Organocatalytic Asymmetric Michael Reaction of Cyclic 1,3-Dicarbonyl Compounds and α,β-Unsaturated Ketones - A Highly Atom-Economic Catalytic One-Step Formation of Optically Active Warfarin Anticoagulant

Article abstract of DOI:10.1002/anie.200352136

A broad range of Michael adducts 3 were obtained by the organocatalytic asymmetric Michael addition of cyclic 1,3-dicarbonyl compounds 1 to α,β-unsaturated ketones 2. The reaction allows a one-step synthesis of the optically active anti-coagulant warfarin and several analogues 3 on a kilogram scale in up to 99% yield with 88% ee (>99.9% ee after a single recrystallization).

Full text of DOI:10.1002/anie.200352136

Angewandte
Chemie
Asymmetric Michael Addition
warfarin will reduce the dosage problem. Another advantage
of optically pure warfarin would be that weakened patients
Organocatalytic Asymmetric Michael Reaction of unable to tolerate the stronger racemic or (S)-warfarin could
[
3]
Cyclic 1,3-Dicarbonyl Compounds and a,b-
be treated with the milder (R)-warfarin. However, probably
Unsaturated Ketones—A Highly Atom-Economic the most important advantage of administering optically pure
Catalytic One-Step Formation of Optically Active warfarin is the possibility of eliminating drug–drug interac-
Warfarin Anticoagulant**
tions, which represents another serious problem with racemic
warfarin, as enzymes that are responsible for metabolizing
warfarin also metabolize many other drugs.
[
2]
Nis Halland, Tore Hansen, and Karl Anker Jørgensen*
Three different approaches towards the synthesis of
optically active warfarin have been reported: Demir et al.
used a diastereoselective Michael addition in which chiral
enamines of 4-hydroxycoumarin were treated with benzyli-
deneacetone in the presence of LDA and superstoichiometric
amounts of Lewis acid to obtain warfarin in moderate yield
and enantiomeric excess. Li and co-workers at DuPont
Merck Pharmaceutical Company obtained enantioenriched
warfarin from racemic warfarin through an oxidation proce-
As optically active drugs become increasingly important for
the treatment of diseases in patients, still more enantiopure
drugs are introduced to the market either as new drugs or as
the result of a racemic switch. An important goal for
asymmetric catalysis is to develop new reactions that afford
optically active compounds from simple and easily available
starting materials and catalysts. However, the ultimate goal
would be if the new reaction could be used directly for a one-
step synthesis of optically active molecules that have impor-
tant biological and pharmaceutical activities. Herein we
present such an advance and its direct application in an
atom-economic synthesis of optically active drugs based on
the development of a new organocatalytic enantioselective
Michael addition of cyclic 1,3-dicarbonyl compounds to a,b-
[
4]
[
5]
dure and subsequent asymmetric hydrogenation. The dia-
stereoselective synthesis by Cravotto et al. involved a tandem
Knoevenagel/hetero-Diels–Alder approach; however, yields
[
6]
were low owing to the somewhat lengthy synthesis.
Herein we present, besides the development of a new
organocatalytic enantioselective reaction, a simple, effective
and highly atom-economical synthesis of optically active
warfarin (1a) from 4-hydroxycoumarin (2a) and benzyli-
deneacetone (3a) in the presence of imidazolidine catalysts
(Table 1). Furthermore, the scope and potential of this new
one-step, organocatalytic enantioselective Michael addition is
demonstrated by the formation of a number of important
[
1]
unsaturated ketones.
The present development leads to a catalytic enantiose-
lective one-step procedure for the formation of one of the
most widely used anticoagulants, warfarin (coumadin), and
related important compounds. Warfarin has been prescribed
as a racemate for more than 40 years and it is well-known that
the anticoagulant activity of the S enantiomer is about 5–8
[
7]
[
2]
times higher than of the R enantiomer. Furthermore, the
enantiomers are metabolized by different pathways, which is
reflected by the different half-lives in the human body, 21–43
Table 1: Screening of catalysts for the organocatalytic asymmetric
[
a]
formation of 1a.
[
2]
and 37–89 h, for (S)- and (R)-warfarin, respectively. Due to
these very different half-lives, one of the major problems with
racemic warfarin is the delivery and maintenance of a stable
dose as too high doses might lead to internal hemorrhages in
the patient. The dosage problem is further complicated by the
fact that the peak pharmacological effect of a single dose is
not achieved until after approximately 48 h, and the pharma-
cological effect lasts 4–5 days. As patients respond differently,
it is expected that treatment of patients with optically pure
[b]
[c]
Entry Catalyst
[mol%] Solvent t [h] Yield [%]
ee [%]
1
2
3
4
5
6
7
8
(S)-proline 50
DMSO
CH Cl
70 85 70 (
EtOH
15 85
70 77
0
[
*] Prof. Dr. K. A. Jørgensen, Dr. N. Halland, Dr. T. Hansen
The Danish National Research Foundation:
Center for Catalysis, Department of Chemistry
Aarhus University
4a
4a
10
5THF
2
2
62 (S)
S)
47 (S)
49 (S)
56 (R)
82 (R)
4a
4a
4b
(R,R)-4c
(S,S)-4c
10
10
10
10
10
70 69
90 22
130 83
150 96
130 90
H O
2
8000 Aarhus C (Denmark)
THF
[
d]
Fax: (+45)8919-6199
E-mail: kaj@chem.au.dk
CH Cl
2
2
[
d]
THF
80 (S)
[
**] We are grateful to Dr. A. Lohse and Dr. N. Jacobsen at Cheminova
[
1
a] Experimental conditions: A mixture of 3a (0.5mmol), 2a (0.525 mol,
.05equiv), and the catalyst was stirred at ambient temperature for the
for performing the scale-up reactions and providing compounds
2
d,f and to Dr. R. G. Hazell for X-ray crystallographic analysis of
time indicated. The crude mixture was then purified by flash chroma-
tography. [b] Yield of product isolated after flash chromatography.
compounds 1a,b. This work was made possible by a grant from The
Danish National Research Foundation.
[c] Enantiomeric excess determined by CSP-HPLC. The absolute config-
Supporting information for this article (including films of hearts
before and after treatment) is available on the WWW under
http://www.angewandte.org or from the author.
uration of the major enantiomer is indicated in parentheses. [d] Enan-
tiomeric purity increased to >99.9% by a single recrystallization in
acetone/water.
Angew. Chem. Int. Ed. 2003, 42, 4955 –4957
DOI: 10.1002/anie.200352136
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4955

Communications
optically, biologically, and pharmaceutically active com-
pounds.
We envisioned that the imidazolidine catalysts 4a–c
of 2a to a number of a,b-unsaturated enones 3b–i that bear
alkyl, branched alkyl, as well as various aromatic and
[
8]
1
heteroaromatic R substituents proceeds smoothly to afford
would be efficient catalysts for the addition of cyclic 1,3-
dicarbonyl compounds to a,b-unsaturated carbonyl com-
pounds. Table 1 shows some screening results for the reaction
of 2a with 3a.
Initially, (S)-proline was investigated as the organocata-
lyst, but only racemic warfarin (1a) was obtained (Table 1,
entry 1). We then turned our attention to the amino acid
derived imidazolidine catalysts 4a,b. To our delight we found
that when the reaction was catalyzed by 4a, optically active
Michael adducts 1b–i in high yields and enantioselectivities.
The ketone substituent (R ) could also be varied from methyl
to ethyl and isopropyl; although a slightly lower yield of the
Michael adduct 1k was obtained, good enantioselectivities
were maintained.
To extend the scope of the reaction further, several other
cyclic 1,3-dicarbonyl compounds were utilized as Michael
donors in the reaction with benzylideneacetone (3a) in the
presence of catalyst 4c (Table 3). The Michael reaction
proceeded in good yields and with high enantioselectivities
when using 4-hydroxycoumarin bearing either electron-with-
drawing or electron-donating substituents (Table 3, entries 1–
4), as well as when using 1-thio-4-hydroxycoumarin 2 f
2
1
a was formed in high yields with up to 70% ee (Table 1,
entries 2–5). However, organocatalyst 4c, formed by the
condensation of 1,2-diphenylethanediamine with glyoxylic
acid, proved to be superior to 4a,b, and 1a was obtained with
up to 82% ee (Table 1, entries 7 and 8). In all cases the
reaction proceeded smoothly at ambient temperature in the
absence of an external base and without the formation of any
by-products. To improve the enantiomeric purity of the
Michael adduct, a single recrystallization from a water/
acetone mixture provided the enantiopure (> 99.9% ee)
warfarin 1a when starting from a sample with 79% ee.
This new organocatalytic asymmetric Michael reaction
also proceeds on a kilogram scale when catalyzed by
imidazolidine 4a without any decrease in yield or enantiose-
lectivity. Recycling of the catalyst was also possible, and thus
the reaction provides very easy and inexpensive access to
large quantities of enantiopure warfarin.
Table 3: Organocatalytic asymmetric Michael addition of Michael donors
[a]
2
b–g to dibenzylideneacetone (3a).
[
b]
[c]
Entry Michael donor
Michael adduct
Yield [%] ee [%]
[
d]
1
2
6579
The scope of the present organocatalytic asymmetric
Michael reaction using catalyst 4c was extended to various
a,b-unsaturated enones and the results are given in Table 2.
The results in Table 2 demonstrate that the Michael addition
81
68
85
83
Table 2: Organocatalytic asymmetric Michael addition of 2a to a,b-
3
[
a]
unsaturated enones 3b–k.
4
5
6
84
84
76
85
78
85
1
2
[b]
Entry
1
R
R
3
Catalyst t [h]
1
Yield [%] ee [%]
[
c]
4-ClPh
4-ClPh
4-NO Ph Me
4-MeOPh Me
Me
nBu
Me
Me
b
b
c
d
e
f
g
h
i
(S,S)-4c 130
(S,S)-4c 200
(S,S)-4c 130
(S,S)-4c 160
(S,S)-4c 130
b
b
c
d
e
f
86
68
81
91
81
99
77
78
82 (S)
87 (S)
83 (S)
82 (S)
83 (S)
84 (S)
83 (S)
[
d]
2
3
4
5
6
7
8
9
0
1
2
[
[
[
[
e]
e]
e]
e]
2-Np
Me
Me
Me
Me
Et
(R,R)-4c
(S,S)-4c
60
90
iPr
g
h
[
e]
e]
2-thienyl
2-furyl
Ph
(R,R)-4c 150
(R,R)-4c 150 (i 7575
(S,S)-4c 130
(S,S)-4c 180
79 (R)
R)
[
[
e]
e]
1
1
j
k
j
k
84
71
88 (S)
85( S)
[
Ph
iPr
[
a] Experimental conditions: The reaction mixture was treated with
catalyst 4c (10 mol%) in CH Cl at ambient temperature for the time
2
2
indicated. [b] Enantiomeric excess determined by CSP-HPLC. The
absolute configuration of the major enantiomer is indicated in
parentheses. [c] Enantiomeric purity increased to >99.9% ee after a
single recrystallization in acetone/water. [d] Performed at 108C. [e] Abso-
lute stereochemistry assigned by analogy to 1a–c.
[a] Reaction conditions: The reaction mixture was treated with catalyst
(S,S)-4c (10 mol%) in CH Cl at ambient temperature for 150 h. [b] Yield of
2
2
product isolated after flash chromatography. [c] Enantiomeric excess
determined by CSP-HPLC. [d] Performed in THF.
4
956
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Angew. Chem. Int. Ed. 2003, 42, 4955 –4957

Angewandte
Chemie
(
Table 3, entry 5) and 4-hydroxy-6-methylpyrone 2g (Table 3,
Keywords: asymmetric catalysis · enones · Michael addition ·
natural products · synthetic methods
.
entry 6) as Michael donors.
The absolute configuration of coumachlor (1b) was
determined by X-ray crystallographic analysis (see Support-
ing Information) and by comparison of optical rotation for
warfarin (1a)
stereochemical outcomes of the reactions catalyzed by 4a is in
accordance with previously proposed iminium-ion intermedi-
ates for the imidazolidine-catalyzed Michael reaction.
[
9]
[1]For general reviews of asymmetric conjugate addition reactions,
see: a) Comprehensive Asymmetric Catalysis, (Eds.: E. N. Jacob-
sen, A. Pfaltz, H. Yamamoto), Springer, Berlin, 1999; b) M. P.
Sibi, S. Manyem, Tetrahedron 2000, 56, 8033; c) N. Krause, A.
Hoffmann-Röder, Synthesis 2001, 171.
[2]For example, see: a) R. A. O'Reilly, N. Engl. J. Med. 1976, 295,
354; b) L. B. Wingard, R. A. O'Reilly, G. Levy, Clin. Pharmacol.
Ther. 1978, 23, 212; c) H. P. Rang, M. M. Dale, J. M. Ritter, P.
Gardner, Pharmacology, 4th ed., Churchill Livingstone, Phila-
delphia, 2001.
[
10a]
[10b]
and acenocoumarin (1c).
The observed
[
7g,h]
For
the imidazolidine catalyst (S,S)-4c, both an iminium-ion and
an aminal intermediate species can be envisaged. Optimiza-
tion using PM3 calculations show very little shielding of the
[
11]
alkene for the iminium-ion intermediate (Figure 1a). On
[
[
3]H. J. Bardsley, A. K. Daly, PCT patent WO 00/43003, 2000.
4]A. S. Demir, C. Tanyeli, V. Gülbeyaz, H. Akgün, Turk. J. Chem.
1996, 20, 139.
[
5]See, for example: a) A. Robinson, H.-Y. Li, J. Feaster, Tetrahe-
dron Lett. 1996, 37, 8321; b) H.-Y. Li, A. Robinson, US patent
5,856,525, 1999.
[
[
6]G. Cravotto, G. M. Nano, G. Palmisano, S. Tagliapietra, Tetrahe-
dron: Asymmetry 2001, 12, 707.
7]For iminium-ion-promoted asymmetric conjugate additions, see:
a) S. P. Brown, N. C. Goodwin, D. W. C. MacMillan, J. Am.
Chem. Soc. 2003, 125, 1192; b) N. A. Paras, D. W. C. MacMillan,
J. Am. Chem. Soc. 2002, 124, 7894; c) N. A. Paras, D. W. C.
MacMillan, J. Am. Chem. Soc. 2001, 123, 4370; d) J. F. Austin,
D. W. C. MacMillan, J. Am. Chem. Soc. 2002, 124, 1172; e) N.
Halland, P. S. Aburel, K. A. Jørgensen, Angew. Chem. 2003, 115,
685; Angew. Chem. Int. Ed. 2003, 42, 661; f) N. Halland, R. G.
Hazell, K. A. Jørgensen, J. Org. Chem. 2002, 67, 8331; see also:
g) M. Yamaguchi, T. Shiraishi, M. Hirama, J. Org. Chem. 1996,
61, 3520; h) M. Yamaguchi, Y. Igarashi, R. S. Reddy, T. Shiraishi,
M. Hirama, Tetrahedron 1997, 53, 11223; i) M. Yamaguchi, T.
Shiraishi, Y. Igarashi, M. Hirama, Tetrahedron Lett. 1994, 35,
8233; j) M. Yamaguchi, T. Shiraishi, M. Hirama, Angew. Chem.
1993, 105, 1243; Angew. Chem. Int. Ed. Engl. 1993, 32, 1176;
k) A. Kawara, T. Taguchi, Tetrahedron Lett. 1994, 35, 8805.
8]Catalysts were formed by condensation of commercially avail-
able glyoxylic acid with the corresponding diamine (see Sup-
porting Information).
9]CCDC-212540 and 212541 contain the supplementary crystallo-
graphic data for this paper (1a and 1b, respectively). These data
can be obtained free of charge via www.ccdc.cam.ac.uk/conts/
retrieving.html (or from the Cambridge Crystallographic Data
Centre, 12, Union Road, Cambridge CB21EZ, UK; fax:
[
[
Figure 1. Possible intermediates for imidazoline-catalyzed Michael
reaction. Left: iminium ion intermediate. Right: aminal intermediate.
(
+ 44)1223-336-033; or deposit@ccdc.cam.ac.uk).
the other hand, the bicyclic protonated aminal intermediate,
formed by a nucleophilic displacement of the hemiaminal
species, shows very good shielding of the Re face of the alkene
[
[
10]a) B. D. West, S. Preis, C. H. Schroeder, K. P. Link, J. Am. Chem.
Soc. 1961, 83, 2676; b) C. R. Wheeler, W. F. Trager, J. Med.
Chem. 1979, 22, 1122.
11]PM3 calculations were performed by using the PC Spartan
software. The alkene part in the hemiaminal species is signifi-
cantly more activated (lower LUMO energy) towards nucleo-
philic addition than the alkene part in benzylideneacetone.
(
Figure 1b). The alkene fragment in the latter intermediate is
[
11]
activated for addition of the 1,3-dicarbonyl compound and
thus provides a possible explanation for the observed stereo-
chemistry in the reaction.
In summary we have developed the first organocatalytic
asymmetric Michael addition of cyclic 1,3-dicarbonyl com-
pounds to a,b-unsaturated enones. This versatile and environ-
mentally friendly Michael reaction affords warfarin and other
Michael adducts in high yields and enantioselectivities in the
presence of an easily available organic catalyst. Furthermore,
it was demonstrated that enantiopure products could be
obtained by a single recrystallization.
Received: June 13, 2003 [Z52136]
Published Online: September 29, 2003
Angew. Chem. Int. Ed. 2003, 42, 4955 –4957
www.angewandte.org
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4957