Catalytic asymmetric Michael reaction under phase-transfer catalysis: Construction of chiral tetrasubstituted carbon and its application to the synthesis of a chiral pyrrolidone

Article abstract of DOI:10.3987/COM-05-S(T)41

A catalytic asymmetric Michael reaction using Schiff bases promoted by D₂-symmetrical ammonium salts as phase-transfer catalysts is described. The reaction of glycine Schiff base (1a) gave the Michael adduct with up to 91% ee and tetrasubstituted carbons was also constructed using alanine Schiff base (3a) with up to 63% ee.

Full text of DOI:10.3987/COM-05-S(T)41

HETEROCYCLES, Vol. 67, No. 2, 2006
495
HETEROCYCLES, Vol. 67, No. 2, 2006, pp. 495 - 501. © The Japan Institute of Heterocyclic Chemistry
Received, 25th July, 2005, Accepted, 18th November, 2005, Published online, 18th November, 2005. COM-05-S(T)41
CATALYTIC
ASYMMETRIC
MICHAEL
REACTION
UNDER
PHASE-TRANSFER CATALYSIS: CONSTRUCTION OF CHIRAL
TETRASUBSTITUTED CARBON AND ITS APPLICATION TO THE
SYNTHESIS OF A CHIRAL PYRROLIDONE
Shigeru Arai,* Fumie Takahashi, Riichiro Tsuji, and Atsushi Nishida*
Graduate School of Pharmaceutical Sciences, Chiba University
1-33 Yayoi-cho, Inage-ku, Chiba, Japan 263-8522
arai@p.chiba-u.ac.jp
Abstract – A catalytic asymmetric Michael reaction using Schiff bases promoted
by D2-symmetrical ammonium salts as phase-transfer catalysts is described. The
reaction of glycine Schiff base (1a) gave the Michael adduct with up to 91% ee
and tetrasubstituted carbons was also constructed using alanine Schiff base (3a)
with up to 63% ee.
INTRODUCTION
Phase-transfer catalysis (PTC), which is one of the most practical synthetic methodologies due to its mild
conditions, operational simplicity and minimal environmental impact, has been a major topic in synthetic
organic chemistry.1 Since the early reports of asymmetric alkylation using chiral quaternary ammonium
salts by Dolling2 and O’Donnel,3 many successful results have been reported regarding asymmetric PTC
chemistry using alkaloid4,5 and non-alkaloid6 derivatives over the past decade. We have previously
introduced new D2-symmetrical ammonium salts,7,8 which are easily prepared from tartrate,9 to the
catalytic asymmetric Michael reaction. In this communication, we describe a modification of the
catalyst structure, its application to the construction of chiral quaternary carbons using α-alkyl Schiff
bases, a facile transformation to chiral nitrogen heterocycles and highly stereoselective [3+2]
cycloaddition.

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HETEROCYCLES, Vol. 67, No. 2, 2006
RESULTS AND DISCUSSION
8
We previously reported that D2-symmetrical quaternary ammonium salts, which promotes the
enantioselective Michael reaction to give an optically active glutamate derivative10-15 with moderate ee
(entry 1 vs. 2).7 Based on the results with a 4-CF3 group with higher catalytic activity, we performed a
further catalyst survey using PTC C-F at –40 °C (entries 2-7). For example, the reaction of 1a with a 2-
CF3 derivative (PTC D, 5 mol%) gave 2a with 74% ee, while lower catalytic activity or enantioselectivity
was observed when PTC B or C was used (entry 5 vs. 3 and 4). Disubstituted PTCs such as 2,4- and
3,5-(CF3)2 resulted in 95% yield with 72% ee and 92% yield with 38% ee, respectively (entries 6 and 7).
Theese results suggest that the position of the CF3 groups strongly affects the enantioselectivity. Finally,
the reaction using catalyst (D) proceeded even at –60 °C to give 2a in 89% yield with 91% ee within 12 h
(entry 8). This result indicates PTC D shows the maximum activity among the results reported for the
catalytic Michael reaction of 1a. These results are summarized in Table 1.
#$%&'()
CO2Me
CO2Me
Ph
Ph
H
PTC* (5 mol%)
Ph
N
CO2-t-Bu
Ph
N
CO2-t-Bu
CsOH·H2O (10 mol%)
t-BuOMe, -40 °C
1a
2a
yield of ee of
2a (%) 2a (%)
entry
PTC!
A : Ar = Ph
B : Ar = 4-(CF3)C6H4
B : Ar = 4-(CF3)C6H4
C : Ar = 3-(CF3)C6H4
D : Ar = 2-(CF3)C6H4
mol% condition"
1
2
3
4
5
6
7
8
10 -60 °C, 70 h
10 -60 °C, 26 h
86
73
45
99
95
73
77
61
52
74
Ar
Ar
Br
5
5
5
-40 °C, 24 h
-40 °C, 24 h
-40 °C, 24 h
O
O
N
O
O
Ar
E : Ar = 2,4-(CF3)2C6H3
F : Ar = 3,5-(CF3)2C6H3
D : Ar = 2-(CF3)C6H4
5
5
5
-40 °C, 24 h
-40 °C, 35 h
-60 °C, 12 h
95
92
89
72
38
91
Ar
PTC*
After successfully completing the highly enantioselective Michael reaction, we next investigated an
alanine Schiff base (3) with the construction of tetrasubstituted chiral carbons. There have been no
previous reports on producing quaternary glutamates via a catalytic asymmetric Michael reaction. We
chose aldimines (3)16 and surveyed PTCs under the optimized conditions (entries 1-4). When PTC D
was used, 4a was obtained in 88% yield with 45% ee.17 Although other ethereal solvent effects were
considered, no better results were obtained (Et2O: 44%, 36% ee; n-Bu2O: 83%, 37% ee; i-Pr2O: 78%,
43% ee).

HETEROCYCLES, Vol. 67, No. 2, 2006
497
CO2Me
Table 2
X
CO2Me
R
R
PTC D (5 mol%)
N
CO2-t-Bu
N
CO2-t-Bu
X
CsOH·H2O (10 mol%)
t-BuOMe
4
3
yield of ee of
entry
Schiff base (3)
3a : X = 4-Cl, R = Me
3a : X = 4-Cl, R = Me
3a : X = 4-Cl, R = Me
3a : X = 4-Cl, R = Me
PTC
conditions
4 (%)
4 (%)
1
2
-40 °C, 24 h
-40 °C, 24 h
4a: 71
4a : 57
22
30
A
B
3
-40 °C, 24 h
4a : 65
32
C
D
D
D
4
5
6
7
-40 °C, 24 h
-40 °C, 24 h
-40 °C, 24 h
-40 °C, 24 h
4a : 88
4b: 66
4c : trace
4d : 65
45
54
-
3b : X = H, R = Me
3c : X = 4-MeO, R = Me
3d : X = 4-CF3, R = Me
3e : X = 3-Cl, R = Me
3f : X = 2-Cl, R = Me
25
D
D
D
8
9
-40 °C, 24 h
-40 °C, 24 h
4e : 56
4f : 5
34
28
10
11
3b : X = 4-H, R = Me
3a : X = 4-Cl, R = Me
-60 °C, 60 h
-60 °C, 61 h
4b: 51
4a: 45
45
63
D
D
12
3g : X = 4-Cl, R = Bn
-40 °C, 40 h
4g : 72
9
D
D
D
13
14
3h : X = 4-Cl, R = Ph
3i : X = 4-Cl, R = i-Pr
-40 °C, 24 h
-40 °C, 40 h
4h : 84
4i : 0
0
-
"#$%&%!'
Me
Me
15% citric acid
THF, rt, 45 h
90%
(Boc)2O, DMAP
4a
(41% ee)
N
H
N
O
O
MeCN, rt, 5 h
95%
CO2-t-Bu
CO2-t-Bu
Boc
5
6
1) DIBAL, PhMe,
-78 °C, 2 h
21
[!]D -35.1° (c, 0.5, MeOH)
Me
3N HCl, THF, reflux, 1 h
Me
CO2H
litref. 18![!]D -71.9° (c, 1.0, MeOH)
25
then propylene oxide
EtOH, reflux, 30 min
2) BF3·Et2O, Et3SiH
CH2Cl2, -78 °C, 2 h
N
Boc
N
H
CO2-t-Bu
for S-isomer, >99% ee
8 (65%, 2 steps)
7 (63%, 2 steps)
While the reaction of 3b gave 4b in 66% yield, electron-donating group such as 4-MeO reduced the
reactivity due to the lower acidity of the α-proton of 3c (entries 5 and 6). On the other hand, a 4-CF3
group, which is expected to enhance proton abstraction, gave 4d in 65% yield, although its ee was lower
(entry 7). 3e and 3f were less effective than 3a with regard to both chemical yield and ee (entries 8 and
9). The reaction of 3a at –60 °C gave 4a with 63% ee (entry 11). We observed the electron density on
the aromatic rings in both the catalysts and substrates is important in achieving a higher catalytic activity
and ee. Unfortunately, this asymmetric reaction is not suitable for other alkyl groups (entries 12-14).
For example, while α-benzyl and phenyl substrates (3g and 3h) gave respective yields of 72 and 84% of 4,
no asymmetric induction was observed. In the case of i-Pr (1i), no reaction occurred. These results are
summarized in Table 2.

498
HETEROCYCLES, Vol. 67, No. 2, 2006
Absolute configuration of 4a was determined as follows (Scheme 1): the acid-treatment promoted
deprotection and subsequent cyclization to give 5 in 90% yield. The protection of amide (5) by (Boc)2O
gave 6 in 95% yield, and subsequent reduction and hydrosilylation gave 7 in 63% yield. Conversion to
α-methylproline (8) was accomplished by aq. HCl in the presence of propylene oxide (65% yield in 2
steps). According to the reported value for the optical rotation, the absolute configuration of 8 was
determined to be S.18
!"#$%$&'
O
MeO2C
HO
CO2Me
O
OH
Me
CO2-t-Bu
Me
Me
(n-hex)4N Br (10 mol%)
+
N
N
H
CO2-t-Bu
N
H
CO2-t-Bu
CsOH·H2O (20 mol%)
t-BuOMe,rt, 42 h
3j
9 : 46%
10: 12%
(n-hex)4N Br (10 mol%)
CsOH·H2O (20 mol%)
with methyl acrylate
t-BuOMe,rt, 42 h
18%
(recovery of 9, 63%)
Figure 1
During our study of the asymmetric Michael reaction of 3, we observed [3+2] cycloaddition between 3j
and methyl acrylate to give 9 and 10 (Scheme 2).19,20 A hydroxyl group at the ortho position on the
benzene ring promoted cycloaddition exclusively to give pyrrolidine 9 and lactone 10 in respective yields
of 46 and 12%. Both 3- and 4-hydroxy derivatives also gave the desired cycloadducts, but their
reactions were much slower (3-OH: 47% at 120 h, 4-OH: <30% at 120 h).21 The relative configuration
of 9 was determined by X-ray analysis to be all-cis (Figure 1) and basic treatment of 9 gave 10 in 18%
yield, which suggests that the stereochemistry of 10 is similar to that of 9. This reaction seems to
include the initial abstraction of a phenolic proton, and the resulting cesium phenoxide would activate an
imine carbon to promote the cyclization. We next turned to asymmetric synthesis using 3j with PTC D
(5 mol%), as shown in Table 3. The solvent effect indicates that t-BuOMe is better than non-polar

HETEROCYCLES, Vol. 67, No. 2, 2006
499
solvents (entries 1-3) and ether is a solvent of choice to give 25% ee (entry 4).22 The enantioselectivity
of 9 was determined by chiral HPLC analysis after N,O-bisbenzoylation and the absolute configuration
was assigned to be similar to those in Michael adducts of 2a and 4a.
ee of
9 (%)
yield
of 9 (%)
yield
of 10 (%)
entry solvent
Table 3
CO2Me
1
2
3
4
50
36
44
43
12
23
25
13
17
2
t-BuOMe
toluene
PTC D (5 mol%)
3j
9
+
10
7
25
CH2Cl2
Et2O
CsOH·H2O (20 mol%)
t-BuOMe,rt, 42 h
Enantiomeric excess of 9 was determined by HPLC analysis (CHIRALCEL
OD) after N,O-bisbenzoylation (BzCl, CH2Cl2, rt, 24 h, quant).
In conclusion, we succeeded in the asymmetric Michael reaction using a Schiff base catalyzed by D2-
symmetrical PTCs. A large increase in the reaction rate using 1 was observed with up to 91% ee, and
construction of a quaternary carbon was also achieved (with up to 63% ee). This method should provide
chiral pyrrolidones and pyrrolidines, which are considered to be useful building blocks for biologically
important compounds. We also noted the diastereospecific [3+2] cycloaddition directed by an ortho-
hydroxyl group with up to 25% ee. Further studies on catalyst tuning with regard to catalytic activity
and enantioselectivity are currently in progress.
ACKNOWLEDGEMENTS
We are grateful for financial support from the TAKEDA SCIENCE FOUNDATION and the Ministry of
Education, Science, Sports, Culture and Technology, Japan (16790007 and 17035014).
REFERENCES AND NOTES
1. T. Shioiri and S. Arai, ‘Stimulating Concepts in Chemistry,’ ed. by F. Vögtle, J. F. Stoddart, and M.
Shibasaki, John Wiley & Sons: New York, 2000, pp. 123-143.
2. U. –H. Dolling, E. J. J. Davis, and J. Grabowski, J. Am. Chem. Soc., 1984, 106, 446.
3. M. J. O’Donnell, W. D. Bennett, and S. Wu, J. Am. Chem. Soc., 1989, 111, 2353.
4. M. J. O'Donnell, Acc. Chem. Res., 2004, 37, 506.
5. B. Lygo and B. I. Andrews, Acc. Chem. Res., 2004, 37, 518.
6. K. Maruoka and T. Ooi, Chem. Rev., 2003, 103, 3013.

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HETEROCYCLES, Vol. 67, No. 2, 2006
7. S. Arai, R. Tsuji, and A. Nishida, Tetrahedron Lett., 2002, 43, 9535.
8. R. Tsuji, S. Arai, and A. Nishida, Synthesis, 2004, 960.
9. Shibasaki and co-workers reported a chiral PTC of bis-ammonium salts derived from tartrate in
asymmetric alkylation, see: T. Shibuguchi, Y. Fukuta, Y. Akachi, A. Sekine, T. Ohshima, and M.
Shibasaki, Tetrahedron Lett., 2002, 43, 9539.
10. D. Ma and K. Cheng, Tetrahedron Asymmetry, 1999, 10, 713.
11. T. Ishikawa, Y. Araki, T. Kumamoto, H. Seki, K. Fukuda, and T. Isobe, Chem. Commun., 2001, 245.
12. E. J. Corey, M. C. Noe, and F. Xu, Tetrahedron Lett., 1998, 39, 5347.
13. T. Ohshima, V. Gnanadesikan, T. Shibuguchi, Y. Fukuta, T. Nemoto, and M. Shibasaki, J. Am.
Chem. Soc., 2003, 125, 11206.
14. S. Arai, K. Tokumaru, and T. Aoyama, Chem. Pharm. Bull., 2004, 52, 646.
15. B. Lygo, B. Allbutt, and E. H. M. Kirton, Tetrahedron Lett., 2005, 46, 4461.
16. K. W. Laue and G. Haufe, Synthesis, 1998, 1453.
17. Typical experimental procedure for a PTC-catalyzed asymmetric Michael reaction (synthesis of
(S)-4a, Table 2, entry 4): To a solution of cesium hydroxide monohydrate (1.6 mg, 0.01 mmol), PTC
D (4.5 mg, 0.005 mmol) and 3a (26.7 mg, 0.1 mmol) in t-BuOMe (0.33 mL) was added methyl
acrylate (45 µL, 0.5 mmol) at –40 °C. After being stirred for 24 h, the reaction was quenched with
water and the resulting mixture was extracted with CH2Cl2 (5 mL X 3). The organic layers were
washed with brine and dried over Na2SO4, and the solvents were removed under reduced pressure.
Subsequent purification by flash column chromatography (hexane:Et2O = 2:1) gave 4a as a colorless
oil (31.1 mg, 88% yield, 45% ee). The enantiomeric excess was determined by HPLC analysis
using a chiral column. [α]D23 –6.1° (c, 0.3, CHCl3, 50% ee); 1H NMR (CDCl3, 400 MHz) δ: 1.45 (s,
3H), 1.46 (s, 9H), 2.11 (ddd, J = 13.2, 10.4, 5.6 Hz, 1H), 2.31 (ddd, J = 14.0, 10.4, 5.6 Hz, 1H),
2.39-2.57 (m, 2H), 3.65 (s, 3H), 7.37 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 8.25 (s, 1H); 13C
NMR (CDCl3, 100 MHz) δ: 23.5, 27.9, 29.5, 35.0, 51.6, 67.6, 81.5, 128.7, 129.4, 134.9, 136.7, 158.4,
172.5, 174.0; IR (neat) ν: 2922, 1737, 1644, 1118 cm-1; LRMS (FAB) m/z 354 (M++H); HRMS
(FAB) calcd for C18H25NO4Cl 354.1472, found 354.1500; HPLC: DAICEL CHIRALCEL OD, 254
nm, flow rate: 1.0 mL/min, hexane:i-PrOH = 99:1, retention time: 9.36 min (major, S-isomer) and
10.6 min (minor, R-isomer).

HETEROCYCLES, Vol. 67, No. 2, 2006
501
18. R. Chinchilla, N. Galindo, and C. Nájera, Synthesis, 1999, 704.
19. For a recent example of a highly enantioselective [3+2] cycloaddition initiated by Michael addition,
see: C. Chen, X. Li, and S. L. Schreiber, J. Am. Chem. Soc., 2003, 125, 10174.
20. One example of asymmetric [3+2] cycloaddition promoted by a chiral PTC has been reported: J.
Casas, R. Grigg, C. Nájera, and J. M. Sansano, Eur. J. Org. Chem., 2001, 1971.
21. Upon the addition of phenol (1 eq.) to the reaction of 3a and 3b, Michael adducts (4a) and (4b) were
predominantly obtained under similar conditions (80 and 62%) with the corresponding cycloadducts
in respective yields of 11 and 18%.
22. Synthesis of 9 (Table 3, entry 1): According to the procedure described in ref. 17, the reaction was
performed using cesium hydroxide monohydrate (3.3 mg, 0.02 mmol), PTC D (4.5 mg, 0.005 mmol),
3j (24.9 mg, 0.1 mmol), methyl acrylate (45 µL, 0.5 mmol) and t-BuOMe (0.33 mL) for 24 h at
–40 °C to give 9 (16.7 mg, 50%) and 10 (3.5 mg, 12%), respectively. 9; mp: 105-107 °C (Et2O);
25
1
[α]D +11.5° (c, 0.24, CHCl3, 17% ee); H NMR (CDCl3, 400 MHz) δ: 1.52 (s, 3H), 1.53 (s, 9H),
2.02 (dd, J = 13.6, 7.6 Hz, 1H), 2.88 (dd, J = 13.6, 4.0 Hz, 1H), 3.30-3.35 (m, 1H), 3.33 (s, 3H), 4.78
(d, J = 7.6 Hz, 1H), 6.74 (dt, J = 7.6, 1.2 Hz, 1H), 6.80 (dd, J = 16.0, 1.2 Hz, 1H), 6.94 (dd, J = 7.6,
13
1.6 Hz, 1H), 7.12 (dt, J = 7.6, 1.2 Hz, 1H); C NMR (CDCl3, 100 MHz) δ: 26.5, 27.9, 39.0, 49.0,
51.6, 64.2, 65.3, 81.6, 117.2, 118.5, 121.1, 128.4, 129.0, 158.1, 172.3, 174.1; IR (neat) ν: 3305, 2978,
1731, 1260, 1132, 752 cm-1; LRMS (FAB) m/z 336 (M++H); HRMS (FAB) calcd for C18H26NO5
336.1811, found 336.1794; Anal. Calcd for C18H26NO5: C, 66.46; H, 7.51; N, 4,18, Found: C, 64.50;
H, 7.47; N, 4.08.