Asymmetric addition of dimethylzinc to α-ketoesters catalyzed by (-)-MITH

Article abstract of DOI:10.1021/jo801034q

(Chemical Equation Presented) This investigation describes the catalytic asymmetric addition of dimethylzinc to α-ketoesters in the presence of (-)-MITH (5) and triethyl borate as an additive to give the corresponding chiral α-hydroxy esters with good yie

Full text of DOI:10.1021/jo801034q

Asymmetric Addition of Dimethylzinc to
r-Ketoesters Catalyzed by (-)-MITH
Hsyueh-Liang Wu, Ping-Yu Wu, Ying-Ying Shen, and
Biing-Jiun Uang*
Department of Chemistry, National Tsing Hua UniVersity,
Hsinchu, Taiwan 30013, Republic of China
bjuang@mx.nthu.edu.tw
ReceiVed May 14, 2008
FIGURE 1. Catalysts of catalytic addition of dialkylzinc to R-ke-
toesters.
R-ketoesters, are important precursors in synthetic organic
chemistry because they can be further functionalized to complex
and biologically active molecules. The optically active R-hy-
droxy esters can be prepared by the diastereoselective addition
of organometallic reagents to R-ketoesters with the employment
of chiral auxiliaries.3 Only a few catalytic enantioselective
methods have been developed for such a purpose.4 Unlike
aldehydes and ketones, R-ketoesters can act as chelating agents:
alkylzinc reagents are self-activated, so that the rapid back-
ground reaction of alkylzincs with R-ketoester proceeds without
enantioselection. A method that is based on the bifunctional
titanium-salen catalyst 14a,b effects the catalytic asymmetric
Et2Zn addition to R-ketoesters (Figure 1). This approach was
recently applied as a key step in constructing the quaternary
chiral center in the synthesis of (S)-camptothecin.5 A chiral
prolinol derivative 24c was developed to promote the asymmetric
addition of Me2Zn to R-ketoesters, providing the corresponding
R-hydroxy esters with up to 96% ee. These two ligand systems
exploit the concept of bifunctional catalysts, in which the
substrate is activated by a Lewis acid metal center and the
alkylzinc reagent is independently activated by a Lewis base
center in a cooperative manner; therefore, the reaction was
accelerated through the dual activation of both a substrate and
a nucleophile. The enantioselective Al-catalyzed transformation
of Me2Zn and Et2Zn to R-ketoesters in the presence of an amino
acid-based ligand 34d has been reported to afford the product
in high yields and ee’s. Recently, mandelamide 44e was utilized
in the addition of Me2Zn to R-ketoesters to generate good yields
This investigation describes the catalytic asymmetric addition
of dimethylzinc to R-ketoesters in the presence of (-)-MITH
(5) and triethyl borate as an additive to give the correspond-
ing chiral R-hydroxy esters with good yields and high
enantioselectivities.
Catalytic asymmetric carbon-carbon bond-forming reactions
are important in the synthesis of natural products and active
pharmaceutical compounds. Enantioselective addition of orga-
nozincs to carbonyl compounds, one of the most powerful
methods for constructing chiral carbon-carbon bonds, has been
widely studied. The enantio-enriched alcohols thus obtained are
valuable building blocks and intermediates. However, since
ketones are less reactive than aldehydes, the development of
chiral ligands for the asymmetric addition of organozinc reagents
to aldehydes is more popular than that to simple ketones.1
Recently, effective ligand systems have been reported to catalyze
the asymmetric addition of organozinc reagents to ketones;2 they
exhibited levels of reactivity and enantioselectivity similar to
those of aldehydes. This method is an effective tool for
constructing tetrasubstituted chiral centers but still raises a
tremendous interest for synthetic chemists.
R-Hydroxy esters that contain quaternary stereogenic centers,
(3) (a) Schuster, C.; Knollmueller, M.; Gaertner, P. Tetrahedron: Asymmetry
2006, 17, 2430–2441. (b) Boireau, G.; Deberly, A.; Loupy, A.; Monteux, D.
Tetrahedron Lett. 1999, 40, 6919–6922. (c) Akiyama, T.; Nishimoto, H.;
Ishikawa, K.; Ozaki, S. Chem. Lett. 1992, 447–450. (d) Solladie-Cavallo, A.;
Suffert, J. Tetrahedron Lett. 1984, 25, 1897–1900. (e) Whitesell, J. K.; Deyo,
D.; Bhattacharya, A. J. Chem. Soc., Chem. Commun. 1983, 391.
(4) (a) DiMauro, E. F.; Kozlowski, M. C. Org. Lett. 2002, 4, 3781–3784.
(b) DiMauro, E. F.; Kozlowski, M. C. J. Am. Chem. Soc. 2002, 124, 12668–
12669. (c) Funabashi, K.; Jachmann, M.; Kanai, M.; Shibasaki, M. Angew. Chem.,
Int. Ed. 2003, 42, 5489–5492. (d) Wieland, L. C.; Deng, H.; Snapper, M. L.;
Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 15453–15456. (e) Blay, G.;
Ferna´ndez, I.; Marco-Aleixandre, A.; Pedro, J. R. Org. Lett. 2006, 8, 1287–
1290.
which are synthesized by the addition of nucleophiles to
(1) For reviews, see: (a) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed.
Engl. 1991, 30, 49–69. (b) Soai, K.; Niwa, S. Chem. ReV. 1992, 92, 833–856.
(c) Soai, K.; Shibata, T. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: Berlin, Germany, 1999; Vol.
2, pp 911-922. (d) Pu, L.; Yu, H.-B. Chem. ReV. 2001, 101, 757–824. (e) Pu,
L. Tetrahedron 2003, 59, 9873–9886.
(2) (a) Ramo´n, D. J.; Yus, M. Tetrahedron Lett. 1998, 39, 1239–1242. (b)
Dosa, P. I.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 445–446. (c) Yus, M.;
Ramo´n, D. J.; Prieto, O. Tetrahedron: Asymmetry 2002, 13, 2291–2293. (d)
Garc´ıa, C.; LaRochelle, L. K.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 10970–
10971.
(5) Tang, C.-J.; Babjak, M.; Anderson, R. J.; Greene, A. E.; Kanazawa, A.
Org. Biomol. Chem. 2006, 4, 3757–3759.
10.1021/jo801034q CCC: $40.75
Published on Web 07/23/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 6445–6447 6445

TABLE 2. Effects of Additives on Asymmetric Addition of Me2Zn
to r-Ketoester
yielda (%)
eeb (%)
FIGURE 2. Asymmetric addition of organozincs to aldehydes catalyzed
by ligand 5.
entry
1c
2
3
4
5
6
7
8
additive
time (h)
10% DiMPEG
25% IPA
45
20
20
20
20
20
20
20
20
20
20
18
65
75
90
74
78
79
97
92
90
38
27
59
62
71
63
60
51
73
71
66
15
TABLE 1. Asymmetric Addition of Me2Zn to r-Ketoesters 6
Catalyzed by Ligand 5
10% B(OMe)3
25% B(OMe)3
50% B(OMe)3
100% B(OMe)3
200% B(OMe)3
25% B(OEt)3
25% B(Oi-Pr)3
25% B(Ot-Bu)3
25% B(OPh)3
Me2Zn
(equiv) solvent
time
(h)
yield of
eeb
(%)
9
10
11
entry
R
7a (%)
1
2
3
4
5
6
6a Me
1.5
3
6
6
6
6
6
6
6
toluene
toluene
toluene
hexane
hexane
hexane
hexane
hexane
hexane
23
23
12
5
5
7
5
24
65
7a
52
75
80
99
92
88
87
85
78
22
29
32
37
36
24
31
52
61
a Isolated yields after column chromatography. b Determination by
chiral HPLC. c Reaction was conducted in toluene.
6b Et
7b
7c
7d
7a
6c
i-Pr
when the ketoesters had bulkier ester substituents (entries 6 and
7). The enantioselectivity was improved (up to 61% ee) when
the reaction was carried out at -35 °C as the reaction time
increased (entry 9).
Whether additives enhance the level of enantioselectivity was
examined. DiMPEG8 and 2-propanol2b,4c are reportedly effective
additives in parallel reactions and were tested first (Table 2,
entries 1 and 2). The addition of these additives did not improve
the reaction in terms of yields and enantioselectivities. Interest-
7
6d t-Bu
6a Me
8c
9d
a Isolated yields after column chromatography. b Determination by
chiral HPLC. c Reaction was conducted at -20 °C. d Reaction was
conducted at -35 °C.
and ees, based on the concept of the control of electron-donating
capabilities of the coordinating groups.
9
ingly, the reaction rate increased when 10 mol % of B(OMe)3
As part of our early endeavors to develop camphor-derived
chiral ligands for use in catalytic asymmetric reactions,6 (-)-
2-exo-morpholinoisobornane-10-thiol (5)7 ((-)-MITH), has
been demonstrated to be an effective promoter of the
asymmetric addition of Et2Zn, alkenylzinc,7a and arylzinc7b
reagents to aldehydes, affording the corresponding optically
active alcohols with excellent enantioselectivities (95 to
>99% ee) (Figure 2). In principle, the employment of ligand
5 for the asymmetric addition of Me2Zn to R-ketoesters is
anticipated to exhibit a level of asymmetric induction that is
comparable to that of aldehydes. This work presents findings
concerning the asymmetric addition of Me2Zn to R-ketoesters
catalyzed by ligand 5.
Our study started with the addition of Me2Zn to methyl
benzoyl formate 6a in the presence of 10 mol % of ligand 5 at
0 °C using toluene as a solvent. The reaction gave the
corresponding product 7a with 52% yield and 22% ee when
1.5 equiv of Me2Zn was employed after 23 h (Table 1, entry
1). When the amount of Me2Zn was increased to 6 equiv, the
ee of 7a was increased to 32% (entry 3). A better chemical
yield and enantioselectivity were obtained when hexane was
used as a reaction medium (entry 4), and notably, the reaction
in toluene required a longer reaction time than that conducted
in hexane (entries 3 and 4). Subsequently, R-ketoesters with
diverse ester functional groups, including ethyl 6b, isopropyl
6c, and tert-butyl 6d, were examined under the above-mentioned
reaction conditions (entries 5-7). The corresponding products
7c,d were obtained with lower yields and enantioselectivities
was added, giving the corresponding product 7a with similar
yield and ee as obtained without additives (Table 2, entry 3 vs
Table 1, entry 9). The yield and enantioselectivity of 7a
depended on the amount of B(OMe)3 and an optimal result of
up to 90% yield and 71% ee was obtained in the presence of
25% B(OMe)3 (entry 4). Increasing the amount of additive
reduced enantioselectivities (entries 5-7). Next, various com-
mercially available borates were studied (entries 8-11), and in
the presence of 25% B(OEt)3, the reaction gave 7a with
improved yield (97%) and ee (73%) (entry 8).
Higher asymmetric induction was anticipated when the
reaction was conducted at a temperature lower than -35 °C. In
the presence of 25 mol % of B(OEt)3, the addition of Me2Zn to
R-ketoester 6a catalyzed by 10 mol % of ligand 5 at -50 °C
yielded compound 7a with 74% ee (Table 3, entry 1). The
reaction, using 20 mol % of ligand 5, gave compound 7a in a
better yield and ee (entry 2). No improvement in the enanti-
oselectivity was observed when the reaction was conducted at
-65 °C (entry 3); at -80 °C, the yield of the product was less
than 5% (entry 4). The slow addition (24 h) of compound 6a
was investigated to diminish the competitive self-catalyzed
background reaction of substrate and Me2Zn. The product 7a
was obtained in 81% ee and 85% yield (entry 5), giving results
similar to those obtained without the slow addition of the starting
material (entry 2).
To elucidate substrate generality, various R-ketoesters 8 were
subjected to the reaction conditions described in Table 3, entry
2. The ee of the corresponding product obtained from an
(6) (a) Chang, C.-W.; Yang, C.-T.; Hwang, C.-D.; Uang, B.-J. Chem.
Commun. 2002, 54–55. (b) Wu, H.-L.; Uang, B.-J. Tetrahedron: Asymmetry 2002,
13, 2625–2628. (c) Uang, B.-J.; Fu, I.-P.; Hwang, C.-D.; Chang, C.-W.; Yang,
C.-T.; Hwang, D.-R. Tetrahedron 2004, 60, 10479–10486.
(8) DiMPEG, dimethoxypoly(ethylene glycol), could enhace the chemical
yields and ee’s in the catalytic asymmetric arylzinc addition reaction; see:
Rudolph, J.; Hermanns, N.; Bolm, C. J. Org. Chem. 2004, 69, 3997–4000.
(9) B(OMe)3 was utilized to promote the Reformatsky reaction; see: Rathke,
M. W.; Lindert, A. J. Org. Chem. 1970, 35, 3966–3967.
(7) (a) Wu, H.-L.; Wu, P.-Y.; Uang, B.-J. J. Org. Chem. 2007, 72, 5935–
5937. (b) Wu, P.-Y.; Wu, H.-L.; Uang, B.-J. J. Org. Chem. 2006, 71, 833–835.
6446 J. Org. Chem. Vol. 73, No. 16, 2008

TABLE 3. Optimization of Reaction Conditions
yielda
(%)
eeb
(%)
entry
5 (mol %)
time (h)
26
22
68
1
10
20
20
20
20
83
74
79
75
2
85
43
<5
85
3c
4d
5f
e
92
-
(24 + 20)
81
a Isolated yields after column chromatography. b Determination by
chiral HPLC. c Reaction was conducted at -65 °C. d Reaction was
conducted at -80 °C. e Not determined. f Toluene solution of compound
6a was introduced within 24 h.
FIGURE 3. Correlation, with and without the additive, of ee between
adduct and ligand 5 using 0.73 M Me2Zn, 0.12 M PhCOCO2Me, and
20% of ligand 5 in hexane at -35 °C.
TABLE 4. Asymmetric Addition of Me2Zn to Various
r-Ketoesters
In conclusion, the application of ligand 5 for the catalytic
asymmetric addition of Me2Zn to R-ketoesters using B(OEt)3
as an additive is described. Notably, the adduct 9d obtained
from the reaction of methyl 4-methoxylbenzoyl formate (8d)
was isolated with up to 89% ee and 54% yield. Good to
moderate ee’s and yields of the corresponding product were
normally obtained. This result is comparable to those obtained
using bifunctional prolinol 2 and activated mandelamide deriva-
tive 4. The advantages of this methodology are that ligand 5
can be employed to prepare tetrasubstituted R-hydroxyl esters
with good enantioselectivities without the modification of its
parent structure, and both enantiomers are easily prepared.
Studies of nonlinear effect with and without B(OEt)3 exhibited
positive nonlinearity. The role of additive, B(OEt)3, in this
reaction and the studies concerning the asymmetric addition of
various dialkylzinc reagents to R-ketoesters catalyzed by ligand
5 are currently under investigation.
entrya
Ar
time (h)
yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
6a
8a
8b
8c
8d
8e
8f
8g
8h
8i
Ph
22
24
27
72
96
41
22
12
96
18
23
24
7a
9a
9b
9c
9d
9e
9f
9g
9h
9i
85
84
79
85
84
76
89
59
55
16
75
85
82
19
4-Me-Ph
3-Me-Ph
2-Me-Ph
4-MeO-Ph
4-Cl-Ph
4-Br-Ph
4-CF3-Ph
2-furyl
76
46d
54e
79
52f
71
9
82
87
70
83
10
11
12
2-thienyl
2-naphthyl
PhCH2CH2
8j
8k
9j
9k
a In entries 2-11, R-ketoesters were added as a mixture with toluene.
b Isolated yields after column chromatography. c Determination by chiral
HPLC. d 8c was recovered in 25% yield. e 8d was recovered in 32%
yield. f 8f was recovered in 18% yield.
Experimental Section
Representative Experimental Procedures of (-)-MITH
Catalyzed Asymmetric Methylation to r-Ketoesters. To a flame-
dried flask containing (-)-MITH (25.5 mg, 0.1 mmol) was added
dimethylzinc solution (3.0 mmol, 0.73 M in hexane). After the
mixture was stirred at room temperature for 10 min, triethyl borate
(21 µL, 0.125 mmol) was added. The mixture was kept at room
temperature for another 5 min before it was cooled to -50 °C.
After 10 min, methyl benzoylformate (71 µL, 0.5 mmol) was added
to the mixture, and the mixture was stirred at -50 °C for another
22 h. Saturated NH4Cl(aq) (3 mL) was added to stop the reaction,
and the mixture was acidified with 1 N HCl(aq) (20 mL) and
extracted with CH2Cl2 (30 mL × 3). The combined organic solution
was dried over anhydrous Na2SO4 and concentrated to give a light
yellow oil, which was purified through column chromatography
(ethyl acetate/hexanes ) 1:6) to yield a colorless oil (77 mg, 85%).
Chiral HPLC analysis (Chiralcel OD-H, 2-propanol/hexane (2:98),
0.5 mL/min flow rate, uv 254 nm) showed 79% ee.
R-ketoester bearing ortho-substituted benzene ring (Table 4,
entry 4) is lower than those obtained from meta- or para-
substituted ones (entries 2 and 3). The reaction depends on the
electronic nature of the substituent; high ee’s were obtained with
aromatic ketoesters that bore electron-donating groups (entries
1-5), while addition to those with electron-withdrawing groups
gave moderate ee’s (entries 6-8). Heteroaromatic R-ketoesters
are good reaction partners, and the corresponding products were
isolated in good yields and ee’s (entries 9 and 10). An aliphatic
R-ketoester was also examined, though with lower asymmetic
induction (entry 12).
To understand the mechanism and the role of additive in the
catalytic reaction, investigations of nonlinear effect10 with and
without the additive were conducted.11 As shown in Figure 3,
positive nonlinear effects were observed in the reactions with
and without additives, suggesting that a dimeric species exists
in the catalytic reaction. It is conceivable that the presence of
B(OEt)3 is favorable to the turnover of the active complex,
which facilitates the whole catalytic cycle and thus enhances
the reaction rate.
Acknowledgment. We thank the National Science Council
of the Republic of China for financial support.
Supporting Information Available: Experimental proce-
dures and spectroscopic data of the addition products, including
1H NMR spectra and HPLC chromatographs. This material is
available free of charge via the Internet at http://pubs.acs.org.
(10) Blackmond, D. G. Acc. Chem. Res. 2000, 33, 402–411.
(11) For detailed reaction conditions, see the Supporting Information.
JO801034Q
J. Org. Chem. Vol. 73, No. 16, 2008 6447