Activation of 1,2- and 1,3-ketoamides with thiourea organocatalyst for the enantioselective domino synthesis of functionalized cyclohexanes

Article abstract of DOI:10.1055/s-0033-1338844

Several reactive sites of 1,2- and 1,3-ketoamides were successively exploited in two complementary domino transformations for the synthesis of polysubstituted monocyclic or bridged bicyclic cyclohexanes, with the creation of up to six stereogenic centers.

Full text of DOI:10.1055/s-0033-1338844

SPECIAL TOPIC
▌1659
sApeccitalitvopaiction of 1,2- and 1,3-Ketoamides with Thiourea Organocatalyst for the
Enantioselective Domino Synthesis of Functionalized Cyclohexanes
Enantioselective Domino Synthesis of Functionalized Cyclohexanes
Wilfried Raimondi, Maria del Mar Sanchez Duque, Sébastien Goudedranche, Adrien Quintard, Thierry Constantieux,
Xavier Bugaut,* Damien Bonne,* Jean Rodriguez
Aix Marseille Université, CNRS, iSm2 UMR 7313, 13397 Marseille, France
Fax +33(491)289187; E-mail: damien.bonne@univ-amu.fr; E-mail: xavier.bugaut@univ-amu.fr
Received: 28.02.2013; Accepted after revision: 03.05.2013
stereogenic carbon atoms with controlled stereochemis-
Abstract: Several reactive sites of 1,2- and 1,3-ketoamides were
tries. Most of these strategies employ simple substrates
successively exploited in two complementary domino transforma-
with multiple reactive sites that are involved in successive
formation of several carbon–carbon and/or carbon–het-
tions for the synthesis of polysubstituted monocyclic or bridged bi-
cyclic cyclohexanes, with the creation of up to six stereogenic
centers. In both cases, a chiral bifunctional thiourea organocatalyst eroatom bonds. In this context, dicarbonyl compounds
allowed efficient control of chirality in the final carbocycle.
and, especially, ketoamides are attractive substrates be-
cause of their high density of potential reactive sites; these
substrates are therefore well suited for use in designing
new stereoselective domino transformations for asymmet-
ric syntheses of functionalized six-membered carbocy-
cles.5
Key words: domino reactions, ketones, amides, cyclizations, cy-
cloalkanes, stereoselectivity, catalysis, thioureas
The development of domino enantioselective organocata-
lytic methodologies has received intense attention from
researchers, as demonstrated by the large number of re-
cent reports on stereoselective constructions of heterocyl-
ic and carbocyclic scaffolds.1 Among these scaffolds,
substituted chiral cyclohexanes are important building
blocks for organic synthesis,2 and many of the reported
approaches permit control of the relative and absolute
configurations of these versatile molecular architec-
tures.3,4 These methods have the advantage of permitting
efficient assembly of the desired target from easily acces-
sible starting materials, as well as the creation of multiple
We recently showed that the 1,2- and 1,3-ketoamides 1
and 4, respectively, can be specifically activated by using
a thiourea–tertiary amine bifunctional organocatalyst, and
we successfully developed enantioselective Michael addi-
tions of these substrates with either nitroalkenes 2 or α,β-
unsaturated carbonyl compounds 5 as the electrophilic
partners (Scheme 1).6 We wished to exploit this work by
using the Michael adducts 3 and 6 as versatile synthetic
platforms for subsequent transformations into more com-
plex molecular frameworks, such as substituted cyclohex-
anes.
R2
O
NO2
chiral thiourea
organocatalyst
O
H
H
R1
N
+
O2N
N
Ar1
Ar1
R2
R1
O
O
1
2
3
six-membered
carbocycles
O
O
O
chiral thiourea
organocatalyst
R3
O
Ar2
R3
O
+
N
H
when R3 = H
HN Ar2
6
4
5
O
Scheme 1 Access to optically active six-membered carbocycles from 1,2-ketoamides 1 and 1,3-ketoamides 4
SYNTHESIS 2013, 45, 1659–1666
Advanced online publication: 03.06.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338844; Art ID: SS-2013-C0168-ST
© Georg Thieme Verlag Stuttgart · New York

1660
W. Raimondi et al.
SPECIAL TOPIC
In the case of 1,2-ketoamides 1, we reasoned that once the
Michael adduct 3 is formed (Scheme 2), addition of a sec-
ond equivalent of a nitroalkene should trigger another
conjugate addition leading to intermediate 7. This should
then undergo an intramolecular Henry reaction, complet-
ing the domino transformation and affording the desired
hexasubstituted cyclohexane 8.7
Table 1 Optimization of the Domino Michael–Michael–Henry
Reaction
R2
I–IV
O2N
R2
R1
NO2
(10 mol%)
O
Ar = 3,5-(CF3)2C6H3
H
R1
N
+
CONHPh
Ph
solvent, r.t., 96 h
R2
OH
NO2
O
1a (R1 = Me)
2a (R2 = 4-FC6H4)
8a
R2
O
H
R2
O
O2N
R2
N
S
H
2
Ar
*
*
O2N
N
Ar
N
R1
NO2
O
Ar
Michael
reaction
NH
S
H
R1
O
Ar
N
H
N
N
H
H
3
7
NMe2
N
O
I
II
Henry
reaction
O
O
O
R2
*
Ar
NH
NH
O2N
R2
R1
Ar
N
*
*
*
*
N
H
N
H
CONHAr
H
*
N
OH
NO2
Me2N
8
III
IV
Scheme 2 Strategy for the synthesis of hexasubstituted cyclohex-
anes 8
Entrya
Catalyst Solvent
Yieldb (%) drc
of 8a
erd
1
2
3
4
5
6
7
I
EtOAc
EtOAc
EtOAc
EtOAc
CH2Cl2
DMSO
MTBE
<5
62
<5
<5
45
n.d.e
>20:1
n.d.
28:1
n.d.
n.d.
n.d.
–
We began our investigations by screening various bifunc-
tional organocatalysts I–IV bearing either thiourea or
squaramide hydrogen-bond donor subunits (Table 1). Cat-
alyst I,8 derived from cinchonine, produced only traces of
8a, the sequence stopping at the Michael adduct stage (en-
try 1). However, we were very pleased to find that
Takemoto’s catalyst II9 was efficient in this domino trans-
formation, affording 8a in good yield (67%) and very
good diastereomeric and enantiomeric ratios (>20:1 and
28:1 respectively) (entry 2). Remarkably, one of the sixty-
four possible stereoisomers was obtained predominantly.
The use of catalysts III and IV with squaramide subunits
gave poor results (entries 3 and 4),10 and only traces of cy-
clohexane 8a were formed (<5%). The highest yield and
stereoselectivity were achieved by using ethyl acetate as
solvent (entry 2); switching to dichloromethane led to a
lower yields and poorer selectivity of the desired product
(entry 5). Other solvents such as dimethyl sulfoxide or
methyl tert-butyl ether were not suitable, causing decom-
position and poor reactivity, respectively (entries 6 and 7).
II
III
IV
II
II
II
n.d.
n.d.
1:1.5
–
f
–
<5%
n.d.
n.d.
a Reaction conditions: 1a (0.2 mmol), 2a (0.42 mmol), solvent (0.4
mL).
b Yield of analytically pure isolated product.
c Diastereomeric ratios were determined by 1H NMR spectroscopic
analysis of the crude reaction mixtures.
d Enantiomeric ratios were determined by HPLC analysis on a chiral
stationary phase.
e n.d. = not determined.
f Decomposed.
the use of ketoamide 1c (R1 = Et; Ar = 2,5-Cl2C6H3),
bearing the sterically demanding 2,5-dichlorophenyl sub-
stituent, had a negative effect on the enantioselectivity of
the domino reaction (8c; er = 4:1). With regard to the ni-
troalkene partner 2, both phenyl- and (4-fluorophenyl)ni-
troalkenes are found to be suitable substrates for this
reaction.
Having optimized the reaction conditions, we studied the
possibility of using a range of ketoamides 1 and ni-
troalkenes 2 to synthesize various hexasubstituted cyclo-
hexane derivatives 8a–e (Scheme 3). By using
Takemoto’s catalyst II in ethyl acetate at room tempera-
ture for four days, we were delighted to obtain cyclohex-
anes 8 in fair yields and, more importantly, generally very
good stereoselectivities. Electron-withdrawing as well as
electron-donating groups on the aryl substituent of the ke-
toamide 1 were well tolerated in this reaction, although
In our earlier studies, we found that Takemoto’s catalyst
II is also an efficient promoter of the enantioselective
Michael addition of 1,3-ketoamides 4 to α,β-unsaturated
Synthesis 2013, 45, 1659–1666
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Enantioselective Domino Synthesis of Functionalized Cyclohexanes
1661
carbonyl compounds.6b If acrolein (9) is used as the elec- tained in a 3.5:1 ratio (entry 1). In attempts to favor the
trophilic reaction partner, two modes of cyclization can be formation of the bicyclic product, we examined the effects
envisaged for the initial adducts 6 (Scheme 4). The first of various reaction conditions after the completion of the
involves the formation of hemiaminal 10, which we have Michael addition. At room temperature, without the addi-
already exploited (path a). The second might involve an tion of any other reagent, a slow evolution toward a 1.5:1
intramolecular aldol reaction, leading directly to the cor- ratio of 10a and 11a occurred after stirring for an addition-
responding bicyclo[3.2.1]octane 11, which contains a al two days (entry 2). We were able to verify that Takemo-
bridged six-membered ring with three stereogenic centers to’s catalyst II is involved in this process, as no
(path b). Given the prevalence of this skeleton in natural interconversion between the products occurred in its ab-
products and the challenges associated with its synthe- sence. As expected, increasing the temperature to 60 °C
sis,11 new modular enantioselective techniques for access- led to the formation of 11a as the major product with a
ing this skeleton are of great interest.
12:1 dr and a 4.7:1 er (entry 3). We then searched for ad-
ditives that might affect the thermodynamic interconver-
sion of 10a into 11a. Whereas the addition of a catalytic
amount of L-proline (V) had a limited effect (entry 4), the
presence of a stoichiometric amount of the N-heterocyclic
carbene VI (entry 5)12 or 1,8-diazabicyclo[5.4.0]undec-7-
ene (VII; DBU) (entry 6) completely shifted the equilib-
rium towards the desired product 11a, albeit with very
modest diastereoselectivities; in the latter case, the er of
the major diastereomer was 4.1:1.
In our initial study with an N-tosyl ketoamide, the hemi-
aminal was obtained as the sole product.6b However, when
we extended this reaction to the N-aryl ketoamide 4a, a
spontaneous evolution towards a mixture of the two prod-
ucts 10a and 11a occurred (Table 2), indicating that an
equilibrium exists between the kinetically favored prod-
uct 10a and the thermodynamically favored product 11a.
When the reaction was performed at –20 °C in the pres-
ence of catalyst II for 48 hours, products 10a and 11a,
with the hydroxyl group in the axial position, were ob-
CF3
S
R2
F3C
N
N
H
H
NMe2
NO2
R1
O2N
R2
O
II (10 mol%)
H
R1
N
+
CONHAr
Ar
R2
OH
EtOAc, r.t., 96 h
O
NO2
1
8a–e
2 (2 equiv)
F
F
F
Cl
O2N
O2N
O2N
HN
HN
Cl
HN
O Cl
O
O
OH
OH
OH
NO2
NO2
NO2
F
F
F
8a
62%
8b
51%
8c
47%
> 20:1 dr
28:1 er
20:1 dr
19:1 er
>20:1 dr
4:1 er
F
O2N
O2N
HN
OMe
HN
OMe
O
O
OH
OH
NO2
NO2
F
8d
67%
8e
53%
>20:1 dr
28:1 er
>20:1 dr
28:1 er
Scheme 3 Scope of the Michael–Michael–Henry reaction leading to cyclohexanes 8
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1659–1666

1662
W. Raimondi et al.
SPECIAL TOPIC
1,8-Diazabicyclo[5.4.0]undec-7-ene was selected as the
best promoter of the isomerization, because it allowed an
efficient reaction with a short reaction time. We then in-
vestigated the behavior of several other 1,3-ketoamides13
under these reaction conditions (Scheme 5). With the N-
aryl 1,3-ketoamides 4b and 4c, we found that evaporation
of the excess acrolein was required before addition of 1,8-
diazabicyclo[5.4.0]undec-7-ene to prevent a double
Michael addition. Products 11b and 11c were obtained in
reasonable yields, but moderate stereoselectivities. Inter-
estingly, the N-tosyl 1,3-ketoamide 4d could also be con-
verted into the bicyclic product 11d. Because of the higher
stability of the hemiaminal in this case, the isomerization
with 1,8-diazabicyclo[5.4.0]undec-7-ene had to be con-
ducted at 60 °C. Once again, the reaction showed no dia-
stereoselectivity, but both diastereoisomers were obtained
with high enantioselectivities (66:1 and 14:1 er, respec-
tively). The differences in the enantiomeric ratios ob-
served between the various cyclization modes14 clearly
indicate that these compounds are prone to racemization.
As a result, particular care must be taken to avoid this
problem during the cyclization reaction or any later func-
tionalization reactions.
O
O
R
N
O
O
H
R
II
4
N
H
toluene
+
a
O
H
b
H
9
O
6
path a
path b
R
O
*
O
NR
*
HN
O
O
OH
*
*
*
10
HO
11
Scheme 4 Divergent pathways for the cyclization of the adducts of
1,3-ketoamides with acrolein
Table 2 Optimization of the Reaction Conditions for the Synthesis of Bicyclo[3.2.1]octane 11a
NO2
NO2
O
O
NO2
N
H
O
O
HN
O
1) II (10 mol%)
toluene, –35 °C, 48 h
4a
+
O
N
+
OH
2) conditions
O
HO
10a
11a
H
N
N
N
CO2H
N
H
N
V
VII
VI
Entrya
Post-Michael reaction conditions
10a/11ab
dr (OHax/OHeq)b
erc
d
1
2
3
4
5
6
–
3.5:1
1.5:1
1:9.3
1:1.1
<1:20
<1:20f
>20:1
>20:1
12:1
n.d.e
r.t., 2 d
n.d.
60 °C, 2 d
4.7:1
V (20 mol%), r.t., 2 d
VI (1.1 equiv), r.t., 3 d
VII (1 equiv), r.t., 10 min
>20:1
1:2
n.d.
n.d.
1.4:1
4.1:1 and 3.7:1
a Reaction conditions for Michael addition: 4a (0.2 mmol), 9 (0.4 mmol), solvent (0.4 mL), –35 °C, 48 h.
b Determined by 1H NMR spectroscopic analysis of the crude reaction mixture.
c The er for the major diastereomer of 11a (OH in axial position) was determined by HPLC analysis on a chiral stationary phase.
d Analyses were conducted directly at the end of the Michael addition step.
e n.d. = not determined.
f 82% yield after purification.
Synthesis 2013, 45, 1659–1666
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Enantioselective Domino Synthesis of Functionalized Cyclohexanes
1663
All reagents were obtained from commercial sources and used as
supplied unless otherwise stated. NMR data were recorded on a
Bruker Avance 400 spectrometer in CDCl3, and chemical shifts (δ)
are given in ppm relative to the residual nondeuterated solvent sig-
nal for 1H NMR (CHCl3, 7.26 ppm) or the deuterated solvent signal
for 13C NMR (CDCl3, 77.16 ppm). High-resolution mass spectra
were obtained from the Spectropole (http://www.spectropole.u-
3mrs.fr/). Optical rotations were measured with a Perkin-Elmer 241
micropolarimeter. Melting points were determined with a Büchi B-
450 apparatus and are uncorrected. TLC was performed on silica
Merck 60F254 plates; visualization was performed by illumination
with a UVP mineralight UVGL-58 lamp or by developing the plates
with phosphomolybdic acid and 4-methoxybenzaldehyde reagents.
The products were purified by flash column chromatography on sil-
ica gel 60 (Merck 1.09386.9025, 230–400 mesh).
O
O
R
N
H
R
1) II (10 mol%)
toluene, –35 °C, 48 h
HN
O
4b–d
O
+
2) DBU (1 equiv)
toluene, r.t. or 60 °C
O
HO
H
11b–d
Ph
1-naphthyl
Ts
HN
HN
HN
O
O
O
O
O
O
HO
HO
HO
Cyclohexanes 8; General Procedure
1,2-Ketoamide 1 (1.00 equiv), nitroalkene 2 (2.10 equiv), and thio-
urea catalyst II (0.10 equiv) were added successively as solids to a
sealed tube and dissolved in EtOAc to form a 0.5 M soln. After 96
h at r.t., the solvent was evaporated and the crude product was puri-
fied by flash chromatography [silica gel, EtOAc–PE (30:70 then
11c
62%
11d
49%
11b
73%
1:1.2 dr (OHax/OHeq
7.5:1 and 8.0:1 er
)
1:1 (OHax/OHeq
66:1 and 14:1 er
)
1:1.2 dr (OHax/OHeq
4.8:1 and 4.9:1 er
)
1
Scheme 5 Study of the scope of substrates for the formation of bicy-
clo[3.2.1]octanes 11
50:50)]. The dr of the products was determined by H NMR spec-
troscopy of the crude product and the er was determined by HPLC
on a chiral stationary phase.
Bicyclic alcohol 11d could also be derivatized by oxida-
tion with 2-iodoxybenzoic acid in refluxing ethyl acetate
to give the bicyclo[3.2.1]octanedione 12 quantitatively
(Scheme 6). Most importantly, an excellent 24:1 er was
observed for the formation of this valuable structure.
(1R,2R,3R,4S,5R,6S)-3,5-Bis(4-fluorophenyl)-1-hydroxy-2-
methyl-4,6-dinitro-N-phenylcyclohexanecarboxamide (8a)
Synthesized according to the general procedure from 1a (R1 = Me;
Ar = Ph; 36 mg, 0.2 mmol) and 2a (R2 = 4-FC6H4; 70 mg, 0.42
mmol) as a white solid; yield: 63 mg (62%); mp 181–182 °C; [α]D
–22.3 (c = 1.0, CH2Cl2); Rf = 0.30 (EtOAc–PE, 3:7).
30
Chiral HPLC: ChiralPak AD-H [hexane–i-PrOH (9:1), flow
rate = 1.0 mL/min], λ = 306 nm; tminor = 24.7 min, tmajor = 28.0 min,
er = 99:1.
Ts
HN
Ts
HN
O
O
IBX (2 equiv)
O
O
1H NMR (400 MHz, CD2Cl2): δ = 8.65 (br s, 1 H, NH), 7.62 (br s,
2 H), 7.52 (d, J = 8.0 Hz, 2 H), 7.42–7.36 (m, 4 H), 7.20 (d, J = 8.0
Hz, 1 H), 7.08 (d, J = 8.0 Hz, 2 H), 7.02 (d, J = 8.0 Hz, 2 H, ArH),
5.76 (d, J = 12.0 Hz, 1 H), 5.60 (dd, J = 12.0, 7.2 Hz, 1 H), 4.61 (dd,
J = 12.0, 12.0 Hz, 1 H), 4.61 (s, 1 H, OH), 4.00 (dd, J = 7.2, 7.2 Hz,
1 H), 3.05–2.99 (m, 1 H), 0.98 (d, J = 7.2 Hz, 3 H).
EtOAc, reflux, 18 h
HO
O
11d
12
quant
24:1 er
13C NMR (100 MHz, CD2Cl2): δ = 169.1, 163.4 (d, J = 248 Hz),
163.3 (d, J = 248 Hz), 138.8 (d, J = 8 Hz, 2 C), 136.7 (2 C), 130.5
(d, J = 8 Hz, 2 C), 129.9 (d, J = 4 Hz), 129.7, 129.5 (d, J = 4 Hz),
126.1, 120.7 (2 C), 116.8 (d, J = 17 Hz, 2 C), 115.7 (d, J = 17 Hz, 2
C), 92.0, 89.3, 80.1, 49.7, 42.2, 39.3, 14.0.
Scheme 6 Oxidation of the bicyclic alcohol 11d with 2-iodoxyben-
zoic acid (IBX)
In summary, we have demonstrated that 1,2- and 1,3-ke-
toamides can be specifically activated with thiourea or-
HRMS (ES+): m/z calcd for C26H24F2N3O6: 512.1628; found:
ganocatalysts and used in domino transformations for the 512.1619.
enantioselective synthesis of polysubstituted cyclohex-
(1R,2R,3R,4S,5R,6S)-N-(4-Chlorophenyl)-2-ethyl-3,5-bis(4-
anes. In the case of 1,2-ketoamides, we exploited their
pronucleophilic character15 and the presence of the ketone
moiety as an electrophilic site to permit the synthesis of
hexasubstituted cyclohexanes by reaction with ni-
troalkenes. Amazingly, one of the 64 possible stereoiso-
mers was formed almost exclusively. Alternatively, 1,3-
ketoamides where used as efficient C-bisnucleophiles
with acrolein as the electrophilic partner to give bicyc-
lo[3.2.1]octanes in optically active forms with formation
of two new carbon–carbon bonds and three stereogenic
carbon atoms. Further studies are currently under way in
our laboratory in attempts to extend the scope of these
promising cascade reactions.
fluorophenyl)-1-hydroxy-4,6-dinitrocyclohexanecarboxamide
(8b)
Synthesized according to the general procedure from 1b (R1 = Et,
Ar = 4-ClC6H4; 45 mg, 0.2 mmol) and 2a (R2 = 4-FC6H4; 70 mg,
0.42 mmol) as a white solid; yield: 57 mg (51%); mp 248 °C (dec.);
Rf = 0.30 (EtOAc–PE, 1:4).
Chiral HPLC: ChiralPak IA [hexane–EtOH–CHCl3 (5:3:2), flow
rate = 1.0 mL/min], λ = 254 nm; tminor = 4.0 min, tmajor = 5.8 min,
er = 19:1.
1H NMR (400 MHz, CD2Cl2): δ = 8.68 (br s, 1 H, NH), 7.70 (br s,
2 H), 7.50 (d, J = 8.9 Hz, 2 H), 7.37–7.31 (m, 4 H), 7.08 (d, J = 8.9
Hz, 2 H), 7.03 (d, J = 8.9 Hz, 2 H), 5.61 (d, J = 12.5 Hz, 1 H), 5.43
(dd, J = 12.5, 6.9 Hz, 1 H), 4.65 (s, 1 H, OH), 4.45 (dd, J = 12.5,
12.5 Hz, 1 H), 4.16 (dd, J = 6.9, 6.9 Hz, 1 H), 2.75–2.70 (m, 1 H),
1.44–1.33 (m, 2 H), 0.87 (d, J = 7.3 Hz, 3 H).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1659–1666

1664
W. Raimondi et al.
SPECIAL TOPIC
13C NMR (100 MHz, CD2Cl2): δ = 169.3, 163.2 (d, J = 248 Hz),
163.1 (d, J = 248 Hz), 135.3, 133.8 (d, J = 8 Hz, 2 C), 130.9, 130.4
(d, J = 8 Hz, 2 C), 129.7 (d, J = 4 Hz), 129.6 (2 C), 129.0 (d, J = 4
Hz), 121.9 (2 C), 116.7 (d, J = 22 Hz, 2 C), 115.8 (d, J = 22 Hz, 2
C), 92.1, 89.8, 80.2, 46.7, 46.1, 41.6, 20.8, 12.0.
Chiral HPLC: ChiralPak IB [hexane–EtOH (7:3), flow rate = 1.0
mL/min], λ = 254 nm; tminor = 6.6 min, tmajor = 5.3 min, er = 28:1.
1H NMR (400 MHz, CDCl3): δ = 8.59 (br s, 1 H, NH), 7.69 (br s, 2
H), 7.40–7.36 (m, 8 H), 7.34–7.28 (m, 2 H), 6.86 (d, J = 9.0 Hz, 2
H), 5.69 (d, J = 12.5 Hz, 1 H), 5.48 (dd, J = 12.5, 6.7 Hz, 1 H), 4.54
(dd, J = 12.5, 12.5 Hz, 1 H), 4.52 (s, 1 H, OH), 4.13 (dd, J = 6.7, 6.7
Hz, 1 H), 3.77 (s, 3 H), 2.81–2.76 (m, 1 H), 1.45–1.37 (m, 2 H), 0.91
(d, J = 7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 168.8, 157.3, 133.7, 132.9 (2 C),
131.3 (2 C), 129.2 (2 C), 129.0, 128.7 (2 C), 128.6, 128.2 (2 C),
122.0 (2 C), 114.3 (2 C), 92.0, 89.4, 79.7, 55.5, 47.0, 45.7, 41.9,
20.4, 11.9.
MS (ES+): m/z 582 [M + Na]+.
HRMS (ES+): m/z calcd for C27H25ClF2N3O6: 560.1394; found:
560.1395.
(1R,2R,3R,4S,5R,6S)-N-(2,5-Dichlorophenyl)-2-ethyl-3,5-bis(4-
fluorophenyl)-1-hydroxy-4,6-dinitrocyclohexanecarboxamide
(8c)
Synthesized according to the general procedure from 1c (R1 = Et,
Ar = 2,5-Cl2C6H3; 52 mg, 0.2 mmol) and 2a (R2 = 4-FC6H4, 70 mg,
0.42 mmol) as a white solid; yield: 57 mg (47%); mp 203–205 °C;
[α]D22 –12.9 (c = 0.52, CH2Cl2); Rf = 0.41 (EtOAc–PE, 1:4).
MS (ES+): m/z 542 [M + Na]+.
HRMS (ES+): m/z calcd for C28H30N3O7: 520.2078; found:
520.2077.
Chiral HPLC: ChiralPak IA [hexane–EtOH–CHCl3 (3:1:1), flow
rate = 1.0 mL/min], λ = 254 nm; tminor = 4.1 min, tmajor = 5.8 min,
er = 4:1.
1H NMR (400 MHz, CD2Cl2): δ = 9.21 (br s, 1 H, NH), 8.35 (br s,
1 H), 7.72–7.69 (m, 2 H), 7.38–7.34 (m, 4 H), 7.14–7.04 (m, 4 H),
5.56 (d, J = 12.5 Hz, 1 H), 5.39 (dd, J = 12.5, 6.8 Hz, 1 H), 4.72 (s,
1 H, OH), 4.46 (dd, J = 12.5, 12.5 Hz, 1 H), 4.17 (dd, J = 6.8, 6.8
Hz, 1 H), 2.72–2.67 (m, 1 H), 1.55–1.37 (m, 2 H), 0.88 (d, J = 7.3
Hz, 3 H).
13C NMR (100 MHz, CD2Cl2): δ = 169.5, 163.3 (d, J = 248 Hz),
163.2 (d, J = 248 Hz), 134.4, 133.8 (d, J = 8 Hz, 2 C), 130.5 (2 C),
130.4 (d, J = 8 Hz), 129.6 (d, J = 4 Hz), 128.9 (d, J = 4 Hz), 126.4,
122.6, 121.8, 116.7 (d, J = 22 Hz, 2 C), 115.9 (d, J = 22 Hz, 2 C),
92.1, 89.8, 80.5, 46.7, 46.2, 41.6, 20.7, 12.0.
Bicyclo[3.2.1]octanes 11; General Procedure
A soln of 1,3-ketoamide 4 (0.2 mmol, 1 equiv) and thiourea catalyst
II (8.3 mg, 0.02 mmol, 0.1 equiv) in dry toluene (4 mL) was
cooled to –35 °C, and acrolein (9; 27 µL, 0.4 mmol, 2 equiv) was
added. The mixture was stirred for 24–48 h until the ketoamide 4
was consumed. DBU (30 µL, 0.2 mmol, 1 equiv) was then added
and the mixture was warmed to r.t. and stirred for 1 h then concen-
trated under reduced pressure. 1 M aq HCl was added and the mix-
ture was extracted with CH2Cl2 (2 × 10 mL). The organic phases
were combined, washed with brine (10 mL), dried (Na2SO4), and
concentrated under reduced pressure. The crude product was puri-
fied by flash column chromatography (EtOAc–PE).
(1R,5R)-4-Hydroxy-N-(4-nitrophenyl)-8-oxobicyclo[3.2.1]oc-
tane-1-carboxamide (11a)
Synthesized according to the general procedure from 4a (R = 4-
O2NC6H4; 50 mg, 0.2 mmol) as a pale yellow solid (1.4:1 mixture
of diastereomers); yield: 50 mg (82%); mp 137–139 °C; Rf = 0.33
(EtOAc–CH2Cl2, 2:3).
MS (ES+): m/z 616 [M + Na]+.
HRMS (ES+): m/z calcd for C27H24Cl2F2N3O6: 594.1005; found:
594.1003.
(1R,2R,3R,4S,5R,6S)-2-Ethyl-3,5-bis(4-fluorophenyl)-1-hy-
droxy-N-(4-methoxyphenyl)-4,6-dinitrocyclohexanecarbox-
amide (8d)
Chiral HPLC: Lux-Amylose-2 [hexane–i-PrOH (7:3), flow
rate = 1.0 mL/min], λ = 220 nm; diastereomer OHax: tminor = 18.0
min, tmajor = 21.0 min, er = 4.1:1; diastereomer OHeq: tminor = 10.1
min, tmajor = 11.3 min, er = 3.7:1.
1H NMR (400 MHz, CDCl3): δ (diastereomer OHax) = 10.21 (s, 1 H,
NH), 8.21 (d, J = 9.2 Hz, 2 H), 7.77 (d, J = 9.2 Hz, 2 H), 4.45 (s, 1
H), 2.67 (dd, J = 7.1, 5.4 Hz, 1 H), 2.46–2.40 (m, 1 H), 2.39–2.31
(m, 2 H), 2.31–2.12 (m, 2 H), 2.03–1.92 (m, 1 H), 1.84–1.71 (m, 2
H); δ (diastereomer OHeq) = 10.07 (s, 1 H, NH), 8.21 (d, J = 9.2 Hz,
2 H), 7.77 (d, J = 9.2 Hz, 2 H), 4.14 (br s, 1 H), 2.75 (dd, J = 7.0,
3.1 Hz, 1 H), 2.46–2.40 (m, 1 H), 2.39–2.31 (m, 2 H), 2.31–2.12 (m,
2 H), 2.03–1.92 (m, 1 H), 1.84–1.71 (m, 2 H).
13C NMR (75 MHz, DMSO-d6): δ (diastereomer OHax) = 213.0,
171.0, 145.42, 142.21, 124.88 (2 C), 119.3 (2 C), 76.9, 57.5, 52.3,
34.1, 26.6, 25.4, 18.9; δ (diastereomer OHeq) = 213.1, 170.7,
145.36, 142.23, 124.94 (2 C), 119.2 (2 C), 73.6, 57.7, 54.8, 31.8,
28.2, 26.4, 16.3.
Synthesized according to the general procedure from 1d (R1 = Et,
Ar = 4-MeOC6H4; 44 mg, 0.2 mmol) and 2a (R2 = 4-FC6H4; 70 mg,
0.42 mmol) as a white solid; yield: 74 mg (67%); mp 109–111 °C;
[α]D30 +29.5 (c = 0.57, CH2Cl2); Rf = 0.11 (EtOAc–PE, 1:4).
Chiral HPLC: ChiralPak IB [hexane–EtOH (4:1), flow rate = 1.0
mL/min], λ = 254 nm; tminor = 10.9 min, tmajor = 6.6 min, er = 28:1.
1H NMR (400 MHz, CD2Cl2): δ = 8.60 (br s, 1 H, NH), 7.69–7.66
(m, 2 H), 7.41 (d, J = 9.0 Hz, 2 H), 7.34–7.30 (m, 2 H), 7.05 (d,
J = 9.0 Hz, 2 H), 6.96 (d, J = 9.0 Hz, 2 H), 6.88 (d, J = 9.0 Hz, 2 H),
5.70 (d, J = 12.3 Hz, 1 H), 5.50 (dd, J = 12.3, 6.9 Hz, 1 H), 4.69 (s,
1 H, OH), 4.41 (dd, J = 12.3, 12.3 Hz, 1 H), 4.11 (dd, J = 6.9, 6.9
Hz, 1 H), 3.77 (s, 3 H, OCH3), 2.82–2.76 (m, 1 H), 1.47–1.36 (m, 2
H), 0.87 (d, J = 7.3 Hz, 3 H).
13C NMR (100 MHz, CD2Cl2): δ = 168.7, 162.8 (d, J = 248 Hz),
162.7 (d, J = 248 Hz), 157.5, 133.2 (d, J = 8 Hz, 2 C), 129.9 (d,
J = 8 Hz, 2 C), 129.0 (d, J = 4 Hz), 128.9, 128.5 (d, J = 4 Hz), 122.0
(2 C), 116.3 (d, J = 22 Hz, 2 C), 115.6 (d, J = 22 Hz, 2 C), 114.4 (2
C), 91.7, 89.3, 79.7, 55.5, 46.4, 45.5, 41.2, 20.3, 11.8.
MS (ES+): m/z 327 [M + Na]+.
HRMS (ES+): m/z calcd for C15H17N2O5: 305.1132; found:
305.1130.
MS (ES+): m/z 579 [M + Na]+.
(1R,5R)-4-Hydroxy-8-oxo-N-phenylbicyclo[3.2.1]octane-1-car-
boxamide (11b)
HRMS (ES+): m/z calcd for C28H28F2N3O7: 556.1890; found:
Synthesized by an adaptation of the general procedure from 4b
(R = Ph; 41 mg, 0.2 mmol). After full conversion of 4b, excess of
acrolein was eliminated by distillation at a reduced pressure (100
mbar) without evaporation of toluene. DBU (30 µL, 0.2 mmol, 1
equiv) was then added and the mixture was stirred at r.t. for 1 h to
give, after workup, a colorless viscous liquid (1:1.2 mixture of dia-
stereomers); yield: 38 mg (73%); Rf = 0.28 (EtOAc–CH2Cl2, 2:3).
556.1889.
(1R,2R,3R,4S,5R,6S)-2-Ethyl-1-hydroxy-N-(4-methoxyphenyl)-
4,6-dinitro-3,5-diphenylcyclohexanecarboxamide (8e)
Synthesized according to the general procedure from 1d (R1 = Et,
Ar = 4-MeOC6H4; 44 mg, 0.2 mmol) and 2b (R2 = Ph; 63 mg, 0.42
mmol) as a white solid; yield: 55 mg (53%); mp 139–141 °C;
Rf = 0.18 (EtOAc–PE, 1:4); [α]D22 +9.7 (c = 9.9, CH2Cl2).
Synthesis 2013, 45, 1659–1666
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Enantioselective Domino Synthesis of Functionalized Cyclohexanes
1665
Chiral HPLC: Chiralcel OD-3 [hexane–i-PrOH (9:1), flow
rate = 1.0 mL/min], λ = 254 nm; diastereomer OHax: tminor = 18.9
min, tmajor = 23.0 min, er = 4.8:1, diastereomer OHeq: tminor = 17.0
min, tmajor = 20.4 min, er = 4.9:1.
1H NMR (400 MHz, CDCl3): δ (diastereomer OHax) = 9.79 (s, 1 H,
NH), 7.60–7.51 (m, 2 H), 7.32 (t, J = 7.9 Hz, 2 H), 7.10 (td, J = 7.3,
1.2 Hz, 1 H), 4.42–4.30 (m, 1 H), 2.64–2.57 (m, 1 H), 2.44–2.19 (m,
4 H), 2.16–1.99 (m, 1 H), 1.96–1.64 (m, 3 H); δ (diastereomer
OHeq) = 9.67 (s, 1 H, NH), 7.60–7.51 (m, 2 H), 7.32 (t, J = 7.9 Hz,
2 H), 7.10 (td, J = 7.3, 1.2 Hz, 1 H), 4.18–4.03 (m, 1 H), 2.72 (dd,
J = 6.9, 3.2 Hz, 1 H), 2.44–2.19 (m, 3 H), 2.16–1.99 (m, 2 H), 1.96–
1.64 (m, 3 H).
Hz, 1 H), 2.60 (dd, J = 6.9, 5.5 Hz, 1 H), 2.42 (s, 3 H), 2.35–2.26
(m, 1 H), 2.15–1.98 (m, 4 H), 1.92–1.64 (m, 3 H); δ (diastereomer
OHeq) = 10.12 (s, 1 H, NH), 7.93 (d, J = 8.4, 2 H), 7.31 (d, J = 8.4
Hz, 2 H), 4.10–4.07 (m, 1 H), 2.70 (dd, J = 6.9, 3.2 Hz, 1 H), 2.42
(s, 3 H), 2.35–2.26 (m, 1 H), 2.15–1.98 (m, 4 H), 1.92–1.64 (m, 3
H).
13C NMR (75 MHz, CDCl3): δ (diastereomer OHax) = 216.0, 169.4,
145.1, 135.8, 129.7 (2 C), 128.5 (2 C), 78.2, 55.5, 52.5, 37.9, 26.4,
25.5, 21.8, 18.6; δ (diastereomer OHeq) = 215.1, 169.4, 145.2,
135.7, 129.7 (2 C), 128.5 (2 C), 74.4, 55.1, 54.5, 35.1, 26.6, 25.4,
21.8, 15.6.
HRMS (ES+): m/z calcd for C16H20NO5S: 338.1057; found:
338.1061.
13C NMR (75 MHz, CDCl3): δ (diastereomer OHax) = 217.9, 170.0,
137.7, 129.1 (2 C), 124.5, 120.3 (2 C), 78.5, 54.4, 53.2, 38.5, 26.3,
25.8, 18.6; δ (diastereomer OHeq) = 216.9, 169.9, 137.6, 129.1 (2
C), 124.6, 120.3 (2 C), 74.7, 55.2, 53.9, 35.6, 27.5, 26.7, 15.5.
(1R,5R)-4,8-Dioxo-N-tosylbicyclo[3.2.1]octane-1-carboxamide
(12)
A soln of 11d (67.4 mg, 0.2 mmol, 1 equiv) and 2-iodoxybenzoic
acid (112 mg, 0.4 mmol, 2 equiv) in EtOAc (1 mL) was refluxed in
a sealed tube for 18 h. The mixture was then cooled to r.t., filtered
through a short pad of Celite, and concentrated under reduced pres-
sure to afford quantitatively the crude product, which could not be
further purified because of its instability on silica gel; yield 67 mg
(quant); Rf = 0.22 (EtOAc–PE, 1:3).
MS (ES+): m/z 282 [M + Na]+.
HRMS (ES+): m/z calcd for C15H18NO3: 260.1281; found:
260.1284.
(1R,5R)-4-Hydroxy-N-1-naphthyl-8-oxobicyclo[3.2.1]octane-1-
carboxamide (11c)
Synthesized by an adaptation of the general procedure from 4c
(R = 1-naphthyl; 51 mg, 0.2 mmol). After full conversion of 4c, ex-
cess of acrolein was eliminated by distillation at reduced pressure
(100 mbar) without evaporation of toluene. DBU (30 µL, 0.2 mmol,
1 equiv) was then added and the mixture was stirred at r.t. for 1 h to
give, after workup, a viscous liquid (1:1.2 mixture of diastereo-
mers); yield: 38 mg (62%); Rf = 0.30 (EtOAc–CH2Cl2, 2:3).
Chiral HPLC: Chiralpak IC [hexane–EtOH–TFA (8:2:0.01), flow
rate = 1.0 mL/min], λ = 254 nm; tmajor = 12.1 min, tminor = 13.9 min,
er = 24:1.
1H NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 8.3 Hz, 2 H), 7.32 (d,
J = 8.3 Hz, 2 H), 3.35 (d, J = 6.8 Hz, 1 H), 2.79 (ddd, J = 17.0, 12.6,
9.4 Hz, 1 H), 2.50 (dd, J = 17.0, 6.7 Hz, 1 H), 2.45–2.37 (m, 1 H),
2.42 (s, 3 H), 2.28–2.10 (m, 3 H), 1.97 (ddd, J = 14.3, 8.0, 3.1 Hz,
1 H), 1.84–1.73 (m, 1 H).
Chiral HPLC: Lux-Amylose-2 [hexane–i-PrOH (7:3), flow
rate = 1.0 mL/min], λ = 254 nm; diastereomer OHax: tminor = 10.2
min, tmajor = 33.5 min, er = 7.5:1; diastereomer OHeq: tminor = 6.9
min, tmajor = 7.9 min, er = 8.0:1.
13C NMR (75 MHz, CDCl3): δ = 206.0, 203.5, 168.3, 145.3, 135.5,
129.7 (2 C), 128.5 (2 C), 64.9, 56.1, 33.6, 30.4, 26.2, 21.8, 21.2.
1H NMR (400 MHz, CDCl3): δ (diastereomer OHax) = 10.38 (s, 1 H,
NH), 8.18–8.12 (m, 2 H), 7.86 (d, J = 7.7 Hz, 1 H), 7.67 (d, J = 8.2
Hz, 1 H), 7.61–7.55 (m, 1 H), 7.54–7.44 (m, 2 H), 4.41–4.30 (m, 1
H), 2.64 (dd, J = 7.1, 5.2 Hz, 1 H), 2.55–2.21 (m, 4 H), 2.20–2.07
(m, 1 H), 1.88–1.65 (m, 3 H); δ (diastereomer OHeq) = 10.24 (s, 1
H, NH), 8.18–8.12 (m, 1 H), 8.09 (d, J = 8.4 Hz, 1 H), 7.87 (d,
J = 7.8 Hz, 1 H), 7.67 (d, J = 8.2 Hz, 1 H), 7.61–7.55 (m, 1 H),
7.54–7.44 (m, 2 H), 4.17–4.04 (m, 1 H), 2.76 (dd, J = 6.9, 3.2 Hz, 1
H), 2.55–2.21 (m, 3 H), 2.20–2.07 (m, 1 H), 2.06–1.89 (m, 2 H),
1.88–1.65 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ (diastereomer OHax) = 170.5, 134.2,
132.6, 128.8, 126.6, 126.5, 126.1, 125.8, 125.3, 120.9, 119.3, 78.7,
54.9, 53.2, 38.9, 26.4, 25.9, 18.7; δ (diastereomer OHeq) = 217.6,
170.3, 134.2, 132.5, 128.8, 126.6, 126.5, 126.1, 125.8, 125.3, 120.7,
119.4, 74.8, 55.2, 54.4, 35.9, 27.6, 26.8, 15.6.
MS (ES+): m/z 358 [M + Na]+.
HRMS (ES+): m/z calcd for C16H18NO5S: 336.0900; found:
336.0898.
Acknowledgment
Financial support from the Agence Nationale pour la Recherche
(ANR-11-BS07-0014), the Centre National de la Recherche Scien-
tifique (CNRS), and the Aix-Marseille Université is gratefully
acknowledged.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are copies of 1H and 13C NMR spectra of all new compounds. SunpIgfopi
o
nr
irtSatnuIfopigrmotriato
n
MS (ES+): m/z 332 [M + Na]+.
HRMS (ES+): m/z calcd for C19H20NO3: 310.1438; found:
310.1443.
References
(1) For reviews on organocatalytic domino reactions, see:
(1R,5R)-4-Hydroxy-8-oxo-N-tosylbicyclo[3.2.1]octane-1-car-
boxamide (11d)
(a) Enders, D.; Grondal, C.; Hüttl, M. R. M. Angew. Chem.
Int. Ed. 2007, 46, 1570. (b) Yu, X.; Wang, W. Org. Biomol.
Chem. 2008, 6, 2037. (c) Alba, A.-N.; Companyo, X.;
Viciano, M.; Rios, R. Curr. Org. Chem. 2009, 13, 1432.
(d) Grondal, C.; Jeanty, M.; Enders, D. Nature Chem. 2010,
2, 167. (e) Pellisier, H. Adv. Synth. Catal. 2012, 354, 237.
(2) Name Reactions for Carbocyclic Ring Formations; Li, J. J.,
Ed.; John Wiley: Hoboken, 2010, Chap. 4 197.
(3) For selected examples of two-component approaches, see:
(a) Halland, N.; Aburel, P. S.; Jørgensen, K. A. Angew.
Chem. Int. Ed. 2004, 43, 1272. (b) Zhou, J.; List, B. J. Am.
Chem. Soc. 2007, 129, 7498. (c) Reyes, E.; Jiang, H.;
Milelli, A.; Elsner, P.; Hazell, R. G.; Jørgensen, K. A.
Synthesized by an adaptation of the general procedure from 4d
(R = Ts; 56 mg, 0.2 mmol). After addition of DBU (30 µL, 0.2
mmol, 1 equiv), the mixture was heated to 60 °C for 6 h to give, af-
ter workup, a viscous liquid (1:1 mixture of diastereomers); yield:
33 mg (49%); Rf = 0.55 (EtOAc–CH2Cl2, 2:3).
Chiral HPLC: Chiralpak IC [hexane–i-PrOH–TFA (7:3:0.01), flow
rate = 1.0 mL/min], λ = 254 nm; diastereomer OHax: tminor = 45.6
min, tmajor = 48.3 min, er = 66:1; diastereomer OHeq: tminor = 26.6
min, tmajor = 32.6 min, er = 14:1.
1H NMR (400 MHz, CDCl3): δ (diastereomer OHax) = 10.23 (s, 1 H,
NH), 7.93 (d, J = 8.4, 2 H), 7.31 (d, J = 8.4 Hz, 2 H), 4.36 (d, J = 1.7
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1659–1666

1666
W. Raimondi et al.
SPECIAL TOPIC
Angew. Chem. Int. Ed. 2007, 46, 902. (d) McGarraugh, P.
G.; Brenner, S. E. Org. Lett. 2009, 11, 5654. (e) Hayashi, Y.;
Okano, T.; Aratake, S.; Hazelard, D. Angew. Chem. Int. Ed.
2007, 46, 4922. (f) Anwar, S.; Chang, H.-J.; Chen, K. Org.
Lett. 2011, 13, 2200.
Huang, H. Angew. Chem. Int. Ed. 2012, 51, 1248. For a
related three-component one-pot sequence, see: (c) Varga,
S.; Jakab, G.; Drahos, L.; Holczbauer, T.; Czugler, M.; Soós,
T. Org. Lett. 2011, 13, 5416.
(8) Vakulya, B.; Varga, S.; Csámpai, A.; Soós, T. Org. Lett.
2005, 7, 1967.
(9) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y.
J. Am. Chem. Soc. 2005, 127, 119.
(10) Malerich, J. P.; Hagihara, K.; Rawal, V. H. J. Am. Chem.
Soc. 2008, 130, 14416.
(11) For recent reviews, see: (a) Presset, M.; Coquerel, Y.;
Rodriguez, J. ChemCatChem 2012, 4, 172. (b) Presset, M.;
Coquerel, Y.; Rodriguez, J. Chem. Rev. 2013, 113, 525.
(12) For examples of N-heterocyclic carbene-catalyzed
enolization and Michael additions, see: (a) Boddaert, T.;
Coquerel, Y.; Rodriguez, J. Adv. Synth. Catal. 2009, 351,
1744. (b) Boddaert, T.; Coquerel, Y.; Rodriguez, J. Chem.
Eur. J. 2011, 17, 2266.
(4) For selected examples of multicomponent approaches, see:
(a) Ramachary, D. B.; Chowdari, N. S.; Barbas, C. F. III
Angew. Chem. Int. Ed. 2003, 42, 4233. (b) Enders, D.; Hüttl,
M. R. M.; Runsik, Y.; Raabe, G.; Wendt, B. Angew. Chem.
Int. Ed. 2007, 46, 467. (c) Penon, O.; Carlone, A.; Mazzanti,
A.; Locatelli, M.; Sambri, L.; Bartoli, G.; Melchiorre, P.
Chem. Eur. J. 2008, 14, 4788. (d) Wang, Y.; Han, R. G.;
Zhao, Y. L.; Yang, S.; Xu, P. F.; Dixon, D. J. Angew. Chem.
Int. Ed. 2009, 48, 9834. (e) Jiang, K.; Jia, Z.-J.; Yin, X.; Wu,
L.; Chen, Y.-C. Org. Lett. 2010, 12, 2766. (f) Jia, Y.; Mao,
Z.; Wang, R. Tetrahedron: Asymmetry 2011, 22, 2018.
(5) (a) For the concept underlying this subject, see: Bonne, D.;
Constantieux, T.; Coquerel, Y.; Rodriguez, J. Chem. Eur. J.
2013, 19, 2218. (b) For a review, see: Bonne, D.;
(13) For the method used to prepare the 1,3-ketoamides, see:
Presset, M.; Coquerel, Y.; Rodriguez, J. J. Org. Chem. 2009,
74, 415.
Constantieux, T.; Coquerel, Y.; Rodriguez, J. Tetrahedron:
Asymmetry 2010, 21, 1085.
(6) (a) Baslé, O.; Raimondi, W.; Sanchez Duque, M. M.; Bonne,
D.; Constantieux, T.; Rodriguez, J. Org. Lett. 2010, 12,
5246. (b) Sanchez Duque, M. M.; Baslé, O.; Isambert, N.;
Gaudel-Siri, A.; Génisson, Y.; Plaquevent, J.-C.; Rodriguez,
J.; Constantieux, T. Org. Lett. 2011, 13, 3296.
(7) For similar sequences with 1,2-keto esters and a chiral
copper(II) complex, see: (a) Nakamura, A.; Lectard, S.;
Hashizume, D.; Hamashima, Y.; Sodeoka, M. J. Am. Chem.
Soc. 2010, 132, 4036. (b) Shi, D.; Xie, Y.; Zhou, H.; Xia, C.;
(14) HPLC analysis of the corresponding hemiaminal 10d after
oxidation showed that it was obtained with an er of 84:1. See
ref. 6b for details.
(15) For reviews on the use of 1,2-dicarbonyls as
pronucleophiles, see: (a) Raimondi, W.; Bonne, D.;
Rodriguez, J. Angew. Chem. Int. Ed. 2012, 51, 40.
(b) Raimondi, W.; Bonne, D.; Rodriguez, J. Chem.
Commun. 2012, 48, 6763.
Synthesis 2013, 45, 1659–1666
© Georg Thieme Verlag Stuttgart · New York