Synthesis of quinazolinone-based aziridine diols as chiral ligands: Dual stereoselectivity in the asymmetric ethylation of aryl aldehydes Dedicated to Professor Dr. Metin Balci on the occasion of his retirement

Article abstract of DOI:10.1016/j.tetasy.2014.12.011

A new class of quinazoline-based enantiomerically pure aziridine diols 4a-d were prepared from the aziridination of mesityl oxide 3 with in situ generated 3-acetoxyaminoquinazolinone (S)-2b followed by NaBH₄ reduction. Aziridine diols 4a-d were purified by means of column chromatography on silica gel and their stereochemistries were assigned by X-ray crystallography and NMR analysis. These aziridine diols 4 were evaluated as chiral ligands in the asymmetric addition of diethylzinc to aryl aldehydes, and ligand (S,R,R)-4a yielded (R)-1-phenylpropanol derivatives with up to 92% ee, while the diastereomer (S,S,R)-4c gave the opposite enantiomers (S)-1-phenylpropanol derivatives with up to 86% ee. The results demonstrate that switching the configuration of the aziridine alcohol moiety in ligand gives a remarkable reversal of enantioselectivity in the asymmetric addition of diethylzinc to aryl aldehydes.

Full text of DOI:10.1016/j.tetasy.2014.12.011

Tetrahedron: Asymmetry 26 (2015) 152–157
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of quinazolinone-based aziridine diols as chiral ligands:
dual stereoselectivity in the asymmetric ethylation of aryl aldehydes
⇑
Saffet Celik, Murat Cakici, Hamdullah Kilic , Ertan Sahin
Faculty of Sciences, Department of Chemistry, Ataturk University, 25240 Erzurum, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 November 2014
Accepted 22 December 2014
A new class of quinazoline-based enantiomerically pure aziridine diols 4a–d were prepared from the
aziridination of mesityl oxide 3 with in situ generated 3-acetoxyaminoquinazolinone (S)-2b followed
by NaBH4 reduction. Aziridine diols 4a–d were purified by means of column chromatography on silica
gel and their stereochemistries were assigned by X-ray crystallography and NMR analysis. These aziridine
diols 4 were evaluated as chiral ligands in the asymmetric addition of diethylzinc to aryl aldehydes, and
ligand (S,R,R)-4a yielded (R)-1-phenylpropanol derivatives with up to 92% ee, while the diastereomer
(S,S,R)-4c gave the opposite enantiomers (S)-1-phenylpropanol derivatives with up to 86% ee. The results
demonstrate that switching the configuration of the aziridine alcohol moiety in ligand gives a remarkable
reversal of enantioselectivity in the asymmetric addition of diethylzinc to aryl aldehydes.
Ó 2015 Elsevier Ltd. All rights reserved.
Dedicated to Professor Dr. Metin Balci on
the occasion of his retirement
1. Introduction
addition of diethylzinc to aldehydes, catalysed by (S)-1b, to afford
(S)-1-phenyl-1-propanol in moderate selectivity (50% ee). 3-
Catalytic asymmetric synthesis using chiral auxiliaries, ligands
or catalysts1 remains one of the most attractive research areas in
both academia and industry. Chiral ligands are highly promising
tools for the efficient construction of chiral building blocks in the
asymmetric synthesis of natural products and biologically active
compounds, and much effort has been devoted to the design of
new efficient chiral ligands capable of chirality transfer.2 Among
the asymmetric C–C bond-forming reactions using chiral ligands,
the enantioselective addition of organozinc reagents to aldehydes
has been extensively studied in the field of asymmetric synthesis
and serves as a test reaction for new catalytic systems.3 Since the
pioneering report by Oguni and Omi,4 several oxygen- and nitro-
gen-based chiral ligands have been synthesized, such as amino
alcohols,5 BINOLs,6 TADDOLs,7 salen ligands8 and pyridyl alcohols.9
Quinazolinones and quinazolines are an important class of het-
erocyclic compounds that exhibit a broad range of biological activ-
ities.10 Moreover, the simple synthesis of the corresponding
homochiral derivatives and their potential use in asymmetric
applications make them an important class of compounds for syn-
thetic organic chemistry. Recently, we reported the synthesis of
some quinazoline- and quinazolinone-based chiral ligands,11 that
were effective catalysts for asymmetric C–C bond formation
reactions. Ulukanli et al.12 reported the catalytic enantioselective
Aminoquinazolinones are also used as aziridination reagents for
electron-rich and electron-deficient alkenes.13 For example, we
recently reported the diastereoselective aziridination of chiral
allylic alcohols with aziridinating reagent 3-acetoxyaminoquinaz-
olinone 2a, generated in situ from 3-amino-2-ethylquinazolin-
4(3H)-one 1a in the presence of lead(IV) acetate (LTA) or (diacet-
oxyiodo)benzene (PIDA) to give threo-aziridine alcohols with up
to >99:1 stereoselectivity (Scheme 1).14
Aziridines are known to efficiently coordinate to organozinc
compounds,15 and aziridine alcohols containing a three-membered
cyclic b-amino alcohol moiety are efficient chiral catalysts for
asymmetric synthesis.16 Herein, we report the successful synthesis
of quinazolinone-based chiral aziridine diols 4a–d via oxidative
aminoaziridination of mesityl oxide 3 with chiral 3-aminoquinaz-
olinone (S)-1b followed by NaBH4 reduction and chromatographic
separation (Fig. 1), and their applications in the asymmetric addi-
tion of diethylzinc to aryl aldehyde as a test reaction.
2. Results and discussion
The chiral aziridination agent 3-aminoquinazolinone (S)-1b was
readily synthesized from (S)-lactic acid according to literature17
procedures with over 99% ee. Aziridination of mesityl oxide 3 with
3-acetoxyaminoquinazolinone (S)-2b, generated in situ from (S)-
1b and phenyliodine diacetate (PIDA) as the oxidant, produced
the desired diastereomeric mixture of aziridine 5 in approximately
⇑
Corresponding author. Tel.: +90 442 231 4426; fax: +90 442 231 4109.
E-mail address: hkilic@atauni.edu.tr (H. Kilic).
http://dx.doi.org/10.1016/j.tetasy.2014.12.011
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.

S. Celik et al. / Tetrahedron: Asymmetry 26 (2015) 152–157
153
R2
R3
R1
OH
Het
N
Het
N
Het
N
LTA
or
N
Et
R2
Et
Et
R2
R3
H
PIDA
Me
R1
R1
N
N
N
Et
N
O
O
H
Me
Me
+
- AcOH
NH2
O
R3
Me
H
H
OH
OH
2a
1a
threo
erythro
threo : erythro ratio up to >99:1
Scheme 1. Diastereoselective aziridination of chiral allylic alcohols.
N
4
(S,a*,b*)-
O
Me
4a
4b
4c
N
(S,R,R)-
(S,R,S)-
(S,S,R)-
1
2
Me
Me
Me
. aziridination
. NaBH4
N
N
O
+
Me
OH
a*
b*
Me
N
O
Me
OH
NH2
4d
(S,S,S)-
HO
Me
1b
(S)-
3
Figure 1. Novel quinazolinone-based chiral aziridine diols synthesized in this work.
a 1:1 ratio (Scheme 2). Fortunately, the two diastereomers were
easily separated through a silica gel column with n-hexane/EtOAc
to give (S,R)-5a and (S,S)-5b as the pure diastereomer in a total
yield of 83%.
This result clearly assigned the absolute stereochemistry as
(S,R) for 5a and (S,S) for 5b. The pure diastereoisomers (S,R)-5a
and (S,S)-5b were each reacted with NaBH4 in methanol at room
temperature to give diastereomeric mixtures (Scheme 4). The
N
N
N
Me
Me
Me
PhI(OAc)2 (1.1 equiv)
K2CO3 (2 equiv)
N
N
O
N
N
O
N
N
O
3 (2 equiv)
OH
Me
OH
Me
(S)-1b
OH
DCM, 20 oC, 1h
O
H
83%
O
Me
O
Me
O
Me
Me
5a
Me
5b
2b
(S)-
(S,R)-
(S,S)-
Scheme 2. Aziridination of mesityl oxide 3 with 3-aminoquinazolinone (S)-1b and PIDA.
The enantiomeric purities of (S,R)-5a and (S,S)-5b were con-
firmed by chiral HPLC to be more than 99% ee after the purification
step. The absolute stereochemistry of the diastereomers was deter-
mined by X-ray analysis of the corresponding p-nitrobenzoate
derivative (S,R)-5aa of aziridine (S,R)-5a as a single crystal from
hexane/EtOAc. The absolute configuration of the newly formed
asymmetric centre of the aziridine moiety in 5aa was unambigu-
ously determined to be (R) by the reference to the (S)-absolute con-
figuration of the 2-position of quinazolinone ring part (Scheme 3).
mixtures were successfully separated by column chromatography
and aziridine alcohols 4a,b and 4c,d were isolated as single stereo-
isomers with a total yield of 83% and 79%, respectively. The struc-
tures of 4a–d were confirmed by IR, NMR, elemental analysis and
HRMS. The stereochemical purity of the all aziridine alcohols was
determined to be >99% by chiral HPLC analysis.
The assignment of the relative configurations of each of the
resulting threo 4a and 4d and erythro 4b and 4c diastereomeric
pairs was based using characteristic signals in the 1H NMR spectra.
O2N
N
O
p-nitrobenzoyl chloride
(S,R)-5a
N
O
pyridine
80%
O
Me
N
Me
O
Me
Me
5aa
(S,R)-
Scheme 3. Synthesis and X-ray structures of p-nitrobenzoate derivative (S,R)-5aa. Thermal ellipsoids are shown at 30% probability level. Selected bond lengths (Å) and angles
(°): C7–C9 1.535(8), N2–N3 1.441(5), N1–C7 1.269(6), O5–C9 1.463(7), N2–C8 1.384(8), O1–N4 1.214(7), N3–C18 1.539(7), C11–O5–C9 115.1(5), N2–N3–C21 116.1(4), N2–
N3–C18 113.8(4), C8–N2–C7–N1 16.0(8), N3–N2–C7–N1 À170.1(5).

154
S. Celik et al. / Tetrahedron: Asymmetry 26 (2015) 152–157
N
N
N
N
Me
Me
Me
Me
NaBH4 (1 equiv)
MeOH, 20 oC
N
N
O
N
N
O
N
N
O
N
N
O
5b
5a
(S,R)-
(S,S)-
+
+
OH
Me
OH
Me
OH
Me
OH
Me
79%
83%
HO
Me
HO
Me
HO
Me
HO
Me
Me
(S,S,R)-4c
Me
(S,S,S)-4d
Me
(S,R,R)-4a
Me
(S,R,S)-4b
Scheme 4. Synthesis of enantiomerically pure aziridine alcohols 4a–d.
For example, in the 1H NMR spectra, there is a distinct difference in
the chemical shift for the methine protons (Ha) on the hydroxy-
bearing carbon atom of the erythro- and threo-isomers (Fig. 2).
comparison of the NMR spectra to authentic threo-aziridine
alcohols 4a and 4d produced independently.
Following the successful synthesis of ligands 4a–d, we tested
their efficiencies as catalysts in the enantioselective addition of
diethylzinc to arylaldehydes. Initial experiments were performed
with benzaldehyde as a model substrate using 2 equiv of diethyl-
zinc in the presence of 10 mol % 4a–d at 0 °C. Enantioselectivities
were assessed by GC on a b-DEX 120 column after 20 h and some
representative results are shown in Table 1. Ligand (S,R,R)-4a affor-
ded (R)-1-phenyl-propan-1-ol with 86% ee (Table 1, entry 1),
whereas ligands 4b–d provided the corresponding (S)-alcohol with
50%, 70% and 58% ee, respectively, (Table 1, entries 2, 3 and 4). The
reaction conditions were then optimized with ligands (S,R,R)-4a
and (S,S,R)-4c, because they gave the best enantioselectivities in
the formation of (R)- and (S)-1-phenyl-propan-1-ol. Detailed
screening was carried out in order to optimize the reaction condi-
tions including the choice of solvent and reaction temperature,
which might play an important role in the enantioselectivities of
the reaction. For (S,R,R)-4a: Et2O/hexane (2:1, v/v) was found to
be the most effective solvent mixture at À15 °C in terms of selec-
tivity (92% ee) (Table 1, entry 9). On the other hand, (S,S,R)-4c gave
the best result with a solvent mixture of toluene/hexane (2:1, v/v)
at À30 °C (86% ee) (Table 1, entry 16). For entries 9 and 16 in
Table 1, the recovered ligand was also reused in subsequent cycles
as the catalyst without any detectable loss in its activity.
Various other reaction parameters, such as ligand loadings, addi-
tion methods and the amount of diethylzinc were examined (data
not shown). Using the optimized conditions for benzaldehyde,
ligands (S,R,R)-4a and (S,S,R)-4c were also utilized in the asymmet-
ric ethylation of other aromatic aldehydes with different steric and
electronic properties. The results are summarized in Table 2. Alde-
hydes with electron donating groups exhibited lower reactivity
compared to the aldehydes substituted with electron withdrawing
groups. In all cases, catalyst (S,R,R)-4a induced the formation of
the corresponding (R)-alcohols while (S,S,R)-4c induced the forma-
tion of the (S)-alcohols. We found that both (S,R,R)-4a and (S,S,R)-
4c gave the best enantioselectivity with benzaldehyde (Table 2,
entries 1 and 2). With (S,R,R)-4a, para-substituted benzaldehydes
generally exhibited higher enantiomeric excesses (p-Cl, 74%; p-
OMe, 84%) (Table 2, entries 19 and 25), while the ortho- and meta-
substituted benzaldehydes showed lower enantiomeric excesses,
Het
N
Het
N
Me
Me
OH
Me
OH
Me
N
N
OH
OH
Hb
Me
Hb
Ha
Me
Me
Ha
threo
Me
erythro
Figure 2. Model for the assignment of absolute configuration of 4.
It is known that the Ha proton gives a signal further up-field in the
threo-isomer as compared to the erythro-isomer, as observed for
epoxides and aziridines of the chiral allylic alcohols.14,18 For aziri-
dine diols obtained from (S,R)-5a, the Ha proton of the threo-isomer
4a appears at 3.80 ppm, while in the erythro-isomer 4b, this reso-
nance is shifted downfield to 4.17 ppm. In the other diastereomeric
pair of the aziridine diols, the Ha proton of the erythro-isomer 4c sim-
ilarly resonatesdownfield (4.21 ppm) from the corresponding threo-
isomer 4d (3.77 ppm). Furthermore, the coupling constant between
the two neighbouring methine protons (Ha and Hb) of the threo-iso-
mers is always larger (J = 9.0 Hz for 4a and 4d) than that between the
corresponding protons in the erythro-isomers (J = 5.7 Hz for 4b and
5.8 Hz for 4c).18b Thus, the relative and absolute configurations of
all aziridine diols 4a–d were determined.
We have recently found that the oxidative aminoaziridination
of chiral allylic alcohols with reactive intermediate 2a shows high
threo-diastereoselectivity (up to >99:1) due to the hydrogen bond-
ing between the hydroxy functionality of the allylic alcohol and the
remote carbonyl group of the quinazolinone (Scheme 1).14 To con-
firm the stereochemistry of the aziridine alcohols 4, we carried out
the diastereoselective aziridination of mesityl alcohol 6 with 3-
acetoxyaminoquinazolinone (S)-2b, which was generated in situ
from (S)-1b (Scheme 5).
In this reaction, threo-aziridine alcohols (S,R,R)-4a and (S,S,S)-4d
were obtained with high diastereoselectivity (>99:1). The
stereochemistries of aziridine alcohols 4 were also confirmed by
OH
Me
Me
Me
N
4a
4d
4c
(S,R,R)- and (S,S,S)-
Me
PhI(OAc)2 (1.1 equiv)
K2CO3 (2 equiv)
O
threo isomers
N
6
O
1b
2b
(S)-
OH
(S)-
+
H
DCM, 20 oC, 1h
O
H
4b
(S,R,S)- and (S,S,R)-
N
H
O
Me
Me
erythro isomers
Me
threo:erythro ratio: >99:1
Scheme 5. Diastereoselective aziridination of mesityl alcohol 6 with 3-acetoxyaminoquinazolinone (S)-2b.

S. Celik et al. / Tetrahedron: Asymmetry 26 (2015) 152–157
155
Table 1
Table 2
Asymmetric addition of diethylzinc to benzaldehyde using 4a–d as catalystsa
Asymmetric addition of Et2Zn to aryl aldehydes catalysed by ligand (S,R,R)-4aa and
(S,S,R)-4cb
4a
d
–
Ligand
OH
*
Et2Zn
Ligand 4a or 4c
OH
PhCHO
Et2Zn
Ph
solvent
ArCHO
Ar
solvent, T oC
*
Entry
Ligand
Solvent (2:1, v/v)
T (°C)
eeb (%)
Entry
Aldehyde
C6H5CHO
Ligand
Convnc (%)
MBc,d (%)
eee (%)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4a
4a
4a
4a
4ac
4a
4c
4c
4c
4c
4c
4cc
Toluene/hexane
Toluene/hexane
Toluene/hexane
Toluene/hexane
Decane/hexane
Hexane
TBME/hexane
Et2O/hexane
Et2O/hexane
Et2O/hexane
Decane/hexane
Hexane
0
0
0
0
0
0
0
0
À15
À30
0
0
0
86 (R)
50 (S)
70 (S)
58 (S)
70 (R)
76 (R)
82 (R)
90 (R)
92 (R)
86 (R)
24 (S)
44 (S)
54 (S)
56 (S)
70 (S)
86 (S)
1
2
3
4
5
6
7
8
(S,R,R)-4a
(S,S,R)-4c
(S,R,R)-4a
(S,S,R)-4c
(S,R,R)-4a
(S,S,R)-4c
(S,R,R)-4a
(S,S,R)-4c
(S,R,R)-4a
(S,S,R)-4c
(S,R,R)-4a
(S,S,R)-4c
(S,R,R)-4a
(S,S,R)-4c
(S,R,R)-4a
(S,S,R)-4c
(S,R,R)-4a
(S,S,R)-4c
(S,R,R)-4a
(S,S,R)-4c
(S,R,R)-4a
(S,S,R)-4c
(S,R,R)-4a
(S,S,R)-4c
(S,R,R)-4a
(S,S,R)-4c
(S,R,R)-4a
(S,S,R)-4c
(S,R,R)-4a
(S,S,R)-4c
80
54
89
84
80
82
81
37
49
70
58
63
59
60
56
50
71
30
87
69
78
61
60
33
55
20
46
38
82
54
95
81
90
92
99
83
74
95
87
90
96
91
99
95
87
82
73
96
70
75
58
88
99
97
85
97
93
92
70
81
92 (R)
86 (S)
64 (R)
62 (S)
52 (R)
52 (S)
80 (R)
84 (S)
36 (R)
72 (S)
64 (R)
80 (S)
70 (R)
62 (S)
60 (R)
60 (S)
78 (R)
48 (S)
74 (R)
76 (S)
60 (R)
66 (S)
76 (R)
70 (S)
84 (R)
44 (S)
82 (R)
32 (S)
76 (R)
46 (S)
o-ClC6H4CHO
o-BrC6H4CHO
o-MeC6H4CHO
o-OMeC6H4CHO
m-ClC6H4CHO
m-BrC6H4CHO
m-MeC6H4CHO
m-OMeC6H4CHO
p-ClC6H4CHO
p-BrC6H4CHO
p-MeC6H4CHO
p-OMeC6H4CHO
9
10
11
12
13
14
15
16
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
Et2O/hexane
DCM/hexane
Toluene/hexane
Toluene/hexane
0
À15
À30
a
Reaction conditions: benzaldehyde (1 mmol), Et2Zn (2 mmol), catalyst
(10 mol %), argon atmosphere.
Enantiomeric ratios were assessed by GC on a b-DEX 120 column after 20 h.
The recovered ligand (S,R,R)-4a and (S,S,R)-4c could be reused in subsequent
cycles without any loss in activity.
4
b
c
with the exception of o-methylbenzaldehyde (80% ee) (Table 2,
entries 7), m-bromobenzaldehyde (70% ee) (Table 2, entries 13)
and m-methoxybenzaldehyde (78% ee) (Table 2, entries 17). Ethyla-
tion of
a-naphthaldehyde and b-naphthaldehyde showed good
a-Naphthaldehyde
enantioselectivities (82% and 76% ee, respectively) (Table 2, entries
27 and 29). When (S,S,R)-4c was used as the catalyst, halogens at the
meta- or para-position, and electron donating substituents (induc-
tive or mesomeric) at the ortho-position exhibited higher enantio-
meric excesses (o-Me, 84%; o-OMe, 72%; m-Cl, 80%; p-Br, 66%)
(Table 2, entries 8, 10, 12 and 22). a- and b-naphthaldehyde yielded
low enantioselectivities when (S,S,R)-4c was used as the chiral
catalyst.
b-Naphthaldehyde
a
Reaction conditions: 10 mol % (S,R,R)-4a, 2.0 equiv Et2Zn, Et2O/hexane (2:1, v/v),
48 h, À15 °C, argon atmosphere.
b
Reaction conditions: 10 mol % (S,S,R)-4c, 3.0 equiv Et2Zn, toluene/hexane (2:1,
v/v), 48 h, À30 °C, argon atmosphere.
The conversions and mass balances (MB) were assessed by 1H NMR analysis
c
with diphenylmethane as an internal standard.
d
MB refers to the sum of the yields of the characterized product 1-phenylpropan-
1-ol, benzyl alcohol and the recovered aldehyde.
3. Conclusion
e
Determined by GC on a b-DEX 120 column.11b
Wehave prepared a newclass ofchiral aziridine diol ligands 4a–d
from aminoquinazolinone (S)-1b and mesityl oxide, and the abso-
lute stereochemistry of each isomer was successfully identified by
NMR and X-ray analysis. Their catalytic efficiencies were evaluated
by the reaction of Et2Zn with aldehydes. Ligands (S,R,R)-4a and
(S,S,R)-4c provide access to both enantiomers with good enantio-
meric excess in the enantioselective addition of diethylzinc to
various substituted benzaldehydes. Ligand (S,R,R)-4a directed the
catalytic process towards the formation of the (R)-1-phenylpropa-
nol derivatives. Switching the configuration of the aziridine alcohol
moiety in ligand (S,R,R)-4a switches the facial preference and (S,S,R)-
4c induces the formation of the (S)-1-phenylpropanol derivatives. In
conclusion, we have developed a new class of aziridine diol ligands,
which can easily be derivatized with different substituents for
asymmetric synthesis.
Gallenkamp apparatus and are not corrected. Infrared spectra were
recorded on a Perkin–Elmer spectrophotometer. 1H NMR and 13C
NMR spectra were recorded on a Varian Mercury (400 MHz) and
a Bruker Avance (400 MHz) spectrometer as solutions in CDCl3.
Chemical shifts are expressed in parts per million (ppm, d) down-
field from tetramethylsilane (TMS) and are referenced to CHCl3 as
an internal standard. All coupling constants are absolute values
and J values are expressed in Hertz (Hz). Enantiomeric excesses
were determined by HPLC analysis using a chiral column or chiral
GC analysis using a Supelco b-DEX 120 column. Optical rotations
were measured with a Bellingham + Stanley, ADP220, 589 nm
spectropolarimeter in a 1 dm tube; concentrations are given in
g/100 mL. Air- and moisture-sensitive reactions were performed
using oven-dried glassware under a dry argon atmosphere.
4. Experimental
4.1. General
4.2. Representative procedure for the aziridination of mesityl
oxide 3
(S)-3-Amino-2-(1-hydroxyethyl)quinazolin-4(3H)-one 1b (1.026 g,
5.0 mmol), mesityl oxide 3 (0.981 g, 10 mmol) and anhydrous K2CO3
(1.382 g, 10 mmol) were placed into a 25 mL round bottom flask
equipped with a magnetic stirrer bar and dissolved in 20 mL of DCM
at room temperature. Next, PIDA (1.772 g, 5.5 mmol) was added in
All reagents and solvents were purchased from commercial
sources with the highest purity available and were used without
further purification unless otherwise stated. All reactions were car-
ried out in anhydrous solvents. Melting points were obtained on a

156
S. Celik et al. / Tetrahedron: Asymmetry 26 (2015) 152–157
small portions (within 15 min) to the reaction mixture and stirring was
continued for 30 min, while the reaction progress was monitored by
TLC. After completion of the reaction, the reaction mixture was washed
with water (15 mL) and the aqueous phase was extracted with DCM
(2 Â 25 mL). The combined organic phases were washed with
saturated NaHCO3 (10 mL) and dried over Na2SO4. After removal of
the solvents under reduced pressure, the diastereoisomers were
separated on a silica gel column by elution with hexane–EtOAc in a
yield of 83%.
20.6, 19.0, 18.6; HRMS (TOF MS ES+) m/z calcd for C16H22N3O3
[M+H]+ 304.1661, found 304.1667; [
a]
20 = À103 (c 1, DCM); 99%
D
ee; retention time: 24.1 min, Chiralcel OD-H, n-hexane/iPrOH,
90:10, flow rate of 1 mL/min, 254 nm.
4.7. 2-[(1S)-1-Hydroxyethyl]-3-{(3R)-3-[(1S)-1-hydroxyethyl]-2,
2-dimethylaziridin-1-yl}quinazolin-4(3H)-one 4b
Colourless oil. Yield: 41%; Rf 0.19 (hexane–EtOAc = 1:1); 1H
NMR (400 MHz, CDCl3, ppm) d = 8.19 (ddd, J = 8.0, 1.4, 0.5 Hz,
1H), 7.76–7.68 (m, 2H), 7.48 (ddd, J = 8.0, 6.8, 1.5 Hz, 1H), 5.05
(dq, J = 6.4, 3.8 Hz, 1H), 4.72 (d, J = 3.8 Hz, 1H), 4.21–4.13 (m, 1H),
3.50 (d, J = 5.7 Hz, 1H), 2.14 (d, J = 3.9 Hz, 1H), 1.70 (d, J = 5.9 Hz,
3H), 1.62 (s, 3H), 1.57 (d, J = 6.4 Hz, 3H), 1.21 (s, 3H); 13C NMR
(100 MHz, CDCl3, ppm) d = 160.8, 156.9, 145.2, 133.9, 127.5,
127.0, 126.2, 121.8, 66.3, 66.2, 57.0, 51.4, 21.0, 20.9, 19.2, 18.9;
HRMS (TOF MS ES+) m/z calcd for C16H22N3O3 [M+H]+ 304.1661,
4.3. 3-[(3R)-3-Acetyl-2,2-dimethylaziridin-1-yl]-2-[(1S)-1-hydr-
oxyethyl]quinazolin-4(3H)-one 5a
Colourless oil. Yield: 46%; Rf 0.30 (hexane–EtOAc = 1:1); 1H
NMR (400 MHz, CDCl3, ppm) d = 8.18 (dd, J = 8.0, 1.1 Hz, 1H),
7.78–7.73 (m, 1H), 7.71–7.69 (m, 1H), 7.46 (ddd, J = 8.0, 7.0,
1.2 Hz, 1H), 5.05–4.99 (m, 1H), 4.65 (d, J = 4.2 Hz, 1H), 4.26
(s, 1H), 2.46 (s, 3H), 1.64 (d, J = 5.6 Hz, 3H), 1,46 (s, 3H), 1,38
(s, 3H); 13C NMR (100 MHz, CDCl3, ppm) d = 202.3, 161.1, 157.2,
145.2, 134.2, 127.4, 127.1, 126.3, 121.6, 65.9, 57.0, 53.2, 29.4,
20.1, 19.9, 19.5; HRMS (TOF MS ES+) m/z calcd for C16H20N3O3
found 304.1668; [
9.2 min, Chiralcel OD-H, n-hexane/iPrOH, 90:10, flow rate of
a
]
20 = À192 (c 1, DCM); 99% ee; retention time:
D
1 mL/min, 254 nm.
[M+H]+ 302.1505, found 302.1506; [
ee; retention time: 11.3 min, Chiralcel OD-H, n-hexane/iPrOH,
a]
20 = À16 (c 1, DCM); 99%
4.8. 2-[(1S)-1-Hydroxyethyl]-3-{(3S)-3-[(1R)-1-hydroxyethyl]-2,
2-dimethylaziridin-1-yl}quinazolin-4(3H)-one 4c
D
90:10, flow rate of 1 mL/min, 254 nm.
Colourless oil. Yield: 32%; Rf 0.21 (hexane–EtOAc = 1:1); 1H
NMR (400 MHz, CDCl3, ppm) d = 8.15 (dd, J = 8.0, 1.2 Hz, 1H), 7.69
(ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.64–7.62 (m, 1H), 7.43 (ddd, J = 8.0,
7.0, 1.3 Hz, 1H), 4.91–4.85 (m, 1H), 4.56 (d, J = 7.9 Hz, 1H), 4.24–
4.18 (m, 1H), 3.12 (d, J = 5.8 Hz, 1H), 2.46 (br s, 1H), 1.57 (s, 3H),
1.55 (d, J = 6.3 Hz, 3H), 1.51 (d, J = 6.4 Hz, 3H), 1.15 (s, 3H); 13C
NMR (100 MHz, CDCl3, ppm) d = 160.4, 159.7, 144.9, 134.2, 127.0,
126.9, 126.6, 121.7, 66.1, 65.8, 57.6, 52.0, 22.1, 21.2, 20.8, 19.1;
HRMS (TOF MS ES+) m/z calcd for C16H22N3O3 [M+H]+ 304.1661,
4.4. 3-[(3S)-3-Acetyl-2,2-dimethylaziridin-1-yl]-2-[(1S)-1-hydr-
oxyethyl]quinazolin-4(3H)-one 5b
Colourless oil. Yield: 37%; Rf 0.37 (hexane–EtOAc = 1:1); 1H
NMR (400 MHz, CDCl3, ppm) d = 8.18 (dd, J = 8.0, 1.4 Hz, 1H), 7.76
(ddd, J = 8.2, 7.0, 1.4 Hz, 1H), 7.69–7.67 (m, 1H), 7.49 (ddd, J = 8.0,
7.0, 1.2 Hz, 1H), 4.88 (qd, J = 8.2, 6.4 Hz, 1H), 4.49 (d, J = 8.2 Hz,
1H), 3.65 (s, 1H), 2.47 (s, 3H), 1.62 (d, J = 6.4 Hz, 3H), 1.45 (s, 3H),
1.29 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm) d = 203.6, 160.0,
158.8, 144.8, 134.3, 127.0, 126.8, 126.5, 121.4, 65.7, 58.4, 54.0,
29.3, 22.0, 19.9, 19.4; HRMS (TOF MS ES+) m/z calcd for
found 304.1667; [a]
20 = +240 (c 1, DCM); 99% ee; retention time:
D
7.1 min, Chiralcel OD-H, n-hexane/iPrOH, 90:10, flow rate of
1 mL/min, 254 nm.
C
16H20N3O3 [M+H]+ 302.1505, found 302.1492; [ 20 = +73 (c 1,
a]
D
DCM); 99% ee; retention time: 8.5 min, Chiralcel OD-H, n-hex-
ane/iPrOH, 90:10, flow rate of 1 mL/min, 254 nm.
4.9. 2-[(1S)-1-Hydroxyethyl]-3-{(3S)-3-[(1S)-1-hydroxyethyl]-2,
2-dimethylaziridin-1-yl}quinazolin-4(3H)-one 4d
4.5. Representative procedure for the reduction of aziridinyl
ketones 5
Colourless oil. Yield: 47%; Rf 0.35 (hexane–EtOAc = 1:1); 1H
NMR (400 MHz, CDCl3, ppm) d = 8.19 (dd, J = 8.1, 1.4 Hz, 1H), 7.75
(ddd, J = 8.4, 7.1, 1.4 Hz, 1H), 7.68–7.66 (m, 1H), 7.49–7.45
(m, 1H), 5.26 (d, J = 1.2 Hz, 1H), 4.91–4.84 (m, 1H), 4.48 (d,
J = 8.4 Hz, 1H), 3.80–3.72 (m, 1H), 2.71 (d, J = 9.0 Hz, 1H), 1.55 (d,
J = 6.4 Hz, 3H), 1.46 (s, 3H), 1.29 (d, J = 6.4 Hz, 3H),1.19 (s, 3H);
13C NMR (100 MHz, CDCl3, ppm) d = 161.1, 159.2, 144.9, 134.5,
127.2, 126.9, 126.7, 121.3, 67.2, 66.0, 60.0, 52.0, 22.2, 20.8, 20.6,
19.0; HRMS (TOF MS ES+) m/z calcd for C16H22N3O3 [M+H]+
To a stirring solution of aziridinyl ketone 5 (301 mg, 1 mmol) in
ethanol (10 mL), NaBH4 (38 mg, 1 mmol) was added in small por-
tions over 10 min, after which the reaction mixture was allowed
to stir until the starting aziridinyl ketone was consumed as moni-
tored by TLC (10 min). Approximately 5 mL of water was added to
the reaction mixture, and the majority of the ethanol was removed
in vacuo. The residual solution was extracted with DCM
(3 Â 15 mL), and the combined organic phases were dried over
Na2SO4. After removal of the solvent, the crude diastereomeric
mixture was subjected to column chromatography on silica gel
using a 3:1 hexane/ethyl acetate mixture to obtain enantiomeri-
cally pure aziridine diols 4a–d.
304.1661, found 304.1669; [a]
20 = +126 (c 1, DCM); 99% ee; reten-
D
tion time: 8.9 min, Chiralcel OD-H, n-hexane/iPrOH, 90:10, flow
rate of 1 mL/min, 254 nm.
4.10. (1S)-1-{3-[(3R)-3-Acetyl-2,2-dimethylaziridin-1-yl]-4-oxo-
3,4-dihydroquinazolin-2-yl}ethyl 4-nitrobenzoate 5aa
4.6. 2-[(1S)-1-Hydroxyethyl]-3-{(3R)-3-[(1R)-1-hydroxyethyl]-2,
2-dimethylaziridin-1-yl}quinazolin-4(3H)-one 4a
To a stirring solution of (S,R)-5a (30 mg, 0.10 mmol) in DCM
(2 mL), pyridine (16 mg, 0.20 mmol) and p-nitrobenzoyl chloride
(56 mg, 0.30 mmol) were added at 0 °C. The reaction was stirred
at room temperature for 6 h and then quenched by the addition
of saturated aqueous sodium bicarbonate. The phases were sepa-
rated, and the aqueous phase was extracted with dichloromethane
(2 Â 5 mL). The combined organic layers were washed with brine,
dried over Na2SO4, filtered and concentrated under vacuum. The
residue was subjected to column chromatography with silica gel
and a 3:1 hexane/ethyl acetate ratio to afford (S,R)-5aa (36 mg,
Colourless oil. Yield: 42%; Rf 0.23 (hexane–EtOAc = 1:1);
1H NMR (400 MHz, CDCl3, ppm) d = 8.17–8.15 (m, 1H), 7.75–7.68
(m, 2H), 7.49–7.44 (m, 1H), 5.08 (br s, 1H), 5.03–4.98 (m, 1H),
4.50 (d, J = 2.0 Hz, 1H), 3.83–3.76 (m, 1H), 2.95 (d, J = 9.0 Hz, 1H),
1.69 (d, J = 6.3 Hz, 3H), 1.51 (s, 3H), 1.32 (d, J = 6.4 Hz, 3H), 1.18
(s, 3H); 13C NMR (100 MHz, CDCl3, ppm) d = 161.5, 156.1, 145.5,
134.3, 127.9, 127.4, 126.4, 121.7, 67.2, 66.87 59.9, 52.3, 20.9,

S. Celik et al. / Tetrahedron: Asymmetry 26 (2015) 152–157
157
0,08 mmol, 80% yield) as
a
colourless needles crystal. mp
CCDC-986551 contains the supplementary crystallographic
data for (S,R)-5aa. These data can be obtained free of charge via
http://www.ccdc.cam.ac.uk/conts/retrieving.html, or from the
Cambridge Crystallographic Data Center, 12 Union Road, Cam-
bridge CB2 1EZ, UK; fax: +44 1223 336 033; or e-mail: deposit@
ccdc.cam.ac.uk.
161–163 °C (EtOH); Rf 0.60 (hexane–EtOAc = 1:1); 1H NMR
(400 MHz, CDCl3, ppm) d = 8.26 (m, 5H), 7.76 (m, 2H), 7.53
(m, 1H), 6.36 (q, J = 6.4 Hz, 1H), 3.84 (s, 1H), 2.31 (s, 3H), 1.90
(d, J = 6.4 Hz, 3H), 1.51 (s, 3H), 1.36 (s, 3H); 13C NMR (100 MHz,
CDCl3, ppm) d = 203.2, 164.3, 160.5, 152.7, 150.7, 145.3, 135.0,
134.1, 131.0, 127.7, 127.5, 126.3, 123.5, 121.9, 69.0, 58.7, 54.4,
29.0, 20.4, 20.0, 17.6; HRMS (TOF MS ES+) m/z calcd for
Acknowledgments
C
23H23N4O6 [M+H]+ 451.1618, found 451.1613; [ 20 = +220 (c 1,
a]
D
DCM); 99% ee; retention time: 18.1 min, Chiralcel OD-H, n-hex-
ane/iPrOH, 90:10, flow rate of 1 mL/min, 254 nm.
This study was supported by Ataturk University Research Fund
(Project number: 2011/90). The authors would like to thank
Dr. Graham Eaton from the Leicester University for the HRMS
measurements.
4.11. Typical procedure for the addition of diethylzinc to aldehyde
To a solution of 4 (0.05 mmol) in freshly distilled diethyl ether
(1 mL) diethylzinc (1 mL of 1 M hexane solution, 1 mmol) was
added at ambient temperature under argon. The mixture was stir-
red for 1 h and then cooled to À15 °C. A solution of aldehyde
(0.5 mmol) in diethyl ether (1 mL) was added via syringe and the
mixture was stirred for 48 h. The reaction was then quenched by
the addition of saturated NH4Cl solution (4 mL), and diphenylme-
thane (0.25 mmol) was added as an internal standard. The mixture
was extracted with EtOAc (3 Â 10 mL) and the combined organic
extracts were washed with water (10 mL) and brine (10 mL). The
organic layer was dried over anhydrous Na2SO4 and concentrated
in vacuo. Conversion and yield were determined from the crude
mixture by 1H NMR analysis. The crude product was purified by
preparative thin layer chromatography on silica gel (hexane/EtOAc,
90:10) and the enantiomeric excess of the addition product was
determined by GC on a Chiral b-DEX 120 capillary column.11b
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4.12. X-Ray structure analysis
For the crystal structure determination, a single-crystal of
compound (S,R)-5aa was used for data collection on a four-circle
Rigaku R-AXIS RAPID-S diffractometer (equipped with a two-
dimensional area IP detector). Graphite-monochromated Mo-K
a
radiation (k = 0.71073 Å) and oscillation scans technique with
w = 5° for one image were used for data collection. The lattice
parameters were determined by the least-squares methods on the
basis of all reflections with F2 > 2 (F2). Integration of the intensities,
D
r
correction for Lorentz and polarization effects and cell refinement
were performed using CrystalClear (Rigaku/MSC Inc., 2005) soft-
ware.19 The structures were solved by direct methods using SHEL-
XS-9720 and refined by a full-matrix least-squares procedure using
the program SHELXL-97.20 H atoms were positioned geometrically
and refined using a riding model. The final difference Fourier maps
showed no peaks of chemical significance. Crystal data for (S,R)-
5aa: C23H22N4O6, crystal system, space group: monoclinic, C2; (no:
5); unit cell dimensions: a = 22.9393(17), b = 6.7784(10), c =
14.3646(11) Å,
a = 90, b = 97.507(5), c = 90 Å; volume: 2214.4
(4) Å3; Z = 4; calculated density: 1.351 g/cm3; absorption coeffi-
cient: 0.100 mmÀ1 ; F(000): 944; h-range for data collection 2.1–
26.6°; refinement method: full matrix least-square on F2; data/
parameters: 2911/299; goodness-of-fit on F2: 0.995; final R-indices
[I > 2r(I)]: R1 = 0.071, wR2 = 0.184; largest diff. peak and hole: 0.211
and À0.178 e ÅÀ3
.