Asymmetric bisprolinamide-catalyzed cross-aldol reaction of aldehydes

Article abstract of DOI:10.1055/s-2007-992412

A C₂-symmetric para-orientation bisprolinamide catalyst has been designed to effectively promote the enantioselective coupling reactions of aldehydes, which delivered the systematic investigation on amine-amide catalysis. Transforming the monop

Full text of DOI:10.1055/s-2007-992412

LETTER
73
Asymmetric Bisprolinamide-Catalyzed Cross-Aldol Reaction of Aldehydes
A
symmetric Bispr
a
olinamide-C
n
atalyzedCross-A
l
X
dol Reactionof
A
l
i
dehyde
o
s
ng,a Fei Wang,a Shunxi Dong,a Xiaohua Liu,a Xiaoming Feng*a,b
a
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064,
P. R. of China
State Key Laboratory of Oral Diseases, Sichuan University, Chengdu 610041, P. R. of China
Fax +86(28)85418249; E-mail: xmfeng@scu.edu.cn
b
Received 26 September 2007
compounds.2 Several efficient asymmetric methodologies
for this reaction using proline and its derivative organo-
catalysts have been developed, in which the secondary
amine of pyrrolidine has been confirmed to efficiently
Abstract: A C2-symmetric para-orientation bisprolinamide cata-
lyst has been designed to effectively promote the enantioselective
coupling reactions of aldehydes, which delivered the systematic in-
vestigation on amine–amide catalysis. Transforming the monopro-
linamide 1a into the bisprolinamide 2a improved not only the provide the active enamine intermediate.3 According to
the Houk–List model,4 hydrogen bonding undoubtedly
stereoselectivities but also the reactivities. With this strategy, the
functionalized b-hydroxyaldehydes could be furnished in high
plays the crucial role in stabilizing the transition state. In
yields (up to 99%) with good selectivities (up to 8:92 syn/anti and
cross-aldol reaction of aldehydes, although hydrogen
99% ee) even in the presence of 5 mol% of catalyst 2a. Based on the
bond between carbonyl oxygen of aldehydes and carbox-
preliminary experiment and the absolute configuration of cross-al-
yl, protonated amine or sulfonyl amide has been intro-
duced successfully, investigation on the amide has not yet
been specialized systematically. In addition, it is appar-
ently troublesome to control the occurrence of unexpected
aldol condensation in coupling reaction of aldehydes.
Herein, we report amine–amide-catalyzed cross-aldol re-
action of aldehydes, with secondary amine activating the
donor via enamine and hydrogen of amide activating the
acceptor via hydrogen bond.
dol adduct, a rational transition state A was proposed to explain the
origin of reactivity and selectivity.
Key words: asymmetric catalysis, bisprolinamide, cross-aldol re-
actions, hydroxyaldehydes, nonlinear effect
Asymmetric organocatalysis has recently provided a new
research approach to explore the fundamental chemical
characterizations such as reactivity, selectivity, and mech-
anism, which has also led to the discovery of many valu-
able reactions and catalysts.1 In this endeavor, the design
and development of multifunctional chiral organocata-
lysts are of great importance: One catalyst molecule pos-
sesses two or more reaction-promoting functionalities, so
that reactivity and selectivity can be tuned by a simple
structural modification of the catalyst.
Based on the skeleton of L-proline, the monoprolinamide
catalysts 1a–e (Figure 1) were synthesized.5 With a phe-
nyl substituent on nitrogen atom of amide 1a, the solvent
effects were initially investigated.
Although good enantioselectivities (90% ee) could be ob-
tained in different media such as CH2Cl2, ClCH2CH2Cl,
DMSO and N-methyl-2-pyrrolidinone (NMP), the diaste-
reoselectivities were generally better when the reaction
was conducted in DMSO (75:25) or NMP (70:30). With
DMSO, the unsubstituted 1b and t-Bu-substituted 1c pro-
vided inferior selectivities (Table 1, entries 2 and 3). On
The cross-aldol reaction of aldehydes ranks among the
most important carbon–carbon bond-forming reactions in
organic synthesis and provides b-hydroxyaldehydes,
which could be transferred to some biologically active
Y
Y
Y
2a:
2b:
1a: X =
H
N
H
HN
O
X
HN
O
N
Y
Y =
H
1b: X =
1c: X =
Y
Y
Y
2c:
2d:
OMe
1d: X =
1e: X =
Br
Y
Figure 1 The studied catalysts.
SYNLETT 2008, No. 1, pp 0073–0076
x
x.
x
x.
2
0
0
7
Advanced online publication: 11.12.2007
DOI: 10.1055/s-2007-992412; Art ID: W18207ST
© Georg Thieme Verlag Stuttgart · New York

74
Y. Xiong et al.
LETTER
Table 1 Optimization Studies
OH
O
O
catalyst (20 mol%)
DMSO, 0 °C, 15 h
+
n-Bu
CHO
n-Bu
O2N
O2N
3a
Entry
Catalyst
1a
Yield (%)a
dr (syn/anti)b
25:75
35:65
46:54
20:80
18:82
12:88
35:65
22:78
34:66
13:87
8:92
ee (%) (anti)c
1
2
56
91
73
96
99
84
69
81
99
56
99
90
87
65
97
98
98
53
91
84
98
99
1b
3
1c
4
1d
5
1e
6
2a
7
2b
8
2c
9
2d
10d
11d,e
2a
2a
a Isolated yields.
b Determined by 1H NMR.
c Determined by HPLC analysis.
d Catalyst loading: 5 mol%.
e Reaction conditions: NMP as solvent, 30 h.
the other hand, p-methoxyphenyl (1d) and p-bromophen- bonyl phenylacryloyl-functionalized aldehydes were all
yl (1e) substituents gave better results (dr ≥ 80:20 and ee obtained in good yield and enantioselectivities.
≥ 97%), which signaled that a para substituent could fur-
Comparing C2-symmetric bisprolinamide 2a with mono-
prolinamide 1a revealed that the former provided the aldol
adduct with higher yield and selectivity (Table 1, entry 6
vs. 1), which indicated that the two prolinamide units
ther improve the stereoselectivities. Accordingly another
catalytic active site was introduced to the para orienta-
tion. C2-Symmetrical bisprolinamide 2a6 delivered the ef-
ficient formation of cross-aldol product in 15 hours (84%
might act cooperatively. The relation between the enanti-
yield, 88:12 anti/syn and 98% ee) (Table 1, entry 6).
omeric excess of product 3a and the enantiopurity of cat-
Adjusting the relative position of two prolinamide units alyst 2a was examined to be directly proportional, which
demonstrated that the ortho and meta substituted (2b and indicated that asymmetric catalysis with partially resolved
2c) or another phenyl ring inserted (2d) did not give better chiral catalysts were not amplified and depleted
results (Table 1, entries 7–9). In NMP, using the best cat- (Figure 2).8 Furthermore, the catalyst loading in an inves-
alyst 2a, improved selectivities could be found (92:8 anti/ tigated range of 2.5–20 mol% had no influence on the ste-
syn and 99% ee) (Table 1, entry 11).
reoselectivity.
Under the optimal conditions, asymmetric inductivities of Based on the preliminary experiment and the absolute
the bisprolinamide 2a were investigated on other selected configuration of 3a, we proposed a transition state A,
aldehydes, with the results summarized in Table 2. Good which also represents the lowest energy conformation
enantioselectivities were attained for linear and branched (Figure 3). In transition state A, the Re face of the carbo-
aliphatic aldehydes. The absolute configuration of the nyl of 4-nitrobenzaldehyde is much more accessible to the
anti-aldol adduct 3a was determined to be 2S,3R by com- Re face of enamine to provide the product with absolute
parison of the sign of the optical rotation value with that configuration of 2S,3R. The interaction of two Si faces
in the literature.3m The aldol adduct 3c was obtained in will strongly increase the repulsion between phenyl sub-
99% yield with 95% ee, which could be transformed into units as seen in transition state B. The repulsion between
biologically active trichostatin A.2e Selecting hexanal as pyrrolidine and the carbon chain of donor would also be
the donor, prochiral benzoyl-, naphthalene-2- and 3-car- unfavorable to the formation of (2R,3S)-product. syn-
Conjugate addition would increase the repulsion either
Synlett 2008, No. 1, 73–76 © Thieme Stuttgart · New York

LETTER
Asymmetric Bisprolinamide-Catalyzed Cross-Aldol Reaction of Aldehydes
75
Table 2 Investigation on Other Selected Aldehydes7
O
OH
O
2a (x mol%)
+
R
O
R
NMP, 0 °C
R'
R'
3a–h
Products
x
Time Yield dr
(h)
ee (%)
(%)a (syn/anti)b (anti)c
O
OH
99
(2R,3S)
5
30
99
99
99
87
51
8:92
10:90
25:75
15:85
–
n-Bu
NO2
NO2
NO2
NO2
NO2
Figure 2 The relation between product 3a and catalyst 2a in enan-
tioselectivity.
3a
O
OH
10
20
20
20
15
30
80
80
99
O
OH
(S)
O
n-Pr
N
H
anti
anti
syn
O
N
H
Ar (R)
3b
O
n-Bu
Ar
OH
OH
OH
OH
n-Bu
A
95
97
77
O
O
OH
O
N
(R)
O
O
(S)
Ar
N
H
n-Bu
3c
O
n-Bu
Ar
H
B
OH
O
-Bu
O
N
(S)
N
H
(S)
Ar
Ar
3d
O
Ar
H
n
n-Bu
C
O
OH
N
O
(R)
syn
N
H
(R)
n-Bu
3e
O
n-Bu
H
Ar
D
Ph
10
10
20
20
88
93
15:85
22:78
99
96
Figure 3 Proposed transition state A → D (another prolinamide unit
was omitted). Ar = 4-nitrophenyl.
n-Bu
O
O
O
3f
organocatalytic strategy to some important carbon–car-
bon bond formations. The rational introduction of two cat-
alytic active sites improves not only the stereoselectivities
but also the reactivities. Further work is underway to de-
velop, understand and apply this new method of enantio-
selective coupling reaction of aldehydes.
O
OH
n-Bu
3g
O
OH
10
20
95
19:81
92
Acknowledgment
n-Bu
We thank the National Natural Science Foundation of China (Nos.
20732003 and 20602025) and the Sichuan University for financial
support. We also thank the Sichuan University Analytical & Testing
Center for NMR analysis.
3h
a Isolated yields.
b Determined by 1H NMR.
c Determined by HPLC analysis.
References and Notes
between phenyl subunits or between the pyrrolidine ring
(1) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed. 2004, 43,
5138.
(2) (a) Reyes, E.; Córdova, A. Tetrahedron Lett. 2005, 46,
6605. (b) Córdova, A.; Engqvist, M.; Ibrahem, I.; Casas, J.;
Sundén, H. Chem. Commun. 2005, 2047. (c) Córdova, A.;
and the carbon chain of donor as in C or D, respectively.
In summary, enantioselective secondary amine–amide-
catalyzed cross-aldol reaction of aldehydes has been de-
veloped, which could provide a practical, enantioselective
Synlett 2008, No. 1, 73–76 © Thieme Stuttgart · New York

76
Y. Xiong et al.
LETTER
Ibrahem, I.; Casas, J.; Sundén, H.; Engqvist, M.; Reyes, E.
Chem. Eur. J. 2005, 11, 4772. (d) Casas, J.; Engqvist, M.;
Ibrahem, I.; Kaynak, B.; Córdova, A. Angew. Chem. Int. Ed.
2005, 44, 1343. (e) Zhang, S. L.; Duan, W. H.; Wang, W.
Adv. Synth. Catal. 2006, 348, 1228.
(162.2 mg, 1.5 mmol) was added. The mixture was allowed
to be stirred for 10 h and filtered. The filtrate was washed
with 1 M KHSO4, sat. NaHCO3 and brine and was then dried
over anhyd Na2SO4 and concentrated.
(ii) To the residue in CH2Cl2, TFA (3.15 mL) was added and
stirring was continued for an hour. Then the solution was
concentrated in vacuo to a glutinous phase and H2O (4 mL)
was added. The pH of the mixture was brought into the
range of 8–10 by the addition of 2 M NaOH. The aqueous
phase was extracted with EtOAc. The EtOAc extracts were
pooled, washed with brine, dried over anhyd Na2SO4 and
evaporated in vacuo. The residue was purified by flash
column chromatography using MeOH–EtOAc (1:2) as
eluent to afford the bisprolinamide 2a as a white solid (390.1
mg, 86% yield). 1H NMR (400 MHz, CDCl3): d = 9.71 (s, 2
H), 7.56 (s, 4 H), 3.86 (dd, J1 = 9.2 Hz, J2 = 5.2 Hz, 2 H),
3.06–3.12 (m, 2 H), 2.96–3.02 (m, 2 H), 2.38 (s, 2 H), 2.17–
2.26 (m, 2 H), 2.00–2.08 (m, 2 H), 1.80–1.82 (m, 4 H).
(7) Typical Procedure for the Catalytic Asymmetric Cross-
Aldol Reaction of Aldehydes:
(3) (a) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc.
2002, 124, 6798. (b) Cauble, D. F. J.; Krische, M. J.
Chemtracts 2002, 15, 380. (c) Mase, N.; Tanaka, F.; Barbas,
C. F. III Org. Lett. 2003, 5, 4369. (d) Mase, N.; Tanaka, F.;
Barbas, C. F. III Angew. Chem. Int. Ed. 2004, 43, 2420.
(e) Storer, R. I.; MacMillan, D. W. C. Tetrahedron 2004, 60,
7705. (f) Córdova, A. Tetrahedron Lett. 2004, 45, 3949.
(g) Northrup, A. B.; Mangion, I. K.; Hettche, F.; MacMillan,
D. W. C. Angew. Chem. Int. Ed. 2004, 43, 2152.
(h) Mangion, I. K.; Northrup, A. B.; MacMillan, D. W. C.
Angew. Chem. Int. Ed. 2004, 43, 6722. (i) Thayumanavan,
R.; Tanaka, F.; Barbas, C. F. III Org. Lett. 2004, 6, 3541.
(j) Wang, W.; Li, H.; Wang, J. Tetrahedron Lett. 2005, 46,
5077. (k) Zhang, F.; Su, N.; Gong, Y. Synlett 2006, 1703.
(l) Hayashi, Y.; Aratake, S.; Okano, T.; Takahashi, J.;
Sumiya, T.; Shoji, M. Angew. Chem. Int. Ed. 2006, 45,
5527. (m) Kano, T.; Yamaguchi, Y.; Tanaka, Y.; Maruoka,
K. Angew. Chem. Int. Ed. 2007, 46, 1738. For review
articles, see: (n) Modern Aldol Reaction, Vol. 1; Mahrwald,
R., Ed.; Wiley-VCH: Weinheim, 2004. (o) Modern Aldol
Reaction, Vol. 2; Mahrwald, R., Ed.; Wiley-VCH:
To the mixture of bisprolinamide 2a (1.5 mg, 0.005 mmol)
and 4-nitrobenzaldehyde (15.1 mg, 0.1 mmol) in NMP (0.2
mL) was added hexanal (24.5 mL, 0.2 mmol) at 0 °C. The
mixture was stirred for 30 h and purified by flash column
chromatography using EtOAc–PE (1:2) as eluent to afford
(2S)-2-[(1R)-hydroxy(4-nitrophenyl)methyl]hexanal (3a;
24.8 mg, 99% yield, 8:92 syn/anti, 99% ee).
Weinheim, 2004. (p) Guillena, G.; Nájera, C.; Ramón, D. J.
Tetrahedron: Asymmetry 2007, 18, 2249.
Typical Procedure for Determining the Enantiomeric
Excess of 3a–e (Table 2):
(4) (a) Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc. 2001,
123, 12911. (b) Hoang, L.; Bahmanyar, S.; Houk, K. N.;
List, B. J. Am. Chem. Soc. 2003, 125, 16. (c) Bahmanyar,
S.; Houk, K. N.; Martin, H. J.; List, B. J. Am. Chem. Soc.
2003, 125, 2475. For the vital role of the amide hydrogen
bond, also see: (d) Tang, Z.; Jiang, F.; Yu, L. T.; Cui, X.;
Gong, L.-Z.; Mi, A.-Q.; Jiang, Y. Z.; Wu, Y. D. J. Am.
Chem. Soc. 2003, 125, 5262. (e) Tang, Z.; Jiang, F.; Cui, X.;
Gong, L. Z.; Mi, A. Q.; Jiang, Y. Z.; Wu, Y. D. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5755.
(5) Monoprolinamides 1a,c–e were prepared according to our
previous work: (a) Xiong, Y.; Huang, X.; Gou, S. H.;
Huang, J. L.; Wen, Y. H.; Feng, X. M. Adv. Synth. Catal.
2006, 348, 538. (b) Liu, Y. L.; Liu, X. H.; Xin, J. G.; Feng,
X. M. Synlett 2006, 1085. (c) Xiong, Y.; Wen, Y. H.; Wang,
F.; Gao, B.; Liu, X. H.; Huang, X.; Feng, X. M. Adv. Synth.
Catal. 2007, 349, 2156. (d) Wang, F.; Xiong, Y.; Liu, X. H.;
Feng, X. M. Adv. Synth. Catal. 2007, 349, 2665.
To a solution of (2S)-2-[(1R)-hydroxy(4-nitrophenyl)meth-
yl]hexanal (3a; 24.8 mg) in CH2Cl2 (1 mL) were added 2,2-
dimethyl-1,3-propanediol (10.4 mg, 0.10 mmol), triethyl
orthoformate (13.3 mL, 0.08 mmol) and p-toluenesulfonic
acid (catalytic amount) in this sequence at r.t. After 2 h of
stirring, the reaction was quenched with H2O and extracted
with EtOAc. The combined organic layers were washed with
brine, dried over Na2SO4 and concentrated. The residue was
purified by flash column chromatography on silica gel (PE–
EtOAc, 15:1) to afford (1R,2S)-2-(5,5-dimethyl-1,3-dioxan-
2-yl)-1-(4-nitrophenyl)hexan-1-ol quantitatively as a
colorless oil; [a]D25 +9.5 (c = 0.50, CHCl3). 1H NMR (400
MHz, CDCl3): d = 8.22 (d, J = 8.8 Hz, 2 H), 7.54 (d, J = 8.8
Hz, 2 H), 5.00 (dd, J1 = 6.0 Hz, J2 = 4.8 Hz, 1 H), 4.47–4.48
(m, 2 H), 3.64–3.71 (m, 2 H), 3.37–3.41 (m, 2 H), 1.97–1.99
(m, 1 H), 1.23–1.26 (m, 9 H), 0.84–0.86 (m, 3 H), 0.75 (m,
3 H). HPLC (Chiralcel OJ-H, hexane–i-PrOH, 96:4; flow
rate: 0.5 mL/min, 23 °C, UV: l = 215 nm): tR(minor) =
20.665 min, tR(major) = 22.750 min.
(6) Typical Procedure for the Preparation of
Bisprolinamides 2a–d:
(i) To a solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-
2-carboxylic acid (678.0 mg, 3.15 mmol) in CH2Cl2, dicyclo-
hexylcarbodiimide (DCC; 649.9 mg, 3.15 mmol) and
benzotriazol-1-ol (HOBt; 425.6 mg, 3.15 mmol) were added
at r.t. under stirring. After 10 min, benzene-1,4-diamine
(8) (a) Avalos, M.; Babiano, R.; Cintas, P.; Jiménez, J. L.;
Palacios, J. C. Tetrahedron: Asymmetry 1997, 8, 2997.
(b) Girard, C.; Kagan, H. B. Angew. Chem. Int. Ed. 1998, 37,
2922.
Synlett 2008, No. 1, 73–76 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.