Catalytic enantioselective intermolecular reductive aldol reaction to ketones

Article abstract of DOI:10.1016/j.tetlet.2005.12.097

We describe the first example of a catalytic enantioselective intermolecular reductive aldol reaction. Three types of reactions were studied: (1) reactions between acetophenone and methyl acrylate; (2) reactions between symmetric ketones and β-substituted

Full text of DOI:10.1016/j.tetlet.2005.12.097

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1403–1407
Catalytic enantioselective intermolecular reductive aldol
reaction to ketones
Dongbo Zhao, Kounosuke Oisaki, Motomu Kanai* and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan
Received 19 November 2005; revised 12 December 2005; accepted 19 December 2005
Abstract—We describe the first example of a catalytic enantioselective intermolecular reductive aldol reaction. Three types of reac-
tions were studied: (1) reactions between acetophenone and methyl acrylate; (2) reactions between symmetric ketones and b-substi-
tuted a,b-unsaturated esters; and (3) reactions between acetophenone derivatives and an allenic ester. Although only moderate
enantioselectivity was obtained in the first reaction type, high to excellent enantioselectivity was realized in the enantio-induction
at the a-position in the second reaction type and at the d-position in the third reaction type. Specifically, the third reaction type
afforded the corresponding tertiary alcohols with up to 99% ee. Pre-activation of the nucleophile by silyl enolate formation is
not necessary in these one-pot catalytic enantioselective reductive aldol reactions.
Ó 2005 Elsevier Ltd. All rights reserved.
The development of catalytic enantioselective carbon–
carbon bond-forming reactions using simple ketones as
substrates has been intensively studied.1–4 This type of
reaction produces optically active tertiary alcohols,
which are important building blocks in many biologi-
cally active naturally occurring compounds and artificial
pharmaceuticals. Synthetically useful catalytic enantio-
selective reactions that can target ketones, however,
are limited due to both the attenuated reactivity of
ketones and the difficulty in differentiating subtle changes
between the two substituents on a ketone carbonyl
group. Among these types of reactions, the catalytic
enantioselective aldol reaction to ketones is the least well
established. Denmark reported the pioneering reaction
in this category.4a,b Due to its unsatisfactory enantio-
selectivity (8–86% ee), low substrate generality, and
required use of sensitive trichlorosilyl enolate, this
approach requires further improvement. Recently, Cam-
pagne reported a catalytic asymmetric vinylogous aldol
reaction using silyl dienolate as the nucleophile.4c In this
reaction, the chemical yield of the desired d-lactone is
not necessarily high (17–81% yield). To broaden the
scope of this field, the development of a catalytic reac-
tion that can overcome the low reactivity of ketones is
necessary, and such studies should allow for further
development of catalytic enantioselective tertiary alco-
hol synthesis using a novel approach. In this letter, we
describe the first catalytic enantioselective intermole-
cular reductive aldol reaction to ketones using a chiral
CuF catalyst.5
We previously reported a general method for the cata-
lytic aldol reaction of ketene trimethylsilyl acetals to
simple ketones using CuF as a catalyst.6,7 In this meth-
od, the addition of a stoichiometric amount of (EtO)3-
SiF was critical. Mechanistic studies suggested that a
copper enolate generated through transmetalation be-
tween silicon and copper atoms is the actual nucleophile,
and (EtO)3SiF facilitates the rate-determining copper
enolate formation via the generation of triethoxysilyl
enolates from trimethylsilyl enolates. This method
almost completely overcame the reactivity problem of
ketones in the aldol reaction, producing a high chemical
yield and reaction rate from a wide range of ketones
and silyl enolates. Moreover, this reaction was recently
extended to a catalytic enantioselective aldol reaction
to ketones.8 By developing new chiral diphosphine
ligands, ketone aldol products were produced with up
to 66% ee.
In parallel with our development of the CuF-catalyzed
aldol reaction to ketones, the Buchwald and Lipshutz
groups independently reported a catalytic enantioselec-
tive conjugate reduction of a,b-unsaturated carbonyl
Keywords: Asymmetric catalysis; Aldol reaction; Ketones; Copper
fluoride; Conjugate reduction; Multi-component reaction.
*
Corresponding authors. Fax: +81 3 5684 5206 (M.S.); e-mail:
mshibasa@mol.f.u-tokyo.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.097

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D. Zhao et al. / Tetrahedron Letters 47 (2006) 1403–1407
compounds using chiral Cu(I) catalysts.9–11 These asym-
metric reactions are based on the findings by Mori
et al.12 and Hosomi et al.13 that conjugate reduction of
enones and a,b-unsaturated esters proceeds using hyd-
rosilane and Cu(I) salts (20–200 mol %). The intermedi-
ate of the asymmetric conjugate reduction should be a
chiral copper enolate, therefore we thought it would
be possible to use this intermediate as a nucleophile in
an aldol reaction to ketones in the second step of a
one-pot sequential reductive aldol reaction (Scheme 1).
An advantage of this methodology compared to the
previous catalytic enantioselective aldol reactions to
ketones using silyl enolates is that pre-activation of the
nucleophile by silyl enolate formation is not necessary.
Thus, we planned to investigate a catalytic enantioselec-
tive reductive aldol reaction to ketones using a chiral
CuF catalyst. A catalytic enantioselective intermolecular
reductive aldol reaction between aldehydes and acrylate
esters was initially developed by Morken using Rh–chi-
ral bisphosphine or Ir–pybox complex as a catalyst and
Et2MeSiH as the reducing reagent.14,15 Syn-aldol prod-
ucts were obtained using Morken’s reaction. Recently,
Nishiyama reported an anti-selective enantioselective
reductive aldol reaction of aldehydes using a chiral
Rh-complex with an N–C–N ligand.16,17 In contrast, a
catalytic enantioselective intermolecular reductive aldol
reaction to ketones has not yet been reported. The pre-
viously reported reductive aldol reaction to ketones is
restricted to only an intramolecular version.5,18
the first step.19 When CuOtBu (prepared in situ from
CuCl and NaOtBu), a catalyst in the Buchwald and Lip-
shutz conjugate reduction, was applied to the catalytic
reductive aldol reaction (entry 1), the desired product
3aa was obtained in only 37% yield. The major product
was 1-phenylethanol, generated through a 1,2-reduction
of 1a. The yield of 3aa was improved to 47% when Cu-
FÆ3PPh3Æ2EtOH was used as a catalyst (entry 2).
The 1,2-reduction of 1a, however, was still a problematic
side reaction pathway. To more efficiently differentiate
between the desired conjugate reduction of 2a and the
undesired 1,2-reduction of 1a, we tried a slow addition
of (EtO)3SiH. When (EtO)3SiH was added slowly to a
mixture of the catalyst, 1a, and 2a over 8 h, the desired
reductive aldol product was obtained in quantitative
yield (entry 3). Although the diastereoselectivity (1.2:1)
and enantioselectivity (up to 29% ee) were low in this
case,20 we determined the reaction conditions for the
intermolecular reductive aldol reaction to ketones. Pin-
acolborane could also be used instead of (EtO)3SiH to
promote this reductive aldol reaction (entry 4). Compa-
rable results were obtained between these two reducing
reagents, which suggested that a copper enolate is the
actual nucleophile. The reductive aldol reaction between
1a and 2a did not proceed at all with other catalysts, such
as [Rh(COD)Cl]2 (the catalyst for reductive aldol reac-
tion to aldehydes reported by Morken14), AgF, NiF2,
Co2(CO)8,21 Fe2(CO)9,21 or In(OAc)3.17a Preliminary
screening of the chiral bisphosphines (entries 5 and 6)
slightly improved the diastereoselectivity (entry 6 using
iPr-DUPHOS); however, the enantioselectivity and total
chemical yield decreased.
To determine the reaction conditions, a reductive aldol
reaction between methyl acrylate (2a) and acetophenone
(1a) was first studied using (R)-tol-BINAP (5 mol %) as
a ligand (Table 1). (EtO)3SiH was selected as a reducing
reagent under the assumption that the second aldoliza-
tion step would proceed even if the reductively generated
copper enolate was trapped by the triethoxysilyl group in
Substrate generality in terms of both nucleophile pre-
cursors and ketones was then investigated under the
optimized reaction conditions. Because meaningful
enantio- and diastereoselectivity was not produced from
Scheme 1. Mechanistic speculation for reductive aldol reaction to ketones.

D. Zhao et al. / Tetrahedron Letters 47 (2006) 1403–1407
1405
Table 1. Optimization of catalytic enantioselective intermolecular reductive aldol reaction to ketones
Entry
Cu catalyst
Ligand
Yield (%)a
ee (%)b
1c
2c
3d
4e
5d
6d
CuCl+NaOtBu
(R)-tol-BINAP
(R)-tol-BINAP
(R)-tol-BINAP
(R)-tol-BINAP
(R)-DTBM-SEGPHOS
(S,S)-iPr-DUPHOS
37 (57/43)
47 (47/53)
100 (55/45)
100 (47/53)
41 (44/56)
66 (71/29)
30/7
24/5
29/1
28/5
15/27
22/7
CuFÆ3PPh3Æ2EtOH
CuFÆ3PPh3Æ2EtOH
CuFÆ3PPh3Æ2EtOH
CuFÆ3PPh3Æ2EtOH
CuFÆ3PPh3Æ2EtOH
a Isolated yield. Diastereomer ratio (2S,3S/2S,3R) is in parenthesis.20
b Determined by chiral HPLC.
c Ratio of 2a/(EtO)3SiH/1 = 1.2:3.0:1. (EtO)3SiH was added in one portion. Reaction time = 12 h.
d Ratio of 2a/(EtO)3SiH/1 = 1.5:1.6:1. (EtO)3SiH was added slowly over 8 h using a syringe pump. Total reaction time = 12 h.
e Pinacolborane (1.6 equiv) was used instead of (EtO)3SiH with slow addition for 8 h. Reaction time = 12 h.
ketones with a prochiral carbonyl carbon such as 1a, we
examined asymmetric induction at the a-position using
symmetrical ketones, such as 3-pentanone (1b) and
cyclopentanone (1c) (Table 2). A series of b-substituted
a,b-unsaturated esters were chosen as pre-nucleophiles.
Due to the relatively higher reactivity of aliphatic
ketones compared with aromatic ketones, the reaction
proceeded at À25 °C. Moderate to high asymmetric
induction at the a-position was realized in reactions
between ketone 1b and b-methyl, ethyl, and phenyl
substituted a,b-unsaturated esters 2b–d (Table 2, entries
1–3). Unfortunately, other symmetric ketones such as 1c
produced only low enantioselectivity (30% ee, entry 4).
Although the enantioselectivity was still not satisfactory,
the fact that a similar level of enantioselectivity was in-
duced in the present reductive aldol reaction compared
to the previously developed aldol reaction using silyl
enolates6 (ee values shown in parentheses) further sug-
gested that both of these reactions proceed through
the same active nucleophile, a copper enolate. More-
over, the present reaction is more convenient because
pre-activation of the nucleophile through silyl enolate
formation is not necessary.
Finally, promising results for optically active tertiary
alcohol synthesis were obtained using allenic ester 4 as
a pre-nucleophile (Table 3).22 This reaction is signifi-
cantly more complex than that using a,b-unsaturated
esters 2 as the nucleophile. After conjugate reduction
of 4, the aldol reaction of the corresponding copper
dienolate23 would produce a-adducts 5 (diastereomix-
tures) and c-adducts (trans-6 and cis-7). There was a
significant difference in reactivity in the reaction between
1a and 4 when either pinacolborane or (EtO)3SiH was
used as the reducing reagent. Although reactions using
(EtO)3SiH were very sluggish and the reductive aldol
products were obtained in less than 30% yield in most
cases, the reaction using pinacolborane proceeded
smoothly (Table 3). Thus, using (R)-tol-BINAP as a
chiral ligand, aldol products were obtained in 82%
Table 2. Asymmetric induction at a-position in reductive aldol reaction to symmetric ketonesa
Entry
R1
R2
Yield%b
ee (%)c
1
2
3
4
Et (1b)
Et (1b)
Et (1b)
–(CH2)4– (1c)
Me (2b)
Et (2c)
Ph (2d)
H (2a)
93
96
52
60
71 (70)
76 (72)
80 (82)d
30 (29)
a (EtO)3SiH was added slowly over 8 h using a syringe pump. Total reaction time = 12 h.
b Isolated yield.
c Determined by chiral HPLC or GC. Ee values in parentheses were obtained in the corresponding aldol reaction using ketene trimethylsilyl acetals
(1.2 equiv) in the presence of (EtO)3SiF (1.2 equiv).6
d Absolute configuration was determined to be R.6

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D. Zhao et al. / Tetrahedron Letters 47 (2006) 1403–1407
Table 3. Catalytic asymmetric reductive aldol reaction with allenic ester as nucleophile precursora
Entry
Ligand
Ketone (R3)
Yield (%)b
5 (diastereo ratio)
6
7 (ee (%)c)
1
2
3
4
5
(R)-tol-BINAP
1a (H)
1a (H)
1a (H)
1d (Cl)
1e (Me)
38 (21/79)
68 (22/78)
22 (10/90)
31 (50/50)
16 (25/75)
20
8
4
3
4
24 (98)d
23 (87)d
46 (99)d
33 (98)
47 (99)
(S,S)-iPr-DUPHOS
(R)-DTBM-SEGPHOS
(R)-DTBM-SEGPHOS
(R)-DTBM-SEGPHOS
a Pinacolborane was added slowly over 8 h using a syringe pump. Total reaction time = 16 h.
b Calculated from 1H NMR of the crude mixture using an internal standard.
c Determined by chiral HPLC.
d Absolute configuration was determined to be R after conversion to the known d-lactone.4c
combined yield (Table 3, entry 1). The regioselectivity
Acknowledgements
(c/a selectivity), diastereoselectivity of the a-adducts,
and trans/cis selectivity of the c-adducts were not
high. The c-cis adduct 7a, however, was obtained with
extremely high enantiomeric excess (up to 98%). Other
products 5a and 6a were obtained with less than 30%
ee.24
Financial support was provided by Grant-in-Aid for
Specially Promoted Research of MEXT. K.O. thanks
to JSPS for a research fellowship.
References and notes
After obtaining this preliminary result, chiral ligand
effects were screened using other bisphosphine ligands
such as iPr-DUPHOS and (R)-DTBM-SEGPHOS.
c-cis/c-trans (7/6) selectivity was improved to 3:1 for
iPr-DUPHOS, but the yield and enantioselectivity of
7a decreased (entry 2). On the other hand, the best
results were obtained with respect to yield and enantio-
selectivity of the desired 7a (46% yield and 99% ee, entry
3) using (R)-DTBM-SEGPHOS as a chiral ligand.
Although the c/a selectivity (6+7/5) was still only mod-
erate at the current stage, the cis/trans selectivity (7/6) of
the c-adducts was satisfactory [with up to 10:1 (entry 3)].
Subsequently, this catalytic system was applied to
substituted acetophenone analogues using DTBM-SEG-
PHOS as the chiral ligand. Excellent enantioselectivity
was produced in the c-cis adducts 7b and 7c (entries 4
and 5). These results are significant considering that
the asymmetric catalyst selectively promotes one specific
reaction pathway with enantio-, regio-, chemo-, and cis/
trans-selectivities from a number of possible reaction
pathways involved in this one-pot multi-component cat-
alytic asymmetric process.25
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selective inter-molecular reductive aldol reaction to
ketones. This ‘one-pot’ method produces optically
active aldol products containing a tetrasubstituted
carbon without a silyl enolate formation step. Excel-
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denied also in this case, because the similar level of
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