Aminocatalytic enantioselective 1,6a additions of alkyl thiols to cyclic dienones: Vinylogous iminiuma ion activation

Article abstract of DOI:10.1002/anie.201202392

Remote transmission: In the presence of chiral amines, 2,4-dienones are activated toward the attack of a nucleophile at the a position, a mode of activation that is termed vinylogous iminiuma ion catalysis. Specifically, the 1,6a addition of alkyl thiols to β-substituted cyclic dienones was catalyzed by a cinchona-based primary amine; the reaction was highly stereoselective and displayed high selectivity for reaction at the a position. Copyright

Full text of DOI:10.1002/anie.201202392

Angewandte
Chemie
DOI: 10.1002/anie.201202392
Asymmetric Organocatalysis
Aminocatalytic Enantioselective 1,6 Additions of Alkyl Thiols to
Cyclic Dienones: Vinylogous Iminium Ion Activation **
Xu Tian, Yankai Liu, and Paolo Melchiorre*
The field of asymmetric aminocatalysis[1] has developed from
two pioneering studies,[2,3] wherein it was recognized that
chiral amines could activate carbonyl compounds according
to fundamental concepts on reactivity (Scheme 1).[4] The
LUMO-lowering effect is the underlying principle that
governs activation in iminium ion catalysis.[1,2] This type of
led to the development of novel aminocatalytic activation
modes. Indeed, propagation of the HOMO-raising electronic
effect through the conjugated p system of polyunsaturated
carbonyl compounds has been recently used to induce
vinylogous nucleophilicity in extended enamines. Diena-
mine-[6] and trienamine-based[7] activation has been used for
the direct, stereoselective, and site-selective functionalization
of unsaturated carbonyl compounds at remote positions, such
as the g and e positions.
However, the mergence of iminium ion catalysis with the
concept of vinylogy has not yet been reported.[8] This is
surprising, because the transmission of the LUMO-lowering
effect within the extended p system of 2,4-unsaturated
carbonyl compounds, upon iminium ion formation, could be
used to effect direct and stereoselective functionalization at
the remote d position, a transformation for which few
catalytic methods are available.[9,10]
Herein, we report on the realization of this idea. When
a cinchona-based primary amine[11] condenses with b-substi-
tuted cyclic dienones, an iminium ion intermediate of
extended conjugation is formed (species I in Scheme 1 and
2); the electrophilicity of the d-carbon atom of this inter-
mediate is higher than that of the cyclic dieneone substrate.
This aminocatalytic activation mode, termed “vinylogous
iminium ion catalysis”, accounts for a highly stereo- and
d-position-selective addition of alkyl thiols to cyclic a,b,g,d-
unsaturated dienones.
From the outset, we recognized two critical issues. We
needed a chiral aminocatalyst that, i) condenses easily with
a dienone substrate to form the desired electrophilic iminiu-
m ion intermediate of extended conjugation I, and ii) ensures
configurational control and p-facial discrimination of inter-
mediate I, which are essential factors in enforcing high levels
of enantioselectivity. The choice of the catalyst and the
suitable polyunsaturated enone substrate was motivated by
our previous studies on vinylogous reactivity.[12] In these
previous studies, we found that cinchona-based primary
amines A and B (Scheme 2a) activate b-substituted cyclo-
hexenones toward reaction with electrophiles at the g-carbon
atom.[12a] The relatively high-energy HOMO of the transiently
generated cyclic dienamine intermediate II allowed for
intermolecular vinylogous Michael additions to take place
exclusively at the g position with high levels of enantioselec-
tivity (Scheme 2b). To be successful, the cinchona amino-
catalyst needed to communicate its inherent stereochemical
information while forging the new stereocenter at the remote
g position, several atoms apart from the catalyst binding point
within the cyclic dienamine II.
Scheme 1. Established activation modes in aminocatalysis and the
vinylogous iminium ion strategy; the gray circle represents the primary
aminocatalyst scaffold.
aminocatalysis is based on the ability of an amine to reversibly
condense with a,b-unsaturated carbonyl substrates to form
the corresponding a,b-unsaturated iminium ion, the b-carbon
atoms of which are more susceptible to nucleophilic attack
than those of the substrate because of the lower energy of
their LUMO. Conversely, enamine catalysis[1,3] induces
a nucleophilic character at the a-carbon atom of the covalent
enamine intermediate, which is generated from enolizable
carbonyl substrates, by means of a HOMO-raising effect.
Enamine catalysis has shown unique versatility and its
successful combination with the principle of vinylogy[5] has
[*] Prof. Dr. P. Melchiorre
ICREA—Instituciꢀ Catalana de Recerca i Estudis AvanÅats
Passeig Lluꢁs Companys 23, 08010 Barcelona (Spain)
X. Tian, Dr. Y. Liu, Prof. Dr. P. Melchiorre
ICIQ—Institute of Chemical Research of Catalonia
Avenida Paꢂsos Catalans 16, 43007 Tarragona (Spain)
E-mail: pmelchiorre@iciq.es
Homepage: http://www.iciq.es/portal/862/default.aspx
[**] Research support from the ICIQ Foundation, MICINN (grant
CTQ2010-15513), and the European Research Council (ERC Starting
grant agreement no. 278541—ORGA-NAUT) is gratefully acknowl-
edged. Y.L. is grateful to the European Union for a Marie Curie
fellowship (grant FP7-PEOPLE-2010-IIF no. 273088). The authors
thank Eduardo Escudero-Adꢃn for X-ray crystallographic analysis.
This previous work allowed us to recognize the unique
ability of cinchona-based amines to stereochemically bias
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201202392.
Angew. Chem. Int. Ed. 2012, 51, 6439 –6442
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6439

.
Angewandte
Communications
Table 1: Optimization studies for the asymmetric 1,6-addition reaction
of cyclic dienones 1.[a]
Scheme 2. Outline for the vinylogous iminium ion strategy. Central to
the study is the structural analogy of species I and II, and the idea that
the ability of cinchona-based primary amines to effectively control the
molecular topology of the cyclic dienamine II can be translated to the
cyclic vinylogous iminium ion I.
Entry
Amine
Acid
2
1
Conv. [%] [b]
ee [%][c]
1
2
3
4
5
6
7
8
A
A
B
C
D
D
D
D
D
D
D
D
PhCO2H
–
PhCO2H
PhCO2H
PhCO2H
d-E
d-F
l-F
l-G
l-F
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
58
<5
32
56
67
55
63
55
65
84
90
91
81
–
69
78
83
85
87
89
85
79
86
91
intermediary cyclic species thus ensuring highly predictable
reaction outcomes. We envisioned that we could further
exploit this ability to address the challenge of developing
a method for a stereoselective 1,6 addition reaction involving
cyclic dienones 1 (Scheme 2c and d). In addition, we reasoned
that the b substituent of 1 would represent an additional
control element for securing selective reaction at the d posi-
tion because, through steric hindrance, 1,4-addition reaction
would be disfavored.
9
10[d]
11[d,e]
12[e,f]
l-F
l-F
[a] Reactions were performed on a 0.05 mmol scale using 1.2 equiv of
thiol with [1]0 =0.5m in toluene, without any precaution for excluding air.
[b] Conversion determined by 1H NMR analysis of the crude reaction
mixture. A product derived from sequential 1,6 and 1,4-addition
reactions leading to products of type 4 (see Table 3) were sometimes
observed. Products derived from a selective 1,4-addition reaction were
not detected. Further details can be found in the footnotes of Table 2 and
in the Supporting Information. [c] Determined by HPLC analysis using
a chiral stationary phase. [d] Reaction time: 60 h. [e] Reaction performed
using a 10:1 toluene/H2O mixture as the solvent with [1]0 =0.25m and
3 equiv of 2a. [f] 5 mol% of amine D and 7.5 mol% of acid l-F were
used; reaction time: 36 h.
To test the feasibility of the vinylogous iminium ion based
strategy, we investigated the potential of the quinine-derived
primary amine A (20 mol%)[13] to activate cyclic dienone 1a
toward a 1,6-addition reaction (Table 1; more extensive
documentation of the optimization studies can be found in
the Supporting Information, Tables S1-8). Among the differ-
ent nucleophiles investigated (see the Supporting Informa-
tion, Table S1 for details), benzylthiol (2a)[13d–e] afforded
promising reaction conversion to the 1,6-addition adduct 3
with promising optical purity (Table 1, entry 1; 81% ee).
When the reaction was conducted in the absence of benzoic
acid as a co-catalyst, no conversion to 3 was observed
(Table 1, entry 2); this result suggests that a reaction pathway
involving general-base activation of 2a is unlikely. These
results further establish cinchona-based primary amines as
highly versatile catalysts for the covalent activation of keto
compounds and demonstrate their potential as catalysts in
vinylogous iminium ion catalysis. To achieve improved levels
of stereocontrol, we tested other cinchona-based amines as
catalysts. The use of the bifunctional catalyst B gave a poorer
result (Table 1, entry 3). Gratifyingly, the stereoselectivity of
the reaction was sensitive to structural modification of the
catalyst at the 2’ position of the quinoline ring. This observa-
tion is in agreement with a recent report by List and co-
workers, wherein this type of modification of a cinchona
amine was used for fine tuning the stereoselectivity of an
aminocatalyzed reaction.[14] Among the catalysts investigated
(more details can be found in the Supporting Information,
Table S5), amine D provided the best result (Table 1, entry 5)
and was therefore selected as the catalyst for further reaction
optimization.
An extensive screening of acid co-catalysts (more details
given in the Supporting Information, Tables S4 and S6)
revealed that chiral acids could be used as an additional
handle for modulating reaction efficiency (Table 1, entries 5–
9).[11,13b–d] In particular, the use of inexpensive N-Boc
protected l-valine (l-F) gave increased levels of stereoselec-
tivity (89% ee; Table 1, entry 8); the use of the other
enantiomer (d-F) resulted in slightly poorer results (Table 1,
entry 7). We were satisfied with the level of enantioselectivity
of the reaction catalyzed by the amine D/acid F combination
(1:1.5 ratio) and we then focused on improving the yield of the
1,6 addition. When the reaction was allowed to proceed for
a longer time, a higher reaction conversion was obtained but
the optical purity of the product 3 was lower (Table 1,
entry 10). Experimental observations that have been detailed
in the Supporting Information, Figure S1 and Table S8, reveal
that the erosion of the enantiomeric excess was mainly due to
the presence of a retroaddition pathway. When the reaction
was conducted in a toluene/water mixture (10:1) and under
more dilute reaction conditions, the use of longer reaction
times gave increased reaction conversion without any erosion
6440 www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 6439 –6442

Angewandte
Chemie
in ee value over time (Table 1, entry 11). When the sterically
less encumbered substrate, (E)-3-styryl-2-cyclohexenone
(1b), was used, the catalyst loading could be reduced
(5 mol% of amine D together with 7.5 mol% of l-F) while
maintaining synthetically useful results (91% ee; Table 1,
entry 12); 1b was more reactive than 1a presumably because
of a more facile condensation reaction with the aminocatalyst.
The optimized conditions were then used for examining the
scope of the 1,6-addition reaction.
As highlighted in Table 2, the presence of a wide range of
dienone d substituents are compatible with the reaction.
Substrates containing a variety of substitution patterns at the
aromatic moiety were well tolerated, regardless of their
electronic properties, and the corresponding adducts 3 were
obtained in good yields and with high ee values (Table 2,
entries 1–10). The reaction was compatible with heteroaryl
frameworks, as shown in the synthesis of the thiophenyl-
substituted adduct 3j (Table 2, entry 11). Remarkably, the
scope of the reaction was successfully extended to include
substrates containing an aliphatic substituent at the d position
(R1 = Me; Table 2, entry 12). The use of a cyclopentenone-
based dienone resulted in lower conversion and enantiose-
lectivity (Table 2, entry 13), thus highlighting how strongly
the cyclic geometry is connected with the propagation of the
LUMO-lowering effect and with an effective control over the
molecular topology of the vinylogous iminium ion intermedi-
ate. Consistent with this hypothesis, an acyclic 2,4-dienone did
not react under the optimized reaction conditions (Support-
ing Information, Figure S2). The pseudoenantiomeric catalyst
of amine D, derived from quinidine (structure given in the
Supporting Information, Figure S3), showed a similar reac-
tivity profile and gave the other enantiomer of the product 3b
with a similar ee value (Table 2, entry 3). The absolute
configuration of the stereogenic center of compounds 3c
and 3 f was unambiguously determined by anomalous-dis-
persion X-ray crystallographic analysis.[15,16]
The scope of the 1,6-addition reaction with respect to the
nucleophilic component was also explored. Remarkably,
a broad range of alkyl thiols, containing either aromatic or
vinyl moieties, can also be used in the reaction (Table 2,
entries 14–16).
The products 3 contain functional groups that are
amenable toward further transformations. In particular, the
presence of the a,b-unsaturated carbonyl moiety can be used
for rapidly increasing the stereochemical and structural
complexity of adducts 3 by means of an organocascade
reaction.[17] We explored the potential of amine D to activate
cyclic dienones 1 toward a cascade reaction involving both 1,6
and 1,4 additions of thiols. The cascade reaction was success-
fully implemented by using a large excess of thiol 2b and
a relatively long reaction time (Table 3), thus providing
adducts 4 with moderate diastereoselectivity but with high
ee value. X-ray crystallographic analysis of suitable crystals of
compound 4a established the stereochemical outcome of the
cascade reaction.[16]
Table 2: Generality of the 1,6-addition reactions.[a]
Entry R1
n
R2 R3
Me Ph
3
Yield [%][b] ee [%][c]
1[d]
2
Ph
Ph
Ph
1
1
1
1
1
1
1
1
1
1
1
1
0
1
1
1
3a 68
3b 66
3b 56
3c 63
3d 65
3e 70
3 f 58
3g 56
3h 63
3i
3j
3k 54
3l 35
86
91
89[e]
91
88
91
91
87
92
93
87
89
55
93
90
91
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3[e]
4
4-NO2C6H4
4-MeOC6H4
4-MeC6H4
4-BrC6H4
4-FC6H4
4-ClC6H4
3-ClC6H4
3-thiophenyl
Me
Me
Ph
Ph
Ph
In summary, we have discovered that the LUMO-low-
ering activating effect can be transmitted through the
conjugated p system of 2,4-dienones upon selective conden-
sation with a cinchona primary amine catalyst. The resulting
5
6
7
8
9
10
11
12[f]
13[f]
14
15
16
60
60
Table 3: Cascade reactions involving sequential 1,6 and 1,4-addition
reactions.[a]
4-MeOC6H4 3m 65
4-ClC6H4
CH CH2
3n 62
3o 60
=
[a] Reactions performed on a 0.2 mmol scale. Results represent the
average of two runs per substrate. For all the dienones 1 used, the E/Z
ratio was >95:5. See also Ref. [15]. [b] Yield of the isolated compound 3
after purification by column chromatography on silica gel. The yields are
partially affected by a difficulty in separating the product from the
starting material, dienone 1 in the case when reactions did not reach
completion, and/or by the presence of products, 4, derived from the
competing reaction that involves sequential 1,6 and 1,4-addition
reactions, products, which were sometimes formed in a low amounts
(generally approximately 15% yield, see the Supporting Information for
details). Products derived from a selective 1,4-addition reaction were not
detected. [c] Determined by HPLC analysis using a chiral stationary
phase. [d] 20 mol% of D and 30 mol% of F was used; reaction time:
60 h. [e] The use of pseudoenantiomeric quinidine-derived catalyst in
combination with N-Boc l-valine (l-F) gave the other enantiomer of 3b.
[f] Toluene was used as the reaction solvent.
Entry
R
4
Yield [%][b]
d.r.[c]
ee [%][d]
1
2
3
4
5
Ph
a
b
c
d
e
50
45
54
50
48
4:1
4:1
3.5:1
4:1
5:1
97
97
95
95
97
4-MeC6H4
3-ClC6H4
4-BrC6H4
4-FC6H4
[a] Reactions performed on a 0.1 mmol scale using 12 equiv of (4-
methoxyphenyl)methanethiol (2b). [b] Yield of isolated product 4. The
yields are partially affected by a difficult separation of adducts 4 from the
1,6-addition adducts 3, which were generally formed in approximately
15% yield. [c] Determined by 1H NMR analysis and confirmed by HPLC
analysis. [d] The ee value refers to the major diastereoisomer of 4 and
was determined HPLC analysis using a chiral stationary phase.
Angew. Chem. Int. Ed. 2012, 51, 6439 –6442
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
6441

.
Angewandte
Communications
2008, 120, 9262 – 9264; Angew. Chem. Int. Ed. 2008, 47, 9122 –
9124; f) K. Lee, A. H. Hoveyda, J. Am. Chem. Soc. 2010, 132,
2898 – 2900; for metal-catalyzed processes involving acyclic
unsaturated carbonyl compounds, see: g) T. den Hartog, S. R.
Harutyunyan, D. Font, A. J. Minnaard, B. L. Feringa, Angew.
Chem. 2008, 120, 404 – 407; Angew. Chem. Int. Ed. 2008, 47, 398 –
401; h) T. Nishimura, Y. Yasuhara, T. Sawano, T. Hayashi, J. Am.
Chem. Soc. 2010, 132, 7872 – 7873; for an intriguing umpolung
strategy, in which the d position has nucleophilic character, see:
i) C. C. Ventocilla, K. A. Woerpel, J. Am. Chem. Soc. 2011, 133,
406 – 408.
vinylogous iminium ion activation was used to develop a rare
example of asymmetric organocatalytic 1,6-addition proceed-
ing with high stereocontrol and good selectivity. We believe
this reactivity will rapidly find application in the design of
other asymmetric d functionalizations of unmodified carbon-
yl compounds and the implementation of more sophisticated
cascade sequences.
Received: March 27, 2012
Published online: May 22, 2012
[10] The only two precedents dealing with enantioselective organo-
catalytic 1,6 additions are based on the selective activation of the
nucleophiles, see: a) L. Bernardi, J. Lꢃpez-Cantarero, B. Niess,
K. A. Jørgensen, J. Am. Chem. Soc. 2007, 129, 5772 – 5778;
b) J. J. Murphy, A. Quintard, P. McArdle, A. Alexakis, J. C.
Stephens, Angew. Chem. 2011, 123, 5201 – 5204; Angew. Chem.
Int. Ed. 2011, 50, 5095 – 5098.
Keywords: asymmetric synthesis · iminium ions ·
nucleophilic addition · organocatalysis · vinylogous reactivity
.
[1] For insightful perspectives on the historical origins of amino-
catalysis, see: a) C. F. Barbas III, Angew. Chem. 2008, 120, 44 –
50; Angew. Chem. Int. Ed. 2008, 47, 42 – 47; b) B. List, Angew.
Chem. 2010, 122, 1774 – 1779; Angew. Chem. Int. Ed. 2010, 49,
1730 – 1734; c) G. Lelais, D. W. C. MacMillan, Aldrichimica Acta
2006, 39, 79 – 87; for an overview: d) P. Melchiorre, M. Marigo,
A. Carlone, G. Bartoli, Angew. Chem. 2008, 120, 6232 – 6265;
Angew. Chem. Int. Ed. 2008, 47, 6138 – 6171.
[2] K. A. Ahrendt, C. J. Borths, D. W. C. MacMillan, J. Am. Chem.
Soc. 2000, 122, 4243 – 4244.
[3] B. List, R. A. Lerner, C. F. Barbas III, J. Am. Chem. Soc. 2000,
122, 2395 – 2396.
[11] a) L. Jiang, Y.-C. Chen, Catal. Sci. Technol. 2011, 1, 354 – 365;
b) G. Bartoli, P. Melchiorre, Synlett 2008, 1759 – 1771.
[12] a) G. Bencivenni, P. Galzerano, A. Mazzanti, G. Bartoli, P.
Melchiorre, Proc. Natl. Acad. Sci. USA 2010, 107, 20642 – 20647;
b) G. Bergonzini, S. Vera, P. Melchiorre, Angew. Chem. 2010,
122, 9879 – 9882; Angew. Chem. Int. Ed. 2010, 49, 9685 – 9688.
[13] For selected examples, see: a) W. Chen, W. Du, L. Yue, R. Li, Y.
Wu, L.-S. Ding, Y.-C. Chen, Org. Biomol. Chem. 2007, 5, 816 –
821; b) G. Bartoli, A. Carlone, F. Pesciaioli, L. Sambri, P.
Melchiorre, Org. Lett. 2007, 9, 1403 – 1405; c) X. Wang, C. M.
Reisinger, B. List, J. Am. Chem. Soc. 2008, 130, 6070 – 6071; d) X.
Tian, C. Cassani, Y. Liu, A. Moran, A. Urakawa, P. Galzerano, E.
Arceo, P. Melchiorre, J. Am. Chem. Soc. 2011, 133, 17934 –
17941; for a review on the sulfa-Michael reaction, see: e) D.
Enders, K. Lꢄttgen, A. Narine, Synthesis 2007, 959 – 980.
[14] a) A. Lee, A. Michrowska, S. Sulzer-Mosse, B. List, Angew.
Chem. 2011, 123, 1745 – 1748; Angew. Chem. Int. Ed. 2011, 50,
1707 – 1710; for the first report that described how to modify the
cinchona scaffold at the 2’ quinoline position, see: b) L. Hinter-
mann, M. Schmitz, U. Englert, Angew. Chem. 2007, 119, 5256 –
5259; Angew. Chem. Int. Ed. 2007, 46, 5164 – 5167.
[15] NMR spectroscopic analysis showed that the substrate bearing
a nitro group at the 4 position of the R1 aryl moiety has the
Z geometry (Table 2, entry 4). This is in agreement with: S. Luo,
X. Mi, H. Xu, P. G. Wang, J.-P. Cheng, J. Org. Chem. 2004, 69,
8413 – 8422. We established that adducts 3c and 3 f have the
same absolute configuration (see Ref.[15]), thus suggesting that
an enantioconvergent 1,6-addition pathway is operating. We
excluded the possibility that the geometry of the g,d double bond
of the substrate undergoes scrambling under the reaction
conditions (see the Supporting Information, Figure S4); the
origin of the enantioconvergence thus remains unclear. Further
studies, based on computational investigations, are underway.
[16] CCDC 868862 (3c), 868863 (3 f), and 872092 (4a) contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif..
[17] a) C. Grondal, M. Jeanty, D. Enders, Nat. Chem. 2010, 2, 167 –
178; for the use of cinchona-based primary amines in cascade
reactions that combine iminium ion and enamine activation, see:
b) L.-Y. Wu, G. Bencivenni, M. Mancinelli, A. Mazzanti, G.
Bartoli, P. Melchiorre, Angew. Chem. 2009, 121, 7332 – 7335;
Angew. Chem. Int. Ed. 2009, 48, 7196 – 7199; c) P. Galzerano, F.
Pesciaioli, A. Mazzanti, G. Bartoli, P. Melchiorre, Angew. Chem.
2009, 121, 8032 – 8034; Angew. Chem. Int. Ed. 2009, 48, 7892 –
7894.
[4] HOMO- and LUMO-activations are general catalytic concepts,
which permeate the whole area of asymmetric catalysis (e.g.
LUMO activation is the principle behind the classical Lewis acid
activation of a carbonyl compound by a metal salt).
[5] R. C. Fuson, Chem. Rev. 1935, 16, 1 – 27.
[6] For the seminal study, see: S. Bertelsen, M. Marigo, S. Brandes, P.
Dinꢀr, K. A. Jørgensen, J. Am. Chem. Soc. 2006, 128, 12973 –
12980.
[7] For landmark reports, see: a) Z. J. Jia, H. Jiang, J.-L. Li, B.
Gschwend, Q.-Z. Li, X. Yin, J. Grouleff, Y.-C. Chen, K. A.
Jørgensen, J. Am. Chem. Soc. 2011, 133, 5053 – 5061; b) X.-F.
Xiong, Q. Zhou, J. Gu, L. Dong, T.-Y. Liu, Y.-C. Chen, Angew.
Chem. 2012, 124, 4477 – 4480; Angew. Chem. Int. Ed. 2012, 51,
4401 – 4404; for a contribution from our research group, see:
c) Y. Liu, M. Nappi, E. Arceo, S. Vera, P. Melchiorre, J. Am.
Chem. Soc. 2011, 133, 15212 – 15218.
[8] We note that iminium ion catalysis (Refs. [1c] and [2]) is
inherently connected with the vinylogy concept. Indeed, it was
conceived through mechanistic analogy with the reductive
amination of a saturated aldehyde, where the formation of the
positively charged iminium ion effectively lowers the LUMO of
the isolated p system. Extension to the conjugated p system of
an enal conceptualized the iminium ion activation strategy.
[9] The most versatile method for achieving catalytic stereoselective
d functionalizations of carbonyl compounds is the stereoselec-
tive 1,6 addition to a,b,g,d-unsaturated carbonyl compounds. In
addition to the challenge of stereoselectivity, this approach has
the additional challenge of site selectivity. For reviews, see:
a) A. C. Csꢁkꢂ, G. de La Herrꢁn, M. C. Murcia, Chem. Soc. Rev.
2010, 39, 4080 – 4102; b) A. T. Biju, ChemCatChem 2011, 3,
1847 – 1849; for metal-catalyzed processes involving cyclic
unsaturated carbonyl compounds, see: c) T. Hayashi, S. Yama-
moto, N. Tokunaga, Angew. Chem. 2005, 117, 4296 – 4299;
Angew. Chem. Int. Ed. 2005, 44, 4224 – 4227; d) E. Fillion, A.
Wilsily, E.-T. Liao, Tetrahedron: Asymmetry 2006, 17, 2957 –
2959; e) H. Hꢀnon, M. Mauduit, A. Alexakis, Angew. Chem.
6442 www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 6439 –6442