Warfarin A

Tetrahedron: Asymmetry 25 (2014) 813820
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric synthesis of warfarin and its analogues on water

Maria Rogozinska-Szymczak a, Jacek Mlynarski a,b,
a
b
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland
a r t i c l e
i n f o
Article history:
Received 25 February 2014
Accepted 16 April 2014
Available online 28 May 2014
a b s t r a c t
The asymmetric Michael addition of 4-hydroxycoumarin to a,b-unsaturated ketones on water without
organic co-solvents is reported to be catalysed by organic primary amines. The application of enantiomerically pure (S,S)-diphenylethylenediamine affords a series of important pharmaceutically active compounds in good to excellent yields (7398%) and with good enantioselectivities (up to 76% ee) via
reactions accelerated by ultrasound. In particular, our developments led to an efcient protocol for the
solids on water formation of the anticoagulant warfarin in both enantiomeric forms. The presented scalable and environmentally friendly organocatalytic approach affords the target drug in enantiomerically
pure form.
2014 Elsevier Ltd. All rights reserved.
1. Introduction
The conjugate addition of enolates to a,b-unsaturated acceptors
(Michael reaction) is one of the most important carboncarbon
bond-forming reactions in organic synthesis.1 This reaction can
be controlled by chiral catalysts resulting in a formation of enantiomerically pure Michael adducts. For this reason there is a continuing need for the development of enantioselective catalytic
protocols leading to the asymmetric synthesis of drugs and bioactive compounds by means of conjugate Michael additions.2
Since the beginning of this century, asymmetric organocatalysis3 has emerged as a parallel and more environmentally acceptable methodology4 for the production of enantiomerically pure
compounds and is also a way to introduce chirality into Michael
reactions.5 The application of purely organic catalysts is now presented to be an enabling technology for the efcient synthesis of
the drug and several biologically relevant molecules.6 Recent
achievements in chemical efciency have also focused on the economic and ecological aspects of organocatalysis.7 From a green
chemistry perspective, the use of water instead of even a small
additive of organic solvent is preferred to decrease environmental
contamination. Thus additional efforts have also been made to
develop efcient organocatalysts for asymmetric reactions in pure
water.8
The use of asymmetric Michael reactions to generate biologically relevant molecules has been actively investigated over the
Corresponding author. Tel./fax: +48 12 663 2035.
E-mail address: jacek.mlynarski@gmail.com (J. Mlynarski).
URL: http://www.jacekmlynarski.pl (J. Mlynarski).
http://dx.doi.org/10.1016/j.tetasy.2014.04.008
0957-4166/ 2014 Elsevier Ltd. All rights reserved.
last few decades. Recently some organocatalytic procedures for

the synthesis of drug-like scaffolds have been recorded. One successful and instructive example is the straightforward production
of chiral warfarin via the well-established Michael addition of
4-hydroxycoumarin to benzylideneacetone (Scheme 1).
OH
O
+
O
1
OH
Ph
chiral amine
Ph
2
solvent
3
(S)-warfarin
Scheme 1. Asymmetric synthesis of warfarin by the Michael addition of 4hydroxycoumarin to benzylideneacetone.
As one of the most effective anticoagulants, warfarin has been

introduced for clinical use (warfarin, jantoven, uniwarn,
coumadin, marevan) as a racemate. However, the activity and
metabolism of both enantiomeric forms are dissimilar. The
(S)-form was proved to be more active to its mirror image.9 Taking
into account this feature, the asymmetric synthesis of anticoagulant
drugs seems to be not only rational but indispensable.
In 2003, Jrgensen reported the rst one-step synthesis of enantiomerically enriched warfarin from simple materials catalysed by
secondary amine catalysts.10 Primary11 and secondary12 aminoacid based amines have also been shown to be efcient in this
asymmetric procedure. Usually 20 mol % catalyst loading was
needed for the long reaction carried out in organic solvents.
ska-Szymczak, J. Mlynarski / Tetrahedron: Asymmetry 25 (2014) 813820

M. Rogozin
814
However, some catalysts seemed to be superior to others resulting

in the formation of the adduct in good to excellent enantioselectivities,11b,12b even with small catalyst loading (5 mol %).13
Applied catalysts have been derived from amino acids or cinchona alkaloids and their preparation required further efforts. In
2006, Chin demonstrated that the application of 10 mol % of
(R,R)-diphenylethylenediamine in THF resulted in the selective formation of (R)-warfarin in 94% yield after 48 h (ca. 80% ee).14
Recently, the efciency of this catalyst was further improved upon
by tosylation (Ts-DPEN catalyst) and metal salt additive.15 The
reaction in THF gave warfarin in 64% yield after 24 h with
5 mol % of amine and metal salt combination. In all cases, harmful
organic solvents were used as reaction media. The application of
small amounts of low molecular organocatalysts in aqueous solvents has so far been unsuccessful.16
Despite the signicant advances in this eld, the synthesis of
optically active warfarin and its analogues represent a considerable
synthetic challenge. Moreover, it is still desirable to develop environmentally and economically acceptable protocols for this
important transformation. Herein we report our studies on the
asymmetric organocatalytic preparation of anticoagulant warfarin
and its analogues by using green chemistry type Michael reactions
controlled by a readily available commercial chiral primary amine
(diphenylethylenediamine) on water.17
Table 1
Initial catalyst screeninga
Entry
Catalyst
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
9
10
11
12
4
5
6
7
8
9 (S,S)
10 (R,R)
11
12
13
14
55
30
34
22
22
98
91
56
31
44
40
rac.
24 (S)
20 (R)
18
20 (R)
55 (S)
53 (R)
44
31
13
30
a
The reaction was performed by employing 1 (0.50 mmol), 2 (0.60 mmol), catalyst (0.05 mmol, 10 mol %) and mixture THF/H2O (9:1) as a solvent (1 mL) at rt for
20 h.
b
Isolated yield after silica gel chromatography.
c
Ees were determined by HPLC analysis on a chiral phase (Daicel AD-H column).
formation of warfarin in various yields ranging from 22% to almost

the quantitative formation of the adduct (98%). The most promising catalyst in terms of ee and yield was the commercially available
(S,S)-diphenylethylenediamine (Table 1, entry 6). This catalyst can
be obtained in both enantiomeric forms by using a reliable protocol
on a multigram scale.19 Thus, the application of the (S,S)-congured amine gave (S)-warfarin while enantiomeric catalyst 10
resulted in the preferential formation of (R)-enantiomer (Table 1,
entry 7). This simple and promising catalyst surpassed the application of other tested amines in terms of efciency and stereoselectivity. Another promising catalyst was diaminocyclohexane 11 but
the observed yield was worse when compared to the best catalyst
9. The reaction catalysed by structurally modied amines 1214
gave poor to moderate enantioselectivities only (Table 1, entries
1012).
After (S,S)-catalyst 9 was identied as being the most effective,
we then evaluated the solvent effect and possible diminishing of
catalyst loading. Dry THF and its solution with water provided warfarin in similar yields and stereoselectivities (Table 2, entries 1 and
2). Increasing the amount of water led to no change in reaction efciency (Table 1, entry 4). However, the good enantioselectivity
observed for the reaction when carried out in pure water at rt
2. Results and discussion

To select promising catalysts, we rst examined the reaction of
4-hydroxycoumarin 1 to a,b-unsaturated ketone 2 leading to warfarin 3. This model Michael addition reaction was investigated
using a series of primary amine organocatalysts 414 (Scheme 2).
By using readily available primary amines 411 as catalysts and
also the natural starting point for more sterically hindered
examples, we prepared a series of hydrophobic amines equipped
with an alkyl chain 121418 for test reactions in an aqueous
environment.
In order to assess the efciency of Michael reactions promoted
by selected catalysts, initial screening was conducted in wet THF
(10 vol % water) at room temperature in the presence of 10 mol %
of amines. The results are summarised in Table 1. The application
of all of the tested chiral catalysts resulted in the stereoselective
NH 2
NH 2
NH2
NH2
NH2
NH2
NH2
NH2
OH
OH
NH2
NH2
NH2
10
11
NH2
NH 2
NH2
N
12
13
Scheme 2. Chiral primary amines tested in Michael reaction.
14

M. Rogozin
Table 2
Temperature and reaction timea
Table 4
Acid additives screeninga
Entry
Catalyst (mol %)
Solvent
1
2
3
4
5
6
7
10
10
5
10
10
10
10
THF
THF/H2O
THF/H2O
THF/H2O
H2O
THF/H2O
THF/H2O
Yield (%)b
89
98
88
94
8
98
98
(9:1)
(9:1)
(1:1)
(9:1)
(9:1)
ee (%)c
Entry
Additive
Yield (%)b
62
55
60
62
62
62d
55e
1
2
3
AcOH
CF3COOH
98
68
25
68
44
7
4
5
HCl
L-Tartaric
42
16
39
24 (R)
6
7
8
9
10
11
12
13
14
15
PhCOOH
PhCOOH
PhCOOH
HCOOH
C2H5COOH
(CH2COOH)2
PhOH
AcOH
PhCOOH
PhCOOH
98
87
78
86
98
84
94
92
88
90
72
68d
70e
50
60
65
58
64f
67 (S)f
68 (R)g
a
The reaction was performed by employing 1 (0.50 mmol), 2 (0.60 mmol), (S,S)catalyst 9 and solvent (1 mL) at rt for 20 h.
b
c
d
The reaction was performed by employing 1 (0.50 mmol), 2 (0.60 mmol), catalyst 9 and solvent (1 mL) at 40 C for 20 h.
e
The reaction was performed by employing 1 (0.50 mmol), 2 (0.60 mmol), catalyst 9 and solvent (1 mL) at 60 C for 12 h.
(62% ee) encouraged us to exclude organic solvents from the reaction mixture. Unfortunately, the observed reaction yield was too
low and needed further efforts. We assumed that better contact
between the insoluble substrates and water would lead to far better yields.
By using a green chemistry protocol and pure water as the solvent the reaction achieved good enantioselectivity, but careful foraging of the reactant was essential for a reasonable yield. It is
important to note that both solid reactants 1 and 2 are practically
insoluble in water creating a suspension of solids on water. Reaction on water efciency depends on appropriate contact between
the reactants; intense mechanical stirring was not efcient in this
case. We tried to accelerate the reaction by using sonication which
enables the rapid dispersion of solids on a water surface thus
allowing better contact between water and the reactants. The use
of ultrasound as a means of accelerating reactions is an important
technique and one which is rapidly developing for green processes.20 When the reaction was carried out in water by using
10 mol % of catalyst 9 under ultrasound acceleration, warfarin 3
was obtained in high yield and the same enantioselecitivity as in
organic solvents (Table 3, entry 1).
Table 3
Reaction on water accelerated by ultrasounda
Entry
Catalyst
1
2
3
9 (10 mol %)
10 (10 mol %)
11 (10 mol %)
815
Yield (%)b
ee (%)c
92
90
70
60
56 (R)
29
a
The reaction was performed by employing 1 (0.50 mmol), 2 (0.60 mmol), catalyst (10 mol %) and water (1 mL) at rt for 10 h in an ultrasound bath.
b
c
To further improve the reaction enantioselectivity, the effect of

acid additives and catalyst loading was investigated. As summarised in Table 4, various acid additives showed some benecial
effects on the reaction stereoselectivity. High yield and a slight
increase in reaction enantioselectivity were obtained when using
acetic (entry 1) and benzoic acid (entry 6). For benzoic acid, we
tried to reduce the loading of catalyst to 5 and 2 mol % (entries 7
and 8, respectively). The reaction afforded warfarin maintaining
enantioselectivity and good yield. Similar reactions carried out in
a larger scale (entries 1315) showed that this protocol could be
useful for the practical synthesis of a Michael adduct.
When the reaction was scaled up to 2 g with 2 mol % catalyst at
rt in an open vessel, excellent results were still obtained in 10 h
(Table 5). To take advantage of this elaborated green protocol,
the solid product was separated from the water phase by ltration,
D-Camphorosulfonic
acid
acid
ee (%)c
a
The reaction was performed by employing 1 (0.50 mmol), 2 (0.60 mmol), (S,S)catalyst 9 (0.05 mmol, 10 mol %), acid as additive (0.10 mmol, 20 mol %), and water
(1 mL) at rt for 10 h in an ultrasound bath.
b
c
d
The reaction was performed by employing 1 (0.50 mmol), 2 (0.60 mmol), (S,S)catalyst 9 (0.025 mmol, 5 mol %), acid as additive (0.05 mmol, 10 mol %) and water
e
f
g
The reaction was performed by employing 1 (5.0 mmol), 2 (6.0 mmol), (R,R)catalyst 10 (0.50 mmol, 10 mol %), acid as additive (1.0 mmol, 20 mol %) and water
Table 5
Reaction on water on a 2 g scale accelerated by ultrasound and crystallisation from
hexanea
Entry
Catalyst
Additive
1
2
3
4
10 mol %
2 mol %
2 mol %
5 mol %
AcOH (20 mol %)

AcOH (4 mol %)
PhCOOH (4 mol %)
PhCOOH (10 mol %)
Yield (%)b
61
52
50
55
ee (%)c
>99
>99
>99
>99
a
The reaction was performed by employing 1 (5.0 mmol), 2 (6.0 mmol), catalyst
9, acid as additive and water (10 mL) at rt for 10 h in an ultrasound bath.
b
Isolated yield after one crystallisation from hexane.
c
Ees were determined by HPLC analysis on a chiral phase (Daicel AD-H column)
after one crystallisation from hexane.
and after one crystallisation from hexane, gave enantiomerically

pure (S)-warfarin (Table 5, entries 2 and 3). This procedure
excluded the use of expensive silica gel chromatography; the application of a small amount of hexane instead of chromatography eluents seems to be promising from a green chemistry perspective.
Finally, we found that the aqueous phase containing a soluble
catalyst could be re-used for the reaction at least 3 times without
any loss in efciency. Both the yield and selectivity of the each
reaction after the rst, second and third run are shown in Table 6.
After the reaction, the aqueous phase was separated by ltration
and another portion of the reactants allowed us to obtain a Michael
product 3.
With the optimal reaction conditions in hand, we next examined a variety of a,b-unsaturated ketones to establish the general
utility of this on water catalytic Michael reactions. The reaction
was conducted with 10 mol % of catalyst 9 at ambient temperature
for 10 h in an ultrasound bath. As illustrated in Table 7, for the
reaction of 4-hydroxycoumarin 1, excellent results were achieved
with all of the tested ketones bearing aromatic (entries 111) or
aliphatic substituents (entries 1213). High yields and satisfactory

M. Rogozin
816
Table 6
Recycling of the catalysta
Yield (%)b
Entry
1
2
3
4
5
98
95
95
30
n.d.
ee (%)c
ee (%)d
74
73
74
70
>99
>99
>99
>99
a
The reaction was performed by employing 1 (0.50 mmol), 2 (0.60 mmol), catalyst 9 (0.05 mmol, 10 mol %), PhCOOH (0.10 mmol, 20 mol %) and water (1 mL) at
rt for 10 h in an ultrasound bath. After this time the aqueous phase was separated
and the addition of another portion of substrates allows to obtain a product.
b
c
d
Ees were determined by HPLC analysis on a chiral phase (Daicel AD-H column)
after one crystallisation from hexane.
Table 7
Extension of the developed procedure for a wide range of substratesa
OH
2a-m
4.2. General procedure for the organocatalytic Michael reaction

of unsaturated enones with cyclic 1,3-dicarbonyl compounds
chiral amine
+
O
OH
O
solvent
O
3a-m
Entry
1
2
3
4
5
6
7
8
9
10
11
12
13
Ph 3a
2-ClC6H4 3b
3-ClC6H4 3c
4-ClC6H4 3d
2-MeOC6H4 3e
4-MeOC6H4 3f
2-NO2C6H4 3g
4-NO2C6H4 3h
2-CH3C6H4 3i
3-CH3C6H4 3j
2-Naftyl 3k
C4H9 3l
iPr 3m
Yield (%)
98
90
93
89
93
94
93
93
91
92
97
81
73
recorded on a Fourier transform infrared (FT-IR) spectrometer. 1H

NMR spectra were measured at 300 MHz in CDCl3. Data were
reported as follows: chemical shifts in parts per million (ppm)
from tetramethylsilane as an internal standard, integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, dd = doubledoublet, m = multiplet, br = broad), coupling constants (in Hz)
and assignment. 13C NMR spectra were measured at 100 MHz with
complete proton decoupling. Chemical shifts are reported in ppm
from the residual solvent as an internal standard. High resolution
mass spectra (HRMS) were performed on an electrospray ionisation time-of-ight (ESI-TOF) mass spectrometer. Optical rotations
were measured on a digital polarimeter at room temperature.
Reactions were controlled using TLC on silica [alu-plates
(0.2 mm)]. All reagents and solvents were puried and dried
according to common methods. All organic solutions were dried
over anhydrous magnesium sulfate. Reaction products were puried by ash chromatography using silica gel 60 (240400 mesh).
HPLC analysis was performed on HPLC system equipped with chiral stationary phase columns, detection at 254 nm.
ee (%)
72
68
67
72
76
71
66
60
76
73
70
74
72
a
The reaction was performed by employing 1 (0.50 mmol), 2am (0.60 mmol),
catalyst 15 (0.05 mmol, 10 mol %), PhCOOH (0.10 mmol, 20 mol %) and water (1 mL)
at rt for 10 h in an ultrasound bath.
b
c
Ees were determined by HPLC analysis on a chiral phase.
enantioselectivities were observed for all sets of substrates proving

that the elaborated on water protocol is general in terms of substrate scope.
3. Conclusion
In conclusion, we have successfully demonstrated that (S,S)diphenylethylenediamine is an excellent enamine organocatalyst
for enantioselective Michael addition reactions of 4-hydroxycoumarin to a,b-unsaturated ketones under mild conditions. We have
also described a water compatible and scalable protocol for the
synthesis of enantiomerically pure warfarin in both enantiomeric
forms by using primary diamines as organocatalysts. By modifying
the reaction conditions, we were able to obtain the warfarin with
excellent ee under mild conditions without the application of silica
gel chromatography.
4. Experimental
4.1. General
Unless otherwise stated, all reagents were purchased from commercial sources and used as received. Infrared (IR) spectra were
A suspension of 4-hydroxycoumarin 1 (81.0 mg, 0.5 mmol), a,bunsaturated enone (0.6 mmol), (S,S)-diphenylethylenediamine 9 as
a catalyst (0.05 mmol, 10 mol %), an appropriate carboxylic acid
(0.1 mmol, 20 mol %) and water (1 mL) was sonicated at rt for
10 h in an ultrasound bath. After extraction between EtOAc and
water, the crude product was puried by column chromatography
on silica gel (hexaneethyl acetate, 4:1) to yield the pure product.
The enantiomeric excess of the products was determined by HPLC
using a chiral stationary phase. The Michael addition product was
found to exist in rapid equilibrium with a pseudodiastereomeric
hemiketal form in solution. However, the equilibrium was very
rapid and therefore no pseudodiastereomers were observed during
HPLC analysis. The equilibrium was slow enough that it showed up
as a mixture of ketone and hemiketal by 1H NMR spectroscopy.
4.2.1. (S)-4-Hydroxy-3-(3-oxo-1-phenylbutyl)-chromen-2-one
(warfarin) 3a10,11b,12a,17
The compound was isolated as a white solid. The enantiomeric
excess was determined by HPLC analysis of the puried product
with an Daicel AD-H column (hexane/i-PrOH, 4:1, 1.0 mL min 1,
k = 254 nm): tR = 6.3 min (minor) and tS = 15.2 min (major). Data
for sample with 99% ee (S): [a]D24 = 10.7 (c 1.0, acetonitrile),
{Lit.11b [a]D22 = 12.0 (c 0.3, acetonitrile), 96% ee (S)}; IR (KBr)
3409, 3029, 2839, 2738, 1719, 1548, 1456, 1380, 759, 698 cm 1;
1
H NMR (600 MHz CDCl3): d = 9.47 (0.3H, s, OH, keto), 7.93 (0.3H,
d, J 7.6 Hz, ArH), 7.88 (0.9H, d, J 7.8 Hz, ArH), 7.80 (1.1H, d, J
7.6 Hz, ArH), 7.55 (1.0H, t, J 7.6 Hz, ArH), 7.47 (1.5H, m, ArH),
7.347.18 (18.0H, m, ArH), 4.69 (0.3H, d, J 10.0 Hz, CH, keto),
4.27 (1.0H, dd, J 6.2, 2.4 Hz, CH, ketal), 4.15 (1.1H, dd, J 11.2,
6.7 Hz, CH, ketal), 3.85 (0.3H, dd, J 19.5, 10.3 Hz, CH2, keto), 3.38
(1.0H, br s, OH, ketal), 3.30 (0.3H, d, J 19.1 Hz, CH2, keto), 3.21
(1.1H, bs, OH, ketal), 2.53 (1.0H, dd, J 14.3, 2.9 Hz, CH2, ketal),
2.46 (1.1H, dd, J 13.8, 6.8 Hz, CH2, ketal), 2.40 (1.0H, dd, J 14.0,
6.9 Hz, CH2, ketal), 2.28 (0.9H, s, CH3, keto), 2.00 (1.1H, dd, J 13.5,
11.8 Hz, CH2, ketal), 1.70 (3.3H, s, CH3, ketal), 1.66 (3.0H, s, CH3,
ketal); 13C NMR (150 MHz, CDCl3): d = 162.1, 161.2, 159.6, 158.7,
152.9, 152.8, 143.1, 141.4, 131.9, 131.7, 131.5, 129.2, 128.6,
128.1, 127.9, 127.2, 127.0, 126.9, 126.6, 126.4, 123.9, 123.8,
123.5, 123.0, 122.6, 116.6, 116.4, 116.1, 115.8, 115.5, 104.1,
101.1, 100.4, 98.9, 45.1, 42.5, 39.9, 35.3, 34.8, 34.1, 30.0, 28.1,
27.7, 26.9; m/z (EI) 308 (22, [M]+), 265 (100), 251 (11), 187 (14),
121 (22), 44 (16%); HRMS (EI): MH+, found 308.1045 C19H16O4
required 308.1049.

M. Rogozin
4.2.2. (R)-3-[1-(2-Chlorophenyl)-3-oxobutyl]-4-hydroxy-chromen-2-one 3b12a

with an Daicel AD-H column (hexane/i-PrOH, 4:1), 1.0 mL min 1,
k = 254 nm): tS = 7.2 min (minor) and tR = 11.1 min (major). Data
for sample with 68% ee (R): [a]D24 = 28.9 (c 1.0, acetonitrile),
{Lit.12a [a]D25 = +35.1 (c 0.61, acetonitrile), 79% ee (S)}; IR (KBr)
3364 (br), 3066, 2969, 2933, 1689, 1621, 1570, 1492, 1382, 1072,
756 cm 1; 1H NMR (600 MHz CDCl3): d = 9.54 (0.2H, s, OH, keto),
7.96 (0.3H, dd, J 7.9, 1.6 Hz, ArH), 7.87 (0.9H, dd, J 7.9, 1.6 Hz,
ArH), 7.80 (1.0H, dd, J 8.2, 1.50 Hz, ArH), 7.68 (0.3H, dd, J 7.9,
1.5 Hz, ArH), 7.567.53 (1.0H, m, ArH), 7.507.43 (1.7H, m, ArH),
7.417.39 (1.1H, m, ArH), 7.357.29 (3.0H, m, ArH), 7.267.23
(4.0H, m, ArH), 7.187.08 (6.5H, m, ArH), 4.81 (0.3H, dd, J 11.1,
1.8 Hz, CH, keto), 4.53 (1.0H, dd, J 7.9, 3.0 Hz, CH, ketal), 4.01
(1.0H, m, CH, ketal), 3.97 (0.3H, dd, J 19.3, 11.1 Hz, CH2, keto),
3.22 (0.9H, br s, OH, ketal), 3.16 (0.3H, dd, J 19.2, 1.8 CH2, keto)
2.56 (2.0H, dd, J 14.3, 3.0, CH2, ketal), 2.35 (1.0, dd, J 14.4, 7.6,
CH2, ketal), 2.27 (0.9H, s, CH3, keto), 1.72 (3.0H, s, CH3, ketal),
1.68 (3.0H, s, CH3, ketal); 13C NMR (150 MHz, CDCl3): d = 161.7,
161.0, 159.9, 152.9, 152.8, 138.9, 133.7, 131.9, 131.6, 130.2,
129.2, 128.2, 128.1, 127.6, 127.1, 126.8, 126.1, 124.1, 123.8,
123.6, 122.9, 122.7, 116.6, 116.5, 116.1, 115.8, 115.5, 101.2,
100.3, 99.1, 45.8, 37.1, 32.6, 29.9, 28.2, 28.0, 25.3; m/z (EI) 342
(19, [M]+), 307 (52), 299 (65), 263 (66), 249 (100), 187 (11), 121
(54), 92 (21), 65 (20), 45 (49), 43 (80%); HRMS (EI): MH+, found
342.0667 C19H15O4Cl required 342.0659.
4.2.3. (S)-3-[1-(3-Chlorophenyl)-3-oxobutyl]-4-hydroxy-chromen-2-one 3c12a
The compound was isolated as a light yellow solid. The enantiomeric excess was determined by HPLC analysis of the puried
product with an Daicel AD-H column (hexane/i-PrOH, 4:1),
1.0 mL min 1, k = 254 nm): tR = 5.8 min (minor) and tS = 12.3 min
(major). Data for sample with 67% ee (S): [a]D24 = +1.3 (c 1.0, acetonitrile), {Lit.12a [a]40526 = +17.8 (c 0.36, acetonitrile), 75% ee (R)}; IR
(KBr) 3307 (br), 2958, 2929, 2852, 1686, 1623, 1575, 1495, 1381,
1071, 759 cm 1; 1H NMR (600 MHz CDCl3): d = 9.55 (0.3H, s, OH,
keto), 7.94 (0.3H, d, J 7.9 Hz, ArH), 7.86 (0.9H, d, J 7.9 Hz, ArH),
7.79 (1.4H, d, J 7.8 Hz, ArH), 7.617.41 (2.9H, m, ArH), 7.377.05
(17.4H, m, ArH), 4.63 (0.35H, dd, J 10.3, 1.7 Hz, CH, keto), 4.18
(1.0H, dd, J 7.0, 3.5 Hz, CH, ketal), 4.13 (1.6H, m, CH, ketal), 3.82
(0.35H, dd, J 19.4, 10.3 Hz, CH2, keto), 3.47 (1.1H, br s, OH, ketal),
3.27 (0.35H, dd, J 19.4, 1.7 CH2, keto), 2.44 (2.7H, m, CH2, ketal),
2.37 (1.1H, ddd, J 10.9, 7.0, 3.5, CH2, ketal), 2.28 (1.0H, s, CH3, keto),
1.93 (1.7H, m, CH2, ketal), 1.72 (3.0H, s, CH3, ketal), 1.71 (3.0H, s,
CH3, ketal); 13C NMR (150 MHz, CDCl3): d = 161.9, 161.2, 159.7,
159.0, 152.9, 152.8, 145.4, 144.2, 134.6, 134.3, 132.1, 131.9,
131.7, 129.9, 129.8, 129.3, 128.2, 127.5, 127.1, 127.0, 126.8,
126.7, 126.2, 125.5, 125.3, 123.9, 123.9, 123.7, 122.9, 122.7,
116.7, 116.5, 116.2, 115.7, 115.4, 103.5, 100.9, 100.2, 98.9, 44.9,
42.3, 39.8, 35.2, 34.5, 34.4, 30.0, 28.2, 27.8; m/z (EI) 342 (23,
[M]+), 299 (100), 249 (10), 121 (22), 43 (15%); HRMS (EI): MH+,
found 342.0666 C19H15O4Cl requires 342.0659.
4.2.4. (S)-3-[1-(4-Chlorophenyl)-3-oxobutyl]-4-hydroxy-chromen-2-one 3d10,11b,12a
for sample with 72% ee (S): [a]D23 = +10.0 (c 1.0, acetonitrile),
{Lit.12a [a]D25 = 8.8 (c 0.28, acetonitrile), 79% ee (R)}; IR (KBr)
3377, 2984, 2934, 2855, 1686, 1608, 1565, 1490, 1385, 1377,
1071 cm 1, 1H NMR (600 MHz CDCl3): d = 9.47 (0.2H, s, OH, keto),
817
7.93 (0.2H, dd, 8.0 1.5 Hz, ArH), 7.86 (0.7H, dd, J 8.0, 1.5 Hz, ArH),
7.78 (1.0H, dd, J 8.2, 1.43 Hz, ArH), 7.55 (0.7H, dt, J 8.7, 1.5 Hz,
ArH), 7.487.46 (1.3H, m, ArH), 7.337.13 (12.7H, m, ArH), 4.63
(0.2H, dd, J 10.4, 2.3 Hz, CH, keto), 4.17 (0.7H, dd, J 6.8. 3.7 Hz,
CH, ketal), 4.13 (1.1H, dd, J 11.7, 6.8 Hz, CH, ketal), 3.82 (0.2H,
dd, J 19.3, 10.3 Hz, CH2, keto), 3.44 (0.8H, br s, OH, ketal), 3.25
2.43 (1.8H, dd, J 14.1, 6.7 Hz, CH2, ketal), 2.37 (0.7H, dd, J 14.2,
7.2 Hz, CH2, ketal), 2.28 (0.7H, s, CH3, keto), 1.92 (1.1H, CH2, ketal),
1.72 (3.3H, s, CH3, ketal), 1.67 (2.1H, s, CH3, ketal); 13C NMR
(150 MHz, CDCl3): d = 161.9, 161.2, 159.6, 158.9, 152.9, 152.8,
152.8, 141.7, 140.5, 138.2, 132.5, 132.4, 132.1, 131.9, 131.7,
131.7, 129.4, 128.9, 128.7, 128.6, 128.4, 128.2, 123.9, 123.9,
123.7, 122.9, 122.7, 116.7, 116.5, 116.5, 116.5, 116.2, 115.7,
115.4, 107.5, 103.7, 101.2, 100.2, 98.9, 98.9, 45.1, 42.3, 39.8, 34.8,
34.1, 30.0, 28.2, 27.8, 26.8; m/z (EI) 342 (44, [M]+), 299 (100),
285 (16), 187 (24), 121 (39), 92 (13), 43 (37%); HRMS (EI): MH+,
found 342.0668 C19H15O4Cl required 342.0659.
4.2.5. (S)-4-Hydroxy-3-[1-(2-methoxyphenyl)-3-oxobutyl]-chromen-2-one 3e12a
The compound was isolated as a yellow solid The enantiomeric
for sample with 70% ee (S): [a]D24 = 19.5 (c 1.0, acetonitrile),
{Lit.12a [a]D25 = +52.0 (c 0.2, acetonitrile), 89% ee (R)}; IR (KBr)
3373 (br), 3034, 2935, 2838, 1681, 1619, 1571, 1492, 1394, 1063,
748 cm 1; 1H NMR (600 MHz CDCl3): d = 9.13 (0.9H, br s, OH, keto),
7.907.87 (2.7H, ArH), 7.79 (0.9H, dd, J 7.9, 1.3 Hz, ArH), 7.68 (1.0H,
dd, J 7.8, 1.3 Hz, ArH), 7.557.52 (2.0H, m, ArH), 7.34 (1.8H, d, J
8.2 Hz, ArH), 7.487.43 (2.0H, m, ArH), 7.317.23 (2H, m, ArH),
7.267.17 (9.0H, m, ArH), 7. 05 (2.0H, d, J 7.7 Hz, ArH), 7.016.98
(2H, m, ArH), 6.93 (2.0H, d, J 8.2 Hz, ArH), 6.896.82 (5H, m,
ArH), 4.95 (1.0H, dd, J 8.5, 5.4 Hz, CH, keto), 4.52 (2.0H, m, CH,
ketal), 3.92 (3.0H, s, OCH3, keto), 3.89 (6.0H, s, OCH3, ketal), 3.82
(1.0H, m, CH2, keto), 3.51 (1.7H, br s, OH, ketal), 3.45 (1.0H, br s,
OH, ketal), 2.63 (2.0H, dd, J 14.5, 2.0 Hz, CH2, ketal), 2.47 (1.0H,
dd, J 13.8, 6.9, CH2, keto), 2.28 (2.0H, dd, J 14.5, 7.2 Hz, CH2, ketal),
2.17 (3H, s, CH3, keto), 1.67 (3.0H, s, CH3, ketal), 1.65 (3.0H, s, CH3,
ketal); 13C NMR (150 MHz, CDCl3): d = 162.2, 161.9, 161.2, 160.9,
159.8, 157.1, 156.8, 155.2, 152.93, 152.8, 152.6, 131.8, 131.5,
131.3, 129.1, 128.8, 128.7, 127.9, 127.5, 126.3, 123.8, 123.7,
123.6, 123.5, 123.0, 122.6, 121.7, 121.0, 120.7, 116.6, 116.4,
116.3, 116.0, 115.6, 111.2, 110.9, 110.7, 106.2, 101.2, 100.7, 99.2,
56.2, 55.5, 55.3, 45.3, 36.9, 30.2, 29.1, 28.2, 28.1; m/z (EI) 338
(58, [M]+), 295 (100), 249 (28), 175 (83), 121 (56), 43 (35%); HRMS
(EI): MH+, found 338.1152 C20H18O5 required 338.1154.
4.2.6. (S)-4-Hydroxy-3-[1-(4-methoxyphenyl)-3-oxobutyl]-chromen-2-one 3f10,12a
The compound was isolated as a yellow solid. The enantiomeric
for sample with 71% ee (S): [a]D25 = +4.3 (c 1.0, acetonitrile), {Lit.12a
[a]D24 = 8.7 (c 0.37, acetonitrile), 87% ee (R)}; IR (KBr) 3387 (br),
2987, 2937, 2837, 1683, 1608, 1512, 1377, 1250, 1070, 764 cm 1;
1
H NMR (600 MHz CDCl3): d = 9.48 (0.3H, br s, OH, keto), 7.91
(0.3H, dd, J 8.0, 1.3 Hz, ArH), 7.88 (0.9H, dd, J 8.0, 1.3 Hz, ArH),
7.78 (0.9H, dd, J 7.8, 1.5 Hz, ArH), 7.54 (1.0H, m, ArH), 7.487.44
(1.4H, m, ArH), 7.337.27 (2H, m, ArH), 7.237.19 (3.7H, m, ArH),
7.17 (2H, m, ArH), 7.137.11 (2H, m, ArH), 6.856.78 (4.4H, m,
ArH), 4.64 (0.3H, dd, J 10.0, 2.6 Hz, CH, keto), 4.22 (1.0H, dd, J 7.0,
3.0 Hz, CH, ketal), 4.11 (1.0H, dd, J 11.3, 7.0 Hz, CH, ketal), 3.81
(0.6H, dd, J 19.0, 10.0 Hz, CH2, keto), 3.76 (0.9H, s, OCH3, keto),
818

M. Rogozin
3.75 (6H, s, OCH3, ketal), 3.51 (1H, br s, OH, ketal), 3.33 (1H, br s,
OH, ketal),2.50 (1.0H, dd, J 14.0, 3.0 Hz, CH2, ketal), 2.43 (1H, dd,
J 14.0, 7.0 Hz, CH2, ketal), 2.36 (1.0H, dd, J 14.0, 7.0 Hz, CH2, ketal),
2.26 (0.9H, s, CH3, keto), 1.98 (1H, dd, J 14.0, 11.0 Hz, CH2, ketal),
1.69 (3H, s, CH3, ketal), 1.66 (3.0H, s, CH3, ketal); 13C NMR
(150 MHz, CDCl3): d = 162.1, 161.3, 159.5, 158.7, 158.6, 158.1,
153.0, 152.9, 135.1, 133.0, 131.9, 131.5, 129.1, 128.0, 123.9,
123.6, 123.0, 122.7, 116.7, 116.5, 115.9, 115.6, 114.7, 114.0,
113.6, 104.4, 101.3, 100.5, 99.0, 99.0, 55.2, 55.2, 42.6, 39.8, 34.5,
33.2, 28.2, 27.8; m/z (EI) 338 (60, [M]+), 295 (100), 281 (38), 187
(51), 121 (37), 43 (24%), HRMS (EI): MH+, found 338.1154
C20H18O5 required 338.1154.
4.2.7. (S)-4-Hydroxy-3-[1-(2-nitrophenyl)-3-oxobutyl]-chromen2-one 3g
The compound was isolated as a light yellow solid. The enantiomeric excess was determined by HPLC analysis of the puried
product with an Daicel OD-H column (hexane/i-PrOH, 4:1),
0.5 mL min 1, k = 220 nm): tR = 21,5 min (minor) and tS = 34.2 min
(major). Data for sample with 66% ee (S): [a]D25 = +74.5 (c 1.0, acetonitrile); IR (KBr) 3336 (br), 3073, 2938, 2868, 1687, 1622, 1572,
1526, 1384, 1176, 1079, 760 cm 1; 1H NMR (600 MHz CDCl3):
d = 9.66 (0.3H, s, OH, keto), 8.05 (0.3H, dd, J 8.3, 1.3 Hz, ArH),
7.98 (2.0H, dd, J 8.2, 1.0 Hz, ArH), 7.86 (2.0H, dd, J 8.2 1.5 Hz,
ArH), 7.80 (1.4H, d, J 7.6 Hz, ArH), 7. 69 (1.0H, dd, J 8.2, 1.3 Hz,
ArH), 7.567.52 (1.0H, m, ArH), 7.517.36 (5.0H, m, ArH), 7.34
7.28 (4.6H, m, ArH), 7.277.18 (5.0H, m, ArH), 5.27 (0.3H, dd, J
8.0 5.1 Hz, CH, keto), 4.77 (2.0H, dd, J 7.6, 4.1 Hz, CH, ketal), 3.70
3.49 (0.3H, dd, J 19.1, 5.1 Hz, CH2, keto), 3.34 (1.0H, br s, OH, ketal),
2.53 (1.0H, dd, J 14.5, 7.7 Hz, CH2, ketal), 2.41 (1.0H, dd, J = 14.5,
4.2 Hz, CH2, ketal), 2.20 (0.9H, s, CH3, keto), 1.991.85 (1.0H, m,
CH2, ketal), 1.78 (4.0H, s, CH3, ketal), 1.68 (3.0H, s, CH3, ketal);
13
C NMR (150 MHz, CDCl3): d = 161.7, 161.1, 160.1, 159.5, 152.9,
152.8, 149.7, 148.9, 138.5, 137.8, 137.7, 135.2, 133.0, 132.8,
132.8, 132.3, 132.1, 131.8, 131.4, 130.1, 129.9, 128.9, 128.4,
128.1, 127.9, 127.4, 127.2, 126.0, 125.1, 124.6, 124.4, 124.2,
124.0, 123.8, 122.9, 122.8, 116.7, 116.5, 116.1, 115.9, 115.7,
115.5, 104.7, 103.7, 101.7, 100.4, 99.1, 47.2, 40.8, 38.8, 31.8, 31.7,
30.7, 30.3, 29.8, 29.0, 28.2, 27.7; m/z (EI) 353 (3, [M]+), 293 (35),
276 (38), 264 (35), 248 (27), 215 (60), 198 (18), 156 (21), 121
(100), 92 (20), 43 (56%); HRMS (EI): MH+, found 353.0906
C19H15NO6 required 353.0899.
4.2.8. (S)-4-Hydroxy-3-[1-(4-nitrophenyl)-3-oxobutyl]-chromen2-one 3h10,11b,13
{Lit.13 [a]D25 = +1.8 (c 1.0, dichloromethane), 91% ee (R)}; IR (KBr)
3326 (br), 3076, 2934, 2852, 1688, 1619, 1515, 1346, 1068,
8.168.13 (2.0H, m, ArH), 8.128.10 (1.4H, m, ArH), 7.96 (0.2H,
dd, J 7.9, 1.6 Hz, ArH), 7.86 (0.6H, dd, J 7.9, 1.5 Hz, ArH), 7.80
(1.0H, dd, J 7.9, 1.5 Hz, ArH), 7.57 (0.6H, ddd, J 8.7, 7.5, 1.6 Hz,
ArH), 7.537.50 (1.2H, m, ArH), 7.467.44 (0.4H, m, ArH), 7.40
7.21 (6.0H, m, ArH), 4.73 (0.2H, dd, J 10.5, 1.9 Hz, CH, keto), 4.26
(1.6H, m, CH, ketal), 3.88 (0.2H, dd, J 19.3, 10.5 Hz, CH2, keto),
3.38 (0.8H, s, OH, ketal), 3.33 (0.2H, dd, J 19.3, 2.0 Hz, CH2, keto),
3.01 (0.5H, s, OH, ketal), 2.46 (1.6H, m, CH2, ketal), 2.40 (0.6H, s,
CH3, keto), 1.941.89 (1.1H, m, CH2, ketal), 1.77 (3.0H, s, CH3,
ketal), 1.72 (2.0H, s, CH3, ketal); 13C NMR (150 MHz, CDCl3):
d = 161.9, 161.2, 159.8, 159.3, 152.9, 152.9, 151.3, 150.4, 146.7,
146.5, 132.3, 132.0, 128.9, 128.4, 127.9, 124.1, 124.0, 123.8,
123.6, 123.2, 122.9, 122.7, 116.8, 116.6, 116.3, 115.5, 115.3,

103.0, 100.9, 99.8, 98.7, 41.8, 39.3, 35.4, 34.9, 34.8, 30.0, 28.3,
28.1; m/z (EI) 353 (41, [M]+), 310 (100), 249 (11), 121 (41), 92
(12), 43 (22%); HRMS (EI): MH+, found 353.0912 C19H15NO6
required 353.0899.
4.2.9. (S)-4-Hydroxy-3-[1-(2-methylphenyl)-3-oxobutyl]-chromen-2-one 3i
for sample with 76% ee (S): [a]D23 = +3.8 (c 2.0, acetonitrile); IR
(KBr) 3377 (br), 3080, 2961, 2926, 2871, 1712, 1681, 1615, 1569,
1492, 1385, 1046, 757 cm 1; 1H NMR (600 MHz CDCl3): d = 9.53
(0.2H, s, OH, keto), 7.93 (0.2H, dd, J 7.9, 1.6, ArH), 7.90 (0.5H, dd,
J 7.9, 1.5, ArH), 7.78 (0.9H, dd, J 8.2, 1.5, ArH), 7.587.53 (0.7H,
m, ArH), 7.497.42 (1.2H, m, ArH), 7.337.30 (1.0H, m, ArH),
7.267.16 (3.6H, m, ArH), 7.167.11 (2.0H, m, ArH), 7.107.06
(3.2H, m, ArH), 6.97 (1H, d, J 7.2, ArH), 4.61 (0.2H, dd, J 10.6, 2.2,
CH, keto), 4.404.35 (1.4H, m, CH, ketal), 3.93 (0.2H, dd, J 19.3,
10.6, CH2, keto), 3.60 (0.7HH, s, OH, ketal), 3.47 (0.7H, s, OH, ketal),
3.23 (0.2H, dd, J 19.3, 2.2, CH2, keto), 2.48 (3.0H, s, Ar-CH3, ketal),
2.452.42 (1.4H, m, CH2, ketal), 2.392.30 (1.4H, m, CH2, ketal),
2.28 (0.7H, s, Ar-CH3, keto) 2.15 (0.7H, s, CH3, keto), 1.71 (3.0H, s,
CH3, ketal), 1.66 (2.0H, s, CH3, ketal); 13C NMR (150 MHz, CDCl3):
d = 161.9, 161.1, 159.7, 158.6, 152.9, 152.8, 141.4, 139.4, 136.0,
135.6, 131.9, 131.7, 131.7, 131.3, 130.5, 130.3, 129.1, 127.3,
126.9, 126.6, 126.3, 126.2, 125.6, 125.0, 123.8, 123.7, 123.5,
122.9, 122.5, 116.6, 116.4, 116.2, 115.9, 115.5, 105.1, 101.8,
100.5, 98.9, 46.3, 40.8, 37.8, 32.3, 31.8, 31.7, 29.9, 28.2, 27.8; m/z
(EI) 322 (32, [M]+), 279 (100), 265 (11), 249 (11), 187 (39), 121
(34), 115 (19), 65 (10), 44 (41%); HRMS (EI): MH+, found
322.1204 C20H18O4 required 322.1205.
4.2.10. (S)-4-Hydroxy-3-[1-(3-methylphenyl)-3-oxobutyl]-chromen-2-one 3j12a
for sample with 74% ee (S): [a]D23 = 9.4 (c 1.0, acetonitrile), {Lit.12a
[a]D24 = +6.1 (c 0.39, acetonitrile), 87% ee (R)}; IR (KBr) 3299 (br),
2985, 2960, 2933, 1721, 1689, 1625, 1575, 1495, 1380, 1073,
7.93 (0.3H, dd, J 7.9, 1.6, ArH), 7.89 (0.9H, dd, J 7.9, 1.5, ArH),
7.78 (1.0H, dd, J 7.8, 1.5, ArH), 7.577.53 (1.0H, m, ArH), 7.50
7.43 (1.4H, m, ArH), 7.347.29 (2.0H, m, ArH), 7.277.14 (6.0H,
m, ArH), 7.077.00 (7.0H, m, ArH), 4.66 (0.3H, dd, J 10.0, 2.5, CH,
keto), 4.24 (1.0H, dd, J 6.9, 3.2, CH, ketal), 4.12 (1.0H, dd, J 11.4,
6.9, CH, ketal), 3.81 (0.3H, dd, J 19.3, 10.0, CH2, keto), 3.63 (1.0H,
s, OH, ketal), 3.38 (1.0H, s, OH, ketal), 3.29 (0.3H, dd, J 19.3, 2.5,
CH2, keto), 2.52 (1.0H, dd, J 14.2, 3.2, CH2, ketal), 2.44 (1.0H, dd, J
14.2, 6.9, CH2, ketal), 2.37 (1.0H, dd, J 14.2, 6.9, CH2, ketal), 2.29
(7.0H, s, Ar-CH3, ketal, keto), 2.27 (0.9H, s, CH3, keto), 1.97 (1.0H,
dd, J 14.1, 11.4, CH2, ketal), 1.68 (3.0H, s, CH3, ketal), 1.67 (4.0H,
s, CH3, ketal); 13C NMR (150 MHz, CDCl3): d = 162.2, 161.3, 160.9,
159.6, 158.7, 152.9, 152.8, 152.7, 143.1, 141.2, 139.6, 139.0,
138.1, 137.7, 131.9, 131.7, 131.4, 129.2, 128.7, 128.5, 128.2,
128.0, 127.7, 127.6, 127.5, 127.3, 126.0, 124.9, 124.1, 123.9,
123.8, 123.5, 123.1, 122.7, 116.6, 116.6, 116.5, 116.4, 116.2,
115.9, 115.5, 107.9, 104.2, 101.1, 100.6, 99.0, 98.9, 45.2, 42.6,
39.9, 35.4, 35.2, 34.8, 33.9, 30.0, 28.1, 28.0; m/z (EI) 322 (36,
[M]+), 279 (100), 265 (10), 187 (20), 121 (19), 43 (12%); HRMS
(EI): MH+, found 322.1202 C20H18O4 required 322.1205.

M. Rogozin
4.2.11. (S)-4-Hydroxy-3-(1-naphthalen-2-yl-3-oxobutyl)-chromen-2-one 3k10,12a

{Lit.12a [a]D26 = 9.8 (c 0.61, acetonitrile), 83% ee (R)}; IR (KBr)
3321 (br), 3050, 2931, 1717, 1686, 1621, 1572, 1492, 1381, 1072,
7.947.91 (1.2H, m, ArH), 7.837.81 (2.0H, m, ArH), 7.787.73
(5.5H, m, ArH), 7.717.64 (3.4H, m, ArH), 7.597.56 (1.0H, m,
ArH), 7.497.46 (1.5H, m, ArH), 7.437.30 (9.0H, m, ArH), 7.27
7.20 (3.5H, m, ArH), 4.85 (0.3H, dd, J 9.8, 2.2 Hz, CH, keto), 4.41
(1.0H, dd, J 6.9, 3.1 Hz, CH, ketal), 4.32 (1.2H, dd, J 11.3, 6.9 Hz,
CH, ketal), 3.94 (0.3H, dd, J 19.2, 9.8 Hz, CH2, keto), 3.60 (1.0H, s,
OH, ketal), 3.42 (0.3H, dd, J 19.2, 2.2 Hz, CH2, keto), 3.37 (1.1H, s,
OH, ketal), 2.61 (1.0H, dd, J 14.2, 3.2 Hz, CH2, ketal), 2.47 (1.0H,
dd, J 14.1, 6.7 Hz, CH2, ketal), 2.43 (1.0H, dd, J 14.2, 6.9 Hz, CH2,
ketal), 2.31 (0.9H, s, CH3, keto), 2.072.03 (1.3H, m, CH2, ketal),
1.66 (6.0H, s, CH3, ketal); 13C NMR (150 MHz, CDCl3): d = 162.2,
161.3, 159.8, 158.9, 153.0, 152.9, 140.6, 138.9, 133.6, 133.5,
132.6, 132.4, 132.0, 131.8, 131.6, 129.2, 128.3, 127.8, 127.6,
127.5, 126.5, 126.3, 126.0, 125.9, 125.7, 125.6, 125.3, 125.2,
124.9, 123.9, 123.6, 123.1, 122.7, 116.7, 116.5, 116.2, 115.9,
115.6, 104.0, 101.1, 100.6, 99.0, 45.2, 42.4, 39.6, 35.4, 35.1, 34.4,
30.1, 28.1, 27.7, 26.9; m/z (EI) 358 (63, [M]+), 315 (100), 299 (19),
187 (39), 152 (21) 121 (27), 43 (19%); HRMS (EI): MH+, found
358.1212 C23H18O4 required 358.1205.
4.2.12. (R)-4-Hydroxy-3-(2-oxooctan-4-yl)-chromen-2-one 3l10
The compound was isolated as a colourless oil, but solidied
upon standing. The enantiomeric excess was determined by HPLC
analysis of the puried product with an Daicel AD-H column (hexane/i-PrOH, 9:1), 1.0 mL min 1, k = 254 nm): tS = 8.9 min (minor)
and tR = 15.4 min (major). Data for sample with 74% ee (R):
[a]D24 = 32.5 (c 0.65, acetonitrile); IR (liquid lm) 3374 (br),
2958, 2929, 2861, 1710, 1684, 1619, 1572, 1493, 1393,
1108 cm 1; 1H NMR (600 MHz CDCl3): d = 9.56 (1.8H, br s, OH,
keto), 7.90 (2.0H, dd, J 7.9, 1.5 Hz, ArH), 7.74 (1.5H, ddd, J 13.2,
7.9, 1.5 Hz, ArH), 7.527.41 (3.7H, m, ArH), 7.287.17 (8.0H, m,
ArH), 3.35 (3.0H, dd, J 19.9, 10.5 Hz, CH2, keto), 3.18 (3.0H, dd, J
16.4, 8.2, CH, keto), 3.002.93 (1.0H, m, CH, ketal), 2.80 (1.0H,
ddd, J 14.3, 7.1, 3.6 Hz, CH, ketal), 2.75 (2.0H, d, J 19.9 Hz, CH2,
keto), 2.31 (1.0H, dd, J 13.8, 7.0 Hz, CH2, ketal), 2.272.21 (1.0H,
m, CH2, ketal), 2.272.21 (1.0H, m), 2.18 (6.6H, s, CH3, keto),
2.162.08 (2.6H, m), 2.041.97 (1.0H, m), 1.93 (1.0H, dd, J 14.2,
6.9 Hz, CH2, ketal), 1.76 (3.0H, s, CH3, ketal), 1.811.72 (2.0H, m),
1.70 (2.3H, s, CH3, ketal), 1.651.51 (1.0H, m, CH2, ketal), 1.65
1.51 (3.0H, m), 1.491.42 (1.0H, m), 1.411.29 (4.3H, m), 1.29
1.21 (7.5H, m), 1.161.09 (5.0H, m), 0.89 (5.2H, dt, J 12.5, 7.1 Hz,
CH3, n-Bu-ketal), 0.82 (7.0H, t, J 7.3 Hz, CH3, n-Bu-keto); 13C NMR
(150 MHz, CDCl3): d = 213.9, 162.5, 161.8, 161.7, 157.9, 157.3,
152.7, 152.5, 131.5, 131.2, 131.2, 123.8, 123.7, 123.6, 123.5,
122.6, 122.5, 116.6, 116.4, 116.2, 116.1, 116.0, 115.8, 107.0,
105.3, 105.1, 99.9, 98.8, 47.9, 37.9, 34.0, 31.1, 30.9, 30.8, 30.5,
30.3, 29.7, 29.3, 28.7, 28.4, 28.1, 22.8, 22.6, 22.4, 14.1, 13.9; m/z
(EI) 288 (27, [M]+), 245 (64), 231 (66), 203 (15), 189 (100), 175
(69), 121 (56), 43 (31%), HRMS (EI): MH+, found 288.3503
C17H20O4 required 288.3508.
4.2.13. (S)-4-Hydroxy-3-(2-methyl-5-oxohexan-3-yl)-2-chromen-2-one 3m10,12a
The compound was isolated as a colourless oil, but solidied
upon standing. The enantiomeric excess was determined by HPLC
analysis of the puried product with an Daicel AD-H column
819
(hexane/i-PrOH, 9:1), 1.0 mL min 1, k = 254 nm): tR = 7.8 min

(minor) and tS = 15.8 min (major). Data for sample with 72% ee
(S): [a]D24 = 72.1 (c 2.0, acetonitrile), {Lit.12a [a]D21 = +48.7 (c
0.5, acetonitrile), 57% ee (R)}; IR (KBr) 3383 (br), 3080, 2963,
2871, 1712, 1681, 1615, 1569, 1492, 1384, 1077, 757 cm 1; 1H
NMR (600 MHz CDCl3): d = 9.48 (0.7H, s, OH, keto), 7.90 (0.9H,
dd, J 7.8, 1.1 Hz, ArH), 7.73 (0.3H, dd, J 7.9, 1.5 Hz, ArH), 7.51
7.41 (1.4H, m, ArH), 7.307.17 (3.0H, m, ArH), 3.29 (1.2H, dd, J
20.0, 10.2 Hz, CH2, keto), 3.25 (0.4H, m, CH, ketal), 3.072.97
(0.5H, m, CH, ketal), 2.94 (1.0H, d, J 20.0 Hz, CH2, keto), 2.74
(1.0H, t, J 9.9 Hz, CH, keto), 2.612.48 (1.0H, m, CH, i-Pr-keto),
2.18 (3.0H, s, CH3, keto), 2.12 (0.4H, dd, J 13.8, 7.1 Hz, CH2, ketal),
2.02 (0.8H, m, CH2, ketal), 1.79 (0.4H, m, CH2, ketal), 1.79 (1.2H,
s, CH3, ketal), 1.56 (0.4H, m, CH, i-Pr-ketal), 0.99 (1.2H, d, J
7.0 Hz, CH3, i-Pr-ketal), 0.97 (3.0H, d, J 6.5 Hz, CH3, i-Pr-keto),
0.74 (3.0H, d, J 6.5 Hz, CH3, i-Pr-keto), 0.65 (1.2H, d, J 7.0 Hz, CH3,
i-Pr-ketal); 13C NMR (150 MHz, CDCl3): d = 214.2, 161.7, 161.6,
158.6, 152.7, 152.6, 131.5, 131.4, 131.2, 123.8, 123.7, 123.6,
123.5, 122.7, 122.6, 116.5, 116.3, 116.2, 116.1, 116.0, 107.6,
104.9, 101.6, 98.9, 45.6, 38.5, 33.3, 33.1, 31.2, 29.9, 28.7, 27.1,
25.4, 25.3, 21.7, 21.5, 21.0, 20.6, 20.3, 16.9, 15.7; m/z (EI) 231
(29), 217 (40), 102 (100), 121 (29), 43 (16%), HRMS (EI): MH+,
found 274.1207 C16H18O4 requires 274.1205
Acknowledgments
This project was operated within the Foundation for Polish Science TEAM Programmes co-nanced by the EU European Regional
Development Fund. Financial support from the Polish National Science Centre (grant number NCN 2011/03/B/ST5/03126) is gratefully acknowledged.
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Tetrahedron: Asymmetry 25 (2014) 813820

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Asymmetric synthesis of warfarin and its analogues on water

last few decades. Recently some organocatalytic procedures for

Scheme 1. Asymmetric synthesis of warfarin by the Michael addition of 4hydroxycoumarin to benzylideneacetone.

As one of the most effective anticoagulants, warfarin has been

ska-Szymczak, J. Mlynarski / Tetrahedron: Asymmetry 25 (2014) 813820

However, some catalysts seemed to be superior to others resulting

formation of warfarin in various yields ranging from 22% to almost

2. Results and discussion

Scheme 2. Chiral primary amines tested in Michael reaction.

ska-Szymczak, J. Mlynarski / Tetrahedron: Asymmetry 25 (2014) 813820

To further improve the reaction enantioselectivity, the effect of

AcOH (20 mol %)

and after one crystallisation from hexane, gave enantiomerically

ska-Szymczak, J. Mlynarski / Tetrahedron: Asymmetry 25 (2014) 813820

4.2. General procedure for the organocatalytic Michael reaction

recorded on a Fourier transform infrared (FT-IR) spectrometer. 1H

enantioselectivities were observed for all sets of substrates proving

ska-Szymczak, J. Mlynarski / Tetrahedron: Asymmetry 25 (2014) 813820

4.2.2. (R)-3-[1-(2-Chlorophenyl)-3-oxobutyl]-4-hydroxy-chromen-2-one 3b12a

ska-Szymczak, J. Mlynarski / Tetrahedron: Asymmetry 25 (2014) 813820

123.6, 123.2, 122.9, 122.7, 116.8, 116.6, 116.3, 115.5, 115.3,

ska-Szymczak, J. Mlynarski / Tetrahedron: Asymmetry 25 (2014) 813820

4.2.11. (S)-4-Hydroxy-3-(1-naphthalen-2-yl-3-oxobutyl)-chromen-2-one 3k10,12a

(hexane/i-PrOH, 9:1), 1.0 mL min 1, k = 254 nm): tR = 7.8 min

ska-Szymczak, J. Mlynarski / Tetrahedron: Asymmetry 25 (2014) 813820

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