Stereoselective synthesis of multiple stereocenters by using a double aldol reaction

Article abstract of DOI:10.1002/anie.201209848

Triple play: The title reaction of an alkyl methyl ketone and two aldehydes using chiral (S)-binapo as a Lewis base catalyst allows access to 1,5-dihydroxy-3-pentanone derivatives with multiple chiral centers in good yields with high diastereo- and enantioselectivities in a single operation (see scheme).

Full text of DOI:10.1002/anie.201209848

Angewandte
Chemie
DOI: 10.1002/anie.201209848
Asymmetric Catalysis
Stereoselective Synthesis of Multiple Stereocenters by Using a Double
Aldol Reaction**
Yasushi Shimoda, Tatsunori Kubo, Masaharu Sugiura, Shunsuke Kotani,* and
Makoto Nakajima*
Asymmetric multicomponent reactions have attracted much
attention in organic synthesis because they both simplify
synthetic processes and permit the construction of multiple
chiral centers in a single operation.[1] Although several
asymmetric aldol reactions have been developed,[2] relatively
few examples of sequential aldol reactions which lead to the
formation of multiple carbon–carbon bonds with chiral
centers are available. Among the various sequential aldol
reactions, double aldol reactions involving one aldol donor
and two aldol acceptors have two types of reaction modes
(Scheme 1): a) two aldol reactions may occur at a single a-
In 2000, the first asymmetric double aldol reaction was
reported by Masamune, Abiko, and co-workers, who used
boron triflate in the reaction of a chiral ester and an aldehyde
to afford a double aldol adduct diastereoselectively.[3] We
recently developed the first enantioselective double aldol
reaction[4] using a chiral phosphine oxide[5] as a Lewis base
catalyst,[6] thus producing double aldol adducts with high
stereoselectivities. In both cases, enol ether intermediates
were generated at a single a-position of the aldol donor to
give the branched aldol adducts. Linear enantioselective
double aldol reactions have not yet been achieved. The
stepwise stereoselective synthesis of chiral 1,5-dihydroxy-3-
pentanone derivatives from aldolates was reported by Den-
mark et al.,[7] Dias et al.,[8] and Yamaoka and Yamamoto.[9]
The development of an enantioselective sequential method
could potentially provide an important alternative synthetic
route. Herein, we demonstrate the first enantioselective
linear double aldol reaction using silicon tetrachloride and
a chiral phosphine oxide as an organocatalyst.
First, we started our studies with the reaction of 2-
butanone (1a) and benzaldehyde (2a) in the presence of
10 mol% (S)-binap dioxide (binapo) in dichloromethane at
À608C, based on our previous report[4] (Scheme 2). Surpris-
Scheme 1. Classification of the double aldol reactions. a) Branched-
type double aldol reaction (previous work). b) Linear-type double aldol
reaction (this work).
position on an aldol donor to give a branched double aldol
adduct with three contiguous stereogenic centers; or, b) a
reaction at both a-positions of a carbonyl group in an aldol
donor provides a linear double aldol adduct having a 1,5-
dihydroxy group with at most four chiral centers in a single
operation.
Scheme 2. Preliminary result of the linear-type double aldol reaction.
[*] Y. Shimoda, T. Kubo, Prof. Dr. M. Sugiura, Prof. Dr. M. Nakajima
Graduate School of Pharmaceutical Sciences, Kumamoto University
5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973 (Japan)
E-mail: nakajima@gpo.kumamoto-u.ac.jp
ingly, a branched-type adduct did not form. Instead, the
linear-type adduct 3a was obtained in a 65% yield with a high
diastereoselectivity (d.r. = 90:10)[10] and a high enantioselec-
tivity (93% ee) for the major isomer. This observation
prompted further investigations, as described below.
Prof. Dr. S. Kotani
Priority Organization for Innovation and Excellence
Kumamoto University
5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973 (Japan)
E-mail: skotani@gpo.kumamoto-u.ac.jp
To improve both the yield and selectivity, we conducted
the double aldol reaction under various reaction conditions
using (S)-binapo[11] as a Lewis base catalyst (Table 1). Several
amines were screened,[12] and dicyclohexylmethylamine gave
the corresponding product in a better yield than diisopropyl-
[**] This work was supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science and
Technology of Japan.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201209848.
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Table 1: Double aldol reaction of 2-butanone (1a) and benzaldehyde
(2a) catalyzed by (S)-binapo.[a]
Table 2: Double aldol reaction of various ketones (1a–h) and benz-
aldehyde (2a) catalyzed by (S)-binapo.[a]
Entry R (1)
3
Yield [%][b]
86
d.r.[c]
ee [%][d]
Entry
Solvent
T [8C]
Yield [%][b]
d.r.[c]
ee [%][d]
1[e]
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
EtCN
CH2Cl2/EtCN (1:1)
À60
À60
À60
À40
À40
À40
65
71
73
80
28
86
90:10
91:9
91:9
90:10
89:11
90:10
93
95
94
86
97
91
1
Me (1a)
3a
90:10
–
91
91
95
94
79
92
94
81
2[e]
3
H (1b)
Et (1c)
nPr (1d)
Bn (1e)
3b 84
3c 87
3d 86
3[f]
4
90:10
89:11
89:11
89:11
89:11
90:10
4
5
3e
69
5
6
=
6
-CH2CH C(CH3)2 (1 f) 3 f
-(CH2)2CO2Et (1g)
-(CH2)3C(O)Ph (1h)
84
7[f]
8[f]
3g
3h 67
65 (15)[g]
[a] Unless otherwise noted, reactions were carried out by adding of SiCl4
(2.0 mmol) to a solution of 1a (0.5 mmol), 2a (1.5 mmol), Cy2NMe
(2.5 mmol), and (S)-binapo (10 mol%) in solvent (5 mL). [b] Yield of
isolated product. [c] The ratio of the major isomer to the minor isomer
was determined by 1H NMR analysis. [d] The ee value (major isomer)
was determined by HPLC analysis. [e] iPr2NEt was used in place of
Cy2NMe. [f] For 48 h.
[a] Unless otherwise noted, reactions were carried out in the presence of
1a–h (0.5 mmol), 2a (1.5 mmol), SiCl4 (2.0 mmol), Cy2NMe (2.5 mmol),
and (S)-binapo (10 mol%) in EtCN (2.5 mL) and CH2Cl2 (2.5 mL) at
À408C. [b] Yield of isolated product. [c] The ratio of the major isomer to
the minor isomer was determined by 1H NMR analysis. [d] The ee value
(major isomer) was determined by HPLC analysis. [e] The reaction was
conducted with iPr2NEt in place of Cy2NMe in CH2Cl2 at À608C. [f] For
48 h. [g] The yield of lactonized product is given within the parentheses.
ethylamine (Table 1, entry 2).[13] To improve the chemical
yield, we extended the reaction time to 48 hours, but almost
the same chemical yield was obtained (Table 1, entry 3).
Increasing the reaction temperature to À408C improved the
chemical yield, although the selectivity decreased slightly
(Table 1, entry 4). Among the solvents tested, propionitrile
provided a high enantioselectivity but the reactivity was
reduced (Table 1, entry 5). The mixture of dichloromethane
and propionitrile (1:1) efficiently promoted the transforma-
tion without incurring a significant loss in either the reactivity
or the selectivity (Table 1, entry 6).
Table 3: Double aldol reaction of 2-pentanone (1c) and various
aldehydes (2a–i) catalyzed by (S)-binapo.[a]
Entry
R (2)
3
Yield [%][b]
d.r.[c]
ee [%][d]
With the optimal reaction conditions in hand (Table 1,
entry 6), we next conducted the double aldol reaction of
various ketones (1a–h) in benzaldehyde (2a; Table 2).
Acetone (1b) gave the C2-symmetrical 1,5-diol 3b as
1
2
Ph (2a)
3c
3i
3j
3k
3l
3m
3n
3o
3p
87
89
66
76
72
78
58
65
71
90:10
90:10
92:8
91:9
92:8
90:10
89:11
90:10
92:8
95
92
98
97
91
93
93
88
95
4-BrC6H4 (2b)
4-MeOC6H4 (2c)
4-MeC6H4 (2d)
3,5-Me2C6H3 (2e)
2-naphthyl (2 f)
1-naphthyl (2g)
2-furyl (2h)
3[e]
4
5[e]
6
a
single diastereomer with a high enantioselectivity
(Table 2, entry 2). Various alkyl methyl ketones (1c–f)
reacted with 2a to afford the corresponding double aldol
adducts in good yields with high stereoselectivities (Table 2,
entries 3–6). In the reaction of the ketone 1g and 2a, the
obtained aldol adduct 3g was partially cyclized to give the
lactonized adduct (Table 2, entry 7). The ketone 1h, contain-
ing a benzoyl moiety, reacted specifically at the acetyl group
to afford the corresponding aldol adduct (Table 2, entry 8).
Using 2-pentanone (1c) as an aldol donor, we investigated
the double aldol reaction with various aldehydes (2a–i;
Table 3). p-Bromobenzaldehyde (2b) bearing an electron-
withdrawing group gave the product 3i in good yield with
a high enantioselectivity (Table 3, entry 2). Although p-
anisaldehyde (2c) was less reactive than 2a or 2b and
required a long reaction time, the observed enantioselectivity
of 3j was excellent (Table 3, entry 3). Other aromatic
aldehydes 2d–i also gave the corresponding double aldol
adducts in good yields with high diastereo- and enantioselec-
tivities (Table 3, entries 4–9).
7
8
9
2-thienyl (2i)
[a] All reactions were carried out in the presence of 1c (0.5 mmol),
2a–i (1.5 mmol), SiCl4 (2.0 mmol), Cy2NMe (2.5 mmol), and (S)-binapo
(10 mol%) in CH2Cl2 (2.5 mL) and EtCN (2.5 mL) at À408C. [b] Yield of
isolated product. [c] The ratio of the major isomer to the minor isomer
was determined by 1H NMR analysis. [d] The ee value (major isomer)
was determined by HPLC analysis. [e] For 48 h.
The relative configuration of the major diastereomer was
determined to be 1,2-syn-1,5-anti by the X-ray crystallo-
graphic analysis of 3 f (Figure 1). The relative configurations
of the other compounds were analogously assigned by
comparison with the 1H NMR spectra.
Two routes to the double aldol product 3 were possible
from the alkyl methyl ketone 1, as shown in Scheme 3. The
first aldol reaction could have occurred at either the methyl or
2
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Scheme 4. NMR experiment for the enolization of the aldol adduct 4.
chairlike transition state involving a hypervalent silicon
species, thus affording the 1,2-syn adduct stereoselectively.[16]
Based on these results and previous observations,[9,16,17] we
propose a reaction mechanism for the double aldol reaction
(Scheme 5). The first aldol reaction occurs at the methyl
Figure 1. X-ray crystallographic structure of the double aldol adduct 3 f.
Thermal ellipsoids are shown at 30% probability.[14]
Scheme 5. Proposed reaction mechanism for the double aldol reaction.
group to give the silylated aldol adduct. The second enoliza-
tion step at the less congested exo position affords a chiral
cyclic Z-silyl enol ether. The enol ether reacts with another
aldehyde via a bicyclic six-membered transition state with the
assistance of a Lewis base silicon complex, thus giving the 1,2-
syn-1,5-anti product.
Scheme 3. Possible reaction routes of the double aldol reaction.
Si=SiCl3.
alkyl group to give the silylated aldol adducts A or B,
respectively, both of which would then convert into the same
double aldol adduct 3 after the second aldol transformation.
To investigate the first aldolization process, we performed
the reaction of 3-pentanone with benzaldehyde under the
same reaction conditions. No aldol adducts were obtained.
This result indicated a low reactivity for any alkyl ketones
other than methyl ketones, thus substantiating that the silyl
enol ether Aꢀ was selectively generated to give the aldolate A
for the first aldol reaction.
To investigate the second aldolization process, we exam-
ined the NMR spectra associated with the enolization of the
mono-aldol adduct 4 (Scheme 4). The 1H NMR analysis
showed the clean generation of the enol ether 5 as almost
a single isomer.[15] The NOESY correlation revealed that the
geometry of 5 was the Z isomer. The (Z)-trichlorosilyl enol
ethers are known to react with aldehydes via a six-membered
In summary, we demonstrated a novel enantioselective
double aldol reaction of an alkyl methyl ketone and two
aldehydes using a chiral phosphine oxide as an organo-
catalyst. The present reaction allows ready access to the 1,2-
syn-1,5-anti-1,5-dihydroxy-3-pentanones with high stereose-
lectivity in a single operation. Investigations focused on
achieving higher reactivity and selectivity for double aldol
reaction are in progress.
Received: December 10, 2012
Published online: && &&, &&&&
Keywords: aldol reaction · asymmetric catalysis · Lewis bases ·
.
silanes · synthetic methods
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4
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Angew. Chem. Int. Ed. 2013, 52, 1 – 5
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Angewandte
Chemie
Communications
Asymmetric Catalysis
Y. Shimoda, T. Kubo, M. Sugiura,
S. Kotani,* M. Nakajima*
&&&& — &&&&
Stereoselective Synthesis of Multiple
Stereocenters by Using a Double Aldol
Reaction
Triple play: The title reaction of an alkyl
methyl ketone and two aldehydes using
chiral (S)-binapo as a Lewis base catalyst
allows access to 1,5-dihydroxy-3-penta-
none derivatives with multiple chiral
centers in good yields with high dia-
stereo- and enantioselectivities in a single
operation.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!