Highly functionalised cyclohexa-1,3-dienes by sulfonyl Nazarov reagents

Article abstract of DOI:10.1016/j.tet.2014.04.076

The Hayashi-J?rgensen organocatalyst has made possible a sulfonyl Nazarov analogue reagent to give a Diels-Alder reaction at the double bond, without involving the activated methylene affording chiral highly functionalised cyclohexa-1,3-dienes.

Full text of DOI:10.1016/j.tet.2014.04.076

Tetrahedron xxx (2014) 1e9
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Highly functionalised cyclohexa-1,3-dienes by sulfonyl Nazarov
reagents
a
,
,
,
,
,
Javier Pena y, Rosalina F. Moro a y, Isidro S. Marcos a y, F. Sanz b z, David Díez a
*
~
a
ꢀ
Departamento de Química Organica, Facultad de Ciencias Químicas, Universidad de Salamanca, Plaza de los Caídos 1-5, 37008 Salamanca, Spain
b
ꢀ
Servicio de Difraccion de Rayos X, Universidad de Salamanca, Salamanca, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The HayashieJørgensen organocatalyst has made possible a sulfonyl Nazarov analogue reagent to give
a DielseAlder reaction at the double bond, without involving the activated methylene affording chiral
highly functionalised cyclohexa-1,3-dienes.
Received 13 March 2014
Received in revised form 21 April 2014
Accepted 23 April 2014
Available online xxx
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Sulfones
Asymmetric DielseAlder
Nazarov reagents
Cyclohexa-1,3-dienes
HayashieJørgensen organocatalyst
1. Introduction
The chemistry of Nazarov reagents has increased in the last
years due to their versatility and possibility to be excellent starting
materials for the synthesis of biologically active compounds.1 The
sulfone group, both as a powerful electron withdrawing group and
as an easily removable substituent,2 is ideal for the substitution of
the carboethoxymethyl group in the Nazarov reagent. Sulfone and
sulfoxide analogues of Nazarov reagents have been used as dien-
ophiles in asymmetric DielseAlder reactions with dienes and
employing a chiral metallic Lewis acid as catalyst or in anionic
polycyclisations.3 In our group, the reactivity of Nazarov reagent 1
has been developed in a divergent manner for diversity oriented
syntheses (Scheme 1).4,5 The interest of a compound like 1 is, be-
sides the fact that it can act as a Nazarov reagent, the extra func-
tionality provided by the hydroxyl group, which can be further
employed for the synthesis of diversity oriented compounds or as
a linker in solid support chemistry.6 It was observed that employing
Scheme 1. Reactivity of Nazarov reagent 1 with unsaturated aldehydes and prenal
derivatives.
b,b-disubstituted aldehydes, racemic pyrans B were obtained in-
organocatalyst I and
cyclohexenones A were obtained diastereoselectively.4 On the
other hand, using -Proline or derivatives, MacMillan catalysts,
L-Proline in a tandem reaction different
stead of the cyclohexenone ring (Scheme 1).5
Monosubstituted unsaturated aldehydes have been widely used
in organocatalysis for the synthesis of very interesting com-
L
thioureas or even chiral phosphoric acids in the reaction of 1 with
pounds.7 However,
b-methyl-b-disubstituted unsaturated alde-
hydes have been much less used in organocatalysis. Prof.
Serebryakov et al. have developed the asymmetric synthesis of
cyclohexa-1,3-dienes from prenal and unsaturated esters or de-
rivatives,8 Watanabe et al., using Proline as organocatalyst, made
citral to dimerise through a DielseAlder reaction9 and Christmann
* Corresponding author. Tel.: þ34 923294500; fax: þ34 923294574; e-mail ad-
dresses: sdrayosx@usal.es (F. Sanz), ddm@usal.es (D. Díez).
y
Tel.: þ34 923294474; fax: þ34 923294574.
z
Tel.: þ34 923294500; fax: þ34 923294574.
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.04.076
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2
et al. reported an intramolecular RauhuteCurier-type reaction via
dienamine activation.10 We realised that neither us, nor Prof. Ser-
ebryakov had employed the HayashieJørgensen organocatalyst.11
Thus, we decided to test the reactivity of sulfone 1 with citral 4b
using organocatalyst (S)-3. To our delight the reaction worked and
surprisingly led to a new structure, namely cyclohexa-1,3-dienes,
instead of cyclohexenones or pyran rings, constituting the first time
that a Nazarov reagent acts as dienophile using organocatalysis
(Scheme 1). This fact gives an idea that organocatalysis is still an
undeveloped area and that a reaction can be diversely directed just
by tuning the organocatalyst used.
conditions except for benzoic acid (entry 3). Brønsted bases had
similar effect, and although lithium or sodium acetate made a good
improvement, the reaction time increased (entries 6e10). Lewis
acids did not produce any reaction (entries 11 and 12). Solvent
screening (entries 13e20) proved EtOH to be the best solvent. After
testing the sulfone/aldehyde ratio (entries 21 and 22) and the use of
benzoic acid (entry 23) we found the best conditions were a sul-
fone/aldehyde ratio of 2/1 and 20% of benzoic acid in EtOH. The ee
was measured for the best conditions (entries 20 and 23) observing
that the use of benzoic acid slightly increased the yield and the
enantiomeric excess (ee) as before. Finally we carried out a study of
catalyst loading (Table 2), finding that a 50 mol % catalyst was the
optimum amount needed for the best yield and ee. The absolute
stereochemistry was determined by X-ray analysis of an analogue
as shown later on.
2. Results and discussion
Cyclohexa-1,3-dienes and their derivatives are structurally im-
portant since they are versatile intermediates for the synthesis of
natural products and biologically active compounds.12 We started
our study (Table 1) using commercially available 3-methyl-butenal
4a and sulfone 2 since, as we previously demonstrated,4,5 it behaves
exactly the same as 1 but the tetrahydropyranyl (THP) protecting
group is much more easily removable.
Table 2
Catalyst load screeninga
Entry
Catalyst (S)-3 (mol %)
Yieldb (%)
eec (%)
1
2
3
4
5
5
10
20
50
100
S.M.
S.M.
39
79
75
d
d
89
92
90
Table 1
Reaction of Nazarov reagent 2 with 4aa
Bold value signifies the best conditions with the best results found.
a
All the reactions were carried out at rt, in EtOH at 0.18 M in 48 h, with a 2/1 ratio
of 2/4a and 20 mol % benzoic acid.
b
Isolated yield of 6a after chromatography on silica gel.
ee determined by HPLC analysis, carried out on a CHIRALCEL IC column; n-
c
hexane/2-propanol [60/40 (v/v)]; flow rate: 1.0 mL/min.
Once the best conditions were established for this reaction,
several b,b-alkylsubstituted aldehydes 4aef, were tested with dif-
ferently protected sulfones 1 and 2 (Table 3).
Entry
2/4a Ratio
Additive (20 mol %)
Solvent
Timeb
Yieldc (%)
1
2
3
4
5
6
7
8
2/1
1/2
2/1
2/1
2/1
2/1
2/1
2/1
2/1
2/1
2/1
2/1
2/1
2/1
2/1
2/1
2/1
2/1
2/1
2/1
1/2
1/1
2/1
d
2-Propanol
2-Propanol
2-Propanol
2-Propanol
2-Propanol
2-Propanol
2-Propanol
2-Propanol
2-Propanol
2-Propanol
2-Propanol
2-Propanol
Hexane
Toluene
CH2Cl2
CHCl3
Et2O
THF
MeOH
EtOH
EtOH
EtOH
47 h
44 h
47 h
46 h
40 h
7 days
6 days
2 days
3 days
6 days
42 h
47 h
80 h
79 h
74 h
71 h
30 h
46 h
56 h
49 h
24 h
45 h
48 h
42
49
50
27
13
17
31
60
65
63
S.M.
S.M.
23
66
67
73
26
32
DEC
75d
40
7
d
When sulfone 1 was used, yields were from moderate to good
except for compounds 5c and 5e (entries 3 and 5) due to a possible
oxo-Michael reaction.13 The enantiomeric excess in all cases vary
from good to excellent. Similar behaviour was observed when using
sulfone 2. In this case and in order to corroborate the obtained
results, enantiomeric catalyst (R)-3 was used (entries 7, 9 and 13)
obtaining the corresponding enantiomers with similar ee, adding
more versatility to this procedure.
B.A.
BinapOH
p-TsOH
Na2CO3
K2CO3
CsCO3
LiOAc$ H2O
NaOAc
FeCl3$6H2O
ZnCl2
d
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
It can be concluded that when both
b-substituents are alkyl
groups, cyclohexa-1,3-diene derivatives 5/6 are obtained from low
to good yields (16e79%) and in good to excellent ee (75e92%).
Compounds 5/6 obtention can be understood through a Diel-
seAlder mechanism between dienamine II formed between the
d
d
d
d
d
catalyst and the a,b
-unsaturated aldehyde,14 and the Nazarov re-
d
d
agent acting as dienophile similarly as in the cases of Prof. Sere-
bryakov et al.8 It is noteworthy that in this reaction the diene is
established with the methyl group and not with the methylene
group as in the case of the RauhuteCurier-type reaction of Christ-
mann et al. (Fig. 1).10a Intermediate III is demonstrated by NMR and
HRMS experiments and observed its slowly transformation into the
final products.
d
d
B.A.
EtOH
79e
Bold value signifies the best conditions with the best results found.
a
All the reactions were carried out at rt, in the corresponding solvent at 0.18 M
and 50 mol % (S)-3.
b
Time in which highest yield was observed with no decomposition (the con-
sumption of starting materials was monitored by TLC).
With these results in hand we decided to test the behaviour
when one of the alkyl groups is changed to an aromatic ring. Using
Nazarov reagent 2 with different aromatic aldehydes under the
same conditions, cyclohexa-1,3-dienes 7 were formed instead of
cyclohexa-1,3-dienes 6 (Table 4). The stereochemistry at the new
chiral centre in 7 is proposed to come from a 1,5-H sigmatropic
rearrangement, since the formation of the same intermediate III is
observed with both aliphatic and aromatic substituents. As shown
in Table 4, yields and enantiomeric excesses are good in all cases.
In order to see the value of this reaction, different compounds in
a diversity oriented strategy were obtained. Compound 5a was
submitted to oxygen atmosphere and direct sunlight using Rose
c
Isolated yield after chromatography on silica gel.
89% ee determined by HPLC.
d
e
92% ee determined by HPLC. B.A.¼benzoic acid. BinapOH¼(S)-(þ)-1,19-
binaphthyl-2,29-diyl
hydrogen
phosphate.
S.M.¼Starting
Material.
DEC¼decomposition.
A screening of different sulfone/aldehyde ratios, solvents and
additives was carried out in order to test the importance of the
substituent.
As shown in Table 1, the sulfone/aldehyde ratio did not change
the reaction yield substantially, (entries 1 and 2). Use of acid ad-
ditives (entries 3e5) decreased yields comparing to initial
b-
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3
Table 3
Table 4
Reaction of Nazarov reagents 1,2 with prenals 4aefa
Reaction of Nazarov reagent 2 with aromatic-
b
-substituted unsaturated aldehydesa
Entry
Aldehyde
Product
Yieldb (%)
eec (%)
1
2
3
4
4g
4h
4i
7g
7h
7i
59
69
59
81
91
90
91
93
4j
7j
Bold value signifies the best conditions with the best results found.
a
All the reactions were carried out at rt, in EtOH at 0.18 M in 48 h, with a 2/1 ratio
of 2/4gej, 50 mol % (S)-3 and 20 mol % benzoic acid.
b
Isolated yield after chromatography on silica gel.
ee determined by HPLC analysis, carried out on a CHIRALCEL AD-H column;
c
n-hexane/isopropyl alcohol [80/20e70/30 (v/v)]; flow rate: 1.0 mL/min.
Entry
Sulfone
Aldehyde
Product
Yieldb (%)
eec (%)
1
2
3
4
1
1
1
1
1
2
2
2
2
2
2
2
2
2
4a
4b
4c
4d
4e
4a
4a
4b
4b
4c
4d
4d
4e
4f
5a
5b
5c
5d
5e
6a
ent-6a
6b
ent-6b
6c
62
69
20
58
24
79
75
62
65
49
16
33
36
32
79
82
80
75
39
5
6
92
7d
8
ꢀ92
90
9d
10
11
12
13d
14
ꢀ91
80
88
6d
6e
ent-6e
6f
89
ꢀ89
91
Bold value signifies the best conditions with the best results found.
a
All the reactions were carried out at rt, in EtOH at 0.18 M in 48 h, with a 2/1 ratio
of sulfone/aldehyde, 50 mol % (S)-3 and 20 mol % benzoic acid.
b
Isolated yield after chromatography on silica gel.
ee determined by HPLC analysis, carried out on a CHIRALCEL IC column; n-
c
Scheme 2. (a) O2 atmosphere, Rose Bengal (25 mol %), sunlight, MeOH, rt, 4 h; (b)
acrolein (2 equiv), K2CO3 (8 equiv), THF, rt, 4 h; (c) p-TsOH$H2O (50 mol %), THF/H2O
(1/1), rt; (d) MsCl, Et3N, DMAP, DCM, rt; (e) DBU, DCM, rt.
hexane/2-propanol [60/40 (v/v)]; flow rate: 1.0 mL/min.
d
Using catalyst (R)-3.
cyclohexadienes 6 and 7 formed in the organocatalytic reaction
(Fig. 2).15 Mesylation of 10 afforded 11, which by treatment in basic
conditions led to triene 12. The double bond stereochemistry of this
enolether was established by NOE’s experiments (Scheme 2). Aro-
matic derivatives 7gej were submitted to the same conditions, i.e.,
deprotection and mesylation, but the resulting compounds were
more unstable than aliphatics and only mesylated phenyl de-
rivative 14 obtained from 13g could be isolated. Aromatic triene 15
was observed by NMR, after basic treatment of 14, but was not
stable enough to be fully characterised. Compounds as 13g are
precursors of carbonyliron complexes and further studies will be
conducted in this way.16
Fig. 1. Proposed DielseAlder mechanism for the synthesis of 5/6.
Bengal as catalyst to provide 8 in moderate yield (Scheme 2). Diene
6a was made to react with acrolein affording 9 in good yield. Un-
fortunately compound 9 was much less reactive than expected and
did not react when submitted to intramolecular hetero-Diel-
seAlder conditions, and when compound 6a was submitted to
a variety of dienophiles (dihydropyran, maleimide and N-phenyl-
maleimide, maleic anhydride, 2-pentenal or diphenylmethani-
mine) only starting materials or degradation products were
obtained. Thus compound 6a was deprotected affording 10, al-
though with some racemisation, but we were able to crystallise it
and allowing us to establish the absolute configuration of
Fig. 2. ORTEP diagram for compound 10.
More diversity oriented structures were obtained from re-
activity studies of diene 10 and triene 12 (Scheme 3, Table 5). When
10 was treated with m-CPBA a 1/1 mixture of tetrahydrofuran and
tetrahydropyran 16/17 was obtained in moderate yield. However, if
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4
chemical ionisation (ammonia as gas) or Fast Atom Bombardment
(FAB) technique. For some of the samples, electrospray ionisation
(ESI) was employed. Optical rotations were determined in 1 dm cell.
HPLC analysis were carried out on a chiral column [amylose
tris(3,5-dimethylphenycarbamate)]
or
[cellulose
tris(3,5-
dichlorophenycarbamate)] on silica gel using n-hexane/2-
propanol. Column chromatography was performed using silica gel
60 (230e400 mesh), with solvent systems indicated in the relevant
experimental procedures. Dichloromethane was distilled from
calcium hydride. Tetrahydrofuran and diethyl ether were distilled
from sodium/benzophenone ketyl under argon atmosphere prior to
use. Hexane was distilled prior to use.
Scheme 3. (a) m-CPBA, CDCl3, 0 ꢂC e rt; (b) CHCl3, heat (37 ꢂC).
Table 5
4.2. General procedure for the synthesis of cyclohexadienes,
5aee, 6aef and 7gej
Reactivity of compounds 9 and 10a
Entry
S.M.
Conditions
Time (h)
Product
Yieldb (%)
1
2
3
4
10
12
12
12
m-CPBA
15
6
72
2.5
16þ17 (1/1)
38
62
53
42
b
-Ketosulfone (1,2) (0.18 mmol) and the corresponding alde-
m-CPBA
16
16
19
hyde (0.08 mmol) were dissolved in 1 ml of EtOH. Next, catalyst (S)-
3 (50 mol %), and benzoic acid (20 mol %) were added successively
and left stirring at room temperature for 48 h. All products were
purified by flash chromatography on silica gel using different
mixtures of n-hexane/ethyl acetate.
Heatc (37 ꢂC)
PVS,d 90 ꢂC
a
For more details see ESI.
Isolated yield after chromatography on silica gel.
Under air atmosphere.
b
c
d
Phenylvinylsulfone.
4.2.1. (S)-1-(6-((Methoxymethoxy)methyl)-4-(methyl)-cyclohexa-
compound 12 was submitted to the same conditions, or just heat-
ing, only 16 was obtained in better yields in a chemo, regio- and
stereocontrolled way. This substructure is present in quinocycline
and isoquinocycline compounds with antibiotic and cytotoxic ac-
tivities.17 In this case it was possible to isolate intermediate epoxide
18, corroborating the mechanism of the reaction. Analogues of
these compounds have been used for the synthesis of natural
products.18 This kind of compounds is related to Bruceantin, an
antitumour agent isolated from Bruceas species.19 When compound
12 was heated in benzene in the presence of phenylvinylsulfone
(PVS) cyclobutane 19 was obtained by a [2þ2] cycloaddition in
moderate yield, adding even more versatility to these compounds.
1,3-dien-1-yl)-2-(phenylsulfonyl)ethan-1-one
(5a). Yellow
oil
(17.4 mg, 62%): nmax (liquid film) 2929, 1718, 1629, 1570, 1448, 1383,
1309, 1290, 1151; dH (200 MHz; CDCl3) 7.89 (2H, d, J¼6.9 Hz),
7.81e7.24 (3H, m), 7.03 (1H, d, J¼5.9 Hz), 6.02e5.78 (1H, m), 4.54
(2H, s), 4.45 (2H, d, J¼8.1 Hz), 3.31 (3H, s), 3.21e3.16 (3H, m),
2.55e2.28 (1H, m), 1.92 (3H, s), 1.65e1.58 (1H, m); dC (50 MHz;
CDCl3) 186.6, 148.4, 140.7, 139.0, 134.3, 133.1, 129.4 (2CH), 128.8
(2CH),119.2, 96.6, 66.0, 62.8, 55.4, 31.1, 30.8, 24.4; EIHRMS: calcd for
C
18H22O5S (MþNa): 373.1086; found: 373.1080 (MþNa). ee: de-
termined by HPLC: CHIRALPAK IC column; n-hexane/isopropyl al-
cohol [60/40 (v/v)]; flow rate: 1.0 mL/min;
l
¼325 nm; tR (minor)¼
37.5 min; tR (major)¼41.6 min; ½a D25
ꢁ
ꢀ9.57 (c 1.42, CHCl3).
3. Conclusions
4.2.2. (S)-1-(6-((Methoxymethoxy)methyl)-4-(4-methylpent-3-en-1-
yl)cyclohexa-1,3-dien-1-yl)-2-(phenylsulfonyl)ethan-1-one
(5b). Yellow oil (23.1 mg, 69%): nmax (liquid film) 2956, 2929, 2873,
1715, 1651, 1566, 1446, 1323, 1288, 1153; dH (400 MHz; CDCl3) 7.89
(2H, d, J¼7.0 Hz), 7.72e7.47 (3H, m), 7.06 (1H, d, J¼6.0 Hz),
6.02e5.80 (1H, m), 5.12e4.76 (1H, m), 4.54 (2H, s), 4.54e4.51 (1H,
m), 4.49e4.41 (1H, m), 3.31 (3H, s), 3.19e3.14 (3H, m), 2.53 (1H, d,
J¼17.8 Hz), 2.23e2.11 (4H, m), 1.69 (3H, s), 1.61 (3H, s), 1.40e1.35
(1H, m); dC (100 MHz; CDCl3) 186.6, 152.0, 140.7, 139.0, 134.3, 133.4,
132.7, 129.4 (2CH), 128.8 (2CH), 123.3, 118.6, 96.6, 65.9, 62.8, 55.4,
38.2, 30.7, 29.7, 26.0, 25.9, 17.9; EIHRMS: calcd for C23H30O5S
(MþNa): 441.1712; found: 441.1706 (MþNa). ee: determined by
HPLC: CHIRALPAK IC column; n-hexane/isopropyl alcohol [60/40
In conclusion, it has been made a sulfone Nazarov reagent to
react in organocatalytic conditions in a DielseAlder manner for the
first time. This reaction has made possible to obtain diverse chiral
highly functionalised cyclohexa-1,3-dienes, depending on whether
the aldehyde substitution is an alkyl or aryl group. These kinds of
cyclohexadienes have been used in DielseAlder bioconjugation of
diene modified oligonucleotides.20 Herein, we report their appli-
cation for the synthesis of different bicyclic or tricyclic compounds
in a diversity oriented synthesis, opening the way for the use of
these compounds in bioconjugation chemistry.
4. Experimental section
(v/v)]; flow rate: 1.0 mL/min;
l
¼325 nm; tR (minor)¼31.6 min; tR
(major)¼34.5 min; ½a D25
ꢁ
ꢀ4.56 (c 0.57, CHCl3).
4.1. General experimental methods
4.2.3. (S,E)-1-(6-((Methoxymethoxy)methyl)-4-(4-methyl-5-
hydroxy-pent-3-en-1-yl)cyclohexa-1,3-dien-1-yl)-2-(phenylsulfonyl)
ethan-1-one (5c). Yellow oil (6.9 mg, 20%): nmax (liquid film) 3452,
2935, 2885, 1716, 1637, 1564, 1446, 1379, 1309, 1292, 1151; dH
(200 MHz; CDCl3) 7.89 (2H, d, J¼7.0 Hz), 7.75e7.48 (3H, m), 7.06
(1H, d, J¼5.8 Hz), 5.94 (1H, d, J¼4.9 Hz), 5.43e5.32 (1H, m), 4.54
(2H, s), 4.54e4.35 (2H, d, J¼9.1 Hz), 4.00 (2H, s), 3.31 (3H, s),
3.22e3.19 (3H, m), 2.53 (1H, d, J¼18.2 Hz), 2.35e2.19 (4H, m), 1.69
(3H, s), 1.33e1.08 (1H, m); dC (50 MHz; CDCl3) 186.6, 151.5, 140.5,
139.0,136.1, 134.3,133.5,129.4 (2CH), 128.7 (2CH),124.4,118.9, 96.6,
68.8, 65.9, 62.8, 55.5, 37.6, 30.6, 29.7, 25.6, 13.9; EIHRMS: calcd for
Unless otherwise stated, all chemicals were purchased as the
highest purity commercially available and were used without fur-
ther purification, except for 1,4 2,5 10-hydroxycitral 4c,21 4d, far-
nesal 4e22 and 4f,23 which were synthesised according to the
literature procedures. Melting points are uncorrected. 1H and 13C
NMR spectra were measured on 200, 400 and 600 MHz spec-
trometers and performed in CDCl3 or C6D6, and referenced to the
residual peak of CHCl3 at
sidual peak of C6H6 at 7.15 ppm and
respectively. Chemical shifts are reported in
d
7.26 ppm and
128.6 ppm, for 1H and 13C,
parts per million and
d 77.0 ppm or to the re-
d
d
d
coupling constants (J) are given in hertz. High-resolution mass
spectra were recorded on an ESI-Q-TOF mass spectrometer, using
C
23H30O6S (MþNa): 457.1661; found: 457.1655 (MþNa). ee: de-
termined by HPLC: CHIRALPAK IC column; n-hexane/isopropyl
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5
alcohol [60/40 (v/v)]; flow rate: 1.0 mL/min;
l
¼325 nm; tR
(50 MHz; CDCl3) 186.7, 152.1, 140.6, 139.1, 134.3, 133.4, 132.6, 129.3
(2CH), 128.8 (2CH), 123.3, 118.7, 99.1, 65.5, 62.9, 62.4, 38.2, 30.8,
30.7, 29.8, 25.9, 25.8, 25.7, 19.5, 17.9; EIHRMS: calcd for C26H34O5S
(MþNa): 481.2025; found: 481.2019 (MþNa). ee: determined by
HPLC: CHIRALPAK IC column; n-hexane/isopropyl alcohol [60/40
(minor)¼58.8 min; tR (major)¼67.9 min; ½a D25
ꢁ
ꢀ1.02 (c 1.08, CHCl3).
4.2.4. 1-((6S)-(6-((Methoxymethoxy)methyl)-4-(2-((1S,4aS,8aS)-
5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)ethyl)-2-
(phenylsulfonyl))ethan-1-one (5d). Yellow oil (25.7 mg, 58%): nmax
(liquid film) 2937, 2848, 1718, 1649, 1566, 1446, 1321, 1309, 1151; dH
(200 MHz; CDCl3) 7.89 (2H, d, J¼7.9), 7.71e7.40 (3H, m), 7.06 (1H, d,
J¼5.7 Hz), 5.97e5.79 (1H, m), 4.84 (1H, s), 4.54 (2H, s), 4.54e4.42
(4H, m), 4.27 (1H, s), 3.31 (3H, s), 3.21e3.16 (3H, m), 2.59e2.40 (1H,
m), 2.44e0.74 (24H, m); dC (50 MHz; CDCl3) 186.6, 153.2, 148.6,
140.9,138.9,134.3,133.7,129.4 (2CH),128.8 (2CH),118.2,106.6, 96.6,
65.9, 62.8, 56.7, 55.7, 55.4, 42.3, 40.0, 39.9, 39.3, 38.5, 33.8, 33.5,
30.7, 28.6, 24.7, 21.9, 19.6, 19.2, 14.7; EIHRMS: calcd for C33H46O5S
(MþNa): 577.2964; found: 577.2958 (MþNa). ee: determined by
HPLC: CHIRALPAK IC column; n-hexane/isopropyl alcohol [60/40
(v/v)]; flow rate: 1.0 mL/min;
l
¼325 nm; tR (minor)¼36.6 min; tR
(major)¼43.4 min, 56.8 min; ½a D25
ꢀ15.1 (c 2.63, CHCl3).
ꢁ
4.2.9. (R)-1-(6-((Tetrahydro-2H-pyran-2-yl)oxy)methyl)-4-(4-
methylpent-3-en-1-yl)cyclohexa-1,3-dien-1-yl)-2-(phenylsulfonyl)
ethan-1-one (ent-6b). Yellow oil (23.8 mg, 65%): ½a D25
þ7.81 (c 0.71,
ꢁ
CHCl3).
4.2.10. (S)-1-(6-((Tetrahydro-2H-pyran-2-yl)oxy)methyl)-4-(4-
methyl-5-hydroxy-pent-3-en-1-yl)cyclohexa-1,3-dien-1-yl)-2-(phe-
nylsulfonyl)ethan-1-one (6c). Yellow oil (18.6 mg, 49%): nmax (liquid
film) 3449, 2943, 2870, 1718, 1651, 1564, 1446, 1383, 1321, 1309,
1290, 1153; dH (200 MHz; CDCl3) 7.89 (2H, d, J¼7.6 Hz), 7.68e7.49
(3H, m), 7.04 (1H, d, J¼5.7 Hz), 6.01e5.85 (1H, m), 5.49e5.31 (1H,
m), 4.66e4.40 (3H, m), 3.99 (2H, s), 3.84e3.64 (1H, m), 3.57e3.31
(2H, m), 3.26e3.00 (2H, m), 2.71e2.50 (1H, m), 2.37e2.20 (4H, m),
1.67 (3H, s), 1.59e1.35 (7H, m); dC (50 MHz; CDCl3) 186.7, 151.3,
140.5, 139.1, 136.1, 134.3, 133.4, 129.4 (2CH), 128.8 (2CH), 124.4,
118.9, 99.0, 68.7, 65.6, 62.8, 62.1, 37.6, 30.8, 30.6, 29.7, 25.6, 25.0,
19.5, 13.9; EIHRMS: calcd for C26H34O6S (MþNa): 497.1974; found:
497.1947 (MþNa). ee: determined by HPLC: CHIRALPAK IC column;
n-hexane/isopropyl alcohol [60/40 (v/v)]; flow rate: 1.0 mL/min;
(v/v)]; flow rate: 1.0 mL/min;
l
¼325 nm; tR (minor)¼31.4 min; tR
(major)¼33.3 min; ½a D25
ꢁ
þ13.98 (c 2.21, CHCl3).
4.2.5. (S,E)-1-(6-((Methoxymethoxy)methyl)-4-(4,8-dimethylnon-
3,7-dien-1-yl)cyclohexa-1,3-dien-1-yl)-2-(phenylsulfonyl)ethan-1-
one (5e). Yellow oil (9.3 mg, 24%): nmax (liquid film) 2926, 2856,
1716, 1651, 1566, 1448, 1379, 1309, 1288, 1153; dH (200 MHz; CDCl3)
7.89 (2H, d, J¼8.2 Hz), 7.68e7.42 (3H, m), 7.06 (1H, d, J¼5.8 Hz),
6.02e5.83 (1H, m), 5.28e4.93 (2H, m), 4.54 (2H, s), 4.50e4.40 (2H,
m), 3.31 (3H, s), 3.22e3.11 (3H, m), 2.54 (1H, d, J¼18.2 Hz),
2.31e2.14 (8H, m), 1.68 (3H, s), 1.61 (6H, s), 1.35e1.10 (1H, m); dC
(50 MHz; CDCl3) 186.9, 152.1, 140.8, 136.3, 134.3, 133.4, 133.3, 130.4,
129.4 (2CH), 128.8 (2CH), 124.4, 123.3, 118.6, 96.6, 66.0, 62.8, 55.4,
39.9, 38.3, 30.7, 29.7, 26.9, 25.9 (2CH2), 17.9, 16.3; EIHRMS: calcd for
l
¼360 nm; tR (minor)¼60.4, 64.0 min; tR (major)¼89.7, 124.6 min;
½
a 2D5
ꢁ
ꢀ5.78 (c 2.49, CHCl3).
C
28H38O5S (MþNa): 509.2338; found: 509.2332 (MþNa). ee: de-
4.2.11. 1-((6S)-6-((Tetrahydro-2H-pyran-2-yl)oxy)methyl)-4-(2-
((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-
yl)ethyl)-2-(phenylsulfonyl)ethan-1-one (6d). Yellow oil (7.6 mg,
16%): nmax (liquid film) 2941, 2868, 1718, 1649, 1564, 1448, 1321,
1309, 1155; dH (200 MHz; CDCl3) 7.97e7.83 (2H, m), 7.73e7.40 (3H,
m), 7.05 (1H, d, J¼5.8 Hz), 6.03e5.84 (1H, m), 4.85 (1H, s), 4.61e4.31
(4H, m), 3.93e3.68 (1H, m), 3.57e3.28 (2H, m), 3.22e2.94 (2H, m),
2.63e2.43 (1H, m), 2.40e0.69 (32H, m); dC (50 MHz; CDCl3) 186.7,
153.4, 148.6, 140.8, 139.0, 134.3, 133.6, 129.3 (2CH), 128.8 (2CH),
118.3, 106.6, 98.7, 65.4, 62.9, 62.1, 57.9, 55.8, 42.4, 40.0, 39.9, 39.3,
38.6, 37.1, 33.8, 33.5, 30.6, 29.9, 25.6, 24.7, 21.9, 19.6 (2CH2), 19.2,
14.7; EIHRMS: calcd for C36H50O5S (MþNa): 617.3277; found:
617.3271 (MþNa). ee: determined by HPLC: CHIRALPAK IC column;
n-hexane/isopropyl alcohol [60/40 (v/v)]; flow rate: 1.0 mL/min;
termined by HPLC: CHIRALPAK IC column; n-hexane/isopropyl al-
cohol [60/40 (v/v)]; flow rate: 1.0 mL/min;
l
¼325 nm; tR (major)¼
29.1 min; tR (minor)¼34.8 min; ½a D25
ꢁ
ꢀ12.07 (c 1.42, CHCl3).
4.2.6. (S)-1-(6-((Tetrahydro-2H-pyran-2-yl)oxy)methyl)-4-(methyl)
cyclohexa-1,3-dien-1-yl)-2-(phenylsulfonyl)ethan-1-one (6a). Note:
The presence of THP protecting group makes many of NMR signals,
both 1H and 13C, to appear twice. Hence, for compounds with THP
group only NMR shift values for one isomer are given here.
Yellow oil (24.6 mg, 79%): nmax (liquid film) 2941, 2868, 1718,
1637, 1570, 1446, 1383, 1323, 1309, 1288, 1153; dH (200 MHz; CDCl3)
7.89 (2H, d, J¼8.3 Hz), 7.71e7.50 (3H, m), 7.02 (1H, d, J¼5.9 Hz),
6.02e5.73 (1H, m), 4.57e4.33 (3H, m), 3.83e3.69 (1H, m),
3.50e3.35 (2H, m), 3.21e3.10 (1H, m), 3.09e2.98 (1H, m),
2.67e2.48 (1H, m), 1.92 (3H, s), 1.84e1.39 (7H, m); dC (50 MHz;
CDCl3) 186.6, 148.6, 140.7, 139.0, 134.3, 133.1, 129.4 (2CH), 128.8
(2CH), 119.2, 99.2, 65.5, 62.8, 62.4, 31.4, 31.1, 30.8, 25.6, 24.4, 19.7;
EIHRMS: calcd for C21H26O5S (MþNa): 413.1399; found: 413.1393
(MþNa). ee: determined by HPLC: CHIRALPAK IC column; n-hex-
ane/isopropyl alcohol [60/40 (v/v)]; flow rate: 1.0 mL/min;
l
¼360 nm; tR (minor)¼35.4 min; tR (major)¼40.0, 49.0 min; ½a D25
ꢁ
þ22.90 (c 1.43, CHCl3).
4.2.12. (S,E)-1-(6-((Tetrahydro-2H-pyran-2-yl)oxy)methyl)-4-(4,8-
dimethylnon-3,7-dien-1-yl)cyclohexa-1,3-dien-1-yl)-2-(phenyl-
sulfonyl)ethan-1-one (6e). Yellow oil (14.1 mg, 33%): nmax (liquid
film) 2937, 2868, 1716, 1651, 1566, 1448, 1381, 1321, 1309, 1288,
1155; dH (200 MHz; CDCl3) 7.95e7.82 (2H, m), 7.73e7.40 (3H, m),
7.04 (1H, d, J¼6.0 Hz), 5.98e5.82 (1H, m), 5.21e4.98 (2H, m),
4.60e4.32 (3H, m), 3.87e3.66 (1H, m), 3.57e3.28 (2H, m),
3.25e2.98 (2H, m), 2.66e2.42 (1H, m), 2.35e2.12 (4H, m), 2.11e1.83
(4H, m), 1.78e1.45 (16H, m); dC (50 MHz; CDCl3) 186.7, 152.0, 140.6,
139.1, 134.3, 133.8, 133.5, 130.3, 129.3 (2CH), 128.8 (2CH), 124.4,
123.3, 118.5, 98.7, 66.1, 62.9, 62.4, 39.9, 38.3, 30.8, 30.7, 29.8, 26.9,
25.9, 25.7, 25.6, 23.6, 19.5, 17.9; EIHRMS: calcd for C31H42O5S
(MþNa): 549.2641; found: 549.2645 (MþNa). ee: determined by
HPLC: CHIRALPAK IC column; n-hexane/isopropyl alcohol [60/40
l
¼325 nm; tR (minor)¼41.5 min; tR (major)¼49.9, 66.5 min; ½a D25
ꢁ
ꢀ15.0 (c 0.16, CHCl3).
4.2.7. (R)-1-(6-((Tetrahydro-2H-pyran-2-yl)oxy)methyl)-4-(methyl)
cyclohexa-1,3-dien-1-yl)-2-(phenylsulfonyl)ethan-1-one (ent-6a).
Yellow oil (23.4 mg, 75%); ½a D25
þ8.9 (c 0.9, CHCl3).
ꢁ
4.2.8. (S)-1-(6-((Tetrahydro-2H-pyran-2-yl)oxy)methyl)-4-(4-
methylpent-3-en-1-yl)cyclohexa-1,3-dien-1-yl)-2-(phenylsulfonyl)
ethan-1-one (6b). Yellow oil (22.7 mg, 62%): nmax (liquid film) 2941,
2870, 1716, 1651, 1566, 1446, 1381, 1321, 1309, 1288, 1153; dH
(200 MHz; CDCl3) 7.89 (2H, d, J¼8.1 Hz), 7.68e7.40 (3H, m), 7.04
(1H, d, J¼5.9 Hz), 5.98e5.83 (1H, m), 5.11e5.01 (1H, m), 4.62e4.33
(3H, m), 3.88e3.60 (1H, m), 3.59e3.27 (2H, m), 3.26e2.92 (2H, m),
2.57e2.39 (1H, m), 2.25e2.13 (4H, m), 1.72e1.39 (13H, m); dC
(v/v)]; flow rate: 1.0 mL/min;
l
¼360 nm; tR (minor)¼29.3 min; tR
(major)¼33.6, 40.8 min; ½a D25
ꢁ
ꢀ3.87 (c 1.60, CHCl3).
4.2.13. (R)-1-(6-((Tetrahydro-2H-pyran-2-yl)oxy)methyl)-4-(4,8-
dimethylnon-3,7-dien-1-yl)cyclohexa-1,3-dien-1-yl)-2-
~
Please cite this article in press as: Pena, J.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.04.076

~
J. Pena et al. / Tetrahedron xxx (2014) 1e9
6
(phenylsulfonyl)ethan-1-one (ent-6e). Yellow oil (15.1 mg, 36%):
a 2D5
þ18.57 (c 0.56, CHCl3).
1.0 mL/min;
l
¼350 nm; tR (major) 30.3, 31.8 min; tR (minor)¼
½
ꢁ
34.6 min; ½a 2D5
ꢁ þ46.80 (c 1.02, CHCl3).
4.2.14. (S)-1-(6-((Tetrahydro-2H-pyran-2-yl)oxy)methyl)-4-(4-
methyl-4-hydroxy-pentan-1-yl)cyclohexa-1,3-dien-1-yl)-2-(phenyl-
sulfonyl)ethan-1-one (6f). Yellow oil (12.2 mg, 32%): nmax (liquid
film) 3460, 2943, 2870, 1716, 16,457, 1566, 1448, 1379, 1323, 1309,
1290, 1153; dH (200 MHz; CDCl3) 7.89 (2H, d, J¼8.5 Hz), 7.75e7.46
(3H, m), 7.02 (1H, d, J¼5.8 Hz), 5.97e5.79 (1H, m), 4.57e4.29 (3H,
m), 3.93e3.63 (1H, m), 3.51e3.24 (2H, m), 3.21e2.92 (2H, m),
2.74e2.41 (1H, m), 2.30e2.01 (4H, m), 1.76e1.33 (9H, m), 1.32e1.14
(6H, m); dC (50 MHz; CDCl3) 186.6, 152.4, 140.7, 139.1, 134.3, 133.3,
129.4 (2CH), 128.8 (2CH), 119.1, 99.3, 70.6, 65.6, 62.8, 62.3, 43.5,
38.3, 38.0, 31.1, 30.8, 29.7, 29.6, 28.9, 25.6, 19.6; EIHRMS: calcd for
4.2.18. (R)-2-(6-((Tetrahydro-2H-pyran-2-yl)oxy)methyl)-5-(3-
bromophenyl)cyclohexa-1,3-dien-1-yl)-2-(phenylsulfonyl)ethan-1-
one (7j). Yellow oil (34.3 mg, 81%): nmax (liquid film) 2943, 2870,
1717, 1651, 1547, 1448, 1408, 1323, 1309, 1290, 1155; dH (200 MHz;
CDCl3) 7.91 (2H, d, J¼7.8 Hz), 7.74e7.39 (3H, m), 7.33e7.13 (5H, m),
6.50 (1H, dd, J¼6.0, 2.6 Hz), 4.64e4.39 (3H, m), 3.83e3.65 (1H, m),
3.63e3.26 (3H, m), 3.23e2.94 (2H, m), 2.78e2.55 (1H, m),
1.88e1.34 (6H, m); dC (50 MHz; CDCl3) 186.8, 144.7, 141.9, 141.7,
139.7, 138.9, 134.4 (2CH), 132.0, 130.4, 129.4 (2CH), 128.7 (2CH),
124.7, 123.1, 120.6, 98.7, 65.1, 63.0, 62.2, 31.2, 30.8, 28.2, 25.6, 19.7;
EIHRMS: calcd for
553.0655 (MþNa). ee: determined by HPLC: CHIRALPAK AD-H
C
26H27BrO5S (MþNa): 553.0660; found:
C
26H36O6S (MþNa): 499.2130; found: 499.2125 (MþNa). ee: de-
termined by HPLC: CHIRALPAK IC column; n-hexane/isopropyl
column; n-hexane/isopropyl alcohol [60/40 (v/v)]; flow rate:
alcohol [60/40 (v/v)]; flow rate: 1.0 mL/min;
l
¼350 nm; tR
1.0 mL/min;
l
¼350 nm; tR (major)¼23.6 min; tR (minor)¼26.9 min;
(minor)¼44.6; tR (major)¼51.4, 61.9 min; ½a D25
ꢁ
þ13.91 (c 1.86,
½ ꢁ
a 2D5
þ30.09 (c 1.29, CHCl3).
CHCl3).
4.3. Synthesis of 1-((1S,4S,7R)-7-((methoxymethoxy)methyl)-
4-methyl-2,3-dioxabicyclo[2.2.2]oct-5-en-1-yl)-2-(phenyl-
sulfonyl)ethan-1-one (8)
4.2.15. (R)-2-(1-((Tetrahydro-2H-pyran-2-yl)oxy)methyl)-5-(phenyl)
cyclohexa-1,3-dien-1-yl)-2-(phenylsulfonyl)ethan-1-one
(7g). Yellow oil (21.3 mg, 59%): nmax (liquid film) 2941, 2870, 1718,
1647, 1545, 1447, 1323, 1309, 1292, 1153; dH (400 MHz; CDCl3) 7.91
(2H, d, J¼7.3 Hz), 7.73e7.48 (3H, m), 7.47e7.34 (5H, m), 7.22 (1H, d,
J¼6.3 Hz), 6.53 (1H, dd, J¼6.1, 2.6 Hz), 4.65e4.38 (3H, m), 3.89e3.69
(1H, m), 3.49e3.35 (2H, m), 3.35e3.27 (1H, m), 3.15e3.00 (2H, m),
2.84e2.53 (1H, m), 1.89e1.30 (6H, m); dC (100 MHz; CDCl3) 186.5,
146.2, 140.0, 138.7, 134.6, 134.5, 134.1, 129.3, 129.1 (2CH), 128.6
(4CH), 126.0 (2CH), 119.2, 98.9, 64.9, 62.8, 61.9, 30.5, 30.9, 30.3, 25.3,
19.3; EIHRMS: calcd for C26H28O5S (MþNa): 475.1555; found:
475.1549 (MþNa). ee: determined by HPLC: CHIRALPAK AD-H
column; n-hexane/isopropyl alcohol [70/30 (v/v)]; flow rate:
Compound 5a (22 mg, 0.06 mmol) and Rose Bengal (15 mg,
0.015 mmol) were dissolved in 1 ml of MeOH and left to stir under
O2 atmosphere and solar light for 4 h. After the solvent was evap-
orated in vacuo, flash chromatography (n-hexane/EtOAc, 6:4)
afforded 8 as a yellow oil (7 mg, 33%). nmax (liquid film) 2957, 2929,
2873, 1728, 1448, 1323, 1311, 1290, 1149; dH (200 MHz; CDCl3) 8.01
(2H, d, J¼8.2 Hz), 7.75e7.52 (3H, m), 6.80 (1H, d, J¼8.5 Hz), 6.46 (1H,
d, J¼8.5 Hz), 4.74e4.36 (2H, m), 4.22 (2H, s), 3.45e3.26 (2H, m), 3.19
(3H, s), 3.18e3.06 (1H, m), 2.41e2.15 (2H, m), 1.48 (3H, s); dC
(50 MHz; CDCl3) 191.3, 139.9, 137.4, 134.2, 129.3 (2CH), 129.0 (2CH),
128.0, 96.5, 83.6, 76.3, 68.9, 62.4, 55.8, 39.0, 33.1, 21.1; EIHRMS:
calcd for C18H22O7S (MþNa): 405.0984; found: 405.0978 (MþNa).
1.0 mL/min;
l¼340 nm; tR (major)¼25.4, 27.0 min; tR (minor)¼
36.1 min; ½a 2D5
ꢁ þ18.42 (c 1.33, CHCl3).
½
a 2D5
ꢁ
þ8.15 (c 0.92, CHCl3).
4.2.16. (R)-2-(1-((Tetrahydro-2H-pyran-2-yl)oxy)methyl)-5-(4-
methylphenyl)cyclohexa-1,3-dien-1-yl)-2-(phenylsulfonyl)ethan-1-
one (7h). Yellow oil (25.7 mg, 69%): nmax (liquid film) 2941, 2870,
1720, 1645, 1539, 1448, 1383, 1323, 1309, 1292, 1155; dH (400 MHz;
CDCl3) 7.96e7.83 (2H, m), 7.74e7.37 (3H, m), 7.22e7.16 (5H, m),
6.50 (1H, ddd, J¼6.1, 2.7, 1.3 Hz), 4.60e4.49 (3H, m), 3.81e3.70
(1H, m), 3.49e3.35 (2H, m), 3.35e3.27 (1H, m), 3.15e3.00 (2H, m),
2.72e2.57 (1H, m), 2.37 (3H, s), 1.80e1.26 (6H, m); dC (100 MHz;
CDCl3) 186.4, 146.5, 140.2, 139.5, 139.0, 138.7, 136.7, 134.6, 128.8
(2CH), 128.6 (2CH), 129.6 (2CH), 126.2 (2CH), 118.4, 98.8, 64.9,
62.7, 61.8, 30.9, 30.8, 27.8, 25.3, 21.2, 19.3; EIHRMS: calcd for
4.4. Synthesis of 5-((6S)-4-methyl-6-(((tetrahydro-2H-pyran-
2-yl)oxy)methyl)cyclohexa-1,3-dien-1-yl)-5-oxo-4-(phenyl-
sulfonyl)pentanal (9)
A mixture of compound 6a (26 mg, 0.067 mmol) and potassium
carbonate (74 mg, 0.536 mmol) was suspended in THF (0.7 ml)
under an Argon atmosphere. The suspension was stirred at room
temperature for 10 min, and acrolein (9 mL, 0.133 mmol) was then
added. The reaction mixture was stirred for 17 h and then filtered
through CeliteÒ, which was washed with ethyl acetate. The com-
bined organic layers were washed with water, dried over Na2SO4,
filtered and all the volatiles evaporated. Flash chromatography (n-
hexane/EtOAc, 7:3) afforded 9 as a yellow oil (15 mg, 48%). nmax
(liquid film) 2941, 2870, 1722, 1651, 1637, 1566, 1446, 1386, 1321,
1309, 1288, 1149; dH (200 MHz; CDCl3) 9.68 (1H, s), 7.91e7.29 (5H,
m), 6.97 (1H, dd, J¼11.7, 5.8 Hz), 5.99e5.79 (1H, m), 4.93 (1H, dd,
J¼9.3H, 4.8 Hz), 4.61e4.40 (1H, m), 3.97e3.62 (1H, m), 3.62e3.24
(2H, m), 3.24e2.89 (2H, m), 2.75e2.10 (3H, m), 1.92 (3H, s),
1.77e1.39 (9H, m); dC (50 MHz; CDCl3) 200.5, 190.3, 148.8, 140.0,
136.9, 133.9, 133.8, 129.9 (2CH), 129.1 (2CH), 119.2, 98.7, 67.0, 62.6,
62.4, 40.6, 31.1, 30.9, 30.7, 25.7 (2CH2), 24.4, 19.7; EIHRMS: calcd for
C
27H30O5S (MþNa): 489.1712; found: 489.1706 (MþNa). ee: de-
termined by HPLC: CHIRALPAK AD-H column; n-hexane/isopropyl
alcohol [70/30 (v/v)]; flow rate: 1.0 mL/min;
l
¼420 nm; tR (mi-
nor) 13.6, 15.6 min; tR (major)¼18.7, 20.8 min; ½a D25
þ44.70 (c
ꢁ
0.97, CHCl3).
4.2.17. (R)-2-(6-((Tetrahydro-2H-pyran-2-yl)oxy)methyl)-5-(4-
bromophenyl)cyclohexa-1,3-dien-1-yl)-2-(phenylsulfonyl)ethan-1-
one (7i). Yellow oil (25.0 mg, 59%): nmax (liquid film) 2947, 2870,
1718, 1647, 1544, 1448, 1383, 1323, 1309, 1290, 1155; dH (200 MHz;
CDCl3) 7.98e7.85 (2H, m), 7.75e7.33 (3H, m), 7.27e7.16 (5H, m),
6.60e6.42 (1H, m), 4.67e4.34 (3H, m), 3.86e3.67 (1H, m),
3.57e3.38 (2H, m), 3.35e3.23 (1H, m), 3.19e3.03 (2H, m),
2.78e2.58 (1H, m), 1.84e1.29 (6H, m); dC (50 MHz; CDCl3) 186.7,
144.7, 139.9, 139.5, 139.0, 135.0, 134.4, 129.4 (2CH), 128.7 (2CH),
127.8 (2CH),127.6 (2CH),123.4,119.9, 98.6, 65.2, 63.1, 62.2, 27.9, 31.1,
30.6, 25.6, 19.7; EIHRMS: calcd for C26H27BrO5S (MþNa): 553.0660;
found: 553.0655 (MþNa). ee: determined by HPLC: CHIRALPAK AD-
H column; n-hexane/isopropyl alcohol [80/20 (v/v)]; flow rate:
C
24H30O6S
(MþNaþMeOH):
501.1923;
ꢀ2.34 (c 1.45, CHCl3).
found:
501.1917
(MþNaþMeOH). ½a D25
ꢁ
4.5. General procedure for the deprotection with pTsOH:
synthesis of compounds 10, 13gej
Tetrahydropyranyl derivative (1 mmol) and p-toluenesulfonic
acid monohydrate (0.5 mmol) were dissolved in 10 ml of a 1:1
~
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~
J. Pena et al. / Tetrahedron xxx (2014) 1e9
7
mixture of THF/H2O, and the whole mixture was stirred until no
starting material was observed (typically 3e7 days). The reaction
was quenched with H2O, extracted with EtOAc and the combined
organics were washed with NaHCO3 (5%), H2O and brine, dried
(Na2SO4), filtered and concentrated in vacuo to afford the desired
product.
mg, 98%): nmax (liquid film) 3502, 3062, 2929, 2872, 1718, 1645,
1545, 1473, 1446, 1312, 1309, 1153; dH (200 MHz; CDCl3) 8.00e7.82
(2H, m), 7.77e7.41 (6H, m), 7.30 (1H, s), 7.25e7.19 (1H, m), 6.52 (1H,
dd, J¼6.2, 2.7 Hz), 4.61 (1H, d, J¼13.5 Hz), 4.43 (1H, d, J¼13.5 Hz),
3.42 (1H, d, J¼12.3 Hz), 3.29e3.11 (2H, m), 2.99 (1H, d, J¼1.7 Hz),
2.86e2.60 (1H, m); dC (50 MHz; CDCl3) 187.5, 144.5, 141.3, 139.6,
138.7, 138.7, 134.3, 132.1, 131.9, 130.2, 129.3 (2CH), 128.9 (2CH),
124.5, 122.9, 120.1, 62.7, 62.3, 33.5, 27.9; EIHRMS: calcd for
4.5.1. (S)-1-(6-(Hydroxymethyl)-4-(4-methyl)cyclohexa-1,3-dien-1-
yl)-2-(phenylsulfonyl)ethan-1-one (10). Pale yellow solid (293.8 mg,
96%): mp 116e118 ꢂC; nmax (liquid film) 3446, 2932, 2872, 1718,
1635, 1566, 1446, 1321, 1309, 1288, 1152; dH (200 MHz; CDCl3)
7.95e7.82 (2H, m), 7.76e7.49 (3H, m), 7.05 (1H, d, J¼5.8 Hz),
6.01e5.81 (1H, m), 4.55 (1H, d, J¼13.5 Hz), 4.38 (1H, d, J¼13.5 Hz),
3.51e3.27 (2H, m), 3.15e2.90 (1H, m), 2.46e2.37 (2H, m), 1.93 (3H,
s); dC (50 MHz; CDCl3) 187.6, 149.0, 141.0, 139.0, 134.4, 133.4, 129.4
(2CH), 128.7 (2CH), 119.1, 62.7, 62.6, 33.5, 31.2, 24.3; EIHRMS: calcd
for C16H18O4S (MþNa): 329.0823; found: 329.0818 (MþNa). ee:
determined by HPLC: CHIRALPAK IC column; n-hexane/isopropyl
C
21H19O4SBr (MþNa): 469.0085; found: 469.0079 (MþNa). ee:
determined by HPLC: CHIRALPAK AD-H column; n-hexane/iso-
propyl alcohol [60/40 (v/v)]; flow rate: 1.0 mL/min;
l
¼360 nm; tR
(minor)¼31.2 min; tR (major)¼35.1 min; ½a D25
ꢁ
þ23.29 (c 0.97,
CHCl3).
4.6. General procedure for mesylation reaction: synthesis of
compounds 11 and 14
Hydroxyl derivative (1 mmol), 4-(dimethylamino)pyridine
(0.2 mmol) and triethylamine (1.3 mmol) were dissolved in 10 ml of
DCM, and then methanesulfonyl chloride (1.2 mmol) was added.
The mixture was stirred at room temperature for 40 min. The re-
action was quenched with H2O and extracted with ethyl acetate
after 10 min. The organic layers were washed with HCl (2 M),
NaHCO3 (5%), H2O and brine, dried (Na2SO4), filtered and concen-
trated in vacuo to afford the desired product.
alcohol [60/40 (v/v)]; flow rate: 1.0 mL/min;
l
¼325 nm; tR
(minor)¼28.5 min; tR (major)¼53.6 min; ½a D25
ꢁ
ꢀ27.40 (c 0.16,
CHCl3).
4.5.2. (R)-2-(6-(Hydroxymethyl)-5-(phenyl)cyclohexa-1,3-dien-1-
yl)-2-(phenylsulfonyl)ethan-1-one (13g). Yellow oil (364.3 mg,
99%): nmax (liquid film) 3487, 3061, 2931, 2872, 1718, 1645, 1544,
1446, 1314, 1309, 1153; dH (200 MHz; CDCl3) 7.92 (2H, d, J¼7.0 Hz),
7.74e7.48 (3H, m), 7.47e7.32 (5H, m), 7.24 (1H, d, J¼6.2 Hz), 6.53
(1H, dd, J¼6.2, 2.7), 4.52 (1H, d, J¼13.5 Hz), 4.28e4.10 (1H, m),
3.61e3.32 (2H, m), 3.29e3.09 (1H, m), 3.04 (1H, d, J¼1.6 Hz), 2.76
(1H, dd, J¼17.9, 8.6 Hz); dC (50 MHz; CDCl3) 187.5, 146.4, 140.3,
139.2,134.8 (2C),134.2,129.2 (2CH),128.7 (2CH),128.5,125.9 (4CH),
119.2, 62.5, 62.7, 33.6, 28.1; EIHRMS: calcd for C21H20O4S (MþH):
369.1161; found: 369.1155 (MþH). ee: determined by HPLC: CHIR-
ALPAK AD-H column; n-hexane/isopropyl alcohol [60/40 (v/v)];
4.6.1. (S)-1-(6-(Methanesulfonyl)oxymethyl)-4-(4-methyl)cyclo-
hexa-1,3-dien-1-yl)-2-(phenylsulfonyl)ethan-1-one (11). Yellow oil
(380.2 mg, 99%): nmax (liquid film) 2939, 1718, 1651, 1637, 1568,
1446, 1323, 1309, 1292, 1153; dH (200 MHz; CDCl3) 7.95e7.84 (2H,
m), 7.72e7.50 (3H, m), 7.10 (1H, d, J¼5.9 Hz), 5.94 (1H, d, J¼5.9 Hz),
4.51 (1H, d, J¼13.5 Hz), 4.38 (1H, d, J¼13.5 Hz), 3.91 (1H, dd, J¼10.7,
8.3 Hz), 3.79 (1H, dd, J¼10.7, 5.0 Hz), 3.31e3.16 (1H, m), 2.95 (3H, s),
2.50e2.35 (2H, m), 1.94 (3H, s); dC (50 MHz; CDCl3) 186.6, 148.9,
142.2, 139.0, 134.5, 130.7, 129.5 (2CH), 128.6 (2CH), 119.4, 67.8, 62.7,
37.5, 30.8, 30.4, 24.3; EIHRMS: calcd for C17H20O6S2 (MþNa):
407.0599; found: 407.0593 (MþNa). ee: determined by HPLC:
CHIRALPAK IC column; n-hexane/isopropyl alcohol [60/40 (v/v)];
flow rate: 1.0 mL/min;
l
¼430 nm; tR (minor)¼35.9 min; tR
(major)¼39.3 min; ½a D25
ꢁ
þ13.62 (c 0.94, CHCl3).
4.5.3. (R)-2-(6-(Hydroxymethyl)-5-(4-methylphenyl)cyclohexa-1,3-
dien-1-yl)-2-(phenylsulfonyl)ethan-1-one (13h). Yellow oil
flow rate: 1.0 mL/min;
l
¼350 nm; tR (minor)¼69.0 min; tR
(378.2 mg, 99%): nmax (liquid film) 3442, 2923, 2873, 1714, 1643,
1514, 1446, 1354, 1309, 1153; dH (200 MHz; CDCl3) 7.96e7.81 (2H,
m), 7.73e7.41 (3H, m), 7.28e7.13 (5H, m), 6.50 (1H, dd, J¼6.2, 2.6),
4.60 (1H, d, J¼13.5 Hz), 4.43 (1H, d, J¼13.5 Hz), 3.57e3.30 (2H, m),
3.26e3.08 (1H, m), 3.02 (1H, d, J¼4.7 Hz), 2.73 (1H, dd, J¼20.5,
8.6 Hz), 2.37 (3H, s); dC (50 MHz; CDCl3) 187.6, 146.7, 140.8, 139.8,
138.9 (2C), 136.4, 134.4, 130.0 (2CH), 128.9 (2CH), 128.8 (2CH), 126.1
(2CH), 118.5, 62.9, 62.8, 33.8, 28.3, 21.5; EIHRMS: calcd for
(major)¼79.0 min; ½a D25
ꢁ
ꢀ9.00 (c 1.1, CHCl3).
4.6.2. (R)-1-(6-(Methanesulfonyl)oxymethyl)-4-(4-phenyl)cyclo-
hexa-1,3-dien-1-yl)-2-(phenylsulfonyl)ethan-1-one (14). Yellow oil
(223.0 mg, 50%): nmax (liquid film) 2963, 2932, 1718, 1650, 1541,
1446, 1354, 1323, 1309, 1292, 1174, 1153; dH (200 MHz; CDCl3) 7.92
(2H, d, J¼7.9 Hz), 7.76e7.49 (3H, m), 7.49e7.37 (5H, m), 7.34 (1H, d,
J¼6.2 Hz), 6.58 (1H, dd, J¼6.3, 2.7 Hz), 4.58 (1H, d, J¼13.4 Hz), 4.44
(1H, d, J¼13.4 Hz), 4.22 (1H, d, J¼5.7 Hz), 3.96 (1H, t, J¼6.7 Hz),
3.49e3.38 (1H, m), 2.93 (3H, s), 2.78 (2H, ddd, J¼11.3, 9.0, 2.8 Hz); dC
(50 MHz; CDCl3) 186.3, 146.4, 141.5, 138.6, 134.4, 132.1, 130.9, 129.6,
129.4 (2CH), 128.5 (4CH), 126.1 (2CH), 119.2, 67.6, 62.7, 37.2, 30.4,
27.8; EIHRMS: calcd for C22H22O6S2 (MþNa): 469.0755; found:
469.0750 (MþNa). ee: determined by HPLC: CHIRALPAK AD-H
column; n-hexane/isopropyl alcohol [70/30 (v/v)]; flow rate:
C
22H22O4S (MþNa): 405.1136; found: 405.1141 (MþNa).
4.5.4. (R)-2-(6-(Hydroxymethyl)-5-(4-bromophenyl)cyclohexa-1,3-
dien-1-yl)-2-(phenylsulfonyl)ethan-1-one (13i). Yellow oil
(441.5 mg, 99%): nmax (liquid film) 3477, 2941, 2872, 1718, 1643,
1543, 1489, 1446, 1312, 1309, 1153; dH (200 MHz; CDCl3) 7.91 (2H, d,
J¼8.3 Hz), 7.73e7.48 (3H, m), 7.47e7.36 (4H, m), 7.23 (1H, d,
J¼6.1 Hz), 6.52 (1H, dd, J¼6.2, 2.7 Hz), 4.60 (1H, d, J¼13.4 Hz), 4.43
(1H, d, J¼13.5 Hz), 3.62e3.26 (1H, m), 3.26e3.05 (2H, m), 3.00 (1H,
d, J¼1.7 Hz), 2.87e2.64 (1H, m); dC (50 MHz; CDCl3) 187.4, 144.9,
139.9, 138.7, 138.0, 135.1, 134.3, 129.3 (2CH), 128.5 (2CH), 127.5
(2CH), 127.4 (2CH), 123.4, 119.5, 62.7, 62.3, 33.5, 27.8; EIHRMS: calcd
for C21H19O4SBr (MþNa): 469.0085; found: 469.0079 (MþNa). ee:
determined by HPLC: CHIRALPAK AD-H column; n-hexane/iso-
1.0 mL/min;
l
¼325 nm; tR (minor)¼17.9 min; tR (major)¼23.2 min;
½
a 2D5
ꢁ
þ7.22 (c 0.36, CHCl3).
4.7. Synthesis of (Z)-5-methyl-1-((phenylsulfonyl)methy-
lene)-1,3,3a,4-tetrahydroisobenzofuran (12)
Compound 11 (162 mg, 0.38 mmol) was dissolved in 4 ml of DCM,
propyl alcohol [60/40 (v/v)]; flow rate: 1.0 mL/min;
l
¼350 nm; tR
and then 1,8-diazabicyclo[5.4.0]undec-7-ene (85 ml, 0.57 mmol) was
(major)¼30.6 min; tR (minor)¼38.8 min; ½a D25
ꢁ
þ5.88 (c 1.75, CHCl3).
added. The mixture was stirred at room temperature for 35 min. The
reaction was quenched with H2O and extracted with ethyl acetate
after 10 min. The organic layers were washed with H2O, dried
(Na2SO4), filtered and concentrated in vacuo. Flash chromatography
4.5.5. (R)-2-(6-(Hydroxymethyl)-5-(4-bromophenyl)cyclohexa-1,3-
dien-1-yl)-2-(phenylsulfonyl)ethan-1-one (13j). Yellow oil (437.1
~
Please cite this article in press as: Pena, J.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.04.076

~
J. Pena et al. / Tetrahedron xxx (2014) 1e9
8
(n-hexane/EtOAc, 6:4) afforded 12 as a yellowoil (56.1 mg, 50%). nmax
(liquid film) 3066, 2929, 2900, 1610, 1579, 1446, 1304, 1140; dH
(200 MHz; benzene-d6) 8.32e8.21 (2H, m), 7.14e6.97 (3H, m), 5.92
(1H, s), 5.84e5.73 (1H, m), 5.43e5.35 (1H, m), 4.01 (1H, t, J¼8.6 Hz),
3.19e3.02 (1H, m), 2.26e2.01 (1H, m),1.37 (3H, s),1.32e1.08 (2H, m);
dC (50 MHz; benzene-d6) 162.1,145.4,140.2,131.9,130.4,128.6 (2CH),
127.9 (2CH), 122.8, 120.2, 97.0, 77.9, 35.3, 31.2, 22.9; EIHRMS: calcd
for C16H16O3S (MþH): 289.0898; found: 289.0893 (MþH). ee: de-
termined by HPLC: CHIRALPAK AD-H column; n-hexane/isopropyl
mixture was stirred at reflux for 2.5 h. Flash chromatography (n-
Hexane/EtOAc, 6:4) afforded 19 as a yellow oil (36.2 mg, 42%). nmax
(liquid film) 3062, 2970, 2926, 1714, 1381, 1146, 1319, 1148; dH
(600 MHz; benzene-d6) 8.01e7.83 (4H, m), 7.08e6.70 (9H, m), 5.26
(1H, dd, J¼9.8, 4.3 Hz), 5.04 (1H, d, J¼15.0 Hz, 4.70 (1H, d, J¼4.8 Hz),
3.90 (1H, d, J¼15.0 Hz), 2.04 (3H, s),1.90e1.75 (2H, m); dC (150 MHz;
benzene-d6) 145.3, 143.7, 142.0 (2C), 138.0, 129.1 (2CH), 128.7 (2CH),
128.2 (2CH), 127.9 (2CH), 127.8 (2CH), 121.4, 119.9, 119.4, 85.5, 78.9,
62.7, 56.2, 33.2, 19.6; EIHRMS: calcd for C24H22O5S2 (MþNH4):
alcohol [70/30 (v/v)]; flow rate: 1.0 mL/min;
l¼350 nm; tR (minor)¼
472.1247; found: 472.1247 (MþNH4). ½a D25
ꢀ6.67 (c 0.81, MeOH).
ꢁ
16.9 min; tR (major)¼19.4 min; ½a D25
ꢁ
ꢀ86.50 (c 1.57, MeOH).
Acknowledgements
4.8. Synthesis of compounds 16, 17 (and 18)
The authors gratefully acknowledge the help of A. Lithgow of
Universidad de Salamanca and J. Rodilla of Universidade da Beira
Interior for NMRs and C. Raposo (MS) of Universidad de Salamanca.
Procedure a: To a solution of 1 mmol of starting material (10,
45.9 mg, 0.15 mmol or 12, 46.1 mg, 0.16 mmol) in CDCl3 (10 ml) was
added m-CPBA (70% pure, 1 equiv) and the reaction was left to stir
for the specified time (15 h for compound 10 and 6 h for compound
12). Flash chromatography (EtOAc/MeOH, 95:5) afforded the cor-
responding product (1/1 mixture of 16/17, 18.4 mg, 38% starting
from 10; only 16, 31.9 mg, 62% starting from 12).
ꢀ
FSE and Junta de Castilla y Leon (GR 178, BIO/SA74/13) are ac-
knowledged for financial support. J.P. is grateful to the Ministry of
Economy and Competitiveness for his FPU fellowship.
Procedure b: A solution of 12 (38.4 mg, 0.13 mmol) in CHCl3
(1 ml) was heated at 37 ꢂC under normal air atmosphere for 72 h.
Flash chromatography (EtOAc/MeOH, 95:5) afforded 16 (22.1 mg,
53%).
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.04.076.
4.8.1. 1-((1S,4R,5R)-4-Hydroxy-5-methyl-6-oxabicyclo[3.2.1]oct-2-
en-2-yl)-2-(phenylsulfonyl)ethan-1-one (16). Yellow oil: nmax (liquid
film) 3471, 2970, 2932, 2873, 1712, 1666, 1625, 1448, 1379, 1321,
1309, 1259, 1150; dH (600 MHz; CDCl3) 7.95e7.80 (2H, m), 7.75e7.47
(3H, m), 6.72 (1H, d, J¼3.9 Hz), 4.49 (2H, s), 3.91e3.85 (1H, m),
3.85e3.79 (1H, m), 3.48e3.38 (1H, m), 3.34 (1H, d, J¼7.5 Hz), 1.63
(1H, d, J¼8.0 Hz), 1.56 (1H, dd, J¼8.0 Hz, 4.0 Hz), 1.45 (3H, s); dC
(150 MHz; CDCl3) 187.3, 144.2, 141.9, 138.7, 134.4, 129.4 (2CH), 128.5
(2CH), 81.4, 73.7, 72.4, 62.4, 35.7, 35.3, 21.8; EIHRMS: calcd for
References and notes
ꢀ
1. (a) Audran, S.; Brermond, P.; Feuerstein, M.; Marque, S. R. A.; Santelli, M. Tet-
rahedron 2013, 69, 8325; (b) Lepage, O.; Stone, C.; Deslongchamps, P. Org. Lett.
2002, 4, 1091.
2. (a) Patai, S.; Rappoport, Z.; Stirling, C. The Chemistry of Sulphones and Sulfoxides;
John Wiley and Sons: Chichester, UK, 1988; (b) Simpkins, N. S. Sulphones in
Organic Synthesis; Pergamon: Oxford, UK, 1993; (c) Paquette, L. A. Synlett 2001,
ꢀ
1; (d) Najera, C.; Sansano, J. M. Recent Res. Dev. Org. Chem. 1998, 2, 637; (e)
ꢀ
Chinchilla, R.; Najera, C. Recent Res. Dev. Org. Chem. 1997, 1, 437.
3. (a) Ravindar, K.; Caron, P.-Y.; Deslongchamps, P. Org. Lett. 2013, 15, 6270; (b)
Barroso, S.; Blay, G.; Al-Midfa, L.; Munoz, M. C.; Pedro, J. R. J. Org. Chem. 2008,
C
16H18O5S (MþNa): 345.0773; found: 345.0767 (MþNa). ½a D25
ꢁ
~
ꢀ13.05 (c 0.95, CHCl3).
73, 6389; (c) Pei, W.; Wang, Y.-G.; Wang, Y.-J.; Sun, L. Synthesis 2008, 3383.
~
ꢀ
4. Pena, J.; Anton, A. B.; Moro, R. F.; Marcos, I. S.; Garrido, N. M.; Díez, D. Tetra-
hedron 2011, 67, 8331.
4.8.2. 1-((4S,7S)-7-Hydroxy-7-methyl-2-oxabicyclo[2.2.2]oct-5-en-
5-yl)-2-(phenylsulfonyl)ethan-1-one (17). Yellow oil: nmax (liquid
film) 3464, 2929, 1710, 1664, 1626, 1448, 1321, 1309, 1153; dH
(600 MHz; CDCl3) 7.98e7.80 (2H, m), 7.74e7.50 (3H, m), 7.32 (1H, d,
J¼4.6 Hz), 4.59 (1H, d, J¼13.6 Hz), 4.38 (1H, d, J¼13.6 Hz), 3.59e3.30
(3H, m), 2.21 (1H, d, J¼15.4 Hz), 2.09e1.83 (2H, m), 1.51 (3H, s); dC
(150 MHz; CDCl3) 187.6, 141.9, 141.1, 138.5, 134.4, 129.3 (2CH), 128.5
(2CH), 82.0, 66.3, 63.0, 53.8, 35.2, 30.9, 21.8; EIHRMS: calcd for
~
5. Pena, J.; Moro, R. F.; Basabe, P.; Marcos, I. S.; Díez, D. RSC Adv. 2012, 2, 8041.
6. (a) Feldgitscher, C.; Peterlik, H.; Puchberger, M.; Kickelbick, G. Chem. Mater.
2009, 21, 695; (b) Arbore, A.; Dujardin, G.; Maignan, C. Eur. J. Org. Chem. 2003,
4118.
7. (a) Dalko, P. I. Enantioselective Organocatalysis, Reactions and Experimental Pro-
cedures; Wiley-VCH: Weinheim, Germany, 2007; (b) Giacalone, F.; Gruttadauria,
M.; Agrigento, P.; Noto, R. Chem. Soc. Rev. 2012, 41, 2406; (c) Bertelsen, S.;
Marigo, M.; Brandes, S.; Diner, P.; Jørgensen, K. A. J. Am. Chem. Soc. 2006, 128,
12973.
8. (a) Serebryakov, E. P.; Shcherbakov, M. A.; Gamalevich, G. D.; Struchkova, M. I.
Russ. Chem. Bull. Int. Ed. 2003, 52, 734; (b) Serebryakov, E. P.; Nigmatov, A. G.;
Shcherbakov, M. A.; Struchkova, M. I. Russ. Chem. Bull. Int. Ed. 1998, 47, 82; (c)
Nigmatov, A. G.; Serebryakov, E. P. Russ. Chem. Bull. Int. Ed. 1996, 45, 623; (d)
Nigmatov, A. G.; Kornilova, I. N.; Serebryakov, E. P. Russ. Chem. Bull. Int. Ed. 1996,
45, 144; (e) Nigmatov, A. G.; Serebryakov, E. P. Russ. Chem. Bull. Int. Ed. 1993, 42,
213.
ꢀ
ꢀ
C
16H18O5S (MþNa): 345.0773; found: 345.0771 (MþNa). ½a D25
ꢁ
ꢀ99.95 (c 0.19, CHCl3).
4.8.3. (1aS,2aS,6aR,Z)-1a-Methyl-5-((phenylsulfonyl)methylene)-
1a,2,2a,3,5,6a-hexahydrooxireno[2,3-f]isobenzofuran (18). Yellow
9. Bench, B. J.; Liu, C.; Evett, C. R.; Watanabe, C. M. H. J. Org. Chem. 2006, 71, 9458.
oil: nmax (liquid film) 2961, 2928, 1614, 1446, 1304, 1142; dH
(600 MHz; benzene-d6) 8.22 (2H, dd, J¼7.8, 1.8 Hz), 7.06e6.92 (3H,
m), 5.84 (1H, s), 5.51 (1H, t, J¼3.7 Hz), 3.71 (1H, t, J¼8.7 Hz),
3.00e2.80 (1H, m), 2.47 (1H, d, J¼3.7 Hz), 2.19e2.03 (1H, m), 1.18
(1H, dd, J¼13.9, 7.5 Hz), 0.91 (3H, s), 0.14 (1H, dd, J¼13.9, 11.5 Hz); dC
(150 MHz; benzene-d6) 161.5, 144.7, 137.8, 131.9, 128.4 (2CH), 127.5
(2CH), 122.7, 98.2, 76.6, 59.9, 53.1, 34.6, 29.0, 20.5; EIHRMS: calcd
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J. Pena et al. / Tetrahedron xxx (2014) 1e9
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