LETTER
Asymmetric Intramolecular Michael Reaction
1077
(
10) Hayashi, Y.; Gotoh, H.; Tamura, T.; Yamaguchi, H.; Masui,
Table 4 Other Substrates
R.; Shoji, M. J. Am. Chem. Soc. 2005, 127, 16028.
O
O
R
R
(11) Catalyst Preparation
O
O
*
cat. 1a
To a solution of N-Boc-protected proline (50 g, 0.23 mol) in
H
(30 mol%)
H
anhyd DMF (250 mL), Et N (39 mL, 0.28 mol) was added
3
*
and the mixture was cooled to 0 °C, then ethyl chloroformate
(22 mL, 0.23 mol) was added dropwise over 30 min. The
reaction temperature was maintained at 0 °C for 40 min, and
then diisopropylaniline (44 mL, 0.23 mol) was added at
AcOH (30 mol%)
CHCl3–H2O
30 °C
2
b: R = Ph
3b: R = Ph
t
t
2c: R = Bu
3c: R = Bu
0
°C. The reaction mixture was stirred at 65 °C for 14 h. The
Entry
Product Time (h) Yield (%) dr
ee (%)
mixture was poured into H O (150 mL) and crashed ice (150
mL). The precipitated solid was filtered and dried in air. A
2
(
cis:trans) cis/trans
part of the crude N-Boc-protected anilide (50 g) was
1
2
3
3b
3b
3c
4.5
18
55
91
92
97
23:77
17:83
7:93
94/88
95/93
84/81
dissolved in CHCl (100 mL) and TFA (98%, 100 mL) was
3
added at r.t. The reaction mixture was stirred at 50 °C for
2
h. The solvent was removed and the pH of the residue was
adjusted to 8–9 by the addition of aq NaOH (2 N), the
product was extracted with CHCl , and dried over MgSO .
3
4
After removal of the solvent, the residue was purified by
recrystallization from hexane–TBME–CHCl (1:1:0.1; ca.
3
with good selectivity but it demanded longer latency
period for the full consumption of 2c (entry 3).
400 mL) to give 1d (30 g, 82%). The catalysts 1a–c were
prepared in the same manner. Anilide 1a is also available
from Fluorochem, Ltd. (order # 032341).
In summary, proline-derived anilides 1 promoted the
intramolecular Michael reaction in good yields and excel-
lent selectivity. Further studies into the scope and mecha-
nism of this catalytic reaction are in progress.
The spectral data for catalyst 1b: colorless needles; mp
26
1
7
9 °C; [a]D –77.6 (c 1.00, CHCl ). H NMR (300 MHz,
3
CDCl ): d = 9.19 (br s, 1 H), 7.06 (m, 3 H), 3.92 (dd, J = 9.3,
5.1 Hz, 1 H), 3.14–2.99 (m, 2 H), 2.22 (s, 6 H), 2.14–2.03 (m,
H), 1.91–1.74 (m, 2 H). C NMR (75 MHz, CDCl ): d =
72.9, 134.6, 133.7, 127.8, 126.4, 60.8, 47.5, 31.1, 26.4,
18.6. IR (KBr): 3281, 3003, 1669, 1501, 1098 cm . HRMS:
m/z calcd for C H ON [M ]: 218.1419; found 218.1414.
3
1
3
1
1
3
–
1
Acknowledgment
+
1
3
18
2
This work was supported by a Grant-in-Aid for Scientific Research
from the Japan Society of the Promotion of Science (JSPS, Project
No. 18750083). We are also grateful for financial support from the
Tatematsu Foundation.
25
Catalyst 1c: colorless needles; mp 78 °C; [a] –67.2 (c
D
1
1
.00, CHCl ). H NMR (300 MHz, CDCl ): d = 9.22 (br s, 1
3
3
H), 7.21–7.09 (m, 3 H), 3.91 (dd, J = 9.3, 5.1 Hz, 1 H), 3.13–
2
.97 (m, 2 H), 2.56 (q, J = 7.5 Hz, 4 H), 2.25–2.03 (m, 2 H),
1
3
1.90–1.75 (m, 2 H), 1.79 (t, J = 7.5 Hz, 6 H). C NMR (75
MHz, CDCl ): d = 173.7, 140.8, 132.7, 127.2, 126.1, 65.0,
3
References and Notes
6
0.7, 47.5, 30.9, 26.4, 25.0, 14.5. IR (KBr): 3280, 2969,
–
1
(
1) For important recent reviews, see: (a) Krause, N.;
Hoffmann-Röder, A. Synthesis 2001, 171. (b) Christoffers,
J.; Baro, A. Angew. Chem. Int. Ed. 2003, 42, 1688.
2) For reviews, see: (a) Dalko, P. I.; Moisan, L. Angew. Chem.
Int. Ed. 2004, 43, 5138. (b) Berkessel, A.; Gröger, H.
Asymmetric Organocatalysis; Wiley-VCH: Weinheim,
1668, 1500, 1298, 1240, 1100 cm . HRMS: m/z calcd for
+
C H ON [M ]: 246.1732; found: 246.1741.
1
5
22
2
2
5
Catalyst 1d: colorless needles; mp 155 °C; [a] –58.7 (c
D
1
(
1.00, CHCl ). H NMR (300 MHz, CDCl ): d = 9.14 (br s, 1
3
3
H), 7.29–7.15 (m, 3 H), 3.94 (dd, J = 9.3, 5.1 Hz, 1 H), 3.17–
2.94 (m, 4 H), 2.30–2.05 (m, 2 H), 1.90–1.75 (m, 2 H), 1.22
1
3
2004, and references cited therein.
(d, J = 3.9 Hz, 6 H), 1.20 (d, J = 3.9 Hz, 6 H); C NMR (75
(
(
(
(
3) List, B.; Pojarliev, P.; Martin, H. J. Org. Lett. 2001, 3, 2423.
4) Betancort, J. M.; Barbas, C. F. III Org. Lett. 2001, 3, 3737.
5) Alexakis, A.; Andrey, O. Org. Lett. 2002, 4, 3611.
6) Thiourea-catalyzed asymmetric intermolecular Michael
reactions: (a) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am.
Chem. Soc. 2003, 125, 12672. (b) Okino, T.; Hoashi, Y.;
Furukawa, T.; Xu, X. N.; Takemoto, Y. J. Am. Chem. Soc.
MHz, CDCl ): d = 174.2, 145.5, 131.4, 127.7, 123.2, 60.8,
3
47.6, 31.0, 28.9, 26.5, 23.7, 23.6. IR (KBr): 3289, 2966,
–
1
1667, 1498, 1100 cm . Anal. Calcd for C H N O: C,
1
7
26
2
74.41; H, 9.55; N, 10.21. Found: C, 74.30; H, 9.68; N, 10.10.
(12) The use of both AcOH and H O is critical. The cyclization
2
of 2a without AcOH and H O furnished lower reactivity in
2
moderate enantioselectivity (catalyst 1a, 5 h, 92%, cis/
trans = 44:56, 81% ee for cis, 62% ee for trans). The
advantage of additives in aldol reaction, see: (a) Mase, N.;
Tanaka, F.; Barbas, C. F. III Org. Lett. 2003, 5, 4369.
(b) Pihko, P. M.; Laurikainen, K. M.; Usano, A.; Nyberg, A.
I.; Kaavi, J. A. Tetrahedron 2006, 62, 317. For the
2005, 127, 119. (c) Tsogoeva, S. B.; Yalalov, D. A.;
Hateley, M. J.; Weckbecker, C.; Huthmacher, K. Eur. J.
Org. Chem. 2005, 4995.
(7) For the leading reviews, see: (a) Connon, S. J. Chem. Eur. J.
2006, 12, 5418. (b) Takemoto, Y. Org. Biomol. Chem. 2005,
3
, 4299. (c) Taylor, M. S.; Jacobsen, E. N. Angew. Chem.
important correspondences about the water effect, see:
(c) Brogan, A. P.; Dickerson, T. J.; Janda, K. D. Angew.
Chem. Int. Ed. 2006, 45, 8100. (d) Hayashi, Y. Angew.
Chem. Int. Ed. 2006, 45, 8103; and references cited therein.
(13) General Procedure for Intramolecular Michael Reaction
To a mixture of anilide 1 (0.06 mmol, 30 mol%) and the
corresponding formyl enone 2 (0.2 mmol) were added
CHCl (2.5 mL), H O (50 mL) and AcOH (0.06 mmol, 30
Int. Ed. 2006, 45, 1520.
(
8) Pioneering work of the intramolecular Michael reaction
mediated by stoichiometric amount of L-proline:
(
a) Kozikowski, A. P.; Mugrage, B. B. J. Org. Chem. 1989,
4, 2274. (b) The use of chiral amine: Hirai, Y.; Terada, T.;
Yamazaki, T.; Momose, T. J. Chem. Soc., Perkin Trans. 1
992, 509.
9) Fonseca, M. T. H.; List, B. Angew. Chem. Int. Ed. 2004, 43,
958.
5
1
3
2
(
mol%) at 30 °C. The mixture was stirred at 30 °C until TLC
indicated complete reaction. The reaction was quenched at
3
Synlett 2007, No. 7, 1075–1078 © Thieme Stuttgart · New York