Highly diastereo- and enantioselective organocatalytic domino michael/aldol reaction of acyclic 3-halogeno-1,2-diones to α,β-unsaturated aldehydes

Article abstract of DOI:10.1021/ol400697n

The first organocatalytic diastereo- and enantioselective domino Michael/aldol reaction of 3-halogeno-1,2-diones to α,β-unsaturated aldehydes has been achieved. This transformation tolerates a large variety of electronically different substituents on both reactive partners and allows the synthesis of challenging cyclopentanone derivatives with four contiguous stereogenic centers in excellent diastereoselectivities (>20:1 dr) as well as good yields (69-97%), and enantioselectivities (up to 94% ee).

Full text of DOI:10.1021/ol400697n

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Highly Diastereo- and Enantioselective
Organocatalytic Domino Michael/Aldol
Reaction of Acyclic 3‑Halogeno-1,2-
Diones to r,β-Unsaturated Aldehydes
†
‡
,†
ꢀ ꢀ
Alice Lefranc, Laure Guenee, and Alexandre Alexakis*
Department of Organic Chemistry, University of Geneva, quai Ernest Ansermet 30,
CH-1211 Geneva 4, Switzerland, and Laboratory of Crystallography,
University of Geneva, quai Ernest Ansermet 24, CH-1211 Geneva 4, Switzerland
Alexandre.Alexakis@unige.ch
Received March 16, 2013
ABSTRACT
The first organocatalytic diastereo- and enantioselective domino Michael/aldol reaction of 3-halogeno-1,2-diones to R,β-unsaturated aldehydes
has been achieved. This transformation tolerates a large variety of electronically different substituents on both reactive partners and allows the
synthesis of challenging cyclopentanone derivatives with four contiguous stereogenic centers in excellent diastereoselectivities (>20:1 dr) as well
as good yields (69À97%), and enantioselectivities (up to 94% ee).
The formation of CÀC bonds with a limited number of
steps is one of the most important challenges in organic
synthesis.1 For this purpose, organocatalytic cascade or
domino reactions representa particularlypowerful tool for
accessing versatile chiral building blocks with functional
and molecular diversity in an atom-economical manner.2,3
1,2-Dicarbonyl compounds are very attractive scaffolds
due to their diverse number of reactive centers.4 They have
two nucleophilic and two electrophilic potentially reactive
sites.5 Thanks to their functional complexity, 1,2-dicarbonyl
compounds represent very interesting pronucleophiles for
organocatalytic cascade or domino reactions.6
† Department of Organic Chemistry.
‡ Laboratory of Crystallography.
(1) Selected reviews: (a) Newhouse, T.; Baran, P. S.; Hoffmann,
R. W. Chem. Soc. Rev. 2009, 38, 3010. (b) Wender, P. A.; Verma,
V. A.; Paxton, T. J.; Pillow, T. H. Acc. Chem. Res. 2008, 41, 40.
(2) Selected recent reviews: (a) Pellissier, H. Adv. Synth. Catal. 2012,
354, 237. (b) Grondal, C.; Jeanty, M.; Enders, D. Nat. Chem. 2010, 2,
Recently, this type of compound has been widely uti-
lized in asymmetric organocatalytic transformations.7À9
€
167. (c) Enders, D.; Grondal, C.; Huttl, M. R. M. Angew. Chem., Int. Ed.
2007, 46, 1570. (d) Walji, A. M.; MacMillan, D. W. C. Synlett 2007,
1477.
(5) Bonne, D.; Constantieux, T.; Coquerel, Y.; Rodriguez, J.
Chem.;Eur. J. 2013, 19, 2218.
(6) (a) Raimondi, W.; Bonne, D.; Rodriguez, J. Chem. Commun.
2012, 48, 6763. (b) Raimondi, W.; Bonne, D.; Rodriguez, J. Angew.
Chem., Int. Ed. 2012, 51, 40.
(3) Selected recent examples: (a) Zeng, X.; Ni, Q.; Raabe, G.; Enders,
D. Angew. Chem., Int. Ed. 2013, 52, 2977. (b) Hayashi, Y.; Umemiya, S.
Angew. Chem., Int. Ed. 2013, 52, 3450.
(4) Selected examples for the application of 1,2-dicarbonyls in or-
ganic synthesis: (a) Trost, B. M.; Dong, G.; Vance, J. A. Chem.;Eur. J.
2010, 16, 6265. (b) Shibasaki, M.; Kanai, M. Chem. Rev. 2008, 108, 2853.
(c) Svennebring, A.; Nilsson, P.; Larhed, M. J. Org. Chem. 2007, 5851.
(d) Nair, V.; Vellalath, S.; Poonoth, M.; Mohan, R.; Suresh, E. Org.
(7) For the utilization of 1,2-ketoesters as pronucleophiles in organo-
catalytic reactions: (a) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.;
Yamamoto, H. Angew. Chem., Int. Ed. 2004, 43, 1983. (b) Raimondi, W.;
€
€
ꢀ
Lett. 2006, 8, 507. (e) Schuster, T.; Bauch, M.; Durner, G.; Gobel, M.
Org. Lett. 2000, 2, 179. (f) Trost, B. M.; Schroeder, G. M. J. Am. Soc.
Chem. 2000, 122, 3785. (g) Ponaras, A. A. Tetrahedron Lett. 1980, 21,
4803.
Basle, O.; Bonne, D.; Constantieux, T.; Rodriguez, J. Adv. Synth. Catal.
2012, 354, 563. (c) Terada, M.; Amagai, K.; Ando, K.; Kwon, E.; Ube,
H. Chem.;Eur. J. 2011, 17, 9037. Corrigendum: Chem.;Eur. J. 2011,
17, 9858.
r
10.1021/ol400697n
XXXX American Chemical Society

The development of different activation modes, increasing
their nucleophilicity instead of competitive useless self-
condensation, has become a very attractive challenge.10
In contrast, 1,2-diones have rarely been described as
pronucleophiles in organocatalytic reactions. Only the re-
activity of the cyclic commercially available 1,2-cyclohex-
adione and 2-hydroxy-1,4-naphthoquinone has been
explored. This fact is probably due to the difficulty in
synthesizing new 1,2-diones. Rueping et al. reported succes-
sively the first domino Michael/acetalization CÀO hetero-
cyclization sequence of 2-hydroxy-1,4-naphthoquinone11
and the domino Michael/aldol reaction of 1,2-cyclo-
hexadione12 with R,β-unsaturated aldehydes catalyzed by
the HayashiÀJørgensen catalyst forming respectively chiral
1,4-pyranonaphthoquinones and bicyclo(3,2,1)octane-6-
carbaldehydes. Furthermore, other Michael acceptors,
such as nitroolefins,13 arylidenemanonitriles,14 and R,β-
unsaturated pyruvates,15 have been also reported as a
replacement for R,β-unsaturated aldehydes catalyzed by a
bifunctional Bronsted acid/base catalyst affording similar
bicyclic structures.
Herein, we describe the first organocatalytic domino
Michael/aldol reaction of acyclic 3-halogeno-1,2-diones
with R,β-unsaturated aldehydes to form cyclopentanones
with four contiguous stereogenic centers. Activation
of position 3 by the halogen atom could increase the
nucleophilicity of these 1,2-dicarbonyls at the expense of
the electrophilic sites. Higher flexibility and molecular
complexity could also be obtained by the use of acyclic
1,2-diones.
of four contiguous stereogenic centers, with a good yield
and enantioselectivity. The other diarylprolinol silylether
catalyst II16 was also tested in this reaction; only prod-
uct 3a was observed with a perfect diastereoselectivity
(>20:1 dr) as well as excellent yield (91%) and enantios-
electivity (91% ee). But when the catalyst loading was
decreased to 10 mol %, the reactivity and stereocontrol of
the reaction were reduced (Table 1, entries 3 and 4). In
the same manner, the use of the Macmillan type catalyst
III16 showed a dramatic drop in the diastereoselectivity
(Table 1, entry 5).
After this first optimization, we decided to examine
the influence of different solvents. The new asymmetric
domino Michael/aldol reaction was carried out in various
solvents without any improvements in terms of reactivity
and selectivity (Table 1, entries 6À11). Experimentation at
low temperature showed the formation of products 3a and
4a in a ratio of 5:1 and the diastereoselectivity was reduced
(Table 1, entry 12). NMR monitored investigations
indicated that the reaction was finished after 30 min, and
product 3a was obtained with the same diastereoselectivity
(>20:1 dr), a better yield (97%), and a similar enantio-
selectivity (88% ee) (Table 1, entry 13).
Table 1. Optimization of the Reaction Conditionsa
We began our investigations by examining the organo-
catalytic reaction of 3-chloro-1,2-dione 1a with cinnamal-
dehyde 2a in toluene catalyzed by the HayashiÀJørgensen
catalyst I.16 Degradation of the reactive mixture was
observed with a catalyst loading of 20 mol % (Table 1,
entry 1). But with 10mol % of the same catalystI, products
3a and 4a were formed in a ratio of 6:1 (Table 1, entry 2).
Product 4a corresponds to the dehydrated derivative of 3a.
Remarkably, product 3a was obtained exclusively as a
single diastereoisomer, indicating the perfect stereocontrol
yieldc
(%)
eed
entrya
cat.
solvent
3a:4ab
drb
(%)
1e
2f
3
4f
5
I
toluene
toluene
toluene
toluene
toluene
MeOH
CH2Cl2
EtOAc
MeCN
DMF
À
À
À
À
I
6:1
70
91
83g
86h
53
80
74
53
78
77
83h
97
>20:1
>20:1
9:1
87
91
89g
À
II
II
III
II
II
II
II
II
II
II
II
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
3:1
(8) For the utilization of 1,2-ketoamides as pronucleophiles in organo-
ꢀ
catalytic reactions: Basle, O.; Raimondi, W.; Sanchez Duque, M. M.;
5:1
Bonne, D.; Constantieux, T.; Rodriguez, J. Org. Lett. 2010, 12, 5246.
(9) For the utilization of 1,2-ketoacids as pronucleophiles in organo-
catalytic reactions: Vincet, J.-M.; Margottin, C.; Berlande, M.;
Cavagnat, D.; Buffeteau, T.; Landais, Y. Chem. Commun. 2007, 4782.
(10) (a) Dambruoso, P.; Massi, A.; Dondoni, A. Org. Lett. 2005, 7,
4657. (b) Basak, A. K.; Shimada, N.; Bow, W. F.; Vicic, D. A.; Tius,
M. A. J. Am. Chem. Soc. 2010, 132, 8266.
(11) Rueping, M.; Sugiono, E.; Merino, E. Angew. Chem., Int. Ed.
2008, 47, 3046.
(12) Rueping, M.; Kuenkel, A.; Tato, F.; Bats, J. W. Angew. Chem.,
Int. Ed. 2009, 48, 3699.
6
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
4:1
84
88
90
80
87
53
À
7
8
9
10
11
12i
13j
>20:1
>20:1
5:1
CHCl3
toluene
toluene
>20:1
>20:1
88
€
(13) (a) Rueping, M.; Kuenkel, A.; Frohlich, R. Chem.;Eur. J. 2010,
16, 4173. (b) Ding, D.; Zhao, C.-G.; Guo, Q.; Arman, H. Tetrahedron
2010, 66, 4423.
a 1,2-Dione (0.1 mmol), cinnamaldehyde (0.5 mmol), solvent
(0.2 mL). b Ratio determined by 1H NMR of the crude reaction mixture
for product 3a. c Isolated yield for product 3a. d Determined by chiral
SFC for product 3a. e Degradation of the reactive mixture was observed.
f 10 mol % of the catalyst was used. g Determined for the major
diastereoisomer. h Determined for the mixture of the two diastereo-
isomers. i Reaction was performed at 0 °C. j Reaction was performed with
1,2-dione (0.1 mmol), cinnamaldehyde (0.2 mmol) in toluene (0.2 mL) at
room temperature for 30 min.
(14) Ding, D.; Zhao, C.-G. Tetrahedron Lett. 2010, 51, 1322.
(15) (a) Ren, Q.; Gao, Y.; Wang, J. Org. Biomol. Chem. 2011, 9, 5297.
(b) Gao, Y.; Ren, Q.; Ang, S.-M.; Wang, J. Org. Biomol. Chem. 2011, 9,
3691.
(16) Selected general reviews on aminocatalysis: (a) Jensen, K. L.;
Dickmeiss, G.; Jiang, H.; Albrecht, L.; Jørgensen, A. Acc. Chem. Res. 2011,
45, 248. (b) List, B. Chem. Commun. 2006, 819. (c) Melchiorre, P.; Marigo,
M.; Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138.
B
Org. Lett., Vol. XX, No. XX, XXXX

Under the optimized reaction conditions, the substrate
scope of this diarylprolinol silylether catalyzed enantio-
selective domino Michael/aldol reaction using various
R,β-unsaturated aldehydes 2 was investigated (Table 2).
Aromatic R,β-unsaturated aldehydes 2bÀh with electron-
donating (Table 2, entries 1À4) and electron-withdrawing
(Table 2, entries 5À7) substituents were involved success-
fully in the reaction. Various new cyclopentanones with
four contiguous stereogenic centers were synthesized in
good yields (77À94%) and enantioselectivities (82À90% ee).
The diastereoselectivity was also perfectly controlled in the
same manner (>20:1 dr). Additionally, a heteroaromatic
R,β-unsaturated aldehyde could be also involved in this
transformation (Table 2, entry 8). Finally, less reactive
trans-2-pentenal was used, and almost no reaction occurred.
Table 3. Organocatalytic Domino Michael/Aldol Reactions of
3-Chloro-1,3-diphenylpropane-1,2-diones and Cinnamaldehyde
(2a) Catalyzed by the Catalyst IIa
yield
(%)b
ee
entrya
1
R2, R3
1
3
drc
(%)d
R2 = o-Cl-,
R3 = H
R2 = p-Br-,
R3 = H
R2 = p-MeO-,
R3 = H
R2 = m-Me-,
R3 = H
R2 = R3 =
p-Cl-
R2 = H,
R3 = m-MeO-
R2 = H,
R3 = p-Me-
R2 = H,
R3 = p-NO2-
R2 = H,
R3 = o-Br-
R2 = H,
R3 = o-Me-
1b
3j
80
85
95
95
75
95
80
69
À
>20:1
94
89
90
88
91
90
90
77
À
2
1c
1d
1e
1f
3k
3l
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
À
3
Table 2. Organocatalytic Domino Michael/Aldol Reactions
of 3-Chloro-1,3-diphenylpropane-1,2-dione (1a) and
R,β-Unsaturated Aldehydes Catalyzed by the Catalyst IIa
4
3m
3n
3o
3p
3q
3r
3s
5
6
1g
1h
1i
7
8
yieldb
(%)
eed
9e
10e
1j
entrya
R1
3
drc
(%)
1
2
3
4
5
6
7
8
m-MeOC6H4 (2b)
p-MeOC6H4 (2c)
p-MeC6H4 (2d)
o-MeOC6H4 (2e)
p-FC6H4 (2f)
3b
3c
3d
3e
3f
83
77
90
83
94
92
85
81
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
90
86
86
82
90
88
83
82
1k
À
À
À
a Reaction was performed with 1,2-dione (0.2 mmol) and R,β-
unsaturated aldehyde (0.4 mmol) in toluene (0.2 mL). b Isolated yield.
c Determined by 1H NMR of the crude reaction mixture. d Determined
by chiral SFC. e No conversion was observed. Starting materials were
recovered.
m-BrC6H4 (2g)
o-BrC6H4 (2h)
2-furanyl (2i)
3g
3h
3i
a Reaction was performed with 1,2-dione (0.2 mmol) and R,β-
unsaturated aldehyde (0.4 mmol) in toluene (0.2 mL). b Isolated yield.
c Determined by 1H NMR of the crude reaction mixture. d Determined
by chiral SFC.
The absolue configuration of product 3k was deter-
mined by X-ray crystallographic analysis (Figure 1; see
the Supporting Information). The stereochemistry of these
new cyclopentanones with four contiguous stereogenic
centers was then established.
After the first application of this new methodology, we
decided to apply the same optimized conditions to various
3-chloro-1,2-diones 1bÀk with electron-withdrawing and
-donating substituents on the aryl moiety in position 1.
Products were obtained with excellent diastereoselectivities
(>20:1 dr), good yields (80À95%), and enantioselectivities
(88À94% ee) (Table 3, entries 1À4). Other 3-chloro-1,3-
diphenylpropane-1,2-diones with electron-donating and -
withdrawing substituents on the aryl moiety in position 3
were also employed successfully in the new transformation.
A diverse set of new cyclopentanones with four contiguous
stereogenic centers was isolated in good yields (69À95%)
and enantioselectivities (77À91% ee). Only one diastereo-
isomer was still observed (>20:1 dr) (Table 3, entries 5À8).
It is interesting to note that whatever the electronic proper-
ties of the substituent in the ortho position, noreactivity was
observed (Table 3, entries 9 and 10). This lack of reactivity
is probably due to the steric hindrance of the substituents.
Figure 1. X-ray structure of product 3k. Thermal ellipsoids are
shown at the 50% probability level.
In order to study other modes of activation of 1,2-diones,
we decided to test 3-fluoro-1,3-diphenylpropane-1,2-dione
5 in the reaction (Scheme 1).
Org. Lett., Vol. XX, No. XX, XXXX
C

synthesized after 30 min in an excellent diastereoselectivity
(>20:1 dr) as well as good yield (68%) and enantioselec-
tivity (90% ee). The formation of the corresponding
hydrated compound was not observed (Scheme 1).
Scheme 1. Reaction of 3-Fluoro-1,3-diphenylpropane-1,2-
dione (5) and Cinnamaldehyde (2a)
In the present transformation, we assume that diaryl
prolinol silylether catalyst II forms the reactive imminium
intermediate A with the R,β-unsaturated aldehyde 2. Then,
a 1,4-addition occurs with the enol form of the acyclic
1,2-diketone 1, forming the Michael adduct B. This
enamine intermediate B achieves the intramolecular aldol
reaction. After hydrolysis, product 3 is obtained and the
catalyst II is regenerated (Scheme 2).
In conclusion, we described a new highly diastereo- and
enantioselective organocatalyzed domino Michael/aldol
reaction in which the formation of four contiguous stereo-
genic centers was controlled. Several acyclic 3-chloro-1,2-
diones and R,β-unsaturated aldehydes could be used pro-
viding an access to challenging chiral cyclopentanones in
excellent diastereoselectivities as well as good yields and
enantioselectivities. In addition, the reactivity of 3-fluoro-
1,2-dione was also evaluated in the transformation. New
chiral cyclopentenone was obtained with the same excellent
diastereoselectivity, in a good yield and enantioselectivity.
The expansion of the scope and synthetic applications of this
reaction constitute our future investigations.
Scheme 2. Proposed Catalytic Cycle for the Organocatalytic
Domino Michael/Aldol Reaction
Acknowledgment. This research was supported by
the Swiss National Research Foundation (Grant No.
200020_144344) and COST action CM905 “Organocatalysis”
(SER Contract No. C11.0080).
Supporting Information Available. Experimental pro-
cedures, NMR spectra, and chiral separations for all
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
Unlike chloro derivatives, 3-fluoro-1,3-diphenylpropane-
1,2-dione 5 did not react with cinnamaldehyde 2a in the
presence of catalyst II. But with catalyst I, a new cyclo-
pentenone with two contiguous stereogenic centers, 6, was
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX