Highly enantioselective Michael reactions catalyzed by a chiral quaternary ammonium salt. Illustration by asymmetric syntheses of (S)-ornithine and chiral 2-cyclohexenones.

Article abstract of DOI:10.1021/ol0056527

[formula: see text] The use of the chiral quaternary ammonium salts 1a and 1b makes possible enantioselective Michael reactions which have been applied to the asymmetric syntheses of (S)-ornithine (2) and the chiral 2-cyclohexenone 6.

Full text of DOI:10.1021/ol0056527

ORGANIC
LETTERS
2
000
Vol. 2, No. 8
097-1100
Highly Enantioselective Michael
Reactions Catalyzed by a Chiral
Quaternary Ammonium Salt. Illustration
by Asymmetric Syntheses of
1
(
2
S)-Ornithine and Chiral
-Cyclohexenones
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 February 11, 2000
ABSTRACT
The use of the chiral quaternary ammonium salts 1a and 1b makes possible enantioselective Michael reactions which have been applied to
the asymmetric syntheses of (S)-ornithine (2) and the chiral 2-cyclohexenone 6.
Chiral quaternary N-(9-anthracenylmethyl)cinchonidinium
cations 1 have been shown to be extraordinarily effective
are based upon the experimentally determined three-
dimensional geometry of contact ion pairs of cation 1 with
1,2
3
1-6
and useful catalysts for enantioselective alkylation, Michael,
various anions. For example, (S)-R-amino acid derivatives
4
5
6
aldol, nitroaldol, and epoxidation reactions. With 1 as
catalyst, enantioselectivities of >20:1 have frequently been
obtained in the above reactions. In addition, the absolute
configuration of the predominating enantiomer can be
predicted from mechanistic models for these reactions, which
can be synthesized with enantioselectivities of up to 400:1
by alkylation of the tert-butyl glycinate Schiff base of
7
benzophenone (O’Donnell’s substrate). In this case, the
enolate oxygen of the glycinate ester is held in close
proximity with the only sterically open face of the cation 1,
as van der Waals attractive interactions between the gege-
nions hold them in an energetically preferred relative
(
(
1) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414.
2) Corey, E. J.; Bo, Y.; Busch-Petersen, J. J. Am. Chem. Soc. 1998,
1
20, 13000.
(3) Corey, E. J.; Noe, M. C.; Xu, F. Tetrahedron Lett. 1998, 39, 5347.
4) Horikawa, M.; Busch-Petersen, J.; Corey, E. J. Tetrahedron Lett.
(
1
999, 40, 3843.
5) Corey, E. J.; Zhang, F.-Y. Angew. Chem., Int. Ed. Engl. 1999, 38,
931.
(
1
(
(
6) Corey, E. J.; Zhang, F.-Y. Org. Lett. 1999, 1, 1287.
7) For earlier work on the enantioselective alkylation of the benzophe-
none Schiff base of tert-butyl glycinate see: (a) O’Donnell, M. J.; Bennett,
W. D.; Wu, S. J. Am. Chem. Soc. 1989, 111, 2353. (b) O’Donnell, M. J.;
Wu, S.; Huffman, J. C. Tetrahedron 1994, 50, 4507. (c) Lipkowitz, K. B.;
Cavanaugh, M. W.; Baker, B.; O’Donnell, M. J. J. Org. Chem. 1991, 56,
5
181.
1
0.1021/ol0056527 CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/29/2000

Scheme 1
1
addition of ClO- due to stabilization of the developing
enolate (by the proximate N ) of the Michael adduct. In this
orientation that favors alkylation to form the S product. A
variation on this pathway is observed in the hypochlorite-
mediated epoxidation of R,â-enones, such as benzalac-
etophenone, in which the contact ion pair of 1 with
hypochlorite can bind the enone substrate so that the
+
paper, we describe the application of these two mechanistic
modes of reaction to novel enantioselective Michael addi-
tions.
The first type of asymmetric Michael reaction has been
utilized for a remarkably simple synthesis of the natural
R-amino acid (S)-ornithine (2) from glycine and acrylonitrile
using the chiral catalyst 1a, as outlined in Scheme 1. Reaction
-
nucleophilic oxygen of ClO is in proximity with the
â-carbon of the enone. Here, the Michael addition is
facilitated not only by the favorable alignment of the two
reactants but also by charge acceleration of the conjugate
Scheme 2
1098
Org. Lett., Vol. 2, No. 8, 2000

of the benzophenone Schiff base of tert-butyl glycinate with
acrylonitrile in the presence of 10 mol % of cinchonidinium
bromide 1a in CH Cl and 50% aqueous potassium hydroxide
2 2
at -55 °C for 15 h produced the Michael adduct 4 of 91%
enantiomeric purity in 85% yield after chromatography on
silica gel. The determination of ee of 4 was made by HPLC
analysis using a Regis Whelk-O1 column with 20% isopropyl
alcohol in hexane for elution at 23 °C and UV detection at
254 nm (retention times at flow rate 1 mL/min: minor
enantiomer, 9.3 min; major, 11.0 min). The catalyst 1a was
recovered (82%) during workup. Reduction of 4 with the
8
cobalt boride-NaBH
4
reagent in methanol at 55 °C afforded
the diamino ester 5 (78% yield). Cleavage of the benzhydryl
group from 5 (H , Pd-C) followed by acid-catalyzed
2
hydrolysis (aqueous HCl) of the tert-butyl ester produced
the dihydrochloride of (S)-ornithine, identified by comparison
2
3
with an authentic sample: mp 194-196 °C; [R]
D
+16.7
(c ) 2, 6 N HCl). The absolute configuration of the key
chiral intermediate 4 in this synthesis of (S)-ornithine agrees
with the prediction based on the previous described mecha-
nistic model.1 A typical experimental procedure for the
synthesis of 4 is provided.9
-3
The application of the chiral quaternary ammonium salt
1
b to an enantioselective Michael reaction leading to the
chiral Robinson annulation product 6 is depicted in Scheme
. Michael reaction of 4-methoxychalcone (7) and acetophe-
2
none (8) in toluene at -10 °C in the presence of 10 mol %
of catalyst 1b and 50% aqueous potassium hydroxide for
36 h gave the S adduct 9 in 72% yield and 80% ee.
Figure 1.
Determination of enantioselection was made by HPLC
analysis using a Chiracel OD column (Daicel Technologies),
1
0% isopropyl alcohol in hexane, UV detection at 254 nm,
established by conversion to the corresponding methyl ester
10a and HPLC analysis. Treatment of keto acid 10 with
excess oxalyl chloride and a catalytic amount of dimethyl-
formamide at 23 °C for 1 h furnished cleanly the enol
δ-lactone 11 (93%), which upon sequential reaction with
methylmagnesium iodide in ether (to form the corresponding
methyl ketone) and sodium isopropoxide in isopropyl alcohol
(to effect aldol cyclization) produced the (S)-R,â-enone 6:
and a flow rate of 1.0 mL/min (retention times: ent-9, 36.2
min; 9, 54 min). The S absolute configuration of the dominant
Michael adduct (9) was established by Baeyer-Villiger
oxidation (selective for the 4-methoxybenzoyl subunit of 9)
and subsequent saponification with lithium hydroxide in
aqueous methanol, which gave the known dextrorotatory keto
acid 10 (S-form).10 Recrystallization of 10 from ethyl
acetate-hexane provided 99% enantiomerically pure mate-
2
3
[R]
D
2 2
+36.9 (c ) 2, CH Cl ), mp 91-93 °C; FTIR (film)
rial, [R]23
D
2 2
+2.8 (c ) 1.0, CH Cl ), mp 158-160 °C, as
(10) (S)-3,5-Diphenyl-5-oxopentanoic acid (10) has previously been
synthesized from a chiral starting material; see: Diaz-Ortiz, A.; Diez-Barra,
E.; de la Hoz, A.; Prieto, P.; Moreno, A. J. Chem. Soc., Perkin Trans. 1
1996, 259.
(
(
8) Heinzman, S. W.; Ganem, B. J. Am. Chem. Soc. 1982, 104, 6801.
9) To a solution of 3 (502 mg, 1.7 mmol) and chiral quaternary
ammonium salt 1a (103 mg, 0.17 mmol) in CH2Cl2 (5 mL) was added
dropwise 1 mL of 50% aqueous potassium hydroxide solution. After being
cooled to -55 °C, the mixture was treated with acrylonitrile (1.1 mL, 17
mmol), stirred at -55 °C for 15 h, concentrated, and diluted with 50 mL
of Et2O and 10 mL of hexanes. The solid quaternary ammonium salt 1a
was collected by filtration and the solid was dissolved in 20 mL of CH2-
Cl2, washed with water and dried over MgSO4. After evaporation of solvent,
the catalyst 1a was recovered (84 mg, 82% yield). The filtrate was washed
with water and brine, dried and purified by flash chromatography (silica
gel, 5:1 hexanes/ethyl acetate) to afford the product 4 (503 mg, 85% yield)
(11) Experimental procedure for 7 + 8 f 9: To a cold (-10 °C) mixture
of 4-methoxychalcone (7) (119 mg, 0.5 mmol), acetophenone (8) (120 mg,
1.0 mmol), and chiral quaternary ammonium salt 1b (28.3 mg, 0.05 mmol)
in toluene (2.5 mL) was added 0.5 mL of 50% KOH aqueous solution.
After the mixture was stirred at -10 °C for 36 h, the reaction was quenched
by addition of 10 mL of Et2O and 5 mL of water. The organic phase was
purified by flash chromatography (silica gel, 3:1 hexanes/ethyl acetate) to
2
3
afford the product (S)-9 (129 mg, 72% yield, 80% ee) as an oil: [R] D )
-2.1 (c ) 1.5, CH2Cl2); FTIR (film) 2923.4, 2851.7, 1680.1, 1600.1, 1510.0,
-
1 1
1449.4, 1260.6, 1170.6 cm ; H NMR (500 MHz, CDCl3) 7.94 (m, 4H),
7.54 (m, 1H), 7.44 (t, J ) 7.5 Hz, 2H), 7.28 (m, 4H), 7.17 (m, 1H), 6.91
(m, 2H), 4.06 (dt, J ) 14.0, 7.5 Hz, 1H), 3.86 (s, 3H), 3.50 (dd, J ) 16.5,
6.5 Hz, 1H), 3.43 (dd, J ) 16.5, 7.0 Hz, 1H), 3.34 (dd, J ) 16.5, 7.0 Hz,
2
3
as colorless crystals: mp 57-58 °C; [R] D ) -120.5 (c ) 1.0, CHCl3);
FTIR (film) 3061.5, 3001.3, 2977.7, 2246.8, 1732.0, 1624.7, 1598.0, 1446.4,
-
1 1
1
1
369.0, 1289.3, 1151.6 cm ; H NMR (400 MHz, CDCl3) 7.71-7.18 (m,
13
13
0H), 4.06 (m, 1H), 2.46 (m, 2H), 2.32-2.17 (m, 2H), 1.43 (s, 9H);
C
1H), 3.29 (dd, J ) 16.5, 6.5 Hz, 1H); C NMR (125 MHz, CDCl3) δ
NMR (100 MHz, CDCl3) δ 172.0, 169.8, 139.1, 136.0, 130.6, 128.9, 128.8,
198.9, 197.4, 163.7, 144.1, 137.2, 133.3, 130.7, 130.2, 128.9, 128.8, 128.4,
+
+
1
28.6, 128.1, 127.6, 119.4, 81.8, 63.7, 29.4, 27.9, 13.7 ppm; HRMS (EI )
127.7, 126.9, 114.0, 55.7, 45.2, 44.9, 37.6 ppm; HRMS (CI ) calcd
+
+
calcd [C22H24N2O2] 348.1838, found 348.1827. The ee value was
determined by HPLC analysis with a Regis Whelk-O1 column, 20%
isopropyl alcohol in hexane, 1.0 mL/min, l ) 254 nm, retention times:
minor, 9.3 min; major, 11.0 min.
[C24H22O3 + H] 359.1647, found 359.1631. The ee value was determined
by HPLC analysis with a Chiralcel OD column, 10% isopropyl alcohol in
hexane, 1.0 mL/min, λ ) 254 nm, retention times: minor, 36.2 min; major,
54.0 min.
Org. Lett., Vol. 2, No. 8, 2000
1099

-
1
1
+
1
662.0, 1605.7, 1496.6, 1447.2, 1260.7 cm ; H NMR (400
MHz, CDCl ) 7.57-7.26 (m, 10H), 6.52 (d, J ) 2.0 Hz,
H), 3.47 (s, 1H), 3.07 (dd, J ) 17.6, 4.4 Hz, 1H), 2.94
ddd, J ) 17.6, 11.2, 2.4 Hz, 1H), 2.79 (dd, J ) 16.4, 5.2
acetophenone enolate is contact ion paired with N of the
3
quaternary ammonium catalyst. The R,â-enone is wedged
between the ethyl and quinoline substituents on the quinu-
clidine ring and the carbonyl oxygen is so positioned that
1
(
1
3
+
Hz, 1H), 2.73 (dd, J ) 16.4, 12.8 Hz, 1H); C NMR (100
MHz, CDCl ) δ 199.3, 158.9, 143.4, 138.6, 130.4, 129.1,
29.0, 127.3, 127.0, 126.4, 125.4, 44.3, 41.4, 36.7 ppm. The
ee value was determined by HPLC analysis with a Chiralcel
OJ column, 10% isopropyl alcohol in hexane, 1.0 mL/min,
λ ) 254 nm (retention times: 6, 20.5 min; ent-6, 23.0 min).
The correct absolute configuration for the chiral products
6-11) shown in Scheme 2 are those predicted by the
previously described mechanistic model for the Michael
epoxidation of R,â-enones using potassium hypochlorite as
reagent with the chiral catalyst 1a. Two different views of
the three-dimensional arrangement of 4-methoxychalcone,
acetophenone enolate ion and the chiral quaternary am-
monium ion 1b are shown in Figure 1 which corresponds to
the mechanistic model. In Figure 1, the two views shown
are related by a 180° rotation about the vertical axis. The
close ion pairing with N of the catalyst can occur in the
3
Michael transition state. The phenyl group of acetophenone
enolate is positioned to π-stack with the 9-anthracenyl
subunit of the catalyst.
1
On the basis of this mechanistic model and previous results
on the cinchonidinium cation accelerated Michael epoxida-
tion of R,â-enones, it was expected that 4-fluorochalcone
would undergo highly enantioselective Michael reaction with
acetophenone enolate. Indeed, it was determined experimen-
tally that such was the case since the (S)-4-fluoro analogue
of 9 was produced in 87% ee and 84% yield, i.e., with >14:1
enantioselection.
The synthesis of (S)-ornithine described herein is the
simplest catalytic asymmetric synthesis developed thus far.12
The enantioselective Michael process outlined in Scheme 2
is also novel.
11
(
6
6
Acknowledgment. This research was assisted financially
by grants from the National Science Foundation and the
National Institutes of Health.
(
12) The only other catalytic route for the asymmetric synthesis of
ornithine reported utilized Knowles-Monsanto-type reduction of an R-N-
benzoylaminoacrylic acid derivative with a chiral Rh(I) catalyst; see:
Baldwin, J. E.; Merritt, K. D.; Schofield, C. J. Tetrahedron Lett. 1993, 34,
3
919.
OL0056527
1100
Org. Lett., Vol. 2, No. 8, 2000