Design of organocatalysts for asymmetric direct syn-aldol reactions

Article abstract of DOI:10.1021/ol701798x

Two new organocatalysts 3a and 3b, derived from L-leucine and (S)-β-amino alcohols that were prepared from L-valine, were designed and afforded the direct syn-aldol reactions of a wide scope of aldehydes with various ketones with an excellent diastereomer

Full text of DOI:10.1021/ol701798x

ORGANIC
LETTERS
2
007
Vol. 9, No. 21
247-4249
Design of Organocatalysts for
Asymmetric Direct Syn-Aldol Reactions
4
Xiao-Ying Xu,†,‡ Yan-Zhao Wang, and Liu-Zhu Gong*,§
§
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu
610041, China, Graduate School of Chinese Academy of Sciences, Beijing, China, and
Hefei National Laboratory for Physical Sciences at the Microscale and Department of
Chemistry, UniVersity of Science and Technology of China, Hefei 230026, China
gonglz@ustc.edu.cn
Received July 26, 2007
ABSTRACT
Two new organocatalysts 3a and 3b, derived from L-leucine and (S)-â-amino alcohols that were prepared from L-valine, were designed and
afforded the direct syn-aldol reactions of a wide scope of aldehydes with various ketones with an excellent diastereomeric ratio of up to >20/1
and enantioselectivities of up to 99% ee.
Direct asymmetric aldol reactions, which provide straight-
anti-selective variants have been obtained with impressive
3,4
forward access to optically active â-hydroxy carbonyls, are
results. However, there have been a limited number of syn-
selective organocatalytic asymmetric direct aldol reactions
available for a spectrum of aromatic aldehdye acceptors and
1,2
highly useful in organic synthesis and thus have received
2
much research interest. As a result, great advances have been
5
made in asymmetric direct aldol reactions, in particular, in
those using organic molecules as catalysts.3 Of diastereo-
and enantioselective organocatalytic direct aldol reactions,
highly activated aldehydes. The design of new organocata-
,4
lysts with high enantio- and diastereoselectivities for a wide
scope of substrates to serve as donors and acceptors of syn-
direct aldol reactions therefore remains an important chal-
lenge. Herein, we will report a new type of organocatalyst
(Figure 1) for highly enantioselective syn-direct aldol reac-
tions.
†
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences.
Graduate School of Chinese Academy of Sciences.
University of Science and Technology of China.
‡
§
(
1) Kim, B. M.; Williams, S. F.; Masamune, S. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Heathcock, C. H., Eds.;
6
Our previous studies have shown that the direct aldol
Pergamon Press: Oxford, England, 1991; Vol. 2, p 229.
(
2) (a) Palomo, C.; Oiarbide, M.; Garc ´ı a, J. M. Chem. Soc. ReV. 2004,
3, 65. (b) Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH:
Weinheim, Germany, 2004; Vols. 1 and 2.
3) For pioneering work using proline as a catalyst, see (a) Hajos, Z. G.;
reaction using a butanone donor catalyzed by proline amides
3
(
(5) (a) Ramasastry, S. S. V.; Zhang, H.; Tanaka, F.; Barbas, C. F., III.
J. Am. Chem. Soc. 2007, 129, 288. (b) Luo, S.; Xu, H.; Li, J.; Zhang, L.;
Cheng, J.-P. J. Am. Chem. Soc. 2007, 129, 3074. (c) Kano, T.; Yamaguchi,
Y.; Tanaka, Y.; Maruoka, K. Angew. Chem., Int. Ed. 2007, 46, 1738. (d)
Diner, P.; Amedjkouh, M. Org. Biomol. Chem. 2006, 2091. (e) Utsumi,
N.; Imai, M.; Tanaka, F.; Ramasastry, S. S. V.; Barbas, C. F., III. Org.
Lett. 2007, 9, 3445. (f) Ramasastry, S. S. V.; Albertshofer, K.; Utsumi, N.;
Tanaka, F.; Barbas, C. F., III. Angew. Chem., Int. Ed. 2007, 46, 5572. (g)
Wu, X.; Jiang, Z.; Shen, H.-M.; Lu, Y. AdV. Synth. Catal. 2007, 349, 812.
(6) (a) 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. (b) 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. (c) Tang, Z.; Yang, Z.-H.; Chen,
X.-H.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. J. Am. Chem. Soc.
2005, 127, 9285.
Parrish, D. R. J. Org. Chem. 1974, 39, 1615. (b) Eder, U.; Sauer, R.;
Wiechert, R. Angew. Chem., Int. Ed. 1971, 10, 496. (c) List, B.; Lerner, R.
A.; Barbas, C. F., III J. Am. Chem. Soc. 2000, 122, 2395. (d) Sakthivel, K.;
Notz, W.; Bui, T.; Barbas, C. F., III. J. Am. Chem. Soc. 2001, 123, 5260.
(
e) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386. For reviews on
direct aldol reactions catalyzed by secondary amine-based organic molecules,
see (f) List, B. Acc. Chem. Res. 2004, 37, 548. (g) Notz, W.; Tanaka, F.;
Barbas, C. F., III. Acc. Chem. Res. 2004, 37, 580. (h) Saito, S.; Yamamoto,
H. Acc. Chem. Res. 2004, 37, 570. (i) List, B. Chem. Commun. 2006, 819.
(4) For primary amino acid-catalyzed asymmetric aldol reactions, see
(
a) Cørdova, A.; Zou, W.; Ibrahem, I.; Reyes, E.; Engqvist, M.; Liao, W.-
W. Chem. Commun. 2005, 3586. (b) Cørdova, A.; Zou, W.; Dziedzic, P.;
Ibrahem, I.; Reyes, E.; Xu, Y. Chem.sEur. J. 2006, 12, 5383. (c) Jiang,
Z.; Liang, Z.; Wu, X.; Lu, Y. Chem. Commun. 2006, 2801.
1
0.1021/ol701798x CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/04/2007

Table 1. Screening of Catalysts and Optimization of Reaction
Conditionsa
Figure 1. Organocatalysts in this study.
cat.
temp yield
(°C)
dr
ee
(%)b
(syn/anti)c (%)
d
entry (mol %)
solvent
1
2
3
4
5
6
7
8
9
10
2a (20)
2b (20)
2c (20)
3a (20)
3b (20)
3a (20) THF
3a (20) THF
3b (20) m-xylene
3b (20) m-xylene
3b (5)
CH2Cl2
CH2Cl2
CH Cl
CH2Cl2
CH2Cl2
25
25
25
25
25
25
0
25
0
25
89
77
91
95
99
95
82
92
96
92
4/1
4/1
4/1
5/1
7/1
19/1
19/1
12/1
19/1
19/1
67
61
71
86
89
96
98
94
96
96
1
provided anti-selective aldol adducts with an excellent
6c
diasetereomeric ratio (>99:1 dr). The high diastereoselec-
tivity can be explained by transition states, shown in TS-1a
and TS-1b (Scheme 1). TS-1a, which adopts a Z-enamine
2
2
e
f
g
h
Scheme 1. General Strategy for the Design of New
Organocatalysts for Syn-Aldol Reactions
m-xylene
a
The reaction mixture of p-nitrobenzadehyde (6a), hydroxyacetone (7a),
and catalytic amounts of catalyst was stirred for 12 h unless indicated
otherwise. b Isolated yield. c Determined by H NMR. The ee of the syn
1
d
e
f
diastereomer was determined by HPLC. Stirred for 36 h. Stirred for 96
g
h. Stirred for 24 h. h Stirred for 48 h.
ee for syn-5a, Table 1, entry 1). Under these conditions,
organic molecules 3a and 3b, which are derived from
L-leucine and (S)-â-amino alcohols that are prepared from
10
L-valine, afforded superior diastereo- and enantioselectivi-
11
ties to their structural analogues (entries 4 and 5). A survey
of solvents indicated that THF was a suitable solvent for
the aldol reaction catalyzed by 3a. In THF, 3a delivered 96%
ee and 19/1 dr for aldol adduct 5a (entry 6). The enantio-
selectivity could be further improved to 98% ee at 0 °C (entry
structure and principally generates syn-aldol adducts, is less
favorably formed than TS-1b, which adopts an E-enamine
structure and generates anti-aldol products, because of the
2
steric repulsion between R and the pyrrolidine ring in the
Z-enamine of TS-1a. To achieve a syn-aldol reaction, the
reaction should proceed via a transition state similar to type
TS-1a, and thus the Z-enamine should be predominately
formed.5 Antibodies and primary amine-based organic
molecules may catalyze the nucleophilic addition of an
7
3
). Interestingly, m-xylene is the solvent of choice for the
b-catalyzed reaction (entries 8-10). Notably, the presence
of 5 mol % 3b is sufficient to afford the reaction in high
yield (92%), with an excellent stereochemical outcome (19/1
dr, 96% ee, entry 10).
The optimal protocol was expanded to aldol reactions of
hydroxyacetone with a variety of aromatic and aliphatic
aldehydes (Table 2). The aldol reactions promoted by 5 mol
a
5
,7
acyclic ketone by forming a Z-enamine in some cases,
resulting in a diastereoselectivity distinct from that observed
5
with secondary amine catalysts. According to the model that
Barbas proposed for a primary amino acid-catalyzed syn-
%
3b afforded syn-diols in high yields (80-97%) with high
5
a
aldol reaction and the mode of carbonyl activation by
diastereomeric ratios (10/1->20/1 dr) and excellent enantio-
selectivities (91-98% ee). Generally, the electron-withdraw-
6
double hydrogen bonds, we think that the direct aldol
reactions involving acyclic ketone donors catalyzed by 2 and
3
probably proceed via transition state TS-2b to give syn-
(
8) (a) Huang, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7170.
2
aldol products 5 because the steric interaction between R
and R makes TS-2a, which generates an anti-aldol adduct,
less favorable than TS-2b.
We first examined a direct aldol reaction of hydroxy-
acetone with p-nitrobenzaldehyde catalyzed by 20 mol %
(
b) Lalonde, M. P.; Chen, Y.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006,
3
45, 6366. (c) Tsogoeva, S. B.; Wei, S. Chem. Commun. 2006, 1451. (d)
Cørdova, A.; Xu, Y. Chem. Commun. 2006, 460. (e) Davie, S. G.; Sheppard,
R. L.; Smith, A. D.; Thomson, J. E. Chem. Commun. 2005, 3802. (f) Tanaka,
F.; Thayumanavan, R.; Mase, N.; Barbas, C. F., III. Tetrahedron Lett. 2004,
4
5, 325.
(
(
9) Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc. 2001, 123, 11273.
10) Raj, M.; Vishnumaya; Ginotra, S. K.; Singh, V. K. Org. Lett. 2006,
2
2 2
a in CH Cl . To our delight, the reaction proceeded
smoothly at 25 °C to give syn-5a in high yield (89%) with
fairly good diastereo- and enantioselectivities (4/1 dr, 67%
8, 4097.
(11) For the reaction catalyzed by organic molecules structurally similar
to 2a-c and 3a-b, see Table S1 in Supporting Information.
(
12) For organocatalytic asymmetric anti-aldol reactions of fluoroacetone
(
7) (a) Barbas, C. F., III; Heine, A.; Zhong, G.; Hoffmann, T.;
with aldehydes, see (a) Zhong, G.; Fan, J.; Barbas, C. F., III. Tetrahedron
Lett. 2004, 45, 5681. (b) Xu, X.-Y.; Wang, Y.-Z.; Cun, L.-F.; Gong, L.-Z.
Tetrahedron: Asymmetry 2007, 18, 237. (c) Chen, X.-H.; Luo, S.-W.; Tang,
Z.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. Chem.sEur. J. 2007,
13, 689.
Gramatikova, S.; Bj o¨ rnestedt, R.; List, B.; Anderson, J.; Stura, E. A.; Wilson,
I. A.; Lerner, R. Science 1997, 278, 2085. (b) Hoffmann, T.; Zhong, G.;
List, B.; Shabat, D.; Anderson, J.; Gramatikova, S.; Lerner, R.; Barbas, C.
F., III. J. Am. Chem. Soc. 1998, 120, 2768.
4248
Org. Lett., Vol. 9, No. 21, 2007

Table 2. Asymmetric Syn-Aldol Reactions of Hydroxyacetone
with Aldehydesa
Table 3. Asymmetric Syn-Aldol Reactions of Acyclic Ketones
with Aldehydesa
time yield
(h)
dr
ee
(%)
time yield
(h)
dr
ee
(%)b (syn/anti)
c
d
entry
5
R
d
entry
5
R
7
(%)b (syn/anti)c (%)
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5h
5i
4-NO2C6H4
4-CNC6H4
4-MeO2CC6H4
3-NO2C6H4
3-BrC6H4
2-NO2C6H4
2-ClC6H4
2-FC6H4
12
36
36
24
48
24
48
36
36
48
48
48
60
48
60
60
92
86
95
97
95
92
91
90
91
90
82
97
86
80
68
45
19/1
19/1
13/1
16/1
13/1
>20/1
16/1
10/1
19/1
13/1
16/1
10/1
10/1
16/1
>20/1
>20/1
96
96
95
96
96
98
97
94
96
95
94
96
94
91
e
1
2
3
4
5
6
7
8
5q 4-NO2C6H4
5q 4-NO2C6H4
5r 2-NO2C6H4
5s 3-NO2C6H4
7b
48
7b 120
76
45
82
79
81
61
64
82
5/1
13/1
>15/1
6/1
2.5/1
2/1
94
99
98
93
89
93
88
80
f
e
e
g
g
7b
7b
7c
72
48
40
72
72
48
5t
4-NO2C6H4
5u 4-CO2MeC6H4 7c
5v 4-CNC6H4
5w 3-NO2C6H4
7c
7d
2/1
4/1
h
2-BrC6H4
10
11
12
13
14
15
16
5j
5k
5l
3,5-F2C6H3
3,5-Br2C6H3
3,5-(CF3)2C6H3
a
b
See Supporting Information for the exact reaction procedure. Isolated
yield. c Determined bye H NMR. d The ee of the syn diastereomer was
1
determined by HPLC. The reaction was performed in CH2Cl2 (0.5 mL).
f
g
Catalyzed by 5 mol % 3b in m-xylene (1 mL). The reaction was
performed in Et2O (0.5 mL) with chloroacetone (0.5 mL). h Reaction with
0 equiv of ketones under neat conditions.
5m 3-Cl-4-FC6H3
5n
5o
5p
1-BrC10H6
c-C6H11
i-Pr
2
e
98
98
e
a
b
See Supporting Information for the exact reaction procedure. Isolated
In summary, we have designed a type of organocatalyst,
yield. c Determined by H NMR. The ee of the syn diastereomer was
determined by HPLC. Catalyzed by 20 mol % 3b.
1
d
e
which was prepared from primary amino acids and â-amino
alcohols, for the catalytic syn-selective direct aldol reactions
of aldehydes with hydroxy-, fluoro-, and chloroacetones and
3-pentanone. We found that organic molecules 3a and 3b,
derived from L-leucine and (S)-â-amino alcohols that were
prepared from L-valine, offered superior diastereo- and
enantioselectivities. The presence of 5 mol % catalyst 3b
significantly catalyzes the direct aldol reactions of a wide
range of aromatic and aliphatic aldehydes with hydroxy-
acetone to give syn-diols with excellent dr (10/1->20/1) and
enantioselectivities ranging from 91 to 98% ee. The direct
aldol reactions of aldehydes with either fluoro- and chloro-
acetones or 3-pentanone proceeded in the presence of 20 mol
ing group on the aldehyde facilitates the reaction proceeding
to completion. Interestingly, the substituents of benzalde-
hydes, regardless of their size and electron nature, have little
effect on the enantioselectivity (entries 1-13). Importantly,
aliphatic aldehydes smoothly underwent reactions to give
syn-aldol adducts 5o and 5p with excellent diastereo- and
enantioselectivities (entries 15 and 16).
The aldol reactions of various ketones such as fluoro-
acetone, chloroacetone, and 3-pentanone were examined in
the presence of 20 mol % 3a (Table 3). Fluoroacetone
underwent the direct aldol reaction to afford predominantly
syn-R-fluoro-â-hydroxy ketones 5q-s, which so far have been
reached only by antibody catalysis, with diastereomeric
ratios ranging from 5/1 to >15/1 and excellent enantio-
selectivities (entries 1-4). In contrast, the secondary amine-
based organocatalysts provided predominantly anti diaster-
eomers.12 The aldol reactions involving chloroacetone also
%
3a to afford predominantly syn products with high
enantioselectivities.
7
Acknowledgment. We are grateful for financial support
from NSFC (20472082 and 20325211) and the Chinese
Academy of Sciences.
13
favorably generated syn-aldol adducts with enantioselec-
tivities of up to 93% ee (entries 5-7). Notably, 3-pentanone,
a much less reactive donor, smoothly underwent the aldol
reaction to afford the syn product with 4/1 dr and 80% ee
Supporting Information Available: Experimental pro-
cedures, spectra data, characterization data, and copies of
(
entry 8).
1
13
H and C NMR spectra. This material is available free of
(
13) For organocatalytic asymmetric anti-aldol reactions of chloroacetone
charge via the Internet at http://pubs.acs.org.
with aldehydes, see He, L.; Tang, Z.; Cun, L.-F.; Mi, A.-Q.; Jiang Y.-Z.;
Gong, L.-Z. Tetrahedron 2006, 62, 346.
OL701798X
Org. Lett., Vol. 9, No. 21, 2007
4249