Enantio- and diastereoselective construction of vicinal quaternary and tertiary carbon centers by catalytic Michael reaction of α-substituted β-keto esters to cyclic enones

Article abstract of DOI:10.1016/j.tetlet.2005.05.139

A catalytic enantio- and diastereoselective Michael reaction was achieved to construct vicinal quaternary and tertiary carbon centers in one step. Using 5 mol % of La(O-i-Pr)₃ and 10 mol % of a new N-linked-BINOL type ligand, the reaction of α-

Full text of DOI:10.1016/j.tetlet.2005.05.139

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5377–5381
Enantio- and diastereoselective construction of vicinal quaternary
and tertiary carbon centers by catalytic Michael reaction
of a-substituted b-keto esters to cyclic enones
Keisuke Majima, Shin-ya Tosaki, Takashi Ohshima and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received 19 May 2005;revised 27 May 2005;accepted 30 May 2005
Available online 15 June 2005
Abstract—A catalytic enantio- and diastereoselective Michael reaction was achieved to construct vicinal quaternary and tertiary car-
bon centers in one step. Using 5 mol% of La(O-i-Pr)3 and 10 mol% of a new N-linked-BINOL type ligand, the reaction of a-substi-
tuted b-keto esters to cyclic enones provided the corresponding Michael adducts in up to quantitative yield with a diastereomeric
ratio up to 86/14 and enantiomeric excess up to 86% for the major isomer. An alternative catalyst preparation method using
La(OTf)3 instead of La(O-i-Pr)3 was also examined.
Ó 2005 Elsevier Ltd. All rights reserved.
The enantioselective construction of quaternary carbon
centers, that is, carbon centers with four different non-
hydrogen substituents, represents a very challenging
and dynamic area in organic synthesis.1 An attractive
approach to this goal involves the generation of nucleo-
philic species by in situ generation of acidic hydro-
carbons because of its operationally simple, atom
economical, and functional group-tolerant features. A
catalytic enantioselective direct Michael reaction2 of
prochiral trisubstituted carbon nucleophiles to elec-
tron-deficient C–C double bonds is one of the most effi-
cient candidates. In fact, several efficient catalytic
enantioselective Michael reactions of a-substituted b-
keto esters to methyl vinyl ketone, which construct a
quaternary carbon center at the Michael donor, were re-
ported.3 To expand the usefulness of this catalysis, a cat-
alytic stereoselective Michael reaction of prochiral
trisubstituted carbon nucleophiles to prochiral b-substi-
tuted electron-deficient C–C double bonds is highly
desirable because it can construct vicinal quaternary
and tertiary carbon centers from simple precursors in
one step. This reaction, however, requires a catalyst that
simultaneously constructs both the quaternary and ter-
tiary carbon centers in sterically demanding positions.
Thus, only a few highly enantio- and diastereoselective
catalytic reactions have been reported, such as Michael
reactions of a-substituted b-keto esters to acyclic b-
substituted enones3i and b-substituted nitroolefins,4 a-
substituted a-cyanoester to a,b-unsaturated imides,5
substituted indoles to b-substituted a,b-unsaturated
aldehydes,6 and a,a-disubstituted aldehydes to b-substi-
tuted nitroolefins.7 On the other hand, there are no re-
ports of a Michael reaction of prochiral trisubstituted
carbon nucleophiles to s-trans type Michael acceptors
such as cyclic enones. Herein, we report a catalytic enan-
tio- and diastereoselective Michael reaction of a-substi-
tuted b-keto esters to cyclic enones to construct vicinal
quaternary and tertiary carbon centers in one step.
Tuning the linker length and the N-substituent in
NR-linked-BINOL ligands was critical to achieve high
reactivity and good stereoselectivity. Moreover, we
describe a new convenient catalyst preparation method
of La complexes from La(OTf)3.
The catalytic asymmetric Michael reaction of malonates
to b-substituted enones, which constructs tertiary car-
bon centers at the Michael acceptors, has been widely
examined by our group8 and others9 with much success.
Recently, we also developed a catalytic asymmetric
Michael reaction of a-non-substituted b-keto esters to
cyclic enones using a chiral La complex prepared from
La(O-i-Pr)3 and NR-linked-BINOLs (R = H: 1a, R =
Me: 1b, Scheme 1) in a ratio of 1:1, in which the newly
generated stereocenter at the a-position of b-keto ester is
Keywords: Catalytic enantio- and diastereoselective Michael reaction;
La complex; a-Substituted b-keto ester.
*
Corresponding author. Tel.: +81 3 5684 0651;fax: +81 3 5684
5206;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.2005.05.139

5378
K. Majima et al. / Tetrahedron Letters 46 (2005) 5377–5381
complex.12 To create enough chiral space for the reaction
of a-substituted b-keto ester, we designed and synthe-
sized various new types of NMe-linked-BINOL 6b
(n = 1) and 7 (n = 2) (Table 1).13 When 10 mol% of
La–6b (1:1) complex was used, reactivity was greatly im-
proved (entry 2). On the other hand, ligand 7, which has
a longer linker than 6, negatively affected this reaction
(entry 9). Thus, the reaction conditions, such as solvent
composition, concentration of the substrates, equiva-
lence of the substrates, and ratio of La and ligand, were
optimized using the La–6b complex. As a result, using
DME, 2.0 equiv of 4a to 3a, and a 1:2 ratio of La and
6b produced much higher reactivity and stereoselectivity
to afford 5aa in 72% yield, although the enantiomeric ex-
cess of the major diastereomer was still moderate (55%
ee, entry 3). To further improve the enantioselectivity,
the N-substituent of the ligand was investigated. In our
previous studies on the catalytic enantioselective
Michael reaction of a-non-substituted b-keto esters to
cyclic enones, the N-substituent electronically tuned the
Lewis acidity of the central metal and sterically tuned
the chiral environment. Therefore, ligands 6a,c–g were
synthesized and examined for the reaction of 4a to 3a.
The La–6c (1:2) complex, which has an ethyl group as
the N-substituent, produced the highest reactivity and
enantio- and diastereoselectivity among the La–6 com-
plexes examined (entry 4). The electronic effects of the
N-substituent were demonstrated by comparing the
ligands 6c and d.10 More electron-withdrawing ligand
Scheme 1. Catalytic enantio- and diastereoselective Michael reaction
of 4a to 3a using chiral La complex.
readily epimerized and affords an almost 1:1 mixture of
diastereomers.10 Based on these results, we first exam-
ined a Michael reaction of ethyl 2-methylacetoacetate
(4a) to 2-cyclohepten-1-one (3a) using La–1 (1:1) com-
plexes.11 The Michael reaction using these complexes,
however, gave the corresponding Michael adduct 5aa
in low yield and selectivity (La–1a complex: 19% yield,
65/35 dr, 8% ee for the major isomer;La– 1b complex:
25% yield, 63/37 dr, 25% ee for the major isomer). The
use of the La–2 (1:1) complex, which is an efficient cat-
alyst for the Michael reaction of malonates,8d,f produced
very low reactivity (4% yield).
The steric effects of the substituent at the a-position of b-
keto ester might prevent formation of an active catalyst
Table 1. Ligand screening for the catalytic enantio- and diastereoselective Michael reaction
Entry
Ligand
b-Keto ester
Yielda (%)
dr (major/minor)b
ee (%) (major/minor)c
1
6a
6b
6b
6c
6d
6e
6f
4a
4a
4a
4a
4a
4a
4a
5
58
72
86
33
88
82
60
30
67
89
65/35
70/30
76/24
83/17
80/20
77/23
79/21
74/26
62/38
75/25
86/14
ndd
2e
3
43/41
55/72
75/81
8f/20
61/76
59/77
47/64
14/3f
81/76
82/82
4
5
6
7
8
6g4a
7
9e
10
11
4a
4b
4b
6b
6c
a Isolated yield.
b dr was determined by 1H NMR analysis of the crude product.
c ee was determined by chiral GC analysis after acetalization of the cyclic ketone of 5.
d Not determined.
e Reaction conditions were the same as those in Scheme 1.
f Enantiomer was obtained.

K. Majima et al. / Tetrahedron Letters 46 (2005) 5377–5381
5379
Table 2. The catalytic enantio- and diastereoselective Michael reaction of a-substituted b-keto esters to cyclic enones
Entry
Enone 3
b-Keto ester 4
Product
Time (h)
Yield (%)a
dr (major/minor)b
ee (%) (major/minor)c
1
3c: n = 0
3c: n = 0
3c: n = 0
3c: n = 0
3c: n = 0
3c: n = 0
3b: n = 1
3b: n = 1
3b: n = 1
3b: n = 1
3b: n = 1
3b: n = 1
3b: n = 1
3a: n = 2
3a: n = 2
3a: n = 2
3a: n = 2
4b: R2 = Me, R3 = Me
4c: R2 = allyl, R3 = Me
4d: R2 = propargyl, R3 = Me
4f: R2 = (CH2)3Ph, R3 = Me
4g: R2 = Me, R3 = Et
4h: R2 = Me, R3 = i-Pr
4b: R2 = Me, R3 = Me
4c: R2 = allyl, R3 = Me
4d: R2 = propargyl, R3 = Me
4e: R2 = Et, R3 = Me
4f: R2 = (CH2)3Ph, R3 = Me
4g: R2 = Me, R3 = Et
4h: R2 = Me, R3 = i-Pr
4b: R2 = Me, R3 = Me
4c: R2 = allyl, R3 = Me
4d: R2 = propargyl, R3 = Me
4f: R2 = (CH2)3Ph, R3 = Me
5cb
5cc
5cd
5cf
24
70
70
48
38
96
24
48
48
48
70
38
96
24
96
96
96
100
86
76
80
93
71
92
75
64
65
37
83
42
89
69
58
45
76/24
77/23
73/27
73/27
80/20
86/14
86/14
72/28
79/21
77/23
68/32
80/20
84/16
86/14
74/26
84/16
81/19
79d/73d
56/63
2e
3e
4e
5
61d/50d
41/81
5cg
5ch
5bb
5bc
5bd
5be
5bf
5bg
5bh
5ab
5ac
5ad
5af
64d/60d
63/16
86/80
6e
7
8
62/84
66d/42d
67/78
9
10e
11e
12
13e
14
15
16
17
56/86
85d/55d
80d/35d
82d/82d
42/72
70/84
39/67
a Isolated yield.
b dr was determined by 1H NMR analysis of the crude product.
c ee was determined by chiral GC analysis (entry 14) or chiral HPLC analysis (entries 1–13 and 15–17).
d ee was determined after acetalization of the cyclic ketone.
e 4.0 equiv of compound 4 was used.
6d had much lower reactivity and enantioselectivity than
ligand 6c (entry 5). Ligands 6e–g had lower enantioselec-
tivity than 6c, probably due to the steric and electronic
nature of these ligands (entries 6–8). In contrast to our
previous studies,10 the NH ligand 6a had quite low reac-
tivity and selectivity (entry 1). Furthermore, when steri-
cally less demanding 4b (R1 = Me) was used as a
Michael donor, 5ab was obtained in 89% yield, 86/14
dr, and 82% ee for both diastereomers (entry 11).
To further enhance the usefulness of this reaction, we
investigated use of La(OTf)3 as an alternative La metal
source because of the commercial availability of
La(OTf)3 and its high tolerance to air and water. Our
preliminary studies revealed that alkali metal salts had
negative effects on this system. Thus, we investigated
the combination of La(OTf)3 and an amine base. Using
5 mol% of La(OTf)3, 15 mol% of i-Pr2NEt, and
10 mol% of ligand 6c, almost the same reactivity and
diastereoselectivity were obtained as with the original
catalyst preparation method, although the enantioselec-
tivity was decreased (Scheme 2). The new catalyst prep-
aration method was also applicable to the catalytic
enantioselective Michael reaction of a-non-substituted
b-keto ester to cyclic enone. In this case, identical
We then investigated the scope and limitations of several
substrates.14 The results are summarized in Table 2.15
The Michael reaction of variety of a-substituted b-keto
esters 4 to cyclic enones 3 (5- to 7-membered rings)
was promoted by the La–6c (1:2) complex to afford
the corresponding Michael adducts 5 with moderate dia-
stereoselectivity (68/32–86/14 dr) and moderate to good
enantioselectivity for the major isomers (39–86% ee).
Substitution at the c-position of 4 (R3) was tolerated
(4g and h, entries 5, 6, 12, and 13). When 3c was used
as a Michael acceptor, high reactivity was obtained
(71–100% yield, entries 1–6). The reactivity decreased
as the ring size of 3 increased in this reaction system.
Thus, when 3a was used as a Michael acceptor, a long
reaction time (96 h) was necessary except when using
4b as a Michael donor. For several low reactive
substrates, 4.0 equiv of 4 were used to obtain better re-
sults (entries 2–4, 6, 10, 11, and 13). Although there is
room for improvement in the reactivity and the enantio-
selectivity, to the best of our knowledge, this is the first
example of a catalytic enantio- and diastereoselective
Michael reaction of a-substituted b-keto esters to cyclic
enones.
Scheme 2. Catalytic enantioselective Michael reaction using a catalyst
prepared from La(OTf)3 and i-Pr2NEt.

5380
K. Majima et al. / Tetrahedron Letters 46 (2005) 5377–5381
11240;(j) Hamashima, Y.;Takano, H.;Hotta, D.;
Sodeoka, M. Org. Lett. 2003, 5, 3225.
enantioselectivity was obtained. These observations sug-
gest that the combination of lanthanide triflate
(Ln(OTf)3) and an amine base can also be used to access
a chiral alkali metal free lanthanide complex.
4. (a) Li, H.;Wang, Y.;Tang, L.;Wu, F.;Liu, X.;Guo, C.;
Foxman, B. M.;Deng, L. Angew. Chem., Int. Ed. 2005, 44,
105;(b) Okino, T.;Hoashi, Y.;Furukawa, T.;Xu, X.;
Takemoto, Y. J. Am. Soc. Chem. 2005, 127, 119.
5. (a) Taylor, M. S.;Jacobsen, E. N. J. Am. Chem. Soc. 2003,
125, 11204;(b) Taylor, M. S.;Zalatan, D. N.;Lerchner, A.
M.;Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 1313.
6. Austin, J. F.;Kim, S.-G.;Sinz, C. J.;Xiao, W.-J.;
MacMillan, D. W. C. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5482.
In conclusion, we developed a catalytic enantio- and
diastereoselective Michael reaction of a-substituted b-
keto esters to cyclic enones to construct vicinal quater-
nary and tertiary carbon centers using the La–6c (1:2)
complex. The linker length of the NR-linked-BINOL
type ligand and the N-substituent were critical to obtain
good reactivity and stereoselectivity. This reaction was
also promoted by a catalyst prepared from La(OTf)3
and i-Pr2NEt. Further studies of the reaction mecha-
nism, catalyst structure, and application to natural
product synthesis are in progress.
7. Mase, M.;Thayumanavan, R.;Tanaka, F.;Barbas, C. F.,
III. Org. Lett. 2004, 6, 2527.
8. For catalytic asymmetric Michael reaction of malonates
reported by our group, see: (a) Sasai, H.;Arai, T.;
Shibasaki, M. J. Am. Chem. Soc. 1994, 115, 1571;(b)
Sasai, H.;Arai, T.;Satow, Y.;Houk, K. N.;Shibasaki, M.
J. Am. Chem. Soc. 1995, 117, 6194;(c) Arai, T.;Sasai, H.;
Aoe, K.;Okamura, K.;Date, T.;Shibasaki, M.
Angew.
Acknowledgments
Chem., Int. Ed. 1996, 35, 104;(d) Kim, Y. S.;Matsunaga,
S.;Das, J.;Sekine, A.;Ohshima, T.;Shibasaki, M. J. Am.
Chem. Soc. 2000, 122, 6506;(e) Xu, Y.;Ohori, K.;
Ohshima, T.;Shibasaki, M. Tetrahedron 2002, 58, 2585;(f)
Takita, R.;Ohshima, T.;Shibasaki, M. Tetrahedron Lett.
2002, 43, 4661;(g) Ohshima, T.;Xu, Y.;Takita, R.;
Shimizu, S.;Zhong, D.;Shibasaki, M. J. Am. Chem. Soc.
2002, 124, 14546.
This work was supported by RFTF and a Grant-in-Aid
for Encouragements for Young Scientists (A) from the
Japan Society for the Promotion of Science (JSPS).
We thank Dr. Tsuneaki Yamagata (Osaka University)
for X-ray analysis.
9. (a) Yamaguchi, M.;Shiraishi, T.;Hirama, M.
J. Org.
Chem. 1996, 61, 3520;(b) Perrard, T.;Plaquevent, J.-C.;
Desmurs, J.-R.;Hebrault, D. Org. Lett. 2000, 2, 2959;(c)
Supplementary data
Halland, N.;Aburel, P. S.;Jørgensen, K. A.
Angew.
Supplementary data associated with this article can be
found, in the online version at doi:10.1016/j.tetlet.
2005.05.139.
Chem., Int. Ed. 2003, 42, 661;(d) Annamalai, V.;
DiMauro, E. F.;Carroll, P. J.;Kozlowski, M. C. J. Org.
Chem. 2003, 68, 1973.
10. Majima, K.;Takita, R.;Okada, A.;Ohshima, T.;Shiba-
saki, M. J. Am. Chem. Soc. 2003, 125, 15837.
11. For the screening of reaction conditions, we used 3a and
4a as substrates because enantiomeric excess of the
product 5aa was easily determined by chiral GC analysis
after acetalization of the cyclic ketone.
12. In the catalytic enantioselective Michael reaction of
a-non-substituted b-keto esters to cyclic enones, we
proposed that at least one b-keto ester should be included
in the active catalyst complex. See Ref. 10.
References and notes
1. For representative reviews of enantioselective construction
of quaternary carbon centers, see: (a) Corey, E. J.;
Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388;
(b) Christoffers, J.;Mann, A. Angew. Chem., Int. Ed. 2001,
40, 4591.
2. For representative reviews on the catatytic asymmetric
Michael reaction, see: (a) Krause, N.;Hoffmann-Ro¨der,
A. Synthesis 2001, 171;(b) Sibi, M. P.;Manyem, S.
Tetrahedron 2000, 56, 8033;(c) Kanai, M.;Shibasaki, M.
In Catalytic Asymmetric Catalysis, 2nd ed;Ojima, I., Ed.;
Wiley: New York, 2000, pp 569–592;(d) Tomioka, K.;
Nagaoka, Y. In Comprehensive Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, Germany, 1999;Vol. 3, Chapter 31.1;
(e) Alexakis, A.;Benhaim, C. Eur. J. Org. Chem. 2002,
3221;(f) Christoffers, J.;Baro, A. Angew. Chem., Int. Ed.
2003, 42, 1688.
3. (a) Hermann, K.;Wynberg, H. J. Org. Chem. 1979, 44,
2238;(b) Cram, D. J.;Sogah, G. D. Y. J. Chem. Soc.,
Chem. Commun. 1981, 625;(c) Brunner, H.;Hammer, B.
Angew. Chem., Int. Ed. Engl. 1984, 23, 312;(d) Desimoni,
G.;Dusi, G.;Faita, G.;Quadrelli, P.;Righetti, P.
Tetrahedron 1995, 51, 4131;(e) Sasai, H.;Emori, E.;Arai,
T.;Shibasaki, M. Tetrahedron Lett. 1996, 37, 5561;(f)
Christoffers, J.;Ro¨ßler, U.;Werner, T. Eur. J. Org. Chem.
2000, 701;(g) Nakajima, M.;Yamaguchi, Y.;Hashimoto,
S. Chem. Commun. 2001, 1596;(h) Suzuki, T.;Torii, T.
Tetrahedron: Asymmetry 2001, 12, 1077;(i) Hamashima,
Y.;Hotta, D.;Sodeoka, M. J. Am. Chem. Soc. 2002, 124,
13. For the syntheses of ligands 6a–g and 7, see Supplemen-
tary data.
14. General procedure for the catalytic enantio- and diaste-
reoselective Michael reaction promoted by La(O-i-Pr)3
and ligand–6c (1:2) complex: to a stirred solution of 6c
(14.4 mg, including 7.0 w/w% solvent (THF and hexane),
0.02 mmol) in THF (0.18 mL) at À78 °C was added a
solution of La(O-i-Pr)3 (50 lL, 0.01 mmol, 0.2 M in THF,
freshly prepared from the powder of La(O-i-Pr)3 and dry
THF, La(O-i-Pr)3 was purchased from Kojundo Chemical
Laboratory CO., LTD., 5-1-28, Chiyoda, Sakado-shi,
Saitama 350-0214, Japan (fax: +81 492 84 1351)). The
solution was stirred for 2.5 h at room temperature and
then the solvent was evaporated under reduced pressure.
DME (0.2 mL) were added to the catalyst complex in a
flask at À78 °C and the mixture was stirred for 5 min at
the same temperature. Then, 2-cyclohepten-1-one (3a)
(22.3 lL, 0.2 mmol) and methyl 2-methylacetoacetate (4b)
(49.6 lL, 0.4 mmol) were added. The mixture was stirred
at À78 °C for 5 min, then the dry-ice acetone bath was
removed, and the reaction mixture was stirred at room
temperature. After 24 h, the reaction mixture was diluted
with ethyl acetate, washed with saturated aqueous NH4Cl,
and dried over Na2SO4. After evaporation, the residue was

K. Majima et al. / Tetrahedron Letters 46 (2005) 5377–5381
5381
purified by flash column chromatography (SiO2, hexane/
ethyl acetate, 9/1) to give 5ab (43.3 mg, 0.18 mmol, 89%,
86/14 dr, 82% ee for both diastereomers).
by NOE (5ab and bc), X-ray (5bh), and chemical corre-
lation (5aa,ac,ad,af,bb,bd,be,bf,bg,cc,cd, and cf). For
details, see Supplementary data.
15. In all entries, the absolute configurations of b-position of
the acceptors were determined to be R by chemical
correlation. The relative configurations were determined
Crystallographic data for 10bh have been deposited with
the Cambridge Crystallographic Data Centre as supple-
mentary publication numbers CCDC 272617.