Alkylative aziridine ring-opening reactions

Article abstract of DOI:10.3390/molecules26061703

In this study, the highly strained three-membered aziridine ring was successfully activated as the aziridinium ion by alkylation of the ring nitrogen with a methyl, ethyl or allyl group, which was followed by ring opening with external nucleophiles such as acetate and azide. Such alkylative aziridine ring opening provides an easy route for the synthesis of various N-alkylated aminecontaining molecules with concomitant introduction of an external nucleophile at either its α- or β-position.

Full text of DOI:10.3390/molecules26061703

molecules
Article
Alkylative Aziridine Ring-Opening Reactions
Jieun Choi, Taehwan Yu and Hyun-Joon Ha *
Department of Chemistry, Hankuk University of Foreign Studies, Yongin 17035, Korea;
jieun3369@gmail.com (J.C.); sunjew03221@naver.com (T.Y.)
* Correspondence: hjha@hufs.ac.kr; Tel.: +82-31-330-4369
Abstract: In this study, the highly strained three-membered aziridine ring was successfully activated
as the aziridinium ion by alkylation of the ring nitrogen with a methyl, ethyl or allyl group, which
was followed by ring opening with external nucleophiles such as acetate and azide. Such alkylative
aziridine ring opening provides an easy route for the synthesis of various N-alkylated amine-
containing molecules with concomitant introduction of an external nucleophile at either its α- or
β-position.
Keywords: aziridine; non-activated; aziridinium ion; alkylative; ring-opening; amine; regioselectivity
1. Introduction
Aziridine, a nitrogen-containing three-membered ring, has high ring strain similar to
oxirane and cyclopropane [1–12]. However, the non-activated aziridine-bearing electron
donating group at the ring nitrogen is relatively stable and inert toward almost all nucle-
ophiles. It should be activated properly as an aziridinium ion or its equivalent prior to
ring-opening reaction, as shown in Scheme 1 [13,14].
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Citation: Choi, J.; Yu, T.; Ha, H.-J.
Alkylative Aziridine Ring-Opening
Reactions. Molecules 2021, 26, 1703.
https://doi.org/10.3390/molecules
26061703
Y
Y
Y
HN
Y
R
HN
Nu:
Nu:
N
N
R
or
N
Nu
H
Nu
R
Nu
Y = EDG
R
Y = EWG
Nu:
Activated aziridine
Academic Editor: Marek
M. Kowalczuk
Y = Electron Attracting Group (EWG)
E
R
Y
E
Non-activated aziridine
Received: 2 March 2021
Accepted: 15 March 2021
Published: 18 March 2021
Y = Electron Donating Group (EDG)
E = Electrophile
Scheme 1. Nucleophilic ring opening of activated and non-activated aziridines.
The reactivity of non-activated aziridine provides an opportunity to introduce another
functional group into the ring nitrogen during activation of the aziridine ring. Electrophiles
for the activation of non-activated aziridine by bond formation, including carbon–carbon
and carbon–silicon, and by Lewis acid (LA) coordination with lone pair electrons at the aziri-
dine ring nitrogen can yield aziridinium ions or their equivalents [15]. These electrophiles
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with regard to jurisdictional claims in
published maps and institutional affil-
iations.
include haloalkanes, acyl halides, trialkylsilyl halides and most Lewis acids [16
ever, most aziridinium ions are quite reactive toward the counter anion (X− in Scheme 2
released from reagents of electrophiles as a nucleophile to be broken down [20 24]. Intro-
–19]. How-
)
–
Copyright:
© 2021 by the authors.
duction of a specific group with concomitant breakage of the ring opening by an external
nucleophile is a challenging problem to be solved to boost the synthetic utility of aziridine.
To make this possible, the aziridinium ion should be stable as it is a quaternary ammonium
salt enduring the strain of a three-membered aziridine ring until the external nucleophile
reacts for ring opening [25,26]. It means that the nucleophilicity of the counter anion from
the reagent of the electrophile should be weak enough for the aziridinium ion to survive.
This is a key requirement for the external nucleophile added to the reaction media that
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Molecules 2021, 26, 1703
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leads to ring opening at either its α- or β-position in a regioselective manner, as shown in
Scheme 2.
−
Scheme 2. Aziridine ring opening either by a counter anion (X ) of an electrophile or by an external
nucleophile (Nu:) added directly to the reaction vessel.
2. Results and Discussion
Every electrophile provides an aziridinium ion with unique characteristics that leads
to ring-opening reactions in distinctive regiochemical pathways; either “a” or “b” in
Scheme 3, as summarized in our previous publication [27]. The ring substituent R and the
−
nucleophile (Nu ) applied in the reaction vessel are also crucial to determine regiochemical
pathways [27,28].
Scheme 3. Aziridine ring opening in either ways “a” or “b”. Activation with an alkyl group from
an electrophile (EX) to make the aziridinium ion in the bracket, followed by aziridine ring-opening
−
reactions with an external nucleophile (Nu ) for alkylative aziridine ring opening.
Our previous study [27,28] showed that the reaction of aziridine (1) bearing a 2-
methylbenzyl group as an electron-donating group (EDG) at the ring nitrogen with methyl
trifluoromethylsulfonate (MeOTf) can provide stable aziridinium ions such as 2 (E = Me,
X = TfO−) (Scheme 3). Among all electrophiles applicable to the activation of non-activated
aziridine, the alkyl group is a good applicant with numerous advantages. It can provide a
good chance to introduce a new alkyl group at the ring nitrogen and nucleophiles either at
the α- or β-carbon of nitrogen, depending on the regiochemical pathways [29–31]. In a pre-
vious study, we were able to introduce a methyl group to generate the N-methylaziridinium
ion and lead to subsequent ring openings for N-methylated acyclic amines in a regio- and
stereoselective manner [32]. This new reaction, called the N-methylative aziridine ring-
opening reaction, was used as a key step for the synthesis of various biologically important
molecules. We succeeded in making N-methylative aziridine ring-opening reactions with
methyl group at the nitrogen coming from MeOTf for the formation of aziridinium ions
and subsequent ring opening by nucleophiles, including acetate for MeBMT [33]; protected
p-hydroxyphenyl magnesium bromide for tyroscherin [34,35]; and nitriles for hygroline,

Molecules 2021, 26, 1703
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pseudohygroline, hygrine [36] and part of PF-00951966 [37] (Figure 1). These examples
showed the value of N-methylative aziridine ring-opening reactions.
Figure 1. Biologically important molecules synthesized through N-methylative aziridine ring-opening reactions. Methyl
groups (Me) shown in blue; nucleophiles shown in red.
Expansion of this reaction with alkylation other than methylation will provide a gen-
eral route for the synthesis of various alkyl- or functionalized amine-containing molecules.
However, there are problems associated with this new reaction that should be overcome
for this reaction to be synthetically valuable. At first, the aziridinium ion derived after
aziridine is alkylated should be stable enough for the external nucleophiles to be reacted. In
other words, the counter anion used to form the aziridinium ion is not nucleophilic enough
to break down the intermediate. Instead, an external nucleophile should be reactive enough
to give a decent yield of the ring-opening reaction [37]. In addition, the regiochemical
pathway should be controllable. It should be either pathway “a” or “b” to yield an
α-
or -amino compound selectively. However, up to now, only N-methylation has been
β
successful, while all other bigger alkyl groups have been unsuccessful, possibly due to the
limitations of the small steric space to accommodate a bigger group under mild reaction
conditions. This intrinsic drawback should be overcome by improving the reactivity of
the incoming reactant as an electrophile-bearing non-nucleophilic leaving group. After
numerous approaches, we finally succeeded in the alkylation of the ring nitrogen, including
ethyl and allyl groups besides methyl, to give rise to the corresponding N-alkylated amines
after aziridine ring opening.
At first, the ethylative aziridine ring opening was tried using the same protocol
used for methylation with MeOTf as the methylating agent and with TfO− as its counter
anion. The ethyl group was introduced into the aziridine ring by addition of EtOTf to
the substrate, followed by the external nucleophile NaOAc. As expected, the reaction
medium CH3CN was the best to yield reaction products (3AEa and 4AEa, overall yield:
49%) from 2-benzyloxymethylaziridine (1A), with the kinetic product as the major one and
regioselectivity of 88:12 in CH3CN among many solvents, including DMF, THF, dioxane
and CH2Cl2 (Table 1, entries 1 and 2). With an increase of the nucleophile from 1.1 to
1.5 equiv., the reaction yield was improved from 49 to 62% (entry 3). Instead of the 2-
benzyloxymethyl group, 2-triethylsilyloxymethyl and 2-t-butyldimethylsilyloxymethyl
substitution (1B and 1C) afforded the expected products (3BEa and 4BEA; 3CEa and 4CEA)
in slightly better yields (64 and 72%, entries 4 and 5).

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Table 1. Ethylative aziridine ring-opening reactions with EtOTf in CH3CN a.
Yield (%) b
Entry
R
MNu (equiv.)
Solvent
Rxn (h)
3:4
1
2
3
4
5
CH2OBn
CH2OBn
CH2OBn
CH2OTES
CH2OTBS
NaOAc (1.1)
NaOAc (1.1)
NaOAc (1.5)
NaOAc (1.5)
NaOAc (1.5)
CH3CN
DMF
CH3CN
CH3CN
CH3CN
6
12
6
12
12
49%
12%
62%
64%
72%
88:12
62:38
96:4
96:4
84:16
a
Reaction conditions: aziridine
(0.561 mmol) and solvent (4 mL), under a nitrogen atmosphere. Isolated yield.
1
(0.374 mmol), ethyl trifluoromethanesulfonate (0.411 mmol), NaOAc
b
All numbered compound in Tables 1 and 2 are classified by: (i) the second notation
based on the starting substrates:
D, R = CO2Et; (ii) the third notation based on the alkyl at the nitrogen N:
and (ii) the fourth notation based on the nucleophile at the carbon: a = OAc; b = N3.
A
, R = CH2OBn;
B
, R = CH2OTES;
C
, R = CH2OTBS;
E
= ethyl; A = allyl
;
Table 2. Allylative aziridine ring-opening reactions with ICH2CHCH2 (1.25 equiv.) and AgOTf
(1.05 equiv.) in CH3CN a.
Yield (%) b
Entry
R
MNu (Equiv.)
Rxn (h)
3:4
1
2
3
4
5
6
7
8
9
CH2OBn
CH2OBn
CH2OBn
CH2OBn
CH2OBn
CH2OBn
CH2OBn
CH2OTES
CH2OTBS
C(=O)OEt
C(=O)OEt
NaOAc (1.5)
NaOAc (3.0)
CsOAc (1.5)
BnNH2 (1.1)
NaN3 (1.1)
NaN3 (2.0)
NaN3 (3.0)
NaOAc (1.1)
NaOAc (1.1)
NaOAc (1.1)
NaN3 (1.1)
8
8
24
24
12
8
8
8
8
12
24
85%
97%
66%
-
59
51
48
78
89
68
50:50
43:57
60:40
-
50:50
50:50
50:50
99:1
99:1
11:89
47:53
10
11
34
a Reaction conditions: aziridine
under a nitrogen atmosphere. Isolated yield.
1
(0.374 mmol), allyl iodide (0.468 mmol), AgOTf (0.393 mmol) and solvent (4 mL),
b
Such successful ethylative aziridine ring-opening reactions prompted us to real-
ize the key structural element of calicheamicine [38] (10) starting from (2S)-2-(((tert-
butyldimethylsilyl)oxy)methyl)-1-((R)-1-phenylethyl)aziridine (
cleophile acetate was added to the ethylated aziridinium ion to give rise to the ring-opened
product in a 75% yield. This was then hydrolyzed to free alcohol ( ). The N-phenylethyl
group in was removed by catalytic hydrogenation in the presence of (Boc)2O to afford 8,
5) (Scheme 4). The nu-
6
7
7

Molecules 2021, 26, 1703
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followed by the treatment with a base to yield (S)-4-(((tert-butyldimethylsilyl)oxy)methyl)-
3-ethyloxazolidin-2-one (9) [21,39,40], whose silyl group was removed by TBAF to give free
alcohol (90). Oxidation of alcohol (90) by the Swern oxidation protocol gave the expected
key structural element (10) for the synthesis of calicheamicine.
Scheme 4. Synthesis of the key structural element of calicheamicine (10) bearing an ethyl group at
the nitrogen from ethylative aziridine ring opening.
This result, including our previous finding, indicates that TfO− is a quite unique
counter anion without much nucleophilicity [25,41]. Once the ethylative aziridine ring
opening has succeeded, it is of interest to add an allyl group, which has an olefin, as
a potentially versatile functional group. However, allyl triflate is not stable or readily
available when it is needed. The reactions with allyl triflate afforded the reaction product
in poor and variable yields. Therefore, we tried to obtain the aziridinium ion with the
addition of an allyl group at the ring nitrogen in different ways. Since iodine anion is a
reactive nucleophile able to break the aziridine ring and its ring-opened product provides
a fast equilibrium back to the aziridinium ion [8], we decided to try with allyl iodide.
Thus, we observed that the iodinated product in the possible thermodynamic pathway
was obtained very slowly. The reaction was not completed after more than 48 h. At that
point, we decided to add AgOTf (1.05 equiv.), the silver of which would capture iodine as
AgI, with the soluble triflate anion leaving the counter anion of the aziridinium ion from
the allylation of aziridine. We finally found that the allylative aziridinium ion was able to
be generated with ICH2CHCH2 (1.25 equiv.), AgOTf (1.05 equiv.) in CH3CN and external
nucleophiles for ring opening (Table 2).
The reaction was performed with the starting substrate (1A) bearing a 2-benzyloxymethyl
group as R with AgOTf, allyl iodide and sodium acetate (NaOAc) as an external nucle-
ophile to afford the ring-opened products (3AAa and 4AAa), whose combined yield was
increased from 85% to 97% by using twice the amount of acetate with comparably poor
regioselectivity from 50:50 to 43:57 (Table 2, entries 1 and 2). We also observed a decrease
of the reaction yield from 85 to 66% by using CsOAc instead of NaOAc (entry 3). A neu-
tral amine nucleophile is not active enough to break down the aziridinium ion to give
a ring-opening product (entry 4). With NaN3 as the nucleophile, the reaction gave rise
to the expected ring-opening products (3AAb and 4AAb) without much difference in
regiochemistry and reaction yield, depending on the amount of reagents added (Table 2
,
entries 5–7). Instead of the benzyloxymethyl group, the starting materials (1B and 1C
)
with triethylsilyloxymethyl and t-butyldimethylsilyloxymethyl as substituents at the C2 of
aziridine gave the expected products (3BAa and 4BAa and 3CAa and 4CAa) with yields of
78% and 89%, respectively, by following the same procedure with NaOAc as a nucleophile
(entries 8 and 9). Regioselectivity of both reactions of 99:1 was astonishing, possibly due
to the steric difficulty imposed for the nucleophile to approach. We also studied reactions
of starting aziridine (1D) bearing ethoxycarbonyl as a substituent at the C2 of aziridine
with NaOAc and NaN3 (entries 10 and 11). Reactions with NaOAc and NaN3 resulted in
the ring-opened products (3DAa and 4BAa and 3DAb and 4Dab) with yields of 68% and
34%, respectively, with regioselectivities of 11:89 and 47:53, showing that the pathway b
in Scheme 3 is more favorable. This regiochemical pathway b is always dominant with
starting materials that have vinyl or carbonyl functional groups at the C2 of aziridine, due
to the weakness of the bond between the N and C2.

Molecules 2021, 26, 1703
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As a showcase of this chemistry, the allylated aziridine ring-opened product (12) was
afforded to take advantage of the olefin at the amine nitrogen (Scheme 5). At first, the
starting 2-allyloxydimethylmethylaziridine (11) was prepared by the addition of methyl
magnesium bromide to aziridine-2-carboxylate (1D), followed by the allylation of the
resultant free hydroxy group with allyl iodide and NaH as a base. This aziridine (11
was then used for an N-allylated aziridine ring-opening reaction with allyl iodide, AgOTf
and NaOAc as a nucleophile to give the product 12 in a 71% yield. This reaction product
)
(
12) with two allyl olefins was cyclized in the presence of Grubbs’ catalyst to yield an
eight-membered ring (13). By catalytic hydrogenation in the presence of (Boc)2O, this ring
13) was saturated and the phenylethyl group at the nitrogen was removed to realize a
(
4-azaoxo heterocycle (14) with valuable functional groups.
Scheme 5. Synthesis of the unusual eight-membered ring with nitrogen and oxygen at its 1- and
4-positions from the Ring Closing Metathesis of allylated ether and allylated amine from N-allylative
aziridine ring opening.
3. Experimental Section
3.1. General Information
Chiral aziridines are available from Sigma-Aldrich as reagents. They are also available
from Imagene Co., Ltd. in bulk quantities. All commercially available compounds were
used as received unless stated otherwise. All reactions were carried out under an atmo-
sphere of nitrogen in oven-dried glassware with magnetic stirrer. Dichloromethane was
distilled from calcium hydride. Reactions were monitored by thin layer chromatography
(TLC) with 0.25 mm using a Kieselgel 60 Art 9385 from Merck (Darmstadt, Germany. Visu-
alization was accomplished with either UV light or by immersion in solutions of ninhydrin,
p-anisaldehyde or phosphomolybdic acid (PMA), followed by heating on a hot plate for
about 10 s. Purification of reaction products was carried out by flash chromatography
1
using using a Kieselgel 60 Art 9385 from Merck in Germany. (230–400 mesh). H-NMR
and 13C-NMR spectra were obtained using a Varian Unity INOVA 400WB (400 MHz) or
Bruker AVANCE III HD (400 MHz) spectrometer. Chemical shifts are reported relative to
chloroform (
δ
= 7.26) for 1H NMR, chloroform (
δ
= 77.2) for 13C NMR, acetonitrile (
δ
= 1.94)
for 1H NMR and acetonitrile (
δ
= 1.32) for 13C NMR (see Supplementary Materials). Data
are reported as br = broad, s = singlet, d = doublet, t = triplet, q = quartet, p = quintet and
m = multiplet. Coupling constants are given in Hz. Ambiguous assignments were resolved
using standard one-dimensional proton decoupling experiments. Optical rotations were
obtained using a Rudolph Autopol III digital polarimeter and JASCO P-2000. Optical
rotation data are reported as follows: [α]
20 (concentration c = g/100 mL, solvent). High-
resolution mass spectra were recorded on a 4.7 Tesla IonSpec ESI-TOFMS, JEOL (JMS-700)
and an AB Sciex 4800 Plus MALDI TOFTM (a 2,5-dihydroxybenzoic acid (DHB) matrix was
used to prepare samples for MS. Data were obtained in the reflector positive mode with
internal standards for calibration).

Molecules 2021, 26, 1703
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3.2. General Procedure for the Synthesis of Ethylative Aziridine Ring-Opening Compounds
Ethyl trifluoromethanesulfonate (0.05 mL, 0.411 mmol) was added to a stirring solution
◦
of aziridine
1
(100 mg, 0.374 mmol) in dry CH3CN (4 mL) under N2 at 0 C. After 5–10 min
,
NaOAc (46 mg, 0.561 mmol) was added to the solution at same temperature. After 10 min
,
the solution was allowed to be warmed to room temperature (RT) and stirred. After
quenching by adding water (10 mL), the reaction product was extracted with CH2Cl2
(20 mL) three times. It was then dried over MgSO4, filtered and concentrated in vacuo. The
reaction product was purified by column chromatography (1:19 = EtOAc:Hex) to provide
an analytically pure product.
3.3. (S)-3-(benzyloxy)-2-(ethyl((R)-1-phenylethyl)amino)propyl Acetate (3AEa)
20
1
Yellow liquid. [
α
]
D
12.1 (c = 1.0, CHCl3). H NMR (400 MHz, CDCl3) δ 7.45–7.10
(m, 10H), 4.33 (s, 2H), 4.24 (dd, J = 11.2, 6.9 Hz, 1H), 4.14 (dd, J = 11.2, 5.5 Hz, 1H), 4.07
(d, J = 6.8 Hz, 1H), 3.35–3.29 (m, 2H), 3.24 (s, 1H), 2.83–2.59 (m, 2H), 2.02 (s, 3H), 1.38 (d,
J = 6.8 Hz, 3H), 1.01 (t, J = 7.0 Hz, 3H). 13C NMR (101 MHz, CDCl3)
δ 171.10, 145.13, 138.37,
128.34, 128.08, 127.59, 127.52, 126.64, 73.07, 69.79, 64.01, 57.80, 55.60, 40.34, 21.13, 19.00,
16.05. HRMS-ESI (m/z): [M + H]+ calcd for C22H30NO3, 356.2160, found 356.2162.
3.4. (S)-1-(benzyloxy)-3-(ethyl((R)-1-phenylethyl)amino)propan-2-yl Acetate (4AEa)
1
Yellow liquid. H NMR (400 MHz, CDCl3)
δ 7.41–7.24 (m, 10H), 5.17–5.08 (m, 1H),
4.54 (d, J = 5.8 Hz, 2H), 3.88 (q, J = 6.8 Hz, 1H), 3.65 (dd, J = 10.7, 3.5 Hz, 1H), 3.59 (dd,
J = 10.7, 5.7 Hz, 1H), 2.72 (dd, J = 13.7, 7.0 Hz, 1H), 2.66–2.44 (m, 3H), 2.08 (s, 3H), 1.35 (d,
J = 6.8 Hz, 3H), 1.02 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3)
δ 170.58, 143.71, 138.02,
128.29, 127.96, 127.68, 126.57, 73.03, 71.94, 69.75, 59.04, 50.11, 44.61, 26.43, 21.27, 16.44, 12.80.
HRMS-ESI (m/z): [M + H]+ calcd for C22H30NO3, 356.2160, found 356.2162.
3.5. (R)-2-(ethyl((R)-1-phenylethyl)amino)-3-((triethylsilyl)oxy)propyl Acetate (3BEa)
20
Yellow liquid. [
α
]
D
1.1 (c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3)
δ 7.38 (d,
J = 7.3 Hz, 2H), 7.33–7.25 (m, 2H), 7.24–7.18 (m, 1H), 4.23 (dd, J = 11.2, 7.0 Hz, 1H), 4.16
(dd, J = 11.2, 5.4 Hz, 1H), 4.09 (q, J = 6.8 Hz, 1H), 3.43 (d, J = 6.3 Hz, 2H), 3.12–2.96 (m, 1H),
2.77 (dd, J = 13.8, 7.0 Hz, 1H), 2.68 (dd, J = 13.9, 7.0 Hz, 1H), 2.06 (s, 3H), 1.37 (d, J = 6.8 Hz,
3H), 1.02 (t, J = 7.0 Hz, 3H), 0.88 (dd, J = 9.5, 6.4 Hz, 9H), 0.48 (q, J = 7.9 Hz, 6H). 13C NMR
(101 MHz, CDCl3) δ 170.98, 145.02, 138.25, 128.22, 127.96, 127.47, 126.52, 77.32, 77.00, 76.68,
72.95, 69.67, 63.89, 57.68, 55.48, 40.22, 21.02, 18.88, 15.93. HRMS-ESI (m/z): [M + H]+ calcd
for C21H38NO3Si, 380.2512, found 380.2515.
3.6. (S)-1-(ethyl((R)-1-phenylethyl)amino)-3-((triethylsilyl)oxy)propan-2-yl Acetate (4BEa)
1
Yellow liquid. H NMR (400 MHz, CDCl3)
δ
7.36–7.17 (m, 5H), 4.94 (dd, J = 5.9, 3.9 Hz,
1H), 3.87 (d, J = 6.8 Hz, 1H), 3.74 (dd, J = 11.1, 3.7 Hz, 1H), 3.66 (dd, J = 11.1, 5.7 Hz, 1H),
2.66 (d, J = 6.6 Hz, 1H), 2.56 (d, J = 7.0 Hz, 1H), 2.52–2.37 (m, 2H), 2.03 (s, 3H), 1.34 (d,
J = 6.8 Hz, 3H), 1.25 (s, 1H), 1.00 (t, J = 7.1 Hz, 3H), 0.94 (t, J = 7.9 Hz, 9H), 0.58 (q, J = 8.0 Hz
,
6H). 13C NMR (101 MHz, CDCl3)
δ
173.02, 170.59, 143.71, 138.03, 128.29, 127.90, 127.61,
126.57, 77.32, 77.00, 76.68, 73.04, 71.94, 69.75, 59.12, 50.11, 44.61, 39.90, 26.37, 21.27, 16.44,
12.80. HRMS-ESI (m/z): [M + H]+ calcd for C21H38NO3Si, 380.2512, found 380.2515.
3.7. (S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-((R)-1-phenylethyl)aziridine (5)
To a stirred solution of ((S)-1-((R)-1-phenylethyl)aziridin-2-yl)methanol (3.191 g, 18.016 mmol)
◦
in CH2Cl2 (40 mL) at 0 C under an inert atmosphere of N2 was added t-butyldimethylsilyl chlo-
ride (4.073 mg, 24.024 mmol) and DMAP (4.402 g, 36.032 mmol). The mixture was stirred
for 5 min and then warmed to RT. After stirring for 6 h at RT, the mixture was treated with
saturated aqueous NaHCO3 solution. The organic layer was separated and the aqueous
layer was extracted with CH2Cl2 (25 mL
with 10 mL of brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The
residue was purified by flash column chromatography on silica gel (EtOAc:hexanes = 1:3)
×
2). Combined organic extracts were washed

Molecules 2021, 26, 1703
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20
to afford a pure product
5
(4.997g, 95.2%). Yellow liquid. [
δ
α
]
+25.7 (c = 1.05, CHCl3).
D
1H NMR (400 MHz, CDCl3)
7.47–7.14 (m, 5H), 3.61 (dd, J = 10.9, 5.6 Hz, 1H), 3.44 (dd,
J = 10.9, 5.9 Hz, 1H), 2.49 (q, J = 6.6 Hz, 1H), 1.79 (d, J = 3.4 Hz, 1H), 1.67 (dd, J = 6.1, 3.4
Hz, 1H), 1.45 (t, J = 7.1 Hz, 4H), 0.84 (s, 9H),
0.01 (d, J = 3.3 Hz, 6H). 13C NMR (101 MHz,
CDCl3) δ 144.42, 128.17, 126.80, 126.65, 69.52, 65.71, 39.97, 32.52, 25.79, 23.08, 18.23, −5.41.
−
3.8. (S)-3-((tert-butyldimethylsilyl)oxy)-2-(ethyl((R)-1-phenylethyl)amino)propyl Acetate (6)
To a stirred solution of (S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-((R)-1-phenylethyl)-
aziridine (
5
) (0.500 g, 1.717 mmol) in dry CH3CN (5.72 m◦L) was added ethyl trifluo-
romethanesulfonate (0.244 mL, 1.889 mmol) under N2 at 0 C. After 5–10 min, NaOAc
(0.154 g, 1.889 mmol) was added to the solution at the same temperature. After 10 min, the
solution was allowed to be warmed to RT and was stirred for 12 h. Then, it was quenched
by adding water (10 mL). The reaction product was extracted with CH2Cl2 (20 mL) three
times. It was then dried over anhydrous MgSO4, filtered and concentrated in vacuo. The
reaction product was purified by column chromatography (1:19 = EtOAc:Hex) to provide
20
an analytically pure product
6
δ
(0.411 g, 75%). Yellow liquid. [
α
]
D
−
6.7 (c = 1.1, CHCl3).
1H NMR (400 MHz, CDCl3)
7.44 (d, J = 7.3 Hz, 2H), 7.34 (dd, J = 10.2, 4.8 Hz, 2H),
7.28–7.20 (m, 1H), 4.17 (d, J = 6.8 Hz, 1H), 4.12 (dd, J = 6.4, 2.1 Hz, 2H), 3.79 (dd, J = 10.2,
5.4 Hz, 1H), 3.72 (dd, J = 10.3, 6.1 Hz, 1H), 3.24–2.98 (m, 1H), 2.84–2.77 (m, 2H), 2.03 (s, 3H),
1.45 (d, J = 6.8 Hz, 3H), 1.07 (t, J = 7.1 Hz, 3H), 0.96 (s, 9H), 0.10 (d, J = 4.9 Hz, 6H). 13
C
NMR (101 MHz, CDCl3) δ 170.78, 145.62, 128.01, 127.55, 126.49, 63.53, 62.70, 57.69, 40.35,
25.94, 21.01, 18.65, 18.22, 16.13,
380.2531, found 380.2534.
−
5.54. HRMS-ESI (m/z): [M + H]+ calcd for C21H38NO3Si,
3.9. (S)-3-((tert-butyldimethylsilyl)oxy)-2-(ethyl((R)-1-phenylethyl)amino)propan-1-ol (7)
To a stirred solution of (S)-3-((tert-butyldimethylsilyl)oxy)-2-(ethyl((R)-1-phenylethyl)-
◦
amino)propyl acetate (
6
) (1.30 g, 3.428 mmol) in MeOH (10 mL) at 0 C under an inert
atmosphere of N2 was added potassium carbonate (0.710 g, 5.142 mmol). The mixture
was stirred for 10 min. The mixture was further stirred for 3 h at RT and was treated with
saturated aqueous NaHCO3 solution. The organic layer was separated and the aqueous
layer was extracted with CH2Cl2 (25 mL
with 10 mL of brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The
×
2). Combined organic extracts were washed
residue was purified by flash column chromatography on silica gel (EtOAc:hexanes = 1:3)
20
to afford a pure product
7
(0.841 g, 94%). Yellow liquid. [
δ
α
]
D
−
53.0 (c = 1.05, CHCl3).
1H NMR (400 MHz, CDCl3)
7.43–7.18 (m, 5H), 4.14 (q, J = 6.8 Hz, 1H), 3.78 (dd, J = 10.3,
5.3 Hz, 1H), 3.64–3.46 (m, 2H), 3.33 (t, J = 10.0 Hz, 1H), 3.15–3.02 (m, 1H), 2.90 (s-br, 1H),
2.70 (q, J = 7.2 Hz, 2H), 1.42 (d, J = 6.8 Hz, 3H), 1.00 (t, J = 7.1 Hz, 3H), 0.89 (s, 9H), 0.05 (s,
6H). 13C NMR (101 MHz, CDCl3) δ 144.94, 128.29, 127.37, 126.81, 62.13, 60.14, 59.32, 56.51,
39.51, 25.75, 18.25, 17.36, 15.45,
338.2402, found 338.2405.
−
5.59. HRMS-ESI (m/z): [M + H]+ calcd for C19H36NO2Si,
3.10. (S)-tert-butyl (1-((tert-butyldimethylsilyl)oxy)-3-hydroxypropan-2-yl)(ethyl)-carbamate (
To a stirred solution of (S)-3-((tert-butyldimethylsilyl)oxy)-2-(ethyl((R)-1-phenylethyl)-
amino)propyl acetate ( ) (1.130 g 2.9980 mmol) in MeOH (12 mL) was added Pd(OH)2
8)
7
(0.052 g, 50% wet) and di-tert-butyl dicarbonate (0.975 g, 4.469 mmol) at RT under H2.
After the reaction was completed, the reaction mixture was filtered with methanol and then
concentrated in vacuo. The residue was purified by flash column chromatography on silica
gel to afford the pure product
1H NMR (400 MHz, CDCl3)
(s, 1H), 3.36–3.29 (m, 1H), 3.25–3.05 (m, 1H), 1.46 (s, 9H), 1.12 (t, J = 6.8 Hz, 3H), 0.89 (s,
9H), 0.06 (s, 6H). 13C NMR (101 MHz, CDCl3)
171.06, 79.64, 63.17, 61.83, 60.31, 43.08,
5.60. HRMS-ESI (m/z): [M + H]+ calcd for C16H36NO4Si,
8
(0.612 g, 75%). Yellow liquid. [
α]
20 3.1 (c = 1.0, CHCl3).
D
δ
3.96 (d, J = 7.3 Hz, 1H), 3.89–3.79 (m, 3H), 3.75 (s, 1H), 3.60
δ
28.33, 25.72, 20.93, 18.09, 14.06,
334.2310, found 380.2313.
−

Molecules 2021, 26, 1703
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3.11. (S)-4-(((tert-butyldimethylsilyl)oxy)methyl)-3-ethyloxazolidin-2-one (9)
To a stirred solution of (S)-3-((tert-butyldimethylsilyl)oxy)-2-(ethylamino)propan-1-ol
(
8
) (0.424 g, 1.818 mmol) in dry THF (9.09 mL) was added NaH (52 mg, 0.455 mmol)
◦
under N2 at 0 C, and after 1 h, was quenched by adding water (10 mL). The reaction
product was extracted with CH2Cl2 (50 mL) three times. Then, it was dried over anhydrous
MgSO4, filtered and concentrated in vacuo. The reaction product was purified by column
chromatography to provide an analytically pure product
9
δ
(0.185 g, 54%). Yellow liquid.
4.23 (ddd, J = 13.8, 6.4, 4.6 Hz,
20
1
[
α
]
−
1.7 (c = 1.05, CHCl3). H NMR (400 MHz, CDCl3)
D
1H), 4.00 (ddd, J = 10.7, 6.9, 5.2 Hz, 1H), 3.81 (dd, J = 8.5, 4.2 Hz, 1H), 3.69–3.53 (m, 2H),
3.52–3.35 (m, 1H), 3.08 (ddd, J = 6.6, 5.9, 3.2 Hz, 1H), 1.13–1.00 (m, 3H), 0.79 (s, 9H), −0.01
(s, 6H). 13C NMR (101 MHz, CDCl3)
δ 157.99, 77.89, 77.16, 76.69, 64.29, 62.20, 55.60, 36.87,
25.43, 17.79, 12.62, -5.83. HRMS-ESI (m/z): [M + H]+ calcd for C12H26NO3Si, 260.1605,
found 260.1607.
3.12. (R)-3-ethyl-4-(hydroxymethyl)oxazolidin-2-one (90)
To a stirred solution of (S)-4-(((tert-butyldimethylsilyl)oxy)methyl)-3-ethyloxazolidin-
2-one (9
) (0.543 g, 2.095 mmol) in dry THF (6.98 mL) at 0 ◦C was added TBAF (2.304 mL
1.0 M in THF, 2.305 mmol) and reaction mixture was stirred for 3 h. Reaction mixture
was quenched with saturated NH4Cl solution and then it was extracted with EtOAc
(
3 × 10 mL). Combined organic layer was dried over anhydrous Mg2SO4. The reaction
product was purified by column chromatography (1:9 = methanol:ethyl acetate) to provide
an analytically pure product 90 (0.294 g, 97%). Yellow liquid. [ 20 40.5 (c = 1.0, CHCl3).
1H NMR (400 MHz, CDCl3)
4.39 (t, J = 8.9 Hz, 1H), 4.26 (dd, J = 8.7, 5.9 Hz, 1H), 4.02–3.89
(m, 1H), 3.86–3.81 (m, 1H), 3.76–3.64 (m, 1H), 3.62–3.53 (m, 1H), 3.25–3.17 (m, 1H), 1.21
α
]
D
δ
(t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3)
δ 158.68, 64.65, 60.48, 55.69, 36.70, 12.42.
HRMS-ESI (m/z): [M + H]+ calcd for C6H12NO3, 146.0724, found 146.0726.
3.13. (S)-3-ethyl-2-oxooxazolidine-4-carbaldehyde (10)
To a stirred dimethyl sulfoxide (0.244 mL, 3.447 mmol) in dry CH2Cl2 (4.60 mL) was
added oxalyl chloride (0.141 mL, 1.654 mmol) under N2 at
−
78 ◦C. The reaction mixture
was stirred for 1 h. Then, (R)-3-ethyl-4-(hydroxymethyl)oxazolidin-2-one (90) (0.200 g,
1.379 mmol) was added to the solution under the same condition. After 1 h, triethylamine
(0.576 mL, 4.136 mmol) was added and stirred for 40 min. After quenching the reaction,
the reaction product was extracted with CH2Cl2 (3
dried over Na2SO4. The reaction product was purified by column chromatography (2:1
×
10 mL). Combined organic layer was
= ethyl acetate:hexane) to provide an analytically pure product 10 (0.134 g, 68%). Yellow
1
liquid. H NMR (400 MHz, CDCl3)
δ
9.68 (d, J = 0.7 Hz, 1H), 3.94–3.90 (m, 1H), 3.84–3.79
(m, 1H), 3.74–3.65 (m, 1H), 3.60–3.51 (m, 1H), 3.24–3.15 (m, 1H), 1.19 (t, J = 7.2 Hz, 3H). 13
C
NMR (101 MHz, CDCl3) δ 197.22, 158.67, 64.65, 55.68, 36.70, 12.42. HRMS-ESI (m/z): [M +
H]+ calcd for C6H10NO3, 144.0612, found 144.0615.
3.14. General Procedure for the Synthesis of Allylative Aziridine Ring Opening Compounds
Silver trifluoromethanesulfonate (0.07 g, 0.393 mmol) and allyl iodide (0.05 mL,
0.468 mmol) were added to a stirring solution of aziridine (100 mg, 0.374 mmol) in
1
dry CH3CN (4 mL) under N2 at 0 ◦C. After 5–10 min, nucleophile (1.1 equiv.) was added
to the solution at same condition. After 10 min, the solution was allowed to be warmed to
RT and was stirred. After quenching by adding water (10 mL), the reaction product was ex-
tracted with CH2Cl2 (20 mL) three times. It was then dried over anhydrous MgSO4, filtered
and concentrated in vacuo. The reaction product was purified by column chromatography
(1:19 = ethyl acetate:hexane) to provide an analytically pure product.
3.15. (S)-2-(allyl((R)-1-phenylethyl)amino)-3-(benzyloxy)propyl Acetate (3AAa)
20
Yellow liquid. [
α
]
D
19.4 (c = 1.0, CHCl3) 1H NMR (400 MHz, CDCl3)
δ 7.42–7.07 (m,
10H), 5.97–5.69 (m, 1H), 5.17 (dd, J = 17.2, 1.7 Hz, 1H), 5.04 (dd, J = 10.1, 1.6 Hz, 1H), 4.30 (s,

Molecules 2021, 26, 1703
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2H), 4.28–4.19 (m, 1H), 4.19–4.02 (m, 2H), 3.36 (dd, J = 15.2, 6.0 Hz, 1H), 3.31–3.20 (m, 4H),
2.00 (s, 3H), 1.36 (d, J = 6.9 Hz, 3H). 13C NMR (101 MHz, CDCl3)
δ 170.74, 144.23, 138.72,
138.09, 128.02, 127.91, 127.38, 126.53, 115.64, 72.84, 69.29, 63.58, 57.53, 54.99, 49.51, 20.90,
18.59. HRMS-ESI (m/z): [M + H]+ calcd for C23H30NO3, 368.2102, found 368.2106.
3.16. (S)-2-(allyl((R)-1-phenylethyl)amino)-3-((tert-butyldimethylsilyl)oxy)propyl Acetate (3CAa
)
10.8 (c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3)
δ 7.37 (d,
20
Yellow liquid. [
α
]
D
J = 7.2 Hz, 2H), 7.33–7.27 (m, 2H), 7.23-7.19 (m, 1H), 5.86-5.76 (m, 1H), 5.24–5.10 (m, 1H),
5.05 (dd, J = 10.1, 1.7 Hz, 1H), 4.13 (q, J = 6.8 Hz, 1H), 4.02 (d, J = 6.4 Hz, 2H), 3.72 (dd,
J = 10.3, 5.5 Hz, 1H), 3.66 (dd, J = 10.3, 5.9 Hz, 1H), 3.34 (d, J = 6.1 Hz, 2H), 3.10 (t, J = 5.9 Hz,
1H), 1.98 (s, 3H), 1.38 (d, J = 6.8 Hz, 3H), 0.88 (s, 9H), 0.03 (d, J = 4.4 Hz, 6H). 13C NMR
(101 MHz, CDCl3) δ 170.96, 145.05, 139.10, 128.05, 127.57, 126.56, 115.71, 63.44, 62.46, 57.30,
56.88, 49.84, 25.85, 21.09, 18.23,
392.2563, found 392.2565.
−
5.54. HRMS-ESI (m/z): [M + H]+ calcd for C22H38NO3Si,
3.17. (R)-ethyl 3-acetoxy-2-(allyl((R)-1-phenylethyl)amino)propanoate (3DAa)
20
1
Yellow liquid. [
α
]
D
18.9 (c = 1.0, CHCl3). H NMR (400 MHz, CDCl3) δ 7.39–7.26
(m, 4H), 7.25–7.18 (m, 1H), 5.78 (dd, J = 17.2, 10.2 Hz, 1H), 5.15 (dd, J = 17.2, 1.8 Hz, 1H),
5.12–5.05 (m, 2H), 4.21–4.12 (m, 2H), 4.00 (q, J = 6.8 Hz, 1H), 3.12 (d, J = 6.4 Hz, 2H), 2.99
(dd, J = 14.1, 4.5 Hz, 1H), 2.89 (dd, J = 14.1, 7.2 Hz, 1H), 2.10 (s, 3H), 1.35 (d, J = 6.8 Hz, 3H),
1.25 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3)
δ 170.15, 169.28, 143.05, 136.27, 127.88,
127.56, 126.65, 116.98, 72.30, 61.05, 58.54, 53.69, 50.03, 20.60, 15.17, 13.95. HRMS-ESI (m/z):
[M + H]+ calcd for C18H26NO4, 320.1812, found 320.1815.
3.18. (R)-ethyl 2-(allyl((R)-1-phenylethyl)amino)-3-azidopropanoate (3DAb)
20
1
Yellow liquid. [
α
]
D
24.8 (c = 1.0, CHCl3). H NMR (400 MHz, CDCl3) δ 7.35–7.28 (m,
4H), 7.27–7.21 (m, 1H), 5.79–5.71 (m, 1H), 5.19–5.12 (m, 1H), 5.10 (dd, J = 10.1, 1.5 Hz, 1H),
4.38–4.20 (m, 2H), 4.18 (dd, J = 10.1, 5.4 Hz, 1H), 3.95 (q, J = 6.9 Hz, 1H), 3.27 (dd, J = 13.6,
10.1 Hz, 1H), 3.05 (t, J = 6.0 Hz, 2H), 2.78 (dd, J = 13.6, 5.4 Hz, 1H), 1.37 (d, J = 6.9 Hz, 3H),
1.32 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3)
δ 169.67, 142.48, 136.55, 128.17, 127.71,
127.02, 117.33, 61.83, 59.90, 55.18, 54.68, 54.59, 54.41, 16.01, 14.14. HRMS-ESI (m/z): [M +
H]+ calcd for C16H23N4O2, 303.1714, found 303.1716.
3.19. (R)-2-(allyl((R)-1-phenylethyl)amino)-3-(allyloxy)-3-methylbutyl acetate (12)
To a stirred solution of (R)-2-(2-(allyloxy)propan-2-yl)-1-((R)-1-phenylethyl)aziridine
(
11) (0.858 g, 3.951 mmol) in dry CH3CN (13.17 mL) was added silver trifluoromethane-
sulfonate (1.116 g, 4.346 mmol) and allyl iodide (0.405 mL, 4.346 mmol) under N2 at 0 ◦C.
After 5–10 min, NaOAc (0.356 g, 4.346 mmol) was added to the solution. After 10 min,
the solution was allowed to be warmed to RT and was stirred for 3 h. After quenching
by adding water (10 mL), the reaction product was extracted with CH2Cl2 (20 mL) three
times. It was then dried over anhydrous MgSO4, filtered and concentrated in vacuo. The
reaction product was purified by column chromatography (1:9 = EtOAc:Hex) to provide
an analytically pure product 12 (0.525 g, 71%). Yellow liquid. [
α]
20 17.6 (c = 1.0, CHCl3).
D
1H NMR (400 MHz, CDCl3) 1H NMR (400 MHz, CDCl3)
δ
δ
7.36–7.24 (m, 4H), 7.23–7.16
(m, 1H), 5.97–5.75 (m, 2H), 5.17 (dq, J = 17.2, 1.8 Hz, 1H), 5.12–5.00 (m, 3H), 4.57 (dd,
J = 11.9, 4.3 Hz, 1H), 4.37 (dd, J = 11.9, 7.1 Hz, 1H), 4.29 (q, J = 6.9 Hz, 1H), 3.79 (dt, J = 5.0,
1.6 Hz, 2H), 3.52 (ddt, J = 14.6, 4.7, 1.6 Hz, 1H), 3.40 (dd, J = 14.6, 8.1 Hz, 1H), 2.96 (dd,
J = 7.1, 4.3 Hz, 1H), 2.08 (s, 3H), 1.36 (d, J = 6.9 Hz, 3H), 1.02 (s, 3H), 0.98 (s, 3H). 13C NMR
(101 MHz, CDCl3)
δ 170.96, 144.49, 138.91, 134.71, 128.05, 127.53, 126.64, 116.60, 115.71,
71.90, 69.40, 63.84, 57.73, 55.19, 49.61, 21.07, 18.73. HRMS-ESI (m/z): [M + H]+ calcd for
C21H32NO3, 346.2373, found 346.2375.

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3.20. ((R,Z)-2,2-dimethyl-4-((R)-1-phenylethyl)-3,4,5,8-tetrahydro-2H-1,4-oxazocin-3-yl)methyl
Acetate (13)
To a solution of (R)-2-(allyl((R)-1-phenylethyl)amino)-3-(allyloxy)-3-methylbutyl ac-
etate (12) (0.150 g, 0.473 mmol) in CH2Cl2 (120 mL) was added benzylidene-bis(tricyclohexyl-
phosphine)dichlororuthenium (0.039 g, 0.048 mmol). The reaction mixture was then stirred
at reflux for 8 h. After completion of the reaction (monitored by TLC), solvent was evap-
orated under reduced pressure. Purification of the crude residue by silica gel column
chromatography (ethyl acetate:hexane = 1:9) afforded 13 (71 mg, 76%). Yellow liquid.
20
1
[
α
]
-3.5 (c = 1.0, CHCl3). H NMR (400 MHz, CDCl3) δ 7.35–7.28 (m, 4H), 7.24–7.20
D
(m, 1H), 5.60–5.47 (m, 1H), 5.45–5.33 (m, 1H), 4.51–4.45 (m, 2H), 4.26 (dd, J = 12.2, 6.9 Hz,
1H), 4.14–4.05 (m, 1H), 4.01 (q, J = 6.8 Hz, 1H), 3.66 (dd, J = 16.2, 6.3 Hz, 1H), 3.10–3.04 (m,
2H), 1.86 (s, 3H), 1.46 (s, 3H), 1.38 (d, J = 6.8 Hz, 3H), 1.24 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 170.84, 145.02, 129.91, 129.50, 128.00, 127.73, 126.66, 77.99, 63.73, 62.89, 62.56, 61.73,
43.80, 27.60, 24.37, 20.88, 20.48. HRMS-ESI (m/z): [M + H]+ calcd for C19H28NO3, 318.2014,
found 318.2017.
3.21. (R)-tert-butyl 3-(acetoxymethyl)-2,2-dimethyl-1,4-oxazocane-4-carboxylate (14)
To a stirred solution of ((R,Z)-2,2-dimethyl-4-((R)-1-phenylethyl)-3,4,5,8-tetrahydro-
2H-1,4-oxazocin -3-yl)methyl acetate (13) (306 mg, 0.965 mmol) in MeOH (9.65 mL) was
added Pd(OH)2 (634 mg, 1.158 mmol, 50% wet) and the resultant reaction mixture was
stirred at RT under atmospheric power of H2 gas. After 30 min, (Boc)2O (421 mg, 1.929 mmol)
was added to the reaction flask at RT. The reaction mixture was stirred for 1.0 h, filtered
with MeOH, and concentrated in vacuo and purified by silica gel chromatography to get
1
the desired product 14 (215 mg, 71%). Yellow liquid. H NMR (400 MHz, CDCl3)
δ
4.82 (d,
J = 9.7 Hz, 1H), 4.34 (dd, J = 11.2, 4.0 Hz, 1H), 4.09 (t, J = 10.1 Hz, 1H), 3.85–3.79 (m, 1H),
3.33–3.29 (m, 2H), 2.05 (d, J = 3.6 Hz, 3H), 1.64 (s, 1H), 1.45 (s, 9H), 1.36–1.30 (m, 3H), 1.22
(s, 3H), 1.18 (s, 3H). 13C NMR (101 MHz, CDCl3)
δ 170.84, 152.05, 79.93, 77.99, 70.12, 63.18,
53.74, 43.80, 28.59, 27.60, 25.91, 24.37, 20.88, 20.42. HRMS-ESI (m/z): [M + H]+ calcd for
C16H30NO5, 316.2034, found 316.2037.
4. Conclusions
In conclusion, the highly strained three-membered aziridine ring is successfully ac-
tivated as the aziridinium ion through alkylation of the ring nitrogen, including with
methyl, ethyl and allyl groups, followed by ring opening with nucleophiles such as acetate
and azide. This so-called N-alkylative aziridine ring opening may provide an easy route
for the synthesis of various N-alkylated amine-containing molecules with concomitant
introduction of an external nucleophile at either its α- or β-position.
Supplementary Materials: All analytical data of compounds other than the representative example
are reported along the copies of 1H and 13C NMR spectra.
Author Contributions: Conceptualization, H.-J.H. and J.C.; methodology, J.C. and T.Y.; investigation,
H.-J.H., J.C. and T.Y.; experiments and data curation, J.C. and T.Y.; writing—original draft preparation,
H.-J.H.; writing—review and editing, H.-J.H. and T.Y.; supervision, H.-J.H.; project administration,
H.-J.H.; funding acquisition, H.-J.H. All authors have read and agreed to the published version of
the manuscript.
Funding: This research was supported by the National Research Foundation of Korea (NRF-
2012M3A7B4049645 and 2021R1A5A6002803 with the Centre for New Directions in Organic Synthe-
sis). Additional financial support from 2020R1A2C1007102 and HUFS Grant 2021 (for the preparation
of this manuscript) are also appreciated.
Data Availability Statement: The data presented in this study are available on request from the
corresponding author.
Acknowledgments: Authors thanks to Jala Ranjith for his help to preparing this manuscript.
Conflicts of Interest: The authors declare no conflict of interest.

Molecules 2021, 26, 1703
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Sample Availability: Samples of the compounds in this paper are available on your request from
the authors.
References
1.
Tanner, D. Chiral Aziridines—Their Synthesis and Use in Stereoselective Transformations. Angew. Chem. Int. Ed. Eng. 1994, 33,
599–619. [CrossRef]
2.
Zwanenburg, B.; ten Holte, P. The Synthetic Potential of Three-Membered Ring Aza-Heterocycles. Top. Curr. Chem. 2001, 216,
93–124. [CrossRef]
3.
4.
5.
6.
Sweeney, J.B. Aziridines: Epoxides’ ugly cousins? Chem. Soc. Rev. 2002, 31, 247–258. [CrossRef] [PubMed]
Hu, X.E. Nucleophilic ring opening of aziridines. Tetrahedron 2004, 60, 2701–2743. [CrossRef]
McCoull, W.; Davis, F.A. Recent Synthetic Applications of Chiral Aziridines. Synthesis 2000, 2000, 1347–1365. [CrossRef]
Watson, I.D.G.; Yu, L.; Yudin, A.K. Advances in Nitrogen Transfer Reactions Involving Aziridines. Acc. Chem. Res. 2006, 39,
194–206. [CrossRef]
7.
8.
Padwa, A.; Murphree, S.S. Epoxides and aziridines—A mini review. Arkivoc 2006, 3, 6–33.
Singh, G.S.; D’Hooghe, M.; De Kimpe, N. Synthesis and Reactivity of C-Heteroatom-Substituted Aziridines. Chem. Rev. 2007, 107,
2080–2135. [CrossRef]
9.
Ha, H.-J.; Jung, J.-H.; Lee, W.K. Application of Regio- and Stereoselective Functional Group Transformation of Chiral Aziri-dine-
2-carboxylate. Asian J. Org. Chem. 2014, 3, 1020–1035. [CrossRef]
10. D’hooghe, M.; Ha, H.-J. (Eds.) Synthesis of 4- to 7-Membered Heterocycles by Ring Expansion; Springer: Berlin/Heidelberg,
Germany, 2016.
11. Akhtar, R.; Naqvi, S.A.R.; Zahoor, A.F.; Saleem, S. Nucleophilic ring opening reactions of aziridines. Mol. Divers. 2018, 22, 447–501.
[CrossRef]
12. D’Hooghe, M.; Ha, H.-J.; Macha, L. Deployment of Aziridines for the Synthesis of Alkaloids and Their Derivatives. Synthesis
2019, 51, 1491–1515. [CrossRef]
13. Cherni, E.; Essalah, K.; Besbes, N.; Abderrabba, M.; Ayadi, S. Theoretical investigation of the regioselective ring opening of
2-methylaziridine. Lewis acid effect. J. Mol. Model. 2018, 24, 309. [CrossRef] [PubMed]
14. Baruah, B.; Deuri, S.; Phukan, P. Reactivity and regioselectivity in the ring opening of 2-substituted non-activated aziridines: A
density functional theory based analysis. Comput. Theor. Chem. 2014, 1027, 197–202. [CrossRef]
15. Lugin, ina, J.; Turks, M. Non-activated aziridines as building blocks for the synthesis of aza-heterocycles. Chem. Heterocycl. Compd.
2016, 52, 773–775. [CrossRef]
16. Pitzer, K.S. Strain energies of cyclic hydrocarbons. Science 1945, 101, 672. [CrossRef]
17. Lewis, L.L.; Turner, L.L.; Salter, E.A.; Magers, D.H. Computation of the conventional strain energy in oxaziridine. J. Mol. Struct.
THEOCHEM 2002, 592, 161–171. [CrossRef]
18. Dudev, T.; Lim, C. Ring Strain Energies from ab Initio Calculations. J. Am. Chem. Soc. 1998, 120, 4450–4458. [CrossRef]
19. Morgan, K.M.; Ellis, J.A.; Lee, J.; Fulton, A.; Wilson, S.L.; Dupart, P.S.; Dastoori, R. Thermochemical Studies of Epoxides and
Related Compounds. J. Org. Chem. 2013, 78, 4303–4311. [CrossRef]
20. Lee, K.-D.; Suh, J.-M.; Park, J.-H.; Ha, H.-J.; Choi, W.G.; Park, C.S.; Lee, W.K.; Dong, Y.; Yun, H. New synthesis and ring opening
of cis-3-alkylaziridine-2-carboxylates. Tetrahedron 2001, 57, 8267–8276. [CrossRef]
21. Sin, T.B.; Kang, S.H.; Lee, K.S.; Lee, W.K.; Yun, H.; Dong, Y.; Ha, H.-J. A Novel Synthesis of 5-Functionalized Oxazolidin-2-ones
from Enantiomerically Pure 2-Substituted N-[(R)-(+)-α-Methylbenzyl]aziridines. J. Org. Chem. 2003, 68, 104–108.
22. Kim, Y.; Ha, H.-J.; Yun, H.; Lee, B.K.; Lee, W.K. Ring opening of 2-acylaziridines by acid chlorides. Tetrahedron 2006, 62, 8844–8849.
[CrossRef]
23. Eum, H.; Choi, J.; Cho, C.G.; Ha, H.J. Regiochemistry-Directed Syntheses of Polyhydroxylated Alkaloids from Chiral Aziridines.
Asian J. Org. Chem. 2015, 4, 1399–1409. [CrossRef]
24. Catak, S.; D’hooghe, M.; Verstraelen, T.; Hemelsoet, K.; Van Nieuwenhove, A.; Ha, H.-J.; Waroquier, M.; Van Speybroeck, V.;
De Kimpe, N. Opposite Regiospecific Ring-opening of 2-(Cyanomethyl)aziridines by Hydrogen Bromide and Benzyl Bromide:
Experimental Study and Theoretical Rationalization. J. Org. Chem. 2010, 75, 4530–4541. [CrossRef]
25. Chen, Y.; Sun, X.; Wu, N.; Li, J.; Jin, S.; Zhong, Y.; Liu, Z.; Rogachev, A.; Chong, H.-S. Synthetic and theoretical investigation on
the one-pot halogenation of
920–939. [CrossRef]
β-amino alcohols and nucleophilic ring opening of aziridinium ions. Org. Biomol. Chem. 2016, 14,
26. Choi, J.; Yadav, N.N.; Ha, H. Preparation of a Stable Bicyclic Aziridinium Ion and Its Ring Expansion toward Piperidines and
Azepanes. Asian J. Org. Chem. 2017, 6, 1292–1307. [CrossRef]
27. Stankovic, S.; D’Hooghe, M.; Catak, S.; Eum, H.; Waroquier, M.; Van Speybroeck, V.; De Kimpe, N.; Ha, H.-J. Regioselectivity in
the ring opening of non-activated aziridines. Chem. Soc. Rev. 2012, 41, 643–665. [CrossRef]
28. D’Hooghe, M.; Catak, S.; Stankovic, S.; Waroquier, M.; Kim, Y.; Ha, H.-J.; Van Speybroeck, V.; De Kimpe, N. Systematic Study of
Halide-Induced Ring Opening of 2-Substituted Aziridinium Salts and Theoretical Rationalization of the Reaction Pathways. Eur.
J. Org. Chem. 2010, 25, 4920–4931. [CrossRef]
29. Arico, F.; Aldoshin, A.S.; Musolino, M.; Crisma, M.; Tundo, P. β-Aminocarbonates in Regioselective and Ring Expansion Reactions.
J. Org. Chem. 2018, 83, 236–243. [CrossRef] [PubMed]

Molecules 2021, 26, 1703
13 of 13
30. Cochi, A.; Pardo, D.G.; Cossy, J. Access to Optically Active 3–Aminopiperidines by Ring Expansion of Prolinols: Thermody-namic
versus Kinetic Control. Eur. J. Org. Chem. 2012, 10, 2023–2040. [CrossRef]
31. Yun, S.Y.; Catak, S.; Lee, W.K.; D’hooghe, M.; De Kimpe, N.; Van Speybroeck, V.; Waroquier, M.; Kim, Y.; Ha, H.-J. Nucle-ophile-
dependent regioselective ring opening of 2-substituted N,N-dibenzylaziridinium ions: Bromide versus hydride. Chem. Commun.
2009, 18, 2508–2510. [CrossRef] [PubMed]
32. Kim, Y.; Ha, H.-J.; Yun, S.Y.; Lee, W.K. Preparation of Stable Aziridinium Ions and Their Ring Openings. Chem. Commun. 2008
,
4363–4365. [CrossRef]
33. Kim, Y.; Yoon, D.-H.; Ha, H.-J.; Kang, K.Y.; Lee, W.K. N-Methylative aziridine ring opening and asymmetric synthesis of MeBmt.
Tetrahedron Lett. 2011, 52, 5918–5920. [CrossRef]
34. Yoon, D.-H.; Kang, P.; Lee, W.K.; Kim, Y.; Ha, H.-J. Alkylative Ring Opening of N-Methylaziridinium Ions and a Formal Synthesis
of Tyroscherin. Org. Lett. 2012, 14, 429–431. [CrossRef]
35. Yoon, D.-H.; Ji, M.-K.; Ha, H.-J.; Park, J.; Kang, P.; Lee, W.K. Synthesis and Biological Activities of Tyroscherin Analogs. Bull.
Korean Chem. Soc. 2013, 34, 1899–1902. [CrossRef]
36. Lee, J.; Lee, J.E.; Ha, H.-J.; Son, S.I.; Lee, W.K. N-Methylative aziridine ring opening: Asymmetric synthesis of hygroline,
pseudohygroline, and hygrine. Tetrahedron Lett. 2015, 56, 856–858. [CrossRef]
37. Jung, J.; Kim, S.; Eum, H.; Lee, W.K.; Ha, H.J. N-methylative aziridine ring opening and the synthesis of (S)-3-methylamino-3-[(R)-
pyrrolidin-3-yl]propanenitrile. Tetrahedron 2017, 73, 5993–5999. [CrossRef]
38. Nicolaou, K.C.; Ogawa, Y.; Zuccarello, G.; Schweiger, E.J.; Kumazawa, T. Cyclic conjugated enediynes related to calicheami-cins
and esperamicins: Calculations, synthesis, and properties. J. Am. Chem. Soc. 1988, 14, 4866–4868. [CrossRef]
39. Ha, H.-J.; Yoon, D.-H.; Kang, L.-S.; Hong, M.C.; Lee, W.K. Synthesis of D-erythro-Sphingosine from D-ribo-Phytosphingosine.
Bull. Korean Chem. Soc. 2009, 30, 535–536. [CrossRef]
40. Park, C.S.; Kim, M.S.; Sim, T.B.; Pyun, D.K.; Lee, C.H.; Choi, D.; Lee, W.K.; Chang, J.-W.; Ha, H.-J. Novel Stereoselective Synthesis
of Functionalized Oxazolidinone from Chiral Aziridines. J. Org. Chem. 2003, 68, 43–49. [CrossRef]
41. Kazakova, A.N.; Vasilyev, A.V. Trifluoromethanesulfonic acid in organic synthesis. Zhurnal Org. Khimii 2017, 53, 479–502.
[CrossRef]