone (1.68 mL, 16.186 mmol) and p-TsOH.H2O (257 mg,
1.35 mmol) at rt. Then reaction mixture was refluxed to remove
H2O azeotropically by using Deanestark apparatus. After 15 h, the
reaction mixture was cooled to z10 ꢀC and 6 mL cold saturated
aqueous NaHCO3 solution was added sequentially. After evapora-
tion of solvent under reduced pressure, H2O (10 mL) was added to
residue and the aqueous layer was extracted with EtOAc (3ꢂ50 mL),
the combined EtOAc layers were washed with brine (20 mL), EtOAc
layer was separated, dried over Na2SO4 and solvent was evaporated.
The silica gel column chromatography for the crude reaction mix-
ture affords 15c (compound numbered in Supplementary data). The
resultant compound was further purified by fractional crystalliza-
tion with CH2Cl2/Hexane (10:1) to afford crystalline compound 15c.
Yield 98% (5.34 g, 13.21 mmol); Rf¼0.9 (10% EtOAc in Hexane, silica
4.5.8. (ꢃ)-(3S,3aS,5S,6aR)-Trimethyl 5-methyltetrahydro-1H-cyclo-
penta[c]furan-1,1,3(3H,3aH)-tricarboxylate (11b). Minor isomer,
colorless liquid, Rf¼0.55 (30% EtOAc in Hexane, silica gel TLC); 1H
NMR (500 MHz, CDCl3);
d
4.50 (d, 1H, J¼5.7 Hz), 3.80 (s, 3H), 3.80 (s,
3H), 3.69 (s, 3H), 3.49e3.55 (m, 1H), 2.98e3.04 (m, 1H), 2.26e2.31
(m, 1H), 1.99e2.05 (m, 1H), 1.80e1.85 (m, 1H), 1.21e1.27 (m, 1H),
1.03 (d, 3H, J¼6.3 Hz), 0.96e1.00 (m, 1H); 13C NMR (125 MHz,
CDCl3)
d 172.0, 168.7, 168.1, 90.3, 85.8, 53.1, 52.6, 52.1, 50.4, 48.7,
41.2, 37.2, 37.2, 19.0; IR nmax (neat): 2955, 2871, 1745, 1436, 1291,
1233 cmꢁ1. HRMS (ESI): m/z calcd for C14H20O7Na [MþNa]þ
323.1101; found 323.1101.
4.5.9. (ꢃ)-(3S,5R)-Trimethyl
3-phenyldihydrofuran-2,2,5(3H)-tri-
gel TLC), Mp 120e122 ꢀC, 1H NMR (500 MHz, CDCl3);
3.55 (s, 3H), 3.53 (s, 3H), 1.56e1.58 (m, 4H), 1.51e1.52 (m, 4H), 1.34
(br s, 2H); 13C NMR (100 MHz, CDCl3)
128.6 (2C), 116.7, 114.1, 85.3
d 4.81 (s, 2H),
carboxylate (13a,syn). The general procedure 1 mentioned above
was followed when compound 12 (200 mg, 0.594 mmol) was
treated with BF3$OEt2 (0.44 mL, 3.57 mmol) for 4 h to afford mix-
ture of regioisomers 13a,b, yield 94% (180 mg, 0.558 mmol), ratio of
regioisomers 13a,b¼52:48, the regioisomers were separated by LC-
908W preparative HPLC [JAIGEL-OA4100 (column), 1% EtOH in
Hexane eluent (v/v)]. Major regioisomer syn/anti¼77:23, com-
pound 13a,syn, colorless liquid; Rf¼0.4 (30% EtOAc in Hexane, silica
d
(2C), 77.6 (2C), 52.5, 51.7, 35.4, 35.1, 24.9, 23.5, 23.3; IR nmax (KBr)
2949, 2846, 1602, 1449, 1371, 1194, 1106 cmꢁ1. HRMS (ESI): m/z
calcd for C15H19Cl4O4 [MþH]þ 403.0037, found 403.0038.
4.5.13. Oxidation of vicinal dichloro alkene 15c to norbornyl a-dike-
tone 16. To a vigorously stirred solution of compound dichloro al-
kene 15c (5.34 g, 13.21 mmol) in MeCN (100 mL) were added
RuLDH [529 mg, 0.9 mol % RuCl3$3H2O loaded on layer double
hydroxide (LDH)] and NaIO4 (4.52 g, 21.13 mmol) sequentially,
followed by addition of 16.6 mL H2O at rt. After 4 h, the reaction
mixture was quenched with i-PrOH (7 mL) and stirred for 1 h. Then
the black residue was filtered through sintered crucible under
vacuum, washed with EtOAc, the combined filtrate was concen-
trated on rotary evaporator. The obtained residue was dissolved in
EtOAc and H2O (20 mL) was added, the product was extracted with
EtOAc (3ꢂ60 mL) and the combined organic layers were washed
with saturated aqueous Na2S2O3 (20 mL), followed by brine
(25 mL), organic layer was separated, dried over Na2SO4 and sol-
vent was evaporated on a rotary evaporator. The silica gel column
chromatography for the crude reaction mixture afforded yellow
solid 16, yield 95% (4.58 g, 12.55 mmol), Rf¼0.5 (10% EtOAc in
Hexane, silica gel TLC), Mp¼194e196 ꢀC; 1H NMR (400 MHz,
gel TLC), 1H NMR (500 MHz, CDCl3);
d 7.25e7.35 (m, 5H, aromatic),
4.74 (dd, 1H, J¼9.3, 7.5 Hz), 4.29 (dd, 1H, J¼10.3, 7.9 Hz), 3.86 (s, 3H),
3.80 (s, 3H), 3.30 (s, 3H), 2.70e2.74 (m, 2H); 13C NMR (125 MHz,
CDCl3)
d 170.5, 168.4, 167.7, 136.0, 128.3, 127.8, 90.5, 77.7, 53.1, 52.5,
52.2, 50.0, 35.0; IR nmax (neat) 2954, 2849, 1740, 1436, 1289, 1230,
1116, 1052 cmꢁ1. HRMS (ESI): m/z calcd for C16H19O7 [MþH]þ
323.1131, found 323.1130.
4.5.10. (ꢃ)-(4S,5S)-Trimethyl
4-phenyldihydrofuran-2,2,5(3H)-tri-
carboxylate (13b). Minor regioisomer (13b), colorless liquid, Rf¼0.4
(30% EtOAc in Hexane, silica gel TLC); 1H NMR (500 MHz, CDCl3);
d
7.18e7.30 (m, 5H, aromatic), 4.93 (d, 1H, J¼8.5 Hz), 3.94e3.99 (m,
1H), 3.88 (s, 3H), 3.82 (s, 3H), 3.27 (s, 3H), 3.19 (dd, 1H, J¼13.0,
12.7 Hz), 2.74 (dd, 1H, J¼13.3, 7.2 Hz); 13C NMR (125 MHz, CDCl3)
d
170.6, 169.9, 168.6, 134.7, 128.5 (2C), 127.8, 127.7 (2C), 87.2, 83.0,
53.3, 53.2, 51.5, 47.3, 36.4; IR nmax (neat) 2955, 2849, 1746, 1498,
1436, 1214, 1093 cmꢁ1. HRMS (ESI): m/z calcd for C16H19O7 [MþH]þ
323.1131, found 323.1132.
CDCl3);
1.38e1.40 (m, 2H), 1.27e1.28 (m, 2H); 13C NMR (100 MHz, CDCl3)
184.4 (2C, eC]O), 116.7, 105.2, 81.8 (2C), 78.2 (2C), 52.4, 52.3,
d 4.93 (s, 2H), 3.64 (s, 3H), 3.47 (s, 3H), 1.46 (br s, 6H),
d
4.5.11. The inseparable tricarboxylate tetrahydrofuran derivatives
(15a and 15b). The general procedure 1 mentioned above was
followed when compound 14 (80 mg, 0.263 mmol) was treated
35.0, 33.3, 24.6, 23.3, 23.1; IR nmax (KBr) 2956, 2866, 1771, 1453,
1218, 1093 cmꢁ1. HRMS (ESI): m/z calcd for C15H19Cl2O6 [MþH]þ
365.0558, found 365.0556.
with BF3$OEt2 (195 mL, 1.58 mmol) for 3 h to afford 15a,b, yield
59% (45.0 mg, 0.155 mmol), colorless liquid, ratio of regioisomers
4.5.14. One pot synthesis of oxa-bridged compound 17 from nor-
15a/15b¼62:38, Rf¼0.5 (40% EtOAc in Hexane, silica gel TLC); From
bornyl a-diketone 16. To a stirred solution of a-diketone 16 (4.87 g,
the mixture, major isomer (15a): 1H NMR (400 MHz, CDCl3);
d
4.70
13.33 mmol) in MeOH (100 mL) was added 30% H2O2 (15.4 mL),
followed by the slow addition of 6 N NaOH solution (6.2 mL) at
0e5 ꢀC. Then the resultant solution was stirred at rt, after 6 h the
reaction mixture was cooled to 0 ꢀC and 30 equiv of NaOH (16.0 g in
10 mL H2O) was added slowly. After completion of addition, the
reaction mixture was refluxed for 30 h. Then the reaction mixture
was cooled to 0e5 ꢀC, acidified up to pHz5 with 5% HCl solution,
then the organic components were extracted with EtOAc
(3ꢂ60 mL), washed with brine solution (20 mL), finally dried over
Na2SO4, and concentrated. The obtained crude dicarboxylic acid
dissolved in MeOH (20 mL), treated with CH2N2/Et2O at 0 ꢀC, the
excess of CH2N2 was quenched with acetic acid and solution was
(dd, 1H, J¼8.5, 4.1 Hz), 4.57 (dd, 1H, J¼4.6, 3.2 Hz), 3.81 (s, 3H),
3.78 (s, 6H), 3.41e3.50 (m, 2H), 2.44e2.62 (m, buried with signal
of minor isomer, 2H), 1.07e1.10 (t, 3H, J¼7.5 Hz); 13C NMR
(125 MHz, CDCl3)
d 171.5, 168.7, 167.9, 91.1, 81.1, 77.8, 65.5, 53.1,
52.7, 52.4, 34.9, 15.0. Minor isomer (15b): 1H NMR (400 MHz,
CDCl3);
d
4.81 (d, 1H, J¼5.1 Hz), 4.37 (q, 1H, J¼5.1 Hz), 3.84 (s, 3H),
3.78 (s, 3H), 3.76 (s, 3H), 3.51e3.57 (m, 2H), 2.92 (dd, 1H, J¼13.5,
4.5 Hz), 2.44e2.62 (m, buried with signal of major isomer, 1H),
1.09e1.13 (t, 3H, J¼6.9 Hz); 13C NMR (125 MHz, CDCl3)
d 169.3,
168.8, 166.5, 86.4, 82.2, 78.9, 65.5, 53.3, 53.2, 52.0, 38.0, 15.0; IR
nmax (neat) 2956, 2851, 1745, 1438, 1291, 1235, 1100, 1032 cmꢁ1
;

8502
S.H. Mahadevegowda, F.A. Khan / Tetrahedron 69 (2013) 8494e8504
concentrated, the resultant residue was purified by silica gel col-
umn chromatography with 20% EtOAc in Hexane as eluent to afford
17, yield 93% (4.61 g, 12.39 mmol), colorless solid, Mp 106e108 ꢀC,
Rf¼0.55 (30% EtOAc in Hexane, silica gel TLC); 1H NMR (400 MHz,
104e106 ꢀC, Rf¼0.7 (20% EtOAc in Hexane, silica gel TLC); 1H NMR
(400 MHz, CDCl3);
d
7.23 (m, 5H), 4.87 (d, 1H, J¼7.5 Hz), 4.70 (d, 1H,
J¼7.3 Hz), 4.57 (dd, 2H, J¼59.6, 11.8 Hz), 3.83 (dd, 2H, J¼53.7,
11.7 Hz), 3.43 (s, 3H), 3.38 (s, 3H), 1.64 (t, 2H, J¼6.1 Hz), 1.50e1.55
CDCl3);
d
5.10 (s, 2H), 3.86 (s, 6H), 3.40 (s, 3H), 3.32 (s, 3H),1.73e1.76
(m, 6H), 1.30e1.31 (m, 2H); 13C NMR (125 MHz, CDCl3)
d 166.3,
(m, 2H), 1.56 (br s, 6H), 1.35 (br s, 2H); 13C NMR (100 MHz, CDCl3)
137.3, 128.3, 127.8, 116.5, 109.3, 87.6, 81.0, 80.9, 75.8, 74.9, 64.5, 51.9,
51.8, 35.2 34.8, 24.9, 23.6, 23.4; IR nmax (KBr) 2941, 2861, 1814, 1450,
1373, 1299, 1219, 1123 cmꢁ1. HRMS (EI): m/z calcd for C22H27ClO7
438.1445; found 438.1446.
d
164.9, 116.7, 114.0, 89.2, 81.6, 52.7, 51.8, 51.7, 35.8, 35.1, 24.9, 23.7,
23.6; IR nmax (neat) 2939, 2854, 1728, 1443, 1385, 1209 cmꢁ1. HRMS
(EI): m/z calcd for C17H24O9 372.1420, found 372.1425.
4.5.15. Synthesis of bridged lactone 18. To a stirred solution of
a
-
4.5.18. Synthesis of oxa-bridged compound 20 from bridged lactone
19b. To a solution of compound 19b (1.3 g, 2.962 mmol) in MeOH
(25 mL) was added 30 equiv of NaOH (3.55 g in 4 mL H2O,
88.86 mmol) at 0e5 ꢀC, then the reaction mixture was refluxed,
after completion of starting material (monitored by TLC) 30 h, the
reaction mixture was cooled to 0 ꢀC and acidified up to pHz5 with
5% HCl, then immediately product was extracted with EtOAc
(3ꢂ30 mL), washed with brine (8 mL), the resultant organic layer
was dried over Na2SO4 and concentrated. The crude acid was dis-
solved in dry EtOAc (10 mL) and treated with CH2N2/Et2O at 0 ꢀC.
The excess of CH2N2 was quenched with acetic acid and the solvent
was evaporated under reduced pressure. The residue was purified
by column chromatography on silica gel (100e200 mesh) with 20%
EtOAc in hexane eluent afforded compound 20. Yield 95% (1.22 g,
2.814 mmol), colorless liquid, Rf¼0.55 (25% EtOAc in Hexane, silica
diketone 16 (810 mg, 2.218 mmol) in MeOH (20 mL) was added 30%
H2O2 solution (1.55 mL), followed by drop wise addition of 6 N KOH
(479 mg in 1.4 mL H2O) at 0 ꢀC, then reaction mixture was stirred at
rt. After 8 h, the reaction mixture was acidified up to pHz5 with 5%
HCl at 0 ꢀC. Then the product was extracted with EtOAc (3ꢂ30 mL),
washed with brine (4 mL), the combined organic layers were dried
over Na2SO4 and solvent was evaporated. The crude carboxylic acid
was treated with CH2N2 in Et2O/MeOH (1:1), after quenching excess
of CH2N2 with acetic acid, the solvent was evaporated and the silica
gel column chromatography for the residue afforded the compound
18, yield 98% (819 mg, 2.173 mmol), colorless crystalline compound,
Mp 182e184 ꢀC, Rf¼0.6 (40% EtOAc in Hexane, silica gel TLC), 1H
NMR (500 MHz, CDCl3);
d
5.31 (d, 1H, J¼7.3 Hz), 4.81 (d, 1H,
J¼7.3 Hz), 3.87 (s, 3H), 3.56 (s, 3H), 3.36 (s, 3H), 1.64e1.67 (m, 2H),
1.51e1.58 (m, 6H), 1.33e1.34 (m, 2H); 13C NMR (100 MHz, CDCl3)
gel TLC); 1H NMR (400 MHz, CDCl3);
d 7.26e7.33 (m, 5H, aromatic),
d
164.6, 164.5, 117.2, 111.0, 83.5, 80.6, 79.9, 76.2, 53.4, 51.9, 51.5, 35.1,
5.06 (1H, d, J¼5.8 Hz), 4.89 (d, 1H, J¼5.8 Hz), 4.60 (dd, 2H, J¼28.3,
11.7 Hz), 3.83 (s, 3H, CO2Me), 3.77 (dd, 2H, J¼77.5, 10.2 Hz), 3.32 (s,
3H, OMe), 3.30 (s, 3H, OMe), 1.69e1.73 (m, 2H), 1.54e1.58 (m, 6H),
34.9, 24.8, 23.5, 23.3; IR nmax (KBr) 2948, 2866, 1824, 1745, 1450,
1322, 1188, 1104 cmꢁ1. HRMS (EI): m/z calcd for C16H21ClO8
376.0925, found 376.0923.
1.29e1.36 (m, 2H); 13C NMR (125 MHz, CDCl3)
d 165.9, 137.6, 128.2,
127.7, 115.9, 112.1, 91.5, 89.6, 81.7, 79.0, 73.7, 62.4, 52.6, 51.9, 51.5,
35.9, 35.3, 25.1, 23.8; IR (neat) 1940, 2859, 1755, 1450, 1266,
1101 cmꢁ1. HRMS (ESI): m/z calcd for C23H31O8 [MþH]þ 435.2019,
found 435.2011.
4.5.16. Chemoselective reduction of bridge-head ester 18. To a stir-
red solution of compound 18 (1.4 g, 3.715 mmol) in dry 1,4-dioxane
(30 mL), was added NaBH4 (422 mg, 11.145 mmol) at rt, then re-
action mixture was refluxed. After 4 h, the reaction mixture was
cooled to 0 ꢀC and quenched with H2O (4 mL), the solvent was
evaporated under reduced pressure. For the obtained crude H2O
(6 mL) was added, product was extracted with EtOAc (3ꢂ30 mL),
washed with H2O (4 mL) and brine (8 mL), organic layer was dried
over Na2SO4 and concentrated. The crude residue was purified on
silica gel column chromatography (20e40% EtOAc in Hexane elu-
ent), afforded compound 19a, yield 96% (1.24 g, 3.56 mmol), col-
orless solid, Mp 98e100 ꢀC, Rf¼0.4 (50% EtOAc in Hexane, silica gel
4.5.19. Partial reduction of meso diester 17. To a stirred solution of
oxa-bridged compound 17 (100 mg, 0.268 mmol) in dry THF/EtOH
(3:3 mL) was added LiCl (29 mg, 0.671 mmol), followed by addi-
tion of NaBH4 (25 mg, 0.671 mmol) at rt, after reaction mixture
was stirred for 40 h, quenched with saturated NH4Cl (4 mL),
product was extracted with EtOAc (3ꢂ15 mL), the combined or-
ganic layers were washed once with brine (8 mL), dried over
Na2SO4 and solvent was evaporated. The silica gel column chro-
matography for the crude residue afforded monoalcohol 21, yield
86% (66 mg, 0.192 mmol, based on starting material recovery),
solidified after cooling, colorless solid, Mp 86e88 ꢀC, Rf¼0.5 (40%
TLC), 1H NMR (400 MHz, CDCl3);
d
4.87 (d, 1H, J¼7.3 Hz), 4.78 (d, 1H,
J¼7.3 Hz), 4.04e4.12 (m, 2H), 3.55 (s, 3H), 3.51(s, 3H), 2.21 (br s,1H),
1.67e1.70 (m, 2H), 1.57e1.62 (m, 6H), 1.36e1.38 (m, 2H); 13C NMR
(100 MHz, CDCl3)
d
166.1, 116.8, 109.4, 87.3, 80.9, 77.6, 75.8, 58.5,
EtOAc in Hexane, silica gel TLC); 1H NMR (400 MHz, CDCl3);
d 5.08
52.0, 51.8, 35.2, 34.8, 24.8, 23.6, 23.4; IR (KBr) 3501 (br), 2941, 2852,
(d, 1H, J¼5.4 Hz), 4.84 (d, 1H, J¼5.4 Hz), 4.01 (qd, 2H, J¼14.5,
5.4 Hz), 3.86 (s, 3H), 3.37 (s, 3H), 3.32 (s, 3H), 2.47e2.52 (m, 1H),
1.69e1.77 (m, 2H), 1.52e1.58 (m, 6H), 1.31e1.38 (m, 2H); 13C NMR
1817, 1450, 1371, 1267, 1250 cmꢁ1. HRMS (EI): m/z calcd for
C
15H21ClO7 348.0976; found 348.0973.
(100 MHz, CDCl3)
d 165.7, 116.4, 112.5, 92.3, 89.5, 81.9, 79.5, 57.3,
4.5.17. Benzylation of alcohol 19a. NaH (688 mg, 17.20 mmol, 60%
dispersion in mineral oil) was taken in a flame dried 100 mL two
necked round bottomed flask under argon atmosphere. The oily
NaH washed with dry hexane (4 mL) and solvent was removed
through syringe. Then dry THF (20 mL) was added to NaH and
cooled to 0 ꢀC, the solution of alcohol 19a (3 g, 8.60 mmol) in dry
THF (40 mL) was added, followed by addition of benzyl bromide
(2.05 mL, 17.20 mmol). Then reaction mixture was slowly brought
to rt. After 6 h, the reaction mixture was cooled to 0 ꢀC and
quenched with H2O (3 mL), the product was extracted with EtOAc
(three times), the combined organic layers were washed once with
brine (8 mL), dried over Na2SO4 and solvent was evaporated. The
residue was purified by silica gel (100e200 mesh) column chro-
matography with 10e20% EtOAc in hexane eluent afforded com-
pound 19b. Yield 78% (2.94 g, 6.71 mmol), colorless solid, Mp
52.7, 51.8, 51.7, 35.8, 35.2, 25.0, 23.8, 23.7; IR nmax (neat) 3501,
2935, 2851, 1749, 1441, 1200, 1130 cmꢁ1. HRMS (APCI): m/z calcd
for C16H28NO8 [MþNH4]þ 362.1815, found 362.1806.
4.5.20. TBDPS ether protection of monoalcohol 21. To a solution of
alcohol 21 (114 mg, 0.331 mmol) in dry CH2Cl2 (12 mL) was
added 1H-imidazole (68 mg, 0.993 mmol), followed by addition
of TBDPSCl (137 mg, 0.496 mmol) at 0 ꢀC, then reaction mixture
was stirred at rt. After 4 h, the reaction mixture was diluted with
H2O (6 mL), product was extracted with CH2Cl2 (3ꢂ15 mL), the
combined organic layers were washed once with brine (8 mL),
dried over Na2SO4 and solvent was evaporated. The silica gel
column chromatography for the crude reaction mixture afforded
monoester 22, yield 95% (183 mg, 0.314 mmol), obtained as
colorless liquid, Rf¼0.6 (25% EtOAc in Hexane, silica gel TLC); 1H

S.H. Mahadevegowda, F.A. Khan / Tetrahedron 69 (2013) 8494e8504
8503
NMR (400 MHz, CDCl3);
d
7.66e7.72 (m, 4H), 7.34e7.44 (m, 6H),
(ESI): m/z calcd for
443.1683.
C
22H28O8Na [MþNa]þ 443.1676, found
5.13 (d, 1H, J¼5.9 Hz), 5.03 (d, 1H, J¼5.4 Hz), 3.93 (dd, 2H, J¼76,
10.2 Hz), 3.82 (s, 3H), 3.39 (s, 3H), 3.36 (s, 3H), 1.71e1.77 (m, 2H),
1.53e1.68 (m, 7H), 1.21e1.28 (m, 1H), 1.06 (s, 9H); 13C NMR
4.5.24. (ꢃ)-(3a0R,40R,60R,6a0S)-Dimethyl 40-((benzyloxy)methyl)tet-
rahydrospiro[cyclohexane-1,20-furo[3,4-d][1,3]dioxole]-40,60-di-
carboxylate (24b). Minor isomer, colorless liquid; Rf¼0.4 (25%
EtOAc in Hexane, silica gel TLC); 1H NMR (400 MHz, CDCl3);
(100 MHz, CDCl3)
d 165.9, 135.7 (2C), 135.5 (2C), 132.9, 132.5,
129.8, 129.7, 127.7 (2C), 127.6 (2C), 115.9, 112.3, 92.7, 89.4, 81.7,
78.6, 56.5, 52.6, 52.1, 51.5, 36.0, 35.3, 26.7 (3C, t-Bu), 25.1, 23.9,
23.8, 19.2. IR nmax (neat) 2937, 2857, 1758, 1735, 1438, 1362, 1208,
1092 cmꢁ1. HRMS (APCI): m/z calcd for C32H46NO8Si [MþNH4]þ
600.2993, found 600.2964.
d
7.19e7.25 (m, 5H, aromatic), 4.97 (d, 1H, J¼5.8 Hz), 4.92 (dd, 1H,
J¼5.8, 4.6 Hz), 4.49 (d, 1H, J¼4.6 Hz), 4.44e4.63 (dd, 1H, J¼65.1,
12.2 Hz), 3.90 (dd, 2H, J¼71.9, 10.2 Hz), 3.71 (s, 3H), 3.68 (s, 3H),
1.55e1.58 (m, 2H), 1.40e1.47 (m, 6H), 1.26e1.28 (m, 2H); 13C NMR
4.5.21. (ꢃ)-(3a0R,60S,6a0S)-Trimethyl dihydrospiro[cyclohexane-1,20-
furo[3,4-d][1,3]dioxole]-40,40,60(3a0H)-tricarboxylate 23a. To a stirred
solution of 17 (1.36 g, 3.65 mmol) in dry 1,2-DCE (20 mL) was added
BF3$OEt2 (1.35 mL, 10.95 mmol) drop wise at 0 ꢀC, after addition
completed the reaction mixture was slowly brought to rt. After 9 h,
the reaction mixture was cooled to 0 ꢀC and quenched with cold
saturated aqueous NaHCO3 solution (8 mL) and 1,2-DCE was
evaporated under reduced pressure. To the obtained crude H2O
(6 mL) was added, aqueous part was extracted with EtOAc
(3ꢂ30 mL), the combined organic layers were washed once with
brine solution (10 mL), organic layer was separated, dried over
Na2SO4, and concentrated under reduced pressure. The SiO2 col-
umn chromatography for the crude reaction mixture (20e30%
EtOAc in Hexane solvent as eluent) afforded the analytically pure
tetrahydrofurans 23a,b, yield 97% (1.26 g, 3.54 mmol), ratio of
epimers 88:12, major isomer (23a), white solid, Mp 102e103 ꢀC,
Rf¼0.6 (30% EtOAc in Hexane, silica gel TLC); 1H NMR (500 MHz,
(100 MHz, CDCl3) d 170.6, 167.2, 137.8, 128.2 (2C), 127.7 (2C), 127.5,
114.5, 89.4, 82.6, 81.5, 80.9, 73.4, 69.9, 52.6, 52.0, 35.5, 34.9, 24.9,
23.8, 23.7; IR nmax (neat) 2973, 1742, 1628, 1442, 1368, 1221,
1101 cmꢁ1. HRMS (EI): m/z calcd for C22H28O8 420.1784; found
420.1787.
4.5.25. Debenzylation of compound 24a, (ꢃ)-(3a0R,40R,60S,6a0S)-di-
methyl 40-(hydroxymethyl)tetrahydrospiro[cyclohexane-1,20-furo[3,4-
d][1,3]dioxole]-40,60-dicarboxylate (24c). To a stirred solution of
compound 24a (34 mg, 0.081 mmol) in EtOAc (4 mL), was added
10% Pd/C (5 mg) and reaction mixture was stirred under hydrogen
atmosphere at rt, after 12 h the reaction mixture was directly
filtered through a small Celite pad, washed with EtOAc and the
resultant solution was concentrated. The obtained residue was
purified on silica gel column chromatography (silica gel,
100e200 mesh, 30e50% EtOAc in Hexane as eluent), afforded
compound 24c. Yield 99% (26 mg, 0.08 mmol), colorless liquid,
Rf¼0.4 (50% EtOAc in Hexane, silica gel TLC). 1H NMR (400 MHz,
CDCl3);
s, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 3.73 (s, 3H), 1.68e1.70 (br m, 2H),
1.55 (br s, 6H), 1.37 (br s, 2H); 13C NMR (100 MHz, CDCl3)
169.5,
d
5.46 (d, 1H, J¼6.1 Hz), 5.08 (dd, 1H, J¼5.9, 1.3 Hz), 4.89 (br
CDCl3);
d
5.22 (d, 1H, J¼6.1 Hz), 5.15 (dd, 1H, J¼6.1, 1.4 Hz), 4.68 (d,
d
1H, J¼1.4 Hz), 3.96e4.13 (m, 2H), 3.78 (s, 3H), 3.75 (s, 3H), 2.31 (br s,
167.3, 165.3, 114.9, 91.2, 84.7, 83.4, 83.1, 53.2, 52.9, 52.4, 35.7, 34.6,
24.8, 23.8, 23.6; IR nmax (KBr) 2945, 2853, 1780, 1760, 1726, 1441,
1227, 1110 cmꢁ1; Anal. Calcd for C16H22O9: C, 53.63; H, 6.19. Found:
C, 53.70; H, 6.18.
1H), 1.74e1.77 (m, 2H), 1.54e1.67 (m, 6H), 1.37e1.43 (m, 2H); 13C
NMR (100 MHz, CDCl3)
d 170.9, 169.9, 114.5, 89.6, 83.9, 83.6, 82.1,
63.5, 52.6, 52.4, 35.9, 34.2, 24.9, 23.9, 23.6; IR nmax (neat) 3489,
2940, 2859, 1738, 1441, 1369, 1283, 1223, 1102 cmꢁ1. HRMS (EI): m/z
calcd for C15H22O8 330.1315, found 330.1316.
4.5.22. (ꢃ)-(3a0R,60R,6a0S)-Trimethyl dihydrospiro[cyclohexane-1,20-
furo[3,4-d][1,3]dioxole]-40,40,60(3a0H)-tricarboxylate 23b. Minor iso-
mer (23b), colorless liquid (solidified after cooling, Mp 68e70 ꢀC),
Rf¼0.5 (30% EtOAc in Hexane, silica gel TLC); 1H NMR (500 MHz,
4.5.26. (ꢃ)-(3a0R,40R,60S,6a0S)-Dimethyl 40-(((tert-butyldiphenylsilyl)
oxy)methyl)tetrahydrospiro[cyclohexane-1,20-furo[3,4-d][1,3]diox-
ole]-40,60-dicarboxylate (25a). Experimental procedure is similar to
compounds 23a,b, when compound 22 (73 mg, 0.125 mmol) was
CDCl3);
d
5.34 (d, 1H, J¼5.7 Hz), 5.12 (dd, 1H, J¼5.8, 4.5 Hz), 4.47
(d, 1H, J¼4.5 Hz), 3.86 (s, 3H), 3.82 (s, 3H), 3.78 (s, 3H), 1.65e1.68
treated with BF3$OEt2 (47 mL, 0.376 mmol) for 5 h to afford 25a,b,
(m, 2H), 1.49e1.53 (m, 6H), 1.33 (br s, 2H); 13C NMR (125 MHz,
yield 94% (67 mg, 0.117 mmol), ratio of epimers 46:54, the two
isomers were separated by column chromatography (silica gel,
100e200 mesh, 10% EtOAc in Hexane as eluent). Minor epimer 25a,
colorless liquid, Rf¼0.5 (20% EtOAc in Hexane, silica gel TLC); 1H
CDCl3)
d 166.8, 166.4, 164.6, 115.1, 89.7, 83.0, 81.2, 81.0, 83.0, 81.2,
81.0, 53.3, 52.9, 52.3, 35.4, 35.3, 24.8, 23.8, 23.7; IR nmax (neat)
2940, 2855, 1776, 1741, 1438, 1369, 1266, 1122, 1038 cmꢁ1. HRMS
(ESI): m/z calcd for
381.1160.
C
16H22O9Na [MþNa]þ 381.1156, found
NMR (400 MHz, CDCl3); d 7.66e7.73 (4H, m), 7.34e7.44 (m, 6H),
5.34 (d, 1H, J¼5.9 Hz), 5.15 (dd, 1H, J¼5.9, 2 Hz), 4.53 (d, 1H, J¼2 Hz),
4.14 (s, 2H), 3.81 (s, 3H), 3.73 (s, 3H), 1.48e1.72 (m, 9H), 1.37 (br s,
4.5.23. (ꢃ)-(3a0R,40R,60S,6a0S)-Dimethyl 40-((benzyloxy)methyl)tet-
rahydrospiro[cyclohexane-1,20-furo[3,4-d][1,3]dioxole]-40,60-di-
carboxylate (24a). Experimental procedure is similar to
compounds 23a,b, when compound 20 (95 mg, 0.218 mmol) was
1H), 1.0 (s, 9H); 13C NMR (100 MHz, CDCl3)
d 170.9,170.4,135.6 (2C),
135.5 (2C), 133.0, 132.9, 129.7, 129.6, 127.6 (2C), 127.5 (2C), 114.0,
90.0, 84.6, 84.0, 81.0, 62.7, 52.4, 52.3, 36.3, 34.8, 26.5 (3C, t-Bu), 25.0,
23.8, 23.7, 19.2; IR nmax (neat) 2940, 2857, 1739, 1435, 1234,
1108 cmꢁ1. HRMS (APCI): m/z calcd for C31H44NO8Si [MþNH4]þ
586.2836, found 586.2819.
treated with BF3$OEt2 (81
mL, 0.656 mmol) for 4 h to afford
24a,b, yield 86% (78.8 mg, 0.187 mmol), ratio of epimers 57:43,
the two isomers were separated by column chromatography
(silica gel, 100e200 mesh, 15% EtOAc in Hexane as eluent). Major
isomer (24a), colorless liquid, Rf¼0.5 (25% EtOAc in Hexane, silica
4.5.27. (ꢃ)-(3a0R,40R,60R,6a0S)-Dimethyl 40-(((tert-butyldiphenylsilyl)
oxy)methyl)tetrahydrospiro[cyclohexane-1,20-furo[3,4-d][1,3]diox-
ole]-4’,60-dicarboxylate (25b). Major epimer, colorless liquid,
Rf¼0.45 (20% EtOAc in Hexane, silica gel TLC); 1H NMR (400 MHz,
gel TLC); 1H NMR (500 MHz, CDCl3);
d 7.26e7.37 (m, 5H, aro-
matic), 5.20 (d, 1H, J¼5.8 Hz), 5.12 (dd, 1H, J¼5.8, 1.5 Hz), 4.59 (d,
1H, J¼1.5 Hz), 4.58 (dd, 2H, J¼37.4, 12.4 Hz), 3.90 (dd, 2H, J¼26.4,
9.0 Hz), 3.74 (s, 3H), 3.73 (s, 3H), 1.66e1.69 (m, 2H), 1.56e1.62
CDCl3);
d
7.69e7.71 (m, 4H), 7.35e7.44 (m, 6H), 5.2 (d, 1H, J¼5.9 Hz),
5.04e5.06 (m, 1H), 4.47 (d, 1H, J¼4.4 Hz), 4.17 (dd, 2H, J¼67.5,
(m, 6H), 1.39 (br s, 2H); 13C NMR (100 MHz, CDCl3)
d 170.7, 170.1,
9.8 Hz), 3.79 (s, 3H), 3.78 (s, 3H), 1.36e1.59 (m, 9H), 1.25e1.29 (m,
137.8, 128.2 (2C), 127.6 (2C), 127.5, 114.0, 89.4, 84.1, 83.5, 81.8,
73.5, 69.3, 52.5, 52.3, 36.1, 34.6, 24.9, 23.9, 23.6; IR nmax (neat)
2937, 2860, 1759, 1736, 1451, 1283, 1228, 1105 cmꢁ1. HRMS
1H), 1.01 (s, 9H); 13C NMR (100 MHz, CDCl3)
d 170.9, 167.3, 135.7
(2C), 135.5 (2C), 133.2, 132.8, 129.7, 129.6, 127.6 (2C), 127.6 (2C),
114.3, 89.5, 81.5, 81.3, 80.9, 63.6, 52.4, 52.0, 35.5, 35.1, 26.5 (3C,

8504
S.H. Mahadevegowda, F.A. Khan / Tetrahedron 69 (2013) 8494e8504
5. (a) Lemonnier, G.; Charette, A. B. J. Org. Chem. 2010, 75, 7465; (b) Lemonnier, G.;
Charette, A. B. J. Org. Chem. 2012, 77, 5832.
6. (a) Khan, F. A.; Rao, C. N. J. Org. Chem. 2011, 76, 3320 and references therein; (b)
t-Bu), 24.9, 23.7, 23.7, 19.2; IR nmax (neat) 2936, 2858, 1767, 1739,
1436, 1222, 1111 cmꢁ1. HRMS (APCI): m/z calcd for C31H44NO8Si
[MþNH4]þ 586.2836, found 586.2816.
Khan, F. A.; Ahmad, S. J. Org. Chem. 2012, 77, 2389.
7. (a) Rodriguez, A. D.; Soto, J. J.; Pina, I. C. J. Nat. Prod. 1995, 58, 1209; (b) Burka, L.
T.; Ganguli, M.; Wilson, B. J. J. Chem. Soc., Chem. Commun. 1983, 544; (c) Stierle,
4.5.28. Methyl 4-methylbenzenesulfonate (29). CAS RN [80-48-8]
ꢀ
D. B.; Carte, B.; Faulkner, D. J.; Tagle, B.; Clardy, J. J. Am. Chem. Soc. 1980, 102,
Lit. reported:18 1H NMR (CDCl3);
d
7.79 (dt, 2H, J¼8.5, 2.0 Hz),
5088; (d) Ospina, C. A.; Rodríguez, A. D. J. Nat. Prod. 2006, 69, 1721; (e)
Malmstrøm, J.; Christophersen, C.; Barrero, A. F.; Oltra, J. E.; Justicia, J.; Rosales,
A. J. Nat. Prod. 2002, 65, 364; (f) Sakabe, N.; Goto, T.; Hirata, Y. Tetrahedron Lett.
1964, 5, 1825; (g) Sakabe, N.; Goto, T.; Hirata, Y. Tetrahedron 1977, 33, 3077.
8. Some methodologies for synthesis of tetrahydrofurans see: (a) Hay, M. B.;
Hardin, A. R.; Wolfe, J. P. J. Org. Chem. 2005, 70, 3099; (b) Ward, A. F.; Wolfe, J. P.
Org. Lett. 2010, 12, 1268; (c) Guindon, Y.; Soucy, F.; Yoakim, C.; Ogilvie, W. W.;
Plamondon, L. J. Org. Chem. 2001, 66, 8992; (d) Chavre, S. N.; Choo, H.; Lee, J. K.;
Pae, A. N.; Kim, Y.; Cho, Y. S. J. Org. Chem. 2008, 73, 7467; (e) Pulido, F. J.;
7.35 (m, 2H), 3.74 (s, 3H), 2.45 (s, 3H). IR nmax (neat) 2956, 1599,
1360, 1179, 993, 767 cmꢁ1. Observed: 1H NMR (400 MHz, CDCl3);
d
7.79 (d, 2H, J¼8.3 Hz), 7.36 (d, 2H, J¼8.3 Hz), 3.74 (s, 3H), 2.45 (s,
3H); IR nmax (neat) 2955, 1598, 1360, 1177, 992, 766 cmꢁ1
.
Acknowledgements
ꢀ
Barbero, A.; Val, P.; Diez, A.; Gonzalez-Ortega, A. Eur. J. Org. Chem. 2012, 5350;
(f) Reddy, L. V. R.; Roy, A. D.; Roy, R.; Shaw, A. K. Chem. Commun. 2006, 3444; (g)
Kang, B.; Mowat, J.; Pinter, T.; Britton, R. Org. Lett. 2009, 11, 1717.
9. (a) Arjona, O.; Csaky, A. G.; Murcia, M. C.; Plumet, J. J. Org. Chem. 1999, 64, 9739;
(b) Benjamin, N. M.; Martin, S. F. Org. Lett. 2011, 13, 450; (c) Fraile, J. M.; García,
J. I.; Gracia, D.; Mayoral, J. A.; Pires, E. J. Org. Chem. 1996, 61, 9479.
F.A.K. gratefully acknowledges CSIR for financial support. S.H.M
thanks CSIR, India for research fellowship.
Supplementary data
10. (a) Luo, S.-H.; Luo, Q.; Niu, X.-M.; Xie, M.-J.; Zhao, X.; Schneider, B.; Gershenzon,
J.; Li, S.-H. Angew. Chem., Int. Ed. 2010, 49, 4471; (b) Flath, R. A.; Forrey, R. R. J.
Agric. Food Chem. 1977, 25, 103; (c) Volz, F.; Wadman, S. H.; Hoffmann-Roder, A.;
Krause, N. Tetrahedron 2009, 65, 1902; (d) Shizuri, Y.; Nishiyama, S.; Imai, D.;
Yamamura, S. Tetrahedron Lett. 1984, 25, 4771; (e) Funk, T. W. Org. Lett. 2009, 11,
4998.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.07.005.
€
References and notes
11. (a) Khan, F. A.; Prabhudas, B.; Dash, J.; Sahu, N. J. Am. Chem. Soc. 2000, 122, 9558;
(b) Khan, F. A.; Dash, J. J. Org. Chem. 2003, 68, 4556; (c) Khan, F. A.; Parasuraman,
K. Beilstein J. Org. Chem. 2010, 6, 64; (d) Khan, F. A.; Satapathy, R.; Dash, J.;
Savitha, G. J. Org. Chem. 2004, 69, 5295; (e) Khan, F. A.; Rout, B. Tetrahedron Lett.
2006, 47, 5251; (f) Khan, F. A.; Rout, B. J. Org. Chem. 2007, 72, 7011.
12. For the complete details of synthesis of oxa-bridged compounds from nor-
1. For reviews see: (a) Grob, C. A.; Schiess, P. W. Angew. Chem., Int. Ed. Engl. 1967, 6,
1; (b) Prantz, K.; Mulzer, J. Chem. Rev. 2010, 110, 3741; (c) Grob, C. A. Angew.
Chem., Int. Ed. Engl. 1969, 8, 535.
2. (a) Xu, C.; Liu, Z.; Wang, H.; Zhang, B.; Xiang, Z.; Hao, X.; Wang, D. Z. Org. Lett.
2011, 13, 1812; (b) Thornton, P. D.; Burnell, D. J. Org. Lett. 2006, 8, 3195; (c) Dong,
J.-Q.; Wong, H. N. C. Angew. Chem., Int. Ed. 2009, 48, 2351; (d) Paquette, L. A.;
Yang, J.; Long, Y. O. J. Am. Chem. Soc. 2002, 124, 6542; (e) Renneberg, D.; Pfander,
H.; Leumann, C. J. J. Org. Chem. 2000, 65, 9069; (f) Mehta, G.; Karmakar, S.;
Chattopadhyay, S. K. Tetrahedron 2004, 60, 5013; (g) Boeckman, R. K., Jr.; Ar-
vanitis, A.; Voss, M. E. J. Am. Chem. Soc. 1989, 111, 2737.
3. (a) Barluenga, J.; Alvarez-Perez, M.; Wuerth, K.; Rodriguez, F.; Fananas, F. J. Org.
Lett. 2003, 5, 905; (b) Kabalka, G. W.; Li, N.-S.; Tejedor, D.; Malladi, R. R.;
Trotman, S. J. Org. Chem. 1999, 64, 3157; (c) Waddell, T. G.; Ross, P. A. J. Org.
Chem. 1987, 52, 4802.
4. For ring cleavage with Lewis acids see: (a) Nagumo, S.; Matsukuma, A.; Inoue,
F.; Yamamoto, T.; Suemune, H.; Sakai, K. J. Chem. Soc., Chem. Commun. 1990,
1538; (b) Draghici, C.; Brewer, M. J. Am. Chem. Soc. 2008, 130, 3766; (c)
Takayanagi, M.; Umamori, N.; Tanino, K.; Kuwajima, I. J. Am. Chem. Soc. 1993,
115, 12635.
bornyl a-diketones see: Khan, F. A.; Dash, J.; Sudheer, C.; Sahu, N.; Parasuraman,
K. J. Org. Chem. 2005, 70, 7565.
13. For our previous works on applications of oxa-bridged compounds see: (a)
Khan, F. A.; Parasuraman, K. Chem. Commun. 2009, 2399; (b) Khan, F. A.;
Parasuraman, K.; Donnio, B. Tetrahedron 2010, 66, 8745.
14. Donohoe, T. J.; Sintim, H. O.; Hollinshead, J. J. Org. Chem. 2005, 70, 7297.
15. Zhou, Y.; Wang, R.; Xu, Z.; Yan, W.; Liu, L.; Kang, Y.; Han, Z. Org. Lett. 2004, 6,
4147.
16. (a) CCDC 875268 (6a). (b) CCDC 875269 (23a) contains the supplementary
crystallographic data for this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
17. Sheldrick, G. M. SHELXL97, Program for the Refinement of Crystal Structures;
€
€
University of Gottingen: Gottingen, Germany, 1997.
18. Asano, K.; Matsubara, S. Org. Lett. 2009, 11, 1757.