An organocatalytic approach to enantiomerically enriched α-arylcyclohexenones and cyclohexanones

Article abstract of DOI:10.1039/c1ob06356a

The presence of a p-nitrophenyl group converts acetone into an excellent and versatile nucleophile in organocatalytic processes, able to react with α,β-unsaturated aldehydes affording β-substituted α-arylcyclohexenones via a Michael reaction/aldol reaction/dehydration sequence, which occurs in good yields, ee up to 96% and complete diastereoselectivity. The resulting compounds are excellent synthons for the diastereoselective preparation of a variety of synthetically useful polysubstituted cyclohexanones and derivatives. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1ob06356a

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PAPER
An organocatalytic approach to enantiomerically enriched
a-arylcyclohexenones and cyclohexanones†‡
Sara Duce, Mar´ıa Jorge, Ine´s Alonso, Jose´ Luis Garc´ıa Ruano and M. Bele´n Cid*
Received 9th August 2011, Accepted 1st September 2011
DOI: 10.1039/c1ob06356a
The presence of a p-nitrophenyl group converts acetone into an excellent and versatile nucleophile in
organocatalytic processes, able to react with a,b-unsaturated aldehydes affording b-substituted
a-arylcyclohexenones via a Michael reaction/aldol reaction/dehydration sequence, which occurs in
good yields, ee up to 96% and complete diastereoselectivity. The resulting compounds are excellent
synthons for the diastereoselective preparation of a variety of synthetically useful polysubstituted
cyclohexanones and derivatives.
Introduction
Optically active cyclohexenones are especially attractive com-
pounds that have found widespread applications in syntheses of
target molecules,1 mainly due to their chemical versatility that
allows them to participate in various interesting transformations.2
Most of the reported procedures for synthesizing these compounds
use classical approaches starting from the chiral pool, usually
terpenes;3 but there are also some methods based on asymmetric
synthesis,4 including enantioselective organocatalysis.5
The particular case of a-aryl cyclohexenones is interesting as
they have been used for the preparation of a wide range of natural
products in racemic versions,6 probably due to the difficulty in
obtaining these compounds in enantiomerically pure forms. None
of the strategies mentioned above provides a general method for
their preparation in an optically pure form, and therefore the
Scheme 1 A nitrophenyl moiety as an activating group of monoactivated
carbanions.
search for new strategies leading to a broad range of substitution
in 2-aryl cyclohexenones is of interest.7
We have recently demonstrated that arylacetonitriles are able
to participate in organocatalytic Michael additions to a,b-
unsaturated aldehydes by incorporating a nitro group at the
phenyl ring.8,9 The nitro group acts as a versatile temporary
activating group in a remote position (Scheme 1, a). In that paper
we were able to get the formal diastereoselective a-arylation of
lactones by in situ reduction of the resulting aldehyde and further
intramolecular acylation. On this basis, we envisioned that a,b-
disubstituted cyclohexenones could be easily obtained by simple
organocatalytic Michael addition of the commercially available
ketone 1 to a,b-unsaturated aldehydes,10 followed by aldol reaction
and a dehydration sequence (Scheme 1, b).
Taking into account that the presence of the NO2 group in
compounds 5 can be used for introducing other substituents at the
aromatic ring and the chemical versatility of the cyclohexenone
moiety, these compounds can be considered as appropriated inter-
mediates for synthesizing enantiomerically pure polysubstituted
2-aryl cyclohexanones. It is worth mentioning that the preparation
of these compounds by other ways is nontrivial11 and usually
requires umpolung strategies of a-arylation12,13 or long reaction
sequences.14
Department of Organic Chemistry. Universidad Auto´noma de Madrid,
Cantoblanco, 28049. E-mail: belen.cid@uam.es
† Dedicated to Amelia Tito on the occasion of her retirement
Results and discussion
‡ Electronic supplementary information (ESI) available: Optimization of
the Michael addition of 1 to crotonaldehyde and aromatic aldehydes;
configurational assignment of 4a and 4a¢, 8a, 9a and 10a; spectra; chiral
HPLC conditions; X-ray crystallographic data of 7a and computational
details. CCDC reference number 838553. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c1ob06356a
As a model reaction we studied the addition of ketone 1 to
crotonaldehyde (2a) looking for the optimal conditions of the
Michael addition. This reaction took place in CH2Cl2 with the
screened pyrrolidine-based catalysts (I–IV) affording a mixture of
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Table 1 Optimization of the sequence Michael addition (1 to 2a)/cyclizationa
Entry
Cat.
Additive
Solvent
t (h)
Conv. step ab (%)
ee (%)c 4a/4a¢
1
2
3
4
5
6
7
8
I
—
—
—
—
—
—
PhCO2H
LiOAc
CsOAc
DABCO
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
24
24
24
24
24
24
20
12
20
20
40
95
75
95
90
90
100
100
100
100
90 : 90
73 : 70
<5%
10 : 16
84 : 88
69 : 70
78 : 80
90 : 90d
80 : 78
80 : 84
II
III
IV
I
II
I
I
9
10
I
I
a The reactions were carried out on a 0.2 mmol scale with 2a (1.5 equiv) and [1] = 1 M in different solvents. b Determined by 1H NMR of the crude of the
Michael addition. c Determined by HPLC analysis of the alcohols 4a and 4¢a. d Identical ee were obtained by decreasing the temperature to 0 ◦C (24 h).
epimers at the benzylic carbon, 3a and 3a¢ (Table 1, entries 1–
4). Their aldol cyclization in the presence of DBU afforded an
equimolecular mixture of 3-hydroxycyclohexanones, 4a and 4a¢,
epimers at the hydroxylic center, which indicated that epimeriza-
tion at the benzylic center towards the presumably most stable
trans 2,3-substituted diastereoisomer had taken place, due to
the high acidity of the benzylic proton. After determining the
enantiomeric excesses of 4a and 4a¢ by chiral HPLC we could
establish that I and II15 were the most promising catalysts (entries
1 and 2). Higher conversions and similar enantioselectivities were
obtained by using EtOH as solvent (entries 5–6).
We next investigated the influence of several additives on the
reaction times and enantioselectivity of the process using I and
II as catalysts in different solvents. Only the best results have
been collected in Table 1 (entries 7–10).16 The use of EtOH and
LiOAc as additives provided the highest levels of conversion and
enantioselectivy (entry 8). Unfortunately, ee was not improved by
decreasing the temperature (see note d).
Fortunately, reaction conditions used in the elimination step
could be applied to the crude mixture resulting after aldol reac-
tion and thus, the sequential procedure (Michael addition/aldol
reaction/elimination) could be applied directly to 1 affording 5a
in 80% yield (Table 2, entry 1). The application of this procedure
only required the elimination of the solvents under vacuum after
the first step, filtration through a short pad of silica gel after the
aldol reaction and a final chromatographic column. This sequence
was scaled up starting from 1 g of product 1 with the same result.
To explore the scope of this protocol a series of a,b-unsaturated
aldehydes were subjected to the conditions previously optimized
(Table 2). This simple sequence was successfully applied to a series
of b-substituted a,b-unsaturated aldehydes with alkyl or alkenyl
substituents (entries 1–6). In all these cases, very high ee values
were obtained (up to 96%). By contrast, reactions of aldehydes
bearing aromatic substituents (entries 7–12) also evolved with high
reactivity and complete diastereoselectivity, but lower ee values
were obtained.17 Additionally, the ee values for ketones 5g and 5h
decreased with time (compare entries 7 and 8 or 9 and 10), and
ketone 5g was even obtained as racemic after 24 h of reaction
(entry 10). Finally, reaction of 2h was more enantioselective in the
presence of benzoic acid and that of 2i in the absence of additives.
The variation of the enantioselectivity observed with time could
be a consequence of the reversibility of the Michael addition.18
The equilibration would avoid an asymmetric (kinetic) control
allowing a thermodynamic pathway that even in some cases affords
racemic products (entry 10).19
With the optimal conditions for the Michael addition and the
aldol reaction established above, the dehydration step was then
investigated (Scheme 2). Diastereomerically pure cyclohexenone
5a was cleanly obtained in high yield, without erosion of the
enantioselectivity, after treatment of the mixture 4a/4a¢ with
p-TsOH.
The lower enantioselectivities found for cinnamaldehyde deriva-
tives had also been observed when arylacetonitriles were used
as nucleophiles.8 In this sense, it is worthwhile to note that
these reactions show a complementary behavior to that observed
with other related carbon nucleophiles, such as thioesters18b or
Scheme 2 Dehydration of aldols 4a/4a¢.
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Table 2 The aldehyde scope of the reaction sequence Michael addition/aldol reaction/dehydrationa
Entry
R
Step a, t (h)
Product
Overall yield (%)
ee 5 (%)
1
2
3
4
5
6
7
8
2a (Me)
12
15
26
48
50
30
2.5
48
1
5a
5b
5c
5d
5e
5f
5g
5g
5h
5h
5h
5i
80
76
78
70
74
56
69
90
91
96
92
80
94
66
46
40
0
2b (Et)
2c (n-Pr)
2d (n-Bu)
2e (iPr)
2f (CH2)2CH CH(CH2CH3)
2g (Ph)
2g (Ph)
2h (p-OMe–C6H4)
2h (p-OMe–C6H4)
2h (p-OMe–C6H4)b
2i (p-NO2–C6H4)c
100d
100d
100d
71
9
10
11
12
24
16
24
75
76
75
a Reactions performed on 0.4 mmol scale. b Reaction carried out with 30 mol% of BzOH instead of LiOAc as additive. c Reaction carried out without
additive. d Conversion.
4-p-nitrobenzyl pyridines.9 These nucleophiles exhibit low reactiv-
ity and enantioselectivity with a,b-unsaturated aldehydes bearing
aliphatic substituents, but better results with aromatic ones. In
fact, nucleophile 1 renders the best average enantioselectivities of
all these comparable nucleophiles (Fig. 1).
Scheme 3 Transformations on the aromatic ring and X-ray structure
of 7.
Fig. 1 Comparison of the results obtained in the organocatalytic Michael
additions of different nucleophiles to a,b-unsaturated aldehydes bearing
aliphatic and aromatic substituents.
Cyclohexenones 5 resulting in these reactions have many
synthetic possibilities that we have illustrated by studying the
Scheme 4 Chemoselective reactions on C C and C O of 5a.
behavior of 5a under different reaction conditions (Schemes 3
and 4).
First, the presence of the NO2 group opens the gate to introduce
stereogenic carbons of 5a (and presumably those of the rest of
the cyclohexenones of Table 2) as (5R, 6R) by X-ray diffraction
studies. The (R) configuration assigned to C-5 agrees with the
predicted one by the models used for explaining the stereochemical
course of the organocatalytic Michael additions to b-substituted
a,b-unsaturated aldehydes involving iminium intermediates.20 The
(R) configuration assigned to C-6 agrees with the expected one
by assuming the thermodynamic equilibration of the carbanion
generated at C-6.
different substituents at the aromatic ring, taking advantage of
the diazonium salt’s chemistry. Thus, chemoselective Zn/AcOH
reduction of the NO2 group in the presence of the enone
moiety afforded amine 6a, which was easily transformed into the
aryliodide 7a. This compound, that could be employed as the
starting material in different coupling reactions, has been used
for unequivocally establishing the absolute configuration of the
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Chemoselective transformations of the C O and C C bonds
at compounds 5 can be easily performed (Scheme 4). The selective
reduction of the carbonyl group of cyclohexenones is a very
interesting transformation because of the high synthetic versatility
of the resulting allylic alcohols.21 Under Luche conditions,22 5a
was transformed into 8a with good stereoinduction (74% de,
Scheme 4).23 In order to explain the observed stereoselectivity, we
performed theoretical calculations at the DFT (B3LYP) level,24 by
using the Gaussian 09 program,25 about the most stable structure
of 5a. These studies revealed the scarce steric differentiation of
the carbonyl faces (see ESI for details‡), thus suggesting that
the observed stereoselectivity must be attributed to the different
torsional effects that take place during the hydride attack on each
face.26
Dihydroxilation and epoxidation reactions of the double bond
at 5a afforded carbocyclic sugar analogs in a highly stereoselective
manner (Scheme 4).27 Compound 9a was obtained as a single
diastereomer under the conditions used in the asymmetric
Sharpless dihydroxylation.28 Its expected stereochemistry and
relative configuration were confirmed from the value of the vicinal
coupling constants J5,6 (11.8 Hz, indicates an anti-periplanar
arrangement) and J2,3 (3.5 Hz, indicates a syn arrangement).
Moreover, the NOE between H2 and H6 and the absence of NOE
between H3 and H5 confirm the stereochemistry indicated in
Scheme 4. Finally, the comparison of chemical shifts obtained
for 9a with those calculated for the two possible diastereoisomers
resulting in the dihydroxylation,16 reinforces the assignment
indicated in Scheme 4.
Procedure for the Michael/cyclization/dehydration reactions of 1
with crotaonaldehyde step by step (from 1 to 5a)
(3R, 4R and 3R, 4S)-3-methyl-4-(4-nitrophenyl)-5-oxohexa-
nal (3a and 3a¢). To a solution of (S)-a-a-bis[3,5-bis(trifluoro-
methyl)phenyl]-2-pyrrolidinemethanol trimethylsilyl ether (I) (10
mol%, 0.04 mmol) in ethanol (0.4 mL) was added crotonaldehyde
(2a) (1.5 equiv., 0.6 mmol). After the resulting mixture was stirred
at room temperature for 15 min nitrophenylacetone 1 (0.4 mmol,
72 mg) and LiOAc (10 mol%, 0.04 mmol) were sequentially added.
After 12 h the reaction mixture was filtered through a plug of silica
gel and the solvent was evaporated under vacuum to give a mixture
of 3a/3a¢ = 2 : 1 in 95%yield. The two diastereomers could be
separated by flash chromatography (4 : 1 n-hexane : EtOAc). Data
of the major diastereomer 3a 1H NMR (300 MHz): d 9.55 (s, 1H),
8.18 (d, J = 8.8 Hz, 2H), 7.42 (d, J = 8.8 Hz, 2H), 3.82 (d, J = 10.3
Hz, 1H), 2.95–2.80 (m, 1H), 2.22 (dd, J = 17.2, 3.8 Hz, 1H), 2.13
(s, 3H), 2.04 (ddd, J = 17.2, 10.4, 1.9 Hz, 1H), 1.06 (d, J = 6.6 Hz,
3H). 13C NMR (75 MHz): d 206.4 (CO), 200.8 (CHO), 147.5 (C),
144.1 (C), 129.6 (2CH), 124.1 (2CH), 64.1 (CH), 47.5 (CH2), 31.2
(CH3), 30.8 (CH), 18.8 (CH3). MS (ESI) m/z 304 (M+Na+MeOH,
100), 250 (M+1, 3), 232 (10). HRMS (ESI) calcd. for C13H16NO4
[M+1]: 250.1073; found, 250.1076. [a]2D0 +98.0 (c 1.0, CHCl3).
(2R, 3R, 5R and 2R, 3R, 5S)-5-hydroxy-3-methyl-2-(4-nitro-
phenyl) cyclohexanone (4a and 4a¢). The mixture of diastereomers
3a/3a¢ was placed in a vial with a stirring bar and dissolved in THF
(0.5 mL). DBU was added (0.4 equiv., 0.16 mmol), the reaction
was stirred at room temperature for 6 h and then filtered through a
plug of silica gel. The solvent was eliminated under vacuum to give
Epoxidation of 5a with TBHP29 yields diastereomerically pure
epoxide 10a. Since NOESY experiments did not allow us to
unequivocally establish the configuration of the only detected
epoxide 10a, we performed a calculation, at the DFT (B3LYP)
level, of the d values corresponding to the two possible epoxides
(see ESI for details†). Their comparison with those experimen-
tally obtained for 10a supports the assignment indicated in
Scheme 4.30
1
the aldol 4 as a mixture of diastereomers (95%). H NMR (300
MHz) (data obtain from the mixture of diastereomers): d 8.12 (d,
J = 8.7 Hz, 2Hmajor, 2Hminor), 7.21 (d, J = 8.7 Hz, 2Hmajor), 7.14
(d, J = 8.7 Hz, 2Hminor) 4.50 (quint, J = 3.0 Hz, 1Hmajor), 4.02 (m,
1Hminor), 3.32 (d, J = 11.7 Hz, 1Hmajor), 3.28 (d, J = 11.7 Hz, 1Hminor),
2.95–2.88 (m, 1Hminor), 2.78–2.51 (m, 4H), 2.40–2.30 (m, 1Hminor),
2.23–2.13 (m, 1Hmajor), 2.09–1.97 (m, 1Hminor), 1.94–1.67 (m, 2H),
0.86 (d, J = 6.6 Hz, 3Hminor), 0.83 (d, J = 6.6 Hz, 3Hmajor). 13C NMR
(75 MHz) (mixture of diastereomers): d 207.1(C), 205.6 (C), 147.1
(C), 147.0 (C), 145.1 (C), 144.7 (C), 130.4 (2CH), 130.3 (2CH),
123.5 (2CH), 123.4 (2CH), 68.5 (CH), 68.4 (CH), 64.8 (CH), 63.5
(CH), 50.9 (CH2), 48.9 (CH2), 43.3 (CH2), 40.3 (CH2), 34.6 (CH),
34.5 (CH), 20.6 (CH3), 20.5 (CH3). MS (EI) m/z 231 (M+, 18), 163
(70), 133 (100), 115 (48). HRMS (EI) calcd. for C13H13NO3 [M+]:
231.0895; found, 231.0903.
Conclusions
In conclusion, p-nitrophenylacetone reacts with a variety of b-
substituted a,b-unsaturated aldehydes activated by I affording b-
substituted a-arylcyclohexenones 5 via a Michael addition/aldol
reaction/dehydration sequence in a highly enantioselective man-
ner, which is especially successful for aldehydes with alkyl sub-
stituents (ee = 80–96%). As the diastereomerically pure resulting
compounds can be easily converted into a-arylcyclohexanones
and derivatives in an efficient and stereoselective manner, this
sequence can be considered as a general, efficient and simple
procedure for the synthesis of a-aryl cyclohexenones and cyclo-
hexanones. Application of other versatile nucleophiles containing
a nitro group as a remote activating moiety is currently ongoing
in our laboratory.
(5R, 6R)-5-methyl-6-(4-nitrophenyl) cyclohex-2-enone (5a).
A
sealed tube equipped with a magnetic stirring bar was charged
with the aldols 4a/4a¢ (0.40 mmol), p-toluenesulphonic acid (20
mol%) and toluene (2 mL). The sealed tube was capped, placed
in a sand bath at 120 ◦C and the mixture was then vigorously
stirred at the same temperature for 5 h. The product can be
purified by flash chromatography (4 : 1 to 2 : 1 n-hexane : EtOAc)
to provide cyclohexenone 5a as a single diastereomer (white solid,
◦
1
90% yield). mp = 103–105 C. H NMR (300 MHz): d 8.20 (d,
J = 8.5 Hz, 2H), 7.26 (d, J = 8.5, 2H), 7.06 (ddd, J = 10.0,
5.7, 2.4 Hz, 1H), 6.17 (ddd, J = 10.0, 2.8, 0.9 Hz, 1H), 3.37
(d, J = 12.2 Hz, 1H), 2.60 (dt, Jt = 5.7 Hz, Jd = 18.4 Hz, 1H),
2.52–2.40 (m, 1H), 2.30 (ddt, Jt = 2.4 Hz, Jd = 18.4, 10.0 Hz,
1H), 0.86 (d, J = 6.4 Hz, 3H). 13C NMR (75 MHz) d 198.1 (C),
Experimental section
More details about the optimization of the Michael addi-
tion of 1 to crotonaldehyde are reported in the supporting
information.†
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149.5 (CH), 147.0 (C), 146.1 (C), 130.1 (2CH), 129.6 (CH), 123.7
(2CH), 61.6 (CH), 36.3 (CH2), 34.6 (CH), 20.1 (CH3). MS (ESI)
m/z 232 (M+1, 100), 150 (16), 149 (59). HRMS (ESI) calcd. for
C13H14NO3 [M+1]: 232.0968; found: 232.0967. The enantiomeric
excess was determined by HPLC using a Chirapack AD column
(ESI) calcd. for C15H18NO3 [M+1]: 260.1281; found: 260.1287. The
enantiomeric excess was determined by HPLC using a Chiralpack
AD column [hexane/iPrOH = 90 : 10]; flow rate 1.0 mL min-1; tmajor
= 13.9 min, tminor = 20.5 min (96% ee). [a]2D0 -37.6 (c 1.0, CHCl3).
IR (KBr) 1670, 1514, 860, 742, 705 cm-1.
[hexane/iPrOH = 90 : 10]; flow rate 1.0 mL min-1; tmajor
=
19.1 min, tminor = 28.5 min (90% ee). [a]2D0 -49.8 (c 1.0, CHCl3).
(5S, 6R)-5-isopropyl-6-(4-nitrophenyl)cyclohex-2-enone (5d).
The title compound was obtained as a single diastereomer
according to the sequential procedure described above (74% yield).
IR (KBr) 1674, 1514, 1342, 742, 706 cm-1.
Sequential procedure for the Michael/cyclization/dehydration
◦
1
mp = 106–108 C. H NMR (300 MHz): d 8.21 (d, J = 8.8 Hz,
2H), 7.27 (d, J = 8.8, 2H), 7.16–7.09 (m, 1H), 6.16 (dd, J = 10.0,
2.6 Hz, 1H), 3.61 (d, J = 12.1 Hz, 1H), 2.54–2.29 (m, 3H), 1.39
(dsept, Jd = 2.4, Jsept = 6.8 Hz, 1H), 0.90 (d, J = 6.8 Hz, 3H),
0.79 (d, J = 6.8 Hz, 3H). 13C NMR (75 MHz) d 198.8 (C), 149.9
(CH), 147.1 (C), 146.2 (C), 130.3 (2CH), 129.5 (CH), 123.8 (2CH),
58.1 (CH), 46.0 (CH), 27.8 (CH), 25.1 (CH2), 20.7 (CH3), 15.3
(CH3). MS (EI) m/z 259 (M+, 60), 243 (100). MS (EI) calcd. for
C15H17NO3 [M+]: 259.1208; found: 259.1208. The enantiomeric
excess was determined by HPLC using a Chiralpack AD column
[hexane/iPrOH = 90 : 10]; flow rate 1.0 mL min-1; tmajor = 15.8 min,
tminor = 20.1 min (80% ee). [a]2D0 -37.6 (c 1.0, CHCl3). IR (KBr)
1677, 1514, 1343, 842 cm-1.
reactions of nucleophile
solution of (S)-a-a-bis [3,5-bis(trifluoromethyl)phenyl]-2-
pyrrolidinemethanol trimethylsilyl ether (10 mol%, 0.04
1 with aldehydes 2a–2i. To a
I
mmol) in ethanol (0.4 mL) the corresponding a,b-unsaturated
aldehyde (2a–i) (1.5 equiv., 0.6 mmol) was added. After the
resulting mixture was stirred at room temperature for 15 min,
4-nitrophenylacetone 1 (0.4 mmol, 72 mg) and LiOAc (10 mol%,
0.04 mmol) were sequentially added. The reactions were followed
by TLC (until the disappearance of the 4-nitrophenylacetone
1), whereupon the solvent was evaporated under vacuum. The
residue was dissolved in THF (0.5 mL) and DBU was added (0.4
equiv., 0.16 mmol). The reaction was stirred at room temperature
during 6 h, and then filtered through a plug of silica gel. The
solvent was evaporated and the crude was placed in a sealed tube
and dissolved in toluene. p-Toluenesulphonic acid (20 mol%)
was added and the reaction mixture was stirred and heated
under reflux during 5 h. The residue was directly purified by
flash chromatography (6 : 1 to 4 : 1 n-hexane : EtOAc) to give the
corresponding cyclohexenones 5a–i in the yields indicated in
Table 2.
(5R, 6R)-5-butyl-6-(4-nitrophenyl)cyclohex-2-enone (5e). The
title compound was obtained as a single diastereomer according to
the sequential procedure described above (70% yield). mp = 130–
133 ◦C. 1H NMR (300 MHz): d 8.14 (d, J = 8.6 Hz, 2H), 7.25 (d,
J = 8.6, 2H), 7.08 (ddd, J = 10.0, 5.9, 2.6 Hz, 1H), 6.18 (d, J = 10.0
Hz, 1H), 3.47 (d, J = 12.0 Hz, 1H), 2. 67 (dt, Jt = 5.2 Hz, Jd = 18.4
Hz, 1H), 2.45–2.19 (m, 2H), 1.40–1.05 (m, 6H), 0.79 (d, J = 6.8
Hz, 3H). 13C NMR (75 MHz) d 198.8 (C), 149.9 (CH), 147.0 (C),
146.2 (C), 130.1 (2CH), 129.6 (CH), 123.7 (2CH), 60.1 (CH), 40.6
(CH), 33.4 (CH2), 31.3 (CH2), 28.1 (CH2), 22.5 (CH2), 13.8 (CH3).
MS (ESI) m/z 274 (M+1, 100), 149 (69). HRMS (ESI) calcd. for
C16H19NO3 [M+1]: 274.1437; found: 274.1440. The enantiomeric
excess was determined by HPLC using a Chiralpack AD column
[hexane/iPrOH = 90 : 10]; flow rate 1.0 mL min-1; tmajor = 12.8 min,
tminor = 19.2 min (92% ee). [a]2D0 -46.1 (c 1.0, CHCl3). IR (KBr)
1669, 1517, 1347 cm-1.
(5R, 6R)-5-ethyl-6-(4-nitrophenyl) cyclohex-2-enone (5b). The
title compound was obtained as a single diastereomer according
to the sequential procedure described above (76% yield). mp =
◦
1
110–112 C. H NMR (300 MHz): d 8.20 (d, J = 8.7 Hz, 2H),
7.26 (d, J = 8.6, 2H), 7.09 (ddd, J = 10.0, 6.2, 2.3 Hz, 1H), 6.18
(ddd, J = 10.0, 2.7, 1.3 Hz, 1H), 3.48 (d, J = 12.0 Hz, 1H), 2.71–
2.60 (m, 1H), 2.43–2.21 (m, 2H), 1.34–1.08 (m, 2H), 0.84 (t, J =
7.3 Hz, 3H). 13C NMR (75 MHz) d 198.3 (C), 149.4 (CH), 147.1
(C), 146.2 (C), 130.1 (2CH), 129.6 (CH), 123.6 (2CH), 59.7 (CH),
42.0 (CH), 30.8 (CH2), 26.4 (CH2), 10.3 (CH3). MS (ESI) m/z
246 (M+1, 100), 150 (11), 149 (49). HRMS (ESI) calcd. for
C14H16NO3 [M+1]: 246.1124; found: 246.1130. The enantiomeric
excess was determined by HPLC using a Chirapack AD column
[hexane/iPrOH = 90 : 10]; flow rate 1.0 mL min-1; tmajor = 17.4 min,
tminor = 24.5 min (92% ee). [a]2D0 -21.4 (c 1.0, CHCl3). IR (KBr)
1685, 1515, 1342, 742, 704 cm-1.
(5R, 6R)-5-((Z)-hex-3-enyl)-6-(4-nitrophenyl)cyclohex-2-enone
(5f). The title compound was obtained as a single diastereomer
according to the sequential procedure described above (56% yield).
◦
1
mp = 110–112 C. H NMR (300 MHz): d 8.20 (d, J = 8.8 Hz,
2H), 7.26 (d, J = 8.8, 2H), 7.08 (ddd, J = 10.0, 5.8, 2.4 Hz, 1H),
6.18 (d, J = 10.0 Hz, 1H), 5.39–5.28 (m, 1H), 5.15–5.05 (m, 1H),
3.48 (d, J = 11.9 Hz, 1H), 2. 69 (dt, Jt = 4.6 Hz, Jd = 18.4 Hz,
1H), 2.50–2.35 (m, 1H), 2.28 (ddt, Jt = 2.4 Hz, Jd = 18.4, 10.0
Hz, 1H), 2.10–1.88 (m, 4H), 1.23 (q, J = 7.5 Hz, 2H), 0.79 (t, J =
7.5 Hz, 3H). 13C NMR (75 MHz) d 198.1 (C), 149.2 (CH), 147.0
(C), 146.1 (C), 132.7 (CH), 130.1 (2CH), 129.6 (CH), 127.4 (CH),
123.7 (2CH), 60.1 (CH), 40.1 (CH), 33.7 (CH2), 31.3 (CH2), 23.6
(CH2), 20.5 (CH2), 14.2 (CH3). MS (EI) m/z 299 (M+, 5), 229 (46),
216 (27), 141 (26), 116(67), 115 (77), 68 (100). HRMS (EI) calcd.
for C18H21NO3 [M+]: 299.1521; found: 299.1525. The enantiomeric
excess was determined by HPLC using a Chiralpack AD column
[hexane/iPrOH = 90 : 10]; flow rate 1.0 mL min-1; tmajor = 11.2 min,
tminor = 17.2 min (94% ee). [a]2D0 -23.3 (c 1.0, CHCl3). IR (KBr)
1675, 1521, 1346 cm-1.
(5R, 6R)-6-(4-nitrophenyl)-5-propylcyclohex-2-enone (5c). The
title compound was obtained as a single diastereomer according
to the sequential procedure described above (78% yield). mp =
◦
1
125–127. C. H NMR (300 MHz): d 8.20 (d, J = 8.7 Hz, 2H),
7.25 (d, J = 8.7, 2H), 7.11–7.04 (m, 1H), 6.18 (dd, J = 10.1, 2.6 Hz,
1H), 3.46 (d, J = 10.1 Hz, 1H), 2.66 (dt, Jt = 4.7 Hz, Jd = 18.1 Hz,
1H), 2.42–2.33 (m, 1H), 2.32–2.20 (m 1H), 1.35 (m 1H), 1.14–1.30
(m 1H), 1.25 (t, J = 6.6 Hz, 1H), 1,14 (m 2H), 0.78 (t, J = 6.6
Hz, 3H). 13C NMR (75 MHz) d 198.3 (C), 149.4 (CH), 147.2 (C),
146.3 (C), 130.2 (2CH), 129.6 (CH), 123.7 (2CH), 60.1 (CH), 40.5
(CH2), 36.0 (CH2), 31.4 (CH),19.2 (CH2), 13.9 (CH3). MS (ESI)
282 (M+22, 929), m/z 260 (M+1, 100), 149 (92), 59 (19). HRMS
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(5R, 6R)-6-(4-nitrophenyl)-5-phenylcyclohex-2-enone (5g).
The title compound was obtained as a single diastereomer
according to the sequential procedure described above (69%
organic layers were washed with brine and dried over MgSO4.
The solvent was evaporated to give the pure product in 97% yield.
mp = 131–134 ◦C. 1H NMR (300 MHz): d 6.96 (ddd, J = 2.6, 5.4,
10.1 Hz, 1H), 6.85 (d, J = 8.4 Hz, 2H), 6.64 (d, J = 8.4 Hz, 2H),
6.13 (ddd, J = 10.0, 2.7, 1.1 Hz, 1H), 3.6 (bs, 2H, NH2), 3.10 (d, J
= 11.6 Hz, 1H), 2.51 (dt, Jt = 5.4 Hz, Jd = 18.3 Hz, 1H), 2.43–2.27
(m, 1H), 2.30 (ddt, Jt = 2.6 Hz, Jd = 18.3, 9.8 Hz, 1H), 0.86 (d,
J = 6.5 Hz, 3H). 13C NMR (75 MHz) d 200.3 (C), 148.6 (CH),
145.3 (C), 130.1 (CH), 129.8 (2CH), 128.3 (C), 115.3 (2CH), 60.9
(CH), 36.5 (CH), 34.4 (CH2), 20.3 (CH3). MS (EI) m/z 201, 133
(100), 132 (23). HRMS (EI) calcd. for C13H15NO [M+]: 201.1154;
found: 201.1151. IR (KBr) 3450, 3400, 2953, 2923, 1671, 1519,
1283, 1154 cm-1.
◦
1
yield). mp = 149–152 C. H NMR (300 MHz): d 7.99 (d, J =
8.5 Hz, 2H), 7.11 (m, 8H), 6.27 (ddd, J = 10.1, 2.4, 1.4 Hz, 1H),
4.00 (d, J = 12.8 Hz, 1H), 3.63–3.53 (m, 1H), 2.90–2.70 (m, 2H).
13C NMR (75 MHz) d 197.4 (C), 149.0 (CH), 145.5 (2C), 141.0
(C), 130.4 (2CH), 129.8 (CH), 128.7 (2CH), 127.4 (2CH), 127.2
(CH), 123.4 (2CH), 59.9 (CH), 48.3 (CH), 34.9 (CH2). MS (EI)
282 (M+), m/z 293 (M+, 6), 225 (100), 195 (23), 178 (46). HRMS
(EI) calcd. for C18H15NO3 [M+]: 293.1052; found: 293.1046. The
enantiomeric excess was determined by HPLC using a Chiralpack
IA column [hexane/iPrOH = 90 : 10]; flow rate 1.0 mL min-1;
tmajor = 28.2 min, tminor = 36.0 min (66% ee). [a]2D0 -45.6 (c 1.0,
CHCl3). IR (KBr) 1674, 1514, 1342, 860, 742, 705 cm-1.
(5R, 6R)-6-(4-iodophenyl)-5-methylcyclohex-2-enone (7a). To
a solution of 6a (0.2 mmol, 26 mg) in HCl 6 N (0.3 mL) cooled
to 0 ◦C, a solution of NaNO2 (1 equiv, 13.8 mg) in water (1 mL)
was added dropwise. The resulting solution was added dropwise
to a solution of KI (4 equiv, 133 mg) in water (1.5 mL), keeping
the bath temperature at 0 ◦C. The reaction mixture was allowed to
warm to room temperature and stirred overnight, then extracted
with ethyl acetate. The combined organic layers were washed in
sequence with 10% Na2S2O3 and brine, then dried over MgSO4
(5R, 6R)-5-(4-methoxyphenyl)-6-(4-nitrophenyl) cyclohex-2-
enone (5h). The title compound was obtained as a single
diastereomer using 30 mol% of PhCO2H as additive instead of
LiOAc in the Michael addition (71% yield). mp = 196–198 ◦C.
1H NMR (300 MHz): d 8.87 (d, J = 8.8 Hz, 2H), 7.16–7.12
(m, 1H), 7.09 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.6 Hz, 2H)),
6.70 (d, J = 8.6 Hz, 2H), 6.30–6.23 (m, 1H), 3.96 (d, J = 13.2
Hz, 1H), 3.59–3.48 (m, 1H), 2.81–2.73 (m, 2H). 13C NMR (75
MHz) d 197.6 (C), 158.5 (C), 149.1 (C), 145.7 (C), 133.0 (CH),
130.3 (2CH), 129.8 (CH),128.3 (2CH), 123.3 (2CH), 114.0 (2CH),
60.4 (CH3), 55.2 (CH), 47.5 (CH), 35.1 (CH2). MS (ESI) m/z 324
(M+1, 100), 282 (14), 149 (59), 121 (30). HRMS (ESI) calcd. for
C19H18NO4 [M+1]: 324.1229; found: 324.1230. The enantiomeric
excess was determined by HPLC using a Chiralpack AD column
[hexane/iPrOH = 80 : 20]; flow rate 1.0 mL min-1; tmajor = 22.9 min,
tminor = 28.5 min (75% ee). [a]2D0 -42.2 (c 1.0, CHCl3). IR (KBr)
1675, 1517, 1349 cm-1.
1
and concentrated under vacuum to give 7a with 75% yield. H
NMR (300 MHz): d 7.66 (d, J = 8.5 Hz, 2H), 7.01 (ddd, J =
2.5, 5.9, 10.0 Hz, 1H), 6.83 (d, J = 8.5, 2H), 6.15 (ddd, J = 0.9,
2.6, 10.0 Hz, 1H), 3.17 (d, J = 11.9 Hz, 1H), 2.55 (dt, Jt = 5.7
Hz, Jd = 18.4 Hz, 1H), 2.46–2.33 (m, 1H), 2.24 (ddt, Jt = 2.5
Hz, Jd = 10.0, 18.4 Hz, 1H), 0.86 (d, J = 6.4 Hz, 3H). 13C NMR
(75 MHz) d 199.0 (C), 149.1 (CH), 138.0 (C), 137.6 (2CH), 131.2
(2CH), 129.9 (CH), 92.5 (C), 61.34 (CH), 36.3 (CH2), 34.6 (CH),
20.3 (CH3). MS (EI) m/z 312 (M+, 60), 243 (100), 117 (20), 115
(27). MS (EI) calcd. for C13H13IO [M+]: 312.0011; found: 312.0013.
[a]2D0 -14.1 (c 0.3, CHCl3). IR (KBr) 1674, 1386, 1262, 1098, 802,
549 cm-1.
(5R, 6R)-5-(4-nitrophenyl)-6-(4-nitrophenyl) cyclohex-2-enone
(5i). The title compound was obtained as a single diastereomer
according to the sequential procedure described above without
using any additive in the Michael addition step (75% yield). mp =
(1S, 5R, 6R)-5-methyl-6-(4-nitrophenyl) cyclohex-2-enol (8a).
To a solution of enone 5a (50 mg, 0.21 mmol) and CeCl3·7H2O
(117 mg, 0.31 mmol) in MeOH (5 mL) at -78 ◦C NaBH4 (16 mg,
0.42 mmol) was added in one portion. The resulting mixture
was stirred for 1 h at -78 ◦C and slowly warmed up to room
temperature during 4 h. The reaction was quenched by addition of
1 mL of acetone and then 1 mL of H2O. The solvent was evaporated
and the residue partitioned between Et2O (10 mL) and H2O (5 mL).
The layers were separated and the aqueous layer was extracted with
Et2O (3 ¥ 10 mL). The combined organic extracts were washed
with brine, dried over MgSO4, filtered and concentrated under
reduced pressure. Purification by flash chromatography (6 : 1 n-
hexa◦ne: EtOAc) gave 8a as a white solid (68% yield). mp: 108–
◦
1
168–170 C. H NMR (300 MHz): d 8.06 (d, J = 8.7 Hz, 2H),
8.04 (d, J = 8.7 Hz, 2H), 7.26 (d, J = 8.7 Hz, 2H), 7.15 (m,1H),
7.11 (d, J = 8.7 Hz, 2H), 6.32 (bd, J = 10.4 Hz, 1H), 4.03 (d, J =
13.4 Hz, 1H), 3.80–3.71 (m, 1H), 2.85–2.79 (m, 2H). 13C NMR
(75 MHz) d 196.2 (C), 148.1 (C), 148.0 (CH), 147.0 (C), 146.9 (C),
144.4 (C), 130.2 (2CH), 130.0 (CH), 128.3 (2CH), 124.1 (2CH),
123.6 (2CH), 59.1 (CH), 47.9 (CH), 34.4 (CH2). MS (EI) m/z
338 (M+, 1), 270 (100), 165 (35), 68 (97). HRMS (EI) calcd. for
C18H14N2O5 [M+]: 338.0903; found: 338.0899. The enantiomeric
excess was determined by HPLC using a Chiralcel OD column
[hexane/iPrOH = 80 : 20]; flow rate 1.0 mL min-1; tmajor = 47.0 min,
tminor = 44.1 min (76% ee). [a]2D0 -40.8 (c 1.0, CHCl3). IR (KBr)
1674, 1514, 1347 cm-1.
1
110 C. H NMR (300 MHz): d 8.20 (d, J = 8.6 Hz, 2H), 7.38
(d, J = 8.6, 2H), 5.89–5.82 (m, 1H), 5.75 (d, J = 10.1 Hz, 1H),
4.42–4.30 (m, 1H), 2.46 (dd, J = 11.4, 11.6 Hz, 1H), 2.28 (dt, Jt
= 2.5 Hz, Jd = 17.9 Hz, 1H), 2.14–2.01 (m, 1H), 1.98–1.84 (m,
1H), 1.44 (d, J = 5.6 Hz, OH), 0.69 (d, J = 6.5 Hz, 3H). 13C NMR
(75 MHz) d 150.6 (C), 146.9 (C), 130.0 (CH), 129.2 (2CH), 128.7
(CH), 123.8 (2CH), 73.3 (CH), 57.1 (CH), 34.6 (CH2), 32.8 (CH),
19.6 (CH3). MS (ESI) m/z 256 (M+Na+, 100), 216 (83), 149 (81).
MS (ESI) calcd. for C13H15NO3Na [M+Na]+: 256.0944; found:
256.0945. [a]2D0 -4.1 (c 0.3, CHCl3). IR (KBr) 3512, 1530, 1348,
751, 700 cm-1. Representative 1H NMR data of 8a¢: d 8.19 (d, J =
(5R, 6R)-6-(4-aminophenyl)-5-methylcyclohex-2-enone (6a).
To a solution of (5R,6R)-6-(4-nitrophenyl)-5-methylcyclohex-
2-enone 5a (0.20 mmol, 40 mg) in CH2Cl2 (2 mL) was added
sequentially Zn dust (2.80 mmol, 177 mg) and AcOH (5.6 mmol,
◦
340 mL) at 0 C. After stirring at room temperature for 10 min,
the reaction mixture was filtered through Celite. The filtrate was
neutralized with a saturated solution of NaHCO3, the aqueous
layer was extracted with ethyl acetate (3 ¥ 5 mL) and the combined
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8.6 Hz, 2H), 7.46 (d, J = 8.6, 2H), 4.08 (m, 1H), 2.69 (dd, J = 11.6,
3.4 Hz, 1H, H6), 0.79 (d, J = 6.3 Hz, 3H). For more information
see supporting information.
Notes and references
1 For some examples, see: (a) A. R. Angeles, D. C. Dorn, C. A. Kou,
M. A. S. Moore and S. J. Danishefsky, Angew. Chem., Int. Ed., 2007,
46, 1451; (b) W. Zhao and J. Zhang, Org. Lett., 2011, 13, 688; (c) H.
Haning, C. Giro-Manas, V. L. Paddock, C. G. Bochet, A. J. P. White,
G. Bernardinelli, I. Mann, W. Oppolzer and A. G. Spivey, Org. Biomol.
Chem., 2011, 9, 2809.
2 (a) X. Wang, C. M. Reisinger and B. List, J. Am. Chem. Soc., 2008,
130, 6070; (b) E. Zang, C-A. Fan, Y-Q. Tu, F. M. Zhang and Y-L.
Song, J. Am. Chem. Soc., 2009, 131, 14626; (c) H. Jiang, N. Holub
and K. A. Jørgensen, Proc. Natl. Acad. Sci. U. S. A., 2010, 107,
20630.
3 (a) Y. Chen and T. Ju, Org. Lett., 2011, 13, 86; (b) G. Mehta, S.
K. Chattopadhyay and J. D. Umarye, Tetrahedron Lett., 1999, 40,
4881.
4 See for example: G. Franck, K. Bo¨rdner and G. Helmchen, Org. Lett.,
2010, 12, 3886. See also ref. 1a.
(2R, 3R, 5R, 6R)-2,3-dihydroxy-5-methyl-6-(4-nitrophenyl)-
cyclohexanone (9a). A 5 mL round-bottomed flask was charged
with 40 mg of a,b-unsaturated ketone 5a (1 equiv., 0.158 mmol)
and dissolved in 800 mL of t-BuOH. Then, 300 mg of AD-
mix-a, 40 mg of NaHCO3 (3 equiv, 0.474 mmol), 15 mg of
methylsulfonamide (1 equiv., 0.158 mmol), 10 mg of K2OsO2(OH)2
(0.16 equiv, 0.027 mmol) and 800 mL of H2O were subsequently
added and the mixture was vigorously stirred at room temperature
for 4 days. Whereupon the mixture was transferred to a 25 mL
Erlenmeyer flask, diluted with 10 mL of EtOAc and stirred for 1
h with 10 mL of a 40% solution of NaHSO3. The aqueous layer
was extracted with EtOAc (15 mL ¥ 4), the combined organic
layers were sequentially washed with a 10% solution of NaOH
and brine, dried over MgSO4 and the solvent evaporated under
vacuum. The crude was purified by flash chromatography (2 : 1 to
1 : 1 n-hexane : EtOAc) to afford 23 mg of diastereomerically pure
9a (50% yield). 1H NMR (500 MHz, CDCl3): d 8.23 (d, J = 8.6 Hz,
2H), 7.28 (d, J = 8.6 Hz, 2H), 4.47 (dd, J = 5.5, 3.5 Hz, 1H), 4.34
(bs, 1H), 3.80 (d, J = 2.0 Hz, OH), 3.38 (d, J = 11.8 Hz), 2.67 (bs,
OH), 2.65 (m, 1H), 2.31 (dt, Jd = 14.7 Hz, Jt = 3.8 Hz, 1H), 1.84
(t, J = 14.3 Hz, 1H), 0.86 (d, J = 6.5 Hz, 3H). 13C NMR (75 MHz)
(benzene-d6): d 206.8(C), 147.6 (C), 143.3 (C), 130.4 (2CH), 123.5
(2CH), 77.1 (CH), 71.8 (CH), 61.6 (CH), 36.8 (CH2), 34.7 (CH),
19.9 (CH3). MS (ESI) m/z 248 (M+1+, 75), 149 (81), 74 (61). MS
(ESI) calcd. for C13H14NO4 [M+1]+: 248.0917; found: 248.0925.
[a]2D0 +32.1 (c 1.0, CHCl3).
5 (a) A. Carlone, M. Marigo, C. North, A. Landa and K. A. Jørgensen,
Chem. Commun., 2006, 4928; (b) P. Bolze, G. Dickmeiss and K. A.
Jørgensen, Org. Lett., 2008, 10, 3753; (c) L-L. Wang, L. Peng, J-F. Bai,
Q-C. Huang, X-Y. Xu and L-X. Wang, Chem. Commun., 2010, 46,
8064.
6 For some examples as intermediates to prepare natural products: (a) A.
Biechy, S. Hachisu, B. Quiclet-Sire, L. Ricard and S. Z. Zard, Angew.
Chem., Int. Ed., 2008, 47, 1436; (b) N. Yamamoto, H. Fujii, S. Imaide,
S. Hirayama, T Nemoto, J. Inokoshi, H Tomoda and H. Nagase, J.
Org. Chem., 2011, 76, 2257; (c) D. Sole, J. Bonjoch and J. Bosch, J. Org.
Chem., 1996, 61, 4194; (d) D Sole, S. Garc´ıa-Rubio, L. Vallverdu and
J. Bonjoch, J. Org. Chem., 2001, 66, 5266.
7 We have not found any method to prepare 6-aryl-5-substituted cyclo-
hexenones in enantiomerically pure form. For the synthesis of a related
compound in racemic version see H. E. Zimmerman and D. Lynch, J.
Am. Chem. Soc., 1985, 56, 7745.
8 M. B. Cid, S. Duce, S. Morales, E. Rodrigo and J. L. Garc´ıa Ruano,
Org. Lett., 2010, 12, 3586.
9 The potential of the nitrophenyl moiety as a non-conventional activat-
ing group for nucleophiles has also been used recently by Melchiorre’s
group incorporating nitrobenzylpyridines into organocatalytic pro-
cesses. See: S. Vera, Y. Liu, M. Marigo, E. C. Escudero-Ada´n and
P. Melchiorre, Synlett, 2011, 489.
10 For some examples on one-pot strategies using a,b-unsuturated
aldehydes that afford complex structures, see: (a) B. Simmons, A. M.
Walji and D. W. C. MacMillan, Angew. Chem., Int. Ed., 2009, 48, 4349;
(b) Ł. Albrecht, L. K. Ransborg, B. Gschwend and K. A. Jørgensen,
J. Am. Chem. Soc., 2010, 132, 17886; (c) K. L. Jensen, P. T. Franke,
C. Arro´niz, S. Kobbelgaard and K. A. Jørgensen, Chem.–Eur. J., 2010,
16, 1750 and references cited therein. For an impressive example see:
(d) M. Reiter, S. Torssell, S. Lee and D. W. C. MacMillan, Chem. Sci.,
2010, 1, 37.
11 See: (a) V. K. Aggarwal and B. Olofsson, Angew. Chem., Int. Ed., 2005,
44, 5516 and references cited therein; (b) A. Yanagisawa, T. Touge and
T. Arai, Angew. Chem., Int. Ed., 2005, 44, 1546. For a recent racemic
example see: (c) X. Huang and M. Maulide, J. Am. Chem. Soc., 2011,
133, 8510.
12 For a-arylation of carbonyl compounds using transition metal catalysis
see: (a) J. M. Fox, X. Huang, A. Chieffi and S. L. Buchwald, J. Am.
Chem. Soc., 2000, 122, 1360; (b) T. Hamada, A. Chieffi, J. Ahman and
S. L. Buchwald, J. Am. Chem. Soc., 2002, 124, 1261; (c) X. Liao, Z.
Weng and J. F. Hartwig, J. Am. Chem. Soc., 2008, 130, 195; (d) P. M.
Lundin, J. Esquivias and G. C. Fu, Angew. Chem., Int. Ed., 2009, 48,
154; (e) For other methods that do not employ transition metal catalysis
see ref. 11c and references cited therein.
(1R, 3R, 4R, 6R)-4-methyl-3-(4-nitrophenyl)-7-oxabicyclo-
[4.1.0]heptan-2-one (10a). To a solution of 5a (50 mg, 0.21
mmol, 1 equiv.) in THF (1 mL) at -78 ◦C, a solution of tert-
butylhydroperoxide (TBPH) (5–6 M in decane, 3 equiv) and 4
drops of benzyl trimethylammonium hydroxide (Triton B) (40% in
MeOH) were sequentially added. The mixture was stirred at room
temperature overnight and then treated with saturated aqueous
solution of Na2SO3 and extracted with EtOAc. The residue was
purified by flash chromatography (n-hexane/EtOAc 5 : 1), to give
1
10a as colourless oil (48% yield). H NMR (500 MHz)(benzene-
d6): d 7.77 (d, J = 8.8 Hz, 2H), 6.69 (d, J = 8.8, 2H), 3.00 (d, J = 4.0
Hz, 1H), 2.82 (t, J = 3.8 Hz, 1H), 2.15 (d,J = 11.8 Hz, 1H), 2.02–
1.92 (m, 1H), 1.66 (dt, Jt = 3.8 Hz, Jd = 15.0 Hz, 1H), 0.87 (dd, J =
15.0, 12.0 Hz, 1H), 0.26 (d, J = 6.5 Hz, 3H). 13C NMR (75 MHz) d
204.1 (CO), 147.2 (C), 146.1 (C), 130.1 (2CH), 123.9 (2CH), 61.6
(CH), 54.6 (CH), 54.4 (CH), 31.5 (CH2), 28.7 (CH), 19.5 (CH3).
MS (ESI) m/z 266 (M+1+, 16), 139 (43), 74 (100). MS (ESI) calcd.
for C13H15NO5Na [M+Na]+: 288.0842; found: 288.0837. [a]2D0 -9.1
(c 0.7, CHCl3).
13 For some organocatalytic examples: (a) K. L. Jensen, P. T. Franke, L.
T. Nielsen, K. Daasbjerg and K. A. Jørgensen, Angew. Chem., Int. Ed.,
2010, 49, 129; (b) J. C. Conrad, J. Kong, B. N. Laforteza and D. W. C.
MacMillan, J. Am. Chem. Soc., 2009, 131, 11640.
14 D. L. J. Clive, P. L. Wickens and G. V. J. da Silva, J. Org. Chem., 1995,
60, 5532.
Acknowledgements
We thank the Spanish Government (CTQ-2009-12168), CAM
(AVANCAT CS2009/PPQ-1634) and UAM-CAM (CCG10-
UAM/PPQ-5769) for financial support. S.D. thanks the Comu-
nidad Auto´noma de Madrid for a predoctoral fellowship. We
also thank the Centro de Computacio´n Cient´ıfica de la UAM
for generous allocation of computer time and the laboratory of
mass spectrometry of the UAM (SIdI).
15 (a) Y. Hayashi, H. Gotoh, T. Hayashi and M. Shoji, Angew. Chem., Int.
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16 For details, see Electronic Supplementary Information‡.
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17 In order to discard that DBU promoted retro aldol/retro Michael
racemizing compounds 4, a sample of alcohols 4g/4g¢ derived from
the Michael addition/aldol reaction of cinnamaldehyde, of known
enantiomeric purity, was treated with DBU during 5 h giving rise the
same mixture without erosion of ee.
18 This phenomenon has been pointed out several times in the literature:
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23 Similar stereoselectivities but lower yields were obtained when using
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27 The synthesis of similar compounds has been reported. See: J. Clayden,
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30 Presumably, torsional effects are again responsible for the observed
stereoselectivity. Axial approach of the reagent to C3 is favored as
equatorial approach would afford an enolate with a near eclipsing
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8260 | Org. Biomol. Chem., 2011, 9, 8253–8260
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