N-Trityl-aziridinyl alcohols as highly efficient chiral catalysts in asymmetric additions of organozinc species to aldehydes

Article abstract of DOI:10.1016/j.tetasy.2014.11.016

A synthetic route leading to a series of new chiral catalysts containing the N-trityl-aziridine moiety and a primary and a secondary hydroxyl group as nucleophilic centers is described. All the new compounds have been tested as chiral catalysts in the enantioselective addition of diethylzinc and phenylethynylzinc to aryl and alkyl aldehydes, yielding the corresponding chiral alcohols in high chemical yields (up to 96%) and with excellent ee's of ca. 90%. The influence of the stereogenic centers located at the carbon atom bonded with the hydroxyl moiety and on the carbon of the aziridine ring on the stereochemistry of the addition reactions is also discussed.

Full text of DOI:10.1016/j.tetasy.2014.11.016

Tetrahedron: Asymmetry 26 (2015) 35–40
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
N-Trityl-aziridinyl alcohols as highly efficient chiral catalysts
in asymmetric additions of organozinc species to aldehydes
⇑
´
´
Szymon Jarzynski, Stanisław Lesniak, Adam M. Pieczonka, Michał Rachwalski
´
´
Department of Organic and Applied Chemistry, University of Łódz, Tamka 12, 91-403 Łódz, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 October 2014
Accepted 21 November 2014
A synthetic route leading to a series of new chiral catalysts containing the N-trityl-aziridine moiety and a
primary and a secondary hydroxyl group as nucleophilic centers is described. All the new compounds
have been tested as chiral catalysts in the enantioselective addition of diethylzinc and phenylethynylzinc
to aryl and alkyl aldehydes, yielding the corresponding chiral alcohols in high chemical yields (up to 96%)
and with excellent ee’s of ca. 90%. The influence of the stereogenic centers located at the carbon atom
bonded with the hydroxyl moiety and on the carbon of the aziridine ring on the stereochemistry of
the addition reactions is also discussed.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
aziridinyl alcohols containing only one stereogenic center located
at the aziridine subunit16,25,26 or aziridinyl alcohols bearing two
The enantioselective production of various chiral compounds
constitutes as one of the central topics in modern organic
chemistry.1–4 In recent years, tremendous efforts have been made
to elaborate upon stereoselective routes for the synthesis of enan-
tiomerically pure compounds.5 A crucial factor influencing the
chemical yield and stereoselectivity of asymmetric reactions is
the use of an appropriate chiral catalyst. Recently, there has been
a growing interest in the synthesis and modification of various chi-
ral amine-functionalized compounds, especially amino alcohols, to
test their catalytic activity in various asymmetric reactions. Among
chiral amine alcohols, aziridine alcohols constitute as a very inter-
esting class of compounds when applied as chiral ligands espe-
cially in the asymmetric additions of organozinc species to
carbonyl compounds.6–10 In continuation of our current interests
in the field of asymmetric synthesis,11,12 especially in the applica-
tion of aziridine-based chiral catalysts13–21 and taking into account
the fact that aziridines strongly coordinate to organozinc
species,22–24 we focused our attention on the synthesis of various
N-trityl-aziridinyl alcohols and checked their catalytic activity
toward the addition of diethylzinc and phenylethynylzinc to alde-
hydes. According to previous literature reports, such types of chiral
catalysts have been tested in model asymmetric additions of dieth-
ylzinc to aldehydes to give the corresponding chiral alcohols in
high chemical yield (around 90%) and with high enantiomeric
excess values (up to 98%).25,26 It should be noted that either
stereogenic centers (located at C-aziridine atom and C–OH carbon
atom8) were very efficient in the aforementioned reactions.
However, studies on the influence of the C–OH stereogenic center
on catalyst effectiveness have not been performed. Savoia
suggested that in the series of aziridine ligands containing two ste-
reogenic centers, only the stereogenic center in the aziridine ring is
crucial for the efficacy of the ligands.27 On the other hand, we21
recently showed that in a series of aziridinyl alcohols constructed
on the chiral monoterpene scaffold, the absolute configuration of
the products of the asymmetric transformation depends on the
configuration of the terpene moiety but not on the aziridine.
Hence, further studies on the influence of the C–OH stereogenic
center on the stereochemical outcome of organozinc species addi-
tion to aldehydes have been conducted. So far, a series of aziridinyl
alcohols containing two asymmetric carbon atoms has been
synthesized and their catalytic activity has been tested in the
aforementioned addition reactions.
2. Results and discussion
2.1. Synthesis of the ligands
The synthetic route leading to N-trityl-aziridinyl alcohols 7–11
is shown in Scheme 1. The first step of the synthesis was the prep-
aration of methyl (S)-N-triphenylmethylaziridinate 1. This ester
was obtained via cyclization of an L-serine derivative following
the literature.28 Compound 1 was then converted into the corre-
sponding Weinreb’s amide, (S)-triphenylmethyl-2-aziridine-
⇑
Corresponding author.
E-mail address: mrach14@wp.pl (M. Rachwalski).
http://dx.doi.org/10.1016/j.tetasy.2014.11.016
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

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S. Jarzynski et al. / Tetrahedron: Asymmetry 26 (2015) 35–40
O
O
OMe
Me
OMe
COOH
NH2
N
HO
Me(MeO)NH.HCl
AlMe3, CH2Cl2
N
N
Trt
Trt
LiBH4,
MeOH
1
2
THF,
0oC - rt
THF,
RMgCl
-78oC
OH
N
Trt
OH
O
R
11
R
ZnCl2, NaBH4
THF, 0oC
3
7
8
R = Me and
N
N
4
R = Ph and
Trt
Trt
R = iPr 5 and 9
R = Bn 6 and 10
7-10
3-6
Scheme 1. Synthetic pathway leading to chiral ligands 7–11.
Table 2
N-methoxy-N-methylcarboxamide 2 using N,O-dimethylhydroxyl-
amine hydrochloride and trimethylaluminum.29 The reaction was
performed under an argon atmosphere in anhydrous methylene
chloride for 5 h and the corresponding product 2 was isolated by
extraction in 94% yield. This substance was used for the next step
without additional purification. Amide 2 was treated with four var-
ious Grignard reagents: methylmagnesium, phenylmagnesium,
isopropylmagnesium and benzylmagnesium chlorides in anhy-
drous tetrahydrofurane at À78 °C under argon.30 Aziridinylketones
3–6 isolated via extraction were subjected to column chromatogra-
phy on silica gel using a mixture of hexane and ethyl acetate (1:9)
as the eluent to afford pure products 3–6. The chemical yields of
the reactions of amide 2 with the Grignard reagents are shown in
Table 1.
Stereoselective reduction of ketones 3–6 to form chiral ligands 7–10
a
Entry
Product
Yield (%)
[a]
D
1
2
3
4
7
8
9
92
94
89
94
À2.7
À2.9
À2.5
À3.0
10
a
In chloroform (c 1 at 20 °C).
Aziridine alcohol 11 bearing a primary hydroxyl group was syn-
thesized from ester 1 via reduction using lithium borohydride and
methanol in anhydrous THF at 0 °C. After extraction with ethyl ace-
tate, compound 11 was isolated in almost quantitative yield (99%).
In order to obtain ligand 12 with an opposite absolute
configuration at the carbon bonded with the OH group, ketone 6
was subjected to reduction using L-Selectride in anhydrous tetra-
hydrofuran at À78 °C (Scheme 2). After extraction with dichloro-
methane and purification via column chromatography, chiral
ligand 12 was obtained in 90% yield.
Table 1
Reactions of amide 2 with Grignard reagents
Entry
Grignard reagent
Product
Yield (%)
1
2
3
4
CH3MgCl
PhMgCl
(CH3)2CHMgCl
BnMgCl
3
4
5
6
88
93
91
95
O
OH
L-selectride
THF, -78 oC
N
Trt
N
Trt
Ketones 3–6 were subjected to reduction using freshly dried
zinc chloride and sodium borohydride.23 Previously, we reported
that such a reduction of aziridinyl ketones without any substituent
on the nitrogen atom proceeded in a fully stereoselective manner
to give the erythro diastereoisomer. Moreover, Lee and Ha
described that this reaction remains fully stereoselective for enan-
6
12
Scheme 2. Reduction of ketone 6 using L-Selectride to form ligand 12.
2.2. Screening of the ligands
tiomerically pure aziridinyl ketones bearing an (R)-(+)-a-methyl-
In order to check the catalytic activity of novel aziridine
alcohols 7–12 in the additions of organozinc species to aldehydes,
the reactions of diethylzinc and phenylethynylzinc with benzalde-
hyde were chosen as the model transformations (Scheme 3). All of
benzyl substituent on the nitrogen atom and, additionally, the
use of L-Selectride led to the second threo diastereoisomer. We
found a significant decrease in the stereoselectivity for aziridinyl
ketones bearing the N-trityl substituent. The reduction reactions
were performed under argon at 0 °C leading to the formation of
an inseparable mixture of diastereoisomers (with the same pre-
dominant isomer, although its absolute configuration was not
determined) in a ratio of 59:41 for NaBH4/ZnCl2 and of 87:13 for
L-Selectride. Chiral ligands 7–10 were obtained as a mixture of dia-
stereoisomers [i.e., possessing an (R)- or (S)-configuration at
C⁄–OH] and were isolated by extraction with diethyl ether and
purified via column chromatography on silica gel (ethyl acetate
and hexane 1:4 as eluent). The chemical yields and specific rota-
tion values are shown in Table 2.
OH
ligand, Et2Zn
PhCHO
Ph
Ph
toluene
14a
OH
Ph
ligand, Et2Zn
THF
PhCHO
Ph
+
15a
Scheme 3. Asymmetric addition of diethyl- and phenylethynylzinc to
benzaldehyde.

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37
S. Jarzynski et al. / Tetrahedron: Asymmetry 26 (2015) 35–40
Table 3
2.3. Asymmetric additions of diethyl- and phenylethynylzinc to
various aldehydes promoted by ligand 10
Screening of the catalysts 7-13
Entry Ligand
Product 14a
Product 15a
With efficient ligands in hand, we next determined the scope of
the catalytic activity of selected ligand 10. Hence, it was used as
the chiral catalyst for the title reactions carried out with a series
of aldehydes (Scheme 5). The results are summarized in Table 4.
a
a
Yield
(%)
[
a
]
D
ee (%)b Abs
config. (%)
Yield
[a
]
D
ee (%)b Abs
config.c
1
2
3
4
5
6
7
7
8
9
10
11
12
13
91 À39.5 88
90 À39.3 87
94 À41.8 93
97 À41.8 93
(S)
(S)
(S)
(S)
nd
(S)
(R)
90
88
93
96
90
89
93
À4.6 91
À4.6 90
À4.6 91
À4.8 94
À4.1 81
À4.4 88
+4.6 92
(S)
(S)
(S)
(S)
(S)
(S)
(R)
nd
85
95
nd
nd
OH
À40.0 89
ligand 10, Et2Zn
+40.9 91
RCHO
R
toluene
a
b
c
In chloroform (c 1).
14a-e
Determined using chiral HPLC.
According to literature data.31
10
OH
R
ligand , Et2Zn
Ph
RCHO
Ph
+
THF
the additions were carried out under standard reaction conditions
(in toluene or THF),13,14 and the results are shown in Table 3.
The results shown in Table 3 clearly prove that all of the
aziridines 7–12 are able to catalyze the model addition reactions
leading to desired products 14a and 15a in high chemical yields
(>90%) and with excellent enantiomeric excesses of >90%. Ligand
11 was only tested in the asymmetric addition of phenylethynyl-
zinc to benzaldehyde due to the fact that it was tested earlier in
the addition of diethylzinc to benzaldehyde by Zwanenburg et al.
leading to alcohol 14a in 90% yield and with moderate ee
(64%).32 The fact, that ligands 7–12 can be used as mixtures of
diastereoisomers, that is, 59:41 (NaBH4/ZnCl2) and 87:13 (L-Select-
ride) and give an identical enantioselectivity suggests that the
C⁄–OH configuration has no influence on the stereochemical
outcome of the addition. The stereogenic center at the aziridine
moiety is probably of crucial importance. The absolute configura-
tions at the newly generated stereogenic centers of 14a and 15a
were assigned according to the literature.31
Finally, in order to prove the decisive influence of the stereo-
genic center located on the aziridine subunit on the stereochemis-
try of the addition reactions, diastereomeric ligand 13 (Scheme 4)
with the opposite absolute configuration of the carbon atom at the
aziridine moiety was synthesized according to the procedure
depicted in Scheme 1 starting from commercially available D-ser-
ine. After reduction of the corresponding ketone, compound 13
was afforded in 91% yield as a 59:41 mixture of diastereoisomers.
15a-e
Scheme 5. Additions of diethyl- and phenylethynylzinc to aldehydes promoted by
ligand 10.
The results collected in Tables 3 and 4 indicate that the selected
ligand 10 should be considered as a highly effective catalyst for the
title reactions leading to the target alcohols in excellent yields and
ee’s.
3. Conclusion
The chiral aziridine ligands synthesized from both enantiomers
of commercially available serine containing two stereogenic cen-
ters were found to be highly effective catalysts for the enantiose-
lective addition of diethylzinc and phenylethynylzinc to various
aldehydes. The stereogenic center located at the carbon atom
bonded with the hydroxyl group is not crucial for the stereochem-
ical outcome of the addition because the use of mixtures with
various contaminations of both diastereoisomers led to the same
stereochemical results. On the other hand, the change of the abso-
lute configuration at the center located at the aziridine subunit led
to the addition products with opposite absolute configurations.
This may prove that for the stereochemical outcome of the
addition of organo zinc reagents to aldehydes, the stereogenic
center at the aziridine moiety is crucial. The above conclusions
are relevant only for ligands containing non-expanded OH-func-
tionalized aziridinyl derivatives, but are not applicable for
aziridinyl alcohols built on more complex chiral scaffolds such as
monoterpenes.
OH
N
Trt
4. Experimental
4.1. General
13
Scheme 4. Ligand 13 (as a mixture of diastereoisomers) obtained from D-serine.
Unless otherwise specified, all reagents were purchased from
commercial suppliers and used without further purification.
Toluene and tetrahydrofuran were distilled from the sodium
benzophenone ketyl radical. 1H NMR spectra were recorded on a
Bruker instrument at 600 MHz with CDCl3 as the solvent and rela-
tive to TMS as the internal standard. Data are reported as s = sin-
glet, d = doublet, t = triplet, q = quartet, m = multiplet, b = broad.
Optical rotations were measured on a Perkin–Elmer 241 MC polar-
imeter with a sodium lamp at room temperature (c 1). Column
chromatography was carried out using Merck 60 silica gel. TLC
was performed on Merck 60 F254 silica gel plates. Visualization
was accomplished with UV light (254 nm) or using iodine vapor.
The enantiomeric excess (ee) values were determined by chiral
HPLC (Knauer, Chiralcel AS).
With enantiomerically pure catalyst 13 in hand, asymmetric
addition reactions of diethylzinc and phenylethynylzinc to benzal-
dehyde were carried out under standard conditions with ligand 13
as the chiral promoter. As can be seen in Table 3 (entry 7), both
reactions proceeded very efficiently in terms of chemical yield
and enantiomeric excess. It should be also mentioned that the
absolute configurations of products 14a and 15a were opposite
to those obtained earlier, thus the change of the absolute
configuration on the carbon atom located at the aziridine subunit
led to addition products with opposite configurations. This
phenomenon may prove that the stereogenic center located at
the aziridine moiety is crucial for the stereochemical outcome of
the addition reactions of organozinc compounds to aldehydes.

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S. Jarzynski et al. / Tetrahedron: Asymmetry 26 (2015) 35–40
38
Table 4
Additions of diethyl- and phenylethynylzinc to aldehydes promoted by ligand 10
Entry
R
Products 14a–e
Products 15a–e
a
a
Yield (%)
[
a
]
ee (%)b
Abs config.c
Yield (%)
[a
]
D
ee (%)b
Abs config.c
D
1
2
3
4
5
Ph
97
94
92
89
93
À41.8
À47.0
+6.4
93
90
91
87
92
(S)
(S)
(S)
(S)
(S)
96
92
90
88
89
À4.8
94
92
86
91
90
(S)
(R)
(S)
(R)
(R)
2-MeOC6H4
n-Pr
4-BrC6H4
2-MeC6H4
À7.7
À3.0
+3.7
À7.6
À41.1
À11.2
a
b
c
In chloroform (c 1, 20 °C).
Determined using chiral HPLC.
According to the literature data.13,14,33,34
4.2. Starting materials
(CH), 74.5 (Cq), 126.9 (Car), 127.6 (Car), 129.3 (Car), 129.3 (Car),
143.7 (Cq ar), 212.2 (C@O).
Methyl (S)-N-triphenylmethyl aziridinate
1
was prepared
Ketone 5 (colorless oil): 1H NMR (CDCl3): d = 1.62 (dd, J = 6.0 Hz,
1.5 Hz, 1H), 2.45 (dd, J = 2.7 Hz, 1.5 Hz, 1H), 2.76 (dd, J = 6.0 Hz,
3.0 Hz, 1H), 7.24–7.34 (m, 9H), 7.41–7.45 (m, 2H), 7.54–7.59 (m,
7H), 7.86–7.88 (m, 2H); 13C NMR (CDCl3): d = 30.7 (CH2), 34.9
(CH), 74.8 (Cq), 126.9 (Car), 127.6 (Car), 128.2 (Car), 128.5 (Car),
129.4 (Car), 133.0 (Ca), 137.3 (Cq ar), 143.8 (Cq ar), 196.9 (C@O).
Ketone 6 (colorless oil): 1H NMR (CDCl3): d = 1.44 (dd, J = 6.4 Hz,
1.0 Hz, 1H), 2.07 (d, J = 6.4 Hz, 2.7 Hz, 1H), 2.28 (dd, J = 3.0 Hz,
1.0 Hz, 1H), 3.83 (d, J = 15.6 Hz, 1H), 3.96 (d, J = 15.6 Hz, 1H),
7.19–7.33 (m, 14H), 7.42–7.44 (m, 6H); 13C NMR (CDCl3): d = 29.6
(CH2), 38.1 (CH), 45.9 (CH2), 74.5 (Cq), 126.9 (Car), 127.6 (Car),
129.3 (Car), 129.6 (Car), 133.9 (Cq ar), 143.4 (Cq ar), 206.1 (C@O).
according to the literature.28
4.3. Synthesis of (S)-N-triphenyl-2-aziridine N-methoxy-N-methyl
carboxamide 2
To a suspension of N,O-dimethylhydroxylamine HCl (880 mg,
9,11 mmol) in anhydrous CH2Cl2 (5 mL) at À20 °C trimethylalumi-
num (2 M, 4.55 mL, 9.11 mmol) was added dropwise under a nitro-
gen atmosphere. The reaction mixture was warmed to 25 °C and
stirred for 1 h. After this time, the reaction mixture was again
cooled to À20 °C and methyl (S)-N-triphenylmethyl aziridinate 1
(0.343 g, 1 mmol) in anhydrous CH2Cl2 (2 mL) was added drop-
wise. After stirring at rt for 4 h, the reaction was cooled to 0 °C,
and then carefully quenched with H2O (2 mL). The resulting mix-
ture was extracted with Et2O (3 Â 10 mL), the combined organic
layers were dried over MgSO4, filtered, and the solvents were
removed under reduced pressure to yield 2 as a colorless oil
(0.350 g, 94%). The product was used in the next step without fur-
ther purification; 1H NMR (CDCl3, 600 MHz): d = 1.43 (dd, J = 6.0,
1.6 Hz, 1H), 2.37–2.39 (m, 2H), 3.24 (s, 3H), 3.42 (s, 3H), 7.18–
7.32 (m, 9H), 7.56–7.58 (m, 6H). Other spectroscopic data were
in agreement with the literature.35
4.5. Stereoselective reduction of aziridinyl ketones 3–6: general
procedure
The corresponding aziridinyl ketone (1 mmol) was dissolved in
5 mL of anhydrous THF at 0 °C. Next a catalytic amount of freshly
dried ZnCl2 (1.5 mmol) was added. The solution was stirred for
1 h, after which the reaction mixture was again cooled to 0 °C,
NaBH4 (2 mmol) was added in portions and the reaction mixture
was stirred at room temperature. The progress of the reaction
was monitored by TLC (AcOEt/hexane 1:1). After completion, the
reaction was quenched with an aqueous solution of NaOH
(5 mL), and the mixture was extracted with Et2O (3 Â 10 mL).
The combined organic layers were dried over MgSO4, filtered,
and the solvents were removed under reduced pressure. The crude
products were purified by flash chromatography on silica gel with
AcOEt/hexane (1:4). The chemical yields and specific rotation val-
ues of alcohols 7–10 are summarized in Table 2.
Alcohol 7 (colorless solid): mp 38–40 °C (as a mixture of diastere-
oisomers); 1H NMR (CDCl3): major diastereoisomer d = 1.07 (d,
J = 6.0 Hz, 1H), 1.13 (d, J = 6.0 Hz, 3H), 1.51–1.53 (m, 1H), 1.89 (d,
J = 3.0 Hz, 1H), 3.08 (s, OH), 4.15–4.19 (m, 1H), 7.29–7.32 (m,
9H), 7.45–7.47 (m, 6H); minor diastereoisomer d = 1.16 (d,
J = 6.4 Hz, 1H), 1.17 (d, J = 6.4 Hz, 3H), 1.41–1.44 (m, 1H), 1.84 (d,
J = 3.0 Hz, 1H), 2.31 (d, J = 4.6 Hz, OH), 3.76–3.79 (m, 1H), 7.23–
7.27 (m, 9H), 7.52–7.54 (m, 6H); 13C NMR (CDCl3): major diaste-
reoisomer d = 21.0 (CH3), 24.5 (CH), 38.8 (CH2), 68.4 (CH), 73.7
(Cq), 126.8 (Car), 127.5 (Car), 129.4 (Car), 144.3 (Cq ar) (as superposi-
tion for both diastereoisomers); minor diastereoisomer d = 19.7
(CH3), 21.8 (CH), 37.2 (CH2), 63.3 (CH), 73.8 (Cq), 126.8 (Car),
127.6 (Car), 129.3 (Car), 142.4 (Cq ar); MS (CI): m/z 330 (M+H); HRMS
(EI): calcd for C23H23NO: 329.1767, found: 329.1779.
4.4. Reactions of aziridine amide with Grignard reagents: general
procedure
To a solution of aziridine amide 2 (0.372 g, 1 mmol) in anhy-
drous THF (5 mL) at À78 °C, the Grignard reagent (2 M, solution
in THF, 1 mL, 2 mmol) was added dropwise. The solution was stir-
red for 1 h at À78 °C, after which the solution was slowly warmed
to room temperature. The progress of the reaction was monitored
by TLC (AcOEt/hexane 1:1). The reaction was cooled to 0 °C, and
then carefully quenched with H2O (5 mL). The reaction mixture
was extracted with Et2O (3 Â 10 mL), the combined organic layers
were dried over MgSO4, filtered, and the solvents were removed
under reduced pressure. The products were purified by flash chro-
matography on silica gel with AcOEt/hexane (1:9). The chemical
yields of ketones 3–6 are collected in Table 1.
Ketone 3 (colorless oil): 1H NMR (CDCl3): d = 1.47 (dd, J = 6.4 Hz,
1.0 Hz, 1H), 2.01 (dd, J = 6.4 Hz, 3.0 Hz, 1H), 2.23 (dd, J = 2.7 Hz,
1.0 Hz, 1H), 2.31 (s, 3H), 7.24–7.32 (m, 9H), 7.47–7.49 (m, 6H);
13C NMR (CDCl3): d = 25.1 (CH3), 28.9 (CH2), 39.4 (CH), 74.5 (Cq),
127.9 (Car), 127.0 (Car), 127.7 (Car), 129.3 (Car), 143.5 (Cq ar), 207.5
(C@O).
Alcohol 8 (colorless solid): mp 47–49 °C (as a mixture of diastere-
oisomers); 1H NMR (CDCl3): major diastereoisomer d = 1.25 (d,
J = 6.2 Hz, 1H), 1.72–1.74 (m, 1H), 1.99 (d, J = 3.2 Hz, 1H), 2.76 (d,
J = 4.2 Hz, OH), 4.65–4.67 (m, 1H), 7.21–7.27 (m, 9H), 7.50–7.52
(m, 6H); minor diastereoisomer d = 1.11 (d, J = 6.2 Hz, 1H), 1.76–
1.78 (m, 1H), 2.10 (d, J = 3.2 Hz, 1H), 3.68 (s, OH), 5.08–5.10
Ketone 4 (colorless oil): 1H NMR (CDCl3): d = 1.07 (d, J = 7.0 Hz,
3H), 1.12 (d, J = 7.0 Hz, 3H), 1.46 (dd, J = 6.0 Hz, 1.5 Hz, 1H), 2.05
(dd, J = 6.0 Hz, 3.0 Hz, 1H), 2.25 (dd, J = 3.0 Hz, 1.5 Hz, 1H), 2.88–
2.93 (m, 1H), 7.23–7.31 (m, 9H), 7.50–7.52 (m, 6H); 13C NMR
(CDCl3): d = 18.1 (CH3), 18.9 (CH3), 29.8 (CH2), 36.5 (CH), 38.1

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S. Jarzynski et al. / Tetrahedron: Asymmetry 26 (2015) 35–40
(m, 1H), 7.30–7.37 (m, 9H), 7.47–7.49 (m, 6H); 13C NMR (CDCl3):
major diastereoisomer d = 25.4 (CH), 37.5 (CH2), 73.8 (CH), 74.9
(Cq), 125.8 (Car), 126.8 (Car), 127.6 (Car), 127.7 (Car), 128.3 (Car),
129.4 (Car), 142.1 (Cq ar), 144.2 (Cq ar) (as superposition for both dia-
stereoisomers); minor diastereoisomer d = 22.4 (CH), 39.8 (CH2),
69.3 (CH), 74.9 (Cq), 126.3 (Car), 126.9 (Car), 127.4 (Car), 127.6
(Car), 128.3 (Car), 129.3 (Car), 141.5 (Cq ar), 144.1 (Cq ar); MS (CI):
m/z 392 (M+H); HRMS (EI): calcd for C28H25NO: 391.1920, found:
391.1936.
Alcohol 9 (colorless solid): mp 43–45 °C (as a mixture of diastere-
oisomers); 1H NMR (CDCl3): major diastereoisomer d = 0.80
(d, J = 6.8 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H), 1.23 (d, J = 6.4 Hz, 1H),
1.48–1.50 (m, 1H), 1.58–1.67 (m, 1H), 1.89 (d, J = 3.2 Hz, 1H),
2.34 (d, J = 4.2 Hz, OH), 3,16–3,19 (m, 1H), 7,23–7,33
(m, 9H), 7,44–7,46 (m, 6H); minor diastereoisomer d = 0.86 (d,
J = 6.8 Hz, 1H), 0.96 (d, J = 6.8 Hz, 3H), 1.10 (d, J = 6.4 Hz, 1H),
1.58–1.67 (m, 2H), 1.93 (d, J = 3.2 Hz, 1H), 3.27 (s, OH), 3.73–3.76
(m, 1H), 7.23–7.33 (m, 9H), 7.44–7.46 (m, 6H); 13C NMR (CDCl3):
major diastereoisomer d = 18.3 (CH3), 18.7 (CH3), 25.6 (CH), 33.0
(CH), 35.5 (CH2), 73.7 (Cq), 77.8 (CH), 126.8 (Car), 127.6 (Car),
129.4 (Car), 144.3 (Cq ar) (as superposition for both diastereoiso-
mers); minor diastereoisomer d = 18.2 (CH3), 18.7 (CH3), 22.2
(CH), 32.5 (CH), 34.4 (CH2), 71.3 (CH), 73.9 (Cq), 126.8 (Car), 127.9
(Car), 129.3 (Car), 144.2 (Cq ar); MS (CI): m/z 358 (M+H); HRMS
(EI): calcd for C25H27NO: 357.2103, found: 357.2093;
Alcohol 10 (colorless solid): mp 51–52 °C (as a mixture of diaste-
reoisomers); 1H NMR (CDCl3): major diastereoisomer d = 1.10
(d, J = 6.4 Hz, 1H), 1.49–1.51 (m, 1H), 1.83 (d, J = 3.2 Hz, 1H),
2.61–2.73 (m, AB part of ABX system, 2H), 2.87–2.92 (m, X part
of ABX system, 1H), 3.84–3.87 (m, 1H), 7.18–7.31 (m, 9H), 7.48–
7.50 (m, 6H); minor diastereoisomer d = 1.09 (d, J = 6.4 Hz, 1H),
1.58–1.60 (m, 1H), 1.92 (d, J = 3.2 Hz, 1H), 2.61–2.73 (m, AB part
of ABX system, 2H), 2.87–2.92 (m, X part of ABX system, 1H),
4.19–5.10 (m, 1H), 7.30–7.37 (m, 9H), 7.47–7.49 (m, 6H); 13C
NMR (CDCl3): major diastereoisomer d = 24.6 (CH), 36.3 (CH2),
41.2 (CH2), 68.4 (CH), 73.7 (Cq), 126.2 (Car), 126.8 (Car), 127.5
(Car), 128.3 (Car), 129.3 (Car), 129.5 (Car), 138.2 (Cq ar), 144.1
(Cq ar) (as superposition for both diastereoisomers); minor diaste-
reoisomer d = 22.3 (CH), 35.9 (CH2), 42.4 (CH2), 72.3 (CH), 73.8
(Cq), 126.2 (Car), 126.9 (Car), 127.6 (Car), 128.2 (Car), 129.2 (Car),
129.4 (Car), 138.3 (Cq ar), 144.2 (Cq ar); MS (CI): m/z 406 (M+H);
HRMS (EI): calcd for C29H27NO: 405.2077, found: 405.2092.
(1.0 M, 2 mL, 2 mmol) was added. The mixture was stirred for
30 min at À70 °C and then warmed to room temperature. The reac-
tion mixture was then treated with 10% aqueous NaOH solution,
and the organic layer was separated. The aqueous layer was
extracted with CH2Cl2 (3 Â 5 mL) and the combined organic phases
were dried over anhydrous magnesium sulfate, filtered and
concentrated in vacuo. Purification via column chromatography
on silica gel (EtOAc/hexane 3:7) provided alcohol 12 as a white
powder, mp 49–51 °C (0.365 g, 90%); [
spectroscopic data were analogous with those for compound 10.
a
]
D = À2.1 (c 1, CHCl3).The
4.8. Synthesis of diastereomeric ligand 13
Alcohol 13 was synthesized following all the aforementioned
procedures starting from
sponding ketone, compound 13 was obtained in 89% yield as a
white powder, mp 52–54 °C; [ D = +5.0 (c 1, CHCl3) (measured
D-serine. After reduction of the corre-
a]
for the 59:41 mixture of diastereoisomers) .The spectroscopic data
were analogous with those for compounds 10 and 12.
4.9. Asymmetric addition of diethylzinc to aldehydes: general
procedure
The chiral catalyst (0.1 mmol) in dry toluene (5 mL) was placed
in a round-bottom flask. The mixture was cooled to 0 °C and a solu-
tion of diethylzinc (1.0 M in hexane, 3.0 mmol) was added under
argon. After stirring for 30 min, an aldehyde (1.0 mmol) was added
at 0 °C, and the mixture was stirred at room temperature over-
night. Next, 5% HCl aqueous solution was added, the layers were
separated and the aqueous phase was extracted with diethyl ether
(4 Â 10 mL). The combined organic layers were washed with brine
(10 mL) and dried over anhydrous MgSO4. The solvents were
evaporated to afford crude alcohols 14, which were purified via
column chromatography on silica gel (hexane with ethyl acetate
in gradient). The yields, specific rotations, enantiomeric excess
values and the absolute configurations of products 14 are shown
in Table 4. The spectroscopic data were in full agreement with
those reported in the literature.13
4.10. Asymmetric addition of phenylethynylzinc to aldehydes:
general procedure
To a solution of ligand (0.2 mmol) in THF (5 mL), was added a
solution of diethylzinc (1.4 mL, 1.4 mmol, 1.0 M in hexane) at room
temperature under argon. After the mixture was stirred at ambient
4.6. Synthesis of (S)-N-triphenylmethyl-aziridinylmethanol 11
To a solution of methyl (S)-N-triphenylmethyl aziridinate 1
(0.858 g, 2.5 mmol) in THF (25 mL) was added LiBH4 (0.202 g,
9.2 mmol) at 0 °C. Methanol (6 mL) was added then dropwise over
a period of 6 h and the mixture was stirred for 16 h at room tem-
perature. After completion of the reaction, water was added, and
it was extracted with AcOEt. The combined organic fractions were
dried over MgSO4, and the solvent was evaporated under vacuum
to afford 11 in 99% yield (0.781 g) as colorless crystals, mp 118–
temperature for 30 min, phenylacetylene (154 lL, 1.4 mmol) was
added, and stirring was continued for another 30 min. The solution
was cooled to 0 °C (ice bath) and treated with the corresponding
aldehyde (1.0 mmol). The resulting mixture was stirred for 2 h at
0 °C and then overnight at room temperature. After completion
of the reaction (TLC monitoring), it was quenched with 5% aqueous
HCl. The resulting mixture was extracted with diethyl ether
(4 Â 10 mL) and the combined organic layers were washed with
brine. After the organics were dried over anhydrous MgSO4 the sol-
vents were removed in vacuo. The residue was purified by column
chromatography (silica gel, hexane with ethyl acetate in gradient)
to afford the corresponding products 15. The yields, specific rota-
tions, enantiomeric excess values, and the absolute configurations
of the products 15 are shown in Table 4. The spectroscopic data
were in full agreement with those reported in the literature.14
120 °C; [a]
D = +7.1 (c 1, CHCl3); 1H NMR (CDCl3): d = 1.05 (d,
J = 6.0 Hz, 1H), 1.49–1.51 (m, 1H), 1.79 (d, J = 3 Hz, 1H), 2.10 (dd,
J = 4.2 Hz, 7.8 Hz, OH), 3.61–3.64 (m, 1H), 3.79–3.82 (m, 1H),
7.14–7.40 (m, 15H); 13C NMR (CDCl3): d = 23.8 (CH2), 33.2 (CH),
61.6 (CH2), 73.8 (Cq), 126.9 (Car), 127.6 (Car), 129.4 (Car), 144.3
(Cq ar). Other spectroscopic data are in agreement with the
literature.36
4.7. Stereoselective reduction of aziridinyl ketone 6 to form
alcohol 1229
Acknowledgement
Financial support by the National Science Centre (NCN), Grant
No. 2012/05/D/ST5/00505 for M.R., is gratefully acknowledged.
To a solution of ketone 6 (0.403 g, 1 mmol) in anhydrous THF
(5 mL) under
a
nitrogen atmosphere at À78 °C, L-Selectride

´
40
S. Jarzynski et al. / Tetrahedron: Asymmetry 26 (2015) 35–40
18. Rachwalski, M.; Jarzyn´ ski, S.; Les´niak, S. Tetrahedron: Asymmetry 2013, 24,
References
1117–1119.
19. Les´niak, S.; Rachwalski, M.; Jarzyn´ ski, S.; Obijalska, E. Tetrahedron: Asymmetry
1. Pellissier, H. Tetrahedron 2007, 63, 9267–9331.
2013, 24, 1336–1340.
20. Rachwalski, M.; Kaczmarczyk, S.; Les´niak, S.; Kiełbasin´ ski, P. ChemCatChem
2014, 6, 873–875.
21. Rachwalski, M. Tetrahedron: Asymmetry 2014, 25, 219–223.
22. Faure, R.; Loiseleur, H.; Bartnik, R.; Les´niak, S.; Laurent, A. Cryst. Struct.
Commun. 1981, 10, 515–519.
23. Bartnik, R.; Les´niak, S.; Laurent, A. Tetrahedron Lett. 1981, 4811–4812.
24. Bartnik, R.; Les´niak, S.; Laurent, A. J. Chem. Res. 1982, 287, 2701–2709.
25. Lawrence, C. F.; Nayak, S. K.; Thijs, L.; Zwanenburg, B. Synlett 1999, 1571–
1572.
26. ten Holte, P.; Wijgergangs, J.-P.; Thijs, L.; Zwanenburg, B. Org. Lett. 1999, 1,
1095–1097.
27. Savoia, D.; Alvaro, G.; Fabio, R.; Fiorelli, C.; Gualandi, A.; Monari, M.; Piccinelli,
F. Adv. Synth. Catal. 2006, 348, 1883–1893.
28. Liu, H.; Pattabiraman, V. R.; Vederas, J. C. Org. Lett. 2007, 9, 4211–4214.
29. Yun, J. M.; Sim, T. B.; Hahm, H. S.; Lee, W. K.; Ha, H.-J. J. Org. Chem. 2003, 68,
7675–7680.
2. Ojima, I. Catalytic Asymmetric Synthesis, 3rd ed.; John Wiley & Sons, 2010.
3. Christmann, M.; Bräse, S. Asymmetric Synthesis II: More Methods and
Applications; Wiley-VCH Verlag GmbH & Co: KGaA, 2012.
4. Gawley, R. E.; Aubé, J. Principles of Asymmetric Synthesis, 2nd ed.; Elsevier:
Amsterdam, 2012.
5. Garcia-Urdiales, E.; Alfonso, I.; Gotor, V. Chem. Rev. 2005, 105, 313–354.
6. Tanner, D.; Kornø, H. T.; Guijarro, D.; Andersson, P. G. Tetrahedron 1998, 54,
14213–14232.
7. Braga, A. L.; Paixão, W. M.; Westermann, B.; Schneider, P. H.; Wessjohann, L. A.
J. Org. Chem. 2008, 73, 2879–2882.
8. Bulut, A.; Aslan, A.; Izgü, Dogan, Ö. Tetrahedron: Asymmetry 2007, 18,
1013–1016.
9. Isleyen, A.; Dogan, Ö. Tetrahedron: Asymmetry 2007, 18, 679–684.
10. Koyuncu, H.; Dogan, Ö. Org. Lett. 2007, 9, 3477–3479.
11. Kiełbasin´ ski, P.; Rachwalski, M.; Kwiatkowska, M.; Mikołajczyk, M.; Wieczorek,
W. M. Tetrahedron: Asymmetry 2007, 18, 2108–2112.
12. Rachwalski, M.; Kwiatkowska, M.; Drabowicz, J.; Kłos, M.; Wieczorek, W. M.;
Szyrej, M.; Sieron´ , L.; Kiełbasin´ ski, P. Tetrahedron: Asymmetry 2008, 19,
2096–2101.
´
30. Mloston, G.; Obijalska, E.; Zie˛bacz, P.; Matyszewski, K.; Urbaniak, K.; Linden, A.;
Heimgartner, H. J. Fluorine Chem. 2013, 156, 192–197.
31. Zhong, J.-C.; Hou, S.-C.; Bian, Q.-H.; Yin, M.-M.; Na, R.-S.; Zheng, B.; Li, Z.-Y.; Liu,
S.-Z.; Wang, M. Chem. Eur. J. 2009, 15, 3069–3071.
32. Lawrence, C. F., PhD-Thesis, Nijmegen 2002.
33. Zhang, C.-H.; Yan, S.-J.; Pan, S.-Q.; Huang, R.; Lin, J. Bull. Korean Chem. Soc. 2010,
31, 869–873.
34. Chen, Y.-J.; Lin, R.-X.; Chen, C. Tetrahedron: Asymmetry 2004, 15, 3561–3571.
35. Lam, S. K.; Lam, S.; Wong, W.-T.; Chiu, P. Chem. Commun. 2014, 1738–1741.
36. Wu, Y.-C.; Zhu, J. Org. Lett. 2009, 11, 5558–5561.
13. Les´niak, S.; Rachwalski, M.; Sznajder, E.; Kiełbasin´ ski, P. Tetrahedron:
Asymmetry 2009, 20, 2311–2314.
14. Rachwalski, M.; Les´niak, S.; Kiełbasin´ ski, P. Tetrahedron: Asymmetry 2010, 21,
2687–2689.
15. Rachwalski, M.; Les´niak, S.; Kiełbasin´ ski, P. Tetrahedron: Asymmetry 2010, 21,
1890–1892.
´
´
16. Rachwalski, M.; Jarzynski, S.; Lesniak, S. Tetrahedron: Asymmetry 2013, 24, 421–
425.
´
´
´
17. Rachwalski, M.; Jarzynski, S.; Jasinski, M.; Lesniak, S. Tetrahedron: Asymmetry
2013, 24, 689–693.