Diastereo- and enantioselective reductive aldol reaction with trichlorosilane using Chiral Lewis bases as organocatalysts

Article abstract of DOI:10.1002/asia.200900450

Chiral Lewis base organocatalysts activate trichlorosilane to promote the tandem conjugate reduction/aldol reaction of α, β-unsaturated ketones with aldehydes to give optically active β-hydroxy ketones with good to high syn diastereo- and enantioselectivi

Full text of DOI:10.1002/asia.200900450

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DOI: 10.1002/asia.200900450
Diastereo- and Enantioselective Reductive Aldol Reaction with
Trichlorosilane Using Chiral Lewis Bases as Organocatalysts
Masaharu Sugiura,*[a] Norimasa Sato,[a] Yuko Sonoda,[a] Shunsuke Kotani,[b] and
Makoto Nakajima*[a]
Dedicated to the 150th anniversary of Japan–UK diplomatic relations
The catalytic enantioselective tandem reaction is an effi-
cient synthetic methodology in which optically active com-
pounds are assembled from simple prochiral substrates via
two (or more) distinct catalytic processes taking place under
the same conditions.[1] The synthetic efficiency is enhanced
by avoiding the time-intensive and yield-reducing isolation
and purification of synthetic intermediates and by decreas-
ing the amounts of chemicals and solvents used. The asym-
metric catalytic reductive aldol reaction is an efficient
tandem transformation involving conjugate reduction of
Scheme 1. The enantioselective reductive aldol reaction with trichlorosi-
a,b-unsaturated carbonyl compounds followed by aldol reac-
tion of the enolate intermediate with aldehydes or ketones.
Chiral transition-metal catalysts have been used to control
the stereochemistry of these transformations.[2,3] We recently
reported that achiral phosphorus oxides function as Lewis
base organocatalysts[4] to promote both the conjugate reduc-
tion of enones with trichlorosilane and the reductive aldol
reaction of enones with aldehydes.[5] Herein we report that
enantioselective catalysis of this tandem reaction by chiral
Lewis bases provides good to high diastereo- and enantiose-
lectivities.
lane catalyzed by a chiral Lewis base catalyst.
Scheme 1 outlines the current catalytic method. Our pre-
vious study had shown that the Lewis base catalyzed conju-
gate reduction with trichlorosilane proceeds via a six-mem-
bered transition state with an enone in the s-cis conforma-
tion to give the (Z)-trichlorosilyl enolate exclusively.[5]
Therefore, high syn selectivity is expected for the subse-
quent aldol process, assuming that the reaction proceeds
through a chair-like cyclic transition state. Moreover, high
enantioselectivity could also be achieved by judicious selec-
tion of chiral Lewis base catalysts (LB*).[6,7]
We first examined various chiral Lewis base catalysts
(Figure 1) for the reductive aldol reaction of chalcone (1a)
and benzaldehyde (2a) with trichlorosilane at À788C
(Table 1). With (S)-BINAPO, the reaction in dichlorome-
thane gave aldol adduct 3a with respectable stereoselectivi-
ties (Table 1, entry 1). By simply changing the solvent from
dichloromethane to propionitrile, both the stereoselectivities
and chemical yield dramatically improved (Table 1, entry 2).
Other Lewis base catalysts were then examined using this
solvent (Table 1, entries 3–6). (R,R)-DIOPO showed a com-
parable activity to BINAPO to afford similar enantioselec-
tivity with a slight loss of diastereoselectivity (Table 1,
entry 3). Although structurally similar to BINAPO, (S)-
[a] Prof. Dr. M. Sugiura, N. Sato, Y. Sonoda, Prof. Dr. M. Nakajima
Graduate School of Pharmaceutical Sciences
Kumamoto University
5-1 Oe-honmachi, Kumamoto 862-0973 (Japan)
Fax : (+81)96-362-7692
E-mail: msugiura@kumamoto-u.ac.jp (M. Sugiura)
nakajima@gpo.kumamoto-u.ac.jp (M. Nakajima)
[b] Prof. Dr. S. Kotani
Priority Organization for Innovation and Excellence
Kumamoto University
5-1 Oe-honmachi, Kumamoto 862-0973 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.200900450.
478
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Chem. Asian J. 2010, 5, 478 – 481

Table 2. Enantioselective reductive aldol reaction of various enones and
aldehydes.[a]
Entry Enone Aldehyde
t
Product Yield
[%]
syn/
anti
ee [%]
(syn)
Figure 1. Chiral Lewis base catalysts used in this study.
[h]
1
2
1b
1c
1c
1d
1a
1a
1a
1a
1a
1a
1a
1a
2a
2a
2a
2a
2b
2c
2d
2e
2 f
2g
2 f
2g
24
24
21
1.5 3d
8
6
24
24
24
8
4.5 3i
24 3j
3b
3c
3c
70
37
67
74
72
84
78
58
91
71
71
92
94:6
99:1
99:1
99:1
95:5
99:1
97:3
95:5
95:5
98:2
95:5
99:1
91
91
96
97
85
90
94
96
51
50
85
98
Table 1. Optimization of reaction conditions for the enantioselective re-
ductive aldol reaction of chalcone (1a) and benzaldehyde (2a).[a]
3[c]
4
5
6
7
8
3e
3 f
3g
3h
3i
9
Entry LB*
Conditions Yield
[%]
syn/
anti
ee [%]
10
11[d]
12[d]
3j
(syn[b]
)
1
(S)-BINAPO
CH2Cl2,
30 h
68
85:15
84
[a] Unless otherwise noted, reactions were carried out by addition of tri-
chlorosilane (1.0 mmol, ca. 3m solution in CH2Cl2) to a solution of an
enone (0.5 mmol), an aldehyde (0.6 mmol), and (S)-BINAPO (10 mol%)
in EtCN (2 mL) at À788C. [b] R=2,6,6-trimethyl-1-cyclohexenyl (b-
ionone). [c] With benzaldehyde (2 equiv) in CH2Cl2 instead of EtCN.
[d] With (R,R)-DIOPO (10 mol%) instead of (S)-BINAPO.
2
3
4
(S)-BINAPO
ACHTUNGTRENNUNG(R,R)-DIOPO
(S)-SEGPHO-
SO
(R)-BQNO
(R)-BIQNO
EtCN, 24 h 87
EtCN, 5 h 80
EtCN, 24 h 17
96:4
92:8
72:28
92
92
61
5
6
EtCN, 24 h 68
EtCN, 24 h 75
94:6
95:5
80[c]
4
[a] All reactions were carried out by addition of trichlorosilane
(1.0 mmol, ca. 3m solution in CH2Cl2) to
a
solution of chalcone
(0.5 mmol), benzaldehyde (0.6 mmol), and
a Lewis base catalyst
vestigated (Table 2, entries 5–10).[10,11] p-Anisaldehyde (2b)
and 2-furaldehyde (2c) having electron-rich aromatic rings
showed higher reactivity than benzaldehyde (2a; see
Table 1, entry 2), but the enantioselectivity was slightly de-
creased (Table 2, entries 5 and 6). On the other hand, an op-
posite tendency was observed for p-bromobenzaldehyde
(2d) and p-nitrobenzaldehyde (2e) having electron-with-
drawing substituents, which resulted in higher enantioselec-
tivity (Table 2, entries 7 and 8). In all cases, high syn diaste-
reoselectivities were observed. The reaction tolerated a,b-
unsaturated aldehydes to give the corresponding adducts in
good yields with high syn diastereoselectivity and moderate
enantioselectivity (Table 2, entries 9 and 10). For the reac-
tion of these enals, significantly improved enantioselectivity
was obtained by using (R,R)-DIOPO instead of (S)-
BINAPO (Table 2, entries 11 and 12). It is noteworthy that
the enone was chemoselectively reduced with trichlorosilane
in the presence of enals. The low reactivity of a,b-unsaturat-
ed aldehydes in the conjugate reduction might be attributed
to unfavorable conformations of enals in the reaction (see
Figure 2).[13] As shown in Figure 2a, the s-trans conformer
predominates for enals. Furthermore, the trichlorosilane–
Lewis base complex predominantly coordinates to the steri-
cally less hindered lone pair of the carbonyl oxygen leading
to anti complex B, even in the s-cis conformation (Fig-
ure 2b). Both the s-trans conformation and anti complex B
(10 mol%) in
[c] 2S,3S configuration.
a
solvent (2 mL) at À788C. [b] 2R,3R configuration.
SEGPHOSO was found to significantly lower the reactivity
and selectivities (Table 1, entry 4). On the other hand, (R)-
BQNO, a bisquinoline N,N’-dioxide developed in our labo-
ratory[8] exhibited good activity and selectivity, while (R)-
BIQNO,
a
bisisoquinoline N,N’-dioxide,[9] afforded low
enantioselectivity (Table 1, entries 5 and 6).[10,11]
Having discovered several effective catalysts, we next in-
vestigated the reductive aldol reaction of a variety of sub-
strates (Table 2). The reactions of several b-monosubstituted
enones (1b-d) with benzaldehyde (2a) were smoothly cata-
lyzed by (S)-BINAPO to afford the corresponding adducts
in good yields with high syn diastereo- and enantioselectivi-
ties (Table 2, entries 1–4).[11] Dichloromethane was found to
provide a higher yield and enantioselectivity than did pro-
pionitrile in the reaction of b-ionone, although diastereose-
lectivities were comparable in the two solvents (Table 2, en-
tries 2 vs. 3). The rapid transformation of enone 1d, which
bears a bulky isopropyl group, presumably results from the
substrateꢁs preference for the s-cis conformation, which is
favorable for the conjugate reduction (Table 2, entry 4).[12,13]
Using chalcone (1a) as the enone component, (S)-
BINAPO-catalyzed reactions with other aldehydes were in-
Chem. Asian J. 2010, 5, 478 – 481
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www.chemasianj.org
479

M. Sugiura, M. Nakajima et al.
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Acknowledgements
This work partially supported by a Grant-in-Aid of Scientific Research
from the Ministry of Education, Culture, Sports, Science and Technology
of Japan.
Keywords: aldol reaction · Lewis bases · organocatalysis ·
reduction · silanes
Figure 2. Conformational preference of a,b-unsaturated aldehydes and
their trichlorosilane complexes.
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Scheme 2. Intramolecular enantioselective reductive aldol reaction.
are unfavorable for the six-membered transition state re-
quired for the conjugate reduction.
Preliminary investigation has indicated that the current
method can be applied to an intramolecular process
(Scheme 2).[14] The (S)-BINAPO-catalyzed reaction of keto-
enone 4[14c] with trichlorosilane proceeded smoothly at
À408C to give the expected cyclized product cis-5 in a good
yield, but with low enantioselectivity. The enantioselectivity
was improved when (R)-BIQNO was used instead of
BINAPO, although the yield was moderate.[15] Further im-
provement of the intramolecular transformation is under in-
vestigation.
In summary, we have demonstrated that the reductive
aldol reaction of enones and aldehydes with trichlorosilane
is catalyzed by chiral Lewis base organocatalysts to afford
optically active b-hydroxy ketones with good to high diaster-
eo- and enantioselectivities. Further investigations including
extension of the scope of the reaction and application to
natural product synthesis are currently underway.
[4] For reviews on Lewis base organocatalysts, see: a) Y. Orito, M. Na-
ˇ
´
kajima, Synthesis 2006, 1391–1401; b) A. V. Malkov, P. Kocovsky,
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3585–3587.
[6] Denmark et al. reported that the aldol reaction of trichlorosilyl enol
ethers proceeds via a six-membered transition state involving hyper-
valent silicon compounds to provide high syn or anti diastereoselec-
tivity as reflected by the geometry of the enol ether. See: a) S. E.
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Experimental Section
General procedure for enantioselective reductive aldol reaction with tri-
chlorosilane: To a solution of a chiral Lewis base (10 mol%), an enone
(0.5 mmol), and an aldehyde (0.6 mmol, 1.2 equiv) in dry propionitrile
(2 mL) was added dropwise trichlorosilane (ca. 3m CH2Cl2 solution,
2 equiv) at À788C. The reaction was monitored by TLC analysis. After
the enone was consumed or no significant change was observed, the reac-
tion was quenched with sat. aqueous NaHCO3 (3 mL). After addition of
ethyl acetate (10 mL), the mixture was stirred for 1 h, filtered through a
celite pad and extracted with ethyl acetate (3ꢂ). The combined organic
layers were washed with brine (1ꢂ), dried over anhydrous MgSO4, fil-
tered, and evaporated. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate=20:1–3:1) to give the corre-
sponding aldol product.
[7] We have also demonstrated that chiral N-oxides or phosphine
oxides catalyze the aldol reaction of trichlorosilyl enol ethers to pro-
vide high diastereo- and enantioselectivities: a) M. Nakajima, T.
Yokota, M. Saito, S. Hashimoto, Tetrahedron Lett. 2004, 45, 61–64;
b) S. Kotani, S. Hashimoto, M. Nakajima, Synlett 2006, 1116–1118;
c) S. Kotani, S. Hashimoto, M. Nakajima, Tetrahedron 2007, 63,
3122–3132. For related chiral phosphine oxide-catalyzed phospho-
nylation of aldehydes, see: d) K. Nakanishi, S. Kotani, M. Sugiura,
M. Nakajima, Tetrahedron 2008, 64, 6415–6419.
[8] M. Nakajima, Y. Sasaki, M. Shiro, S. Hashimoto, Tetrahedron:
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[9] a) M. Nakajima, M. Saito, M. Shiro, S. Hashimoto, J. Am. Chem.
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Chem. Asian J. 2010, 5, 478 – 481

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[10] Small amounts (<5%) of the 1,2-reduction products of aldehydes
were obtained in all cases (Tables 1 and 2).
[11] The relative configurations of b-hydroxy ketones 3 were assigned
based on their characteristic 1H NMR signals of the carbinol me-
thine proton. See: a) S. E. Denmark, K.-T. Wong, R. A. Stavenger, J.
Am. Chem. Soc. 1997, 119, 2333–2334. The absolute configurations
of 3a and 3c were assigned by comparison of the optical rotation
with the literature value: b) G. P. Boldrini, M. Bortolotti, F. Mancini,
E. Tagliavini, C. Trombini, A. Umani-Ronchi, J. Org. Chem. 1991,
56, 5820–5826. The absolute configurations of the other products
were assigned by analogy.
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5743–5746. For enantioselective reductive aldol cyclizations, see ref-
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[12] For related discussions on the stereochemistry of conjugate addi-
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G. C. Fu, J. Org. Chem. 1990, 55, 5678–5680; b) K. Nishimura, K.
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[13] For leading references on the conformational analysis of a,b-unsatu-
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[15] The absolute configuration of the major enantiomer obtained with
(R)-BIQNO was opposite to that obtained with (S)-BINAPO. The
major side reaction was the conjugate addition of chloride anion to
the enone moiety of 4 which prevented the desired conjugate reduc-
tion.
Received: September 12, 2009
Revised: October 8, 2009
Published online: December 23, 2009
Chem. Asian J. 2010, 5, 478 – 481
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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