Regioselective and stereodivergent synthesis of enantiomerically pure Vic-diamines from chiral β-amino alcohols with 2-pyridyl and 6-(2,20-bipyridyl) moieties

Article abstract of DOI:10.3390/molecules25030727

In this report, we describe the synthetic elaboration of the easily available enantiomerically pure β-amino alcohols. Attempted direct substitution of the hydroxyl group by azido-functionality in the Mitsunobu reaction with hydrazoic acid was inefficient or led to a diastereomeric mixture. These outcomes resulted from the participation of aziridines. Intentionally performed internal Mitsunobu reaction of β-amino alcohols gave eight chiral aziridines in 45–82% yield. The structural and configuration identity of products was confirmed by NMR data compared to the DFT calculated GIAO values. For 1,2,3-trisubstituted aziridines slow configurational inversion at the endocyclic nitrogen atom was observed by NMR at room temperature. Moreover, when aziridine was titrated with Zn(OAc)₂ under NMR control, only one of two N-epimers directly participated in complexation. The aziridines underwent ring opening with HN₃ to form the corresponding azido amines as single regio- and diastereomers in 90–97% yield. Different results were obtained for 1,2-disubstituted and 1,2,3-trisubstituted aziridines. For the later aziridines ring closure and ring opening occurred at different carbon stereocenters, thus yielding products with two inverted configurations, compared to the starting amino alcohol. The 1,2-disubstituted aziridines produced azido amines of the same configuration as the starting β-amino alcohols. To obtain a complete series of diastereomeric vic-diamines, we converted the amino alcohols into cyclic sulfamidates, which reacted with sodium azide in S_N2 reaction (25–58% overall yield). The azides obtained either way underwent the Staudinger reduction, giving a series of six new chiral vic-diamines of defined stereochemistries.

Full text of DOI:10.3390/molecules25030727

molecules
Article
Regioselective and Stereodivergent Synthesis of
Enantiomerically Pure Vic-Diamines from Chiral
β-Amino Alcohols with 2-Pyridyl and
6-(2,20-Bipyridyl) Moieties †
Marzena Wosin´ska-Hrydczuk, Przemysław J. Boratyn´ski and Jacek Skarz˙ewski *
Chair of Organic and Medicinal Chemistry, Faculty of Chemistry, Wrocław University of Science and Technology,
Wyb. Wyspian´skiego 27, 50-370 Wrocław, Poland; marzena.wosinska@pwr.edu.pl (M.W.-H.);
przemyslaw.boratynski@pwr.edu.pl (P.J.B.)
* Correspondence: jacek.skarzewski@pwr.edu.pl; Tel.: +48-71-320-2464
† This paper is dedicated to Professor Grzegorz Mloston´ on the occasion of his 70-th birthday.
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editors: Zbigniew Czarnocki and Joanna Szawkało
Received: 11 January 2020; Accepted: 6 February 2020; Published: 7 February 2020
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: In this report, we describe the synthetic elaboration of the easily available enantiomerically
pure β-amino alcohols. Attempted direct substitution of the hydroxyl group by azido-functionality
in the Mitsunobu reaction with hydrazoic acid was inefficient or led to a diastereomeric mixture.
These outcomes resulted from the participation of aziridines. Intentionally performed internal
Mitsunobu reaction of β-amino alcohols gave eight chiral aziridines in 45–82% yield. The structural
and configuration identity of products was confirmed by NMR data compared to the DFT calculated
GIAO values. For 1,2,3-trisubstituted aziridines slow configurational inversion at the endocyclic
nitrogen atom was observed by NMR at room temperature. Moreover, when aziridine was titrated
with Zn(OAc)2 under NMR control, only one of two N-epimers directly participated in complexation.
The aziridines underwent ring opening with HN3 to form the corresponding azido amines as single
regio- and diastereomers in 90–97% yield. Different results were obtained for 1,2-disubstituted and
1,2,3-trisubstituted aziridines. For the later aziridines ring closure and ring opening occurred at
different carbon stereocenters, thus yielding products with two inverted configurations, compared
to the starting amino alcohol. The 1,2-disubstituted aziridines produced azido amines of the same
configuration as the starting
β-amino alcohols. To obtain a complete series of diastereomeric
vic-diamines, we converted the amino alcohols into cyclic sulfamidates, which reacted with sodium
azide in SN2 reaction (25–58% overall yield). The azides obtained either way underwent the Staudinger
reduction, giving a series of six new chiral vic-diamines of defined stereochemistries.
Keywords: chiral β-amino alcohols; Mitsunobu reaction; 2-(2-pyridyl)aziridines; slow inversion at
aziridine nitrogen; stereodivergent synthesis of chiral 1,2-diamines
1. Introduction
Enantiomerically pure
available organocatalysts and chiral building blocks [
natural products (Cinchona [ ] and Ephedra [ ] alkaloids), the others are obtainable in a few simple
synthetic steps, e.g., from natural amino acids. Recently, we have developed the synthesis of new
chiral ].
-amino alcohols, containing metal-complexing 2-pyridyl and 6-(2,20-bipyridyl) fragments [
β-amino alcohols belong to a privileged group of important and easily
1,2
]. Some of them are directly accessible as
3
4
β
5
For their further transformations into the multi-interacting ligands, we explore the exchange of the
hydroxyl group into the nitrogen-containing moieties.
Molecules 2020, 25, 727; doi:10.3390/molecules25030727
www.mdpi.com/journal/molecules

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The preparation of chiral vicinal diamines constitutes an important challenge and several synthetic
approaches have been adopted [ ]. Since chiral vic-diamines offer versatile transition-metal-complexing
6
properties, we intended to develop the required procedures for the conversion of chiral amino alcohols.
However, such modifications are often complicated by the participation of the neighboring amino
group [7,8]. Therefore, different regio- and stereochemical outcomes can be expected [9,10]. In the
present contribution different products, as outlined in Figure 1, were obtained, depending on the
applied procedure and the structure of the starting amino alcohol.
Figure 1. Outline of different regio- and stereochemistries observed in the conversion of amino alcohols
to diamines. Only the pathway in the top row represents simple SN2 displacement.
2. Results and Discussion
We decided to convert chiral amino alcohols into the corresponding diamines using nucleophilic
displacement with an azide anion, followed by Staudinger reduction (Figure 1). In fact, our first
attempts to substitute hydroxyl with azide under the Mitsunobu reaction conditions [11–13] suggested
that aziridine intermediates could be involved. Thus, another pathway relied on the synthesis of
aziridines and later subjecting them to the ring-opening reaction. A literature precedent for the
regioselective ring-opening of 2-(2-pyridyl)-substituted aziridine by nitrogen, sulfur, and oxygen
nucleophiles has already been published by the group of D. Savoia [14]. Finally, to enforce a direct
SN2 pathway, we used cyclic sulfamidate intermediate products [15–17] that could be opened with
sodium azide.
2.1. Attempted Direct Substitution of the Hydroxyl Group by the External Nucleophile
To directly exchange the hydroxyl group of -amino alcohols and for the azide we applied the
Mitsunobu reaction conditions with hydrazoic acid [18 a mixture of
19]. From compound (1S,10S)-
both epimers of (1R,10S)- and (1S,10S)-
in 1:1.25 ratio was obtained in 40% total yield (Scheme 1).
However, from alcohol (1S,10S)- only 17% of (1S,10S)-
could be isolated. Their structures were
unambiguously confirmed by NMR (see Supporting Info, Figure S1). The outcomes suggested that
while the product (1R,10S)-
was formed via direct SN2 substitution of oxyphosphonium leaving
group by the azide anion, the products (1S,10S)- and (1S,10S)-
(overall retention) could result from
β
1
2
,
1
3
3
2
4
3
3
4
ring-opening of the corresponding aziridines, as depicted in Scheme 1. Indeed, activation of the
hydroxyl group resulted in internal ring-closure and formation of aziridine [20,21].

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Scheme 1. Direct synthesis of azides from amino alcohol (Ph3P, DEAD, HN3 in benzene at RT for 3 h).
2.2. Synthesis of Aziridines
Under these circumstances, we turned to the synthesis of aziridines using the Mitsunobu
reaction [22 24]. As has been reported for this type of process, we ran the reaction under reflux in dry
toluene for 24 h [25], but a low yield of the product resulted. In an improved procedure, toluene was
replaced with dry diethyl ether for the amino alcohols , and ] (Method A). In the case of
and the result was still unsatisfactory. However, applying an additional 0.5 eq of the Mitsunobu
reagents (Method B) resulted in further improvement of the yield of aziridines and 10 (Table 1). In an
attempted exchange of the hydroxyl in and into the corresponding bromo-compounds using the
Appel reaction [26] (2 eq of CBr4 and PPh3, then K2CO3), we again obtained aziridines (a known
compound [27]) and . The products were the same as those obtained in the Mitsunobu reaction,
–
1,
2
5–
7
[
5
2
5
9
1
2
8
9
so they were also formed by the direct internal substitution of the oxyphosphonium group by the
secondary amine. Since only one diastereomer of the product was observed in all the cases, it is
assumed that the ring closure process also occurred through SN2 type reaction, and inversion of the
configuration should have been achieved.

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Table 1. Synthesis of aziridines by Mitsunobu reaction (Methods A and B).
Configuration of
Amino Alcohol
Configuration
of Products
R1
R2
R3
Yield a (%)
(1R,10S)-1
Ph
Ph
Py
Py
Py
Py
Bpy
Bpy
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
(2S,10S)-8
76
72
(1S,10S)-1
(2R,10S)-8
(1S,10S)-2
(2R,10S)-9
45, 82 b
33, 74 b
33, 76 b
45
(1S,2S,10S)-5
(1R,2R,10S)-5
(1R,2R,10R)-6
(1S,2S,10S)-7
(1R,2R,10S)-7
(2R,3S,10S)-10
(2S,3R,10S)-10
(2S,3R,10R)-11
(2R,3S,10S)-12
(2S,3R,10S)-12
Ph
cyclohexyl
Ph
65
70
Ph
a
Method A: To the solution of amino alcohol in Et2O 1.5 eq of PPh3 and DEAD was added, the mixture was stirred
b
under argon atmosphere overnight. Method B: An additional 0.5 eq of PPh3 and DEAD was added and the
mixture was stirred overnight. For the details, see Experimental. Py = pyridin-2-yl, Bpy = 2,20-bipyridin-6-yl.
2.3. Aziridine Structural Investigation by NMR
The 1H-NMR spectra of 1,2,3-trisubstituted aziridines 10 and 12 recorded at ambient temperatures
demonstrated significant spectral broadening. At 283 K the NMR experiments reveal distinct
sets of signals corresponding to two equilibrating species in 1:0.95 to 1:0.45 ratio, respectively
(see Supporting Info, Figures S19–S28). This conclusion was further confirmed by positive-phase
cross-peaks in the exchange-correlation spectroscopy experiment (Supporting Info, Figure S8). This
observation can be attributed to the partially restricted inversion at the aziridine tertiary nitrogen
atom [28]; thus, the observed species constituted respective SN and RN diastereomers. In the case of
the aziridines 10 and 12, the substituents at positions 2 and 3 are sterically similar though electronically
different, and thus the chemical shifts of the corresponding nitrogen-epimers SN vs. RN are well
separated while their quantities remain rather similar.
The possible N-epimeric species were modeled and subjected to DFT geometry optimization at
the B3LYP/CC-pVDZ level of theory utilizing Gaussian code [29]. For the most stable conformations,
GIAO isotropic shielding values were calculated at the mPW1PW91/6-311+G(2d,p) level using the
polarization continuum solvent model (PCM). The shieldings were then converted to chemical shifts
using linear scaling factors [30]. These were compared with the experimental data for the very well
resolved aliphatic region and showed good qualitative agreement, which made it possible to assign
stereochemistry at nitrogen for both diastereomeric species (Table 2). RMS error for assignment of
SN and RN configuration to the major and minor components, respectively, was 0.32 ppm, while
the opposite assignment would produce 0.74 ppm RMS error. The energy difference between the
N-diastereoisomers seems to be slightly overestimated by calculation (2.3 kcal/mol).
Table 2. Comparison of experimental and DFT calculated NMR chemical shifts (GIAO DFT/
mPW1PW91/6-311+G(2d,p)) for (2S,3R,10S)-10.
DFT δ, ppm
Experiment δ, ppm
Signal
(1SN)-10
(1RN)-10
Major
Minor
H-2
H-3
1-CH
CH3
3.16
4.20
4.75
1.59
3.74
3.49
3.10
1.46
3.27
3.97
3.91
1.50
3.52
3.49
3.12
1.44

Molecules 2020, 25, 727
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Furthermore, it is known that protonation [31] or incorporation in a metal chelate complex inhibits
inversion at the nitrogen atom [32]. So far, the studied species have mostly been chelates involving
aziridine nitrogen atom and heteroatoms attached to substituents at position 1 [33
involving functional groups attached to carbon atoms of the aziridine ring are also known [35
,
34]. Several chelates
36].
,
In the case of compounds of type 10 such chelate would involve pyridine nitrogen as a donor atom.
Thus, in another experiment, a sample of (2S,3R,10S)-10 in deuterated methanol was titrated with
zinc acetate and sequential 1H-NMR spectra were recorded. Immediately after the addition of zinc salt,
one of the two sets of signals for diastereomeric species broadened significantly. The signals of the other
N-epimer did not undergo noticeable changes in lineshape, although they linearly decreased in intensity
as the quantity of zinc salt increased. With an excess of zinc acetate, one set of well-resolved signals
appeared. The experiment indicated the formation of a thermodynamically sTable 1:1 zinc to ligand
10 complex (apparent equilibrium constant ca. 10−3 M). The complex undergoes a ligand exchange
process at a moderately fast rate (approx. 103 M−1 s−1 at 283 K) so coalescence is observed in the
presence of excess ligand [37]. Only one N-epimer was shown to be directly involved in the formation
of the complex. The configuration of this free ligand was assigned as SN by means of comparison of
DFT and experimental chemical shifts (vide supra). Here, such a configuration makes both heteroatom
lone electron pairs available from one side of the aziridine ring, thus enabling chelation (Scheme 2).
The complex with two acetate counterions was modeled with the help of DFT/B3LYP/CC-pVDZ
level calculation, and chemical shifts were computed the same way as for the free ligand. While the
general downfield change is predicted by the computed data, they display only fair similarity with
the experiment, suggesting that the actual complex likely involves additional coordinated solvent
molecules. Similar results were also obtained for the Zn(OAc)2 titration of bipyridine derivative
(2S,3R,10S)-12. There, the ligand exchange process was slower. Detailed results are shown in the
Supporting Info (Figures S5–S7).
Scheme 2. Equilibration of N-epimeric aziridine (2S,3R,10S)-10 in the presence of zinc acetate. Notation
SN in the complex results from CIP rules; in fact, the nitrogen configuration is the same as RN in the
free ligand.
2.4. Synthesis of Diamines
To prepare the required diamines, we used two different routes. In the first, the azides were
obtained by ring opening reaction of aziridines with HN3. In the second method, we obtained cyclic
sulfamidates, which were transformed into the appropriate azides by the SN2 reaction with sodium
azide. Both pathways were completed with the Staudinger reduction.
2.4.1. Synthesis of Diamines by Ring Opening of Aziridines with Hydrazoic Acid
As a model reaction, we used aziridines
at the more substituted aziridine carbon (Table 3, attack
regioselectivity. The pyridine-containing compound gave mostly
8
and
9
. In these cases, we observed a nucleophilic attack
). From we obtained azide with complete
(90%), but also regioisomer was
a
8
3
9
4
identified in the crude product. In both cases, only one stereoisomer of the product was observed.
A similar outcome has been reported for the reaction of pyridine-substituted aziridine with sodium
azide [14].

Molecules 2020, 25, 727
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Table 3. Regioselective ring opening of aziridines with HN3.
Configuration of
Aziridines
Configuration of
Azides
Yield of
Azides (%)
R1
R2
(2S,10S)-8
H
H
H
Ph
Ph
Ph
Ph
Py
Py
Bpy
(1R,10S)-3
97
90
(2R,10S)-8
(1S,10S)-3
(1R,10S)-9
(2S,10S)-4
93 a
95
(2R,3S,10S)-10
(2S,3R,10S)-12
(1R,2R,10S)-13
(1S,2S,10S)-14
94
a
For the ring opening of aziridine
9 in the crude mixture 10% of minor regioisomer was identified in NMR. Yield is
given for the mixture.
In the reaction of 1,2,3-trisubstituted aziridines 10 and 12 with HN3, we observed a nucleophilic
attack on the aziridine ring at the carbon atoms substituted with the phenyl group. In both cases this
resulted in single regioisomer 13 and 14, respectively (Table 3, attack b). The observed regioselectivity
seems to be due to the protonation, thus activation of the phenyl-substituted carbon in the aziridine
ring (Figure 2). The observed difference in the position of nucleophilic opening for analogous aziridines
has already been reported [9,10,14,38].
Figure 2. Postulated rationale for attack b.
2.4.2. Synthesis of Diamines by Nucleophilic Substitution of Sulfamidates
To obtain different regioisomers, we used another procedure. The synthesis consisted of three
steps (Scheme 3). Firstly oxathiazolidines 15 and 16 were obtained by reaction of appropriate amino
alcohol
1 and 5 with thionyl chloride [39]. Then, they were oxidized to the cyclic sulfamidates 17 and
18 using sodium meta-periodate and a catalytic amount of ruthenium trichloride in acetonitrile. Next,
the compounds 17 and 18 were opened [40] with sodium azide in a regio- and stereoselective reaction
to give
3
and 19. Azide
3
was obtained as the same compound as during ring opening of aziridine
(2S,10S)-8 with HN3.
1
O
2
S
O
O
O
O
N3
1
1. NaN3,
DMF, RT
OH
H
R1
S
N
R1
H
cat RuCl3
1
SOCl2, Et3N
2 N
R2 Ph
(1R,1'S)-3,
3
N
5
R1
2
N
R1
Ph
NaIO4, MeCN
0°C to RT
1'
Ph
2. 20% H2SO4,
Et2O, RT
1'
4
CH2Cl2, -78°C
R2
1'
R2
1'
R2 Ph
51%
R1=Ph, R2=H, (1S,1'S)-1
R1=Py, R2=Ph (1S,2S,1'S)-5
R1=Py, R2=Ph (1R,2R,1'S)-5
(5S,1'S)-15
(5S,4S,1'S)-
(5R,4R,1'S)-
(5S,1'S)-17,
(4S,5S,1'S)-
50%
76%
(1R,2S,1'S)-19, 70%
(1S,2R,1'S)-19, 73%
18,
16
(4R,5R,1'S)-18, 79%
16
Scheme 3. Three-step synthesis of β-azido amines from amino alcohols via sulfamidates.
The structures of the azides (1R,10S)- , (1S,10S)- , (1R,2R,10S)-13, (1S,2S,10S)-14, (1S,2R,10S)-19, and
3 3
(1R,2S,10S)-19 were established based on NMR experiments. The 1H,13C HMBC correlations proved to
be most informative. For all the products, the methine CH in the methylbenzylamine part correlated

Molecules 2020, 25, 727
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with the CH directly attached to the secondary amino group. For products 13 and 14, resulting from
ring opening of aziridines, this CH was found to be attached to the phenyl group while the other CH
connected to the pyridine ring as seen by a 3J C-H correlations. Inverse connectivity was observed for
products 19 obtained via sulfamidate (See Supporting Info, Figure S1).
2.4.3. Reduction of Azido Amines to Vic-Diamines
The azides 3, 4, 13, 14, and 19 were reduced to the primary amines 20–24 via the Staudinger [27,41]
reaction using triphenylphosphine in aqueous dichloromethane in moderate to high yield (Table 4).
Table 4. Synthesis of diamines via the Staudinger reaction.
Configuration of
Azides
Configuration of
Diamines
Yield of
Diamines (%)
R1
R2
(1R,10S)-3
Ph
Py
Ph
Ph
Py
Py
H
H
Py
Bpy
Ph
Ph
(1R,10S)-20
74
75
60
50
70
73
(1S,10S)-4
(1S,10S)-21
(1R,2R,10S)-13
(1S,2S,10S)-14
(1R,2S,10S)-19
(1S,2R,10S)-19
(1R,2R,10S)-22
(1S,2S,10S)-23
(1R,2S,10S)-24
(1S,2R,10S)-24
3. Materials and Methods
3.1. General
Solvents were distilled, and other reagents were used as received. Reactions were monitored by
thin-layer chromatography (TLC) on silica gel 60 F-254 precoated plates, and spots were visualized with
a UV lamp and/or Dragendorff reagent. Separation of products by chromatography was carried out on
silica gel 60 (230–400 mesh) or Florisil (60–100 mesh). Observed rotations at 589 nm were measured
using an Optical Activity Ltd. Model AA-5 automatic polarimeter (Huntington, UK). 1H- and 13C-NMR
spectra (400, 600 MHz and 100, 151 MHz, respectively) were collected on Jeol 400yh and Bruker
Avance II 600 instruments (Karlsruhe, Germany). The spectra were recorded in CDCl3 referenced to
the respective residual signals of the solvent. Chemical shifts are given in parts per million (ppm)
in a deuterated solvent and coupling constants (J) are in Hertz (Hz). High-resolution mass spectra
were recorded using electrospray ionization on Waters LCT Premier XE TOF instrument (Milford, MA,
USA).
3.2. General Procedure for the Synthesis of Aziridines
The synthesis of aziridines was performed according to a modified literature procedure [26].
Method A: Into the solution of the appropriate amino alcohol (1 eq, 0.5 mmol) and
triphenylphosphine (1.5 eq 0.75 mmol, 197 mg) in the dry ether in an ice-water bath under an
argon atmosphere, was slowly added diethyl azodicarboxylate (1.5 eq 0.75 mmol, 116
µ
L) via syringe.
◦
The stirring was continued at 0 C for 15 min and then overnight at room temperature. Then the
solvent was removed, and products were isolated from crude mixture by column chromatography [24].
Method B: The reaction was performed similarly to Method A; however, after 24 h additional
0.5 eq PPh3 and DEAD were added, and the reaction mixture was stirred again overnight. The product
was isolated in the same way as in method A.
In the NMR we observed two N-epimers for aziridines (2S,3R,10S)-10, (2R,3S,10S)-10, (2S,3R,10R)-11
(2R,3S,10S)-12 and (2S,3R,10S)-12 nitrogen atoms in different proportions.
,

Molecules 2020, 25, 727
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(2R)-Phenyl-1-[(S)-1-phenylethyl]-aziridine (2R,10S)-
8
(Method A): Colorless oil, 80 mg, 72% yield,
[α]2D0
=
−
53 (c = 1.1, CHCl3), (lit. [27
]
[α]2D3
=
−
45 (c 1.5, CHCl3), purified by column chromatography
: 7.48–7.46 (m, 2H), 7.39–7.23 (m, 8H), 2.68
1
(SiO2, 30% AcOEt in hexane). H-NMR (400 MHz, CDCl3)
δ
(q, J = 6.4 Hz, 1H), 2.55 (dd, J = 6.4, 3.4 Hz, 1H), 1.85 (d, J = 3.4 Hz, 1H), 1.70 (d, J = 6.4 Hz, 1H), 1.50
(d, J = 6.4 Hz, 3H). The NMR data are in agreement with the reported ones [27].
(2S)-Phenyl-1-[(S)-1-phenylethyl]-aziridine (2S,10S)-
8
(Method A): White solid, 85 mg, 76% yield,
[α]2D3 = 83 (c 1.3, CHCl3), purified by column
chromatography (SiO2, 30% AcOEt in hexane). 1H-NMR (400 MHz, CDCl3)
: 7.37–7.34 (m, 2H),
7.28–7.15 (m, 8H), 2.69 (q, J = 6.7 Hz, 1H), 2.41 (dd, J = 6.7, 3.4 Hz, 1H), 2.05 (d, J = 3.4 Hz, 1H), 1.83
d, J = 6.7 Hz, 1H), 1.49 (d, J = 6.7 Hz, 3H). The NMR data are in agreement with the reported ones [27].
m.p. 53–54 ◦C, [α]D20 = 125 (c = 0.92, CHCl3), (lit. [27
]
δ
(
(2R)-Pyridin-2-yl-1-[(S)-1-phenylethyl]-aziridine (2R,10S)-
9
(Method A and B): Brown oil, 57
63 (c = 0.38, CHCl3), purified by column chromatography
: 8.52 (d, J = 4.9 Hz, 1H), 7.62 (td, J = 7.6,
mg, 82% yield (Method B), [α]D20
Florisil, 5% AcOEt in hexane). H-NMR (400 MHz, CDCl3)
=
−
1
(
δ
1.8 Hz, 1H), 7.47–7.44 (m, 2H), 7.36–7.31 (m, 3H), 7.28–7.24 (m, 1H), 7.15–7.12 (m, 1H), 2.74 (dd, J = 6.4,
3.0 Hz, 1H), 2.71 (d, J = 6.4 Hz, 1H), 1.95 (d, J = 3.0 Hz, 1H), 1.77 (d, J = 6.4 Hz, 1H), 1.47 (d, J = 6.4 Hz,
3H); 13C-NMR (101 MHz, CDCl3)
δ: 160.2, 149.0, 144.6, 136.7, 128.4, 127.2, 127.0, 122.0, 120.3, 70.2, 43.0,
37.2, 23.6; HR-MS (ESI) [C15H16N2 + H]+ requires 225.1386; found 225.1383.
(2S,3R)-2-Pyridin-2-yl-3-phenyl-1-[(S)-1-phenylethyl]-aziridine (2S,3R,10S)-10 (Method A and B):
We observed two epimers on nitrogen atom in ratio 1:0.5 (1H-NMR and 13C-NMR). Colorless oil, 57 mg,
76%, (Method B), [α]2D0 = 8.8 (c = 0.8, CHCl3), purified by column chromatography (Florisil, 5% AcOEt
1
in hexane). H-NMR (600 MHz, 283K, CDCl3) major epimer
δ: 8.61–8.60 (m, 1H), 7.57–7.7.56 (m, 2H),
7.42–7.39 (m, 2H), 7.32–7.01 (m, 9H) 3.97 (d, J = 2.9 Hz, 1H), 3.91 (q, J = 6.6 Hz, 1H), 3.27 (d J = 2.6 Hz,
1H) 1.51 (d, J = 6.6 Hz, 3H); minor epimer : 8.61–8.60 (m, 1H), 7.77–7.74 (m, 1H), 7.57–7.7.56 (m, 1H),
7.32–7.01 (m, 11H), 3.50 (dd, J = 19.4 2.9 Hz, 2H), 3.12 (q, J = 6.6 Hz, 1H), 1.45 (d, J = 6.6 Hz, 3H);
13C-NMR (151 MHz, 283K, CDCl3)
:160.4, 154.8, 149.0, 148.0, 145.4, 140.8, 136.7, 135.6, 135.5, 133.4,
δ
δ
130.44, 130.40, 128.3, 127.7, 127.60, 127,59, 127.0, 126.9, 126.6, 126.5, 126.3, 126.2, 122.1, 121.9, 120.23,
120.18, 60.2, 58.1, 51.4, 51.0, 45.4, 45.3, 24.4, 24.2; HR-MS (ESI) [C21H20N2 + H]+ requires 301.1699;
found 301.1703.
(2R,3S)-2-Pyridin-2-yl)-3-phenyl-1-[(S)-1-phenylethyl]-aziridine (2R,3S,10S)-10 (Method A and
B): We observed two epimers on nitrogen a◦tom in ratio ca. 1:0.95 (1H-NMR and 13C-NMR). White
solid, 57 mg, 74% (Method B), m.p. 67–69 C, [α]2D0 = –184.5 (c = 1.1, CHCl3), purified by column
1
chromatography (Florisil, 5% AcOEt in hexane). H-NMR (600 MHz, 283K, CDCl3) major epimer
δ
:
8.71 (d, J = 4.0 Hz, 1H), 7.74 (td, J = 7.7, 1.8 Hz, 1H), 7.59–7.55 (m, 3H), 7.43–7.41 (m, 1H), 7.36–7.19
(m, 8H), 3.99 (q, J = 6.6 Hz, 1H), 3.45 (d, J = 3.3 Hz, 1H), 3.34 (d, J = 3.7 Hz, 1H), 1.06 (d, J = 6.6 Hz,
3H); minor epimer
(m, 7H), 7.16–7.14 (m, 1H), 3.79 (dd, J = 5.6, 2.9 Hz, 2H), 3.24 (q, J = 6.6 Hz, 1H), 1.19 (d, J = 6.6 Hz,
3H), 13C-NMR (151 MHz, 283K, CDCl3)
: 159.3, 154.7, 149.3, 148.8, 145.3, 145.2, 140.1, 136.5, 136.2,
δ: 8.55 (d, J = 4.0 Hz, 1H), 7.63 (td, J = 7.7, 1.5 Hz, 1H), 7.47–7.45 (m, 4H), 7.36–7.19
δ
133.0, 130.4, 128.31, 128.26, 128.25, 128.23, 128.1, 127.1, 127.0, 126.83, 126.81, 126.80, 126.5, 126.0, 122.2,
122.0, 120.8, 59.9, 58.1, 51.4, 51.0, 45.5, 44.9, 23.6, 23.2; HR-MS (ESI) [C21H20N2 + H]+ requires 301.1699;
found 301.1710.
(2S,3R)-2-Pyridin-2-yl-3-phenyl-1-[(S)-1-cyclohexylethyl]-aziridine (2S,3R,10R)-11 (Method A):
Two epimers on nitrogen atom in ratio 1:0.8 were observed in 1H-NMR and 13C-NMR. Colorless oil,
70 mg, 45%, [α]2D0 = 98 (c = 0.98, CHCl3), purified by column chromatography (Florisil, 5% AcOEt
1
in hexane). H-NMR (600 MHz, 283K, CDCl3) major epimer
δ: 8.62–8.61 (m, 1H), 7.69–7.65 (m, 1H),
7.49–7.26 (m, 6H), 7.22–7.18 (m, 1H), 3.77 (d, J = 2.2 Hz, 1H), 3.22 (d, J = 2.6 Hz, 1H), 2.74–2.73 (m, 1H),
2.13–2.07 (m, 1H), 1.70–1.48 (m, 5H), 1.23–1.00 (m, 5H), 0.63 (d, J = 6.2 Hz, 3H); minor epimer 8.59–8.58
(m, 1H), 7.75–7.70 (m, 1H), 7.49–7.26 (m, 6H), 7.22–7.18 (m, 1H), 3.44 (d, J = 8.8 Hz, 2H), 1.93–1.83
(m, 2H), 1.70–1.48 (m, 5H), 1.23–1.00 (m, 5H), 0.73 (d, J = 5.6 Hz, 3H), 13C-NMR (151 MHz, 283K, CDCl3)
δ
: 167.9, 160.02, 155.32, 155.27, 149.2, 148.6, 148.5, 140.6, 136.7, 136.0, 130.1, 128.3, 128.0, 127.7, 126.8,

Molecules 2020, 25, 727
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126.4, 125.9, 122.0, 121.9, 120.2, 68.2, 65.7, 60.0, 58.6, 49.84, 49.79, 46.8, 46.2, 44.0, 43.8, 36.7, 30.2, 30.1,
28.6, 28.3, 26.9, 26.7, 23.7, 16.3, 15.8; HR-MS (ESI) [C21H26N2 + H]+ requires 307.2169; found 307.2173.
(2S,3R)-2-(2,20-Bipyridin-6-yl)-3-phenyl-1-[(S)-1-phenylethyl]-aziridine (2S,3R,10S)-12 (Method A):
We observed two epimers on nitrogen atom in ratio 1:0.3 (1H-NMR and 13C-NMR). Colorless oil,
124 mg, 66%, [α]2D0
hexane). H-NMR (600 MHz, 283K, CDCl3) major epimer
=
−
59 (c = 1.01, CHCl3), purified by column chromatography (Florisil, 5% AcOEt in
: 8.75–8.74 (m, 1H), 8.54 (d, J = 8.0 Hz, 1H),
1
δ
8.29 (d, J = 7.7 Hz. 1H), 7.96–7.94 (m, 1H), 7.61–7.59 (m, 2H),7.55 (q, J = 7.7 Hz, 1H), 7.43–7.39 (m, 3H),
7.34–7.31 (m, 1H), 7.24–7.21 (m, 2H), 7.11–7.09 (m, 3H), 7.07 (d, J = 7.7 Hz, 1H), 4.09 (d, J = 2.9 Hz, 1H),
4.06 (q, J = 6.6 Hz, 1H), 3.34 (d, J = 2.9 Hz, 1H), 1.55 (d, J = 6.6 Hz, 3H), minor epimer δ: 8.75–8.74
(m, 1H), 8.57 (d, J = 7.7 Hz, 1H), 8.31 (d, J = 7.3 Hz, 1H), 7.90–7.87 (m, 2H), 7.61–7.59 (m, 2H), 7.43–7.39
(m, 2H), 7.34–7.31 (m, 1H), 7.24–7.21 (m, 1H), 7.11–7.09 (m, 2H), 7.07 (d, J = 7.7 Hz, 1H), 7.00–6.98
(m, 3H), 3.65 (d, J = 2.2 Hz, 1H), 3.56 (d, J = 2.2 Hz, 1H), 3.17 (q, J = 6.2 Hz, 1H), 1.49 (d, J = 6.2 Hz,
3H);13C-NMR (151 MHz, 283K, CDCl3)
δ: 159.9, 156.2, 155.3, 154.2, 154.1, 149.23, 149.20, 145.2, 140.7,
137.7, 137.2, 137.0, 137.01, 137.00, 136.7, 133.5, 130.4, 128.4, 127.8, 127.7, 127.6, 127.0, 126.9, 126.7, 126.60,
126.58, 126.5, 126.4, 126.1, 123.9, 123.7, 121.4, 121.1, 120.3, 119.5, 119.0, 60.2, 58.3, 51.1, 50.9, 45.9, 45.6,
24.4, 24.3; HR-MS (ESI) [C26H23N3 + H]+ requires 378.1965; found 378.1970.
(2R,3S)-2-(2,20-bipyridin-6-yl)-3-phenyl-1-[(S)-1-phenylethyl]-aziridine (2R,3S,10S)-12 (Method A):
Two epimers on nitrogen atom in ratio 1:0.4 were observed in 1H-NMR and 13C-NMR. Colorless oil,
132 mg, 70%, [α]2D0 = 163 (c = 1.02, CHCl3), purified by column chromatography (Florisil, 5% AcOEt in
1
hexane). H-NMR (600 MHz, 283K, CDCl3) major epimer
δ
: 8.76 (d, J = 4.7 Hz, 1H), 8.56 (d, J = 8.0 Hz
,
1H), 8.54 (d, J = 7.7 Hz, 1H), 7.93 (qd, J = 7.7, 1.8 Hz, 1H), 7.89 (t, J = 7.7 Hz, 1H), 7.62–7.60 (m, 1H),
7.50–7.44 (m, 3H), 7.42–7.36 (m, 3H), 7.33–7.21 (m, 5H), 4.20 (q, J = 6.2 Hz, 1H), 3.93 (d, J = 2.9 Hz,
1H), 3.52 (d, J = 2.9 Hz, 1H), 1.08 (d, J = 6.6 Hz, 3H); minor epimer
d, J = 8.0 Hz, 1H), 8.24 (d, J = 7.7 Hz, 1H), 7.81 (q, J = 7.7 Hz, 2H), 7.62–7.60 (m, 2H), 7.50–7.44 (m, 1H),
7.42–7.36 (m, 4H), 7.33–7.21 (m, 5H), 3.81 (d, J = 2.9 Hz, 1H), 3.50 (d, J = 3.3 Hz, 1H), 3.28 (q, J = 6.2 Hz,
1H), 1.19 (d, J = 6.2 Hz, 3H), 13C-NMR (151 MHz, 283K, CDCl3)
: 162.0, 159.1, 156.2, 156.1, 155.3, 154.7,
δ: 8.68 (d, J = 4.4 Hz, 1H), 8.42
(
δ
153.9, 149.3, 149.1, 145.5, 145.2, 140.2, 137.6, 137.3, 137.2, 136.9, 133.1, 130.5, 128.3, 128.1, 127.1, 127.0,
126.9, 126.8, 127.8, 126.5, 126.0, 124.02, 123.7, 121.5, 121.1, 121.0, 120.5, 120.4, 119.4, 119.3, 59.9, 57.9, 51.0,
50.8, 46.0, 45.3, 23.6, 23.3; HR-MS (ESI) [C26H23N3 + H]+ requires 378.1965; found 378.1971.
3.3. General Procedure for the Synthesis of Cyclic Sulfamidates
The synthesis of S,S-dioxides was performed according to a modified literature procedure [39,40]
To a solution of amino alcohol or (1 mmol) and triethylamine (3 mmol, 0.42 mL) in dry
dichloromethane (3.5 mL) was added a solution of thionyl chloride (0.8 mmol, 58 L) in dry
dichloromethane (0.25 mL) at
78 ◦C over 20 min. The mixture was stirred at 78 ◦C for 20 min and at
.
1
5
µ
−
−
0 ◦C for the next 20 min. The reaction mixture was partitioned between ether and water, the organic
layer was washed with brine and dried over anhydrous sodium sulfate, filtered and the filtrate was
concentrated in vacuo. The residue was dissolved in acetonitrile (4 mL), cooled to 0 ◦C and NaIO4
(1.2 mmol, 257 mg), RuCl3
stirred at room temperature for 1 h, then diluted with water and extracted 3
·
3H20 (ca. 2 mg) and water (10
µ
L) were added. The reaction mixture was
×
Et2O. The combined
organic extracts were washed with brine and dried over sodium sulfate. The residue was purified by
column chromatography (SiO2, 10% AcOEt in hexane) to provide the cyclic sulfamidate.
(5S)-Phenyl-3-[(S)-1-phenylethyl]-1,2,3-oxathiazolidine-2,2-dioxide (5S,10S)-17
:
White solid,
73 (c = 0.62 CHCl3), 1H-NMR (400 MHz, CDCl3)
: 7.39–7.33
(m, 10H), 5.62 (dd, J = 10.1, 6.1 Hz, 1H), 4.35 (q, J = 6.4 Hz, 1H), 3.40 (dd, J = 10.1, 6.1 Hz, 1H), 3.19
151 mg, 50%, m.p. 100–101 ◦C, [α]D20
=
−
δ
(
t, J = 9.8 Hz, 1H), 1.75 (d, J = 6.7 Hz, 3H); 13C-NMR (101 MHz, CDCl3)
δ: 140.7, 134.7, 129.9, 129.1,
129.0, 128.6, 127.1, 126.5, 80.9, 59.1, 55.3, 20.8, HR-MS (ESI) [C16H17NO3S + Na]+ requires 326.0822;
found 326.0826.
(4S,5S)-4-Phenyl-5-(pyridin-2-yl)-3-[(S)-1-phenylet◦hyl]-1,2,3-oxathiazolidine-2,2-dioxide
(4S,5S,10S)-18: White solid, 288 mg, 76%, m.p. 68–70 C, [α]2D0
=
−
11 (c = 0.73 CHCl3), H-NMR
1

Molecules 2020, 25, 727
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(400 MHz, CDCl3)
δ
: 8.32 (d, J = 4.9 Hz, 1H), 7.36–7.26 (m, 6H), 7.03–6.94 (m, 7H), 5.97 (d, J = 6.1 Hz,
1H), 4.96 (q, J = 6.7 Hz, 1H), 4.75 (d, J = 6.4 Hz, 1H), 1.50 (d, J = 6.7 Hz, 3H); 13C-NMR (101 MHz,
CDCl3) δ: 152.6, 148.7, 138.5, 136.5, 136.1, 128.7, 128.6, 128.1, 128.0, 127.9, 126.9, 123.1, 120.9, 83.1, 65.8,
56.4, 20.2; HR-MS (ESI) [C21H20N2O3S + Na]+ requires 403.1087; found 403.1084.
(4R,5R)-4-Phenyl-5-(pyridin-2-yl)-3-[(S)-1-phenylethyl]-1,2,3-oxathiazolidine-2,2-dioxide
(4R,5R,10S)-18: White solid, 296 mg, 79%, [α]2D0
=
7 (c = 0.89 CHCl3), 1H-NMR (400 MHz, CDCl3)
−
δ
: 8.32 (d, J = 4.9 Hz, 1H), 7.37 (td, J = 7.6, 1.5 Hz, 1H), 7.28–7.21 (m, 5H), 7.01–6.97 (m, 7H), 6.08
(
d, J = 6.1 Hz, 1H), 4.82 (d, J = 6.1 Hz, 1H), 4.33 (q, J = 6.7 Hz, 1H), 1.85 (d, J = 7.0 Hz, 3H); 13C-NMR
(101 MHz, CDCl3) δ: 152.7, 148.7, 140.5, 136.6, 133.5, 128.9, 128.4, 128.33, 128.32, 128.2, 127.2, 123.2,
120.7, 82.5, 67.2, 57.0, 20.1; HR-MS (ESI) [C21H20N2O3S + H]+ requires 381.1261; found 381.1265.
3.4. Synthesis of Azides
Method 1: Synthesis of azides by ring opening of aziridines
The solution of HN3 (1.53 M in C6H6, 0.14 mmol, 200 µL) was added to the aziridines (0.07 mmol)
by a syringe and the reaction mixture was stirred at RT overnight. Then, the solvent was evaporated
under reduced pressure to give the corresponding azide.
Method 2: Synthesis of azides by nucleophilic substitution of sulfamidates
The synthesis was performed according to a modified literature procedure [40]. To a solution
of S,S-dioxide (0.5 mmol) in dry DMF (1.5 mL) sodium azide (2.5 mmol, 162 mg) was added and the
mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo,
and ether (1.6 mL) and 20% H2SO4 were added. The mixture was stirred for 5 h in room temperature,
then neutralized with NaHCO3 and extracted 3 CHCl3. The combined organic layer was dried over
×
sodium sulfate and concentrated. The residue was chromatographed on silica gel (10% AcOEt in
hexane) to give a corresponding product.
Method 3: Synthesis of azides by Mitsunobu reaction conditions with hydrazoic acid
The synthesis was performed according to a modified literature procedure [18]. To a solution of
amino alcohols
was added HN3 (1.53 M in C6H6, 0.65 mmol, 0.7 mL), and next solution of DEAD (0.75 mmol, 116
in benzene (1 mL) at 0 ◦C. The reaction mixture was stirred at room temperature for 3 h (for amino
alcohol ) or 24 h (for ). Then, the solvent was removed and the products were isolated by column
1, or
2
(0.5 mmol) and triphenylphosphine (0.65 mmol, 170 mg) in dry benzene (1.6 mL)
µL)
1
2
chromatography (Florisil, 10% AcOEt in hexane).
N-[(S)-1-Phenylethyl]-(R)-2-azido-2-phenyl-ethylamine (1R,10S)-
3
(Methods 1 and 2): Yellow oil,
: 7.38–7.24
18 mg, 97% (method 1), [α]D20
=
−
129 (c = 1.02, CHCl3), H-NMR (600 MHz, CDCl3)
δ
1
(m, 10H), 4.65 (t, J = 6.6 Hz, 1H), 3.81 (q, J = 6.6 Hz, 1H), 2.74 (d, J = 2.9 Hz, 2H), 1.36 (d, J = 6.6 Hz, 3H);
13C-NMR (151 MHz, CDCl3)
δ: 145.1, 138.1, 128.8, 128.6, 128.4, 127.1, 127.0, 126.5, 66.1, 57.8, 52.9, 24.4;
HR-MS (ESI) [C16H18N4 + H]+ requires 267.1604; found 267.1604.
N-[(S)-1-Phenylethyl]-(S)-2-azido-2-phenyl-ethylamine (1S,10S)-
3
(Method 1): Yellow oil, 60 mg,
: 7.37–7.30 (m, 7H), 7.27–7.23
(m, 3H), 4.61–4.58 (m, 1H), 3.84 (q, J = 6.6 Hz, 1H), 2.82 (dd, J = 12.5, 9.2 Hz, 1H), 2.69 (dd, J = 12.5, 4.8
Hz, 1H), 1.40 (d, J = 6.6 Hz, 3H); 13C-NMR (150 MHz, CDCl3)
: 137.9, 128.9, 128.6, 128.5, 128.0, 127.2,
127.1, 126.7, 66.3, 58.5, 52.9, 24.3; HR-MS (ESI) [C16H18N4 + H]+ requires 267.1604; found 267.1606.
N-[(S)-1-Phenylethyl]-(R/S)-2-azido-2-phenyl-ethylamine (1R,10S)- and (1S,10S)-
in ratio 0.8:1
(Method 3): Yellow oil, 106 mg, 40%, HR-MS (ESI) [C16H18N4 + H]+ requires 267.1604; found 267.1606.
N-[(S)-1-Phenylethyl]-(S)-2-azido-2-pyridin-2-yl-ethylamine (1S,10S)-
(Methods 1 and 3): Yellow
oil, 16 mg, 84% (method 1), [α]D20 = 24 (c = 0.91 CHCl3), 1H-NMR (400 MHz, CDCl3)
: 8.55 (d, J = 4.9 Hz
1H), 7.70–7.66 (m, 1H), 7.34–7.19 (m, 7H), 4.69 (t, J = 7.6 Hz, 1H), 3.85 (q, J = 6.7 Hz, 1H), 2.95–2.91
90% (method 2), [α]2D0 = 97 (c = 0.91, CHCl3), 1H-NMR (600 MHz, CDCl3)
δ
δ
3
3
4
δ
,
(m, 2H), 1.39 (d, J = 6.7 Hz, 3H); 13C-NMR (101 MHz, CDCl3)
δ: 157.7, 149.6, 137.1, 128.7, 127.3,
126.8, 123.3, 121.94, 121.87, 66.0, 58.5, 51.3, 24.2; HR-MS (ESI) [C15H17N5 + H]+ requires 268.1557;
found 268.1559.

Molecules 2020, 25, 727
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N-[(S)-1-Phenylethyl)-(1R,2R)-2-azido-2-phenyl-1-pyridin-2-yl-ethylamine
(1R,2R,10S)-13
(Method 1): Yellow oil, 23 mg, 96%, [α]D20
= 57 (c = 1.05, CHCl3), H-NMR (600 MHz, CDCl3) δ:
−
1
8.60 (d, J = 4.7 Hz, 1H), 4.78 (qd, J = 7.4, 1.5 Hz, 1H), 7.37–7.32 (m, 3H), 7.27–7.25 (m, 2H), 7.20–7.13
(m, 4H), 7.08–7.06 (m, 2H), 6.88 (d, J = 7.7 Hz, 1H), 4.95 (d, J = 7.7 Hz, 1H), 3.95 (d, J = 7.7 Hz, 1H),
3.47 (q, J = 6.2 Hz, 1H), 1.18 (d, J = 6.2 Hz, 3H); 13C-NMR (151 MHz, 283K, CDCl3)
δ: 160.0, 149.4,
145.6, 137.7, 135.9, 128.5, 128.3, 128.2, 127.9, 126.8, 126.6, 123.6, 122.4, 70.0, 65.7, 56.0, 23.2; HR-MS (ESI)
[C21H21N5 + H]+ requires 344.1870; 344.1880.
N-[(S)-1-Phenylethyl]-(1S,2S)-2-azido-1-[2,20-bipyrid-6-yl]-2-phenyl-ethylamine (1S,2S,10S)-14
(Method 1): Yellow oil, 23 mg, 94%, [α]2D0 = 27 (c = 1.1, CHCl3), 1H-NMR (600 MHz, CDCl3)
δ
: 8.72
d, J = 4.7 Hz, 1H), 8.49 (dt, J = 8.1, 1.1 Hz, 1H), 8.37 (dd, J = 7.7, 1.1 Hz, 1H), 7.87–7.84 (m, 1H), 7.76
q, J = 7.7 Hz, 1H), 7.38–7.33 (m, 4H), 7.23–7.20 (m, 5H), 7.02 (d, J = 7.7 Hz, 1H), 6.95–6.93 (m, 2H), 4.86
(
(
(d, J = 8.4 Hz, 1H), 3.72 (d, J = 8.4 Hz, 1H), 3.44 (q, J = 6.6 Hz, 1H), 1.15 (d, J = 6.6 Hz, 3H); 13C-NMR
(
151 MHz, 283K, CDCl3) δ: 149.4, 156.3, 156.1, 149.2, 144.9, 137.8, 136.9, 136.8, 128.4, 128.31, 128.28,
128.2, 127.0, 126.9, 124.3, 123.8, 121.3, 119.9, 70.2, 64.9, 55.6, 25.4; HR-MS (ESI) [C26H24N6 + H]+ requires
421.2135; 421.2147.
N-[(S)-1-Phenylethyl]-(1S,2R)-2-azido-1-phenyl-2-pyridin-2-yl-ethylamine (1R,2S,10S)-19 (Method 2):
Colorless oil, 120 mg, 70%, [α]D20
=
−
4 (c = 0.54 CHCl3), 1H-NMR (400 MHz, CDCl3)
δ
: 8.57 (d, J = 4.6 Hz
1H), 7.51 (td, J = 7.6, 1.8 Hz, 1H), 7.26–7.10 (m, 11H), 7.00–6.98 (m, 1H), 4.64 (d, J = 7.0 Hz, 1H), 4.34
d, J = 7.0 Hz, 1H), 3.60 (q, J = 6.4 Hz, 1H), 1.27 (d, J = 6.4 Hz, 3H); 13C-NMR (101 MHz, CDCl3)
δ:
,
(
157.3, 149.4, 146.1, 140.0, 136.3, 128.4, 128.3, 127.9, 127.5, 126.9, 126.7, 123.0, 122.9, 72.1, 64.0, 54.8, 22.0;
HR-MS (ESI) [C21H21N5 + H]+ requires 344.1870; found 344.1867.
N-[(S)-1-Phenylethyl]-(1R,2S)-2-azido-1-phenyl-2-pyridin-2-yl-ethylamine (1S,2R,10S)-19 (Methods 2
and 3): Colorless oil, 125 mg, 70% (Method 2), [α]D20
CDCl3)
=
−
116 (c = 0.90 CHCl3), H-NMR (600 MHz,
1
δ: 8.47 (d, J = 4.8 Hz, 1H), 7.54 (td, J = 7.3, 1.5 Hz, 1H), 7.26–7.12 (m, 9H), 7.05–7.04 (m, 1H),
6.96–6.94 (m, 2H), 4.60 (d, J = 6.6 Hz, 1H), 3.86 (d, J = 6.6 Hz, 1H), 3.47 (q, J = 6.6 Hz, 1H), 1.29
(
d, J = 6.6 Hz, 3H); 13C-NMR (101 MHz, CDCl3)
δ: 157.2, 149.2, 145.0, 139.9, 136.2, 128.4, 128.3, 128.0,
127.5, 126.8, 126.5, 122.8, 122.7, 72.2, 63.3, 54.7, 25.1; HR-MS (ESI) [C21H21N5 + H]+ requires 344.1870;
found 344.1876.
3.5. General Procedure for the Synthesis of Diamines
The synthesis of diamines was performed according to a modified literature procedure [40]. To
a solution of azide (0.05 mmol) in CH2Cl2 (0.05 mL) was added triphenylphosphine (0.055 mmol,
15 mg) and water (11 µL). The reaction mixture was stirred overnight and the solvent was removed
under vacuum. Then the product was isolated from the crude mixture by column chromatography
(Florisil, CHCl3:AcOEt:MeOH 1:1:0.25).
N-[(S)-1-Phenylethyl]-(1R)-phenyl-1,2-ethanediamine (1R,10S)-20: Colorless oil, 75%, [α]2D0
=
−
97
: 7.23–7.19 (m, 10H), 4.0 (dd, J = 8.6, 4.6 Hz, 1H), 3.76
q, J = 6.7 Hz, 1H), 2.72 (dd, J = 11.6, 4.3 Hz, 1H), 2.51 (dd, J = 11.9, 8.9 Hz, 1H), 1.34 (d, J = 6.4 Hz, 3H);
(c = 0.96 CHCl3), 1H-NMR (400 MHz, CDCl3)
(
δ
13C-NMR (101 MHz, CDCl3)
δ: 143.4, 128.8, 128.7, 128.6, 127.6, 127.5, 126.9, 126.4, 58.3, 55.0, 54.6, 23.7;
HR-MS (ESI) [C16H20N2 + H]+ requires 241.1699; found 241.1696.
N-[(S)-1-Phenylethyl]-(1S)-pyridin-2-yl-1,2-ethanediamine (1S,10S)-21: Colorless oil, 75%, [α]2D0
=
−
27 (c = 0.67 CHCl3), 1H-NMR (600 MHz, CDCl3)
δ: 8.55 (d, J = 4.8 Hz, 1H), 7.65 (td, J = 7.7, 1.8 Hz,
1H), 7.37–7.24 (m, 6H), 7.18 (dd, J = 4.8, 1.1 Hz, 1H), 4.15–4.13 (m, 1H), 3.88 (q, J = 6.7 Hz, 1H), 2.84
(dd, J = 11.7, 4.8 Hz, 1H), 2.76 (dd, J = 11.7, 8.0 Hz, 1H), 1.47 (d, J = 6.6 Hz, 1H); 13C-NMR (151 MHz,
CDCl3) δ: 162.4, 149.1, 144.2, 136.7, 128.6, 127.3, 126.8, 122.3, 121.6, 58.7, 56.0, 54.0, 23.8; HR-MS (ESI)
[C15H19N3 + H]+ requires 242.1652; found 1649.
N-[(S)-1-Phenylethyl]-(1R,2R)-1-pyridin-2-yl-2-phenyl-1,2-ethanediamine (1R, 2R, 10S)-22
:
,
Colorless oil, 60%, [α]D20
=
−
31 (c = 0.49 CHCl3), H-NMR (400 MHz, CDCl3)
δ: 8.52 (d, J = 4.9 Hz
1
1H), 7.39 (td, J = 7.6, 1.8 Hz, 1H), 7.24–7.14 (m, 8H), 7.09–7.05 (m, 3H), 6.71 (d, J = 7.6 Hz, 1H), 4.34
d, J = 6.1 Hz, 1H), 3.94 (d, J = 6.1 Hz, 1H), 3.94 (d, J = 6.1 Hz. 1H), 3.62 (q, J = 6.4 Hz, 1H), 1.26
(

Molecules 2020, 25, 727
12 of 15
(
d, J = 6.4 Hz, 3H); 13C-NMR (101 MHz, CDCl3)
δ
: 160.8, 149.1, 145.9, 143.3, 135.8, 128.30, 128.28, 128.2,
127.2, 127.1, 126.8, 123.6, 122.1, 67.1, 59.8, 55.9, 23.3; HR-MS (ESI) [C21H23N3 + H]+ requires 318.1965;
found 318.1971.
N-[(S)-1-Phenylethyl]-(1S,2S)-1-(2,20-bipyridin-6-yl)-2-phenyl-1,2-ethanediamine (1S,2S,10S)-23
:
Colorless oil, 50%, [α]D20
= δ: 8.67 (d, J = 4.9 Hz, 1H),
30 (c = 0.43 CHCl3), 1H-NMR (400 MHz, CDCl3)
−
8.33 (d, J = 7.9 Hz, 1H), 8.28 (d, J = 7.9 Hz, 1H), 7.81 (td, J = 7.3, 1.8 Hz, 1H), 7.65 (t, J = 7.6 Hz, 1H),
7.32–7.16 (m, 7H), 7.10–7.08 (m, 2H), 7.04–7.01 (m, 2H), 6.86 (d, J = 7.6 Hz, 1H), 4.29 (d, J = 6.4 Hz, 1H),
3.73 (d, J = 6.4 Hz, 1H), 3.46 (q, J = 6.4 Hz, 1H), 1.23 (d, J = 6.7 Hz, 3H); 13C-NMR (101 MHz, CDCl3)
δ:
156.4, 155.7, 149.2, 145.2, 143.1, 137.0, 136.9, 132.1, 128.5, 128.4, 128.0, 127.4, 127.1, 127.0, 124.2, 123.8,
121.3, 119.5, 66.3, 60.6, 55.8, 25.4; HR-MS (ESI) [C26H26N4 + H]+ requires 395.2230; found 395.2256.
N N-[(S)-1-Phenylethyl]-(1S,2R)-1-pyridin-2-yl-2-phenyl-1,2-ethanediamine (1S,2R,10S)-24: Yellow
oil, 12 mg, 73%, [α]D20
=
−
45 (c = 0.52 CHCl3), 1H-NMR (400 MHz, CDCl3)
δ
: 8.43 (d, J = 4.9 HZ, 1H),
7.32 (td, J = 7.6, 1.8, Hz, 1H), 7.25–7.16 (m, 7H), 7.09–7.07 (m, 2H), 7.03–7.00 (m, 3H), 3.99 (d, J = 7.6 Hz,
1H), 3.51–3.48 (m, 2H), 1.31 (d, J = 6.7 Hz, 3H); 13C-NMR (101 MHz, CDCl3)
: 148.8, 144.9, 135.8,
δ
128.54, 128.47, 128.3, 127.9, 127.8, 127.2, 126.9, 126.7, 122.9, 122.0, 65.7, 62.4, 55.0, 25.0; HR-MS (ESI)
[C21H23N3 + H]+ requires 318.1965; found 318.1972.
N-[(S)-1-Phenylethyl]-(1R,2S)-1-pyridin-2-yl-2-phenyl-1,2-ethanediamine (1R, 2S, 10S)-24: Yellow
oil, 11 mg, 70%, [α]D20
CDCl3)
6.79–6.78 (m, 1H), 4.08 (d, J = 8.0 Hz, 1H), 4.04 (d, J = 7.7 Hz, 1H), 3.63 (q, J = 6.6 Hz, 1H), 2.90 (s, 3H),
=
−
83 (c = 0.87 CHCl3), H-NMR (600 MHz, CDCl3)
δ: H-NMR (600 MHz,
1
1
δ
: 8.56 (d, J = 4.8 HZ, 1H), 7.40 (td, J = 7.3, 1.8, Hz, 1H), 7.29–7.08 (m, 8H), 7.10–7.08 (m, 3H),
1.35 (d, J = 6.6 Hz, 3H) 13C-NMR (151 MHz, CDCl3)
δ: 161.0; 149.0, 145.8, 141.0, 135.9, 128.3, 128.1,
127.7, 127.1, 126.9, 126.7, 123.1, 122.2, 66.4, 62.6, 54.9, 21.8; HR-MS (ESI) [C21H23N3 + H]+ requires
318.1965; found 318.1966.
4. Conclusions
We developed two different transformations of pyridine-containing chiral β-amino alcohols to the
respective isomeric vic-diamines (Scheme 4). The first method used an internal Mitsunobu SN2 reaction
to furnish intermediate aziridine, followed by the ring opening with hydrazoic acid and Staudinger
reduction (Scheme 4, method A). The 1,2,3-trisubstituted aziridines exist as observable N-epimeric
forms that exhibit disparate affinity towards zinc ions in the NMR. For these aziridines ring closure
and ring opening occurred at different carbon stereocenters, thus yielding products with two inverted
configurations, compared to the starting amino alcohol. The protonation likely activates the respective
carbon in the aziridine ring leading to the observed regioselectivity. The 1,2-disubstituted aziridines
produced diamines of the same configuration as the starting
inversion at the same stereogenic center.
β-amino alcohols because of double
Scheme 4. Stereodivergent synthesis of chiral vic-diamines as exemplified by the transformations of
(1S,2S,10S)-5.

Molecules 2020, 25, 727
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In the second method (Scheme 4, method B) we adopted the formation of cyclic sulfamidate,
which reacted with sodium azide in SN2 manner and the obtained azide was reduced, thus providing
products with the inverted configuration at one stereogenic center. The usefulness of both methods is
documented by a high-yielding preparation of 6 new chiral vic-diamines.
Supplementary Materials: The following are available online, NMR assignments for azido amines, DFT
computation details, additional NMR experiments, copies of 1H and 13C-NMR spectra.
Author Contributions: Conceptualization, J.S.; methodology, J.S., M.W.-H. and P.J.B.; software, P.J.B.; validation,
M.W.-H. and P.J.B.; formal analysis, P.J.B.; investigation, J.S., M.W.-H.; resources, J.S.; data curation, M.W.-H. and
P.J.B.; writing—original draft preparation, M.W.-H.; writing—review and editing, J.S. and P.J.B.; visualization, J.S.,
M.W.-H. and P.J.B.; supervision, J.S.; project administration, J.S.; funding acquisition, J.S. All authors have read
and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Acknowledgments: The authors thank the Wrocław Center for Networking and Supercomputing for allotment of
computer time (grant 362).
Conflicts of Interest: The authors declare no conflict of interest.
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2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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