Highly enantioselective catalytic Michael reaction of α-substituted malonates using La-linked-BINOL complex in the presence of HFIP (1,1,1,3,3,3-hexafluoroisopropanol)

Article abstract of DOI:10.1016/S0040-4039(02)00882-1

A catalytic asymmetric Michael reaction of α-substituted malonates with broad generality was developed using the La-linked-BINOL complex. To enhance the reactivity of unreactive α-substituted malonates, we examined the effects of concentration and additiv

Full text of DOI:10.1016/S0040-4039(02)00882-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4661–4665
Highly enantioselective catalytic Michael reaction of
a-substituted malonates using La-linked-BINOL complex in the
presence of HFIP (1,1,1,3,3,3-hexafluoroisopropanol)
Ryo Takita, Takashi Ohshima and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received 18 April 2002; revised 30 April 2002; accepted 2 May 2002
Abstract—A catalytic asymmetric Michael reaction of a-substituted malonates with broad generality was developed using the
La-linked-BINOL complex. To enhance the reactivity of unreactive a-substituted malonates, we examined the effects of
concentration and additives; 1.0 M was the best concentration and HFIP (1,1,1,3,3,3-hexafluoroisopropanol) accelerated the
reaction efficiently. Under the optimized conditions, the catalytic asymmetric Michael reaction of a variety of a-substituted
malonates proceeded successfully in high yield (up to 93%) and excellent enantiomeric excess (up to 99% ee). The addition of
HFIP was also effective for the reaction of nonsubstituted malonates. In this case, 5 mol% of the La-linked-BINOL complex was
sufficient for completion of the reaction in approximately 24 h. Moreover, several Michael adducts were readily converted to the
bicyclic compounds. © 2002 Elsevier Science Ltd. All rights reserved.
The development of catalytic asymmetric carbon–car-
bon bond-forming reactions is a major goal in organic
synthesis and a number of excellent asymmetric cataly-
ses have been developed over the last two decades.1
Only a few reactions, however, are commonly utilized
in the catalytic asymmetric synthesis of complex
molecules. One of the main reasons might be the limita-
tion of the substrates. Thus, it is necessary to develop a
useful catalytic asymmetric reaction with extremely
broad substrate generality. The Michael reaction is one
of the most powerful carbon–carbon bond-forming
reactions and considerable efforts have been made to
develop a catalytic asymmetric version of this reac-
tion.2–4 We succeeded in developing two excellent
multifunctional asymmetric catalysts, the AlLibis-
(binaphthoxide) (ALB) complex3a and the La-
linked-BINOL complex,3b for the asymmetric Michael
reaction of malonates to enones. The ALB complex is
highly active and readily applied for practical large-
scale synthesis.3d The La-linked-BINOL complex,
which was developed more recently, is suitable for use
in research because it is stable to moisture, can be
stored as a powder, is easily handled, and is effective
for a variety of enones.5,6 On the other hand, no
catalytic asymmetric Michael reaction of a-substituted
malonates, except for the a-methyl substituted mal-
onate,3a,b has yet been reported,7 despite the greater
utility of substituted Michael adducts than nonsubsti-
tuted adducts for complex molecule synthesis. We
report here the first example of a general catalytic
asymmetric Michael reaction of a-substituted mal-
onates. This reaction was realized by optimization of
the La-linked-BINOL catalyst system in terms of reac-
tivity, including the effects of concentration and addi-
tion of HFIP (1,1,1,3,3,3-hexafluoroisopropanol). We
also report further effective transformation of Michael
adducts to useful bicyclic compounds.
Scheme 1.
Keywords: catalytic asymmetric Michael reaction; a-substituted mal-
onates; La-linked-BINOL complex; additive effects of HFIP
(1,1,1,3,3,3-hexafluoroisopropanol).
* Corresponding author. Tel.: +81-3-5684-0651; fax: +81-3-5684-5206;
e-mail: mshibasa@mol.f.u-tokyo.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00882-1

4662
R. Takita et al. / Tetrahedron Letters 43 (2002) 4661–4665
The Michael adduct 3, which has a substituent at the
a-position of the malonate moiety, is a useful interme-
diate, especially when the substituent contains func-
tional groups, because it can be directly used for further
transformation, such as the next ring construction (vide
infra). Transformation from Michael adduct 4, which is
easily prepared using an already established asymmetric
Michael reaction, to 3 requires three additional steps
and usually the substituent-introduction step makes this
process impractical due to the decreased nucleophilicity
of the ester enolate derived from substrate 5.8 There-
fore, direct preparation of the substituted Michael
adduct 3 using a catalytic asymmetric Michael reaction
of a-substituted malonates is very desirable (Scheme 1).
To further enhance reactivity, we examined several
additives, which were previously reported to be benefi-
cial during the improvement of our multifunctional
catalysts. THF,3b additional bases (KO-t-Bu and LiH-
MDS),3b salts (LiCl, CsCl, MgCl2), Et2Zn,3c Ph3AsꢀO,11
Ph3PꢀO,12 HMPA, MS4A,11 etc. None of them, how-
ever, effectively improved this asymmetric Michael
reaction system in terms of chemical yield and enan-
tiomeric excess. Thus, we examined other types of
additives. Alcohols had interesting effects.13 That is,
HFIP increased the reaction rate and chemical yield
without decreasing the enantiomeric excess. 2,2,2-Trifl-
uoroethanol also had a small positive effect on the
chemical yield. On the other hand, MeOH and ArOH
decreased both chemical yield and enantiomeric excess,
and i-PrOH had almost no effect on the reaction.
Under the best conditions (4°C, 1.0 M in 10/1 mixture
of DME/HFIP), Michael adduct 3a was obtained in
93% yield and 99% ee. The concentration of the reac-
tion was also important in the presence of HFIP. The
chemical yield of 3a dropped to 86% when the concen-
tration was 0.4 M.14 These conditions were applicable
to various a-substituted malonates (shown in Table
2).15 In the presence of HFIP, all of the corresponding
Michael adducts were obtained in higher yield com-
pared with those shown in Table 1.16
We first examined the catalytic asymmetric Michael
reaction of dibenzyl allylmalonate (2a) to 2-cyclopen-
tenone (1) using the ALB complex, however 2a was
unreactive and gave the Michael adduct 3a in only 36%
yield and 19% ee, even when using 20 mol% of the
catalyst. We then examined the La-linked-BINOL com-
plex because it has broad generality with respect to
enones. Fortunately, previously reported conditions (10
mol% of the catalyst, 4°C, 0.4 M in DME)3b gave the
Michael adduct in excellent enantiomeric excess (99%
ee), although there was only moderate chemical yield
(67%) even after 84 h. Therefore, we attempted to
enhance the reactivity of the catalyst. After intensive
optimization, the concentration of the reaction turned
out to be a significant factor for improving chemical
yield. The best concentration was 1.0 M,9 and the
Michael adduct 3a was obtained in 86% yield without
loss of enantiomeric excess (99% ee). In contrast to the
ALB catalyst system,3d increasing the concentration
further did not improve reactivity. The result of the
scope and limitations of these improved conditions is
summarized in Table 1.10 Many types of a-substituted
malonates, which contain additional functional groups,
such as carbon–carbon double bonds, esters, and allylic
acetates, can be used as a Michael donor, and enan-
tioselectivity was nearly complete although the chemical
yield was still unsatisfactory.
In addition, HFIP effectively accelerated the Michael
reaction of nonsubstituted malonates. Thus, only 5
mol% of catalyst forced the reaction to completion in
approximately 24 h with 83–95% yield and >99% ee
(Table 3). Under these decreased catalyst-loading con-
ditions, the best ratio of DME and HFIP was 20:1, and
the best concentration was 0.4 M to substrate (0.02 M
to catalyst).
The reaction profile of the Michael reaction in the
presence or absence of HFIP was investigated (Fig. 1).
The addition of HFIP increased the initial reaction rate
and the reaction proceeded more than twice as fast as
in the absence of HFIP; as a result, nearly 90% conver-
sion was observed within 24 h. The beneficial effect of
Table 1. Catalytic asymmetric Michael reaction of various a-substituted malonates 2a–g
Entry
Malonate (R)
Product
Time (h)
Yielda (%)
Eeb (%)
1
2
3
4
5
6
7c
2a: CH2CHꢀCH2
3a
3b
3c
3d
3e
3f
86
88
106
88
92
89
86
65
66
69
62
55
77
99
99
96
99
98
95
99
2b: (CH2)2CHꢀCH2
2c: (CH2)3CHꢀCH2
2d: (CH2)2CO2Me
2e: (CH2)2CO2Et
2f: (CH2)3CO2Et
2g: CH2CHꢀCHCH2OAc
3g
84
a Isolated yield.
b Determined by HPLC analysis.
c cis/trans (ꢀ1/30) in both 2g and 3g. Enantiomeric excess was determined after ozonolysis.

R. Takita et al. / Tetrahedron Letters 43 (2002) 4661–4665
4663
Table 2. Catalytic asymmetric Michael reaction of various a-substituted malonates 2a–g in the presence of HFIP
Entry
Malonate (R)
Product
Time (h)
Yielda (%)
Eeb (%)
1
2
3
4
5
6
7c
2a: CH2CHꢀCH2
3a
3b
3c
3d
3e
3f
87
85
88
87
92
89
83
93
80
84
83
75
71
87
99
98
96
98
96
95
98
2b: (CH2)2CH=CH2
2c: (CH2)3CH=CH2
2d: (CH2)2CO2Me
2e: (CH2)2CO2Et
2f: (CH2)3CO2Et
2g: CH2CHꢀCHCH2OAc
3g
a Isolated yield.
b Determined by HPLC analysis.
c cis/trans (ꢀ1/30) in both 2g and 3g. Enantiomeric excess was determined after ozonolysis.
Table 3. Catalytic asymmetric Michael reaction of nonsubstituted malonates using 5 mol% of the catalyst
O
O
(S,S)-La-linked-BINOL
(5 mol%)
CO2R'
+
CO R'
CO2R'
CO2R'
DME-HFIP (20/1, 0.4 M)
2
n
n
rt
(1.0 equiv.) (1.0 equiv.)
1: n=1
7: n=2
8: n=3
9: R'=Bn
10: R'=Me
11-14
Entry
Enone
Malonate
Product
Time (h)
Yielda (%)
Eeb (%)
1
1
7
7
7
8
9
9
9
10
9
11
12
12
13
14
25
24
24
18
30
83
95
79
86
85
\99
\99
\99
\99
\99
2
3c
4
5
a Isolated yield.
b Determined by HPLC analysis.
c The reaction was performed in DME without HFIP.
Figure 1. The initial rate and time course of the generation of 3a in the presence or absence of HFIP. The yield of 3a was
1
determined by H NMR: the reaction in the presence of HFIP (ꢀ) and in the absence of HFIP (").
HFIP was most prominent in the early stage of the
reaction. Although the role of HFIP has not yet been
clearly elucidated, we propose that this acidic (pKa 17.9
in DMSO)17 and sterically-hindered additive acts as a
proton source18 and assists in the dissociation of the
product from the La complex.
Finally, the Michael adducts were successfully con-
verted to the corresponding bicyclic compounds.
Ozonolysis of Michael adduct 3b (91% yield) followed
by intramolecular aldol reaction using activated alu-
mina (69% yield) furnished bicyclo[4.3.0]nonane deriva-
tive 15. Reductive cyclization of compound 3g using

4664
R. Takita et al. / Tetrahedron Letters 43 (2002) 4661–4665
Das, J.; Sekine, A.; Ohshima, T.; Shibasaki, M. J. Am.
Chem. Soc. 2000, 122, 6506; (c) Matsunaga, S.; Ohshima,
T.; Shibasaki, M. Tetrahedron Lett. 2000, 41, 8473; (d)
Xu, Y.; Ohori, K.; Ohshima, T.; Shibasaki, M. Tetra-
hedron 2002, 58, 2585.
4. For representative examples of the catalytic asymmetric
Michael reaction of malonates and related nucleophiles,
see: (a) Yamaguchi, M.; Shiraishi, T.; Hirama, M. J. Org.
Chem. 1996, 61, 3520 (malonates); (b) Ji, J.; Barnes, D.
M.; Zhang, J.; King, S. A.; Wittenberger, S. J.; Morton,
H. E. J. Am. Chem. Soc. 1999, 121, 10215 (b-keto esters);
(c) Sawamura, M.; Hamashima, H.; Ito, Y. Tetrahedron
1994, 50, 4439 (a-cyano esters); (d) Sawamura, M.;
Hamashima, H.; Ito, Y. J. Am. Chem. Soc. 1992, 114,
8295 (a-cyano esters).
Scheme 2.
SmI2 directly produced the bicyclo[3.2.1]octane deriva-
tive 16 in 79% yield (Scheme 2). The fact that these
bicyclic frameworks often occur in natural or unnatural
bioactive compounds, such as hydrindan derivatives,
makes these highly enantioselective short processes very
useful.
5. La(O-i-Pr)3 can be purchased from Kojundo Chemical
Laboratory Co., Ltd, 5-1-28, Chiyoda, Sakado-shi,
Saitama 350-0214, Japan (Fax: +(81)-492-84-1351).
Freshly prepared La(O-i-Pr)3 solution was used.
6. Both enantiomers of the La-linked-BINOL complex are
now commercially available from STREM Chemicals,
Inc., 7 Mulliken Way, Dexter Industrial Park, Newbury-
port, MA 01950-4098, USA (Fax: +(1)-978-465-3104).
When they were used for the catalytic asymmetric
Michael reaction of 9 to 7 (10 mol% of the catalyst was
used in the reported conditions in Ref. 3b), the Michael
adduct 12 was obtained in 57% yield and 94% ee.
7. The catalytic asymmetric Michael reaction of more reac-
tive a-substituted b-keto esters and a-substituted a-cyano
esters to very reactive enones were reported by us and
others. See Ref. 2.
8. Only reactive electrophiles, such as allyl bromide (80%),
reacted with 5 to give a reasonable yield, while other
electrophiles, such as 5-bromo-1-pentene (30%), ethyl 4-
bromobutanoate (15%), 4-bromo-1-butene (0%), and
methyl acrylate (0%), gave highly unsatisfactory results.
9. Lower chemical yields were obtained in other concentra-
tions (57% in 0.2 M and 80% in 2.0 M), although the
enantiomeric excesses were unchanged in both cases (99%
ee).
In conclusion, we achieved the first general catalytic
asymmetric Michael reaction of a-substituted mal-
onates using the La-linked-BINOL complex in the pres-
ence of HFIP. HFIP accelerated the reaction of not
only the a-substituted malonates, but also nonsubsti-
tuted malonates, efficiently. In the latter case, 5 mol%
of the La-linked-BINOL complex was sufficient for
completion of the reaction in approximately 24 h.
Moreover, several Michael adducts were readily con-
verted to the bicyclic compounds. Further studies of the
reaction mechanism, catalyst structure, role of HFIP,
and application to natural product synthesis are cur-
rently in progress.
Acknowledgements
This work was supported by RFTF of the Japan Soci-
ety for the Promotion of Science and a Grant-in-Aid
for Scientific Research on Priority Areas (A) ‘‘Exploita-
tion of Multi-Element Cyclic Molecules’’ from the Min-
istry of Education, Culture, Sports, Science and
Technology, Japan.
10. The absolute configurations of 3a, 3c, and 3f were
already determined by transformation of the known com-
pound 4 to 3 via 5 and 6; see Ref. 8. The absolute
configurations of 3b, 3d, 3e, and 3g were tentatively
determined on the basis of the absolute configuration of
3a and previous results. See Ref. 3.
11. (a) Nemoto, T.; Ohshima, T.; Shibasaki, M. J. Am.
Chem. Soc. 2001, 123, 2725; (b) Nemoto, T.; Ohshima,
T.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 9474.
12. Daikai, K.; Kamaura, M.; Inanaga, J. Tetrahedron Lett.
1998, 39, 7353.
13. For representative examples of catalytic asymmetric reac-
tions that utilize HFIP or other alcohols as an additive,
see: (a) Deng, H.; Isler, M. P.; Snapper, M. L.; Hoveyda,
A. H. Angew. Chem., Int. Ed. Engl. 2002, 41, 1009
(MeOH); (b) Evans, D. A.; Scheidt, K. A.; Johnston, J.
N.; Willis, M. C. J. Am. Chem. Soc. 2001, 123, 4480
(HFIP); (c) Evans, D. A.; Rovis, T.; Kozlowski, M. C.;
Downey, W.; Tedrow, J. S. J. Am. Chem. Soc. 2000, 122,
9134 (HFIP); (d) Takamura, M.; Hamashima, Y.; Usuda,
H.; Kanai, M.; Shibasaki, M. Angew. Chem., Int. Ed.
References
1. For general reviews of asymmetric catalyses, see: (a)
Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.;
John Wiley & Sons: New York, 2000; (b) Comprehensive
Asymmetric Catalysis; Jacobsen, E. N.; Pfaltz, A.;
Yamamoto, H., Eds.; Springer: New York; 1999; (c)
Noyori, R. Asymmetric Catalysis in Organic Synthesis;
John Wiley & Sons: New York, 1994.
2. For a representative review of the catalytic asymmetric
Michael reaction, see: Krause, N.; Hoffmann-Ro¨der, A.
Synthesis 2001, 171.
3. (a) Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem., Int.
Ed. Engl. 1997, 36, 1236; (b) Kim, Y. S.; Matsunaga, S.;

R. Takita et al. / Tetrahedron Letters 43 (2002) 4661–4665
4665
Engl. 2000, 39, 1650 (PhOH); (e) Ishitani, H.; Yamashita,
Y.; Shimizu, H.; Kobayashi, S. J. Am. Chem. Soc. 2000,
122, 5403 (PrOH); (f) Yun, J.; Buchwald, S. L. J. Am.
Chem. Soc. 1999, 121, 5640 (MeOH); (g) Funabashi, K.;
Saida, Y.; Kanai, M.; Arai, T.; Sasai, H.; Shibasaki, M.
Tetrahedron Lett. 1998, 39, 7557 (t-BuOH); (h) Kitajima,
H.; Ito, K.; Katsuki, T. Tetrahedron 1997, 53, 17015
(HFIP); (i) Kawara, A.; Taguchi, T. Tetrahedron Lett.
1994, 35, 8805 (HFIP).
mixture was stirred at −78°C for 5 min. The dry-ice
acetone bath was then removed and the reaction mixture
was stirred at 4°C. After 86 h, the mixture was diluted
with ethyl acetate, washed with satd aq. NH4Cl, and
dried over Na2SO4. The solvent was evaporated under
reduced pressure, and the residue was purified by flash
column chromatography (SiO2, hexane/ethyl acetate 5/1)
to give (−)-(S)-3a (94.7 mg, 0.233 mmol, yield 93%) in
99% ee [DAICEL CHIRALCEL OJ-H, hexane/2-
propanol (90:10, v/v), flow rate: 0.8 mL/min, retention
time: 55 min (R)-isomer and 63 min (S)-isomer, detected
at 210 nm].
14. Lower chemical yields were obtained in other concentra-
tions (73% in 0.2 M and 93% in 2.0 M), although the
enantiomeric excesses were unchanged in both cases (99%
ee).
15. General procedure for the catalytic asymmetric Michael
reaction promoted by (S,S)-La-linked-BINOL complex:
DME (0.23 mL) was added to the (S,S)-La-linked-
BINOL complex (18.8 mg, 0.25 mmol, prepared by the
procedure in Ref. 3b) in a test tube at −78°C, and the
mixture was stirred for 5 min at the same temperature.
Then, 2-cyclopentene-1-one (1) (21 mL, 0.25 mmol) and
dibenzyl allylmalonate (2a) (72 mL, d=1.13, 0.25 mmol)
were added. Finally, HFIP (23 mL) was added and the
16. Using the best conditions, Michael reaction of 2a to
2-cyclohexene-1-one (7) gave the corresponding (S)-
Michael adduct in 63% yield and 94% ee, while the
reaction to 2-cycloheptene-1-one (8) gave only trace
amount of the corresponding Michael adduct.
17. The acidity of HFIP is nearly equal to that of phenol
(pKa 18.0 in DMSO).
18. In contrast, the addition of 1,1,1,3,3,3-hexafluoroiso-
propyl methyl ether did not accelerate the reaction.