A simple primary-tertiary diamine-Bronsted acid catalyst for asymmetric direct aldol reactions of linear aliphatic ketones

Article abstract of DOI:10.1021/ja069372j

Compared with the well-explored enamine catalysis with secondary amines, the development of efficient enamine-based primary amine catalysts has remained as an elusive goal until recently. We present herein that a simple chiral primary-tertiary diamine 1d

Full text of DOI:10.1021/ja069372j

Published on Web 02/27/2007
A Simple Primary-Tertiary Diamine-Brønsted Acid Catalyst for Asymmetric
Direct Aldol Reactions of Linear Aliphatic Ketones
Sanzhong Luo,*,† Hui Xu,† Jiuyuan Li,† Long Zhang,‡ and Jin-Pei Cheng*,†,‡
Beijing National Laboratory for Molecular Sciences (BNLMS), Center for Chemical Biology, Institute of Chemistry
and Graduate School, Chinese Academy of Sciences, Beijing 100080, China, and Department of Chemistry and
State Key Laboratory of Elemento-organic Chemistry, Nankai UniVersity, Tianjin 300071, China
Received December 31, 2006; E-mail: luosz@iccas.ac.cn; chengjp@mail.most.gov.cn
Inspired by the exquisite stereocontrol in the enzymatic enamine
processes, chemists have long been pursuing a simple chemical
mimic for asymmetric enamine catalysis, and this aim has now been
partially fulfilled with the renaissance of organocatalysis.1 Since
the pioneering work of List, Barbas, and co-workers in 2000,2 there
has been dramatic advance in developing enamine-based asym-
metric organocatalysts.1 However, unlike the natural enzymes such
Figure 1. Proposed transition state for the reaction of acyclic ketone (A)
as type I aldolases and decarboxylases that normally employ
primary amine of a lysine moiety to form the enamine intermediate,3
most of the presently successful enamine organocatalysts utilize
secondary amines instead (e.g., chiral pyrrolidine derivatives).4 For
example, in the enamine-based organocatalysis of asymmetric direct
aldol reactions,1,5 a large portion of the previous research efforts
has been devoted to the modifications of chiral pyrrolidines, and
many synthetically important ketone donors, such as linear aliphatic
ketones, still remain as difficult substrates.5 It is therefore of great
demand to develop primary amine catalysts to expand the utility
of the enamine-based organocatalysis. In this context, exploration
of efficient and stereoselective primary amine catalysts has become
a much-attempted research endeavor,6 but unfortunately, it has
turned out to be an elusive goal despite of the success of the current
organocatalysts.4 Recently, Jacobsen and Tsogoeva independently
reported primary amine-thiourea conjugates as enantioselective
organocatalysts for Michael addition to nitroolefins.7 Simple primary
amino acids were found to act as stereoselective catalysts for direct
aldol reactions.8 Upon the completion of this paper, Barbas reported
that a primary amino acid, L-threonine, could catalyze the syn-
selective aldol reaction of R-hydroxyketones.8g Those primary
amino acids demonstrated low efficiency (20-30 mol % loading),
however, and only worked for the few selected substrates.
Therefore, new strategies regarding the design of primary amine
catalysts with high efficiency, high stereoselectivity, as well as broad
substrate scope become increasingly desirable.
Although chiral diamines have been frequently explored in
organocatalysis,9 primary-tertiary diamines were mostly overlooked
in catalyst development, and in one earlier investigation, they
exhibited very low catalytic activity.9b,10 We report herein a simple
chiral primary-tertiary diamine catalyst for asymmetric aldol
reactions. We found that simple primary-tertiary diamines such
as chiral trans-N,N-dialkylated diaminocyclohexanes 1 (Figure 1)
would nicely address the challenges mentioned above. Direct aldol
reaction of acetone was selected first as a benchmark for catalyst
screening and evaluation. To our delight, catalyst 1d allowed for
high enantioselectivity, high diastereoselectivity, as well as high
regioselectivity for a broad range of substrates including the once
challenging linear aliphatic ketone donors under ambient temper-
and cyclohexanone (B).
ature. Worthy of noting also is that we obtained herewith
unprecedented syn diastereoselectivity for ethyl ketones.5i
Some screening results are listed in Table 1. As can be seen,
strong acidic additive such as TfOH was shown to be essential for
catalysis. The reaction became very sluggish, affording only trace
product if TfOH was absent (Table 1, entry 3 vs 2). Both catalysts
1 and 2 jointly with TfOH could catalyze the reaction, where 1d
gave the optimal results (Table 1, entry 5). The poor catalytic
performances observed for 1a, 1g, and 2 highlight the importance
of the N,N-dialkylated diaminocyclohexane structure. The catalysis
of 1d could be further improved by adding another less acidic
additive (entry 11). Under the latter conditions, the loading of
catalyst could be reduced to as low as 2 mol % while still
maintaining the same enantioselectivity and a quite significant
activity (entry 12). The role of the second acidic additive is probably
related to its possible function in facilitating the enamine catalytic
cycle.7
Application scope of the catalytic system was then examined,
and the results are summarized in Table 2. It shows that 1d worked
very well with acetone. A range of aromatic aldehydes bearing either
electron-rich or electron-deficient substitutes all underwent reaction
with acetone in high yields and enantioselectivity at room temper-
ature (Table 2, entries 1-7). Unfortunately, the reaction with
aliphatic aldehydes gave poor yields probably due to the self-
condensation of aliphatic aldehydes. With regard to other aldol
donors, a range of small aliphatic ketones was also found to be
applicable under the present conditions. Significantly, the reaction
of ethyl ketones occurred preferentially at the methylene carbon
with good regioselectivity (4 f 20:1 b:l), favoring the branched
aldol products with high enantioselectivity (87-96% ee, Table 2,
entries 8-13). More interestingly, the branched products were
obtained with unexpected diastereoselectivity, favoring the syn
isomers (up to 12:1).11 To the best of our knowledge, no other publi-
cations have reported direct asymmetric aldol reactions of small
aliphatic ketones with syn selectivity.8g In contrast, the reactions
with secondary amine catalysts generated either linear or anti-selec-
tive products with small aliphatic ketones, such as 2-butanone.5d-h
The reactions of benzyloxyacetone and a variety of aromatic
aldehydes also produced branched products with complete regio-
selectivity and good syn selectivity and enantioselectivity (Table,
2, entries 14-17). Further substrate exploration indicated that the
† Chinese Academy of Sciences.
‡ Nankai University.
9
3074
J. AM. CHEM. SOC. 2007, 129, 3074-3075
10.1021/ja069372j CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Screening Results
as our own experimental observations, a bifunctional enamine
catalysis may be assumed in our cases for the asymmetric direct
aldol reaction catalyzed by chiral primary-tertiary diamine 1d/
TfOH. The syn diastereoselectivity could be explained by a
Z-enamine transition state as proposed in Figure 1A.7,8g In this
model, the protonated tertiary amine served as a directing hydrogen-
bonding donor. Consistent with this model, the reaction of cyclo-
hexanone, which is capable only of forming an E-enamine (Figure
1B), should render anti diastereoselectivity, and this was exactly
what was observed (Table 2, entry 20).
To conclude, the simple chiral primary-tertiary diamine catalyst
developed in this work for asymmetric direct aldol reactions not
only demonstrated high enantioselectivity and unprecedented syn
diastereoselectivity but also enlarged the applicable substrate scope
to include the once challenging small aliphatic ketones. Detailed
mechanism study and further exploration of this catalyst in other
important reactions is under our intensive investigations.
time
(h)
entrya
catalyst
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
1a/TfOH
1b
24
24
24
19
19
19
24
24
24
24
19
48
trace
trace
86
86
83
46
12
33
70
1b/TfOH
1c/TfOH
1d/TfOH
1e/TfOH
1f/TfOH
1g/TfOH
1h/TfOH
2/TfOH
1d/TfOH
1d/TfOH
70
82
94
93
53
39
94
75
95
95
Acknowledgment. This work is supported by NSFC and
Institute of Chemistry. We thank Prof. M.-X. Wang, Prof. Q.-H.
Fan, and Prof. D. Wang for helpful discussions.
10
11d
12e
17
94
88
Supporting Information Available: Experimental details and
product characterization. This material is available free of charge via
the Internet at http://pubs.acs.org.
a Reaction in neat acetone (0.5 M). b Isolated yields. c Determined by
chiral HPLC. d 10 mol % of m-nitrobenzoic acid was added. e 2 mol % of
catalyst system 1d/TfOH/m-NO2PhCOOH (1:1:1).
References
Table 2. Asymmetric Direct Aldol Reactions of Ketonesa
(1) For reviews, see: (a) Dalko, P. L.; Moisan, L. Angew. Chem., Int. Ed.
2004, 43, 5138-5176. (b) Berkessel, A.; Groger, H. Asymmetric Orga-
nocatalysis: Wiley-VCH: Weinheim, Germany, 2005.
(2) (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000,
122, 2395-2396. (b) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III.
J. Am. Chem. Soc. 2001, 123, 5260-5267.
entry
R1, R2
R3
yield (%)b
rrc b:l
drc syn:anti
ee (%)d
(3) Heine, A.; DeSantis, G.; Luz, J. G.; Mitchell, M.; Wong, C.-H.; Wilson,
I. A. Science 2001, 294, 369-374.
1
2
3
4
5
6
7
H, H
3-NO2Ph 3b/96
-
-
-
94
94
97
95
92
94
93
96
96
87
92
>95
96
97
92
>99
86
(4) (a) List, B. Acc. Chem. Res. 2004, 37, 548-557. (b) List, B. Chem.
Commun. 2006, 819-824. (c) Notz, W.; Tanaka, F.; Barbas, C. F., III.
Acc. Chem. Res. 2004, 37, 580-591.
H, H
H, H
H, H
H, H
H, H
H, H
4-CNPh
1-Napth
2-ClPh
3-BrPh
Ph
4-MeOPh 3h/21
4-NO2Ph 4a/95
2-NO2Ph 4b/97
3c/95
3d/93
3e/97
3f/92
3g/56
-
-
-
-
-
(5) For recent examples, see: (a) Northrup, A. B.; MacMillan, D. W. C.
Science 2004, 305, 1752-1755. (b) Kano, T.; Takai, J.; Tokuda, O.;
Maruoka, K. Angew. Chem., Int. Ed. 2005, 44, 3055-3057. (c) Enders,
D.; Grondal, C. Angew. Chem., Int. Ed. 2005, 44, 1210-1212. (d) Mase,
N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C.
F., III. J. Am. Chem. Soc. 2006, 128, 734-735. (e) Hayashi, Y.; Sumiya,
T.; Takahashi, J.; Gotoh, H.; Urushima, T.; Shoji, M. Angew. Chem., Int.
Ed. 2006, 45, 958-961. (f) 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,
9285-9289. (g) Torri, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto,
H. Angew. Chem., Int. Ed. 2004, 43, 1983-1986. (h) Kano, T.; Tokuda,
O.; Takai, J.; Maruoka, K. Chem.sAsian J. 2006, 210-215 and references
therein. (i) Mitsumori, S.; Zhang, H.; Cheong, P. H.; Houk, K. N.; Tanaka,
F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 1041-1042.
(6) For earlier examples, see: Reymond, J.-L.; Chen, Y. J. Org. Chem. 1995,
60, 6970-6979 and references therein.
(7) (a) Huang, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7170-
7171. (b) Lalonde, M. P.; Chen, Y. G.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 2006, 45, 6366-6370. (c) Tsogoeva, S. B.; Wei, S. Chem.
Commun. 2006, 1451-1453.
(8) (a) Co´rdova, A.; Zou, W.; Dziedzic, P.; Ibrahem, I.; Reyes, E.; Xu, Y.
Chem.sEur. J. 2006, 12, 5383-5397 and references therein. (b) Tanaka,
F.; Thayumanavan, R.; Mase, N.; Barbas, C. F., III. Tetrahedron Lett.
2004, 45, 325-328. (c) Amedjkouh, M. Tetrahedron:Asymmetry 2005,
16, 1411-1414. (d) Pizzarello, S.; Weber, A. L. Science 2004, 303, 1151-
1151. (e) Davies, S. G.; Sheppard, R. L.; Smith, A. D.; Thomson, J. E.
Chem. Commun. 2005, 3802-3804. (f) Jiang, Z.; Liang, Z.; Wu, X.; Lu,
Y. Chem. Commun. 2006, 2801-2803. (g) Ramasastry, S. S. V.; Zhang,
H.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2007, 129, 288-
289. (h) Hagiwara, H.; Uda, H. J. Org. Chem. 1988, 53, 2308-2311.
-
-
-
-
-
-
8e Me, H
9e Me, H
10e Me, H
9:1
10:1
9:1
12:1
5:1
9:1
4:1
9:1
10:1
5:1
5:1
-
8:1
2-ClPh
1-Napth
4c/85
4d/53
>10:1
11
Me, H
4:1
12e Me, Me
4-NO2Ph 4e/78
4-NO2Ph 4f/75
4-NO2Ph 4g/98
4-ClPh
1-Napth
Ph
-
13
14
15
16
17
18
19
20
Me, Et
BnO, H
BnO, H
BnO, H
BnO, H
H, Et
>20:1
>20:1
>20:1
>10:1
>20:1
1:5
4h/91
4i/99
4j/76
4-NO2Ph 4k/92
4-NO2Ph 4l/56
88
H, iPr
1:>20
-
-
1:9
85
-(CH2)3- 4-NO2Ph 4m/99
98f
a Reaction with 20 equiv of ketones under neat conditions. b Isolated
yields. c Determined by 1H NMR; rr ) regioisomer ratio; b:l ) the ratio of
branched and linear products. d Determined by HPLC. e Reactions under 4
°C with 20 mol % of catalyst. f Enantiomeric excess of the anti isomer,
reaction with 2.0 equiv of cyclohexanone in CH2Cl2 for 12 h.
reaction of longer ketones, such as methyl propyl ketone and methyl
iso-butyl ketone, produced linear products instead of the branched
ones with good regioselectivity (5 and >20:1 l:b) and enantiose-
lectivity (Table 2, entries 18 and 19). Similar switch on linear and
branched product distribution has also been observed previously
on primary amine-thiourea catalysis of asymmetric Michael
additions of small aliphatic ketones.7a
(9) (a) Saito, S.; Yamamoto, H. Acc. Chem. Res. 2004, 37, 570-579. (b)
Nakadai, M.; Saito, S.; Yamamoto, H. Tetrahedron 2002, 58, 8167-8177.
(10) Hine, J. Acc. Chem. Res. 1978, 11, 1-7.
(11) The absolute and relative configuration of the products 3 and 4 was
assigned by comparison with literature; see refs 5f, 5g, 8g and: Jung,
C.-K.; Garner, S. A.; Krische, M. J. Org. Lett. 2006, 8, 519-522.
Following the line of the pioneering study of Hine10 on primary-
tertiary diamine-catalyzed R-hydrogen exchange of ketones as well
JA069372J
9
J. AM. CHEM. SOC. VOL. 129, NO. 11, 2007 3075