A bis-Lewis basic 2-aminoDMAP/prolinamide organocatalyst for application to the enantioselective synthesis of Warfarin and derivatives

Article abstract of DOI:10.1016/j.tetasy.2016.04.001

A new chiral sec-amine/amidine-base hybrid catalyst, 2-aminoDMAP/prolinamide, is reported, which is able to catalyze conjugate addition of 4-hydroxycoumarin and various benzylideneacetones, a reaction that directly gives anticoagulant Warfarin and its analogues, with good yields (70-87%) and enantioselectivities (58-72%).

Full text of DOI:10.1016/j.tetasy.2016.04.001

Tetrahedron: Asymmetry 27 (2016) 384–388
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A bis-Lewis basic 2-aminoDMAP/prolinamide organocatalyst
for application to the enantioselective synthesis of Warfarin
and derivatives
a
c
a,
Murat Ißsık a,b, H. Ufuk Akkoca , I. Mecidog˘lu Akhmedov , Cihangir Tanyeli
⇑
_
a Department of Chemistry, Middle East Technical University, 06800 Ankara, Turkey
b Department of Metallurgical and Materials Engineering, Bingöl University, 12400 Bingöl, Turkey
c Department of Chemistry, Baku State University, Z. Khalilov, Baku, Azerbaijan
a r t i c l e i n f o
a b s t r a c t
Article history:
A new chiral sec-amine/amidine-base hybrid catalyst, 2-aminoDMAP/prolinamide, is reported, which is
able to catalyze conjugate addition of 4-hydroxycoumarin and various benzylideneacetones, a reaction
that directly gives anticoagulant Warfarin and its analogues, with good yields (70–87%) and enantioselec-
tivities (58–72%).
Received 8 March 2016
Accepted 11 April 2016
Available online 20 April 2016
Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction
modality relies on covalent catalysis by chiral primary or
secondary amines, which operates through either enamine3 or
The field of asymmetric organocatalysis abounds with H-bond-
ing catalysts, especially with those carrying both an H-bond donor
and an H-bond acceptor appropriately placed around a chiral
environment—acid/base type bifunctional organocatalysts.1 These
small, purely organic molecules activate substrate(s) with the
H-bond donor part being responsible for lowering the LUMO
energy level of the electrophile and the acceptor part for raising
the HOMO energy level of the nucleophile, and thus creates
stereochemical molecular complexity.2 Besides this attractive design
approach, another equally abundant, powerful, and well-established
iminium4 activation mechanistic pathways. Taken together, and
encouraged by the influential works of Fu,5 Kotsuki,6 Johnston,7
and Wulff8 in particular, we have recently developed several
bifunctional organocatalyst libraries that were built on a new
superbasic unit5–11 (2-aminoDMAP, 1) which might act as Lewis
or Brønsted base depending on the context (Fig. 1).10–12
When coupled with H-bond donors through modification of the
remaining primary amine of the trans-cyclohexane-1,2-diamine
chiral backbone, 1 yielded 2-aminoDMAP/sulfonamides 210 and
2-aminoDMAP/squaramides 3,11 both of which were found to be
O
R
NH
O
SO2R
NH
NH
NH
NH2
NH
Me2N
R
R
NMe2
NH
N
N
N
NH HN
N
N
Me2N
2-aminoDMAP/sulfonamides,
Figure 1. 2-AminoDMAP based organocatalysts.
Me2N
Me2N
2-aminoDMAP, 1
2
3
2-aminoDMAP/squaramides,
C2-symmetrical nucleophiles
⇑
Corresponding author.
E-mail address: tanyeli@metu.edu.tr (C. Tanyeli).
http://dx.doi.org/10.1016/j.tetasy.2016.04.001
0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.

M. Ißsık et al. / Tetrahedron: Asymmetry 27 (2016) 384–388
385
Table 1
Screening of the catalysts 1–3 in Warfarin synthesisa
OH Ph
O
OH
2
R of Cat.3
R of Cat.
O
Cat. 1−3 (20 mol%)
iPr
NO2
iPr
Solvent, rt
O
O
O
O
4-hydroxycoumarin
benzylideneacetone
6a
(R)-(+)-Warfarin,
4
5a
iPr
Entry
Cat.
Solvent
Timeb (h)
Yieldc (%)
eed (%)
1e
2f
3
4
5
3
2
1
1
1
1
1
Dichloromethane
Dichloromethane
Dichloromethane
Dimethyl sulfoxide
Tetrahydrofuran
Toluene
120
120
120
96
96
96
—
—
70
—
—
—
—
—
22
—
—
—
—
6
7g,h
Dichloromethane
96
—
a
b
c
Reactions were carried out in 0.05 M concentration of 4-hydroxycoumarin 4 with 1.5 equiv of benzylideneacetone 5a.
Time for indicated conversion.
Reaction mixture was directly loaded onto silica gel column for isolation.
Enantiomers were separated by HPLC using the chiral stationary phase.
Alkyl group of the sulfonamide is shown on the table scheme.
Alkyl group of the squaramide is shown on the table scheme.
20 mol % Trifluoroacetic acid was added.
d
e
f
g
h
40 mol % Trifluoroacetic acid was added.
highly efficient bifunctional acid/base type catalysts for asymmet-
ric Michael addition of trans-nitroolefins and some b-dicarbonyl
compounds. Among these, squaramides 3 were found to be partic-
ularly active/useful catalysts requiring only 1–2 mol % loadings to
complete conjugate additions (vide supra) in short reaction times
(typically 3–6 h). Because of their swift action and high stereose-
lectivity, we also wanted to exploit them in the Michael addition
of 4-hydroxycoumarin 4 to the benzylideneacetone 5a, a reaction
that directly gives Warfarin 6a,13 an anticoagulant drug active-
compound, for which current organocatalytic protocols typically
take days to week and are rarely truly selective (Table 1).14–21
to 10 or 20 equiv affected the yields a little more, but this time
lowered selectivity.
With these preliminary results in hand, we wondered to couple
( )-Proline with the 1 through an amide bond to create an amidine
L
superbase/sec-amine hybrid catalyst in hope of affording higher
selectivities. Ready availability of 1 in only one-step encouraged
us to synthesize catalysts (R,R,L)-7 and (S,S,L)-7 to investigate the
match-mismatch of the two chiral pools. The first step of the
syntheses involves the activation of N-carboxybenzoyl-protected
( )-proline by converting it to its mixed anhydride of ethyl chloro-
L
formate in basic medium; to which then, a tetrahydrofuran solu-
tion of enantiomers of 1 was added, (R,R)-1 and (S,S)-1. At the
second and last step, the Cbz-group was cleaved by 10% Pd/C under
approx. 1 bar of hydrogen atmosphere (balloon). As a result, the
two catalyst candidates, (R,R,L)-7 and (S,S,L)-7, were synthesized
in 65–68% overall yields. We should here note that also at first
2. Results and discussion
To this end, we have reacted 4 and 5a in the presence of the cat-
alysts we have developed so far (Fig. 1 and Table 1) in dichloro-
methane at room temperature. We saw no trace of Warfarin
formation (TLC monitoring) when using catalyst 2 or 3, respec-
tively (entries 1 and 2 of Table 1). We reasoned that the underlying
causes might be twofold: (1) Although, the catalysts 2 and 3 were
shown to be very active in deprotonating acyclic b-diketones like
acetyl acetone or dibenzoylmethane, here however, they are inac-
tive because of the cyclic nature of the 4 making it impossible to
form double H-bonding with 2-aminoDMAP unit, basic part of
the cat. 2 and 3. (2) Another plausible explanation can be the
low or insufficient activation of 5a by sulfonamide or squaramide
units. The latter reasoning together with the common choice of pri-
mary-amine-catalysts of previous lit. for this very same reaction
provoked us to consider our precatalyst 2-aminoDMAP 1 itself
for this reaction. The primary amine catalysts can form transient
iminium structures when coupled with enone 5a and thereby
lower the LUMO thereof. Despite low in enantioselectivity (entry
3, 22% ee), the reaction was made possible by 1. The use of toluene,
dimethyl sulfoxide, or tetrahydrofuran as the solvent gave no
product. We added trifluoroacetic acid as the co-catalyst; but the
reaction halted (entry 7). Addition of water, with the hope of accel-
erating the reaction, enhanced both yield and enantioselectivity
(entry 8), albeit a little. Increasing the amount of water further
we used N-tBoc-protected
-proline and found it equally helpful
L
to form the amide bond, but when it came to deprotect the
tBoc-group with trifluoroacetic acid we could hardly get free base.
The diastereomeric pair of 2-aminoDMAP/prolinamides made so
were characterized by 1H and 13C NMR and HRMS analysis. The
structure of (R,R,L)-7 was further supported by COSY, HMBC, HMQC,
13C-DEPT-90, and 13C-DEPT-135 NMR experiments (Scheme 1).
Having two new 2-aminoDMAP/prolinamides at hand, namely
(R,R,L)-7 and (S,S,L)-7, we refocused on the conjugate addition of
4 and 5a (Table 2). The first experiments revealed the supremacy
of the (R,R,L)-7 over the (S,S,L)-7, 64% ee versus 23% ee, respectively
(entry 1 vs entry 3 of Table 2). The reaction with (R,R,L)-7 took only
26 hours to give a 90% yield of Warfarin, 6a. Seeing the strong mis-
match of (S,S,)-diamine and ( )-Proline in (S,S,L)-7, we focused on
L
the (R,R,L)-7 for further reaction parameter optimization. In this
regard, a number of solvent were tested; and chlorinated solvents
(entries 4 and 13–15) consistently gave the best results, among all
eleven. Because of its availability and low-cost we chose dichloro-
methane as the reaction solvent. Next, we wanted to add some
external H-bond donors for co-catalytic purposes to improve the
enantioselectivity. To this end, we made use of three carboxylic
acids and four phenolic compounds as co-catalyst, and all were

386
M. Ißsık et al. / Tetrahedron: Asymmetry 27 (2016) 384–388
O
1.2.
1
(R,R)- or
O
N
H
1.1.
O
∗
NH
NH
(S,S)-1
Cl
OEt
CO2H
N
N
(R,R,L)-7
&
O
∗
O
Cbz
Cbz
TEA
in THF, at 0 °C
(S,S,L)-7
2. 10% Pd/C
OEt
(H2, 1 bar)
N
Me2N
Scheme 1. The synthesis of diastereomeric pair of 2-aminoDMAP/prolinamide, (R,R,L)-7 and (S,S,L)-7.
Table 2
Screening of the catalysts (R,R,L)-7 and (S,S,L)-7 in Warfarin synthesisa
OH
OH Ph
O
O
(R,R,L)-7 or (S,S,L)-7
(10 mol%)
solvent,
additive,
T
O
O
O
O
4
5a
(R)-(+)-Warfarin, 6a
Entry
Cat.
Solvent
Additive
Timeb (h)
Yieldc (%)
eed (%)
1e
2e
3e
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23f
24g
25f
(S,S,L)-7
(S,S,L)-7
(R,R,L)-7
(R,R,L)-7
(R,R,L)-7
(R,R,L)-7
(R,R,L)-7
(R,R,L)-7
(R,R,L)-7
(R,R,L)-7
(R,R,L)-7
(R,R,L)-7
(R,R,L)-7
(R,R,L)-7
(R,R,L)-7
(R,R,L)-7
(R,R,L)-7
(R,R,L)-7
(R,R,L)-7
(R,R,L)-7
(R,R,L)-7
(R,R,L)-7
(R,R,L)-7
(R,R,L)-7
(R,R,L)-7
Dichloromethane
Dimethyl sulfoxide
Dichloromethane
Dichloromethane
Dimethyl sulfoxide
Tetrahydrofuran
Toluene
Benzene
Ethyl acetate
Acetone
Methanol
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
96
96
96
26
35
27
27
27
23
260
140
40
27
26
27
53
48
60
40
40
40
40
48
120
55
81
91
75
90
65
65
64
75
92
70
91
65
80
90
90
75
88
84
91
96
93
94
85
78
80
23
7
64
64
25
47
52
40
57
33
22
38
62
63
61
61
62
60
63
58
60
64
70
68
72
Water
Chloroform
1,2-Dichloroethane
Chlorobenzene
Dichloromethane
Dichloromethane
Dichloromethane
Dichloromethane
Dichloromethane
Dichloromethane
Dichloromethane
Dichloromethane
Dichloromethane
Dichloromethane
Trifluoroacetic acid
Benzoic acid
3,5-Dinitrobenzoic acid
Phenol
Picric acid
a
-Naphthol
b-Naphthol
—
—
b-Naphthol
a
b
c
d
e
f
Reactions were carried out in 0.1 M concentration of 4-hydroxycoumarin 4 with 3 equiv of benzylideneacetone 5a.
Time for indicated conversion.
Reaction mixture was directly loaded onto silica gel column for isolation.
Enantiomers were separated by HPLC using the chiral stationary phase.
20 mol % of the catalysts was used.
Reaction was carried out at 10 °C.
Reaction was carried out at 0 °C.
g
found to be almost equally selective (entries 16–22). When the
reactions were carried out at colder temperatures, selectivities
increased a little, but not much. At best, we could get 6a at 80%
yield with 72% ee, when we ran reactions with 10 mol % of both
(R,R,L)-7 and b-naphthol in dichloromethane for 55 h of stirring
at 10 °C.
We also wanted to show the generality of this protocol by
employing different enones 5b–g (Scheme 2). All these enones
gave moderate and virtually similar levels of enantioselectivity,
around 60% or so. Both enantioselectivity and chemical yields of
the reactions were apparently insensitive to the electronic struc-
ture of the aryl unit of enone.
given in Figure 2. According to this model, we propose that the
reaction is mainly driven by iminium reactive formation at pro-
line site. Here, we should note also that b-naphthol may help
facilitate iminium ion formation. Additionally, we think that 4-
hydroxycoumarin is activated by a network of H-bonding, and
therefore is kept close to the si face of the iminium ion, which
gives the enantiomerically enriched product when hydrolysed
by a molecule of water.
3. Conclusion
Overall, we synthesized two bis-Lewis basic 2-aminoDMAP/
prolinamides catalysts, (R,R,L)-7 and (S,S,L)-7, and successfully
employed them in enantioselective synthesis of Warfarin and its
To rationalize the enantioselective reactions catalyzed by
(R,R,L)-7, we suggest following stereochemistry predicting model

M. Ißsık et al. / Tetrahedron: Asymmetry 27 (2016) 384–388
387
O
N
H
Ar
NH
NH
OH
O
OH
O
(R,R,L)-7 (10 mol%)
β-naphthol (10 mol%)
Ar
dichloromethane
O
O
O
O
10 °C
N
4
5b g
−
6b−g
Warfarin derivatives,
Me2N
(R,R,L)-
7
Ar:
S
MeO
O
Me
F3C
O2N
6b
6c
6d
6e
6f
6g
68h, 63% ee,
70% yield
89h, 58% ee
75% yield
86h, 63% ee
85% yield
117h, 60% ee
87% yield
135h, 69% ee
77% yield
65h, 58% ee
71% yield
Scheme 2. The scope of enones.
pre-coated silica gel plates (Merck Silica Gel PF-254). In addition,
generally EtOAc/hexane and DCM/MeOH solvent systems are used
as the eluants in TLC and in flash column chromatography.
Magnesium sulfate and sodium sulfate were used to dry organic
extracts before they were concentrated on a rotary evaporator.
Characterization data of novel compounds are given only. Chiral
2-aminoDMAP (1) was prepared according to published proce-
dure.10 The synthesis of mismatched 2-aminoDMAP/prolinamide
(S,S,L)-7 followed the same procedure as that of (R,R,L)-7.
4.2. Synthesis of 2-aminoDMAP/prolinamide (R,R,L)-7: Prepara-
Figure 2. Plausible TS for conjugate additions of 5a–g and 4 catalyzed by (R,R,L)-7.
tion of Cbz-protected intermediate
analogues. Among the catalysts, (R,R,L)-7 proved to be the
match-pair. Our previously developed catalysts, sulfonamide 2
and squaramide 3 (those lacking a primary or secondary amine
functionality), failed; even no products were observed. Comparing
the activities of catalysts 1–3 and (R,R,L)-7, we conclude that the
reaction demands either a primary or a secondary amine catalyst
for activating these mutually quite unreactive partners, although
alone not enough for a satisfactory enantioselectivity and yield.
The faster reactions obtained with (R,R,L)-7, when compared with
the precedent primary/secondary amine catalysts, reveals the rate
enhancing ability of 2-aminoDMAP superbase as well. Research
along these directions is in progress.
To a 100 mL flask, a 10 mL THF solution of N-carboxybenzoyl-
protected (
this solution, triethylamine (118
formate (174.4 L, 1.25 mmol) was added successively. After 2 h of
L)-Proline (311.4 mg, 1.25 mmol) was added at 0 °C. To
l
L, 1.25 mmol) and ethyl chloro-
l
stirring, 5 mL THF solution of (1R,2R)-2-aminoDMAP 1 (234 mg,
1 mmol) was added. After 45 min of vigorous stirring, the mixture
was washed with saturated NaHCO3 (15 mL). Mixture was
extracted with EtOAc (3 ꢀ 30 mL). The combined organic phase
was washed with brine, dried over anhydrous MgSO4, and concen-
trated in vacuo. The residue was purified by column chromatogra-
phy on silica gel using successively EtOAc, EtOAc/TEA (99:1),
EtOAc/TEA (98:2) solvent systems. The product was obtained as a
white solid (85% yield). 1H NMR (400 MHz, CDCl3) d 0.85 (br s,
1H), 1.17–1.30 (m, 4H), 1.58 (d, J = 48.9 Hz, 3H), 1.81 (s, 1H),
1.92–2.01 (m, 4H), 2.81 (s, 6H), 3.07 (s, 1H), 3.29 (dd, J = 22.6,
44.4 Hz, 2H), 3.76 (s, 1H), 3.99–4.29 (m, 2H), 4.89–5.22 (m, 2H),
5.40 (d, J = 29.8 Hz, 1H), 5.79–5.96 (m, 1H), 7.23–7.33 (m, 5H),
7.57 (s, 1H), 7.69 (dd, J = 5.7, 10.1 Hz, 1H). 13C NMR (100.6 MHz,
CDCl3) d 23.1, 23.3, 23.5, 24.3, 32.5, 38.1, 52.0, 57.3, 60.1, 62.3,
65.8, 98.4, 98.9, 102.8, 126.8, 127.4, 135.6, 146.2, 146.7, 154.7,
4. Experimental
4.1. General
Following instruments and materials were used for purification
and characterization studies. Bruker DPX 400 spectrometer was
used to record 1H NMR and 13C NMR spectra in CDCl3 (triplet cen-
tered at 77.0 ppm at 100 MHz). Chemical shifts were represented
as ppm taking tetramethylsilane as an internal standard. Spin mul-
tiplicities are expressed as; s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet), br (broad). Rudolph Research Analytical
Autopol III, automatic polarimeter was used for measuring Optical
rotations; and Mel-Temp 1002D for determining melting points.
ThermoFinnigan Spectra System instrument was used for HPLC
measurements by making use of Chiralcel AD analytical column
(250 ꢀ 4.60 mm) with hexane/2-propanol/TFA (70:30:0.1) as
eluent. Flash column chromatography was done by employing
thick-walled glass columns with a flash grade silica gel (Merck
Silica Gel 60, particle size: 0.040–0.063 mm, 230–400 mesh ASTM).
Reactions were monitored by thin layer chromatography by using
158.7, 171.4. HRMS (ESI) calculated for
466.2818, found 466.2831.
C
26H35N5O3 [M+H]+
4.3. Synthesis of 2-aminoDMAP/prolinamide (R,R,L)-7: Depro-
tection of Cbz-group
To a 25 mL flask, evacuated and backfilled with argon twice,
10 mL MeOH solution of above-prepared Cbz-protected intermedi-
ate (318 mg, 0.677 mmol) was introduced. Then, 10% Pd/C (72 mg,
0.0677 mmol) was added to the flask, flushed with H2 gas to
replace argon. The mixture was then stirred at overnight under a
balloon of H2 gas. The black suspension was filtered through celite
remove Pd/C, and washed with some MeOH before it was

388
M. Ißsık et al. / Tetrahedron: Asymmetry 27 (2016) 384–388
concentrated in vacuo. The residue was purified by column
chromatography on silica gel by using successively DCM, DCM/
DCM–MeOH–NH3 (90:9:1) (50:50), DCM–MeOH–NH3 (90:9:1)
solvent systems. The product was obtained as white solid (80%
4.4.6. Data for 6f
The use of enone 5f gave chiral Warfarin adduct 6f in 77%
yield in 135 h. HPLC analysis using with Chiralcel AS column,
n-hexane/EtOH/TFA 70:30:0.1, flow rate 1 mL minꢁ1, k = 254 nm,
tmajor = 5.0 min and tminor = 7.3 min, 69% ee. The spectroscopic data
are in accordance with the literature values.14
yield). Mp: 112–114 °C. [
a
]
D
31 = ꢁ10.5 (c 0.25, CH2Cl2). 1H NMR
(400 MHz, CDCl3) d 1.40–1.17 (m, 7H), 169–1.53 (m, 3H), 1.95–
1.86 (m, 2H), 2.02 (d, J = 12.9 Hz, 1H), 2.47 (dt, JAB = 6.4, 10.1 Hz,
1H), 2.72 (dt, JAB = 10.1, 6.7 Hz, 1H), 2.84 (s, 6H), 3.53 (dd, J = 5.3,
9.2 Hz, 1H), 3.60 (ddd, J = 4.9, 9.9, 14.8 Hz, 1H), 3.79 (ddd, J = 4.0,
10.5, 18.7 Hz, 1H), 4.61 (br s, 1H), 5.45 (s, 1H), 5.90 (dd, J = 2.3,
6.2 Hz, 1H), 7.65 (d, J = 6.2 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H). 13C
NMR (100.6 MHz, CDCl3) d 23.7, 24.8, 28.6, 29.7, 31.0, 32.1, 38.2,
45.9, 52.9, 53.3, 59.5, 87.5, 98.1, 145.6, 154.9, 158.2, 174.6. IR (neat)
3284, 2925, 2853, 1603, 1523, 1290, 1164. HRMS (ESI) calculated
for C18H30N5O [M+H]+ 332.2455, found 332.2450.
4.4.7. Data for 6g
The use of enone 5g gave chiral Warfarin adduct 6g in 71%
yield in 65 h. HPLC analysis using with Chiralcel AS column,
n-hexane/EtOH/TFA 70:30:0.1, flow rate 1 mL minꢁ1, k = 254 nm,
tmajor = 5.2 min and tminor = 9.3 min, 58% ee. The spectroscopic data
are in accordance with the literature values.14
Acknowledgements
4.4. General procedure for asymmetric synthesis of Warfarin
and derivatives, 6a–g
This work was supported by the Science Development
Foundation under the President of the Republic of Azerbaijan-
GrantN-EIF-2013-9ð15Þ-46 n 23 n 4.
To a dry Schlenk tube, a DCM solution (1 mL) of 4-hydroxy-
coumarin 4 (16.2 mg, 0.1 mmol),
a
,b-unsaturated ketone 5a–g
References
(0.3 mmol), 2-aminoDMAP/prolinamide (R,R,L)-7 (10–20 mol %),
and b-naphthol (10 mol %) was added. The reaction mixture stirred
at 10 °C for about 55–135 h. The progress of the reactions was
monitored by TLC analysis. After the time given in the Scheme 2,
the solution was loaded onto silica gel filled column to purify the
desired product by using EtOAc/hexane (1:5) eluant systems. The
product (88% yield) was obtained as white solid. The enantiomeric
excess value of the products were measured by HPLC analysis on a
Chiralcel AD or AS columns.
1. (a) Berkessel, A.; Gröger, H. Asymmetric Organocatalysis; Wiley VCH: Weinheim,
2005; (b) Wang, Y.; Deng, L. In Catalytic Asymmetric Synthesis; Ojima, I., Ed., 3rd
ed.; Wiley VCH: New York, 2010; pp 59–94; (c) Dondoni, A.; Massi, A. Angew.
Chem., Int. Ed. 2008, 47, 4638; (d) Macmillan, D. W. C. Nature 2008, 455, 304; (e)
List, B.; Yang, J. W. Science 2006, 313, 1584.
2. Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713.
3. Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471.
4. Erkkilä, A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416.
5. Hodous, B. L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 10006.
6. Ishii, T.; Fujioka, S.; Sekiguchi, Y.; Kotsuki, H. J. Am. Chem. Soc. 2004, 126, 9558.
7. (a) Nugent, B. M.; Yoder, R. A.; Johnston, J. N. J. Am. Chem. Soc. 2004, 126, 3418;
(b) Singh, A.; Yoder, R. A.; Shen, B.; Johnston, J. N. J. Am. Chem. Soc. 2007, 129,
3466; (c) Dobish, M. C.; Johnston, J. N. Org. Lett. 2010, 12, 5744; (d) Vara, B. A.;
Struble, T. J.; Wang, W.; Dobish, M. C.; Johnston, J. N. J. Am. Chem. Soc. 2015, 137,
7302; (e) Schwieter, K. E.; Johnston, J. N. ACS Catal. 2015, 5, 6559.
8. Rabalakos, C.; Wulff, W. D. J. Am. Chem. Soc. 2008, 130, 13524.
9. For reviews see: (a) Ishikawa, T. Superbases for Organic Synthesis; Wiley: New
York, 2009; (b) Ishikawa, T.; Kumamoto, T. Synthesis 2006, 737; For selected
chiral superbase catalysis examples see: (c) Iyer, M. S.; Gigstad, K. M.; Namdev,
N. D.; Lipton, M. J. Am. Chem. Soc. 1996, 118, 4910; (d) Ishikawa, T.; Araki, Y.;
Kumamoto, T.; Seki, H.; Fukuda, K.; Isobe, T. Chem. Commun. 2001, 245; (e)
Terada, M.; Ube, H.; Yaguchi, Y. J. Am. Chem. Soc. 2006, 128, 1454; (f) Yu, Z.; Liu,
X.; Zhou, L.; Lin, L.; Feng, X. Angew. Chem., Int. Ed. 2009, 48, 5195; (g) Sohtome,
Y.; Shin, B.; Horitsugi, N.; Takagi, R.; Noguchi, K.; Nagasawa, K. Angew. Chem.,
Int. Ed. 2010, 49, 7299; (h) Sohtome, Y.; Tanaka, S.; Takada, K.; Yamaguchi, T.;
Nagasawa, K. Angew. Chem., Int. Ed. 2010, 49, 9254; (i) Chen, X.; Dong, S.; Qiao,
Z.; Zhu, Y.; Xie, M.; Lin, L.; Liu, X.; Feng, X. Chem. Eur. J. 2011, 17, 2583; (j)
Uraguchi, D.; Sakaki, S.; Ooi, T. J. Am. Chem. Soc. 2007, 129, 12392; (k) Uraguchi,
D.; Yoshioka, K.; Ueki, Y.; Ooi, T. J. Am. Chem. Soc. 2012, 134, 19370; (l) Corbett,
M. T.; Uraguchi, D.; Ooi, T.; Johnson, J. S. Angew. Chem., Int. Ed. 2012, 51, 4685;
(m) Takeda, T.; Terada, M. J. Am. Chem. Soc. 2013, 135, 15306; (n) Bandar, J. S.;
Lambert, T. H. J. Am. Chem. Soc. 2012, 134, 5552; (o) Bandar, J. S.; Lambert, T. H.
J. Am. Chem. Soc. 2013, 135, 11799; (p) Bandar, J. S.; Sauer, G. S.; Wulff, W. D.;
Lambert, T. H.; Vetticatt, M. J. J. Am. Chem. Soc. 2014, 136, 10700; (r) Bandar, J.
S.; Barthelme, A. P.; Mazori, A. Y.; Lambert, T. H. Chem. Sci. 2015, 6, 1537; (s)
Núñez, M. G.; Farley, A. J. M.; Dixon, D. J. J. Am. Chem. Soc. 2013, 135, 16348; (t)
Farley, A. J. M.; Sandford, C.; Dixon, D. J. J. Am. Chem. Soc. 2015, 137, 15992; (u)
Goldys, A. M.; Núñez, M. G.; Dixon, D. J. Org. Lett. 2014, 16, 6294; (v) Fang, B.;
Liu, X.; Zhao, J.; Tang, Y.; Lin, L.; Feng, X. J. Org. Chem. 2015, 80, 3332.
10. Isik, M.; Tanyeli, C. J. Org. Chem. 2013, 78, 1604.
11. Ißsık, M.; Unver, M. Y.; Tanyeli, C. J. Org. Chem. 2015, 80, 828.
12. Yazıcıog˘lu, E. Y.; Tanyeli, C. Tetrahedron: Asymmetry 2012, 23, 1694.
13. For an indirect, early enantioselective synthesis that use chiral auxiliary
approach, see: Demir, A. S.; Tanyeli, C.; Gülbeyaz, V.; Akgün, H. Turk. J. Chem.
1996, 20, 139.
14. Halland, N.; Hansen, T.; Jorgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 4955.
15. Kim, H.; Yen, C.; Preston, P.; Chin, J. Org. Lett. 2006, 8, 5239.
16. Xie, J. W.; Yue, L.; Chen, W.; Du, W.; Zhu, J.; Deng, J. G.; Chen, Y. C. Org. Lett.
2007, 9, 413.
17. Dong, Z. H.; Wang, L. J.; Chen, X. H.; Liu, X. H.; Lin, L. L.; Feng, X. M. Eur. J. Org.
Chem. 2009, 5192.
18. Kristensen, T.; Vestli, K.; Hansen, F. K.; Hansen, T. Eur. J. Org. Chem. 2009, 5185.
19. Yang, H. M.; Li, L.; Jiang, K. Z.; Jiang, J. X.; Lai, G. Q.; Xu, L. W. Tetrahedron 2010,
66, 9708.
4.4.1. Data for 6a
The use of enone 5a gave chiral Warfarin adduct 6a in 80%
yield in 55 h. HPLC analysis using with Chiralcel AD column,
n-hexane/i-PrOH/TFA 70:30:0.1, flow rate 1 mL minꢁ1, k = 254 nm,
tmajor = 4.5 min and tminor = 8.5 min, 72% ee. The spectroscopic data
are in accordance with the literature values.14
4.4.2. Data for 6b
The use of enone 5b gave chiral Warfarin derivative 6b in 70%
yield in 68 hours. HPLC analysis using with Chiralcel AD column,
n-hexane/i-PrOH/TFA 70:30:0.1, flow rate 1 mL minꢁ1, k = 254 nm,
tmajor = 4.7 min and tminor = 9.9 min, 63% ee. The spectroscopic data
are in accordance with the literature values.14
4.4.3. Data for 6c
The use of enone 5c gave chiral Warfarin adduct 6c in 75%
yield in 89 h. HPLC analysis using with Chiralcel AD column,
n-hexane/i-PrOH/TFA 70:30:0.1, flow rate 1 mL minꢁ1, k = 254 nm,
tmajor = 5.7 min and tminor = 13.8 min, 58% ee. The spectroscopic
data are in accordance with the literature values.14
4.4.4. Data for 6d
The use of enone 5d gave chiral Warfarin adduct 6d in 85%
yield in 86 h. HPLC analysis using with Chiralcel AD column,
n-hexane/i-PrOH/TFA 70:30:0.1, flow rate 1 mL minꢁ1, k = 254 nm,
tmajor = 4.0 min and tminor = 8.9 min, 63% ee. The spectroscopic data
are in accordance with the literature values.14
4.4.5. Data for 6e
The use of enone 5e gave chiral Warfarin adduct 6e in 87%
yield in 117 h. HPLC analysis using with Chiralcel AD column,
n-hexane/i-PrOH/TFA 70:30:0.1, flow rate 1 mL minꢁ1, k = 254 nm,
tmajor = 7.3 min and tminor = 21.2 min, 60% ee. The spectroscopic
data are in accordance with the literature values.14
20. Wong, T. C.; Sultana, C. M.; Vosburg, D. A. J. Chem. Ed. 2010, 87, 194.
´
21. Rogozinska, M.; Adamkiewicz, A.; Mlynarski, J. Green Chem. 2011, 13, 1155.