Multicenter Strategy for the Development of Catalytic Enantioselective Nucleophilic Alkylation of Ketones: Me2Zn Addition to α-Ketoesters

Article abstract of DOI:10.1002/anie.200351650

An array of heteroatoms is essential for the activity and enantioselectivity of the catalyst 2 in the addition of Me₂Zn to α-ketoesters 1 (e.g. see equation). α-Hydroxyesters 3 were obtained with up to 96% ee in the presence of a catalytic amount of additive iPrOH, which serves to generate the catalytically active monomeric species (based on the observation of nonlinear effects).

Full text of DOI:10.1002/anie.200351650

Angewandte
Chemie
Asymmetric Alkylation of Ketones
Multicenter Strategy for the Development of
Catalytic Enantioselective Nucleophilic
Alkylation of Ketones: Me2Zn Addition to
a-Ketoesters**
Ken Funabashi, Markus Jachmann, Motomu Kanai, and
Masakatsu Shibasaki*
The catalytic construction of stereogenic tetrasubstituted
carbon centers through the addition of carbon nucleophiles to
ketones or ketoimines is very challenging, partly because of
the lower reactivity of these substrates relative to aldehydes
and aldoimines.[1] This task requires strong activation of the
substrate and/or the nucleophile by an asymmetric catalyst.
We developed Lewis acid–Lewis base two-center asymmetric
catalysts (titanium and lanthanide complexes of 1) that
promote the cyanosilylation of ketones and ketoimines with
broad substrate generality.[2] The fundamental concept for the
catalyst design was that the Lewis acid metal and the Lewis
base (the phosphane oxide) activate both the substrate and
the nucleophile (TMSCN) simultaneously at defined posi-
tions in the transition state. A logical extension of this concept
is to target the diorganozinc addition to ketones,[3] because
both Lewis acid activation of the substrate and Lewis base
activation of the reagent are required to promote the
reaction.[4] We report herein our initial investigations
toward this goal: the catalytic enantioselective addition of
Me2Zn to a-ketoesters. Our newly designed catalyst 2, which
[*] Prof. Dr. M. Shibasaki, K. Funabashi, Dr. M. Jachmann, Dr. M. Kanai
Graduate School of Pharmaceutical Sciences
The University of Tokyo
Hongo, Bunkyo-Ku, Tokyo 113-0033 (Japan)
Fax: (+81)3-5684-5206
E-mail: mshibasa@mol.f.u-tokyo.ac.jp
Dr. M. Kanai
PRESTO, Japan Science and Technology Corporation
Graduate School of Pharmaceutical Sciences
The University of Tokyo
Hongo, Bunkyo-Ku, Tokyo 113-0033 (Japan)
[**] Financial support was provided by RFTF of the Japan Society for the
Promotion of Science (JSPS) and PRESTO of the Japan Science and
Technology Corporation (JST). K.F. thanks JSPS Research Fellow-
ships for Young Scientists. M.J. is an Alexander von Humboldt
Foundation–JSPS fellow.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2003, 42, 5489 –5492
DOI: 10.1002/anie.200351650
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5489

Communications
contains arranged multicenters (alcohols and an amine),
combination of these two factors should allow the reaction to
proceed through a dual activation pathway with the strongly
activated nucleophilic Me2Zn, and both high catalyst activity
and enantioselectivity should be observed. Based on these
considerations, we designed new enantioselective catalysts 2–
8. These catalysts could be readily synthesized in two steps
from commercially available 2,4-cis-4-hydroxy-d-proline
methyl ester.[8] Catalyst 9, which lacks the 4-hydroxy
group,[9] and the 2,4-trans catalyst 10[10] were also prepared
as control catalysts.
The function of catalysts 2, 9, and 10 (20 mol%) was first
investigated for the reaction of Me2Zn and 13b in toluene at
ꢀ208C for 24 h. As shown in Table 1, 2,4-cis catalyst 2 gave
product 14b in 72% yield with 82% ee (entry 1). Catalysts 9
and 10, however, gave the product in only moderate yield with
very low enantioselectivity (Table 1, entries 2 and 3). It can
therefore be concluded that the 2,4-cis configuration of the
diols is essential for high yield and enantioselectivity. Based
on molecular-modeling studies, these two oxygen atoms must
be in close proximity so that the two alkoxides can chelate
Me2Zn, which acts as a nucleophile. The sharp contrast
between the catalytic activity and enantioselectivity of 2 and 9
or 10 might be due to the ability of the zinc alkoxides to
chelate the nucleophile.[11]
Next, we investigated a decrease in the catalyst loading.
When the amount of 2 was decreased to 10 mol%, the
enantioselectivity was significantly decreased to 53% ee
(Table 1, entry 4). This might be due partly to the competitive
catalyst-independent background reaction. Thus, we tried
slow addition (30 h) of Me2Zn. The product was obtained with
83% ee (Table 1, entry 5), which was comparable to the
results obtained with 20 mol% of the catalyst. Under these
optimized reaction conditions, the catalyst structure was
further modified. When the diaryl alcohol was changed into a
dimethyl alcohol (catalyst 3), a significant loss of enantiose-
lectivity occurred (Table 1, entry 6). The electron-withdraw-
ing or -donating group on the aryl group, however, did not
have a significant effect (Table 1, entries 7 and 8). Finally,
catalyst 2, which contains a benzyl substituent on the nitrogen
atom, produced the best enantioselectivity, and catalysts that
bear smaller (N-allyl; Table 1, entry 9) and larger (N-b-
naphthyl and N-9-anthracenyl; Table 1, entries 10 and 11)
substituents gave lower enantioselectivity. The yield of the
product was dependent on the bulkiness of the ester moiety of
the substrate (Table 1, entries 12–14), and the best results
were obtained with the small methyl ester 13a as the substrate
(Table 1, entry 12).
To improve the enantioselectivity further, several addi-
tives were screened.[12] Although neither coordinating addi-
tives such as Ph3P(O), Et3N, Ph3P, or LiBr, nor Brönsted acids
such as trifluoromethanesulfonic acid or trifluoroacetic acid
produced positive effects, the addition of protic additives such
as MeOH, EtOH, iPrOH, or tBuOH improved both the yield
and enantioselectivity (Figure 2). Although the tendency was
slightly different depending on the alcohol, the chemical yield
increased up to 96% (in the presence of 27 mol% EtOH) and
the enantioselectivity up to 95% ee (in the presence of
18 mol% EtOH). The best results in terms of yield and
enantioselectivity were obtained in the presence of 27 mol%
produced the corresponding products with up to 96% ee from
aromatic and acetylenic a-ketoesters. This type of catalytic
enantioselective reaction was recently reported by DiMauro
and Kozlowski; however the enantioselectivity and substrate
generality were not necessarily high (up to 78% ee).[5] The
products are useful chiral building blocks for the synthesis of
pharmaceutical agents and natural products.[6]
Because 1 did not produce satisfactory catalyst activity
and enantioselectivity in the reaction of Me2Zn with ethyl
benzoylformate (13b; see Table 1), we developed a new
catalyst system. Based on the transition-state model initially
Table 1: Optimization of the reaction conditions.[a]
Entry 13/14 Catalyst x [mol%] t [h][b]
Yield [%][c] ee [%][d]
1
2
3
4
5
6
7
8
b
b
b
b
b
b
b
b
b
b
b
a
c
2
9
10
2
2
3
4
5
6
7
8
2
2
2
20
20
20
10
10
10
10
10
10
10
10
10
10
10
24
24
24
36
72
45
28
63
82
0
7[e]
53
83
4
30+12 69
30+12 89
30+12 85
30+12 89
30+12 78
30+12 55
30+12 89
30+12 85
30+12 74
30+12 17
80
77
33
56
33
81
40
n.d.[f]
9
10
11
12
13
14
d
[a] Me2Zn: 1.8 equiv (entries 1–4) or 2.5 equiv (entries 5–14). [b] In
entries 1–4, Me2Zn was added in one portion, whereas in entries 5–14,
Me2Zn was added slowly over 30 h, and the reaction was continued for
12 h. [c] Yield of isolated product. [d] Determined by chiral HPLC
analysis. [e] The opposite enantiomer was the major isomer. [f] Not
determined.
proposed by Noyori and co-workers (Figure 1, 11),[7] we
expected that the presence of an additional Lewis base
coordinating to Me2Zn would more strongly activate the
nucleophile (Figure 1, 12). Moreover, we planned to use a
zinc alkoxide as the additional Lewis base, because anionic
Lewis bases have a greater electron-donating ability than
neutral Lewis bases such as amines or phosphane oxides. The
Figure 1. Fundamental concepts of catalyst design.
5490
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Angewandte
Chemie
droxy esters. Ketoester 13k that is constrained to the s-cis
form of the ketone and amide carbonyls gave 76% ee
(Table 2, entry 9). Thus, this is the first example of a catalytic
enantioselective addition of Me2Zn to a-ketoesters that
affords products with high enantioselectivity.[13,14]
Although a detailed mechanistic discussion is difficult at
present owing to the lack of information on the structure of
the catalyst, we obtained important information regarding the
role of the additive, based on the differences in the nonlinear
effects[15] in the absence or presence of iPrOH (Figure 3).
Figure 2. Effect of additive alcohol on yield and enantioselectivity.
a) Relationship between yield and amount of additive. b) Relationship
between ee and amount of additive.
iPrOH, and product 14a was obtained in 95% yield with
92% ee.
Substrate generality was then investigated under the
optimized reaction conditions. High ee values were obtained
with aromatic and heteroaromatic ketones (Table 2,
entries 1–7). Although the enantioselectivity was moderate,
the present reaction could also be applied to acetylenic
ketoester 13j (Table 2, entry 8). The product is a versatile
precursor for functionalized or a,a-dialkyl-substituted hy-
Figure 3. Nonlinear effects a) in the absence of and b) in the presence
of iPrOH.
Positive nonlinear effects were observed in the absence of
iPrOH, however the nonlinearity almost disappeared in the
presence of 27 mol% iPrOH. These results suggest that the
additive iPrOH (thus, zinc isopropoxide in the reaction
mixture) changes the catalyst structure into a monomeric
form by mixed aggregate formation, which might be the
actual catalytic species that results in the high enantioselec-
tivity and reactivity.
Table 2: Catalytic enantioselective addition of Me2Zn to a-ketoesters.[a]
Entry
13
2 [mol%]
Yield [%][b]
ee [%][c]
In summary, we developed a new enantioselective catalyst
for the addition of Me2Zn to a-ketoesters. The cis arrange-
ment of the two hydroxy groups on the pyrrolidine ring is
essential for high catalyst activity and enantioselectivity.
Addition of a catalytic amount of iPrOH improved the yield
and enantioselectivity. The nonlinear effects suggest that the
additive forms a monomeric catalyst species. The information
obtained in the present study will be useful for the develop-
ment of an enantioselective catalyst of diorganozinc addition
to simple ketones. Studies toward this end and to clarify the
reaction mechanism are underway.
1
R=Ph (13a)
R=Ph (13a)
R=p-Br-C6H4 (13e)
10
10
10
95
70 (91)
89
92[d]
85[d]
85
2[f]
3
4
5
R=p-MeO-C6H4 (13 f)
10
10
42
77
92
80
6
10
91
96
7
8
20
10
89
75
72
Received: April 14, 2003 [Z51650]
Published Online: August 1, 2003
59[d]
Keywords: alkylation · asymmetric catalysis · homogeneous
.
catalysis · ketoesters · nonlinear effects
9
20
82
76[e]
[a] For experimental procedure, see reference [13]. [b] Yield of isolated
product. [c] Determined by chiral HPLC analysis. [d] The absolute
configuration was determined to be R. [e] The absolute configuration
was determined to be S. [f] Reaction carried out on a 1.6-g scale.
Conversion yield is in parenthesis. Recovery of chiral ligand 2: 98%.
[1] a) E. J. Corey, A. Guzman-Perez, Angew. Chem. 1998, 110, 402 –
415; Angew. Chem. Int. Ed. 1998, 37, 388 – 401; b) J. Christoffers,
A. Mann, Angew. Chem. 2001, 113, 4725 – 4732; Angew. Chem.
Int. Ed. 2001, 40, 4591 – 4597.
Angew. Chem. Int. Ed. 2003, 42, 5489 –5492
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Communications
[2] For a review, see: M. Shibasaki, M. Kanai, K. Funabashi, Chem.
Commun. 2002, 1989 – 2183.
[3] For the catalytic enantioselective addition of diorganozinc
reagents to simple ketones, see: a) P. I. Dosa, G. C. Fu, J. Am.
Chem. Soc. 1998, 120, 445 – 446; b) D. J. Ramón, M. Yus,
Tetrahedron 1998, 54, 5651 – 5666; c) M. Yus, D. J. Ramón, O.
Prieto, Tetrahedron: Asymmetry 2002, 13, 2291 – 2293; d) C.
Garcia, L. K. LaRochelle, P. J. Walsh, J. Am. Chem. Soc. 2002,
124, 10970 – 10971.
[4] a) R. Noyori, M. Kitamura, Angew. Chem. 1991, 103, 34 – 55;
Angew. Chem. Int. Ed. Engl. 1991, 30, 49 – 69; b) R. Noyori,
Asymmetric Catalysis in Organic Synthesis, Wiley, New York,
1994; c) K. Soai, T, Shibata in Comprehensive Asymmetric
Catalysis, Vol. 2 (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto),
Springer, Berlin, 1999, pp. 911 – 922; d) C. Bolm, K. Muæiz,
Chem. Soc. Rev. 1999, 28, 51 – 59; e) L. Pu, H.-B. Yu, Chem. Rev.
2001, 101, 757 – 824.
[5] For a bifunctional asymmetric catalyst that promotes alkylation
selectively with Et2Zn, see: a) E. F. DiMauro, M. C. Kozlowski,
J. Am. Chem. Soc. 2002, 124, 12668 – 12669; b) E. F. DiMauro,
M. C. Kozlowski, Org. Lett. 2002, 4, 3781 – 3784; for highly
enantioselective alkynylation of a-ketoesters, see: B. Jiang, Z.
Chen, X. Tang, Org. Lett. 2002, 4, 3451 – 3453; however, this
method cannot be applied to the synthesis of methyl-substituted
chiral tertiary alcohols (low yield).
[6] Many biologically active compounds contain methyl-substituted
chiral tertiary alcohols.
[7] M. Kitamura, S. Okada, S. Suga, R. Noyori, J. Am. Chem. Soc.
1989, 111, 4028 – 4036.
[8] For details, see Supporting Information.
[9] For enantioselective addition of dialkylzinc to aldehydes with
prolinol-derived catalysts, see: K. Soai, A. Ookawa, T. Kaba, K.
Ogawa, J. Am. Chem. Soc. 1987, 109, 7111 – 7115.
[10] For enantioselective addition of Et2Zn to aldehydes with 2,4-
trans hydroxyproline-derived catalysts, see: a) G. Liu, J. A.
Ellmann, J. Org. Chem. 1995, 60, 7712 – 7713; b) S. J. Bae, S.-
W. Kim, T. Hyeon, B. M. Kim, Chem. Commun. 2000, 31 – 32.
The secondary alcohol groups (C4) were protected as ethers in
these cases.
[11] No useful information was obtained from 1H and 13C NMR
spectroscopic measurements of the [Zn–2] complex. Studies to
determine the catalyst structure by X-ray crystallography are
underway.
[12] For a review on the additive effect on catalytic enantioselective
reactions, see: E. M. Vogl, H. Gröger, M. Shibasaki, Angew.
Chem. 1999, 111, 1672 – 1680; Angew. Chem. Int. Ed. 1999, 38,
1570 – 1577.
[13] General procedure: Me2Zn (1.0m in hexane, 18 mL, 0.018 mmol)
was added to a solution of the catalyst 2 (7.2 mg, 0.020 mmol) in
toluene (0.45 mL), and the mixture was stirred for 30 min at
room temperature. iPrOH (4.13 mL) in toluene (0.050 mL) was
then added and the mixture was stirred for 30 min. The mixture
was cooled to ꢀ208C and the a-ketoester (0.20 mmol) was
added, followed by the dropwise addition of Me2Zn (1.0m in
hexane, 482 mL, 0.482 mmol) over 30 h by using a syringe pump.
The reaction vessel has to be strictly sealed so as not to lose the
volatile Me2Zn. After all the Me2Zn was added, the reaction was
stirred for 12 h and then quenched with aqueous citric acid
(10%). Extraction with EtOAc and purification by column
chromatography (SiO2, EtOAc/hexane, 1:8!1:4) provided the
product.
[14] Further scope and limitations: A vinyl-substituted ketoester
=
[R = (E)-PhCH CH] gave the product in 92% yield with
15% ee. An alkyl-substituted ketoester (R = PhCH2CH2) gave
a complex mixture of products. The reaction of Et2Zn and 13a
did not give any products, and 13a was recovered.
5492
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Angew. Chem. Int. Ed. 2003, 42, 5489 –5492