Asymmetric direct aldol reactions of pyruvic derivatives

Article abstract of DOI:10.1021/ol800471b

Simple chiral primary-tertiary diamine-Bronsted acid conjugates such as 1e can effectively catalyze the direct aldol reactions of pyruvic derivatives with excellent syn diastereoselectivities and enantioselectivities, thus functionally mimicking the pyruv

Full text of DOI:10.1021/ol800471b

ORGANIC
LETTERS
2008
Vol. 10, No. 9
1775-1778
Asymmetric Direct Aldol Reactions of
Pyruvic Derivatives
Sanzhong Luo,*,† Hui Xu,† Liujuan Chen,† 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
luosz@iccas.ac.cn
Received March 2, 2008
ABSTRACT
Simple chiral primary-tertiary diamine-Brønsted acid conjugates such as 1e can effectively catalyze the direct aldol reactions of pyruvic
derivatives with excellent syn diastereoselectivities and enantioselectivities, thus functionally mimicking the pyruvate-dependent type I aldolases.
The aldol reaction represents one of the most powerful
carbon-carbon bond-forming reactions for both nature and
synthetic chemistry.1 Among the variants of asymmetric aldol
reactions, pyruvate-dependent aldol reactions are of particular
interest as these processes are vital steps in the in vivo
formations of sialic acids, which are essential sugar units
for signal transduction in a plethora of biological processes.2
Accordingly, the evolved pyruvate-dependent aldolases have
been explored for the enzymatic synthesis of sialic acid
derivatives.2b On the other hand, chemists have long been
pursuing simple chemical mimics for catalyzing pyruvate-
aldol reactions, but it remains an elusive goal despite the
breakthroughs in many other asymmetric aldol reactions.1
Jørgenson recently developed chiral copper-bisoxazoline
catalysts for asymmetric aldol reactions of pyruvates.3
Though good enantioselectivities were achieved, the reactions
were limited to pyruvate-type acceptors. Asymmetric enam-
ine catalysis, resembling mechanistically natural enzymatic
processes, represents one of the most prominent recent
advances in modern aldol reactions.4 In this context, the
enamine catalysts have also been attempted in pyruvate aldol
reactions but demonstrated poor activity and thus only
worked with a few selected substrates.5 In these cases, the
applied catalysts are exclusively secondary amines, e.g.,
chiral pyrrolidines. This fact stands in contrast to the natural
pyruvate-dependent aldolase wherein the primary amine of
lysine is involved in catalysis.
Recently, chiral primary amines have been shown to be viable
enamine catalysts that attain a new level of catalysis beyond
traditional secondary amine catalysts.6 In this vein, the research
groups of Barbas6f,7 and Gong8 as well as our research group9
have recently reported successful applications of chiral
primary amines as syn-selective aldol catalysts. Inspired by
the natural primary amine catalysis in pyruvate-dependent
† Chinese Academy of Sciences.
‡ Nankai University.
(1) (a) Gijsen, H. J. M.; Qiao, L.; Fitz, W.; Wong, C.-H. Chem. ReV.
1996, 96, 443–473. (b) Wong, C.-H.; Machajewski, T. D. Angew. Chem.,
Int. Ed. 2000, 39, 1352–1375. (c) Schetter, B.; Mahrwald, R. Angew. Chem.,
Int. Ed. 2006, 45, 7506–7525.
(2) (a) Angata, T.; Varki, A. Chem. ReV. 2002, 102, 439–469. (b)
WongC.-H. In Enzymes in Synthetic Organic Chemistry; Wong, C.-H.,
Whitesides, G. M., Eds.; Elsevier: Oxford, 1994; pp 215-219.
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2211–2212. (b) Gathergood, N.; Juhl, K.; Poulsen, T. B.; Thordrup, K.;
Jørgensen, K. A. Org. Biomol. Chem. 2004, 2, 1077–1085.
10.1021/ol800471b CCC: $40.75
Published on Web 04/08/2008
2008 American Chemical Society

aldolase,10 we have explored chiral primary amines in
pyruvate-aldol reactions. Herein, we report chiral primary-
tertiary diamine-Brønsted acid conjugates as effective and
general catalysts for the diastereo- and enantioselective direct
aldol reactions of pyruvic donors, thus functionally mimick-
ing the natural pyruvate-dependent type I aldolase.1a,2a
As a starting point, a variety of pyruvic derivatives were
briefly screened and pyruvic aldehyde acetals (e.g., 4a) were
identified as workable aldol donors in the catalysis of
primary-tertiary diamine 1. Only one report by Enders has
examined pyruvic aldehyde dimethyl acetal as a mask of
Figure 1. Chiral primary amine catalysts and pyruvic derivatives.
(4) For reviews on organocatalysis, see:(a) Dalko, P. I.; Moisan, L.
Angew. Chem., Int. Ed. 2004, 43, 5138–5176. (b) Berkessel, A.; Groger,
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J.; List, B. Org. Biomol. Chem. 2005, 3, 719–724. (d) List, B. Acc. Chem.
Res. 2004, 37, 548. (e) Notz, W.; Tanaka, F.; Barbas, C. F. Acc. Chem.
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2395–2396. (g) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III J. Am.
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pyruvate in the proline-catalyzed direct aldol reactions.5c The
reactions were very sluggish; however, only two aliphatic
aldehydes acceptors were tested which gave low yields but
good ee’s. We then selected the reaction of 4a and p-
nitrobenzaldehyde as a model for subsequent screening.
Notably, while both L-alanine and L-proline were totally
ineffective for catalysis of this reaction (Table 1, entries 1
Table 1. Selected Screening Results
entrya
cat. (mol %)
solvent
yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
L-alanine
L-proline
1a/TfOH
1a
1b/TfOH
1c/TfOH
1d/TfOH
1e/TfOH
2
neat
neat
neat
neat
neat
neat
neat
neat
neat
neat
NMP
NMP
NMP
H2O
trace
trace
44
trace
42
66
6
44
trace
45
nd
nd
64%
nd
84
88
32
91
nd
36
92
93
93
90
(5) (a) Dambruoso, P.; Massi, A.; Dondoni, A. Org. Lett. 2005, 7, 4657–
4660. (b) Vincent, J.-M.; Margottin, C.; Berlande, M.; Cavagnat, D.;
Buffeteau, T.; Landais, Y. Chem. Commun. 2007, 4782–4784. (c) Enders,
D.; Gasperi, T. Chem. Commun. 2007, 88–90.
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A. L. Science 2004, 303, 1151–1151. (d) Davies, S. G.; Sheppard, R. L.;
Smith, A. D.; Thomson, J. E. Chem. Commun. 2005, 3802–3804. (e) Jiang,
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9
10
11c
12c
3
1c/TfOH
1e/TfOH
1e/TfOH
1e/TfOH
62
71
90
71
13d e
,
14d
a Yield of isolated product. b Determined by chiral HPLC analysis. c
5
mol % of m-NO2PhCOOH was added. d In the presence of 20 mol % of
catalyst. e 10 mol % of m-NO2PhCOOH was added. nd: not determined.
and 2), simple primary-tertiary vicinal diamines such as
trans-N,N-dialkylated diaminocyclohexanes 1 turned out to
be very effective catalysts when combined with TfOH.
Among this series of catalysts examined, cyclohexanediamine
1c gave the best yield while 1e offered the best enantiose-
lectivity (Table 1, entries 5 and 6). Similar diphenylethylene
diamine 2 was virtually inactive for catalysis (Table 1, entry
8). The primary-sulfamide conjugate 3 also exhibited much
lower enenatioselectivity (Table 1, entry 9). These results
highlight the importance of the N,N-dialkylated diaminocy-
clohexanes skeleton. Consistent with our previous observa-
tions,9 a strong brønsted acid such as TfOH is essential for
(7) (a) Kano, T.; Yamaguchi, Y.; Tanaka, Y.; Maruoka, K. Angew.
Chem., Int. Ed. 2007, 46, 1738–1740. (b) Utsumi, N.; Imai, M.; Tanaka,
F.; Ramasastry, S. S. C.; Barbas, C. F. Org. Lett. 2007, 9, 3445–3448. For
similar catalysts, see: (c) Wu, X.; Jiang, Z.; Shen, H.-M.; Lu, Y. AdV. Synth.
Catal. 2007, 349, 812–816.
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(9) (a) Luo, S. Z.; Xu, H.; Li, J. Y.; Zhang, L.; Cheng, J.-P. J. Am.
Chem. Soc. 2007, 129, 3074–3075. (b) Luo, S. Z.; Xu, H.; Zhang, L.; Li,
J. Y.; Cheng, J.-P. Org. Lett. 2008, 10, 653–656. (c) Luo, S. Z.; Li, J. Y.;
Zhang, L.; Xu, H.; Cheng, J.-P. Chem. Eur. J. 2008, 14, 1273–1281.
(10) Lawrence, M. C.; Barbosa, J. A.; Smith, B. J.; Hall, N. E.; Pilling,
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Org. Lett., Vol. 10, No. 9, 2008

catalysis, and the reaction barely occurred in the absence of
TfOH (Table 1, entry 4).
Table 2. Substrate Scope
The reaction was further optimized using both catalysts
1c and 1e by screening weak acid additives and solvents
(see the Supporting Information for details). Improved yield
and enantioselectivity were achieved using N-methylpyrro-
lidine (NMP) as the solvent and m-nitrobenzoic acid as the
weak acidic additive. Under these conditions, catalyst 1e gave
slightly better results than that of 1c. The reaction in the
presence of 10 mol % of 1e provided 71% yield and 93%
ee, and the yield could be improved to 90% with 20 mol %
of catalyst loading (Table 1, entries 12 and 13). It is noted
that the catalysis of 1e could also be conducted in bulk water
(>40 equiv) affording comparable results (71% yield, 90%
ee, Table 1, entry 14).
With 1e as the optimal catalyst, we next explored a variety
of pyruvic acetal derivatives and aldehydes to determine the
scopes and limitations of the current catalysis (Table 2).
Aromatic aldehydes were shown to be excellent aldol
acceptors in the reactions with pyruvic aldehyde dimethyl
acetal 4a. Excellent enantioselectivities and good yields were
achieved in most of these reactions (Table 2, entries 1-10).
The reactions with aliphatic aldehydes gave mainly the
dimerization product of 4a instead of the desired cross-aldol
products, probably due to the lower reactivity of aliphatic
aldehydes as acceptors and also their ease to self-condensa-
tion as previously observed in primary aminocatalysis.9,11
Activated carbonyls such as 2,2-dimethoxyacetaldehyde and
2,2,2-trifluoro-1-phenylethanone also worked well in the
present reactions to give quite good yields and moderate
enantioselectivities (Table 2, entries 11 and 12). The reactions
in pure water conditions (conditions B) have also been
examined, showing comparable yields but slightly decreased
enantioselectivities (Table 2, entries 2, 4, and 6).
In regard to the pyruvic aldehyde derivatives, the use of
a cyclic acetal 5 led to improved enantioselectivity compared
with that of dimethyl acetal 4a (Table 2, entries 13 and 14).
For example, the enantioselectivity was increased from 93%
ee to 98% ee by using cyclic acetal 5 instead of 4a. Pyruvic
acetals with longer alkyl chains such as 4b-d are also
applicable in the reactions. Excellent dia- (>90:10, syn/anti)
and enantiostereoselectivities (>99% ee) and moderate yields
were obtained in the reactions of 4b-d with aromatic
aldehydes (Table 2, entries 15-21). It is noted that the
branched aldol products were obtained with remarkably syn
diastereoselectivities. To the best of our knowledge, this
represents the first example of an asymmetric syn-selectiVe
pyruVate-type aldol reaction. Substituted pyruvic acids were
previously examined in chiral pyrrolidine-catalyzed aldol
reaction; however, the resulted isotetronic acids products are
depleted of any diastereoselectivity.5b
* Conditions A: 0.25 mmol of aldehyde, 1.0 mmol of pyruvic derivative,
and 10 mol % of m-NO2PhCOOH in 100 µL of NMP. Conditions B: 0.25
mmol of aldehyde and 1.0 mmol of pyruvic derivative in 200 µL of H2O.
a Yield of isolated product. b Determined by 1H NMR. c Determined by
chiral HPLC analysis.
25 and 26 in high yields and unchanged enantioselectivities
(Scheme 1). These products are important precursors for the
synthesis of bioactive compounds.12
We obtained single crystals of 3-4′-bromobenzoyl-25
(compound 25b, see the Supporting Information), and the
To demonstrate the utility of the current aldol reaction,
the diacetal aldol products, e.g., 7 and 18, were first reduced
by NaBH4 to give 1,3-diol products (syn/anti ) 5:1), which
upon treatment with acid afforded the furanose type products
(12) For examples, see: (a) Lemoine, R. C.; Magon, A.; Hecker, S. J.
Bioorg. Med. Chem. Lett. 2002, 12, 1121–1123. (b) Lin, A. J.; Benjamin,
R. S.; Rao, P. N.; Loo, T. L. J. Med. Chem. 1979, 22, 1096–1110.
(11) In a control reaction without aldehyde acceptors, the dimerization
product of 4a was isolated with 40% yield and 19% ee
.
Org. Lett., Vol. 10, No. 9, 2008
1777

Scheme 1
.
Synthetic Applications
Scheme 2
.
X-ray Crystal Structure of 25b and Proposed
Transition State
absolute configuration was then determined by X-ray crystal-
lographic analysis (see the Supporting Information for
details).13 The absolute configurations of the aldol products
were therefore determined by analogy. The syn-relative
the current pyruvate-aldol reaction an attractive protocol
for the synthesis of furanoses. Applications in natural product
synthesis and further explorations of chiral primary amines
in other enamine reactions are currently underway in our
laboratory.
1
configurations were determined by H NMR and NOESY
analysis of product 18 and 26, respectively. Consistent with
our previous studies, these configurations may be rationalized
by a Z-enamine transition state as illustrated in Scheme 2.
In summary, we have developed highly efficient and
stereoselective pyruvatesaldol reactions catalyzed by simple
chiral primary-tertiary diamines. The present reactions
accommodated a range of pyruvic donors and carbonyl
acceptors with exceedingly high enantioselectivities and
remarkable diastereoselectivities. The rather mild reaction
conditions, the excellent stereocontrol, as well as the avail-
ability of both enantiomers of the chiral primary amines make
Acknowledgment. This work was supported by the
Natural Science Foundation of China (NSFC 20421202,
20632060, and 20702052), the Ministry of Science and
Technology (MoST), and the Chinese Academy of Sciences.
We thank Dr. X. Hao and Dr. T. L. Yang in ICCAS for
X-ray analysis of single crystal.
Supporting Information Available: Experimental details
and characterization of new products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(13) Crystal data for 25b: CCDC 675220 contains the supplementary
crystallographic data for compounds 25b. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
OL800471B
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Org. Lett., Vol. 10, No. 9, 2008