Direct catalytic asymmetric aldol-Tishchenko reaction

Article abstract of DOI:10.1021/ja047906f

A direct catalytic asymmetric aldol reaction of propionate equivalent was achieved via the aldol-Tishchenko reaction. Coupling an irreversible Tishchenko reaction to a reversible aldol reaction overcame the retro-aldol reaction problem and thereby afforde

Full text of DOI:10.1021/ja047906f

Published on Web 06/04/2004
Direct Catalytic Asymmetric Aldol-Tishchenko Reaction
Vijay Gnanadesikan, Yoshihiro Horiuchi, Takashi Ohshima, and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Tokyo 113-0033, Japan
Received April 12, 2004; E-mail: mshibasa@mol.f.u-tokyo.ac.jp
Scheme 1
Development of mild and catalytic methods for the stereo and
enantioselective transformation of nonpreactivated functional groups
is a topic of continuing interest.1 In this regard, we2 and others3
have attempted the direct catalytic asymmetric aldol reaction of
unmodified ketones. Most of the catalytic systems reported to date,
however, are limited to rather simple donors such as methyl
ketones,2a,b,3a,b R-hydroxymethyl ketones,2c,3c,d and easily enolizable
aliphatic aldehydes.3e Direct aldol reaction of ethyl ketones4 are
viewed as a formidable synthetic challenge because of poor
participation of the resulting aldolates in catalyst turnover and a
strong tendency toward retro-aldol reactions. Tremendous effort
has been focused on the propionate aldol reaction of carboxlic acid
derivatives under silylating conditions.5 Here, we report that this
elusive aldol reaction can be accomplished using the aldol-
Tishchenko reaction. By coupling an irreversible Tishchenko
reaction to a reversible aldol reaction, the catalytic aldol-Tishchenko
reaction provides high product yields and high ees from an aldol
process and does not require stoichiometric preactivation of the
ketone as a silyl enolate.
As part of ongoing studies of direct aldol reactions that have
broad utility in asymmetric synthesis, we recently initiated studies
toward a direct aldol reaction of ethyl ketones. Inspired by the
earliest report of an SmI2-catalyzed Tishchenko reaction of â-
hydroxy ketone by Evans et al.6a and an yttrium-salen complex
catalyzed asymmetric cross aldol-Tishchenko reaction by Morken
et al.,6b we hypothesized that the metalated aldolates 1 derived
from our lanthanoid-based heterobimetallic catalyst might be
activated for the addition of another aldehyde molecule (Scheme
1). Accordingly, this activation-addition step would provide Evans
intermediate 2,6a which exhibits the appropriate orientation to rapidly
undergo [3,3] bond reorganization to provide Tishchenko adduct
3. Because of the number of established procedures,7,8 we expected
that this addition-rearrangement sequence would allow us to
prevent the competitive retro-aldol reaction and provide an attractive
platform for the development of highly enantio- and diastereo-
selective aldol-type adducts.
Preliminary studies using propiophenone (4a) with 4-chloroben-
zaldehyde (5a) in the presence of 10 mol % of LLB, which was
prepared from La(O-i-Pr)3,2 revealed that the anticipated sequential
addition was possible with excellent diastereoselectivity and moder-
ate enantiocontrol (>98:2 dr9 and 64% ee for 3aa); however, the
catalytic efficiency was unsatisfactory (Table 1, entry 1). Assuming
that lithium binaphthoxide would not be basic enough for depro-
tonation, we next examined the use of a metal salt additive, which
might competitively coordinate and decrease the pKa of the ketone.
While a variety of lithium salts were productive in this context, 30
mol % LiOTf10 provided the optimal reaction efficiency and high
selectivity (entry 2). Keeping the 1:3:3 ratio of lanthanum, BINOL,
and LiOTf in mind, we investigated whether the same catalytic
system would be accomplished by mixing 6 equiv of BuLi to the
mixture of the 1:3 ratio of La(OTf)3 and BINOL. The commercial
availability of La(OTf)3, high tolerance to air and water, and
Table 1. Optimization Studies
conv.c
(%)
eee
(%)
entry ketonea
catalystb
6:3d
1
2
4a
4a
(R)-LLB
(R)-LLB + LiOTf
(1:3)
20
60
∼1:1
∼1:1
64
78
3
4
5
4a
4b
4b
La(OTf)3 + (R)-BINOL + BuLi
60
75
80
∼1:1
86
(1:3:6)
La(OTf)3 + (R)-BINOL + BuLi
(1:3:6)
La(OTf)3 + (R)-BINOL + BuLi
(1:3:5.6)
2:>98 88
2:>98 93
a
b
4a: Ar1dC6H5, 4b: Ar1dC6H4-4-CF3. All reactions were performed
in tetrahydrofuran (1.0 M) at room temperature (48 h for 4a, 24 h for 4b).
c
Total yield of 6 and 3 was determined by 1H NMR analysis of the crude
sample. Determined by 1H NMR analysis of the crude sample. ee of 3
was determined by HPLC analysis after hydrolysis using NaOMe/MeOH
to the corresponding diol 7. Diastereoselectivity was generally below the
d
e
1
detection limit of 500 MHz H NMR (>98:2).
superior levels of asymmetric induction and efficiency (entry 3)
exhibited by this modified procedure prompted us to further explore
this catalytic condition. Switching to ketone 4b had a significant
effect on the reactivity and Tishchenko selectivity, while maintain-
ing the similar enantiocontrol (entry 4). Superior levels of asym-
metric induction were realized by decreasing the amount of BuLi.
Thus, 1:3:5.6 La(OTf)3/BINOL/BuLi was the appropriate ratio for
a broad range of substrates (entry 5).
Experiments to probe the scope of the aldehyde substrate are
summarized in Table 2.11 A variety of alkyl and heteroatom
substituents can be incorporated on the phenyl ring at both the meta
and para positions (Table 2, entries 1-7, 85-95% ee, 65-96%
yield). The aryl framework can be successfully extended to
naphthalene and heteroaromatic derived systems (entries 8-10, 88-
94% ee, 67-82% yield). In addition, a number of aromatic ketones
can also be used without loss of reaction efficiency or enantiocontrol
(entries 11-15, 84-88% ee, 60-81% yield). Importantly, the R,â-
unsaturated enone resulting from â-elimination of the hydroxyl
group was not formed, confirming the mild reaction conditions
employed in this asymmetric process. Furthermore, reactions were
performed at room temperature, demonstrating the practical utility
of the present catalytic system. We next examined the capacity of
9
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J. AM. CHEM. SOC. 2004, 126, 7782-7783
10.1021/ja047906f CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Direct Aldol-Tishchenko Reactions: Substrate Scope
Scheme 2
time
(h)
eea
(%)
yieldb
(%)
entry
ketone 4 Ar1
aldehyde 5 Ar2
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
4b: 4-F3C-C6H4
4b: 4-F3C-C6H4
4b: 4-F3C-C6H4
4b: 4-F3C-C6H4
4b: 4-F3C-C6H4
4b: 4-F3C-C6H4
4b: 4-F3C-C6H4
4b: 4-F3C-C6H4
4b: 4-F3C-C6H4
4b: 4-F3C-C6H4
4c: 4-Br-C6H4
4d: 3-Cl-C6H4
4e: 3,4-Cl2-C6H4
4f: 3,5-Cl2-C6H4
4g: 3,5-F2-C6H4
4h: 4-F3C-C6H4
4i: 4-F3C-C6H4
5a: 4-Cl-C6H4
5b: 4-Br-C6H4
5c: 4-F-C6H4
5d: 4-Me-C6H4
5e: C6H5
5f: 3-Br-C6H4
5g: 3-MeO-C6H4
5h: 2-naphthyl
5i: 3-furyl
60
48
72
94
84
48
72
80
84
84
48
48
48
48
48
90
90
93
95
92
92
91
86
85
88
93
94
85
84
88
85
87
88
87
95
96
85
67
95
92
65
67
77
82
70
60
81
73
77
90
88
for aromatic donors and acceptors. Moreover, this is the first
example of a direct aldol-Tishchenko reaction of propionate
equivalent. Further studies on broadening the substrate scope to
aliphatic donors and acceptors, useful precursors for the synthesis
of polypropionate natural products, and determining the mechanism
and catalyst structure are ongoing.
5j: 3-thienyl
5b: 4-Br-C6H4
5a: 4-Cl-C6H4
5a: 4-Cl-C6H4
5a: 4-Cl-C6H4
5a: 4-Cl-C6H4
5b: 4-Br-C6H4
5b: 4-Br-C6H4
Acknowledgment. This work was supported by grant aid for
specially promoted research and Grant-in-Aid for Encouragements
for Young Scientists (A) from JSPS. We thank Keitaro Mori and
Hideaki Nakahara (Yamanouchi Pharm. Co., Ltd.) for X-ray
analysis.
a
Determined by HPLC analysis after converting to the corresponding
diol. The diastereoselectivity was generally below the detection limit of
500 MHz 1H NMR (>98:2).9 Isolated yield of the corresponding diol 7.
b
Supporting Information Available: Experimental procedures and
characterization of the products with 13C NMR of diol 7; other detailed
results and discussion (PDF); X-ray crystallographic data (CIF). This
material is available free of charge via the Internet at http://pubs.acs.org.
the present catalytic system to catalyze asymmetric aldol-Tish-
chenko reactions of propyl and butyl ketones (4h and 4i). As
highlighted, the catalyst exhibited similar efficiency without
considerable deterioration of enantiocontrol (entries 16 and 17, 87-
88% ee, 88-90% yield). Despite the single previous use of diethyl
ketone in the direct aldol reaction,4 to our knowledge, this is the
first example of an asymmetric aldol-type reaction of propyl and
butyl ketones.
References
(1) For a recent review, see: Shibasaki, M.; Yoshikawa, N. Chem. ReV. 2002,
102, 2187.
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Mahrwald, R. Org. Lett. 2000, 2, 4011. (b) Mahrwald, R.; Ziemer, B.
Tetrahedron Lett. 2002, 43, 4459.
The uncertain mechanism12 of this direct aldol-Tishchenko
reaction prompted us to inspect the relation between the aldol
product and the Tishchenko product, as well as their stereoselec-
tivities. The aldol byproduct 6aa obtained by the reaction of 4a
(Table 1, entry 3) was with no enantio- or diastereoselectivity. To
obtain further insight, we attempted a deliberate retro-aldolization
of independently prepared racemic aldol adducts 6aa (syn/anti )
7:3 or syn/anti ) 3:7) under representative reaction conditions (10
mol % of La catalyst, room temperature, 72 h). The same mixtures
of 4a, 6aa (syn/anti ) 4:6, racemic), and 3aa (>98:2 dr,9 70%
ee)13 were obtained starting with either a 7:3 or a 3:7 syn/anti ratio
of aldol adducts 6aa. These results are consistent with the rapid
retro-aldol cleavage of metal aldolate and confirm the essential role
of the Tishchenko reaction in controlling the stereoselectiVity.
These unique observations offered us a reasonable mechanistic
explanation as depicted in Scheme 2. Metal enolate reacts reversibly
with aldehyde, yielding all possible isomeric metal aldolates 1.14
An anti-aldolate proceeds through a bicyclic transition state 2 to
give 8. A syn-aldolate can undergo a similar reaction with a slower
rate through transition state 2′, the alkyl group of which occupies
an energetically unfavorable axial position. In such cases, a fast
isomerization from syn-aldolate to anti-aldolate might surpass the
rate of the Tishchenko reaction. Thus, a syn-aldolate might
isomerize to anti-aldolate through a retro-aldol reaction and undergo
the Tishchenko reaction via the more favorable transition state 2,
giving rise to anti-aldol anti-Tishchenko product 3 in high efficiency
and diastereoselectivity.
(5) Evans, D. A.; Downey, C. W.; Hubbs, J. L. J. Am. Chem. Soc. 2003,
125, 8706 and references therein.
(6) (a) Evans, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1990, 112, 6447. (b)
Mascarenhas, C. M.; Miller, S. P.; White, P. S.; Morken, J. P. Angew.
Chem., Int. Ed. 2001, 40, 601.
(7) For racemic reactions, see: (a) Mascarenhas, C. M.; Duffy, M. O.; Liu,
S. Y.; Morken, J. P. Org. Lett. 1999, 1, 1427. (b) Bodnar, P. M.; Shaw,
J. T.; Woerpel, K. A. J. Org. Chem. 1997, 62, 5674. (c) Simpura, I.;
Nevalainen, V. Tetrahedron Lett. 2001, 42, 3905. (d) Mahrwald, R.;
Costisella, B. Synthesis 1996, 1087. (e) Loog, O.; Maeorg, U. Tetrahe-
dron: Asymmetry 1999, 10, 2411. (f) Schneider, C.; Hansch, M. Chem.
Commun. 2001, 1218 and references therein.
(8) For a moderately enantioselective reaction, see: (a) Schneider, C.; Hansch,
M. Synlett 2003, 837.
(9) Diastereomeric ratio represents major anti-aldol anti-Tishchenko isomer
versus all minor diastereomers.
(10) Other metal salts such as NaOTf, KOTf, CuOTf, and Mg(OTf)2 produced
less satisfactory results.
(11) Relative and absolute configurations were determined by chemical
correlation and X-ray analysis. See Supporting Information for more
details.
(12) For mechanistic studies dealing with the reversibility of aldol reaction,
see refs 6b and 7a as well as: (a) Lu, L.; Chang, H. Y.; Fang, J. M. J.
Org. Chem. 1999, 64, 843. (b) Abu-Hasanayn, F.; Streitwieser, A. J. Org.
Chem. 1998, 63, 2954.
(13) Slightly lower ee would be ascribed to the different starting materials
used. See Supporting Information for details.
(14) Presumably, the low aldol selectivities are due to strong retro-aldolization.
In conclusion, we established the Tishchenko reaction as one of
the useful methods for overcoming the retro-aldol reaction problem
JA047906F
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