Asymmetric vinylogous aldol reaction via H-bond-directing dienamine catalysis

Article abstract of DOI:10.1021/ol303312p

The enantioselective direct vinylogous aldol reaction of 3-methyl 2-cyclohexen-1-one with α-keto esters has been developed. The key to success was the design of a bifunctional primary amine-thiourea catalyst that can combine H-bond-directing activation and dienamine catalysis. The simultaneous dual activation of the two reacting partners results in high reactivity while securing high levels of stereocontrol.

Full text of DOI:10.1021/ol303312p

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Asymmetric Vinylogous Aldol Reaction
via H‑Bond-Directing Dienamine Catalysis
‡
‡
‡
‡
ꢀ
David Bastida, Yankai Liu, Xu Tian, Eduardo Escudero-Adan, and
Paolo Melchiorre*,†,‡
ꢀ
´
ICREA - Institucio Catalana de Recerca i Estudis Avanc-ats, Pg. Lluıs Companys,
23 08010 Barcelona, Spain, and ICIQ - Institute of Chemical Research of Catalonia,
Av. Paısos Catalans 16, 43007 Tarragona, Spain
¨
pmelchiorre@iciq.es
Received December 3, 2012
ABSTRACT
The enantioselective direct vinylogous aldol reaction of 3-methyl 2-cyclohexen-1-one with R-keto esters has been developed. The key to success
was the design of a bifunctional primary amine-thiourea catalyst that can combine H-bond-directing activation and dienamine catalysis. The
simultaneous dual activation of the two reacting partners results in high reactivity while securing high levels of stereocontrol.
Asymmetric aminocatalysis has greatly improved chem-
ists’ ability to stereoselectively functionalize unmodified
carbonyl compounds.1 Recently, this strategy has shown
potential for controlling the formation of remote stereo-
centers, which is a difficult synthetic goal.2 Specifically,
the propagation of the HOMO-raising electronic effect
through a conjugated π-system of extended enamines,
such as dienamines3 and trienamines,4 has allowed the
direct, stereoselective functionalization of unsaturated
carbonyls at their γ and ε positions, respectively. While
these aminocatalytic activation modes have been success-
fully exploited for the design of stereoselective pericyclic
reactions,5 their use in nucleophilic addition/substitution
manifolds has remained relatively underexplored.6
Herein, we describe the development of a direct vinylogous
aldol reaction of 3-methyl 2-cyclohexen-1-one 1a with
R-keto esters 2. The key to success was the design of a bi-
functional primary amine-thiourea catalyst that can com-
bine the H-bond-directing activation of the electrophilic
substrate with the dienamine activation of the enone
donor. The dual activation strategy secures direct access
to aldol products 3 with high stereocontrol and perfect
γ-site selectivity.
‡ ICIQ.
† ICREA.
(1) For reviews, see: (a) Barbas, C. F., III. Angew. Chem., Int. Ed.
2008, 47, 42. (b) List, B. Angew. Chem., Int. Ed. 2010, 49, 1730. (c) Lelais,
G.; MacMillan, D. W. C. Aldrichimica Acta 2006, 39, 79. (d) Melchiorre,
P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008,
47, 6138.
(2) Clayden, J. Chem. Soc. Rev. 2009, 38, 817.
(3) For a review on dienamine activation, see: Ramachary, D. B.;
Reddy, Y. V. Eur. J. Org. Chem. 2012, 865.
(4) For an overview on trienamine activation, see: (a) Arceo, E.;
Melchiorre, P. Angew. Chem., Int. Ed. 2012, 51, 5290. For selected
examples: (b) Jia, Z.-J.; Zhou, Q.; Zhou, Q.-Q.; Chen, P.-Q.; Chen, Y.-C.
Angew. Chem., Int. Ed. 2011, 50, 8638. (c) Liu, Y.-K.; Nappi, M.; Arceo,
E.; Vera, S.; Melchiorre, P. J. Am. Chem. Soc. 2011, 133, 15212. (d) Liu,
The vinylogous aldol reaction7 is a powerful way to
directly construct densely adorned δ-hydroxylated R,β-
unsaturated carbonyls, which are common structural motifs
in biologically relevant natural molecules.8a Traditionally,
ꢁ
Y.; Nappi, M.; Escudero-Adan, E. C.; Melchiorre, P. Org. Lett. 2012, 14,
1310.
(5) For an overview: (a) Li, J.-L.; Liu, T.-Y.; Chen, Y.-C. Acc. Chem.
Res. 2012, 45, 1491. Selected examples of dienamine activation:
(6) (a) Bergonzini, G.; Vera, S.; Melchiorre, P. Angew. Chem., Int. Ed.
ꢀ
ꢀ
2010, 49, 9685. (b) Stiller, J.; Marques-Lopez, E.; Herrera, R. P.;
ꢀ
(b) Bertelsen, S.; Marigo, M.; Brandes, S.; Diner, P.; Jørgensen, K. A.
€
Frohlich, R.; Strohmann, C.; Christmann, M. Org. Lett. 2011, 13, 70.
(c) Silvi, M.; Cassani, C.; Moran, A.; Melchiorre, P. Helv. Chim. Acta
J. Am. Chem. Soc. 2006, 128, 12973. (c) Talavera, G.; Reyes, E.; Vicario,
J. L.; Carrillo, L. Angew. Chem., Int. Ed. 2012, 51, 4104. For an example
of trienamine activation: (d) Jiang, H.; Li, J.-L.; Gschwend, B.; Li, Q.-Z.;
Yin, X.; Grouleff, J.; Chen, Y.-C.; Jørgensen, K. A. J. Am. Chem. Soc.
2011, 133, 5053.
2012, 95, 1985.
(7) For a comprehensive review, see: Casiraghi, G.; Battistini, L.;
Curti, C.; Rassu, G.; Zanardi, F. Chem. Rev. 2011, 111, 3076–3154.
r
10.1021/ol303312p
XXXX American Chemical Society

stereoselective, catalytic, vinylogous aldol reactions rely
upon indirect Mukayama-type strategies, which require
the preformation of stable dienolate equivalents.8 There
has been only limited success in achieving the direct in situ
activation of unmodified carbonyl substrates, which
would greatly expand the synthetic potential and atom
economy of this chemical transformation.9
translating the cyclic enone/cinchona-based catalyst sys-
tem tothe vinylogous aldol process. The use of20mol % of
catalyst A or B, in combination with 40 mol % of benzoic
acid as the cocatalyst, led to 3a as the unique product, but
with poor stereocontrol and very low reactivity (entries 1
and 2 in Table 1, reactions conducted in toluene at 60 °C).
Table 1. Development of the Direct Vinylogous Aldolization
under Dienamine Activation of the Cyclic Enone 1aa
Figure 1. The design plan for developing a direct vinylogous aldol
reaction under dienamine activation of cyclic enones: moving from a
Michael to an aldol process by means of chiral primary amine ca-
talysis. The gray circle represents the primary aminocatalyst scaffold.
conv
(%)b
ee
entry
amine
R
3
solvent
(%)c
1d
2d
3
A
B
C
D
E
F
G
E
E
E
E
E
E
E
E
E
Et, 2a
Et, 2a
Et, 2a
Et, 2a
Et, 2a
Et, 2a
Et, 2a
Et, 2a
Et, 2a
Et, 2a
Et, 2a
Bn, 2b
Me, 2c
i-Pr, 2d
t-Bu, 2e
Anth, 2f
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
3e
3f
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CHCl3
10
25
50
<5
43
53
32
19
61
40
70f
72f
68f
65f
65f
80f
23
35
43
À
We selected the combination of the commerically avail-
able 3-methyl cyclohexenone 1a and R-keto ester 2a as a
model for the vinylogous aldol reaction (Table 1). The
choice was motivated by our previous experiences with
vinylogous reactivity.6a,c,9b Recently, we found that the
cinchona-based primary amines A and B10 can promote
vinylogous nucleophilicity upon selective activation of
β-substituted cyclohexenones (Figure 1).11 The transmission
of the HOMO-raising effect through the transiently gen-
erated cyclic dienamine intermediate of type I allowed for
intermolecular vinylogous Michael additions to proceed
with high levels of enantioselectivity and exclusive γ-site
selectivity. To be successful, the cinchona aminocatalyst
needed to coax the regiocontrolled formation of the exo-
cyclic extended dienamine intermediate I, resulting in the
alkylation taking place selectively at the γ position.
This precedent11 persuaded us to test these primary
amine catalysts in the vinylogous aldol addition reaction.
Despite extensive efforts, we have not succeeded in
4
5
89
68
77
89
69
81
89
92
90
88
90
94
6
7
8
9
THF
10
11e
12e
13e
14e
15e
16e
MTBE
toluene
toluene
toluene
toluene
toluene
toluene
a BA: benzoic acid; MTBE: tert-butyl methyl ether; Anth: anthracen-
9-ylmethyl. Catalyst A and B were used with 2 equiv of BA (40 mol %),
while CÀG required a 1:1 combination with the acid (20 mol %).
Reactions on a 0.05 mmol scale using 2 equiv of 1a. b Determined by
1H NMR analysis of the crude reaction mixture. c Determined by HPLC
analysis on a chiral column. d Reaction at 60 °C. e Reaction performed
with 5 equiv of 1a and 50 mol % of BA at 4 °C over 48 h. f Value refers to
the yield of the isolated compound 3 after chromatography.
The quest for a more stereoselective and reactive system
prompted us to undertake an extensive catalyst screening
(Figure S1, Supporting Information (SI)). We wondered if
the application of chiral bifunctional H-bond-directing
amine catalysts could provide a suitable solution (Table 1).
A bifunctional primary amine-thiourea catalyst, which can
combine H-bond-directing activation of the R-ketoester
2 and dienamine catalysis, might result in the simulta-
neous dual activation of the two reacting partners while
(8) For reviews, see: (a) Denmark, S. E.; Heemstra, J. R., Jr.;
Beutner, G. L. Angew. Chem., Int. Ed. 2005, 44, 4682–4698. (b) Pansare,
S. V.; Paul, E. K. Chem.;Eur. J. 2011, 17, 8770–8779. For selected
examples, see: (c) Denmark, S. E.; Heemstra, J. R., Jr. J. Am. Chem. Soc.
2006, 128, 1038. (d) Ratjen, L.; Garcıa-Garcıa, P.; Lay, F.; Beck, M. E.;
List, B. Angew. Chem., Int. Ed. 2011, 50, 754.
(9) For the sole examples dealing with the dienamine activation of
linear enals, see: (a) Liu, K.; Chougnet, A.; Woggon, W.-D. Angew.
Chem., Int. Ed. 2008, 47, 5827. (b) Cassani, C.; Melchiorre, P. Org. Lett.
2012, 14, 5590. For direct strategies based on the use of cyclic 2(5H)-
furanone derivatives, see: (c) Ube, H.; Shimada, N.; Terada, M. Angew.
Chem., Int. Ed. 2010, 49, 1858. (d) Luo, J.; Wang, H.; Han, X.; Xu,
L.-W.; Kwiatkowski, J.; Huang, K.-W.; Lu, Y. Angew. Chem., Int. Ed.
2011, 50, 1861. For a nonstereoselective vinylogous aldol reaction of
unmodified cyclic enones, see: (e) Saito, S.; Shiozawa, M.; Ito, M.;
Yamamoto, H. J. Am. Chem. Soc. 1998, 120, 813.
(12) For selected examples of primary amine-thiourea catalysts in
enamine and iminium ion activations, see: (a) Tsogoeva, S. B.; Wei, S.
Chem. Commun. 2006, 1451. (b) Huang, H.; Jacobsen, E. N. J. Am.
Chem. Soc. 2006, 128, 7170. (c) Galzerano, P.; Bencivenni, G.; Pesciaioli,
F.; Mazzanti, A.; Giannichi, B.; Sambri, L.; Bartoli, G.; Melchiorre, P.
Chem.;Eur. J. 2009, 15, 7846. (d) Yu, F.; Jin, Z.; Huang, H.; Ye, T.;
Liang, X.; Ye, J. Org. Biol. Chem. 2010, 8, 4767.
(10) (a) Melchiorre, P. Angew. Chem., Int. Ed. 2012, 51, 9748.
(b) Jiang, L.; Chen, Y.-C. Catal. Sci. Technol. 2011, 1, 354.
(11) Bencivenni, G.; Galzerano, P.; Mazzanti, A.; Bartoli, G.;
Melchiorre, P. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 20642.
B
Org. Lett., Vol. XX, No. XX, XXXX

positioning them in a proper 3-D molecular assembly.
This could lead to higher levels of both reactivity and
stereoselectivity.12,13
and of the enone 1a (5 equiv) substantially increased the
reactivity, allowing the process to be conducted at 4 °C.15
These conditions provided the product 3a with syntheti-
cally useful results over a 48-h reaction time (entry 11 in
Table 1: 3a isolated in 70% yield, and 89% ee) and were
selected to evaluate the scope of the vinylogous aldol process.
The size of the ester moiety did not alter the stereoche-
mical outcome of the reaction. The corresponding aldol
adducts 3bÀf were produced with similar optical purity
and chemical yield (entries 12À16 in Table 1, ee ranging
from 88% to 94%). The scope of the aromatic R-keto ester
derivatives 2 is detailed in Table 2. Different substitution
patterns were well-tolerated, regardless of their position on
the phenyl ring (entries 1À7). The presence of an electron-
donating group or of a heteroaromatic moiety partially
affected the efficiency of the catalytic system (entries 8
and 9). Aliphatic R-keto esters proved to be competent
electrophiles of the vinylogous aldol reaction, providing
the corresponding aldol adducts 3qÀt with synthetically
useful results (entries 11À14).
Pursuing this dual activation prospect, we explored the
potential of bifunctional primary amine-thiourea catalysts
C and E, easily available from commercially available
chiral diamines, to promote the model reaction. Both bi-
functional catalysts induced a great acceleration of the
reaction rate, even at ambient temperature (entries 3 and 5).
To our delight, the simple bifunctional catalystE inferred a
satisfactory level of stereoinduction (89% ee, entry 5). We
then initiated a catalyst structure/reactivity and stereose-
lectivity correlation study, using modified amine-thiourea
derivatives. This was to identify a role for each functional
group of the catalyst scaffold and to gain preliminary insight
into the mechanism of stereoinduction. Replacing the pri-
mary amine in C with the corresponding N,N-dimethyl
tertiary amine (the Takemoto catalyst,14 D, entry 4) com-
pletely suppressed the reactivity. This is in agreement with a
mechanistic scenario requiring the formation of a dienamine
reactive intermediate. The urea catalyst F was slightly more
reactive but slightly less stereoselective than its thiourea
analogue E (compare entries 5 and 6). This indicates that
the catalysts likely operate by similar mechanisms as H-bond
donors; that is, the Lewis basicity of sulfur in E probably
does not play a direct role during the catalysis. In addition,
the absence of the electron-withdrawing trifluoromethyl
group, which substantially reduces both the acidity and
the H-bond donor propensity of the thiourea moiety, re-
sulted in a lower reactivity and stereoselectivity (catalyst G,
entry 7). All these results suggest a cooperative mechanism
of catalysis of the thiourea and the primary amino moiety,
which synergistically channel the process toward a highly
stereoselective vinylogous pathway by concomitant activa-
tion of both the electro- and nucleophilic partners.
Table 2. Scope of the Direct Vinylogous Aldolizationa
yield
(%)b
ee
entry
R1
R2
Bn
3
(%)c
1
4-Br-C6H4
4-Cl-C6H4
4-I-C6H4
3i
68
89
77
73
91
87
65
32
80
89
65
87
71
86
88
88
90
85
82
80
87
87
46
91
79
90
83
91
2
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Anthd
Bn
Et
3jd
3k
3l
3
4
4-F-C6H4
2-F-C6H4
2-F,4-Br-C6H4
4-Me-C6H4
4-MeO-C6H4
2-thiophenyl
4-Cl-C6H4
Me
5
3m
3n
3g
3h
3o
3pe
3q
3r
To further improve the efficiency of the catalysis by
amine E, different reaction parameters were studied. Ex-
amination of the acid cocatalyst (Table S1) and reaction
media (entries 8À10 in Table 1 and Table S2) identified
benzoic acid and toluene asthe more effective combination
(entry 5). A second cycle of optimization using these con-
ditions revealed that an excess of the benzoic acid (50 mol %)
6
7
8
9
10
11
12
13
14
Ph(CH2)2
c-C6H11
Et
3s
(CH2)2CO2Bn
Bn
3t
(13) Recently, the H-bond-directing approach using chiral secondary
amines has greatly expanded the potential of dienamine and trienamine
catalysis in promoting asymmetric pericyclic reactions; see: (a) Albrecht,
Ł.; Dickmeiss, G.; Cruz Acosta, F.; Rodrıguez-Escrich, C.; Davis, R. L.;
Jørgensen, K. A. J. Am. Chem. Soc. 2012, 134, 2543. (b) lbrecht, , Ł.;
Dickmeiss, G.; Weise, C. F.; Rodrıguez-Escrich, C.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2012, 51, 13109. For the application in trienamine-
mediated asymmetric reactions, see: (c) Albrecht, Ł.; Cruz Acosta, F.;
Fraile, A.; Albrecht, A.; Christensen, J.; Jørgensen, K. A. Angew. Chem.,
Int. Ed. 2012, 51, 9088. (d) Jiang, H.; Rodrıguez-Escrich, C.; Johansen,
T. K.; Davis, R. L.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2012, 51,
10271.
a BA: benzoic acid. Reactions performed on a 0.1 mmol scale using
5 equiv of 1a. b Yield of the isolated products 3 after chromatographic
purification. c Determined by HPLC analysis on a chiral column. d Anth:
anthracen-9-ylmethyl. e The (R) absolute configuration for products 3j
and 3p has been unambiguously inferred by X-ray crystallographic
analysis; see ref 17.
As a limitation of the system, modifying the cyclic
scaffold of the enone (i.e., 3-methyl 2-cyclopenten-1-one) re-
sulted in a complete loss of reactivity.16 Crystals from chlo-
rides 3j and 3p were suitable for anomalous dispersion X-ray
analysis, which established an (R) absolute configuration at
(14) Tomotaka, O.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc.
2003, 125, 12672.
(15) Experimental observations, detailed in Figure S2 and Table S3
within the SI, revealed that prolonging the reaction time to obtain a
higher conversion slightly affected the optical purity of the product 3.
The erosion of the enantiomeric excess was mainly ascribable to a retro-
aldol pathway. An excess of the donor 1a and of the benzoic acid
and a lower reaction temperature were crucial to preserving the en-
antioselectivity, while the conversion of the process increased over time
(Tables S4ÀS6).
(16) Attempts to forge two contiguous stereogenic centers at the λ
and δ positions using differently β-substituted cyclohexanones have
been unsuccessful. Linear enones also proved unreactive under the
reported reaction conditions.
Org. Lett., Vol. XX, No. XX, XXXX
C

the newly formed γ-stereocenter of the vinylogous aldol
adducts.17
Our experimental observations are consonant with a
bifunctional mode of activation where the primary amine-
thiourea catalyst E combines the H-bond activation of the
R-keto ester and the dienamine activation of the enone 1a.
Modifications of the catalyst scaffold, as detailed in entries
4À7 of Table 1, revealed that the primary amine and the
thiourea group play an active role during the catalysis.
Figure 2 depicts a plausible catalytic machinery, which
accounts for the observed stereochemical outcome. The
relative spatial arrangement of the two reacting partners,
as orchestrated by the bifunctional catalyst, determines the
selective attack to the Si-face of the R-keto ester.
Figure 3. Detectable intermediates by ESI-MS analysis in posi-
tive mode of the catalytic vinylogous aldol reaction of 1a and 2c.
Further support for the proposed dual mode of activation
was collected from mass spectrometry investigations.18,19b
As detailed in Figure 3, the ESI-MS spectrum in positive
mode of the reaction mixture20 showed the presence of the
imine precursor IV at m/z 576.1 and of the complex V at m/z
740.2, where both reacting partners are brought together in
close proximity.
Figure 2. Plausible bifunctional mode of action of the primary
amine thiourea catalyst E; possible ground-state association (II)
and stabilization of the generating alkoxy anion (III).
In summary, we have reported a rare example of a direct
vinylogous aldol reaction of an unmodified carbonyl com-
pound. Key to the development of the chemistry was the de-
sign of a bifunctional primary amine-thiourea catalyst that can
combine H-bond-directing activation and dienamine catalysis.
To further support the bifunctional activation mode, we
investigated the possible association of the R-keto methy-
lester 2c with the catalyst E by means of NMR spectro-
scopic analyses. 1H NMR titration studies of the catalytic
system (amine E in the presence of 1 equiv of benzoic
acid)18 were conducted in toluene-d8 and with an increas-
ing amount of 2c (Figure S14). The low-field shifts of the
NH thiourea protons clearly indicated the H-bonding
complexation with the R-keto ester. In agreement with pre-
vious works,18,19 our NMR studies revealed how the ortho
proton of the 3,5-bis(trifluoromethyl)phenyl catalyst moiety,
acting as an H-bond donor, also participated in the
catalystÀsubstrate 2c interaction. In addition, the imine
precursor of the dienamine intermediate was spectro-
scopically detected when mixing the aminocatalyst E
with the enone 1a in CDCl3 and in the presence of 4 A
molecular sieves (Figures S3ÀS8).
Acknowledgment. Research support from the ICIQ
Foundation, MICINN (Grant CTQ2010-15513), and the
European Research Council (Starting Grant No. 278541
to P.M.) is gratefully acknowledged. Y.L. is grateful to the
European Union for a Marie Curie fellowship (Grant FP7-
PEOPLE-2010-IIF No. 273088). The authors thank Dr.
Noemı Cabello (ICIQ) for ESI/MS analysis and Dr.
ꢁ
Antonio Moran (ICIQ), Jordi Amurdanes (ICIQ), and
Mattia Silvi (ICIQ) for useful discussions.
Supporting Information Available. Experimental pro-
cedures, compound characterization, HPLC traces, and
NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
(17) Crystallographic data for 3j and 3p are available free of charge
from the Cambridge Crystallographic Data Centre, accession numbers
CCDC 912144 and CCDC 912145, respectively.
(20) The ESI-MS analysis refers to the reaction under the optimized
conditions (20 mol % of E, 50 mol % of benzoic acid, 5 equiv of 1a, and
[2c]0 = 0.5 M in toluene). The analyzed sample was collected 5 min after
the start of the reaction. A concomitant 1H NMR analysis did not show
any detectable trace of the aldol product 3, which would provide the
same isotopic pattern of intermediate V. On the contrary, a trace amount
of intermediate V was detected from the same NMR experiment; see
Figures S15ÀS16 for full details.
(18) NMR spectroscopic studies of a catalyst E/benzoic acid mixture,
detailed in Figures S9ÀS13, revealed the formation of a new molecular
assembly, presumably as a result of the primary amine protonation. We
note that a cooperative association of thiourea and a benzoic acid
derivative has been reported; see: Zhang, Z.; Lippert, K. M.; Hausmann,
H.; Kotke, M.; Schreiner, P. R. J. Org. Chem. 2011, 76, 9764.
ꢀ
~
(19) (a) Crespo-Pena, A.; Monge, D.; Martın-Zamora, E.; Alvarez,
ꢀ
E.; Fernandez, R.; Lassaletta, J. M. J. Am. Chem. Soc. 2012, 134, 12912.
(b) Jiang, X.; Wang, L.; Kai, M.; Zhu, L.; Yao, X.; Wang, R. Chem.;
Eur. J. 2012, 18, 11465.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX