Asymmetric synthesis of warfarin and its analogues on water

Article abstract of DOI:10.1016/j.tetasy.2014.04.008

The asymmetric Michael addition of 4-hydroxycoumarin to α,β-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 (73-98%) and with good enantioselectivities (up to 76% ee) via reactions accelerated by ultrasound. In particular, our developments led to an efficient 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.

Full text of DOI:10.1016/j.tetasy.2014.04.008

Tetrahedron: Asymmetry 25 (2014) 813–820
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric synthesis of warfarin and its analogues on water
a
a,b,
⇑
´
Maria Rogozinska-Szymczak , Jacek Mlynarski
a Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
b Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
The asymmetric Michael addition of 4-hydroxycoumarin to
a,b-unsaturated ketones on water without
Received 25 February 2014
Accepted 16 April 2014
Available online 28 May 2014
organic co-solvents is reported to be catalysed by organic primary amines. The application of enantiome-
rically pure (S,S)-diphenylethylenediamine affords a series of important pharmaceutically active com-
pounds in good to excellent yields (73–98%) and with good enantioselectivities (up to 76% ee) via
reactions accelerated by ultrasound. In particular, our developments led to an efficient protocol for the
‘solids on water’ formation of the anticoagulant warfarin in both enantiomeric forms. The presented scal-
able and environmentally friendly organocatalytic approach affords the target drug in enantiomerically
pure form.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
last few decades. Recently some organocatalytic procedures for
the synthesis of drug-like scaffolds have been recorded. One suc-
The conjugate addition of enolates to
a
,b-unsaturated acceptors
cessful and instructive example is the straightforward production
of chiral warfarin via the well-established Michael addition of
4-hydroxycoumarin to benzylideneacetone (Scheme 1).
(Michael reaction) is one of the most important carbon–carbon
bond-forming reactions in organic synthesis.1 This reaction can
be controlled by chiral catalysts resulting in a formation of enanti-
omerically pure Michael adducts. For this reason there is a contin-
uing need for the development of enantioselective catalytic
protocols leading to the asymmetric synthesis of drugs and bioac-
tive compounds by means of conjugate Michael additions.2
Since the beginning of this century, asymmetric organocataly-
sis3 has emerged as a parallel and more environmentally accept-
able 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 pre-
sented to be an enabling technology for the efficient synthesis of
the drug and several biologically relevant molecules.6 Recent
achievements in chemical efficiency have also focused on the eco-
nomic 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 efficient organocatalysts for asymmetric reactions in pure
water.8
OH
O
Ph
O
OH
O
chiral amine
solvent
Ph
+
2
O
O
O
3
1
(S)-warfarin
Scheme 1. Asymmetric synthesis of warfarin by the Michael addition of 4-
hydroxycoumarin to benzylideneacetone.
As one of the most effective anticoagulants, warfarin has been
introduced for clinical use (warfarinÒ, jantovenÒ, uniwarfinÒ,
coumadinÒ, marevanÒ) 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.
The use of asymmetric Michael reactions to generate biologi-
cally relevant molecules has been actively investigated over the
In 2003, Jørgensen reported the first one-step synthesis of enan-
tiomerically enriched warfarin from simple materials catalysed by
secondary amine catalysts.10 Primary11 and secondary12 amino-
acid based amines have also been shown to be efficient in this
asymmetric procedure. Usually 20 mol % catalyst loading was
needed for the long reaction carried out in organic solvents.
⇑
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/Ó 2014 Elsevier Ltd. All rights reserved.

´
814
M. Rogozinska-Szymczak, J. Mlynarski / Tetrahedron: Asymmetry 25 (2014) 813–820
Table 1
However, some catalysts seemed to be superior to others resulting
in the formation of the adduct in good to excellent enantioselectiv-
ities,11b,12b even with small catalyst loading (5 mol %).13
Initial catalyst screeninga
Entry
Catalyst
Yield (%)b
ee (%)c
Applied catalysts have been derived from amino acids or cin-
chona 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 for-
mation of (R)-warfarin in 94% yield after 48 h (ca. 80% ee).14
Recently, the efficiency 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 sol-
vents has so far been unsuccessful.16
Despite the significant advances in this field, the synthesis of
optically active warfarin and its analogues represent a considerable
synthetic challenge. Moreover, it is still desirable to develop envi-
ronmentally 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
1
2
3
4
5
6
7
9
4
5
6
7
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
8
9 (S,S)
10 (R,R)
11
12
13
10
11
12
14
a
The reaction was performed by employing 1 (0.50 mmol), 2 (0.60 mmol), cat-
alyst (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.
Ee’s were determined by HPLC analysis on a chiral phase (Daicel AD-H column).
c
formation of warfarin in various yields ranging from 22% to almost
the quantitative formation of the adduct (98%). The most promis-
ing 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)-config-
ured 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 applica-
tion of other tested amines in terms of efficiency and stereoselec-
tivity. Another promising catalyst was diaminocyclohexane 11 but
the observed yield was worse when compared to the best catalyst
9. The reaction catalysed by structurally modified amines 12–14
gave poor to moderate enantioselectivities only (Table 1, entries
10–12).
After (S,S)-catalyst 9 was identified 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 war-
farin in similar yields and stereoselectivities (Table 2, entries 1 and
2). Increasing the amount of water led to no change in reaction effi-
ciency (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 first examined the reaction of
4-hydroxycoumarin 1 to a,b-unsaturated ketone 2 leading to war-
farin 3. This model Michael addition reaction was investigated
using a series of primary amine organocatalysts 4–14 (Scheme 2).
By using readily available primary amines 4–11 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 12–1418 for test reactions in an aqueous
environment.
In order to assess the efficiency 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
NH2
NH2
NH2
4
5
6
NH2
OH
NH2
OH
NH2
NH2
NH2
NH2
NH2
NH2
7
8
9
10
11
NH2
NH2
N
NH2
N
N
12
13
Scheme 2. Chiral primary amines tested in Michael reaction.
14

´
815
M. Rogozinska-Szymczak, J. Mlynarski / Tetrahedron: Asymmetry 25 (2014) 813–820
Table 2
Table 4
Temperature and reaction timea
Acid additives screeninga
Entry
Catalyst (mol %)
Solvent
Yield (%)b
ee (%)c
Entry
Additive
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
10
10
5
10
10
10
10
THF
89
98
88
94
8
62
55
60
62
62
62d
55e
1
2
3
AcOH
CF3COOH
98
68
25
68
44
7
THF/H2O (9:1)
THF/H2O (9:1)
THF/H2O (1:1)
H2O
THF/H2O (9:1)
THF/H2O (9:1)
D
-Camphorosulfonic acid
HCl
-Tartaric acid
4
5
42
16
39
24 (R)
L
98
98
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
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
60
65
Isolated yield after silica gel chromatography.
Ee’s were determined by HPLC analysis on a chiral phase (Daicel AD-H column).
The reaction was performed by employing 1 (0.50 mmol), 2 (0.60 mmol), cat-
c
d
58
64f
alyst 9 and solvent (1 mL) at 40 °C for 20 h.
The reaction was performed by employing 1 (0.50 mmol), 2 (0.60 mmol), cat-
alyst 9 and solvent (1 mL) at 60 °C for 12 h.
67 (S)f
68 (R)g
e
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
(62% ee) encouraged us to exclude organic solvents from the reac-
tion 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 bet-
ter yields.
(1 mL) at rt for 10 h in an ultrasound bath.
b
Isolated yield after silica gel chromatography.
Ee’s were determined by HPLC analysis on a chiral phase (Daicel AD-H column).
The reaction was performed by employing 1 (0.50 mmol), 2 (0.60 mmol), (S,S)-
c
d
catalyst 9 (0.025 mmol, 5 mol %), acid as additive (0.05 mmol, 10 mol %) and water
(1 mL) at rt for 10 h in an ultrasound bath.
By using a green chemistry protocol and pure water as the sol-
vent the reaction achieved good enantioselectivity, but careful for-
aging 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. Reac-
tion ‘on water’ efficiency depends on appropriate contact between
the reactants; intense mechanical stirring was not efficient 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 pro-
cesses.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).
e
The reaction was performed by employing 1 (0.50 mmol), 2 (0.60 mmol), (S,S)-
catalyst 9 (0.01 mmol, 2 mol %), acid as additive (0.02 mmol, 4 mol %) and water
(1 mL) at rt for 10 h in an ultrasound bath.
f
The reaction was performed by employing 1 (5.0 mmol), 2 (6.0 mmol), (S,S)-
catalyst 9 (0.50 mmol, 10 mol %), acid as additive (1.0 mmol, 20 mol %) and water
(10 mL) at rt for 10 h in an ultrasound bath.
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
(10 mL) at rt for 10 h in an ultrasound bath.
Table 5
Reaction on water on a 2 g scale accelerated by ultrasound and crystallisation from
hexanea
Entry
Catalyst
Additive
Yield (%)b
ee (%)c
1
2
3
4
10 mol %
2 mol %
2 mol %
5 mol %
AcOH (20 mol %)
AcOH (4 mol %)
PhCOOH (4 mol %)
PhCOOH (10 mol %)
61
52
50
55
>99
>99
>99
>99
Table 3
a
Reaction on water accelerated by ultrasounda
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.
Entry
Catalyst
Yield (%)b
ee (%)c
b
Isolated yield after one crystallisation from hexane.
Ee’s were determined by HPLC analysis on a chiral phase (Daicel AD-H column)
c
1
2
3
9 (10 mol %)
10 (10 mol %)
11 (10 mol %)
92
90
70
60
56 (R)
29
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 appli-
cation of a small amount of hexane instead of chromatography elu-
ents 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 efficiency. Both the yield and selectivity of the each
reaction after the first, second and third run are shown in Table 6.
After the reaction, the aqueous phase was separated by filtration
and another portion of the reactants allowed us to obtain a Michael
product 3.
a
The reaction was performed by employing 1 (0.50 mmol), 2 (0.60 mmol), cat-
alyst (10 mol %) and water (1 mL) at rt for 10 h in an ultrasound bath.
b
Isolated yield after silica gel chromatography.
Ee’s were determined by HPLC analysis on a chiral phase (Daicel AD-H column).
c
To further improve the reaction enantioselectivity, the effect of
acid additives and catalyst loading was investigated. As summa-
rised in Table 4, various acid additives showed some beneficial
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 13–15) showed that this protocol could be
useful for the practical synthesis of a Michael adduct.
With the optimal reaction conditions in hand, we next exam-
ined 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 1–11) or
aliphatic substituents (entries 12–13). High yields and satisfactory
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 filtration,

´
M. Rogozinska-Szymczak, J. Mlynarski / Tetrahedron: Asymmetry 25 (2014) 813–820
816
recorded on a Fourier transform infrared (FT-IR) spectrometer. 1H
Table 6
Recycling of the catalysta
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, multi-
plicity (s = singlet, d = doublet, t = triplet, q = quartet, dd = double-
doublet, 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 ionisa-
tion time-of-flight (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 purified and dried
according to common methods. All organic solutions were dried
over anhydrous magnesium sulfate. Reaction products were puri-
fied by flash chromatography using silica gel 60 (240–400 mesh).
HPLC analysis was performed on HPLC system equipped with chi-
ral stationary phase columns, detection at 254 nm.
Entry
Yield (%)b
ee (%)c
ee (%)d
1
2
3
4
5
98
95
95
30
n.d.
74
73
74
70
—
>99
>99
>99
>99
—
a
The reaction was performed by employing 1 (0.50 mmol), 2 (0.60 mmol), cat-
alyst 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
Isolated yield after silica gel chromatography.
Ee’s were determined by HPLC analysis on a chiral phase (Daicel AD-H column).
Ee’s were determined by HPLC analysis on a chiral phase (Daicel AD-H column)
c
d
after one crystallisation from hexane.
Table 7
Extension of the developed procedure for a wide range of substratesa
OH
R
O
OH
O
4.2. General procedure for the organocatalytic Michael reaction
of unsaturated enones with cyclic 1,3-dicarbonyl compounds
chiral amine
solvent
R
+
2a-m
O
O
O
O
3a-m
A suspension of 4-hydroxycoumarin 1 (81.0 mg, 0.5 mmol), a,b-
1
unsaturated 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 purified by column chromatography
on silica gel (hexane–ethyl 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.
Entry
R
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
–Ph 3a
98
90
93
89
93
94
93
93
91
92
97
81
73
72
68
67
72
76
71
66
60
76
73
70
74
72
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
9
10
11
12
13
–iPr 3m
a
The reaction was performed by employing 1 (0.50 mmol), 2a–m (0.60 mmol),
catalyst 15 (0.05 mmol, 10 mol %), PhCOOH (0.10 mmol, 20 mol %) and water (1 mL)
4.2.1. (S)-4-Hydroxy-3-(3-oxo-1-phenylbutyl)-chromen-2-one
(warfarin) 3a10,11b,12a,17
at rt for 10 h in an ultrasound bath.
b
Isolated yield after silica gel chromatography.
Ee’s were determined by HPLC analysis on a chiral phase.
c
The compound was isolated as a white solid. The enantiomeric
excess was determined by HPLC analysis of the purified product
with an Daicel AD-H column (hexane/i-PrOH, 4:1, 1.0 mL minÀ1
,
enantioselectivities were observed for all sets of substrates proving
that the elaborated ‘on water’ protocol is general in terms of sub-
strate scope.
k = 254 nm): tR = 6.3 min (minor) and tS = 15.2 min (major). Data
for sample with 99% ee (S): [
a
]
24 = À10.7 (c 1.0, acetonitrile),
D
{Lit.11b
[a
]
D
22 = À12.0 (c 0.3, acetonitrile), 96% ee (S)}; IR (KBr)
3409, 3029, 2839, 2738, 1719, 1548, 1456, 1380, 759, 698 cmÀ1
;
1H 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),
7.34–7.18 (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.
3. Conclusion
In conclusion, we have successfully demonstrated that (S,S)-
diphenylethylenediamine is an excellent enamine organocatalyst
for enantioselective Michael addition reactions of 4-hydroxycoum-
arin 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 com-
mercial sources and used as received. Infrared (IR) spectra were

´
817
M. Rogozinska-Szymczak, J. Mlynarski / Tetrahedron: Asymmetry 25 (2014) 813–820
4.2.2. (R)-3-[1-(2-Chlorophenyl)-3-oxobutyl]-4-hydroxy-chro-
men-2-one 3b12a
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), 7.48–7.46 (1.3H, m, ArH), 7.33–7.13 (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
(0.2H, dd, J 19.3, 2.3 Hz, CH2, keto), 3.11 (0.7H, br s, OH, ketal),
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.
The compound was isolated as a white solid. The enantiomeric
excess was determined by HPLC analysis of the purified product
with an Daicel AD-H column (hexane/i-PrOH, 4:1), 1.0 mL minÀ1
,
k = 254 nm): tS = 7.2 min (minor) and tR = 11.1 min (major). Data
for sample with 68% ee (R): [
{Lit.12a 25 = +35.1 (c 0.61, acetonitrile), 79% ee (S)}; IR (KBr)
[a]
D
a
]
D
24 = À28.9 (c 1.0, acetonitrile),
3364 (br), 3066, 2969, 2933, 1689, 1621, 1570, 1492, 1382, 1072,
756 cmÀ1 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), 7.56–7.53 (1.0H, m, ArH), 7.50–7.43 (1.7H, m, ArH),
7.41–7.39 (1.1H, m, ArH), 7.35–7.29 (3.0H, m, ArH), 7.26–7.23
(4.0H, m, ArH), 7.18–7.08 (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.
4.2.5. (S)-4-Hydroxy-3-[1-(2-methoxyphenyl)-3-oxobutyl]-chro-
men-2-one 3e12a
The compound was isolated as a yellow solid The enantiomeric
excess was determined by HPLC analysis of the purified product
with an Daicel AD-H column (hexane/i-PrOH, 4:1), 1.0 mL minÀ1
,
k = 254 nm): tR = 8.3 min (minor) and tS = 14.4 min (major). Data
for sample with 70% ee (S): [
{Lit.12a 25 = +52.0 (c 0.2, acetonitrile), 89% ee (R)}; IR (KBr)
[a]
D
a]
24 = À19.5 (c 1.0, acetonitrile),
D
3373 (br), 3034, 2935, 2838, 1681, 1619, 1571, 1492, 1394, 1063,
748 cmÀ1; 1H NMR (600 MHz CDCl3): d = 9.13 (0.9H, br s, OH, keto),
7.90–7.87 (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), 7.55–7.52 (2.0H, m, ArH), 7.34 (1.8H, d, J
8.2 Hz, ArH), 7.48–7.43 (2.0H, m, ArH), 7.31–7.23 (2H, m, ArH),
7.26–7.17 (9.0H, m, ArH), 7. 05 (2.0H, d, J 7.7 Hz, ArH), 7.01–6.98
(2H, m, ArH), 6.93 (2.0H, d, J 8.2 Hz, ArH), 6.89–6.82 (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.
4.2.3. (S)-3-[1-(3-Chlorophenyl)-3-oxobutyl]-4-hydroxy-chro-
men-2-one 3c12a
The compound was isolated as a light yellow solid. The enantio-
meric excess was determined by HPLC analysis of the purified
product with an Daicel AD-H column (hexane/i-PrOH, 4:1),
1.0 mL minÀ1, k = 254 nm): tR = 5.8 min (minor) and tS = 12.3 min
(major). Data for sample with 67% ee (S): [
nitrile), {Lit.12a 26 = +17.8 (c 0.36, acetonitrile), 75% ee (R)}; IR
(KBr) 3307 (br), 2958, 2929, 2852, 1686, 1623, 1575, 1495, 1381,
1071, 759 cmÀ1 1H NMR (600 MHz CDCl3): d = 9.55 (0.3H, s, OH,
a]
24 = +1.3 (c 1.0, aceto-
D
[a]
405
;
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), 7.61–7.41 (2.9H, m, ArH), 7.37–7.05
(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.
4.2.6. (S)-4-Hydroxy-3-[1-(4-methoxyphenyl)-3-oxobutyl]-chro-
men-2-one 3f10,12a
The compound was isolated as a yellow solid. The enantiomeric
excess was determined by HPLC analysis of the purified product
with an Daicel AD-H column (hexane/i-PrOH, 4:1), 1.0 mL minÀ1
,
k = 254 nm): tR = 8.8 min (minor) and tS = 24.6 min (major). Data
for sample with 71% ee (S): [a]
25 = +4.3 (c 1.0, acetonitrile), {Lit.12a
D
4.2.4. (S)-3-[1-(4-Chlorophenyl)-3-oxobutyl]-4-hydroxy-chro-
men-2-one 3d10,11b,12a
[a
]
D
24 = À8.7 (c 0.37, acetonitrile), 87% ee (R)}; IR (KBr) 3387 (br),
2987, 2937, 2837, 1683, 1608, 1512, 1377, 1250, 1070, 764 cmÀ1
;
The compound was isolated as a white solid. The enantiomeric
excess was determined by HPLC analysis of the purified product
1H 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), 7.48–7.44
(1.4H, m, ArH), 7.33–7.27 (2H, m, ArH), 7.23–7.19 (3.7H, m, ArH),
7.17 (2H, m, ArH), 7.13–7.11 (2H, m, ArH), 6.85–6.78 (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),
with an Daicel AD-H column (hexane/i-PrOH, 4:1), 1.0 mL minÀ1
,
k = 254 nm): tR = 6.7 min (minor) and tS = 15.7 min (major). Data
for sample with 72% ee (S): [a]
23 = +10.0 (c 1.0, acetonitrile),
D
{Lit.12a
[a]
25 = À8.8 (c 0.28, acetonitrile), 79% ee (R)}; IR (KBr)
D
3377, 2984, 2934, 2855, 1686, 1608, 1565, 1490, 1385, 1377,
1071 cmÀ1 1H NMR (600 MHz CDCl3): d = 9.47 (0.2H, s, OH, keto),
,

´
M. Rogozinska-Szymczak, J. Mlynarski / Tetrahedron: Asymmetry 25 (2014) 813–820
818
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
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]-chro-
men-2-one 3i
The compound was isolated as a white solid. The enantiomeric
excess was determined by HPLC analysis of the purified product
with an Daicel AD-H column (hexane/i-PrOH, 4:1), 1.0 mL minÀ1
,
C20H18O5 required 338.1154.
k = 254 nm): tR = 5.5 min (minor) and tS = 12.8 min (major). Data
for sample with 76% ee (S): [
23 = +3.8 (c 2.0, acetonitrile); IR
(KBr) 3377 (br), 3080, 2961, 2926, 2871, 1712, 1681, 1615, 1569,
1492, 1385, 1046, 757 cmÀ1 1H NMR (600 MHz CDCl3): d = 9.53
a
]
D
4.2.7. (S)-4-Hydroxy-3-[1-(2-nitrophenyl)-3-oxobutyl]-chromen-
2-one 3g
;
The compound was isolated as a light yellow solid. The enantio-
meric excess was determined by HPLC analysis of the purified
product with an Daicel OD-H column (hexane/i-PrOH, 4:1),
0.5 mL minÀ1, k = 220 nm): tR = 21,5 min (minor) and tS = 34.2 min
(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), 7.58–7.53 (0.7H,
m, ArH), 7.49–7.42 (1.2H, m, ArH), 7.33–7.30 (1.0H, m, ArH),
7.26–7.16 (3.6H, m, ArH), 7.16–7.11 (2.0H, m, ArH), 7.10–7.06
(3.2H, m, ArH), 6.97 (1H, d, J 7.2, ArH), 4.61 (0.2H, dd, J 10.6, 2.2,
CH, keto), 4.40–4.35 (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),
2.45–2.42 (1.4H, m, CH2, ketal), 2.39–2.30 (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.
(major). Data for sample with 66% ee (S): [
tonitrile); IR (KBr) 3336 (br), 3073, 2938, 2868, 1687, 1622, 1572,
1526, 1384, 1176, 1079, 760 cmÀ1 1H NMR (600 MHz CDCl3):
a]
25 = +74.5 (c 1.0, ace-
D
;
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), 7.56–7.52 (1.0H, m, ArH), 7.51–7.36 (5.0H, m, ArH), 7.34–
7.28 (4.6H, m, ArH), 7.27–7.18 (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
(0.3H, dd, J 19.1, 8.0 Hz, CH2, keto), 3.54 (1.0H, br s, OH, ketal),
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), 1.99–1.85 (1.0H, m,
CH2, ketal), 1.78 (4.0H, s, CH3, ketal), 1.68 (3.0H, s, CH3, ketal);
13C 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.
4.2.10. (S)-4-Hydroxy-3-[1-(3-methylphenyl)-3-oxobutyl]-chro-
men-2-one 3j12a
The compound was isolated as a white solid. The enantiomeric
excess was determined by HPLC analysis of the purified product
with an Daicel AD-H column (hexane/i-PrOH, 4:1), 1.0 mL minÀ1
,
k = 254 nm): tR = 5.7 min (minor) and tS = 15.2 min (major). Data
for sample with 74% ee (S): [
a
]
D
23 = À9.4 (c 1.0, acetonitrile), {Lit.12a
[a]
24 = +6.1 (c 0.39, acetonitrile), 87% ee (R)}; IR (KBr) 3299 (br),
D
2985, 2960, 2933, 1721, 1689, 1625, 1575, 1495, 1380, 1073,
759 cmÀ1 1H NMR (600 MHz CDCl3): d = 9.41 (0.2H, s, OH, keto),
4.2.8. (S)-4-Hydroxy-3-[1-(4-nitrophenyl)-3-oxobutyl]-chromen-
2-one 3h10,11b,13
;
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), 7.57–7.53 (1.0H, m, ArH), 7.50–
7.43 (1.4H, m, ArH), 7.34–7.29 (2.0H, m, ArH), 7.27–7.14 (6.0H,
m, ArH), 7.07–7.00 (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.
The compound was isolated as a white solid. The enantiomeric
excess was determined by HPLC analysis of the purified product
with an Daicel AD-H column (hexane/i-PrOH, 4:1), 1.0 mL minÀ1
,
k = 254 nm): tR = 12.3 min (minor) and tS = 22.7 min (major). Data
for sample with 60% ee (S): [
25 = +10.9 (c 0.65, acetonitrile),
{Lit.13 25 = +1.8 (c 1.0, dichloromethane), 91% ee (R)}; IR (KBr)
3326 (br), 3076, 2934, 2852, 1688, 1619, 1515, 1346, 1068,
759 cmÀ1 1H NMR (600 MHz CDCl3): d = 9.66 (0.2H, s, OH, keto),
a]
D
[a]
D
;
8.16–8.13 (2.0H, m, ArH), 8.12–8.10 (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), 7.53–7.50 (1.2H, m, ArH), 7.46–7.44 (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), 1.94–1.89 (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,

´
819
M. Rogozinska-Szymczak, J. Mlynarski / Tetrahedron: Asymmetry 25 (2014) 813–820
4.2.11. (S)-4-Hydroxy-3-(1-naphthalen-2-yl-3-oxobutyl)-chro-
(hexane/i-PrOH, 9:1), 1.0 mL minÀ1
,
k = 254 nm): tR = 7.8 min
men-2-one 3k10,12a
(minor) and tS = 15.8 min (major). Data for sample with 72% ee
The compound was isolated as a white solid. The enantiomeric
excess was determined by HPLC analysis of the purified product
(S): [
a
]
24 = À72.1 (c 2.0, acetonitrile), {Lit.12a
[a]
21 = +48.7 (c
D
D
0.5, acetonitrile), 57% ee (R)}; IR (KBr) 3383 (br), 3080, 2963,
with an Daicel AD-H column (hexane/i-PrOH, 4:1), 1.0 mL minÀ1
,
2871, 1712, 1681, 1615, 1569, 1492, 1384, 1077, 757 cmÀ1 1H
;
k = 254 nm): tR = 8.8 min (minor) and tS = 24.6 min (major). Data
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), 7.30–7.17 (3.0H, m, ArH), 3.29 (1.2H, dd, J
20.0, 10.2 Hz, CH2, keto), 3.25 (0.4H, m, CH, ketal), 3.07–2.97
(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), 2.61–2.48 (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
for sample with 70% ee (S): [a]
25 = +28.2 (c 1.0, acetonitrile),
D
{Lit.12a
[a]
26 = À9.8 (c 0.61, acetonitrile), 83% ee (R)}; IR (KBr)
D
3321 (br), 3050, 2931, 1717, 1686, 1621, 1572, 1492, 1381, 1072,
759 cmÀ1 1H NMR (600 MHz CDCl3): d = 9.53 (0.2H, s, OH, keto),
;
7.94–7.91 (1.2H, m, ArH), 7.83–7.81 (2.0H, m, ArH), 7.78–7.73
(5.5H, m, ArH), 7.71–7.64 (3.4H, m, ArH), 7.59–7.56 (1.0H, m,
ArH), 7.49–7.46 (1.5H, m, ArH), 7.43–7.30 (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), 2.07–2.03 (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.
Acknowledgments
This project was operated within the Foundation for Polish Sci-
ence TEAM Programmes co-financed by the EU European Regional
Development Fund. Financial support from the Polish National Sci-
ence Centre (grant number NCN 2011/03/B/ST5/03126) is grate-
fully acknowledged.
4.2.12. (R)-4-Hydroxy-3-(2-oxooctan-4-yl)-chromen-2-one 3l10
The compound was isolated as a colourless oil, but solidified
upon standing. The enantiomeric excess was determined by HPLC
analysis of the purified product with an Daicel AD-H column (hex-
ane/i-PrOH, 9:1), 1.0 mL minÀ1, k = 254 nm): tS = 8.9 min (minor)
and tR = 15.4 min (major). Data for sample with 74% ee (R):
References
1. Perlmutter, P. In Conjugate Addition Reactions in Organic Synthesis, Baldwin, J. E.
Magnus, P. D., Eds., Pergamon Press: Oxford, 1992.
2. (a) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346; (b) Ballini, R.; Bosica, G.; Fiorini,
D.; Palmieri, A.; Petrini, M. Chem. Rev. 2005, 105, 933; (c) Krause, N.; Hoffmann-
Roder, A. Synthesis 2001, 171.
3. (a) Dalko, P. I.; Moisan, L. Enantioselective Organocatalysis: Reactions and
Experimental Procedures; Wiley-VCH, 2007; (b) Berkessel, A.; Gröger, H.
Asymmetric Organocatalysis: From Biomimetic Concepts to Applications in
Asymmetric Synthesis; Wiley-VCH, 2005; (c) Melchiore, P.; Marigo, M.;
Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138; (d) Dondoni, A.;
Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638; (e) Pellissier, H. Tetrahedron
2007, 63, 9267; (f) Erkkilä, A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107,
5416; (g) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107,
5471.
[
a
]
24 = À32.5 (c 0.65, acetonitrile); IR (liquid film) 3374 (br),
D
2958, 2929, 2861, 1710, 1684, 1619, 1572, 1493, 1393,
1108 cmÀ1 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), 7.52–7.41 (3.7H, m, ArH), 7.28–7.17 (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), 3.00–2.93 (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), 2.27–2.21 (1.0H,
m, CH2, ketal), 2.27–2.21 (1.0H, m), 2.18 (6.6H, s, CH3, keto),
2.16–2.08 (2.6H, m), 2.04–1.97 (1.0H, m), 1.93 (1.0H, dd, J 14.2,
6.9 Hz, CH2, ketal), 1.76 (3.0H, s, CH3, ketal), 1.81–1.72 (2.0H, m),
1.70 (2.3H, s, CH3, ketal), 1.65–1.51 (1.0H, m, CH2, ketal), 1.65–
1.51 (3.0H, m), 1.49–1.42 (1.0H, m), 1.41–1.29 (4.3H, m), 1.29–
1.21 (7.5H, m), 1.16–1.09 (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. Hernández, J. G.; Juaristi, E. Chem. Commun. 2012, 48, 5396.
5. Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701.
6. Christmann, M. Eur. J. Org. Chem. 2007, 2575.
7. Blackmond, D. G.; Armstrong, A.; Coombe, V.; Wells, A. Angew. Chem., Int. Ed.
2007, 46, 3798.
8. (a) Paradowska, J.; Stodulski, M.; Mlynarski, J. Angew. Chem., Int. Ed. 2009, 48,
4288; (b) Mlynarski, J.; Paradowska, J. Chem. Soc. Rev. 2008, 37, 1502; (c)
Gruttadauria, M.; Giacalone, F.; Noto, R. Adv. Synth. Catal. 2009, 351, 33; (d) Raj,
M.; Singh, V. K. Chem. Commun. 2009, 6687; (e) Mase, N.; Barbas, C. F., III Org.
Biomol. Chem. 2010, 8, 4043; (f) Mlynarski, J.; Bas´, S. Chem. Soc. Rev. 2014, 43,
577.
9. (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) Fishelovitch, D.; Hazan, C.;
Shaik, S.; Wolfson, H. J.; Nussinov, R. J. Am. Chem. Soc. 2007, 129, 1602.
10. Halland, N.; Hansen, T.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 4955.
11. (a) Kristensen, T. E.; Vestli, K.; Hansen, F. K.; Hansen, T. Eur. J. Org. Chem. 2009,
5185; (b) Xie, J.-W.; Yue, L.; Chen, W.; Du, W.; Zhu, J.; Deng, J.-G.; Chen, Y.-C.
Org. Lett. 2007, 9, 413.
12. (a) Dong, Z.; Wang, L.; Chen, X.; Liu, X.; Lin, L.; Feng, X. Eur. J. Org. Chem. 2009,
5192; (b) Kelleher, F.; Kelly, S.; Watts, J.; McKee, V. Tetrahedron 2010, 66, 3525.
13. Dong, J.; Du, D.-M. Org. Biomol. Chem. 2012, 10, 8125.
14. Kim, H.; Yen, C.; Preston, P.; Chin, J. Org. Lett. 2006, 8, 5239.
15. Yang, H.-M.; Li, L.; Jiang, K.-Z.; Jiang, J.-X.; Lai, G.-Q.; Xu, L.-W. Tetrahedron
2010, 66, 9708.
16. Jorgensen tested the activity of imidazolidine catalysts in pure water and
observed the formation of warfarin in poor yield (22%) and ee (49%) (Ref. 10).
17. Preliminary studies on the ‘‘solid on water’’ synthesis of warfarin have
4.2.13. (S)-4-Hydroxy-3-(2-methyl-5-oxohexan-3-yl)-2-chro-
men-2-one 3m10,12a
The compound was isolated as a colourless oil, but solidified
upon standing. The enantiomeric excess was determined by HPLC
analysis of the purified product with an Daicel AD-H column
´
been reported: (a) Rogozinska, M.; Adamkiewicz, A.; Mlynarski, J. Green

´
M. Rogozinska-Szymczak, J. Mlynarski / Tetrahedron: Asymmetry 25 (2014) 813–820
820
Chem. 2011, 13, 1155; For a review on the synthesis of ‘‘on water’’ and ‘‘in
18. (a) Mitchell, J. M.; Finney, N. S. Tetrahedron Lett. 2000, 41, 8431; (b) Luo, S.; Xu,
H.; Li, J.; Zhang, L.; Cheng, J.-P. J. Am. Chem. Soc. 2001, 129, 3074.
19. (1R,2R)-(+)- and (1S,2S)-(À)-1,2-diphenyl-1,2-ethylenediamine were prepared
according to: Pikul, S.; Corey, E. J. Org. Synth. 1992, 71, 22.
20. (a) Cintas, P.; Luche, J.-L. Green Chem. 1999, 2, 115; (b) Mason, T. J.; Lorimer, J. P.
Applied Sonochemistry; Wiley: VCH Weinheim, 2002.
water’’: (b) Buttler, R. N.; Coynote, A. G. Chem. Rev. 2010, 110, 6302; For
examples of reactions of solids ‘‘on water’’: (c) Butler, R. N.; Coyne, A. G.;
Moloney, E. M. Tetrahedron Lett. 2007, 48, 3501; (d) Tandon, V. K.; Maurya,
H. K. Tetrahedron Lett. 2009, 50, 5896; (e) Tiwari, S.; Kumar, A. Chem.
Commun. 2008, 4445.