Catalytic asymmetric synthesis of α-alkylidene-β-hydroxy esters via dynamic kinetic asymmetric transformation involving Ba-catalyzed direct aldol reaction

Article abstract of DOI:10.1021/ja904575e

(Chemical Equation Presented) A Ba-catalyzed dynamic kinetic asymmetric transformation (DYKAT) involving a direct aldol/retro-aldol reaction of β,γ-unsaturated ester donors is described. A Ba(O-iPr) ₂/BINOL complex promoted the direct aldol rea

Full text of DOI:10.1021/ja904575e

Published on Web 07/16/2009
Catalytic Asymmetric Synthesis of r-Alkylidene-ꢀ-hydroxy Esters via
Dynamic Kinetic Asymmetric Transformation Involving Ba-Catalyzed Direct
Aldol Reaction
Akitake Yamaguchi, Shigeki Matsunaga,* and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received June 5, 2009; E-mail: smatsuna@mol.f.u-tokyo.ac.jp; mshibasa@mol.f.u-tokyo.ac.jp
The direct catalytic asymmetric aldol reaction is a powerful and
atom-economical method for synthesizing chiral ꢀ-hydroxycarbonyl
compounds.1 To date, many metal and organocatalysts for reactions
of ketone and aldehyde donors have been developed.1,2 These catalysts
kinetically control aldol reactions via a simple proton-transfer process,
avoiding undesirable retro-aldol reactions that would cause racemiza-
Figure 1. Structures of (S)-BINOL (1a), (S)-6,6′-(MeO)2-BINOL (1b), and
ꢀ,γ-unsaturated ester 2.
tion of the products. In contrast, direct catalytic asymmetric aldol
reactions with ester donors are limited to reactions with
R-isocyanoacetate,3a R-cyanoacetate,3b R-diazoacetate,4 and glycinate
Schiff base donors.5 Although the utility of several R-alkyl-substituted
ester-equivalent donors in direct aldol reactions has been nicely
demonstrated,6,7 esters without R-heteroatoms and/or electron-
withdrawing substituents have not been utilized, possibly because of
the low acidity of R-protons in esters and/or undesirable retro-aldol
reactions that occur under basic reaction conditions. Herein, we report
the use of ester donors in dynamic kinetic asymmetric transformation
(DYKAT)8 for catalytic asymmetric synthesis of ꢀ-hydroxy esters.
DYKAT involving Ba(O-iPr)2/1a-catalyzed direct aldol/retro-aldol
reactions of ꢀ,γ-unsaturated esters 2 (Figure 1) afforded R-alkylidene-
ꢀ-hydroxy esters in up to 99% ee.
Scheme 1. Working Hypothesis of DYKAT Involving Direct Aldol/
Retro-Aldol Reaction for Catalytic Asymmetric Synthesis of
R-Alkylidene-ꢀ-hydroxy Esters
A retro-aldol reaction is generally considered an undesirable
pathway in kinetically controlled direct asymmetric aldol reactions.
We planned to utilize the direct aldol/retro-aldol process in DYKAT
to obtain chiral R-alkylidene-ꢀ-hydroxy esters. Our working
hypothesis is summarized in Scheme 1. Dienolates generated in
situ from ꢀ,γ-unsaturated ester 2 by a chiral catalyst would react
with aldehyde 3 at the R- and/or γ-position. If the chiral catalyst
promotes rapid retro-aldol reaction of the R-adduct 4, isomerization
of 4 to the more thermodynamically stable R-alkylidene-ꢀ-hydroxy
ester 5 can be a DYKAT.
Table 1. Optimization of Reaction Conditions
entry
M
x
2
solvent
5/6a
% yield of 5 % ee of 5
1
2
3
4
5
6
7
8
9
Ba(O-iPr)2 10 2a THF
Ba(O-iPr)2 10 2a 1:9 THF/toluene
Ba(O-iPr)2 10 2a 1:9 THF/EtOAc 0.8:1
1.8:1
-
41
trace
4
79
8
91
-
69
98
9b
-
99
99
-
On the basis of this hypothesis, we screened chiral catalysts for
the reaction of ester 2a and aldehyde 3a, and 1:1 Ba(O-iPr)2/1a
mixture gave promising results (Table 1).9,10 The desired aldol
reaction/isomerization sequence was promoted by 10 mol % (S)-
Ba-1a in THF at 0 °C, giving 5aa in 41% yield and 91% ee (entry
1). To improve the R/γ selectivity, we optimized the reaction
conditions (entries 2-7). Performing the reaction in THF/DME
drastically improved the R/γ selectivity to 11:1 (entry 4). Other
metal sources, such as alkali metal (entry 5, Li-1a) and rare-earth
metal (entry 6, La-1a), resulted in poor reactivity and selectivity.
The best result was obtained in DME alone with Ba-1a, giving
predominantly the E adduct 5aa with R/γ > 20:1 in 85% yield and
99% ee after 24 h at 0 °C (entry 7). Ethyl ester 2b also gave the
desired product in 99% ee, but both the R/γ selectivity and yield
of the desired product decreased (entry 8). With sterically hindered
t-butyl ester 2c, the reactivity was poor (entry 9).
Ba(O-iPr)2 10 2a 1:9 THF/DME
Li(O-iPr) 2a 1:9 THF/DME
11:1
1.6:1
-
>20:1
5.6:1
-
5
La(O-iPr)3 15 2a 1:9 THF/DME
Ba(O-iPr)2 10 2a DME
Ba(O-iPr)2 10 2b DME
Ba(O-iPr)2 10 2c DME
0
85
69
trace
a Determined by 1H NMR analysis of the crude mixture. b ent-5 was
obtained as the major isomer.
(S)-Ba-1a and (S)-Ba-1b for each aldehyde, and the best results
are shown in Table 2.11 (S)-Ba-1 catalysts were applicable to a
broad range of aldehydes, giving predominantly E adducts 5 in all
entries. Aryl aldehydes 3b-d with either an electron-donating group
(entries 2 and 3) or an electron-withdrawing group (entry 4) gave
the desired products 5ba-5da in 99-96% ee. High enantioselec-
tivity was also achieved with heteroaryl and alkenyl aldehydes 3e-h
(entries 5-8, 99-97% ee). Readily enolizable alkyl aldehydes,
including linear aldehyde 3j, were applicable as well, although the
enantioselectivity was slightly lower than for other aldehydes
The substrate scope of the reaction is summarized in Table 2.
The reactions of some aldehydes in Table 2 gave a better yield
using (S)-Ba-1b rather than (S)-Ba-1a. Thus, we examined both
9
10842 J. AM. CHEM. SOC. 2009, 131, 10842–10843
10.1021/ja904575e CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Ba-Catalyzed Asymmetric Synthesis of
R-Alkylidene-ꢀ-hydroxy Esters via DYKATa
presence of a retro-aldol reaction under the reaction conditions, and
this was further confirmed by the crossover experiment shown in
Scheme 2c. Treatment of aldehyde 3g and racemic 4aa with (S)-Ba-
1a in DME gave both 5aa (24% yield, 87% ee) and 5ga (35% yield,
96% ee) after 24 h. These results confirmed that the present system is
a Ba-1-catalyzed DYKAT involving a direct aldol/retro-aldol process.
In summary, we have developed a Ba-catalyzed DYKAT
involving a direct aldol/retro-aldol reaction of ꢀ,γ-unsaturated ester
donors. R-Alkylidene-ꢀ-hydroxy esters were obtained from aryl,
heteroaryl, alkenyl, and alkyl aldehydes under simple proton-transfer
conditions in 99-87% ee and >20:1 to 15:1 R/γ selectivity. Further
studies to improve the reaction rate and catalyst loading are ongoing.
temp time
(°C) (h)
% yield
of 5c % ee
entry
R
3
1 (x)
5
5/6b
1
2
3
4
5
6
7
8
9
Ph
3a 1a (10)
3b 1a (10)
3c 1b (10) -20 24 5ca
3d 1a (10)
3e 1a (10)
3f 1b (10) -20 40 5fa >20:1
3g 1a (10)
0
0
24 5aa >20:1
42 5ba 17:1
85
77
81
78
80
85
82
63
76
53
84
99
98
99
96
98
97
98
99
91
87
99
4-MeC6H4
3-MeOC6H4
3-BrC6H4
2-thienyl
3-thienyl
3-furyl
15:1
0
0
42 5da >20:1
34 5ea >20:1
Acknowledgment. This work was supported by Grants-in-Aid
for Scientific Research (S) (to M.S.) and Scientific Research on
Priority Areas (20037010, Chemistry of Concerto Catalysis, to
S.M.). A.Y. thanks JSPS for a fellowship.
0
34 5ga >20:1
(E)-PhCHdCH 3h 1b (10) -20 28 5ha >20:1
iBu
3i 1b (10)
3j 1a (10)
3a 1a (5)
0
0
0
42 5ia >20:1
48 5ja >20:1
55 5aa >20:1
10 nPr
11 Ph
Supporting Information Available: Experimental procedures,
spectral data for new compounds, and determination of stereochemistry.
This material is available free of charge via the Internet at http://
pubs.acs.org.
a In entries 1 and 11, 2 equiv of 2a were used; in entries 2-10, 3
equiv of 2a were used. b Determined by 1H NMR analysis of the crude
mixture. c Isolated yield after purification by column chromatography.
References
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fully reduced to 5 mol % without decreasing the yield or
enantioselectivity, but a longer reaction time was required (entry
11, 55 h). (S)-Ba-1a also promoted the aldol/isomerization sequence
of ester 2d with an allenyl moiety at room temperature, giving (E)-
5ad in 79% yield and 97% ee (eq 1).
(1) For a general review of asymmetric aldol reactions, see: Geary, L. M.;
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To gain preliminary insight into the enantiodiscriminating step in
the present reaction, several experiments were performed (Scheme 2).
When the reaction of aldehyde 3a with ester 2a catalyzed by (S)-Ba-
1a was analyzed at the initial stage (0.5 h), only trace amounts of 5aa
and 6aa were observed. Instead, R-adduct 4aa was obtained in 13%
yield, but with poor dr and ee (Scheme 2a, dr ) 1.6:1, major/minor )
0/15% ee). The poor ee for 4aa indicated that the isomerization step
from 4 to 5 was highly enantioselective. In fact, when diastereomixtures
of racemic 4aa were treated with (S)-Ba-1a in the presence of 1 equiv
of 2a, (E)-5aa was obtained in 69% yield and 99% ee after 24 h
(Scheme 2b). The yield and ee of 5aa in Scheme 2b suggested the
(7) For alternative catalytic asymmetric C-C bond-forming reactions for chiral
ꢀ-hydroxy ester synthesis, see the following reviews: (a) Catalytic
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Modern Reduction Methods; Andersson, P. G., Munslow, I. J., Eds.; Wiley-
VCH: Weinheim, Germany, 2008; p 387. (b) Catalytic asymmetric Morita-
Baylis-Hillman reactions: Masson, G.; Housseman, C.; Zhu, J. Angew.
Chem., Int. Ed. 2007, 46, 4614.
(8) For a review of DYKAT, see: (a) Steinreiber, J.; Faber, K.; Griengl, H.
Chem.sEur. J. 2008, 14, 8060. For DYKAT involving a aldol/retro-aldol
sequence, see: (b) Mascarenhas, C. M.; Miller, S. P.; White, P. S.; Morken,
J. P. Angew. Chem., Int. Ed. 2001, 40, 601. (c) Gnanadesikan, V.; Horiuchi,
Y.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 7782. (d)
Co´rdova, A.; Ibrahem, I.; Casas, J.; Sunde´n, H.; Engqvist, M.; Reyes, E.
Chem.sEur. J. 2005, 11, 4772. (e) Steinreiber, J.; Schu¨rmann, M.; Wolberg,
M.; van Assema, F.; Reisinger, C.; Fesko, K.; Mink, D.; Griengl, H. Angew.
Chem., Int. Ed. 2007, 46, 1624.
Scheme 2. Mechanistic Studies of Ba-Catalyzed DYKAT
(9) For a review of alkaline-earth metal catalysts for direct C-C bond-forming
reactions, see: (a) Kazmaier, U. Angew. Chem., Int. Ed. 2009, 48, available
online (DOI: 10.1002/anie.200901261). For examples of chiral Ba aryloxide
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39, 5561. (c) Saito, S.; Kobayashi, S. J. Am. Chem. Soc. 2006, 128, 8704.
(d) Yamatsugu, K.; Yin, L.; Kamijo, S.; Kimura, Y.; Kanai, M.; Shibasaki,
M. Angew. Chem., Int. Ed. 2009, 48, 1070.
(10) ꢀ,γ-Unsaturated esters have been used for direct catalytic asymmetric
Mannich-type reactions (see: Yamaguchi, A.; Aoyama, N.; Matsunaga, S.;
Shibasaki, M. Org. Lett. 2007, 9, 3387. ). Benzyl crotonate (R,ꢀ-unsaturated
ester) was not applicable for the present system because the γ-proton in
crotonate is less acidic than the R-proton in ꢀ,γ-unsaturated esters.
(11) Detailed results comparing (S)-Ba-1a with (S)-Ba-1b are shown in the
Supporting Information.
JA904575E
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J. AM. CHEM. SOC. VOL. 131, NO. 31, 2009 10843