Enantio- and diastereoselective michael reactions of silyl enol ethers and chalcones by catalysis using a chiral quaternary ammonium salt

Article abstract of DOI:10.1021/ol015592k

(Matrix presented) N-(9-Anthracenylmethyl)dihydrocinchonidinium bromide (1) is an effective catalyst for enantioselective Michael additions to chalcones, as shown in the above example, using toluene/50% aqueous KOH biphasic conditions at -20°C.

Full text of DOI:10.1021/ol015592k

ORGANIC
LETTERS
2001
Vol. 3, No. 4
639-641
Enantio- and Diastereoselective Michael
Reactions of Silyl Enol Ethers and
Chalcones by Catalysis Using a Chiral
Quaternary Ammonium Salt
Fu-Yao Zhang and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
12 Oxford Street, Cambridge, Massachusetts 02138
corey@chemistry.harVard.edu
Received January 19, 2001
ABSTRACT
N-(9-Anthracenylmethyl)dihydrocinchonidinium bromide (1) is an effective catalyst for enantioselective Michael additions to chalcones, as
shown in the above example, using toluene/50% aqueous KOH biphasic conditions at −20 °C.
We described in a recent publication the enantioselective
Michael addition of acetophenone to 4-methoxychalcone as
promoted by the chiral N-(9-anthracenylmethyl)dihydrocin-
chonidinium salt 1, in a toluene/50% aqueous KOH two-
phase mixture at -10 °C, to form the (S)-adduct 2 in 72%
yield and 80% ee.1 The utility of this process was illustrated
by the selective conversion of 2 to a chiral δ-keto acid and
to a chiral 2-cyclohexenone derivative. In this manuscript
Table 1 summarizes the results of a number of experiments
on Michael additions of a series of chalcones 3 and
trimethylsilyl enol ethers (4), rather than ketones, as reactants
under standard conditions with 1 (10 mol %) as catalyst,
toluene as organic phase, and 50% aqueous KOH as the
hydroxide source. There are three advantages of the use of
enol ethers 4 as reactants rather than the corresponding
ketones: (1) faster reactions as compared to those of ketones,
(2) higher enantioselectivities and yields, and (3) minimiza-
tion of aldol side reactions. Scrutiny of the data in Table 1
reveals that for the 11 reactions studied good yields (generally
in the 80-90% range) and enantioselectivities (generally 90-
95% ee) could be realized using -20 °C as a convenient
temperature. The procedure for this enantioselective Michael
addition is simple, and the results are readily reproducible.2,3
The (S)-configuration of the products 5 were assigned on
the basis of previously reported results.1 These skeletally,
but not actually, CS symmetric chiral 1,5-diketones would
be difficult to synthesize by other methods.
we report a modification of this chiral quaternary ammonium
salt catalyzed Michael addition that leads to higher yields
and enantioselectivities and also offers a wider scope with
regard to nucleophilic partner.
The catalytic enantioselective Michael process can be
extended to vinyloxysilanes other than the class represented
by 4. This is clearly indicated by the results summarized in
(1) Zhang, F.-Y.; Corey, E. J. Org. Lett. 2000, 2, 1097.
10.1021/ol015592k CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/31/2001

1-propene (6) as nucleophilic component with a variety of
chalcones 3. In general the enantioselectivities were found
to be high (92-99% ee) for the predominating anti dia-
stereomer (7a-7h in Table 2). The assignment of absolute
configuration to the products was based on the rigorous
determination of structure for the Michael adducts shown in
Table 2, entry 7. For this case the syn diastereomer 8g is a
crystalline solid, mp 142-144 °C, which was subjected to
X-ray crystallographic analysis, revealing the molecular
structure shown in Figure 1.4 Treatment of this syn adduct
Table 1. Enantioselective Michael Reactions Catalyzed by
Quaternary Ammonium Salt 1
time yield ee
Ar1
Ar2
Ar3
C6H5
C6H5
C6H5
C6H5
C6H5
(h)
(%) (%)
4-F-C6H4
C6H5
C6H5
C6H5
C6H5
8
4
24
16
4
16
24
10
15
85
91
80
94
87
92
82
81
79
92
81
95
94
92
91
91
94
94
95
92
93
95
4-Cl-C6H4
4-CH3O-C6H4
4-CH3-C6H4
4-F-C6H4
4-F-C6H4
6-CH3O-2-C10H6 C6H5
4-Cl-C6H4
4-CH3O-C6H4 C6H5
C6H5
C6H5
2-CH3-C6H4
4-C6H5-C6H4 16
2-C10H7 10
1-C10H7
C6H5
C6H5
C6H5
C6H5
4-F-C6H4
4-F-C6H4
4-F-C6H4
Figure 1. X-ray crystal structure of compound 8g.
(8g) with alcoholic base effected equilibration to a chro-
matographically separable mixture of diastereomers 7g (anti;
obtained as an oil) and 8g (syn) in a ratio of ca. 2:1. The
anti diastereomer was identical in all respects with the anti
product obtained directly from the Michael reaction of 3 and
6 in the presence of the catalyst 1. The face selectivity with
regard to the chalcone component must therefore be the same
for the formation of the major anti adduct 7g and the minor
syn adduct 8g. The face selectivity for addition to the
chalcone is identical for the Michael additions shown in
Table 1 and Table 2. Furthermore, this same face selectivity
has previously been observed for other Michael-type reac-
tions of chalcones and other R,â-enones, for which a clear
mechanistic rationale has been provided.1,5 The stereochem-
istry of the other products listed in Table 2, entries 1-6 and
8, was assigned by analogy with the configurations of adducts
7g and 8g.6
Table 2, which reveal not only strong enantiocontrol but also
good diastereocontrol for (Z)-1-phenyl-1-(trimethylsilyloxy)-
(2) The following procedure is illustrative. To a cold (-20 °C) mixture
of 4-fluorochalcone (113 mg, 0.5 mmol), 1-phenyl-1-(trimethylsilyloxy)-
ethylene (115 mg, 0.6 mmol), and chiral quaternary ammonium salt 13 (28.7
mg, 0.05 mmol) in toluene (2.5 mL) was added 0.5 mL of 50% KOH
aqueous solution. After stirring at -20 °C for 16 h, the reaction mixture
was diluted with 10 mL of Et2O and 5 mL of water. The toluene phase was
concentrated, and the product was purified by flash chromatography (silica
gel, 6:1 hexanes/ethyl acetate) to afford (S)-5, Ar1 ) 4-F-C6H4, Ar2 ) Ar3
) C6H5, (147 mg, 85% yield, 95% ee) as an oil. [R]23 ) -1.1 (c 2.0,
D
CH2Cl2); FTIR (film) 1683.5 cm-1
;
1H NMR (500 MHz, CDCl3) 8.00-
7.94 (m, 4H), 7.57-7.07 (m, 10H), 4.06 (m, 1H), 3.48 (m, 2H), 3.65 (dd,
J ) 16.5 and 6.5 Hz, 1H), 3.31 (dd, J ) 16.5 and 7.5 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 198.8, 197.2, 165.9 (d, J ) 253.0 Hz), 143.9, 137.1,
133.5 (d, J ) 3.0 Hz), 133.4, 131.0 (d, J ) 11.4 Hz), 129.0, 128.8, 128.4,
127.7, 127.0, 115.9 (d, J ) 22.1 Hz), 45.1, 45.0, 37.4 ppm; HRMS (CI)
calcd [C23H19FO2 + H]+ 347.1447, found 347.1448. The ee value was
determined by HPLC analysis at 23 °C with a Chiralcel OD column, 5%
isopropyl alcohol in hexanes, 1.0 mL/min, λ ) 254 nm; retention times,
minor 26.7 min; major 36.9 min.
(3) Quaternary ammonium salt 1 was synthesized by the following
procedure; see Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997,
119, 12414. A suspension of dihydrocinchonidine (2.96 g, 10.0 mmol) and
9-(bromomethyl)anthracene (2.85 g, 10.5 mmol) in toluene (20 mL) was
heated at reflux for 3 h. The resulting mixture was cooled to ambient
temperature, poured into 300 mL of diethyl ether, and filtered to give 1 as
a yellow powder (5.55 g, 98% yield): mp 180 °C (dec); [R]23D ) -253 (c
1.0, MeOH); FTIR (film) 1620.4, 1699.4, 1509.1, 1420.3, 1265.9, 1065.6
cm-1 1H NMR (400 MHz, CD3OD) 9.00 (d, J ) 4.8 Hz, 1H), 8.82 (s,
;
1H), 8.78 (d, J ) 9.2 Hz, 1H), 8.60 (m, 1H), 8.19 (d, J ) 8.4 Hz, 1H),
8.16 (m, 1H), 8.07 (d, J ) 4.8 Hz, 1H), 7.90 (m, 2H), 7.80 (m, 2H), 7.62
(m, 2H), 7.12 (m, 2H), 6.46 (d, J ) 14.0 Hz, 1H), 5.83 (d, J ) 14.0 Hz,
1H), 4.67 (m, 1H), 4.63 (s, 1H), 4.44 (t, J ) 9.2 Hz, 1H), 3.62 (m, 1H),
3.18 (m, 1H), 2.71 (m, 1H), 2.26 (m, 2H), 2.11 (m, 1H), 1.88 (m, 1H),
1.57 (m, 1H), 1.43 (m, 1H), 1.26 (m, 3H), 0.68 (t, J ) 7.2 Hz, 3H); 13C
NMR (100 MHz, CD3OD) δ 149.9, 147.6, 146.7, 133.6, 132.5, 131.8, 130.1,
130.0, 129.9, 129.2, 128.7, 128.1, 128.0, 127.9, 125.4, 125.3, 125.2, 125.1,
124.6, 123.9, 123.3, 120.4, 118.2, 68.6, 66.0, 64.4, 55.5, 52.2, 36.5, 26.3,
25.6, 23.8, 21.6, 10.4 ppm.
The enantioselective Michael reaction summarized in
Table 2 is advantageous not only for the synthesis of chiral
(4) The coordinates of the syn diastereomer 8g, Ar1 ) C6H5, Ar2 ) 4-Br-
C6H4, can be obtained, on request, from the Director, Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, U.K.
640
Org. Lett., Vol. 3, No. 4, 2001

Table 2. Enantio- and Diastereoselective Michael Additions of Propiophenone Enolate to Chalcones
7 (anti)
8 (syn)
yield (%)
entry
Ar1
Ar2
C6H5
C6H5
C6H5
product
time (h)
anti/syn
yield (%)
ee (%)
ee (%)
1
2
3
4
5
6
7
8
C6H5
a
b
c
d
e
f
10
10
10
40
15
40
10
15
9:1
10:1
10:1
4:1
10:1
3:1
81
86
80
75
78
65
82
82
99
99
99
98
99
97
92
92
9
9
8
18
7
22
12
90
94
84
90
81
95
95
4-F-C6H4
4-Br-C6H4
4-CH3O-C6H4
C6H5
C6H5
4-CH3-C6H4
4-NO2-C6H4
4-Br-C6H4
1-C10H7
C6H5
C6H5
C6H5
g
h
7:1
20:1
min) produced the corresponding free acid 10. δ-Keto acid
derivatives such as 9 or 10 are not otherwise accessible by
catalytic enantioselective routes as far as we are aware.
1,5-diketones of type 7 but also for a variety of products
that can readily be produced therefrom. For instance, the
large difference in reactivity of the two carbonyl groups of
7 (due to differences in steric shielding) allows selective
Baeyer-Villiger oxidation, which leads in the case of 7g to
the phenyl ester 9 in 90% yield using 1.7 equiv of
m-chloroperbenzoic acid in CH2Cl2 at reflux for 40 h.
Saponification of 9 (LiOH in CH3OH/H2O at 0 °C for 10
The enantioselective methodology outlined herein is novel
and promising and, we believe, practical for more general
synthetic purposes.
Acknowledgment. This research was support by a grant
from Pfizer Inc.
(5) (a) Corey, E. J.; Noe, M. C.; Xu, F. Tetrahedron Lett. 1998, 39,
5347. (b) Corey, E. J.; Zhang, F.-Y. Org. Lett. 1999, 1, 1247.
(6) The following experimental procedure for the case of entry 7 of Table
2 is illustrative. To a cold (-20 °C) mixture of 4′-bromochalcone (144
mg, 0.5 mmol), (Z)-1-phenyl-1-(trimethylsilyloxy)-1-propylene (124 mg,
0.6 mmol), and chiral quaternary ammonium salt (28.7 mg, 0.05 mmol) in
toluene (2.5 mL) was added 0.5 mL of 50% KOH aqueous solution. After
stirring at -20 °C for 10 h, the reaction was diluted with of 10 mL of Et2O
and 5 mL of water. The product from the organic phase was purified by
flash chromatography (silica gel, 9:1 hexanes/ethyl acetate) to afford the
product 7g (anti, 2R,3R) (207 mg, 82% yield, 92% ee) and 8g (syn, 2S,3R)
OL015592K
O1 column, 10% isopropyl alcohol in hexanes, 1.0 mL/min, λ ) 254 nm;
retention times, minor 39.7 min, major 43.6 min. For 8g (syn, 2S,3R): mp
142-144 °C; [R]23 ) +17.9 (c 1.0, CH2Cl2); FTIR (film) 1678.7 cm-1
;
D
1H NMR (500 MHz, CDCl3) 8.05-7.84 (m, 4H), 7.62-7.09 (m, 10H),
3.92-3.81 (m, 2H), 3.38 (dd, J ) 16.5 and 4.5 Hz, 1H), 3.23 (dd, J ) 16.0
and 10.0 Hz, 1H), 1.01 (d, J ) 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ 203.7, 198.4, 140.9, 136.9, 136.8, 133.6, 133.3, 131.8, 130.4, 129.1, 128.8,
128.6, 128.4, 120.8, 45.7, 44.0, 43.5, 16.9 ppm. The ee value was determined
by HPLC analysis with a Chiralcel OD column, 10% isopropyl alcohol in
hexanes, 1.0 mL/min, λ ) 254 nm; retention times, minor 10.5 min, major
12.4 min. The absolute configurations of the chiral centers were determined
by X-ray analysis, which demonstrated the structure shown in Figure 1.
(30.0 mg, 12% yield, 95% ee). For 7g (anti, 2R,3R): [R]23 ) -28.8 (c
D
2.0, CH2Cl2); FTIR (film) 1682.4 cm-1; 1H NMR (500 MHz, CDCl3) 7.86-
7.14 (m, 14H), 3.92 (m, 1H), 3.44 (d, J ) 6.0 Hz, 2H), 1.28 (d, J ) 6.5
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 203.2, 198.4, 142.2, 137.1, 136.8,
133.4, 131.7, 130.0, 128.9, 128.8, 128.3, 128.2, 120.6, 45.9, 42.6, 40.4,
14.9 ppm; HRMS (CI) calcd. [C24H21BrO2 + H]+ 421.0803, found
421.0790. The ee value was determined by HPLC analysis with a Whelk
Org. Lett., Vol. 3, No. 4, 2001
641