Diarylprolinol-Mediated Asymmetric Direct Cross-Aldol Reaction of α,β-Unsaturated Aldehyde as an Electrophilic Aldehyde

Article abstract of DOI:10.1002/asia.201901236

The diarylprolinol-mediated asymmetric direct cross-aldol reaction of α,β-unsaturated aldehyde as an electrophilic aldehyde was developed. The reaction becomes accelerated by an acid when a carbonyl group is introduced at the γ-position of the α,β-unsatur

Full text of DOI:10.1002/asia.201901236

DOI: 10.1002/asia.201901236
Communication
Diarylprolinol-Mediated Asymmetric Direct Cross-Aldol Reaction
of a,b-Unsaturated Aldehyde as an Electrophilic Aldehyde
[
a]
Yujiro Hayashi,* Kaito Nagai, and Shigenobu Umemiya
for the generation of chiral allyl alcohol is the asymmetric
cross-aldol reaction of a,b-unsaturated aldehyde, which affords
g,d-unsaturated b-hydroxy aldehyde. To our knowledge, there
are only three examples of the organocatalyst-mediated asym-
metric cross-aldol reaction of a,b-unsaturated aldehyde; that
Abstract: The diarylprolinol-mediated asymmetric direct
cross-aldol reaction of a,b-unsaturated aldehyde as an
electrophilic aldehyde was developed. The reaction be-
comes accelerated by an acid when a carbonyl group is
introduced at the g-position of the a,b-unsaturated alde-
hyde. Synthetically useful g,d-unsaturated b-hydroxy alde-
hydes were obtained with high anti-selectivity and excel-
lent enantioselectivity.
[14]
is, the reactions of tert-butyl-4-oxo-2-butenoate,
3-(p-nitro-
[7]
[14]
phenyl)prop-2-enal, and 2-bromocinnamaldehyde. All three
reactions were catalyzed by the same diarylprolinol organoca-
talyst 1. The cross-aldol reaction of a,b-unsaturated aldehyde
is very useful but rare, and its generality has not been broadly
investigated. In this paper, we describe the optimization of the
cross-aldol reaction of a,b-unsaturated aldehyde with its gen-
erality.
Aldol reaction is one of the most important carbon-carbon
[
1]
bond-forming reactions. Since the seminal paper of proline-
mediated asymmetric direct aldol reaction between aldehyde
We chose the reaction of 4-oxopent-2-enal (2a) and 3-phe-
nylpropanal (3a) as a model reaction and investigated the re-
action conditions (Table 1). As the generated b-hydroxyalde-
hyde was partially decomposed and epimerized during purifi-
cation by silica gel column chromatography, it was treated
with Wittig reagent (Ph P=CHCO Et) in situ to give the corre-
[
2]
and ketone by List, Lerner and Barbas in 2000, the field of or-
ganocatalysis has developed rapidly, and many proline-based
organocatalysts have been developed for the asymmetric aldol
[3]
reaction of aldehyde and ketone with excellent results. As for
the cross-aldol reaction of two different aldehydes, although
MacMillan and co-workers reported such
3
2
sponding a,b-unsaturated ester 4a, which was isolated and
characterized. First, the reaction was carried out in the pres-
ence of catalyst 1 in THF, but the reaction was slow and could
only afford the product in 22% yield after 96 h (entry 1). Water
a reaction catalyzed by proline for the
[
4]
first time in 2002, to date it has not
[5]
[15]
been thoroughly investigated.
Our
is known to accelerate the aldol reaction and 10 equivalents
group is interested in the asymmetric
direct cross-aldol reaction promoted by
the use of organocatalyst, and has found
that the diarylprolinol-bearing 3,5-bis(tri-
fluoromethyl)phenyl as the aryl moiety
of water were added, which led to an increased yield of 56%
after 48 h (entry 2). To increase the reactivity, the additive was
[16]
examined in detail. Although NaOAc was not effective, acid
was found to accelerate the reaction. Among the acids exam-
ined, good yield was obtained when acetic acid was employed
as an additive to afford the product in 74% yield with high
anti-selectivity and excellent enantioselectivity (entry 4). It
shoud be noted that Michael products were not detected as a
by-product under the present reaction conditions, although
Michael reaction is a possible reaction because a,b-unsaturated
aldehyde is a suitable Michael acceptor.
Figure 1. Diarylproli-
nol catalyst.
[
6]
1
is an excellent aldol catalyst
(
Figure 1). It can catalyze the aldol reac-
[7]
tion of acetaldehyde as a nucleophile,
[8]
and also catalyze the aldol reaction of ethyl glyoxylate, chlo-
[
9]
[10]
[11]
ral, chloroacetaldehyde, dichloroacetaldehdye, and alkyn-
[
12]
[13]
yl aldehyde as electrophilic aldehydes.
On the other hand, allyl alcohol is an important building
block in organic synthesis, and one of the synthetic methods
Then, solvent optimization was conducted, which revealed
that THF was more suitable (entry 4). Next, the loading of the
catalyst was investigated. Good results were obtained when
2
0 mol% of the catalyst was used (entry 9). It should be noted
that the reaction also proceeds well in the presence of
0 mol% of the catalyst to afford the product without decreas-
[
a] Prof. Dr. Y. Hayashi (
), K. Nagai (
), Dr. S. Umemiya
(
)
Department of Chemistry
Graduate School of Science
Tohoku University
1
ing the enantioselectivity, although the reaction time was
longer (entry 10). As for the molar ratio of the starting materi-
als, good results were obtained in both cases when the nucle-
ophilic aldehyde 3a was used as two equivalents toward the
electrophilic aldehyde 2a and the opposite combination such
as the electrophilic aldehyde 2a was employed as two equiva-
lents toward the nucleophilic aldehyde 3a (entries 11, 12).
As the best reaction conditions were obtained, the generali-
ty of the reaction was investigated (Table 2). As for the nucleo-
6
-3 Aramaki-Aza Aoba, Aoba-ku, Sendai 980-8578 (Japan)
E-mail: yujiro.hayashi.b7@tohoku.ac.jp
Homepage: http://www.ykbsc.chem.tohoku.ac.jp
Supporting information and the ORCID identification number(s) for the au-
thor(s) of this article can be found under:
https://doi.org/10.1002/asia.201901236.
th
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Communication
of these 4-substituted 4-oxopent-2-enal de-
rivatives afforded the aldol products also
with excellent enantioselectivity (entries 8,
[
a]
Table 1. The effect of additive and solvent in the asymmetric aldol reaction of 2a and 3a.
9). As the solubility of 2e is not good,
dilute THF condition was employed
(
entry 9).
Although we have already reported sev-
eral cross-aldol reactions catalyzed by diary-
lprolinol 1, this is the first aldol reaction in
which acid is an effective additive. In fact,
when we carefully investigated the aldol re-
action of alkynyl aldehyde such as 3-trie-
thylsilylpropinal (5), the acceleration was
not observed in the presence of acid. Given
the special effect of acid in the present re-
action, we further investigated its effect.
It is known that aldehyde and catalyst 1
[
c]
Entry
Solvent
Acid
t
Yield
[%]
anti:syn
Ee
[%]
[
b]
[d]
[h]
[
[
e,f]
e]
1
2
3
4
5
6
7
8
9
1
THF
THF
THF
THF
THF
dioxane
2
Et O
DMF
THF
THF
THF
THF
none
none
96
48
28
30
30
30
25
30
41
137
35
30
22
56
64
74
64
64
59
64
72
62
70
80
1.2:1
2.6:1
10:1
9.1:1
6.7:1
7.7:1
5.3:1
4.8:1
11:1
76
86
97
98
96
96
98
97
97
98
98
98
CCl
CH
PhCO
3
CO
2
H
3
CO
2
H
2
H
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CO
CO
CO
CO
CO
CO
CO
2
2
2
2
2
2
2
H
H
H
H
H
H
H
react
to
generate
N,O-acetal
6
[
g]
[17]
(
Scheme 1). The acid might be involved
[
h]
0
9.1:1
9.1:1
12:1
[i]
in the generation speed of N,O-acetal 6. Al-
kenyl aldehydes 2a and 2d, alkynyl alde-
hyde 5, and alkyl aldehyde 3a were treated
with catalyst 1 in the presence of acetic
acid and water. In all cases, the correspond-
ing N,O-acetals 6 were generated instantly.
Thus, there is no observable difference in
the generation of N,O-acetals 6 between
the various aldehydes (see SI).
1
1
[j]
12
[
2
(
a] Unless otherwise shown, reactions were performed by employing a,b-unsaturated aldehyde
a (0.3 mmol), 3-phenylpropanal (3a) (0.9 mmol), organocatalyst 1 (0.09 mmol) and additive
0.09 mmol), water (3 mmol) in solvent (0.3 mL) at 08C for the indicated time. The aldol product
was treated with Ph P=CHCO Et. [b] Isolated yield of the ester 4a. [c] Dr is determined by
H NMR analysis. [d] Enantiomeric excess (ee) of ester 4a was as determined by HPLC analysis
over a chiral solid phase. [e] The reaction was performed at room temperature. [f] Water was not
used. [g] Catalyst 1 (20 mol%) was used. [h] Catalyst 1 (10 mol%) was used. [i] 2a (0.3 mmol) and
3
2
1
3
a (0.6 mmol, 2 equivalents) were used. [j] 2a (0.6 mmol, 2 equivalents) and 3a (0.3 mmol) were
used.
Another possibility would be that the
acid might be accelerating the exchange of
N,O-acetals in 6. To check this, N,O-acetal of
alkenyl aldehyde 6d was treated with alkynyl aldehyde 5 in
the presence of acetic acid and water. As both aldehydes do
not possess an a-proton, aldol reaction cannot proceed. When
philic aldehyde, not only 3-phenylpropanal but also propanal,
and isovaleraldehyde, and functionalized aldehyde such as b-
alkoxyaldehyde, and aldehyde with cis-alkene moiety can be
successfully employed in the reaction to afford the products
with good anti-selectivity and excellent enantioselectivity (en-
tries 1–5). As for the a,b-unsaturated aldehyde, the reaction of
3-chloro-4-oxo-2-pent-2-enal is fast owing to the electron-with-
drawing group of chloride (entry 6). a-Methyl substituent does
not disturb the reaction to provide the product with excellent
enantioselectivity (entry 7). Not only methyl substituent, but
also phenyl and furyl substituents are suitable and the reaction
Scheme 1.
Figure 2. The effect of acid and water in the exchange reaction of 6d and 7. To a mixture of (E)-4-oxo-4-phenylbut-2-enal (2d) (0.4 mmol, 63.6 mg) and 1,3,5-
trimethoxybenzene (0.1 mmol, 16.8 mg) as internal standard in THF (400 mL) was added catalyst 1 (0.4 mmol, 208 mg) at 238C. H O (4.0 mmol, 72 mL) and
acetic acid (0.4 mmol, 24 mL) were added to the reaction mixture. After stirring the reaction mixture for 2 h at 238C, it was confirmed by NMR that N,O-acetal
2
1
6
d was formed. Then, alkynyl aldehyde 5 was added to the reaction mixture. The reaction was monitored by H NMR spectroscopy. The ratio of each product
1
was calculated by integration of selected peaks in the H NMR spectra and plotted on the graph.
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Communication
aldehyde 2d and catalyst 1 were mixed,
N,O-acetal 6d was formed instantly. Then, al-
kynyl aldehyde 5 was added with or without
water and/or CH CO H (Scheme 2). Ex-
[
a]
Table 2. The generality of the cross-aldol reaction of a,b-unsaturated aldehydes.
3
2
change speeds of N,O-acetals 6d and 5
were similar in all cases in the presence of
water and CH CO H (Figure 2). Thus, the ex-
3
2
change of N,O-acetal 6 is sufficiently fast
even without acid.
Next, we investigated the reaction of 3-
[c]
Entry
1
Aldehyde 2
Aldehyde 3
t
Yield
[%]
anti:syn
9.0:1
Ee
[%]
(
2,5-dichlorophenyl)propenal 2 f (Scheme 3).
[
b]
[d]
[h]
In this case, the effect of acid was not ob-
served. An additional carbonyl group is nec-
essary for the acceleration effect induced by
acid. Thus, we propose that acid protonates
the basic carbonyl moiety, to lower the
LUMO level of a,b-unsaturated aldehyde 2,
which accelerates the re-
55
70
97
98
97
89
97
98
[
e]
2
3
4
5
6
20
15
123
75
14
70
82
61
54
78
8.2:1
action.
The
reaction
is
4.0:1
thought to proceed as
follows: The enamine,
which is generated from
the aldehyde, as shown
in Figure 3, in which the
alkenyl aldehyde is acti-
vated by the hydroxy
group and acetic acid
[
[
e]
e]
6.2:1
6.3:1
Figure 3. The pro-
posed transition
state between en-
amine and alkenyl
aldehyde.
through
bond.
a
hydrogen
>20:1
In summary, we have
developed the asymmet-
ric direct cross-aldol re-
[e,f]
7
14
46
20:1
98
action of a,b-unsaturated aldehyde cata-
lyzed by diarylprolinol 1. Synthetically useful
g,d-unsaturated b-hydroxy aldehydes were
obtained with high anti-selectivity and ex-
cellent enantioselectivity. When there is a
carbonyl group at the g-position of the a,b-
unsaturated aldehyde, acid accelerates the
reaction by the protonation of the carbonyl
moiety, leading to a lowering of the LUMO
level of the electrophilic aldehyde. As the
obtained aldol products possess several
functional groups, they would be useful
chiral synthetic intermediates.
[
g,h]
8
9
32
80
62
63
4.8:1
5.8:1
92
94
[g,h,i]
[
(
a] Unless otherwise shown, reactions were performed by employing a,b-unsaturated aldehyde
0.3 mmol), nucleophilic aldehyde (0.6 mmol), organocatalyst 1 (0.06 mmol), water (3 mmol) and
CH
3 2
CO H (0.06 mmol) in THF (0.3 mL) at 08C for the indicated time. The aldol product was treat-
1
ed with Ph
3
2
P=CHCO Et. [b] Isolated yield. [c] Dr is determined by H NMR analysis. [d] Enantio-
meric excess (ee) is determined by HPLC analysis over a chiral solid phase. See Supporting Infor-
mation for details. [e] Nucleophilic aldehyde (0.9 mmol, 3 equiv) was used. [f] Reaction was per-
formed at 238C. [g] The reaction was performed at 58C. [h] CH
i] THF (0.6 mL) was used.
3
CO
2
H (0.1 mmol) was used.
[
Scheme 2.
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Communication
ist, I. Ibrahem, B. Kaynak, A. Cꢁrdova, Angew. Chem.
Int. Ed. 2005, 44, 1343–1345; Angew. Chem. 2005,
1
17, 1367–1369; c) T. Kano, Y. Yamaguchi, Y.
Tanaka, K. Maruoka, Angew. Chem. Int. Ed. 2007, 46,
738–1740; Angew. Chem. 2007, 119, 1768–1770;
1
d) M. Markert, U. Scheffler, R. Mahrwald, J. Am.
Chem. Soc. 2009, 131, 16642–16643; e) T. Kano, H.
Sugimoto, K. Maruoka, J. Am. Chem. Soc. 2011, 133,
18130–18133; f) T. Kano, R. Sakamoto, K. Maruoka,
Org. Lett. 2014, 16, 944–947.
[
[
6] a) S. Meninno, A. Lattanzi, Chem. Commun. 2013,
4
9, 3821–3832; b) S. Meninno, C. Volpe, A. Lattanzi,
Scheme 3.
ChemCatChem 2019, 11, 3716–3729.
7] Y. Hayashi, T. Itoh, S. Aratake, H. Ishikawa, Angew.
Chem. Int. Ed. 2008, 47, 2082–2084; Angew. Chem.
2008, 120, 2112–2114.
Acknowledgements
[
8] T. Urushima, Y. Yasui, H. Ishikawa, Y. Hayashi, Org. Lett. 2010, 12, 2966–
969.
9] Y. Hayashi, S. Watanabe, Y. Yasui, S. Umemiya, ChemCatChem 2015, 7,
646–1649.
2
This work was supported by JSPS KAKENHI Grant Number
JP18H04380 and JP19H05630.
[
1
[
10] Y. Hayashi, Y. Yasui, T. Kawamura, M. Kojima, H. Ishikawa, Angew. Chem.
Int. Ed. 2011, 50, 2804–2807; Angew. Chem. 2011, 123, 2856–2859.
Conflict of interest
[11] Y. Hayashi, D. Nakamura, Y. Yasui, K. Iwasaki, H. Chiba, Adv. Synth. Catal.
016, 358, 2345–2351.
2
[
12] Y. Hayashi, M. Kojima, Y. Yasui, Y. Kanda, T. Mukaiyama, H. Shomura, D.
Nakamura, I. Sato, ChemCatChem 2013, 5, 2887–2892.
The authors declare no conflict of interest.
[
13] a) Y. Hayashi, Y. Yasui, T. Kawamura, M. Kojima, H. Ishikawa, Synlett 2011,
4
85–488; b) Y. Hayashi, Y. Yasui, M. Kojima, T. Kawamura, H. Ishikawa,
Keywords: aldehydes
asymmetric synthesis · organocatalysis
· aldol reaction · allyl alcohol ·
Chem. Commun. 2012, 48, 4570–4572; c) Y. Hayashi, M. Kojima, Chem-
CatChem 2013, 5, 2883–2885; d) Y. Yasui, M. Benohoud, I. Sato, Y. Haya-
shi, Chem. Lett. 2014, 43, 556–558.
[
1] a) Modern Aldol Reactions, Vols. 1, 2 (Ed.: R. Mahrwald), Wiley-VCH, Wein-
heim, 2004; b) N. Masa, Y. Hayashi, Comprehensive Organic Synthesis
Second Edition, Vol. 2 (Eds.: P. Knochel, G. A. Molander), Elsevier, Oxford,
[
[
14] T. Kano, H. Maruyama, R. Sakamoto, K. Maruoka, Chem. Commun. 2015,
5
1, 10062–10065.
15] a) H. Torii, M. Nakadai, K. Ishihara, S. Saito, H. Yamamoto, Angew. Chem.
Int. Ed. 2004, 43, 1983–1986; Angew. Chem. 2004, 116, 2017–2020;
b) M. Gruttadauria, F. Giacalone, R. Noto, Adv. Synth. Catal. 2009, 351,
2014, pp. 237–339; c) Y. Yamashita, T. Yasukawa, W. J. Yoo, T. Kitanoso-
no, S. Kobayashi, Chem. Soc. Rev. 2018, 47, 4388–4480.
[2] B. List, R. A. Lerner, C. F. Barbas, III, J. Am. Chem. Soc. 2000, 122, 2395–
3
3–57.
16] H. Li, J. Wang, H. Xie, L. Zu, W. Jiang, E. N. Duesler, W. Wang, Org. Lett.
007, 9, 965–968.
17] M. B. Schmid, K. Zeitler, R. M. Gschwind, J. Am. Chem. Soc. 2011, 133,
065–7074.
2396.
[
[
[
3] Selected books on organocatalysis: a) Asymmetric Organocatalysis 1;
Lewis Base and Acid Catalysts (Ed.: B. List), Thieme, Stuttgart, 2012;
b) Asymmetric Organocatalysis 2; Brønsted Base and Acid Catalysts, and
Additional Topics (Ed.: K. Maruoka), Thieme, Stuttgart, 2012; c) Hand-
book of Reagents for Organic Synthesis Reagents for Organocatalysis (Ed.:
T. Rovis), Wiley, Chichester, 2016.
2
7
[
4] A. B. Northrup, D. W. C. MacMillan, J. Am. Chem. Soc. 2002, 124, 6798–
Manuscript received: September 3, 2019
6
799.
5] a) N. Mase, F. Tanaka, C. F. Barbas, III, Angew. Chem. Int. Ed. 2004, 43,
420–2423; Angew. Chem. 2004, 116, 2474–2477; b) J. Casas, M. Engqv-
Revised manuscript received: September 28, 2019
[
2
Version of record online: && &&, 0000
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Communication
COMMUNICATION
Yujiro Hayashi,* Kaito Nagai,
Shigenobu Umemiya
&& – &&
Diarylprolinol-Mediated Asymmetric
Direct Cross-Aldol Reaction of a,b-
Unsaturated Aldehyde as an
Electrophilic Aldehyde
Asymmetric cross-aldol reaction: The
asymmetric direct cross-aldol reaction of
alkenyl aldehydes catalyzed by a tri-
fluoromethyl-substituted diarylprolinol
provides a synthetically useful g,d-unsa-
turated b-hydroxy aldehydes with high
anti-selectivity and excellent enantiose-
lectivity.
Chem. Asian J. 2019, 00, 0 – 0
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