Direct asymmetric Michael reactions of cyclic 1,3-dicarbonyl compounds and enamines catalyzed by chiral bisoxazoline-copper(II) complexes

Article abstract of DOI:10.1021/jo0343026

The catalytic direct Michael addition of cyclic 1,3-dicarbonyl compounds and enamines to unsaturated 2-ketoesters is presented. A series of different 4-hydroxycoumarins, 4-hydroxy-6-methyl-2-pyrone, 3-hydroxy-1H-phenalene-1-one, 2-hydroxy-1,4-naphthoquinone, 5,5-dimethyl-1,3-cyclohexanedione, and various enamines of cyclic 1,3-diketones all add to unsaturated 4-substituted 2-ketoesters in an enantioselective manner. The reaction is catalyzed by chiral bisoxazoline - copper-(II) complexes and proceeds in the absence of base to afford Michael adducts in good to high yields and with up to 98% ee. The products formed are substructures found in skeletons of important biological and pharmaceutical molecules. The scope and potential of the new reaction are discussed as well as the mechanism for the catalytic enantioselective reaction.

Full text of DOI:10.1021/jo0343026

Dir ect Asym m etr ic Mich a el Rea ction s of Cyclic 1,3-Dica r bon yl
Com p ou n d s a n d En a m in es Ca ta lyzed by Ch ir a l
Bisoxa zolin e-Cop p er (II) Com p lexes
Nis Halland, Thomas Velgaard, and Karl Anker J ørgensen*
Danish National Research Foundation: Center for Catalysis, Department of Chemistry,
Aarhus University, DK-8000 Aarhus C, Denmark
kaj@chem.au.dk
Received March 7, 2003
The catalytic direct Michael addition of cyclic 1,3-dicarbonyl compounds and enamines to
unsaturated 2-ketoesters is presented. A series of different 4-hydroxycoumarins, 4-hydroxy-6-methyl-
2-pyrone, 3-hydroxy-1H-phenalene-1-one, 2-hydroxy-1,4-naphthoquinone, 5,5-dimethyl-1,3-cyclo-
hexanedione, and various enamines of cyclic 1,3-diketones all add to unsaturated 4-substituted
2-ketoesters in an enantioselective manner. The reaction is catalyzed by chiral bisoxazoline-copper-
(II) complexes and proceeds in the absence of base to afford Michael adducts in good to high yields
and with up to 98% ee. The products formed are substructures found in skeletons of important
biological and pharmaceutical molecules. The scope and potential of the new reaction are discussed
as well as the mechanism for the catalytic enantioselective reaction.
In tr od u ction
products containing substructure functionalities such as
neoflavonoids and coumarins. These compounds are
widely distributed in nature; many have interesting
biological and pharmaceutical activities,2 and several are
related to anticoagulant agents.6
Recently, we have shown that chiral bisoxazoline-
copper(II) complexes7 are useful catalysts for a Friedel-
Crafts-type alkylation reaction in which heteroaromatic
and aromatic C-H bonds add in an enantioselective
manner to 4-substituted 2-oxo-3-butenoate esters and
alkylidene malonates.8 We envisioned that this approach
could also be applied to the addition of other types of
activated C-H bonds to R,â-unsaturated systems, and
in this paper the catalytic enantioselective Michael
The Michael addition of cyclic 1,3-dicarbonyl com-
pounds to R,â-unsaturated carbonyl compounds is an
important reaction in organic synthesis, as the products
obtained can have biological and pharmaceutical activi-
ties.1,2 Several synthetic procedures have been developed
for the addition of cyclic 1,3-dicarbonyl compounds, and
in particular enol lactones, to R,â-unsaturated carbonyl
systems; however, these methods often require harsh
reactions conditions, the use of strong acids or bases or
heat.3 Very recently, Kanemasa et al. have shown that
especially nickel(II) perchlorate hexahydrate can catalyze
the addition-cyclization of cyclic 1,3-dicarbonyl com-
pounds to 1-(2-alkenoyl)-4-bromo-3,5-dimethylpyrazoles.4
However, to our knowledge, no catalytic asymmetric
Michael reaction of cyclic 1,3-dicarbonyl compounds to
R,â-unsaturated carbonyl systems has been developed.5
The development of a catalytic enantioselective Michael
addition of cyclic 1,3-dicarbonyl compounds to R,â-
unsaturated carbonyl systems can afford optically active
(5) For examples of Lewis-acid-catalyzed enantioselective Michael
additions of 1,3-dicarbonyls to acyclic substrates, see: (a) Hamashima,
Y.; Hotta, D.; Sodeoka, M. J . Am. Chem. Soc. 2002, 124, 11240. (b)
End, N.; Macko, L.; Zehnder, M.; Pfaltz, A. Chem. Eur. J . 1998, 4,
818. (c) J i, J .; Barnes, D. M.; Zhang, J .; King, S. A.; Wittenberger, S.
J .; Morton, H. E. J . Am. Chem. Soc. 1999, 121, 10215. (d) Barnes, D.
M.; J i, J .; Fickles, M. G.; Fitzgerald, M. A.; King, S. A.; Morton, H. E.;
Plagge, F. A.; Preskill, M.; Wagaw, S. H.; Wittenberger, S. J .; Zhang,
J . J . Am. Chem. Soc. 2002, 124, 13097. (e) Christoffers, J .; Ro¨âler, U.;
Werner, T. Eur.
(6) (a) O’Reilly, R. A. N. Engl. J . Med. 1976, 295, 354. (b) Wingard,
L. B.; O’Reilly, R. A.; Levy, G. Clin. Pharmacol. Ther. 1978, 23, 212.
(c) Bardsley, H. J .; Daly, A. K. PCT Patent WO 00/43003. (d) Li, H.-
Y.; Robinson, A. J . U.S. Patent 5,856,525, J anuary 5, 1999. (e) Li, H.-
Y.; Robinson, A. J .; Feaster, J . Tetrahedron Lett. 1996, 37, 8321. (f)
Cravotto, G.; Nano, G. M.; Palmisano, G.; Tagliapietra, S. Tetrahe-
dron: Asymmetry 2001, 12, 707. (g) Demir, A. S.; Tanyeli, C.; Gulbeyaz,
V.; Akgun, H. Turk. J . Chem. 1996, 20, 139. (h) Druzgala, P.; Zhang,
X.; Pfister, J . R. PCT Pat. Appl. WO 02/085882.
(7) For reviews of C2-bisoxazoline-Lewis acid complexes as cata-
lysts, see e.g.: (a) Ghosh, A. K.; Mathivanen, P.; Cappiello, J . Tetra-
hedron: Asymmetry 1998, 9, 1. (b) J ørgensen, K. A.; J ohannsen, M.;
Yao, S.; Audrain, H.; Thorhauge, J . Acc. Chem. Res. 1999, 32, 605. (c)
J ohnson, J . S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325.
(8) (a) J ensen, K. B.; Thorhauge, J .; Hazell, R. G.; J ørgensen, K. A.
Angew. Chem., Int. Ed. 2001, 40, 160. (b) Zhuang, W.; Hansen, T.;
J ørgensen, K. A. Chem. Commun. 2001, 347.
(1) For reviews of enantioselective conjugate addition reactions,
see: (a) Yamaguchi, M. Comprehensive Asymmetric Catalysis; J acob-
sen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999;
Chapter 31.2. (b) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033.
(c) Krause, N.; Hoffmann-Ro¨der, A. Synthesis 2001, 171.
(2) For biological and pharmaceutical activities see, e.g.: (a) Murray,
R. D. H.; Medez, J .; Brown, S. A. The Natural Coumarins: Occurrence,
Chemistry and Biochemistry; Wiley: New York, 1982. (b) The Hand-
book of Natural Flavonoids; Harborne, J . B., Baxter, H., Eds.; Wiley:
Chichester, UK, 1999. (c) Manolov, I.; Danchev, N. D. Eur. J . Med.
Chem. 1995, 30, 531. (d) Mouli, C.; Giridhar, T.; Rao. D. M.; Reddy, R.
B. J . Heterocycl. Chem. 1996, 33, 5. (e) Rehse, K.; Schinkel, W. Arch.
Pharm. 1983, 988.
(3) (a) Ikawa, M.; Stahmann, M. A.; Link, K. P. J . Am. Chem. Soc.
1944, 66, 902. (b) Ivanov, I. C.; Manolov, I.; Alexandrova, L. A. Arch.
Pharm. 1990, 521. (c) Talapatra, S. K.; Chakrabarti, R.; Mukho-
padhyay, P. K.; Das, P. K.; Talapatra, B. Heterocycles 1984, 22, 519.
(4) Itoh, K.; Kanemasa, S. Tetrahedron Lett. 2003, 44, 1799.
10.1021/jo0343026 CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/28/2003
J . Org. Chem. 2003, 68, 5067-5074
5067

J ørgensen
TABLE 1. Scr een in g of Rea ction Con d ition s for th e Ch ir a l Lew is Acid -Ca ta lyzed En a n tioselective Mich a el Ad d ition of
4-Hyd r oxycou m a r in 1a w ith 4-P h en yl-2-Oxo-3-Bu ten oa te Meth yl Ester 2a a
entry
Lewis acid
ligand
solvent
time (h)
temp (°C)
yieldb (%)
Eec (%)
1
2
3
4
5
6
7
8
9
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(SbF6)2
Cu(OTf)2
Cu(OTf)2
Zn(OTf)2
Zn(OTf)2
Ni(ClO4)26H2O
(S)-t-Bu-BOX
(S)-t-Bu-BOX
(S)-t-Bu-BOX
(S)-t-Bu-BOX
(S)-t-Bu-BOX
(S)-t-Bu-BOX
(S)-t-Bu-BOX
(R)-Ph-BOX
(S)-Ph-BOX
CH2Cl2
THF
Et2O
Et2O
Et2O
Et2O
t-BuOMe
Et2O
Et2O
CH2Cl2
CH2Cl2
15
15
15
15
15
20
24
10
15
15
15
rt
rt
rt
0
98
98
98
98
98
34
74
85
98
98
98
60 (R)
13 (R)
84 (R)
61 (R)
86 (R)d
28 (R)
65 (R)
77 (S)
0
reflux
rt
rt
rt
rt
rt
rt
10
11
(S)-Ph-BOX
(R)-Ph-DBFOX
25 (S)
29 (S)
a
b
Catalyst loading ) 10 mol %. Isolated yield. c Ee measured by HPLC using a chiral stationary phase. Absolute configuration assigned
d
by analogy to compound 3b. Catalyst loading ) 3 mol %.
SCHEME 1
addition of cyclic 1,3-dicarbonyl compounds and enamines
to activated R,â-unsaturated carbonyl compounds under
base-free conditions is presented (eq 1).
Resu lts a n d Discu ssion
A variety of different Lewis acids can catalyze the
Michael addition of 4-hydroxycoumarins to 4-substituted
2-oxo-3-butenoate esters. However, to obtain optically
active Michael adducts, the combination of chiral bisox-
azolines and copper(II) turned out to be the best choice
under the reaction conditions investigated.9 Table 1
shows the screening results of the Michael addition of
4-hydroxycoumarin 1a to 4-phenyl-2-oxo-3-butenoate
methyl ester 2a catalyzed by mainly chiral bisoxazolines
and copper(II) salts.
The optimal combination for the catalytic enantiose-
lective Michael reaction of 4-hydroxycoumarin 1a to
4-phenyl-2-oxo-3-butenoate methyl ester 2a is application
of (S)-t-Bu-BOX-Cu(OTf)2 as the catalyst in Et2O, as 98%
yield of 3a is isolated (Table 1, entries 1-5). It is notable
that the reaction takes place under base-free conditions.
Furthermore, it should be pointed out that the Michael
addition adduct 3 is in a rapid equilibrium with the cyclic
hemiketal 3′ (Scheme 1).10 An interesting temperature
effect is observed for the enantioselectivity of the reac-
tion: at room temperature, 84% ee is obtained (entry 3),
while performing the reaction at 0 °C gave only 61% ee
(entry 4); also, an improvement to 86% ee is found at
reflux using 3 mol % of the catalyst (entry 5). The reaction
is very dependent on the copper(II) counterion: a change
from triflate (entry 3) to hexafluoroantimonate (entry 6)
leads to a significant reduction in the yield of the reaction
as well as the enantiomeric excess of the Michael adduct.
The Ph-BOX-Cu(OTf)2 is also applicable as a catalyst for
the reaction; however, the yield and enantiomeric excess
of 3a is reduced (entry 8) compared to that obtained with
the (S)-t-Bu-BOX-Cu(OTf)2 catalyst. Other Lewis acid
catalysts have also been employed for the reaction. For
example, (S)-Ph-BOX-Zn(OTf)2 is an effective catalyst in
terms of yield; unfortunately, however, 3a was formed
as a racemate in Et2O (entry 9), while the reaction in
CH2Cl2 afforded 25% ee (entry 10). The use of the (R)-
Ph-DBFOX-Ni(ClO4)6H2O catalyst, which has been found
to be very useful as a chiral catalyst for Michael addition
reactions, afforded only a low enantiomeric excess of 3a
(entry 11).11
To expand the scope of the Michael reaction of 4-hy-
droxycoumarins 1a-e and 4-substituted 2-oxo-3-butenoate
esters 2a -f using (S)-t-Bu-BOX-Cu(OTf)2 as the catalyst,
several reactions were performed (eq 2) and the results
are presented in Table 2.
The catalytic enantioselective reactions of 4-hydroxy-
coumarin 1a with the different 4-aromatic- and 4-(2-
furyl)-2-oxo-3-butenoate esters 2a -e using (S)-t-Bu-BOX-
Cu(OTf)2 as the catalyst in Et2O all proceeded in moderate
to excellent isolated yields and with good enantioselec-
tivity (up to 86% ee) (Table 2, entries 1-5). The reaction
takes place with only 1-3 mol % of the catalyst and very
high yields of the Michael adducts (3a ,b), and good
enantioselectivities are still obtained (entries 1 and 2).
4-Hydroxy coumarins having different electron-donating
and electron-withdrawing substituents (1b-e) also un-
dergo an enantioselective reaction with 4-phenyl-2-oxo-
3-butenoate methyl ester 2a to give the Michael adducts
(9) Use of chiral bisoxazoline-Lewis acid complexes for enantiose-
lective Michael additions, see e.g.: (a) Kitajima, H.; Katsuki, T. Synlett
1997, 568. (b) Evans, D. A.; Scheidt, K. A.; J ohnston, J . N. J . Am. Chem.
Soc. 2001, 123, 4480. (c) Evans, D. A.; Rovis, T.; Kozlowski, M. C.;
Tedrow, J . S. J . Am. Chem. Soc. 2000, 122, 9134. (d) Sibi. M. P.; Chen,
J . Org. Lett. 2002, 4, 2933 and refs 5c and 5d.
5068 J . Org. Chem., Vol. 68, No. 13, 2003

Direct Asymmetric Michael Reactions
TABLE 2. Ca ta lytic En a n tioselective Mich a el Ad d ition of Su bstitu ted 4-Hyd r oxycou m a r in s to 4-Su bstitu ted
2-Oxo-3-bu ten oa te Ester s in th e P r esen ce of (S)-t-Bu -BOX-Cu (OTf)2 a s th e Ca ta lyst in Et2O
4-hydroxycoumarin
4-substituted 2-ketoester
R4
entry
R1
R2
R3
R5
yielda (%)
Eeb (%)
86c (R)e
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1b
1c
1d
1e
1a
1e
H
H
H
H
H
Cl
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
H
H
2a
2b
2c
2d
2e
2a
2a
2a
2a
2f
Ph
Me
Me
Me
Me
Et
Me
Me
Me
Me
Et
3a 98
3b 98
3c 98
3d 95
3e 95
3f 83
3g 98
3h 47
3i 45
3j 98
3k 45
4-ClC6H4
4-MeOC6H4
4-MeC6H4
2-furyl
Ph
Ph
Ph
Ph
Me
73 (>99.5)d (R)
64 (R)e
78 (R)e
81 (S)e
84f (R)e
78 (R)e
91 (R)e
91 (R)e
90
OMe
F
H
F
10
11
2f
Me
Et
92
a
b
d
Isolated yield. Ee measured by HPLC using a chiral stationary phase. c Catalyst loading ) 3 mol %. Catalyst loading ) 1 mol %;
the product was recrystallized to be >99.5% ee in EtOAc/hexane, and the absolute stereochemistry was assigned by X-ray analysis.
e Absolute configuration assigned by analogy to compound 3b. f Performing this reaction in CH2Cl2 as the solvent gives >98% yield of 3f
having 77% ee.
3f-i in moderate to excellent yield and enantioselectivity
(entries 6-9). The two 4-hydroxycoumarins 1a ,e react
with 4-alkyl-2-oxo-3-butenoate esters in a highly enan-
tioselective fashion; Michael adducts 3j and 3k were
obtained in 98 and 45% yields and 90 and 92% ee,
respectively (entries 10 and 11), while the Michael
addition of 4-hydroxycoumarin to 4-benzyloxy-2-oxo-3-
butenoate methyl ester afforded Michael products that
had eliminated benzyl alcohol.
The optically active 3-substituted 4-hydroxycoumarins
obtained represent a common structural unit found in a
number of naturally occurring biologically active com-
pounds,2 the most important of these being the antico-
agulant dicoumarol and the antibiotics novobiocin and
coumermycin. A very large number of the more than 2000
existing 3-substituted 4-hydroxycoumarins have been
prepared synthetically, and without doubt the single
most important one is the anticoagulant warfarin that
has been marketed as a racemate for more than 40
years.
in CH2Cl2 and THF with enantiomeric excesses of 31 and
49%, respectively, and an improvement to 64% ee could
be obtained in Et2O; however, only 20% of 3n was
isolated. For the latter catalysts CH2Cl2 and THF were
the best solvents in terms of yields, as up to 95% was
isolated of 3n having 49% ee, while performing the
reaction in Et2O afforded 3n in 56% yield and 76% ee.
The scope of the reaction was extended to other 1,3-
dicarbonyl compounds acting as Michael donors in the
reaction with 4-substituted 2-oxo-3-butenoate esters 2.
(S)-t-Bu-BOX-Cu(OTf)2 (10 mol %) in Et2O catalyzes the
enantioselective addition of 4-hydroxy-6-methyl-2-pyrone
1g to the 4-substituted 2-oxo-3-butenoate esters 2a ,b (eq
3), and the optically active Michael adducts 3l,m are
formed in high yields and in 82 and 71% ee, respectively.
3-Hydroxy-1H-phenalene 1h reacts with the 4-phenyl-
2-oxo-3-butenoate methyl ester 2a catalyzed by both (S)-
t-Bu-BOX-Cu(OTf)2 and (S)-Ph-BOX-Cu(OTf)2 (10 mol %),
and excellent yields of Michael adduct 3n can be obtained
(eq 4). The former catalyst gave the best yield of 3n (95%)
J . Org. Chem, Vol. 68, No. 13, 2003 5069

J ørgensen
SCHEME 2
Several other compounds such as 2-hydroxy-1,4-naph-
thoquinone 1i and 5,5-dimethyl-1,3-cyclohexanedione 1j
also react with 4-substituted 2-oxo-3-butenoate esters.
Compound 1i reacted with 4-phenyl-2-oxo-3-butenoate
methyl ester 2a to give the corresponding Michael adduct
3o in 92% yield and 50% ee using (S)-Ph-BOX-Cu(OTf)2
(10 mol %) as the catalyst in CH2Cl2. In the same solvent,
but using 10 mol % (S)-t-Bu-BOX-Cu(OTf)2 as the cata-
lyst, 1j reacted with 2a and the Michael adduct 3p was
formed in 85% yield and 45% ee (Scheme 2).
F IGURE 1. Proposed intermediate and approach of the 1,3-
dicarbonyl compound in the (S)-t-Bu-BOX-Cu(OTf)2-catalyzed
Michael reaction.
The present catalytic enantioselective approach can be
extended to enamines of 1,3-dicarbonyl compounds. The
N-methylenamine of 5,5-dimethyl-1,3-cyclohexanedione,
1k , reacted with 4-(4-chloro-phenyl)-2-oxo-3-butenoate
methyl ester 2b catalyzed by (S)-t-Bu-BOX-Cu(OTf)2 (10
mol %) very slowly, and only a moderate yield (34%) and
enantiomeric excess (47%) of the Michael adduct 3q were
obtained (eq 5). The discouraging results obtained for 1k
prompted us to exchange the N-methyl substituent with
a N-phenyl group, which was expected to be more reactive
because conjugation to the phenyl group would stabilize
the imine intermediate formed in the reaction. To our
delight, it was found that the reaction of the N-phen-
ylenamine of 1,3-cyclohexanedione 1l with 2a and 2b
catalyzed by (S)-t-Bu-BOX-Cu(OTf)2 (10 mol %) in Et2O
(eq 5) proceeded in high yield and with excellent enan-
tiomeric excess of 3r and 3s. The reactivity of the
enamines 1k ,l are much lower compared to the 1,3-
dicarbonyl compounds, but even though 60 h of reflux
was required to obtain full conversion, up to 98% ee was
obtained. Similar to the Michael adducts 3a -n , which
exist predominantly in their hemiketal form, 3r ,s exist
as a mixture of slowly equilibrating hemiaminals 3r ′,s′.
Unlike the hemiketals 3a ′-n ′, the equilibrium for the
hemiaminals 3r ′,s′ is very slow, and thus the diastere-
omers could be isolated by column chromatography and
kept for several hours in solution before the other
diastereomer was observed.
4-(4-chlorophenyl)-2-oxo-3-butenoate methyl ester 2b us-
ing (S)-t-Bu-BOX-Cu(OTf)2 as the catalyst was assigned
by X-ray analysis (See Supporting Information). The
X-ray crystal structure of 3b reveals that the absolute
configuration of the chiral center formed in the reaction
is (R). The observed stereochemistry can be rationalized
from the transition state model in Figure 1 where it is
proposed that the unsaturated 4-substituted 2-oxo-3-
butenoate esters 2 coordinate in a bidentate fashion to
the Lewis acid.
In the transition state model, the Si-face of the alkene
double bond is shielded by the ligand, leaving the Re-
face open for attack to afford an (R)-configuration at the
chiral center formed in the reaction. The observed ster-
eochemistry of the product agrees well with previous
conjugate addition reactions to 4-substituted 2-oxo-3-
butenoate esters 2 using (S)-t-Bu-BOX-Cu(OTf)2 as the
catalyst.8a The geometry of the catalyst-substrate com-
plex is proposed to be intermediate between square-
planar and tetrahedral as shown in Figure 1 and is in
accordance with previous studies of the complex in
various reactions.14
In summary, we have developed a novel base-free
catalytic asymmetric Michael reaction of cyclic 1,3-
dicarbonyl compounds and enamines catalyzed by chiral
bisoxazoline-copper(II) complexes. The addition to a
number of unsaturated 4-substituted 2-ketoesters pro-
ceeds smoothly using various 1,3-dicarbonyl compounds
and quantitative yields, and up to 92% ee was obtained.
The reaction was extended to cyclic enamine Michael
donors, and these also afforded practically quantitative
yields and up to 98% ee. Furthermore, the structure of
the products was discussed and an intermediate for the
(10) Equilibrium is sufficiently rapid so that only enantiomers are
detected upon CSP-HPLC, and no diastereomers are observed. For
equilibrium studies on related compounds, see: (a) Heimark, L. D.;
Trager, W. F. J . Med. Chem. 1984, 27, 1092. (b) Porter, W. R.; Trager,
W. F. J . Heterocycl. Chem. 1982, 19, 475.
(11) (a) Itoh, K.; Kanemasa, S. J . Am. Chem. Soc. 2002, 124, 13394.
(b) Nakama, K.; Seki, S.; Kanemasa, S. Tetrahedron Lett. 2002, 43,
829.
(12) Li, H.-Y.; Boswell, G. A. Tetrahedron Lett. 1996, 37, 1551.
(13) Audrain, H.; Thorhauge, J .; Hazell, R. G.; J ørgensen, K. A. J .
Org. Chem. 2000, 65, 4487.
(14) Thorhauge, J .; Roberson, M.; Hazell, R. G.; J ørgensen, K. A.
Chem. Eur. J . 2002, 8, 1888.
Absolu te Con figu r a tion a n d Mech a n istic Asp ects.
The absolute configuration of the Michael adduct 3b
obtained from the reaction of 4-hydroxycoumarin 1a and
5070 J . Org. Chem., Vol. 68, No. 13, 2003

Direct Asymmetric Michael Reactions
115.0, 116.5, 122.7, 124.4, 126.1, 126.3, 127.3, 127.5, 128.2,
132.4, 141.8, 143.1, 152.3, 152.4, 158.7, 158.9, 160.4, 160.5,
168.1, 168.5; HRMS (TOF ES+) m/z 375.0844 (M + Na+), calcd
for C20H16O6Na+ 375.0845.
4-(4-Ch lor o-p h en yl)-4-(4-h yd r oxy-2-oxo-2H-ch r om en -
3-yl)-2-oxo-bu tyr ic Acid Meth yl Ester (3b) was isolated as
a colorless solid after FC in CH2Cl2/Et2O and was found to
reaction has been proposed to account for the observed
stereochemistry of the products.
Exp er im en ta l Section
Ma ter ia ls. Commercially available compounds were used
without further purification. Solvents were dried according to
standard procedures. 2,2′-Isopropylidenebis[(4S)-4-tert-butyl-
2-oxazoline], 2,2′-isopropylidenebis[(4R)-4-phenyl-2-oxazoline],
methylenebis[(4R,5S)-4,5-diphenyl-2-oxazoline], Cu(OTf)2, and
Zn(OTf)2 were purchased commercially and used without
further purification. 4-Hydroxycoumarins 1a -d , 4-hydroxy-
6-methyl-2-pyrone 1g, dimedone 1l, 3-hydroxy-1H-phenalene
1h , 5,5-dimethyl-3-methylamino-cyclohex-2-enone 1k , and
3-phenylamino-cyclohex-2-enone 1l were also purchased com-
mercially and used as received. 7-Fluoro-4-hydroxycoumarin
1e12 and 4-substituted 2-oxo-3-butenoate esters 2a ,b were
prepared according to reported methods,13 and 4-substituted
2-oxo-3-butenoate esters 2c,d ,f were prepared by the same
procedure. 2-Oxo-pent-3-enoic acid ethyl ester 2f was prepared
according to literature procedures,8a and 4-furan-2-yl-2-oxo-
but-3-enoic acid ethyl ester 2e was prepared by a Wittig
reaction as described below.
4-F u r a n -2-yl-2-oxo-bu t-3-en oic Acid Eth yl Ester (2e).
Ethyl-bromopyruvate (5 g, 0.026 mol) in 25 mL of toluene was
stirred with Ph3P (5.7 g, 0.022 mol) in 50 mL of toluene at
ambient temperature overnight. After evaporation of the
toluene, the residue was dissolved in 30 mL of MeOH and 1
M Na2CO3 was added until pH 10 was reached. The precipitate
was filtered, washed several times with water, dissolved in
CH2Cl2, and dried over Na2SO4. After evaporation of the
solvent, the phosphine was dissolved in 100 mL of toluene;
2-furaldehyde (2.0 mL, 0.024 mol) was added, and the mixture
was refluxed for 3 days. After removal of the solvent, the
precipitate was dissolved in CH2Cl2 and flushed through silica
using CH2Cl2 as the eluent to remove Ph3PO. The compound
was recrystallized in EtOH/hexane to afford 1.7 g (40%) of
4-furan-2-yl-2-oxo-but-3-enoic acid ethyl ester 2e as brown
crystals: 1H NMR (CDCl3) δ 1.31 (t, J ) 7.4 Hz, 3H), 4.29 (k,
J ) 7.4 Hz, 2H), 6.46 (dd, J ) 2.0, 3.5 Hz, 1H), 6.75 (d, J )
3.5 Hz, 1H), 7.12 (d, J ) 15.6 Hz, 1H), 7.50 (d, J ) 2.0 Hz,
1H), 7.52 (d, J ) 15.6 Hz, 1H); 13C NMR (CDCl3) δ 13.8, 62.2,
113.0, 117.7, 118.5, 133.3, 146.2, 150.8, 161.8, 182.1; HRMS
(TOF ES+) m/z 217.0487 (M + Na+), calcd for C10H10O4Na+
217.0477.
exist in
a partly hemiketalized form that gives rise to
pseudodiastereomers. The enantiomers were separated by
HPLC using a Chiralpak AD chiral stationary phase in
hexane/2-propanol 70/30 containing 0.15% TFA: [R]23
)
D
-42.3° (c ) 1.0 g/100 mL, CH2Cl2, 91% ee); repeated recrys-
tallizations in 1H NMR (CDCl3) δ 2.29-2.39 (m, 1.3H), 2.41
(dd, J ) 2.7, 14.3 Hz, 0.35H), 2.72 (dd, J ) 7.8, 14.3 Hz, 0.35H),
3.84 (s, 1.95H), 3.86 (s, 1.05H), 4.11 (dd, J ) 7.4, 11.3 Hz,
0.65H), 4.23 (dd, J ) 2.7, 7.8 Hz, 0.35H), 4.52 (s, 0.35H, OH
position is concentration dependent), 4.72 (s, 0.65H, OH
position is concentration dependent), 7.09-7.31 (m, 6H), 7.45-
7.54 (m, 1H), 7.70 (dd, J ) 1.1, 7.8 Hz, 0.65H), 7.75 (dd, J )
1.6, 8.2 Hz, 0.35H); 13C NMR (CDCl3) δ 33.1, 34.0, 35.1, 37.8,
53.9, 54.1, 95.3, 95.9, 102.4, 104.3, 114.9, 115.1, 116.5, 116.7,
122.8, 122.9, 123.9, 124.1, 128.3, 128.4, 128.8, 128.9, 132.0,
132.1, 132.2, 132.3, 140.2, 140.8, 152.7, 152,8, 158.2, 158.6,
160.7, 161.6, 168.7, 168.9; HRMS (TOF ES+) m/z 409.0462 (M
+ Na+), calcd for C20H15ClO6Na+ 409.0455.
4-(4-H yd r oxy-2-oxo-2H -ch r om en -3-yl)-4-(4-m et h oxy-
p h en yl)-2-oxo-bu tyr ic Acid Meth yl Ester (3c) was isolated
as a colorless solid after FC in CH2Cl2/Et2O and was found to
exist in a hemiketalized form that gives rise to pseudodiaste-
reomers. The enantiomers were separated by HPLC using a
Chiralpak AD chiral stationary phase in hexane/2-propanol
70/30 containing 0.15% TFA: [R]23 ) -22.6° (c ) 1.0 g/100
D
1
mL, CH2Cl2, 64% ee); H NMR (CDCl3) δ 2.44 (d, J ) 9.2 Hz,
1.28H), 2.51 (dd, J ) 3.1, 14.4 Hz, 0.36H), 2.76 (ddd, J ) 1.2,
7.4, 14.4 Hz, 0.36H), 3.76 (s, 1.08H, CH3), 3.78 (s, 1.92H), 3.89
(s, 1.92H), 3.92 (s, 1.08H), 4.16 (t, J ) 9.2 Hz, 0.64H), 4.31
(dd, J ) 3.1, 7.4 Hz, 0.36H), 4.50 (d, J ) 1.2 Hz, 0.36H, OH
position is concentration dependent), 4.68 (s, 0.64H, OH
position is concentration dependent), 6.80-6.86 (m, 2H), 7.14-
7.19 (m, 2H), 7.25-7.38 (m, 2H), 7.50-7.62 (m, 1H), 7.77
(dd, J ) 1.6, 7.8 Hz, 0.64H), 7.83 (dd, J ) 1.6, 7.8 Hz, 0.36H);
13C NMR (CDCl3) δ 32.7, 33.7, 35.5, 38.1, 53.9, 54.0, 55.1,
55.2, 95.5, 96.1, 103.0, 105.0, 113.8, 114.1, 115.0, 115.2, 116.5,
116.6, 122.7, 122.8, 123.7, 124.0, 128.0, 128.3, 131.8, 132.0,
133.3, 134.1, 152.7, 152.8, 157.8, 158.2, 158.3, 160.6, 161.6,
168.9; HRMS (TOF ES+) m/z 405.0947 (M + Na+), calcd for
Gen er a l P r oced u r e for th e Ca ta lytic Asym m etr ic
Mich a el Rea ction . To a flame-dried Schlenk tube equipped
with a magnetic stirrer were added Cu(OTf)2 (18.1 mg, 0.050
mmol) and 2,2′-isopropylidenebis[(4S)-4-tert-butyl-2-oxazoline]
(16.2 mg, 0.055 mmol). The mixture was stirred under vacuum
for 2 h and filled with N2. Dry, freshly distilled Et2O (2 mL)
was added, and the solution was stirred for 1 h. The 2-oxo-3-
butenoate ester (0.5 mmol) was added followed by the addition
of the 1,3-dicarbonyl compound. The crude reaction mixture
was stirred for the indicated time under N2 and then purified
by FC to give the optically active Michael adduct.
C
21H18O7Na+ 405.0950.
4-(4-Hyd r oxy-2-oxo-2H-ch r om en -3-yl)-2-oxo-4-p -tolyl-
bu tyr ic Acid Meth yl Ester (3d ) was isolated as a colorless
solid after FC in CH2Cl2/Et2O and was found to exist in a
hemiketalized form that gives rise to pseudodiastereomers.
The enantiomers were separated by HPLC using a Chiralpak
AD chiral stationary phase in hexane/2-propanol 70/30 con-
taining 0.15% TFA: [R]23 ) -20.3° (c ) 1.0 g/100 mL,
D
1
CH2Cl2, 78% ee); H NMR (CDCl3) δ 2.21 (s, 0.96H), 2.23 (s,
2.04H), 2.35 (d, J ) 8.6 Hz, 1.36H), 2.43 (dd, J ) 3.5, 14.0 Hz,
0.32H), 2.68 (dd, J ) 7.8, 14.0 Hz, 0.32H), 3.75 (s, 2.04H), 3.82
(s, 0.96H), 4.08 (t, J ) 8.6 Hz, 0.68H), 4.21 (dd, J ) 3.5, 7.8
Hz, 0.32H), 4.58 (s, 0.32H, OH position is concentration
dependent), 4.93 (s, 0.68H, OH position is concentration
dependent), 6.98-7.08 (m, 4H), 7.13-7.28 (m, 2H), 7.39-7.49
(m, 1H), 7.69 (dd, J ) 1.2, 7.8 Hz, 0.68H), 7.75 (dd, J ) 1.5,
8.2 Hz, 0.32H); 13C NMR (CDCl3) δ 20.1, 32.2, 33.1, 34.6, 37.2,
52.8, 52.9, 94.5, 95.1, 101.9, 103.9, 114.0, 114.2, 115.5, 115.6,
121.7, 121.9, 122.8, 123.0, 125.9, 126.2, 128.2, 128.4, 130.8,
131.1, 135.2, 135.2, 137.4, 138.2, 151.6, 151.7, 157.0, 157.4,
159.8, 160.7, 168.0; HRMS (TOF ES+) m/z 389.1015 (M + Na+),
calcd for C21H18O6Na+ 389.1001.
4-(4-Hyd r oxy-2-oxo-2H-ch r om en -3-yl)-2-oxo-4-p h en yl-
bu tyr ic Acid Meth yl Ester (3a ) was isolated as a colorless
solid after FC in CH2Cl2/Et2O and was found to exist in a
hemiketalized form that gives rise to pseudodiastereomers.
The enantiomers were separated by HPLC using a Chiralpak
AD chiral stationary phase in hexane/2-propanol 70/30 con-
taining 0.15% TFA: [R]23 ) -20.4° (c ) 1.0 g/100 mL,
D
CH2Cl2, 84% ee); 1H NMR (CDCl3) δ 2.45 (d, J ) 9.0 Hz,
1.34H), 2.55 (dd, J ) 14.4, 3.1 Hz, 0.33H), 2.80 (ddd, J ) 14.4,
7.4, 1.2 Hz, 0.33H), 3.89 (s, 2.04H), 3.92 (s, 0.96H), 4.2 (t,
J ) 9.1 Hz, 0.67H), 4.36 (dd, J ) 7.4, 3.1 Hz, 0.33H), 4.45 (d,
J ) 1.6 Hz, 0.33H, OH, position is concentration dependent),
4.65 (s, 0.67H, OH, position is concentration dependent), 7.15-
7.34 (m, 7H), 7.48-7.55 (m, 1H), 7.78 (dd, J ) 7.8, 1.2 Hz,
0.67H), 7.83 (dd, J ) 7.8, 1.6 Hz, 0.33H); 13C NMR ((CD3)2SO)
δ 34.3, 35.2, 38.1, 38.5, 52.5, 53.3, 96.7, 98.1, 102.3, 103.0,
4-F u r a n -2-yl-4-(4-h yd r oxy-2-oxo-2H -ch r om en -3-yl)-2-
oxo-bu tyr ic Acid Eth yl Ester (3e) was isolated as a colorless
solid after FC in CH2Cl2/Et2O and was found to exist in a
hemiketalized form that gives rise to pseudodiastereomers.
J . Org. Chem, Vol. 68, No. 13, 2003 5071

J ørgensen
The enantiomers were separated by HPLC using a Chiralpak
AD chiral stationary phase in hexane/2-propanol 70/30 con-
dependent), 6.69-6.78 (m, 2H), 7.09-7.28 (m, 5H), 7.57 (d, J
) 9.0 Hz, 0.66H), 7.62 (d, J ) 8.6 Hz, 0.34H); 13C NMR ((CD3)2-
SO) δ 34.1, 35.0, 38.2, 38.6, 52.4, 53.2, 56.0, 96.6, 97.9, 99.4,
100.1, 100.6, 108.1, 112.4, 123.9, 126.0, 126.2, 127.3, 127.5,
128.1, 142.0, 143.3, 154.3, 159.2, 159.3, 160.7, 160.8, 162.7,
168.2, 168.6; HRMS (TOF ES+) m/z 405.0953 (M + Na+), calcd
for C21H18O7Na+ 405.0950.
taining 0.15% TFA: [R ]23 ) -4.9° (c ) 1.0 g/100 mL,
D
CH2Cl2, 81% ee); 1H NMR (CDCl3) δ 1.28 (t, J ) 7.0 Hz, 1.47H),
1.31 (t, J ) 7.0 Hz, 1.53H), 2.31 (dd, J ) 6.2, 13.6 Hz, 0.49H),
2.53-2.68 (m, 1H), 2.72 (dd, J ) 14.0, 2.0 Hz, 1.02H), 4.23-
4.37 (m, 3H), 4.68 (s, 0.49H, OH position is concentration
dependent), 4.73 (s, 0.51H, OH position is concentration
dependent), 6.01 (d, J ) 3.1 Hz, 0.51H), 6.15 (d, J ) 3.5 Hz,
0.49H), 6.24 (dd, J ) 2.0, 3.1 Hz, 0.51H), 6.27 (dd, J ) 2.0, 3.5
Hz, 0.49H), 7.18-7.30 (m, 3H), 7.43-7.52 (m, 1H), 7.69 (dd, J
) 1.6, 8.2 Hz, 0.49H), 7.73 (dd, J ) 1.6, 7.8 Hz, 0.51H); 13C
NMR (CDCl3) δ 13.9, 14.0, 27.3, 28.3, 31.4, 34.2, 63.5, 63.6,
95.3, 95.5, 100.7, 102.5, 106.1, 106.5, 110.5, 110.7,115.0, 115.2,
116.5, 116.7, 122.8, 123.0, 123.8, 124.1, 132.0, 132.3, 141.2,
141.3, 152.7, 153.4, 153.6, 157.9, 158.2, 160.6, 162.7, 168.2,
168.3; HRMS (TOF ES+) m/z 379.0801 (M + Na+), calcd for
4-(7-F lu or o-4-h yd r oxy-2-oxo-2H-ch r om en -3-yl)-2-oxo-
4-p h en yl-bu tyr ic Acid Meth yl Ester (3i) was isolated as a
colorless solid after FC in CH2Cl2/Et2O and was found to exist
in a hemiketalized form that gives rise to pseudodiastereomers.
The enantiomers were separated by HPLC using a Chiralpak
AD chiral stationary phase in hexane/2-propanol 70/30 con-
taining 0.15% TFA: [R]23 ) -19.3° (c ) 1.0 g/100 mL,
D
CH2Cl2, 91% ee); 1H NMR (CDCl3) δ 2.38 (d, J ) 9.0 Hz, 1.40H,
2.47 (d, J ) 14.4 Hz, 0.30H), 2.72 (dd, J ) 7.0, 14.4 Hz, 0.30H),
3.82 (s, 2.10H), 3.85 (s, 0.90H), 4.11 (t, J ) 9.0 Hz, 0.70H),
4.26 (d, J ) 7 Hz, 0.30H), 4.44 (s, 0.30H, OH position is
concentration dependent), 4.67 (s, 0.70H, OH position is
concentration dependent), 6.90-7.03 (m, 2H), 7.15-7.27 (m,
5H), 7.70-7.74 (m, 1H); 13C NMR (CDCl3) δ 33.4, 34.4, 35.4,
38.0, 53.9, 54.0, 95.4, 96.0, 104.0 (d, J ) 25.2 Hz, C-F), 104.1
(d, J ) 25.9 Hz, C-F), 111.9 (d, J ) 22.8 Hz, C-F), 112.0 (d,
J ) 39.9 Hz, C-F), 124.5, 124.6, 124.7, 124.8, 126.8, 126.9,
127.0, 127.3, 128.4, 128.7, 141.2, 142.0, 153.9, 154.0, 157.6,
158.1, 160.3, 161.3, 164.5, (d, J ) 252.4 Hz, C-F), 164.7 (d, J
) 252.4 Hz, C-F), 168.8; HRMS (TOF ES+) m/z 393.0757 (M
+ Na+), calcd for C20H15FO6Na+ 393.0750.
C
19H16O7Na+ 379.0794.
4-(6-Ch lor o-4-h yd r oxy-2-oxo-2H-ch r om en -3-yl)-2-oxo-
4-p h en yl-bu tyr ic Acid Meth yl Ester (3f) was isolated as a
colorless solid after FC in CH2Cl2/Et2O and was found to exist
in a hemiketalized form that gives rise to pseudodiastereomers.
The enantiomers were separated by HPLC using a Chiralpak
AD chiral stationary phase in hexane/2-propanol 70/30 con-
taining 0.15% TFA; [R]23 ) -44.7° (c ) 1.0 g/100 mL,
D
CH2Cl2, 84% ee); 1H NMR (CDCl3) δ 2.46 (d, J ) 9.0 Hz,
1.36H), 2.54 (dd, J ) 3.4, 14.4 Hz, 0.32H), 2.80 (dd, J ) 7.4,
14.4 Hz, 0.32H), 3.92 (s, 2.04H), 3.94 (s, 0.96H), 4.19 (t, J )
9.0 Hz, 0.68H), 4.34 (dd, J ) 3.4, 7.4 Hz, 0.32H), 4.51 (s, 0.32H,
OH position is concentration dependent), 4.71 (s, 0.68H, OH
position is concentration dependent), 7.15-7.39 (m, 6H), 7.48
(dd, J ) 2.7, 9.0 Hz, 0.68H), 7.52 (dd, J ) 2.3, 8.6 Hz, 0.32H),
7.74 (d, J ) 2.3 Hz, 0.68H), 7.79 (d, J ) 2.3 Hz, 0.32H); 13C
NMR (CDCl3) δ 33.8, 34.5, 35.6, 37.9, 53.9, 95.7, 96.3, 105.6,
116.4, 118.0, 118.1, 122.3, 122.4, 126.8, 127.1, 127.3, 128.4,
128.7, 129.3, 131.8, 132.1, 141.2, 141.8, 151.1, 157.1, 160.3,
168.6; HRMS (TOF ES+) m/z 409.0458 (M + Na+), calcd for
4-(4-Hyd r oxy-2-oxo-2H-ch r om en -3-yl)-2-oxo-p en ta n o-
ic Acid Meth yl Ester (3j) was isolated as a colorless solid
after FC in CH2Cl2/Et2O and was found to exist in a hemiket-
alized form that gives rise to pseudodiastereomers. The
enantiomers were separated by HPLC using a Chiralpak AS
chiral stationary phase in hexane/2-propanol 97/3 containing
0.3% TFA: [R]23 ) +12.1° (c ) 1.0 g/100 mL, CH2Cl2, 90%
D
1
ee); H NMR (CDCl3) δ 1.30 (t, J ) 7.0 Hz, 1.83H), 1.34 (t, J
) 7.0 Hz, 1.17H), 1.43 (t, J ) 7.8 Hz, 3H), 2.02-2.12 (m, 1H),
2.21 (dd, J ) 6.6, 13.7 Hz, 0.39H), 2.47 (dd, J ) 7.4, 13.6 Hz,
0.61H), 3.01-3.10 (m, 1H), 4.28-4.38 (m, 2H), 4.65 (br s,
0.39H, OH position is concentration dependent), 4.77 (br s,
0.61H, OH position is concentration dependent), 7.14-7.28 (m,
2H), 7.41-7.53 (m, 1H), 7.65 (dt, J ) 1.6, 9.4 Hz, 0.61H), 7.87
(dd, J ) 1.1, 7.8 Hz, 0.39H, minor ds); 13C NMR (CDCl3) δ
13.9, 18.2, 18.8, 22.7, 23.3, 33.0, 36.6, 63.2, 63.3, 95.4, 96.0,
106.0, 106.4, 115.1, 115.3, 116.1, 116.3, 122.5, 122.6, 123.7,
123.8, 131.5, 132.3, 152.1, 152.2, 156.5, 157.1, 161.8, 162.5,
168.7, 169.1; HRMS (TOF ES+) m/z 327.0848 (M + Na+), calcd
for C16H16O6Na+ 327.0845.
C
20H15ClO6Na+ 409.0455.
4-(6,8-Dich lor o-4-h yd r oxy-2-oxo-2H -ch r om en -3-yl)-2-
oxo-4-p h en yl-bu tyr ic Acid Meth yl Ester (3g) was isolated
as a colorless solid after FC in CH2Cl2/Et2O and was found to
exist in
a partly hemiketalized form that gives rise to
pseudodiastereomers. The enantiomers were separated by
HPLC using a Chiralpak AD chiral stationary phase in
hexane/2-propanol 70/30 containing 0.15% TFA: [R]23D ) -8.2°
1
(c ) 1.0 g/100 mL, CH2Cl2, 72% ee); H NMR (CDCl3) δ 2.40
(d, J ) 9.0 Hz, 1.40H), 2.46 (dd, J ) 3.1, 14.4 Hz, 0.30H), 2.71
(dd, J ) 7.4, 14.4 Hz, 0.30H), 3.80 (s, 2.10H), 3.85 (s, 0.90H),
4.12 (dd, J ) 7.8, 9.0 Hz, 0.7H), 4.25 (dd, J ) 3.1, 7.4 Hz,
0.30H), 4.60 (s, 0.30H, OH position is concentration depend-
ent), 4.92 (s, 0.70H, OH position is concentration dependent),
7.13-7.23 (m, 5H), 7.48 (d, J ) 2.3 Hz, 0.70H), 7.53 (d, J )
2.3 Hz, 0.30H), 7.58 (d, J ) 2.3 Hz, 0.70H), 7.18 (d, J ) 2.3
Hz, 0.30H); 13C NMR (CDCl3) δ 33.8, 34.7, 35.5, 37.9, 54.1,
54.3, 95.9, 96.5, 104.5, 106.5, 117.2, 117.4, 121.0, 121.2, 122.4,
122.6, 126.9, 127.0, 127.2, 127.4, 128.5, 128.8, 129.2, 129.4,
131.9, 132.1, 140.9, 141.5, 147.3, 156.6, 157.1, 159.0, 159.9,
168.6, 168.7; HRMS (TOF ES+) m/z 443.0067 (M + Na+), calcd
for C20H14Cl2O6Na 443.0065.
4-(7-F lu or o-4-h yd r oxy-2-oxo-2H-ch r om en -3-yl)-2-oxo-
p en ta n oic Acid Meth yl Ester (3k ) was isolated as a
colorless solid after FC in CH2Cl2/Et2O and was found to exist
in a hemiketalized form that gives rise to pseudodiastereo-
mers. The enantiomers were separated by HPLC using a
Chiralpak AS chiral stationary phase in hexane/2-propanol
97/3 containing 0.15% TFA: [R]23 ) +17.2° (c ) 1.0 g/100
D
1
mL, CH2Cl2, 92% ee); H NMR (CDCl3) δ 1.37 (t, J ) 7.0 Hz,
1.77H), 1.41 (t, J ) 7.0 Hz, 1.23H), 1.48 (dd, J ) 7.0, 7.0 Hz,
3H), 2.01-2.24 (m, 1H), 2.26 (dd, J ) 6.2, 13.7 Hz, 0.41H, CH),
2.52 (ddd, J ) 1.6, 7.0, 13.7 Hz, 0.59H), 3.04-3.12 (m, 1H,
CH), 4.31-4.48 (m, 2H), 4.66 (d, J ) 1.6 Hz, 0.41H, OH
concentration dependent), 4.80 (d, J ) 2.0 Hz, 0.59H, OH
concentration dependent), 6.87-7.09 (m, 2H), 7.63-7.74 (m,
1H); 13C NMR ((CD3)2SO) δ 13.9, 17.9, 18.7, 23.2, 23.9, 35.5,
37.0, 62.0, 96.6, 97.6, 103.8, 104.0, 104.4, 112.0, 112.1, 112.4,
124.6, 124.66, 124.7, 124.8, 153.1 (d, CF), 153.2 (d, CF), 156.4,
156.7, 160.7, 160.9, 162.6, 165.1, 168.2, 168.4; HRMS (TOF
ES+) m/z 345.0753 (M + Na+), calcd for C16H15FO6Na+
345.0750.
4-(4-Hydr oxy-7-m eth oxy-2-oxo-2H-ch r om en -3-yl)-2-oxo-
4-p h en yl-bu tyr ic Acid Meth yl Ester (3h ) was isolated as
a colorless solid after FC in CH2Cl2/Et2O and was found to
exist in a hemiketalized form that gives rise to pseudodiaste-
reomers. The enantiomers were separated by HPLC using a
Chiralpak AD chiral stationary phase in hexane/2-propanol
70/30 containing 0.15% TFA: [R]23 ) +6.4° (c ) 1.0 g/100
D
1
mL, CH2Cl2, 91% ee); H NMR (CDCl3) δ 2.37 (d, J ) 9.0 Hz,
1.32H), 2.46 (dd, J ) 3.1, 14.2 Hz, 0.34H), 2.71 (dd, J ) 7.3,
14.2 Hz, 0.34H), 3.71 (s, 1.98H), 3.76 (s, 1.98H), 3.78 (s, 1.02H),
3.80 (s, 1.02H), 4.10 (t, J ) 9.0 Hz, 0.66H), 4.24 (dd, J ) 3.1,
7.3 Hz, 0.34H), 4.42 (s, 0.34H, OH position is concentration
dependent), 4.70 (s, 0.66H, OH position is concentration
4-(4-H yd r oxy-6-m et h yl-2-oxo-2H -p yr a n -3-yl)-2-oxo-4-
p h en yl-bu tyr ic Acid Meth yl Eter (3l) was isolated as a
colorless solid after FC in CH2Cl2/Et2O and was found to exist
in a hemiketalized form that gives rise to pseudodiastereomers.
5072 J . Org. Chem., Vol. 68, No. 13, 2003

Direct Asymmetric Michael Reactions
The enantiomers were separated by HPLC using a Chiralpak
AD chiral stationary phase in hexane/2-propanol 70/30: 1H
NMR (CDCl3) δ 2.14 (s, 2.04H), 2.20 (s, 0.96H), 2.27 (d, J )
8.6 Hz, 1.36H), 2.38 (dd, J ) 3.5, 14.4 Hz, 0.32H), 2.61 (dd, J
) 7.4, 14.4 Hz, 0.32H), 3.77 (s, 2.04H), 3.81 (s, 0.96H), 3.97 (t,
J ) 8.6 Hz, 0.68H), 4.12 (br dd, J ) 3.5, 7.4 Hz, 0.32H), 4.22
(br s, 0.32H, OH position is concentration dependent), 4.45 (br
s, 0.68H, OH position is concentration dependent), 5.75 (d, J
exist in a hemiketalized form that gives rise to pseudodiaste-
reomers. The enantiomers were separated by HPLC using a
Chiralpak AD chiral stationary phase in hexane/2-propanol
80/20 containing 0.20% TFA: [R]23 ) -6.4° (c ) 1.0 g/100
D
mL, CH2Cl2, 45% ee): 1H NMR (CDCl3) δ 1.01 (s, 1.89H), 1.04
(s, 1.11H), 1.10 (s, 1.89H), 1.13 (s, 1.11H), 2.12-2.52 (m, 6H),
3.65 (s, 1.89H), 3.77 (s, 1.11H), 3.81 (t, J ) 9.0 Hz, 0.63H),
4.01 (br s, 0.37H), 4.27 (br s, 0.37H, OH position is concentra-
tion dependent), 4.62 (br s, 0.63H, OH position is concentration
dependent), 7.02-7.12 (m, 3H), 7.16-7.24 (m, 2H); 13C NMR
(CDCl3) δ 27.9, 28.5, 29.0, 29.5, 31.9, 32.2, 32.3, 33.5, 36.4,
38.5, 42.6, 42.7, 51.0, 51.1, 53.7, 53.8, 94.9, 95.8, 112.0, 113.7,
126.0, 126.2, 127.0, 127.2, 128.2, 128.3, 142.9, 143.8, 167.1,
167.7, 169.3, 196.4, 196.9; HRMS (TOF ES+) m/z 353.1367 (M
+ Na+), calcd for C19H22O5Na+ 353.1365.
) 0.8 Hz, 0.68H), 5.81 (s, 0.32H), 7.12-7.41 (m, 5H, ArH); 13
C
NMR (CDCl3) δ 19.8, 19.9, 32.4, 33.2, 35.2, 37.8, 53.8, 53.9,
95.2, 95.8, 99.8, 100.3, 100.7, 127.7, 128.0, 128.6, 128.8, 129.0,
129.1, 131.8, 132.0, 140.3, 140.5, 161.7, 162.8, 163.2, 163.4,
163.5, 168.5, 168.7; HRMS (TOF ES+) m/z 339.0847 (M + Na+),
calcd for C17H16O6Na+ 339.0845.
4-(4-Ch lor o-p h en yl)-4-(4-h yd r oxy-6-m et h yl-2-oxo-2H -
p yr a n -3-yl)-2-oxo-bu tyr ic Acid Meth yl Ester (3m ) was
isolated as a colorless solid after FC in CH2Cl2/Et2O and was
found to exist in a hemiketalized form that gives rise to
pseudodiastereomers. The enantiomers were separated by
HPLC using a Chiralpak AD chiral stationary phase in
4-(4,4-Dim eth yl-2-m eth ylam in o-6-oxo-cycloh ex-1-en yl)-
2-oxo-4-p h en yl-bu tyr ic Acid Meth yl Ester (3q) was iso-
lated as a colorless solid after FC in CH2Cl2/Et2O and was
found to exist in
a hemiaminal form that gives rise to
pseudodiastereomers. The pseudodiastereomers were sepa-
rated by FC, and the enantiomers of both diastereomers were
separated by HPLC using a Chiralpak AD chiral stationary
hexane/2-propanol 80/20: [R]23 ) +13.6° (c ) 1.0 g/100 mL,
D
CH2Cl2, 48% ee): 1H NMR (CDCl3) δ 2.21 (s, 1.95H), 2.26 (s,
1.05H), 2.23-2.33 (m, 1.30H), 2.37 (dd, J ) 3.1, 14.4 Hz,
0.35H), 2.67 (dd, 7.0, 14.4 Hz, 0.35H), 3.86 (s, 1.95H), 3.89 (s,
1.05H), 4.02 (dd, J ) 7.4, 10.9 Hz, 0.65H), 4.14 (dd, 3.1, 7.0
Hz, 0.35), 4.34 (s, 0.35H, OH position is concentration depend-
ent), 4.53 (s, 0.65H, OH position is concentration dependent),
5.80 (d, J ) 0.7 Hz, 0.65H, alkene), 5.86 (s, 0.35H), 7.12-7.18
(m, 2H), 7.24-7.29 (m, 2H); 13C NMR (CDCl3) δ 19.8, 19.9,
32.4, 33.2, 35.2, 37.8, 53.8, 53.9, 95.2, 95.8, 99.8, 100.3, 100.7,
127.7, 128.0, 128.6, 128.8, 129.0, 129.1, 131.8, 132.0, 140.3,
140.5, 161.7, 162.8, 163.2, 163.4, 163.5, 168.5, 168.7; HRMS
(TOF ES+) m/z 373.0449 (M + Na+), calcd for C17H15ClO6Na+
373.0455.
phase in hexane/2-propanol 70/30: [R]23 ) -17.1° (c ) 1.0
D
1
g/100 mL, CH2Cl2, 47% ee); H NMR (CDCl3) δ 1.07 (s, 3H),
1.11 (s, 3H), 2.15-2.29 (m, 4H), 2.34 (d, J ) 16.8 Hz, 1H),
2.51 (d, J ) 16.8 Hz, 1H), 2.79 (s, 3H), 3.27 (s, 1H, OH posi-
tion is concentration dependent), 3.78 (s, 3H), 4.19 (br t,
J ) 5.1 Hz, 1H), 7.01-7.05 (m, 2H), 7.11-7.16 (m, 2H); 13C
NMR (CDCl3) δ 28.2, 29.3, 31.9, 32.1, 32.6, 39.8, 40.9, 49.2,
53.7, 85.6, 108.0, 128.2, 128.6, 131.4, 142.1, 158.1, 172.5,
193.6; HRMS (TOF ES+) m/z, 400.1287 (M + Na+), calcd for
C
20H24ClNO4Na+ 400.1292.
4-(4-Ch lor o-p h en yl)-2-oxo-4-(6-oxo-2-p h en yla m in o-cy-
cloh ex-1-en yl)-bu tyr ic Acid Meth yl ester (3r ) was isolated
as a colorless solid after FC in CH2Cl2/Et2O and was found to
exist in a hemiaminal form that gives rise to pseudodiastere-
omers. The pseudodiastereomers were separated by FC, and
the enantiomers of both diastereomers were separated by
HPLC using a Chiralpak AD chiral stationary phase in
hexane/2-propanol 70/30. Dia ster eom er a . Isolated in 92%
4-(3-Hyd r oxy-1-oxo-1H-p h en a len -2-yl)-2-oxo-4-p h en yl-
bu tyr ic Acid Meth yl Ester (3n ) was isolated as a yellow
solid after FC in CH2Cl2/Et2O and was found to exist in a
hemiketalized form that gives rise to pseudodiastereomers.
The enantiomers were separated by HPLC using a Chiralpak
AD chiral stationary phase in hexane/2-propanol 70/30 con-
taining 0.15% TFA: [R]23 ) +101.0° (c ) 1.0 g/100 mL,
ee: [R]23 ) -28.1° (c ) 1.0 g/100 mL, CH2Cl2, 92% ee); 1H
D
D
CH2Cl2, 76% ee); 1H NMR (CDCl3) δ 2.49 (d, J ) 9.0 Hz,
1.20H), 2.56 (dd, J ) 3.1, 14.4 Hz, 0.40H), 2.79 (dd, J ) 7.4,
14.4 Hz, 0.40H), 3.83 (s, 1.80H), 3.91 (s, 1.20H), 4.36 (t, J )
9.0 Hz, 0.60H), 4.44 (s, 0.40H, OH position is concentration
dependent), 4.55 (dd, J ) 3.1, 7.4 Hz, 0.40H), 4.93 (s, 0.60H,
OH position is concentration dependent), 7.14-7.32 (m, 5H),
7.54-7.72 (m, 2H), 7.98-8.26 (m, 3H), 8.40 (dd, J ) 1.2, 7.4
Hz, 0.60H), 8.54 (dd, J ) 1.2, 7.4 Hz, 0.40H); 13C NMR (CDCl3)
δ 32.7, 34.5, 35.5, 38.4, 53.7, 53.8, 95.1, 95.8, 114.8, 116.9,
123.7, 124.0, 126.1, 126.2, 126.3.126.4, 126.5, 126.7, 126.8,
127.1, 127.4, 128.1, 128.3, 128.4, 128.5, 129.9, 130.2, 131.5,
131.7, 131.9, 132.2, 134.0, 134.3, 142.8, 144.2, 158.0, 158.5,
169.5, 169.6, 183.3, 183.4; HRMS (TOF ES+) m/z 409.1050 (M
+ Na+), calcd for C24H18O5Na+ 409.1052.
4-(3-Hyd r oxy-1,4-d ioxo-1,4-d ih yd r o-n a p h th a len -2-yl)-
2-oxo-4-p h en yl-bu tyr ic Acid Meth yl Ester (3o) was iso-
lated as a yellow solid after FC in CH2Cl2/Et2O and was found
to exist in both a hemiketalized form that gives rise to pseu-
dodiastereomers as well as the keto form. The enantiomers
were separated by HPLC using a Chiralpak AD chiral station-
ary phase in hexane/2-propanol 70/30 containing 0.15% TFA:
1H NMR (CDCl3, 60 °C) δ 2.09 (br s, 0.18H), 2.34-2.51 (m,
1.60H), 2.73 (br dd, J ) 7.4, 14.1 Hz, 0.22H), 3.82 (br s, 2.67H),
3.86 (s, 0.33H), 4.15 (br dd, J ) 9.4, 18.7 Hz, 0.28H), 4.28 (br
t, J ) 8.2 Hz, 0.53H), 4.42 (br s, 0.19H), 4.91 (br s, 0.19H),
5.00 (br s, 0.28H, OH), 5.18 (br s, 0.53H), 7.15-7.50 (m, 5H),
7.59-8.12 (m, 4H); HRMS (TOF ES+) m/z 387.0839 (M + Na+),
calcd for C21H16O6Na+ 387.0845.
NMR (CDCl3) δ 1.88-1.98 (m, 2H), 2.06-2.15 (m, 1H),
2.21-2.32 (m, 1H), 2.32-2.45 (m, 3H), 2.71 (dd, J ) 7.0,
13.9 Hz, 1H), 3.62 (s, 3H), 3.87 (s, 1H, OH position is
concentration dependent), 4.35 (br d, J ) 7.0 Hz, 1H), 7.03-
7.10 (m, 1H), 7.15-7.28 (m, 4H), 7.32-7.41 (m, 4H); 13C NMR
(CDCl3) δ 21.7, 29.0, 31.0, 36.4, 38.8, 53.4, 85.2, 109.4, 128.1,
128.7, 128.8, 129.0, 129.4, 129.6, 131.1, 131.3, 139.2, 142.5,
158.7, 171.8, 195.0; HRMS m/z 434.1132 (M + Na+), calcd for
C
23H22ClNO4Na+ 434.1135. Dia ster eom er b. Isolated in 98%
ee: [R]23 ) -64.0° (c ) 1.0 g/100 mL, CH2Cl2, 98% ee): 1H
D
NMR (CDCl3) δ 1.75-1.93 (m, 3H), 2.04-2.15 (m, 3H), 2.19-
2.26 (m, 1H), 2.33 (t, J ) 12.3 Hz, 1H), 3.43 (s, 3H, CH3), 3.99
(br dd, J ) 6.2, 12.3), 4.44 (s, 1H, OH position is concentration
dependent), 7.11-7.19 (m, 5H), 7.25-7.28 (m, 1H), 7.30-7.36
(m, 3H); 13C NMR (CDCl3) δ 21.2, 29.5, 34.2, 36.4, 41.9, 53.2,
84.7, 112.2, 128.3, 128.3, 128.8, 129.0, 129.4, 130.1, 130.7,
131.0, 139.5, 144.3, 159.2, 171.4, 194.4; HRMS (TOF ES+) m/z
434.1136, calcd for C23H22ClNO4Na+ 434.1135.
2-Oxo-4-(6-oxo-2-ph en ylam in o-cycloh ex-1-en yl)-4-ph en -
yl-bu tyr ic Acid Meth yl Ester (3s) was isolated as a colorless
solid after FC in CH2Cl2/Et2O and was found to exist in a
hemiaminal form that gives rise to pseudodiastereomers. The
pseudodiastereomers were separated by FC, and the enanti-
omers of both diastereomers were separated by HPLC using
a Chiralpak AD chiral stationary phase in hexane/2-propanol
70/30. Dia ster eom er a . Isolated in 91% ee: [R]23 ) -7.1° (c
D
) 1.0 g/100 mL, CH2Cl2, 91% ee); 1H NMR (CDCl3) δ
1.82-1.94 (m, 2H), 2.01-2.08 (m, 1H), 2.15-2.41 (m, 3H), 2.43
(dd, J ) 2.7, 13.7 Hz, 1H), 2.68 (dd, J ) 7.0, 13.7 Hz,
1H), 3.52 (s, 3H), 3.58 (s, 1H, OH position is concentration
dependent), 4.37 (br d, J ) 7.0 Hz, 1H), 6.98-7.02 (m, 1H),
4-(2-H yd r oxy-4,4-d im et h yl-6-oxo-cycloh ex-1-en yl)-2-
oxo-4-p h en yl-bu tyr ic Acid Meth yl Ester (3p ) was isolated
as a colorless solid after FC in CH2Cl2/Et2O and was found to
J . Org. Chem, Vol. 68, No. 13, 2003 5073

J ørgensen
7.08-7.14 (m, 1H), 7.20-7.24 (m, 4H), 7.26-7.34 (m, 4H); 13
C
HRMS (TOF ES+) m/z 400.1526 (M + Na+), calcd for C23H23
-
NMR (CDCl3) δ 21.7, 29.0, 32.0, 36.4, 39.0, 53.2, 85.5, 109.5,
126.0, 127.2, 128.2, 128.7, 128.9, 129.4, 129.7, 131.2, 139.4,
143.3, 158.4, 171.6, 195.0; HRMS m/z 400.1532 (M + Na+),
calcd for C23H23NO4Na+ 400.1525. Dia ster eom er b. Isolated
NO4Na+ 400.1525.
Ack n ow led gm en t. This work was made possible by
a grant from The Danish National Research Foundation.
Thanks are expressed to Dr. Rita G. Hazell for solving
the X-ray structure of 3b.
in 95% ee: [R]23 ) -47.2° (c ) 1.0 g/100 mL, CH2Cl2, 95%
D
ee); 1H NMR (CDCl3) δ 1.75-1.94 (m, 3H), 2.04-2.29 (m, 4H),
2.39 (t, J ) 12.7 Hz, 1H), 3.42 (s, 3H), 4.02 (br dd, J ) 6.6,
11.7 Hz, 1H), 4.28 (s, 1H, OH position is concentration
dependent), 7.07-7.11 (m, 1H), 7.11-7.16 (m, 1H), 7.18-7.24
(m, 4H), 7.26-7.36 (m, 4H); 13C NMR (CDCl3) δ 21.2, 29.4,
34.4, 36.2, 41.8, 52.8, 84.8, 111.8, 125.4, 126.9, 128.0, 128.5,
128.8, 129.1, 130.1, 130.8, 149.6, 145.5, 159.1, 171.2, 194.5;
Su p p or tin g In for m a tion Ava ila ble: Complete X-ray
data for compound 3b. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O0343026
5074 J . Org. Chem., Vol. 68, No. 13, 2003