Rationally designed multifunctional supramolecular iminium catalysis: Direct vinylogous michael addition of unmodified linear dienol substrates

Article abstract of DOI:10.1002/anie.201406786

The development of a direct vinylogous Michael addition of linear nucleophilic substrates is a long-standing challenge because of the poor reactivity and the considerable difficulty in controlling regioselectivity. By employing a rationally designed multifunctional supramolecular iminium catalysis strategy, the first direct vinylogous Michael addition of unmodified linear substrates to a,b-unsaturated aldehydes, to afford chiral 1,7-dioxo compounds with good yields and excellent regio-as well as enantioselectivity, has been developed.

Full text of DOI:10.1002/anie.201406786

.
Angewandte
Communications
DOI: 10.1002/anie.201406786
Asymmetric Catalysis
Rationally Designed Multifunctional Supramolecular Iminium
Catalysis: Direct Vinylogous Michael Addition of Unmodified Linear
Dienol Substrates**
Yun Gu, Yao Wang, Tian-Yang Yu, Yong-Min Liang, and Peng-Fei Xu*
Abstract: The development of a direct vinylogous Michael
addition of linear nucleophilic substrates is a long-standing
challenge because of the poor reactivity and the considerable
difficulty in controlling regioselectivity. By employing a ration-
ally designed multifunctional supramolecular iminium catal-
ysis strategy, the first direct vinylogous Michael addition of
unmodified linear substrates to a,b-unsaturated aldehydes, to
afford chiral 1,7-dioxo compounds with good yields and
excellent regio- as well as enantioselectivity, has been devel-
oped.
T
he field of vinylogous addition is one of the most dynamic
and synthetically powerful areas in contemporary organic
synthesis.[1] A broad range of organocatalytic, highly regiose-
lective as well as stereoselective vinylogous Michael addition
reactions have been successfully established.[2] Despite these
significant advances, however, nearly all of these approaches
are restricted to the use of cyclic vinylogous substrates which
have good reactivity and a strong preference for the g-
selectivity (Figure 1a).[2] For these substrates, at least one of
the electron-rich double bonds needs to be incorporated in
the ring systems. Owing to the poor reactivity and difficulty of
controlling regioselectivity (g versus a addition), the develop-
ment of vinylogous Michael additions of linear substrates
remains elusive. Recently, Schneider et al. elegantly devel-
oped the first Mukaiyama-type vinylogous Michael addition
of rationally designed linear substrates to a,b-unsaturated
aldehydes (Figure 1b).[3] To date, however, a direct approach
involving linear nucleophilic vinylogous substrates is unpre-
cedented and further exploration in this direction is highly
desired. In contrast to the indirect approach, the development
of a direct approach will lead to different reaction mode, that
is, a catalyst-controlled reaction as opposed to a substrate-
controlled or substrate-influenced reactivity and regioselec-
tivity (Figure 1c).
Figure 1. Different approaches for vinylogous Michael addition.
Initially, by employing a traditional strategy, we have
investigated numerous different reaction conditions including
catalysts, solvents, and additives etc. (for some typical
reaction conditions, see Table 1). Disappointingly, only very
low conversion and poor regioselectivity were obtained in all
cases.
Recently, we established the concept of supramolecular
iminium catalysis which can significantly activate iminium
ions.[4] We envisioned that a rationally designed multifunc-
tional supramolecular iminium catalysis strategy might be
able to address the reactivity and regioselectivity issues in the
direct vinylogous Michael addition of linear dienols to a,b-
unsaturated aldehydes (Figure 2). By employing this triple-
activation strategy, a,b-unsaturated aldehydes can be acti-
vated by the in situ generated iminium ion while vinylogous
substrates can be activated and stabilized by anion-binding
interactions. In taking a global view of the catalytic system,
the supramolecular iminium ion will further activate the
reaction by generating an ion-pair-separated, and more
reactive iminum ion, in higher concentration. Meanwhile,
the iminium catalyst could control enantioselectivity while
the anion-binding catalyst could govern regioselectivity by
shielding the a position of the vinylogous substrates.
[*] Y. Gu,[+] Dr. Y. Wang,[+] T.-Y. Yu, Prof. Dr. Y.-M. Liang, Prof. Dr. P.-F. Xu
State Key Laboratory of Applied Organic Chemistry
College of Chemistry and Chemical Engineering
Lanzhou University, Lanzhou 730000 (China)
E-mail: xupf@lzu.edu.cn
[+] These authors contributed equally to this work.
[**] We are grateful to the NSFC (21372105, 21302075, 21032005,
21172097), the International S&T Cooperation Program of China
(2013DFR70580), and the “111” program from MOE of P.R. China
for financial support.
Initially, the allylic ketone 1a and cinnamaldehyde (2a)
were used to test the feasibility of our hypothesis (Table 2).
The addition of hydrogen-bonding catalysts such as 6a and 6b
improved the conversion, albeit with no improvement in the
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201406786.
14128
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 14128 –14131

Angewandte
Chemie
Table 1: Initial screening of reaction conditions.[a]
Table 2: Screening of reaction conditions.[a]
Entry Cat. Additive (10 mol%) g/a (3a/4a)[b] Yield [%][c] ee [%][d]
1
2
5a
–
2:1
2:1
–
1:1
1:1
–
15
18
trace
<10
<10
trace
98
98
–
97
98
–
5a PhCOOH
5a CF3COOH
5a TEA
5a DABCO
5b
3[e]
4
5
6
–
[a] The reactions were carried out with 1a (0.2 mmol), 2a (0.2 mmol), 5
(10 mol%), and a cocatalyst (10 mol%) in 1.0 mL toluene at room
temperature. [b] Determined by 1H NMR analysis of the crude reaction
mixture. [c] Yield of isolated 3a. [d] Determined by HPLC analysis, using
a chiral stationary phase, by converting the product into an ester using
Ph3PCHCOOMe. [e] The addition of other acids such as CF3SO3H and
HCl did not show reactivity. DABCO=1,4-diazabicyclo[2.2.2]octane,
TEA=triethylamine, TMS=trimethylsilyl.
Entry[a] Catalyst T [8C] Solvent Yield [%][b] g/a[c] (3a/4a) ee [%][d]
1
2
3
4
5
6
7
8
5a+6a RT
5a+6b RT
5a+6c RT
5a+6d RT
5a+6e RT
5a+6 f RT
5a+6g RT
5a+6h RT
5b+6 f RT
5a+6 f RT
5a+6 f RT
5a+6 f RT
5a+6 f RT
5a+6 f RT
5a+6 f 40
5a+6 f 50
5a+6 f 60
5a+6 f 50
5a+6 f 50
5a+6 f 50
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
27
43
30
18
33
63
44
33
1:1.7
1.2:1
95
98
99
n.d.
93
97
95
93
–
1:1
1.4:1
1.2:1
5.4:1
2:1
2.2:1
–
15:1
>20:1
n.d.
n.d.
4.6:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
2:1
9
toluene <10
CH2Cl2
DCE
10
11
12
13
14
15
16
17
18[e]
19[e,f]
20[e,g]
21[e]
56
72
92
95
–
hexane trace
EtOH
xylene
DCE
DCE
DCE
DCE
DCE
DCE
DCE
12
60
78
82
80
87
88
72
22
–
97
95
95
93
95
95
93
97
5a
50
Figure 2. Strategy for the direct vinylogous Michael addition of linear
dienol.
[a] Unless otherwise noted, all the reactions were carried out with 1a
(0.2 mmol), 2a (0.2 mmol), 5 (10 mol%), and 6 (10 mol%) in 1.0 mL
solvent as indicated at room temperature (about 188C) for 24 h. [b] Yield
of the isolated g-addition product. [c] Determined by 1H NMR analysis of
the crude reaction mixture. [d] Determined by HPLC analysis using
a chiral stationary phase. [e] 1.5 equiv 2a was used. [f] 5 mol% 6 f was
used. [g] 2 mol% 6 f was used. DCE=1,2-dichloroethene, n.d.=not
determined.
regioselectivity (entries 1 and 2). Bifunctional cocatalysts
(6c–e) did not show good reactivity. To our delight, the use of
the catalyst 6 f led to a very encouraging yield with good
regioselectivity and excellent enantioselectivity (entry 6).
However, using 6g and 6h resulted in lower yields and
selectivities. The combination of the catalysts 5b and 6 f did
not show catalytic activity (entry 9). Next, different solvents
were investigated and DCE was found to be an optimal one
(entries 10–14). Further screening of the temperature showed
508C to be promising. When 1.5 equivalents of 2a was used,
a higher yield was obtained with the same excellent selectivity
(entry 18). Furthermore, the reaction worked equally effi-
cient upon reducing the loading of catalyst 6 f to 5 mol%
(entry 19). However, employing 2 mol% of 6 f led to a drop in
the yield and enantioselectivity (entry 20). In sharp contrast,
in the absence of 6 f, only 22% yield and poor regioselectivity
(g/a 2:1, entry 21) were obtained.
With the optimized reaction conditions, substrate scope
was investigated next. The allylic ketone 1 allowed incorpo-
ration of a wide range of substitutions into the desired
products (Table 3). Aromatic substituents bearing both elec-
tron-withdrawing and electron-donating groups, as well as
Angew. Chem. Int. Ed. 2014, 53, 14128 –14131
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 14129

.
Angewandte
Communications
Table 3: Substrate scope.[a]
Entry R1
R2
t [h] g/a[b]
Yield [%][c] ee [%][d]
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
20
36
18
20
15
36
20
22
17
16
22
21
16
18
18
24
>20:1 88 (3a)
13:1 71 (3b)
95
2-ClC6H4
3-ClC6H4
4-ClC6H4
2-FC6H4
2-BrC6H4
87
94
93
94
86
96
91
96
96
97
95
96
96
94
96
94
95
97
86
95
95
96
>20:1 86 (3c)
>20:1 82 (3d)
>20:1 91 (3e)
>20:1 66 (3 f)
15:1 77 (3g)
4-MeOC6H4 Ph
2-MeC6H4
3-MeC6H4
4-MeC6H4
Piperonyl
3,4-Me2C6H3 Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
c-C6H11
n-C6H13
Ph
Ph
Ph
Ph
>20:1 75 (3h)
>20:1 80 (3i)
>20:1 87 (3j)
>20:1 72 (3k)
>20:1 70 (3l)
>20:1 83 (3m)
>20:1 90 (3n)
>20:1 92 (3o)
>20:1 78 (3p)
>20:1 72 (3q)
>20:1 77 (3r)
>20:1 84 (3s)
5:1 80 (3t)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Figure 3. Proposed reaction pathway.
2-ClC6H4
3-BrC6H4
4-NO2C6H4
4-CNC6H4
3,4-Me2C6H3 17
3-MeC6H4
2-MeC6H4
furyl
Ph
Ph
a matched and mismatched combination of the chiral catalyst
pair. The very low concentration of T1 made it difficult to
1
observe this intermediate by H NMR spectroscopy in C6D6.
30
20
24
24
18
24
In sharp contrast, however, upon addition of 6 f to the mixture
of 5a and 2a, the color of the reaction mixture changed
immediately and a high concentration of the iminium ion was
generated (see the Supporting Information). Anion binding
has been heavily involved in enzyme catalysis and recently
emerged as an attractive strategy in artificial catalysis.[5]
Jacobsen et al. observed that the addition of a thiourea
cocatalyst improves the reactivity and enantioselectivity for
[5+2] cycloadditions of cationic oxidopyrilium ions.[6] Our
previous study revealed that it is difficult to form a measurable
concentration of iminium ion without the assistance of an
anion-binding catalyst.[4] The deprotonation of 1a will result
in a reactive multifunctional supramolecular iminium T3.
With the successful shielding of the a position of 1a by 6 f, and
the Si-face of the iminium ion by 5a, a g-selective, Re-face
attack will afford 3.
In summary, we have reported a new strategy for the
direct vinylogous Michael addition of unmodified linear
nucleophilic substrates. The desired 1,7-dioxo products were
obtained with good yields and excellent selectivity. Concep-
tually, this is an attractive strategy for expanding the
capability of supramolecular iminium catalysis, which has
the potential to be a useful platform for studying how
noncovalent interactions between ion pairs give rise to both of
reactivity and selectivity.
4:1 53 (3u)
4:1 45 (3v)
>20:1 82 (3a)
23[e] Ph
Ph
[a] See the Supporting Information. [b] Determined by 1H NMR analysis
of the crude reaction mixture. [c] Yield of the isolated g-addition product.
[d] Determined by HPLC analysis using a chiral stationary phase.
[e] Gram scale (1a, 10 mmol, 1.46 g; see the Supporting Information).
those with various substituents at the ortho, meta, and
para positions, were all tolerated. The aliphatic substituents
could also betolerated and the products were obtained with
moderate yields and good selectivities (entries 21 and 22).
The a,b-unsaturated aldehyde 2 could be varied and both
electron-rich and electron-poor substrates with substituents at
different positions worked effectively to provide products
with good yields and excellent selectivities. However, ali-
phatic-group-substituted aldehydes did not work well under
the optimized reaction conditions. A heteroaromatic group
could also be employed and afforded the adduct 3t, albeit
with lower regio- and enantioselectivity. The absolute con-
figuration was determined by comparing the optical rotation
of the product with that of the reported compound (see the
Supporting Information).[3] Furthermore, the reaction was
amendable to gram-scale synthesis (entry 23).
In the absence of 6 f, only 22% yield and 2:1 g/a selectivity
were obtained. When using acids without anion-binding
capabilities, poor yields and regioselectivities resulted
(Table 1, entries 2 and 3). When the reaction was performed
using racemic 5a and 6 f, the adduct 3a was obtained with
dramatically improved yield (70%) and regioselectivity
(> 20:1; Figure 3). These control experiments demonstrated
that cooperative catalysis gives rise to both of the reactivity
and selectivity. When 5a and the enantiomer of 6 f were
employed, the desired product 3a was obtained with much
lower yield (Figure 3). This observation indicates that there is
Received: July 2, 2014
Revised: September 19, 2014
Published online: October 19, 2014
Keywords: asymmetric catalysis · Michael addition ·
.
regioselectivity · supramolecular chemistry · synthetic methods
[1] For selected reviews on vinylogous-type reactions: a) G. Casir-
aghi, F. Zanardi, G. Appendino, G. Rassu, Chem. Rev. 2000, 100,
1929 – 1972; b) G. Casiraghi, L. Battistini, C. Curti, G. Rassu, F.
Zanardi, Chem. Rev. 2011, 111, 3076 – 3154; c) S. V. Pansare, E. K.
Paul, Chem. Eur. J. 2011, 17, 8770 – 8779; d) V. Bisai, Synthesis
14130 www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 14128 –14131

Angewandte
Chemie
2012, 1453 – 1463; e) C. Schneider, F. Abels, Org. Biomol. Chem.
2014, 12, 3531 – 3543.
12781; for a further update, see: b) S. Basu, V. Gupta, J. Nickel, C.
Schneider, Org. Lett. 2014, 16, 274 – 277.
[4] Y. Wang, T.-Y. Yu, H.-B. Zhang, Y.-C. Luo, P.-F. Xu, Angew.
Chem. Int. Ed. 2012, 51, 12339 – 12342; Angew. Chem. 2012, 124,
12505 – 12508.
[2] For selected examples, see: a) S. P. Brown, N. C. Goodwin,
D. W. C. MacMillan, J. Am. Chem. Soc. 2003, 125, 1192 – 1194;
b) J.-W. Xie, W. Chen, R. Li, M. Zeng, W. Du, L. Yue, Y.-C. Chen,
Y. Wu, J. Zhu, J.-G. Deng, Angew. Chem. Int. Ed. 2007, 46, 389 –
392; Angew. Chem. 2007, 119, 393 – 396; c) J. Alemꢀn, C. B.
Jacobsen, K. Frisch, J. Overgaard, K. A. Jørgensen, Chem.
Commun. 2008, 632 – 634; d) G. Bencivenni, P. Galzerano, A.
Mazzanti, G. Bartoli, P. Melchiorre, Proc. Natl. Acad. Sci. USA
2010, 107, 20642 – 20647; e) H. Huang, Z. Jin, K. Zhu, X. Liang, J.
Ye, Angew. Chem. Int. Ed. 2011, 50, 3232 – 3235; Angew. Chem.
2011, 123, 3290 – 3293; f) A. Quintard, A. Lefranc, A. Alexakis,
Org. Lett. 2011, 13, 1540 – 1543; g) C. Curti, G. Rasu, V.
Zambrano, L. Pinna, G. Pelosi, A. Sartori, L. Battistini, F.
Zanardi, G. Casiraghi, Angew. Chem. Int. Ed. 2012, 51, 6200 –
6204; Angew. Chem. 2012, 124, 6304 – 6308.
[5] For select reviews on anion-binding chemistry, see: a) Z. Zhang,
P. R. Schreiner, Chem. Soc. Rev. 2009, 38, 1187 – 1198. For select
examples of anion-binding catalysis, see: b) M. Kotke, P. R.
Schreiner, Tetrahedron 2006, 62, 434 – 439; c) M. Kotke, P. R.
Schreiner, Synthesis 2007, 779 – 790; d) I. T. Raheem, P. S. Thiara,
E. A. Peterson, E. N. Jacobsen, J. Am. Chem. Soc. 2007, 129,
13404 – 13405; e) H. Xu, S. J. Zuend, M. G. Woll, Y. Tao, E. N.
Jacobsen, Science 2010, 327, 986 – 990; f) C. K. De, E. G. Klauber,
D. Seidel, J. Am. Chem. Soc. 2009, 131, 17060 – 17061; g) R. P.
Singh, B. M. Foxman, L. Deng, J. Am. Chem. Soc. 2010, 132,
9558 – 9560; h) C. Min, N. Mittal, D. X. Sun, D. Seidel, Angew.
Chem. Int. Ed. 2013, 52, 14084 – 14088; Angew. Chem. 2013, 125,
14334 – 14338.
[3] a) V. Gupta, V. S. Sudhir, T. Mandal, C. Schneider, Angew. Chem.
Int. Ed. 2012, 51, 12609 – 12612; Angew. Chem. 2012, 124, 12778 –
[6] N. Z. Burns, M. G. Witten, E. N. Jacobsen, J. Am. Chem. Soc.
2011, 133, 14578 – 14581.
Angew. Chem. Int. Ed. 2014, 53, 14128 –14131
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 14131