Studies on the synthesis of orthogonally protected azalanthionines, and of routes towards β-methyl azalanthionines, by ring opening of N-activated aziridine-2-carboxylates

Article abstract of DOI:10.1016/j.tet.2014.06.011

Orthogonally protected azalanthionines were successfully synthesised by the ring-opening of N-activated aziridine-2-carboxylates with protected diaminopropanoic acids (DAPs). The required DAPs were also prepared by ring-opening of N-activated aziridine-2-carboxylates with para-methoxybenzylamine, but it was found that the choice of aziridine protecting groups dictated both the success of the reaction as well as the regioselectivity of the isolated products. Attempts to extend the methodology to the preparation of the more sterically demanding β-methyl azalanthionines have, so far, been unsuccessful.

Full text of DOI:10.1016/j.tet.2014.06.011

Tetrahedron xxx (2014) 1e11
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Studies on the synthesis of orthogonally protected azalanthionines,
and of routes towards b-methyl azalanthionines, by ring opening of
N-activated aziridine-2-carboxylates
*
ꢀ
Keith O’Brien, Keith o Proinsias, Fintan Kelleher
Molecular Design and Synthesis Group, Centre of Applied Science for Health, Institute of Technology Tallaght, Dublin 24, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
Orthogonally protected azalanthionines were successfully synthesised by the ring-opening of N-activated
aziridine-2-carboxylates with protected diaminopropanoic acids (DAPs). The required DAPs were also
prepared by ring-opening of N-activated aziridine-2-carboxylates with para-methoxybenzylamine, but it
was found that the choice of aziridine protecting groups dictated both the success of the reaction as well
as the regioselectivity of the isolated products. Attempts to extend the methodology to the preparation of
Received 20 January 2014
Received in revised form 19 May 2014
Accepted 2 June 2014
Available online xxx
the more sterically demanding
b
-methyl azalanthionines have, so far, been unsuccessful.
Keywords:
1,2-Diaminopropanoic acids (DAPs)
Lanthionine
Ó 2014 Elsevier Ltd. All rights reserved.
Aziridine-2-carboxylates
Ring-opening
Azalanthionines
b
-Methyl azalanthionines
1. Introduction
The incorporation of amino acid cross-linkers into peptide
structures, which leads to the formation of cyclic peptides, is an
important way that nature uses to give defined peptide and protein
conformations with high biological activity. Importantly the sta-
bility of the peptides can also be increased due to their increased
resistance to proteolytic cleavage.1 There are many such cross-
linkers in nature including lysinoalanine and histidinoalanine,2
while the lanthipeptides contain the lanthionine or
b-methyl-
lanthionine cross-linking amino acids (Fig. 1).3 Nisin is one of the
most studied lanthipeptides and is a highly active antimicrobial
peptide, which has been used worldwide for decades as a food
preservative (E234). The chemical synthesis of orthogonally pro-
tected lanthionines and
b-methyllanthionines has been studied
extensively.4 Vederas has also reported on the replacement of the
thioether bridge of lanthionines and
b-methyllanthionines with
both carbon chain and oxygen bridged analogues.5
Fig. 1. Structures of some cross-linking amino acids.2,3
We recently reported on our preliminary studies on extending
the range of lanthionine thioether bridge replacements that are
available by preparing orthogonally protected azalanthionines,
which have an amine linker, which should have quite different
physicochemical properties to any of the other analogues (lan-
thionines, oxalanthionines or carbalanthionines), including water
solubility at physiological pH.6 To date this is the only reported
method for the preparation of orthogonally protected azalanthio-
nines though a small number of reports on the synthesis of
* Corresponding author. Department of Science, Institute of Technology Tallaght,
Tallaght, Dublin 24, Ireland. Tel.: þ353 1 404 2869; fax: þ353 1 404 2700; e-mail
address: fintan.kelleher@ittdublin.ie (F. Kelleher).
http://dx.doi.org/10.1016/j.tet.2014.06.011
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: O’Brien, K.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.06.011

2
K. O’Brien et al. / Tetrahedron xxx (2014) 1e11
azalanthionines are known, but none gave orthogonally protected
compounds, which would be suitable for use in solid-phase peptide
synthesis.7 The presence of a nitrogen atom in the cross-linker
would also provide a very useful handle for further derivatisation,
or conjugation, where required.
Thus, the goals of the current study were firstly to extend the
range of orthogonally protected azalanthionines using our pre-
viously developed aziridine ring-opening methodology. Our initial
report demonstrated the viability of the methodology but only one
azalanthionine analogue was prepared with the correct stereo-
chemistry, when compared to stereochemistry of natural lanthio-
nine containing peptides. For the future incorporation of
azalanthionines, in order to prepare lantibiotic analogues, a num-
ber of differentially protected analogues would be required with
the desired stereochemistry. Since many lanthipeptides also con-
the nature of the N-substituent and the ester group in the 2-
position, as well as the temperature of the reaction.9 In all cases
two molar equivalents of p-methoxybenzylamine was used.
Aziridine 2a gave a mixture of 4a and 5a in a 70:23 ratio at room
temperature (Table 1, entry 1). However, the selectivity was re-
versed to give 4a and 5a in a 32:41 ratio, when the reaction was
conducted at 80 ꢀC (entry 2). Further reactions in this series were
conducted at room temperature to maximise the yield of the
product obtained from attack at the aziridine
b-position. It was
found that the p-Ns aziridine 2b gave 4b and 5b in a 63:21 ratio
(entry 3). However, the p-Nz substituted aziridine 2c only gave 4c,
the product of attack at the less hindered b-carbon of the aziridine
in a 66% yield (entry 4). For the N-activated aziridine allyl esters
3aec (entries 5e7), only the N-p-Nz substituted derivative 3c un-
derwent reaction with p-methoxybenzylamine, with 6c being ob-
tained in a 66% yield, as the sole product. The N-alloc activated
aziridine 7 gave no product from attack by p-methoxybenzylamine
(entry 10). For the unsuccessful reactions, use of Lewis acid catalysis
(boron trifluoride etherate) and/or heating to 80 ꢀC, did not lead to
any of the desired products. An examination of the results of the
ring-opening reactions shows that the regioselective outcome is
not predictable.9
tain the
b-methyllanthionine moiety, the second goal of this study
was the extension of the methodology to prepare a range of
b
-
methyl azalanthionines, again with the correct stereochemistry at
each stereocentre.
2. Results and discussion
2.1. Synthesis of orthogonally protected azalanthionines
Having prepared a number of the required DAPs they were then
used to prepare orthogonally protected azalanthionines by ring-
opening of the protected N-activated aziridines (Scheme 2). In
these cases, it was found that there was no reaction observed at
25 ꢀC, in the presence of 2 M equivalents of the DAP. When the
reactions were heated to 80 ꢀC, only products from attack at the less
The retrosynthetic analysis of the orthogonally protected aza-
lanthionines shows that they could be prepared by ring-opening of
N-activated aziridine-2-carboxylates with protected dia-
minopropionic acids (DAPs) (Fig. 2). In turn the DAPs could be
obtained by ring-opening of differently protected aziridines with p-
methoxybenzylamine.
sterically hindered aziridine b-position were obtained. It is most
likely that this is due to the increased steric bulk of the secondary
CO2P3
P2O2C
P1HN
P2O2C
CO2P3
P5 NHP4
R
S
P5
CO2P3
R
S
S
N
N
P5 NH2
+
+
N
N
P1
H
NHP4
P4
P = Protecting group
Fig. 2. Retrosynthetic analysis of orthogonally protected azalanthionines.
In order to prepare a range of different orthogonally protected
azalanthionines suitable for solid-phase peptide synthesis the
precursor N-activated aziridine-2-carboxylates were first prepared
to explore the optimal substitution patterns for the synthesis of the
required DAPs (Scheme 1). Starting with the known N-trityl azir-
idine-2-carboxylates, 1a and 1b,8 replacement of the trityl group
with a number of electron-withdrawing groups gave the required
N-activated aziridines (2aec, 3aec and 7). The regioselectivity of
the ring-opening reaction, on treatment of the N-activated azir-
idines with p-methoxybenzylamine, was highly dependent on both
amine nucleophile of the DAP compared to the primary amino
group of the p-methoxybenzylamine. Thus far a range of six di-
astereoisomeric azalanthionines (8e12, 17) have been prepared
using this methodology, with the stereochemistry of the di-
astereoisomer depending on whether L- or D-serine was used as the
starting material for the precursor N-activated aziridines (Scheme 2
and Table 2).
The isolated yields of the azalanthionines, after aqueous
workup, were 27e51%, which are comparable with those obtained
for similar aziridine ring-opening reactions with protected cysteine
H
CO2Me
S
S
PMB
CO2Me
N
b
P
N
H
+
N
P
R
NHP
CO2Me
HN
PMB
2a, P = Ts
4a, P = Ts
2b, P = p-Ns
2c, P = p-Nz
4b, P = p-Ns
4c, P = p-Nz
5a, P = Ts
5b, P = p-Ns
CO2R
S
a
or
N
Trt
CO2All
S
CO2All
S
PMB
CO2All
S
1a, R = Me
1b, R = Allyl
b
N
H
N
P
N
NHP
Alloc
6c, P = p-Nz
3a, P = Ts
3b, P = p-Ns
3c, P = p-Nz
7
Reagents and conditions; (a) See Supporting Information; (b) p-methoxybenzylamine (2 molar equiv.), MeCN, rt, 24 h.
Scheme 1. Synthesis of 1,2-diaminopropanoic acid derivatives (4e6).
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K. O’Brien et al. / Tetrahedron xxx (2014) 1e11
3
Table 1
Regioselectivity of the ring-opening of N-activated aziridine-2-carboxylates with p-methoxybenzylamine
Entry
Aziridine
Temp (ꢀ C)
%
b
-attacka
% a
-attacka
1
2
3
4
5
6
7
10
2a (R¼Me, EWG¼Ts)
25
80
25
25
70 (4a)
32 (4a)
42 (4b)
63 (4c)
d
23 (5a)
41 (5a)
32 (5b)
d
2b (R¼Me, EWG¼p-Ns)
2c (R¼Me, EWG¼p-Nz)
3a (R¼Allyl, EWG¼Ts)
3b (R¼Allyl, EWG¼p-Ns)
3c (R¼Allyl, EWG¼p-Nz)
7 (R¼Allyl, EWG¼alloc)
25 or 80b
25 or 80b
25
d
d
d
66 (6c)
d
d
25 or 80b
d
a
Product number is in parantheses.
No product from a- or b-attack obtained, even in the presence of BF3$OEt2 as Lewis acid catalyst.
b
p-NsHN
S
S
CO2Me
R
p-NsHN
CO2Me
S
PMB
PMB
CO2Me
S
N
a
N
N
H
PMB
MeO2C
NHTs
PMB
MeO2C
NHTs
NHTs
4a
9
8
TsHN
S
CO2All
S
S
CO2All
N
b
N
H
PMB
MeO2C
NHp-Nz
NHp-Nz
6c
10
c
p-NsHN
S
S
CO2All
p-NsHN
R
S
CO2All
N
N
PMB
MeO2C
NHp-Nz
PMB
MeO2C
NHp-Nz
11
12
S
CO2H
S
CO2All
e
d
HO
HO
L
-Serine
NHTrt
NHTrt
13
14
f
TsHN
S
S
CO2All
PMB
CO2All
S
PMB
CO2All
S
h
g
N
N
N
H
PMB
MeO2C
NHAlloc
Ns NHAlloc
NHAlloc
16
15
17
Reagents and conditions; (a) 2b (0.5 molar equiv.), MeCN, 80 oC, 24 h, (for 9 using R-2b (0.5 molar
equiv.)); (b) 2a (0.5 molar equiv.), MeCN, 80 oC, 24 h; (c) 2b (0.5 molar equiv.), MeCN, 80 oC, 24 h, (for 12
using R-2b (0.5 molar equiv.)); (d) i) TMS-Cl, Et3N, DCM: ii) Trt-Cl, Et3N, MeOH, 58%; (e) i) Cs2CO3, MeOH:
ii) allyl bromide, DMF, 91%;(f) Ref 10; (g) thiophenol, K2CO3, DMF, rt, 16 h, 80%; (h) 2a, BF3.OEt2, CH2Cl2,
rt, 24 h, 30%.
Scheme 2. Synthesis of azalanthionines (8e12, 17).
or serine nucleophiles, used to prepare orthogonally protected
lanthionines11 and oxalanthionines.5b,c The mass balance in each
case was made up of the starting DAP and numbers of unidentified
products, which resembled ring-opened aziridines. These were
possibly serine derivatives, though none were conclusively identi-
fied, either by NMR or mass spectrometric analysis. It also is worth
mentioning that all of the synthesised azalanthionines were prone
to decomposition when stored at ambient temperature. Simple TLC
and HPLC analysis showed that they all decomposed to a multitude
of products, particularly when stored in solution (results not
shown). It was necessary to store them free of solvent in a freezer at
ꢁ20 ꢀC in order to increase their stability, but even in these cases
they had almost completely decomposed in a matter of weeks. The
reason for the instability is most likely due to the strongly electron-
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4
K. O’Brien et al. / Tetrahedron xxx (2014) 1e11
Table 2
Synthesis of orthogonally protected azalanthionines 8e12
CO2R1
P1HN
R1O2C
CO2R1
S
80 oC
PMB
CO2R2
S
N
N
H
+
N
P1
PMB NHP2
NHP2
CH3CN
2 molar equivalents
Entry
Aziridine
DAP
% Azalanthioninea
1
2
3
4
5
S-2b (R1¼Me, P1¼p-Ns)
R-2b (R1¼Me, P1¼p-Ns)
S-2a (R1¼Allyl, P1¼p-Nz)
S-2b (R1¼Me, P1¼p-Ns)
R-2b (R1¼Me, P1¼p-Ns)
4a (R2¼Me, P2¼Ts)
46 (8, (S,S))
51 (9, (R,S))
38 (10, (S,S))
27 (11, (S,S))
32 (12, (R,S))
6c (R2¼Me, P2¼p-Ns)
6c (R2¼Me, P2¼p-Ns)
a
% yield and stereochemistry in parantheses.
withdrawing protecting groups present on the nitrogen atoms,
2.2. Routes towards
b-methyl azalanthionines
which increases the acidity of the
a-hydrogens. This makes the
molecules more prone to elimination most likely by a retro-Michael
mechanism. Therefore, the same electron-withdrawing groups that
are necessary for activation of the aziridine ring to nucleophilic
ring-opening are also responsible for the instability of the resulting
products.
Having successfully prepared orthogonally protected azalan-
thionines attempts were then made to extend the methodology to
the
of the known
For the retrosynthesis of the
b
-methyl azalanthionines, which are the amine-linked analogues
-methyllanthionines and
-methyl oxalanthionines.5
-methyl azalanthionines two simple
b
b
b
Azalanthionine 12 is considered the most useful of those pre-
pared, as it contained five orthogonal protecting groups. The next
stage in the synthesis of aza analogues of lanthipeptides would
involve the deprotection of N-p-Nz protecting group of 12 and re-
placement with a Fmoc group. Removal of the allyl group of the
ester, with Pd(PPh3)4, would then give a carboxylic acid, which
could be attached to a resin for solid-phase peptide synthesis. Both
of these deprotections have been successfully achieved by Vederas
in the synthesis of analogues of the lanthipeptide lacticin 3147 A2,
containing oxalanthionine linkers, so it is felt that these particular
deprotections should also be possible for azalanthionine 12. Fur-
thermore the deprotection of the N-Ns group of DAP 15, with thi-
ophenol, has already been shown in the preparation of DAP 14, in
an isolated yield of 80% (Scheme 2).
disconnections were envisaged (Fig. 3). Disconnection A would give
a route involving ring-opening of N-activated 3-methyl-aziridine-2-
carboxylates with the previously prepared DAP derivatives. The
aziridines would come from suitably protected threonine de-
rivatives, as starting materials. The alternative disconnection B
would give N-activated 3-unsubstituted-aziridine-2-carboxylates
and b-methyl DAPs. It was envisaged that the required b-methyl
DAPs would, in turn, be prepared by ring-opening of N-activated 3-
methyl-aziridine-2-carboxylates with p-methoxybenzylamine.
Thus, the N-activated 3-methyl-aziridine-2-carboxylates were
prepared in a similar manner to their des-3-methyl counterparts,
with
material (Scheme 4). The N-trityl aziridine methyl and allyl esters
(20a and 20b) were synthesised from
-threonine in good yield.8 The
L-threonine being used in place of L-serine, as the starting
L
As well as synthesising the azalanthionines two of the isomeric
nor-azalanthionines (18 and 19) were also prepared (Scheme 3).
This was achieved by treating the same N-activated aziridine-2-
trityl group, of each ester was removed and replaced with activating
groups to promote aziridine ring-opening. The groups used were Ts,
p-Ns and p-Nz, all of which had been successfully used previously in
the synthesis of the azalanthionines (vide supra). In all this gave six
different activated aziridines (21aec and 22aec), which were then
carboxylates (2a and 2b) with the
been obtained as a by-product from attack of p-methoxybenzyl-
amine at the -position of the aziridines (Scheme 1). Again, in these
cases, only attack at the less hindered -position occurred to give
b-amino acid 5a, which had
a
used for the synthesis of b-methyl azalanthionines.
b
The ring-opening reactions were attempted using the pre-
viously successful conditions of stirring at reflux temperature in
acetonitrile using a suitably protected DAP. The DAP chosen was 6c,
which was used successfully in the preparation of the corre-
nor-azalanthionines 18 and 19, in 47% and 39% yields, respectively.
The success of these reactions was somewhat surprising because of
the highly hindered nature of the secondary amine nucleophiles
used.
sponding azalanthionines. However, none of the desired b-methyl
azalanthionines were obtained, with only the unreacted DAP and
unidentified products being recovered that appeared, from their 1H
NMR spectra, to be derived from ring-opening of the 3-methyl-
aziridine-2-carboxylates. Use of Lewis acid catalysis, with BF3$OEt2
in dichloromethane at reflux temperature, again gave none of the
required products.
H
N
Ts
R
S
p-NsHN
CO2Me
N
H
N
PMB
MeO2C
a
Using the successful synthesis of the nor-azalanthionines by
ring-opening of an aziridine with a relatively hindered secondary
Ts
18
R
H
amine as a model, the synthesis of the
was then attempted by reaction of -methyl DAPs with N-activated
3-unsubstituted aziridines. The -methyl DAPs were prepared by
ring-opening of the -methyl aziridines (21aec and 22aec) with p-
b-methyl azalanthionines
CO2Me
HN
PMB
b
N
b
Ts
R
b
5a
S
p-NsHN
CO2Me
N
b
PMB
methoxybenzylamine (Scheme 4). For example, when aziridine 21a
was reacted with p-methoxybenzylamine (2 M equivalents) at
room temperature in acetonitrile, again two regioisomers were
obtained in a combined yield of 76% (Table 3, entry 2). In this case
almost equal amounts of both regioisomers were isolated, with the
AllO2C
19
Reagents and conditions; (a) 2a (2 molar equiv.), MeCN, 80 oC,
24 h, 47%; (b) 2b (2 molar equiv.), MeCN, 80 oC, 24 h, 39%;
Scheme 3. Synthesis of isomeric nor-azalanthionines (18 and 19).
product from b-attack (23a) being obtained in 41%, while that from
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K. O’Brien et al. / Tetrahedron xxx (2014) 1e11
5
P2O2C
Me
R
R
P5
CO2P3
NHP4
S
+
N
H
A
N
Me
P1
P1HN
P2O2C
CO2P3
R
S
N
P5
B
A
NHP4
CO2P3
Me
S
P1HN
P2O2C
R
B
+
NH
P5
N
P4
P = Protecting group
P2O2C
Me
R
R
P5 NH2
+
N
P1
Fig. 3. Retrosynthetic analysis of orthogonally protected b-methyl azalanthionines.
H
S
N
CO2Me
S
P
S
PMB
CO2Me
S
c
R
R
N
H
+
L-Threonine
a
N
CO2Me
HN
PMB
NHP
P
21a, P = Ts
21b, P = p-Ns
21c, P = p-Nz
23a, P = Ts
23b, P = p-Ns
24a, P = Ts
24b, P = p-Ns
CO2R
S
S
b
or
H
N
S
N
Trt
P
CO2All
S
S
PMB
S
CO2All
20a, R = Me
20b, R = Allyl
R
c
R
N
H
+
N
CO2All
HN
PMB
NHP
P
22a, P = Ts
22b, P = p-Ns
22c, P = p-Nz
25a, P = Ts
25b, P = p-Ns
25c, P = p-Nz
26b, P = p-Ns
Reagents and conditions; (a) Ref 8; (b) see Scheme 2; (c) p-methoxybenzylamine (2 molar equiv.), MeCN, 24 h.
Scheme 4. Synthesis of -methyl DAPs.
b
Table 3
Regioselectivity of the ring-opening of 3-methyl aziridines with p-methoxybenzylamine
Entry
Aziridine
Temp (ꢀC)
%
b
-attacka
% a
-attacka
1
2
3
4
5
6
7
8
21a (R¼Me, EWG¼Ts)
0
34 (23a)
41 (23a)
15 (23a)
42 (23b)
27 (23b)
21 (23b)
d
32 (24a)
35 (24a)
62 (24a)
32 (24b)
55 (24b)
61 (24b)
d
25
80
0
25
80
NRb
0
25
80c
0
25
80c
0
19b (R¼Me, EWG¼p-Ns)
19c (R¼Me, EWG¼p-Nz)
20a (R¼Allyl, EWG¼Ts)
38 (25a)
42 (25a)
d
d
9
d
10
11
12
13
14
15
16
d
20b (R¼Allyl, EWG¼p-Ns)
20c (R¼Allyl, EWG¼p-Nz)
43 (25b)
21 (25b)
d
35 (26b)
49 (26b)
d
39 (25c)
27 (25c)
d
d
25
d
80c
d
a
Product number is in parantheses.
b
c
No reaction when conducted at 0 ꢀC, 25 ꢀC or 80 ꢀC.
No product from a- or b-attack obtained.
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6
K. O’Brien et al. / Tetrahedron xxx (2014) 1e11
a
-attack (24a) was obtained in 35% yield. When the reaction was
4. Experimental
repeated at reflux temperature the ratio was w4:1 in favour of the
product from
a
-attack (entry 3). When the reaction was conducted
-attack and 32% for
4.1. General
at 0 ꢀC, the ratio was w1:1 (entry 1, 34% for
b
a-
attack). All the other N-activated 3-methyl aziridines previously
synthesised were then reacted with p-methoxybenzylamine at
different temperatures (Table 3).
All isolated products were purified using column chromatog-
raphy with silica gel (Aldrich, 70e230 mesh, 60 A) in the indicated
ꢁ
solvent systems. Melting points were determined with Stuart sci-
entific SMP1 & Mettler FP62 melting point apparatus. Analytical
thin layer chromatography (TLC) was performed on pre-coated
plates (Merck Kieselgel 60 F254) and visualised with UV light
(254 nm), iodine vapour or aqueous potassium permanganate so-
lution. Infrared spectra were recorded as KBr disks or a thin film
between sodium chloride plates, on Avatar 320 and Nicolet impact
410 FT-IR spectrophotometers, run on EZ Omnic E.S.P 5.2a and 3.1a
software packages, respectively. Polarimetry was carried out using
an Optical Activity AA-55 series polarimeter at ambient tempera-
ture with a 2 dm, 1 ml cell. 1H NMR and 13C NMR spectra were
measured on a JOEL JNM-LA300 FT-NMR or a Bruker Avance III
500 MHz FT-NMR with TopSpin 2.16 Software and 5 mm PATXI 1H/
13-C/15N Z-GRD probe, in CDCl3 as solvent. Chemical shift values
are reported relative to tetramethylsilane. Mass Spectrometry was
carried out at the Centre for Synthesis and Chemical Biology in
University College Dublin using Quattro microÔ LCeMS/MS and
Liquid chromatography time-of-flight (LCT) mass spectrometers.
Exact Mass Spectrometry analyses were carried out at the De-
partment of Chemistry, NUI Maynooth, Co. Kildare, Ireland.
When aziridine 21b was used similar results were obtained
(entries 4e6), except for the reaction conducted at 25 ꢀC, where the
product of
product of
a
b
-attack (55% 24b) was obtained in preference to the
-attack (27%, 23b). Surprisingly, when aziridine 21c,
which contains the N-p-Nz group, was used no products from at-
tack at either the - or -positions were obtained at any of the
a
b
temperatures studied (entry 7). This is in contrast to our previous
study, which showed that the 3-unsubstituted N-p-Nz aziridine
methyl ester (2c) gave the product from attack at the b-position
(4c) as the sole product in a 63% isolated yield.9 This study had
found that when the ester group was changed from methyl to allyl
only the 3-unsubstituted aziridine with a N-p-Nz activating group
underwent a ring-opening reaction with p-methoxybenzylamine,
giving the product of b-attack (6c) as the sole product in 66% yield.
However, when the corresponding 3-methyl-substituted aziridines
were used strikingly different results were obtained (entries 8e16).
In all cases, reactions conducted at 80 ꢀC did not give any products
from attack at the
a
or
b
positions. For aziridines 22a and 22c only
- and b-
b-attack was observed, but for 22b products from both
a
attack were isolated. As for the case of the 3-unsubstituted azir-
idines the regioselectivity is highly unpredictable. A computational
study of both the 3-substituted and 3-unsubstituted aziridine de-
rivatives is currently being undertaken in order to try to explain the
observed regioselectivity outcomes.
4.2. Experimental procedures
4.2.1. General procedure for ring-opening of aziridines with p-metho
xybenzylamine for the preparation of DAPs 4aec and 6c. To a solu-
tion of the relevant aziridine (2 mmol) in acetonitrile (5 ml) was
added p-methoxybenzylamine (0.52 ml, 4 mmol) and the solution
was stirred for 24 h at room temperature. The solvent was removed
in vacuo, and then the residue was re-dissolved in ethyl acetate
(20 ml), washed with brine (2ꢂ20 ml), dried over anhydrous
magnesium sulfate and concentrated in vacuo. The crude product
was purified by flash column chromatography on silica gel in pe-
troleum ethereethyl acetate (2:1).
With a selection of the required
b-methyl DAPs (23a, 23b,
25aec) in hand, an attempt was made to ring-open the 3-
unsubstituted aziridines (2aec and 3aec) under reflux conditions
in acetonitrile. A significant number of different combinations were
tried but there was no evidence, in any case, for the desired
methyl azalanthionines. In every reaction only the starting
b
b
-
-
methyl DAPs were recovered after aqueous workup, along with
compounds, which appeared to be derived from opening of the
aziridine ring, as evidenced by the appearance of their NMR spectra
compared with, for example, aziridine ring-opened precursors. As
before, the use of BF3$OEt2 in dichloromethane at reflux tempera-
ture was also unsuccessful. These results were somewhat surpris-
ing owing to the successful synthesis of the nor-lanthionines 18 and
19, using what appeared to be an even more sterically demanding
secondary amine nucleophile.
4.2.1.1. (S)-Methyl 3-(4-methoxybenzylamino)-2-(4-methylphe
nylsulfonamido) propanoate (4a). Colourless oil (0.54 g, 70%); Rf:
0.12 petroleum ethereethyl acetate (1:1); [
20
a
]
þ13.35ꢀ (c 1.0 in
D
CHCl3); 1H NMR (CDCl3,
d
ppm) 7.72 (d, 2H, J¼8.8 Hz), 7.28 (d, 2H,
J¼8.8 Hz), 7.16 (d, 2H, J¼8.8 Hz), 6.85 (d, 2H, J¼8.8 Hz), 4.03 (t, 1H,
J¼4.8 Hz), 3.79 (s, 3H), 3.65 (d, 1H, J¼12.9 Hz), 3.61 (d, 1H,
J¼12.9 Hz), 3.52 (s, 3H), 2.88 (d, 2H, J¼5.2 Hz), 2.40 (s, 3H); 13C NMR
3. Conclusions
(CDCl3, d ppm) 171.2, 158.7, 143.7, 136.6, 131.3, 129.6, 129.3, 127.2,
113.8, 60.4, 55.3, 52.6, 52.3, 50.0, 21.5; IR (thin film, cmꢁ1) 3347,
3089, 2981, 1744, 1188, 1150; HRMS (ESþ) calculated for
The synthesis of a range of orthogonally protected azalan-
thionines, which are amine-linked analogues of the increasingly
important lanthionine containing bioactive peptides, has been
achieved by ring opening of N-activated 3-unsubstituted azir-
idines with protected DAPs. However, the azalanthionines are
unstable to storage at ambient temperature, most probably due
to the strongly electron-withdrawing nitrogen substitutents. Ex-
C
19H25N2O5S, [MþH]þ 393.1479, found [MþH]þ 393.1477.
4.2.1.2. (S)-Methyl 3-(4-methoxybenzylamino)-2-(4-nitrophenyl
sulfonamido) propanoate (4b). Pale yellow oil (0.53 g, 42%); Rf: 0.20
petroleumethereethylacetate(1:1);[
a]
D
20 þ16.51ꢀ (c1.0 in CHCl3);1H
NMR (CDCl3,
d
ppm) 8.32 (d, 2H, J¼9.0 Hz), 8.02 (d, 2H, J¼9.0 Hz), 7.16
tension of the methodology to the preparation of
b
-methyl aza-
(d, 2H, J¼8.7 Hz), 6.86 (d, 2H, J¼8.7 Hz), 4.11 (t, 1H, J¼6.1 Hz), 3.80 (s,
lanthionines has not been achieved so far. This was attempted by
two methods, which involved (i) reaction of DAPs with N-acti-
3H),3.65(s(br), 2H), 3.58(s, 3H), 3.01e2.86(dd,2H, J¼5.0,4.9Hz);13
C
NMR (CDCl3, d ppm) 170.7, 158.9, 150.0, 145.8, 131.2, 129.5, 128.3,
vated 3-methyl-substituted aziridines, or (ii) reaction of
DAPs with N-activated 3-unsubstituted aziridines. In all cases,
there was no indication of the formation of desired -methyl
b
-methyl
124.4, 113.8, 55.5, 55.3, 52.8, 52.6, 49.9; IR (thin film, cmꢁ1) 3375,
3087, 2981, 1743, 1552, 1381, 1177; HRMS (ESþ) calculated for
b
C
18H22N3O7S, [MþH]þ 438.1329, found [MþH]þ 438.1322.
azalanthionines, even by mass spectrometry. It has also been
found that the regioselectivity of the ring opening of N-activated
aziridine-2-carboxylates with p-methoxybenzylamine is not
predictable.
4.2.1.3. (S)-Methyl 3-(4-methoxybenzylamino)-2-((4-nitrobenzyl
oxy)carbonylamino) propanoate (4c). Pale yellow oil (0.46 g, 63%);
Rf: 0.22 petroleum ethereethyl acetate (1:1); [
a
]
20 þ22.48ꢀ (c 1.0 in
D
Please cite this article in press as: O’Brien, K.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.06.011

K. O’Brien et al. / Tetrahedron xxx (2014) 1e11
7
CHCl3); 1H NMR (CDCl3,
d
ppm) 8.20 (d, 2H, J¼8.7 Hz), 7.50 (d, 2H,
nitrophenylsulfonamido) propanoate (9). Compound 9 was syn-
thesised using a similar method to that used to synthesise 8,
except the protected aziridine R-2b was used (0.07 g, 0.25 mmol).
The crude product was purified by preparative TLC on silica gel
J¼8.7 Hz), 7.20 (d, 2H, J¼8.6 Hz), 6.86 (d, 2H, J¼8.6 Hz), 5.19 (d, 2H,
J¼8.6 Hz), 4.43 (m, 1H), 3.78 (s, 3H), 3.75 (s (br), 2H), 3.72 (s, 3H),
3.10e2.98 (dd, 2H, J¼4.8, 4.8 Hz); 13C NMR (CDCl3,
d ppm) 171.3,
158.8, 155.3, 147.5, 143.6, 130.9, 129.5, 128.0, 123.7, 113.6, 65.3, 55.1,
53.5, 52.6, 52.3, 49.1; IR (thin film, cmꢁ1) 3341, 3065, 2981, 1744,
1680, 1212; HRMS (ESþ) calculated for C20H24N3O7, [MþH]þ
418.1609, found [MþH]þ 418.1627.
(petroleum ethereethyl acetate 4:1) to yield 9 as a pale yellow oil
20
(0.09 g, 51%). Rf: 0.18 petroleum ethereethyl acetate (1:1); [a]
D
þ32.96ꢀ (c 1.0 in CHCl3); 1H NMR (CDCl3,
d ppm) 8.34 (d, 2H,
J¼8.7 Hz), 8.06 (d, 2H, J¼8.7 Hz), 7.73 (d, 2H, J¼8.4 Hz), 7.28 (d,
2H, J¼8.3 Hz), 7.13 (d, 2H, J¼8.5 Hz), 6.82 (d, 2H, J¼8.5 Hz), 4.14
(d, 1H, J¼6.5 Hz), 4.06 (dd, 1H, J¼7.0, 6.2 Hz), 3.81 (d, 1H,
J¼12.9 Hz), 3.80 (s, 3H), 3.50 (d, 1H, J¼12.9 Hz), 3.46 (s, 3H), 3.41
(s, 3H), 3.02 (m, 3H), 2.76 (m, 1H), 2.42 (s, 3H); 13C NMR (CDCl3,
4.2.1.4. (R)-Methyl 2-(4-methoxybenzylamino)-3-(4-methoxy
phenylsulfonamido) propanoate (5a). Colourless oil (0.17 g, 41%);
Rf: 0.24 petroleum ethereethyl acetate (1:1); [
a
]
20 þ12.41ꢀ (c 1.0 in
D
CHCl3); 1H NMR (CDCl3,
d
ppm) 7.70 (d, 2H, J¼8.6 Hz), 7.28 (d, 2H,
d ppm) 171.1, 170.8, 159.1, 149.9, 146.1, 143.8, 136.6, 130.8, 130.6,
J¼8.0 Hz), 7.15 (d, 2H, J¼8.6 Hz), 6.85 (d, 2H, J¼8.6 Hz), 5.15 (s (br),
1H) 3.80 (s, 3H), 3.68 (s, 3H), 3.65 (m, 2H), 3.51(d, 1H, J¼12.9 Hz),
3.30 (m, 1H), 3.26 (dd,1H, J¼8.6, 8.6 Hz), 2.95 (dd,1H, J¼7.5, 7.4 Hz);
129.6, 128.4, 127.2, 124.1, 113.8, 58.4, 56.7, 56.2, 55.2, 55.1, 52.7,
52.6, 21.6; IR (thin film, cmꢁ1) 3350, 3081, 2985, 1744, 1732, 1537,
1381, 1177, 1143; HRMS (ESþ) calculated for C29H35N4O11S2,
[MþH]þ 679.1738, found [MþH]þ 679.1748.
13C NMR (CDCl3,
d ppm) 172.9, 158.9, 143.5, 136.6, 131.0, 129.7, 129.4,
127.0, 113.9, 59.0, 55.3, 52.3, 51.2, 44.2, 21.5; IR (thin film, cmꢁ1
)
3359, 3082, 2991, 1743, 1224, 1124.
4.2.1.9. (S)-Allyl 3-(((R)-3-methoxy-2-(4-methylphenylsulfo
namido)-3-oxopropyl)(4-methoxybenzyl)amino)-2-((4-nitrobenzyloxy)
carbonylamino) propanoate (10). Compound 10 was synthesised
using a similar method to that used to synthesise 8, except the
protected aziridine R-2a was used (0.06 g, 0.25 mmol) and the
protected DAP was 6c (0.22 g, 0.5 mmol, 2 equiv). The crude
product was purified by preparative TLC on silica gel (petroleum
ethereethyl acetate 4:1) to yield 10 as a pale yellow oil (0.06 g,
4.2.1.5. (R)-Methyl 2-(4-methoxybenzylamino)-3-(4-nitrophenyl
sulfonamido) propanoate (5b). Pale yellow oil (0.17 g, 32%); Rf:
0.32 petroleum ethereethyl acetate (1:1); 1H NMR (CDCl3,
d ppm)
8.28 (d, 2H, J¼9.0 Hz), 7.94 (d, 2H, J¼9.0 Hz), 7.14 (d, 2H, J¼8.7 Hz),
6.83 (d, 2H, J¼8.7 Hz), 3.80 (s, 3H), 3.71 (s, 3H), 3.65 (d, 1H,
J¼12.9 Hz), 3.54 (d, 1H, J¼12.9 Hz), 3.30e3.26 (m, 2H), 3.05 (m, 1H);
13C NMR (CDCl3,
d
ppm) 172.5, 159.0, 149.9, 145.6, 130.8, 129.4,
38%). Rf: 0.18 petroleum ethereethyl acetate (1:1); [
a
]
20 þ21.31ꢀ (c
D
128.2, 124.4, 113.9, 59.2, 55.5, 52.6, 51.3, 44.3; IR (thin film, cmꢁ1
)
1.0 in CHCl3); 1H NMR (CDCl3,
d
ppm) 8.21 (d, 2H, J¼8.3 Hz), 7.72
3401, 3065, 2971, 1745, 1542, 1371, 1196.
(d, 2H, J¼8.3 Hz), 7.57 (d, 2H, J¼8.0 Hz), 7.27 (d, 2H, J¼8.0 Hz), 7.11
(d, 2H, J¼8.6 Hz), 6.77 (d, 2H, J¼8.6 Hz), 5.88 (m, 2H), 5.79 (d, 1H,
J¼8.2 Hz), 5.29 (m, 4H), 4.60 (pseudo t, 2H, J¼5.7 Hz), 4.43 (dd, 1H,
J¼8.2, 8.1 Hz), 4.14 (m, 1H), 3.77 (s, 3H), 3.70 (d, 1H, J¼12.9 Hz),
3.51 (s, 3H), 3.33 (d, 1H, J¼13.0 Hz), 2.90e2.73 (m, 4H), 2.41 (s,
4.2.1.6. (S)-Allyl 3-(4-methoxybenzylamino)-2-((4-nitrobenzyloxy)
carbonylamino) propanoate (6c). Pale yellow oil (0.58 g, 66%); Rf:
0.11 petroleum ethereethyl acetate (1:1); [
20
a]
þ26.25ꢀ (c 1.0 in
D
CHCl3); 1H NMR (CDCl3,
d
ppm) 8.21 (d, 2H, J¼8.7 Hz), 7.51 (d, 2H,
3H); 13C NMR (CDCl3,
d ppm) 170.9, 170.6, 159.0, 156.0, 147.5, 143.9,
J¼8.7 Hz), 7.19 (d, 2H, J¼8.6 Hz), 6.86 (d, 2H, J¼8.6 Hz), 5.89 (m, 2H),
5.36e5.16 (m, 4H), 4.65 (d, 2H, J¼5.9 Hz), 4.43 (m, 1H), 3.79 (s, 3H),
3.70 (s (br), 2H), 3.10e2.96 (dd, 2H, J¼5.8, 5.7 Hz); 13C NMR (CDCl3,
143.5, 137.1, 131.2, 130.5, 129.5, 129.2, 128.1, 127.1, 123.7, 119.3,
113.7, 66.6, 65.6, 57.6, 55.7, 55.4, 55.2, 54.3, 52.7, 52.4, 21.5; IR (thin
film, cmꢁ1) 3401, 3083, 2971, 1749, 1737, 1671, 1386, 1249; HRMS
(ESþ) calculated for C33H39N4O11S, [MþH]þ 699.2331, found
[MþH]þ 699.2321.
d
ppm) 171.1,158.8,155.6,147.6,143.8,131.6,131.4,129.2,128.0,123.7,
118.9,113.8, 66.1, 65.4, 55.2, 54.1, 53.1, 49.5; IR (thin film, cmꢁ1) 3367,
3075, 2976, 1743, 1674; HRMS (ESþ) calculated for C22H26N3O7,
[MþH]þ 444.1765, found [MþH]þ 444.1754.
4.2.1.10. (S)-Allyl 3-(((S)-3-methoxy-2-(4-nitrophenylsulfonamido)-
3-oxopropyl)(4-methoxybenzyl)amino)-2-((4-nitrobenzyloxy)carbon-
ylamino) propanoate (11). Compound 11 was synthesised using
a similar method to that used to synthesise 8, except the protected
aziridine 2b was used (0.07 g, 0.25 mmol) and the protected DAP
was 6c (0.22 g, 0.5 mmol, 2 equiv). The crude product was purified
by preparative TLC on silica gel in petroleum ethereethyl acetate
4:1, to yield 11 as a pale yellow oil (0.05 g, 27%). Rf: 0.22 petroleum
4.2.1.7. (S)-Methyl 3-(((S)-3-methoxy-2-(4-methylphenylsulfo
namido)-3-oxopropyl)(4-methoxybenzyl)amino)-2-(4-nitrophenylsul
fonamido) propanoate (8). N-p-Nosyl aziridine methyl ester 2b
(0.07 g, 0.25 mmol) was dissolved in MeCN (5 ml) before adding
DAP 4a (0.2 g, 0.5 mmol, 2 equiv) and the solution was stirred at
reflux temperature for 24 h before removing the solvent in vacuo.
The oil was dissolved in ethyl acetate (20 ml), washed with brine
(2ꢂ20 ml) and dried over anhydrous magnesium sulfate before
removing the solvent in vacuo. The crude product was purified by
preparative TLC on silica gel (petroleum ethereethyl acetate 4:1) to
yield 8, as a pale yellow oil (0.08 g, 46%). Rf: 0.37 petroleum
ethereethyl acetate (1:1); 1H NMR (CDCl3,
d ppm) 8.30 (d, 2H,
J¼8.8 Hz), 8.22 (d, 2H, J¼8.1 Hz), 8.00 (d, 2H, J¼8.8 Hz), 7.54 (d, 2H,
J¼8.1 Hz), 7.10 (d, 2H, J¼8.1 Hz), 6.81 (d, 2H, J¼8.1 Hz), 6.24 (s (br),
1H), 5.94 (m, 1H), 5.43e5.24 (m, 5H), 4.60 (m, 2H, J¼5.6 Hz),
4.48e4.34 (m, 1H), 4.14 (m, 1H), 3.78 (s, 3H), 3.76 (d, 1H,
J¼13.2 Hz), 3.51 (s, 3H), 3.46 (d, 1H, J¼13.2 Hz), 2.98e2.85 (m, 2H),
ethereethyl acetate (1:1); 1H NMR (CDCl3,
d ppm) 8.33 (d, 2H,
J¼8.8 Hz), 8.07 (d, 2H, J¼8.8 Hz), 7.70 (d, 2H, J¼8.4 Hz), 7.32 (d, 2H,
J¼8.3 Hz), 7.08 (d, 2H, J¼8.4 Hz), 6.80 (d, 2H, J¼8.4 Hz), 6.20 (s (br),
1H), 4.19 (t, 1H, J¼5.3 Hz), 4.03 (dd, 2H, J¼7.8 Hz, 6.5 Hz) 3.79
(s, 3H), 3.74 (d, 1H, J¼13.4 Hz), 3.50 (d, 1H, J¼13.4 Hz), 3.46 (s, 3H),
3.41 (s, 3H), 2.97 (m, 3H), 2.71 (m, 1H), 2.40 (s, 3H); 13C NMR (CDCl3,
2.78e2.71 (m, 2H); 13C NMR (CDCl3,
d ppm) 170.6, 170.2, 159.2,
156.2, 149.9, 147.8, 146.5, 143.4, 132.4, 131.1, 130.4, 128.3, 128.1,
123.9, 123.7, 119.5, 113.9, 66.5, 65.9, 57.7, 56.6, 55.2, 54.9, 54.1, 52.8,
52.4; IR (thin film, cmꢁ1) 3347, 3074, 2991, 1749, 1733, 1677, 1547,
1386, 1192.
d
ppm) 171.0, 170.7, 159.0, 149.8, 146.3, 143.7, 136.5, 130.7, 130.5,
129.8, 128.5, 127.2, 124.1, 113.9, 58.4, 56.7, 56.2, 55.1, 55.1, 52.68,
52.63, 21.6; IR (thin film, cmꢁ1) 3356, 3089, 2982, 1744, 1732, 1532,
1379, 1173, 1133.
4.2.1.11. (S)-Allyl 3-(((R)-3-methoxy-2-(4-nitrophenylsulfonamido)-
3-oxopropyl)(4-methoxybenzyl)amino)-2-((4-nitrobenzyloxy)carbon-
ylamino) propanoate (12). Compound 12 was synthesised using
a similar method to that used to synthesise 8, except the protected
aziridine used was R-2b (0.07 g, 0.25 mmol). The crude product
was purified by preparative TLC on silica gel in petroleum
4.2.1.8. (S)-Methyl 3-(((R)-3-methoxy-2-(4-methylphenyl
sulfonamido)-3-oxopropyl)(4-methoxybenzyl)amino)-2-(4-
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8
K. O’Brien et al. / Tetrahedron xxx (2014) 1e11
ethereethyl acetate 4:1, to yield 12 as a pale yellow oil (0.06 g,
4.2.1.14. 2-(S)-Allyloxycarbonylamino-3-[(4-methoxy-benzyl)-(2-
nitro-benzenesulfonyl)-amino]-propionic acid allyl ester (15). To
a solution of N-(p-methoxybenzyl)-2-nitrobenzenesulfonamide10
(0.22 g, 0.70 mmol) in THF (3 ml) was added PPh3 (0.34 g,
1.4 mmol), followed by the addition of N-triphenylmethyl-(S)-ser-
ine allyl ester (0.16 g, 1.4 mmol) and then diethyl azodicarboxylate
(0.19 g,1.2 mmol). The resulting mixture was allowed to stir at room
temperature, under a nitrogen atmosphere, for 10 h. The solvent
was removed in vacuo giving an orange oil. Purification by flash
column chromatography on silica gel in petroleum ethereethyl
acetate (4:1) gave 3-[(4-Methoxybenzyl)-(2-nitrobenzenesulfonyl)-
amino]-2-(S)-(tritylamino)-propanoic acid allyl ester as a white solid
(0.23 g, 51%). Rf 0.36, petroleum ethereethyl acetate (2:1); Mp
20
32%). Rf: 0.22 petroleum ethereethyl acetate (1:1); [
a
]
þ67.20ꢀ
D
(c 1.0 in CHCl3); 1H NMR (CDCl3,
d
ppm) 8.30 (d, 2H, J¼8.8 Hz), 8.26
(d, 2H, J¼8.6 Hz), 8.06 (d, 2H, J¼8.8 Hz), 7.57 (d, 2H, J¼8.9 Hz), 7.14
(d, 2H, J¼8.1 Hz), 6.78 (d, 2H, J¼8.1 Hz), 6.51 (s (br), 1H), 5.86 (m,
1H), 5.34e5.22 (m, 5H), 4.60 (m, 2H), 4.44 (pseudo t, 1H, J¼4.8 Hz),
4.30 (pseudo t, 1H, J¼4.9 Hz), 3.77 (d, 1H, J¼13.2 Hz), 3.76 (s, 3H),
3.51 (s, 3H), 3.46 (d, 1H, J¼13.2 Hz), 2.94e2.88 (m, 2H), 2.76 (d, 2H,
J¼6.2 Hz); 13C NMR (CDCl3,
d ppm) 170.6, 170.2, 159.2, 156.2, 149.9,
147.8, 146.5, 143.4, 132.4, 131.1, 130.4, 128.3, 128.1, 123.9, 123.7,
119.5, 113.9, 66.5, 65.9, 57.7, 56.6, 55.2, 54.9, 54.1, 52.8, 52.4; IR (thin
film, cmꢁ1) 3359, 3079, 2998, 1748, 1734, 1678, 1551, 1381, 1199.
4.2.1.12. N-Triphenylmethyl-(S)-serine (13). To a suspension of S-
serine (2.0 g, 18 mmol) in DCM (26 ml) under a nitrogen atmo-
sphere, was added Me3SiCl (7.5 ml, 57 mmol) and the solution was
stirred at reflux temperature for 20 min. The solution was allowed
to cool to 0 ꢀC and Et3N (8.3 ml, 57 mmol) in DCM (26 ml) was
added dropwise over 10 min to the solution, which was then stirred
for 45 min. The solution was cooled to 0 ꢀC and anhydrous meth-
anol (0.9 ml) was added dropwise. The solution was allowed to
warm to room temperature, and Et3N (7.0 ml, 18 mmol) was added
followed by triphenylmethyl chloride (4.6 g, 18 mmol), and the
solution was stirred for 20 h at ambient temperature. An excess of
Et3N (13 ml) and then methanol (94 ml) was added until the white
solid present in the mixture was dissolved. The excess solvent was
then removed in vacuo producing a white solid. The white solid was
partitioned between ethyl acetate (67 ml) and citric acid (40.2 ml,
5% aq w/v), which had been pre-cooled to 4 ꢀC. The organic layer
was washed with 2 M aqueous sodium hydroxide (2ꢂ20 ml) fol-
lowed by water (3ꢂ15 ml). The aqueous layers were combined,
washed with ethyl acetate (15 ml) and neutralised with glacial
acetic acid (3e4 ml) at 0 ꢀC. The precipitated product was extracted
with ethyl acetate (6ꢂ30 ml) and the organic layer was dried over
anhydrous magnesium sulfate. The solvent was removed in vacuo
to produce a white solid (3.1 g, 48%). Mp 109e110 ꢀC; 1H NMR
85e87 ꢀC; 1H NMR (CDCl3,
d
ppm) 8.01 (dd, 1H, J¼4.6, 4.4 Hz), 7.89
(dd,1H, J¼5.1, 5.1 Hz), 7.65 (m, 6H), 7.50e7.40 (m, 2H), 7.24e7.16 (m,
9H), 7.00 (d, 2H, J¼8.7 Hz), 6.70 (d, 2H, J¼8.7 Hz), 5.64e5.60 (m,1H),
5.34 (m, 1H), 5.13 (dd, 2H, J¼10.2, 10.1 Hz), 4.46 (s, 2H), 4.34 (dd, 2H,
J¼7.1, 6.9 Hz), 3.95e3.90 (m, 1H), 3.80 (s, 3H), 3.79e3.55 (m, 2H);
13C NMR (CDCl3,
d ppm) 169.2, 159.3, 145.5, 145.0, 135.2, 134.0,
132.6,131.1,130.1,129.6,129.3,128.0,126.5,125.2,124.2,118.8,114.0,
67.2, 64.2, 55.3, 55.0, 49.9, 47.4. IR (KBr, cmꢁ1) 3347, 3163, 2901,
1721, 1605, 1561, 1130. MS (ESþ) calculated for C39H37N3O7S,
[MþH]þ 692.2, found [MþH]þ 692.1.
3-[(4-Methoxybenzyl)-(2-nitrobenzenesulfonyl)-amino]-2-(S)-
(tritylamino)propanoic acid allyl ester (0.10 g, 0.16 mmol) was treated
with 50% TFA in CHCl3 (2.2 ml), under a nitrogen atmosphere, for 1 h.
NaHCO3 (0.10 g, 2.2 mmol) was added with water (5 ml) and stirred
for 5 min, then further NaHCO3 (0.10 g, 2.2 mmol) was added fol-
lowed by allyl chloroformate (0.5 ml, 0.5 mmol). The mixture was
stirred at room temperature for 12 h, diluted with ethyl acetate
(20 ml) and washed with water (2ꢂ10 ml), dried over magnesium
sulfate, and concentrated in vacuo producing a yellow oil. Purifica-
tion by flash column chromatography on silica gel in petroleum
ethereethylacetate(4:1)gave15 asayellowoil(0.050g, 63%). Rf 0.57,
petroleum ethereethyl acetate (1:2); 1H NMR (CDCl3,
d ppm) 7.99 (d,
1H, J¼7.3 Hz), 7.69e7.60 (m, 3H), 7.11 (d, 2H, J¼8.6 Hz), 6.78 (d, 2H,
(CDCl3,
d
ppm) 7.43 (d, 6H, J¼6.0 Hz), 7.32e7.29, 7.28 (m, 3H),
J¼8.6 Hz), 5.89e5.85 (m, 2H), 5.31e5.29 (m, 4H), 4.68e4.41 (m, 5H),
3.73e3.71 (m, 1H), 3.50 (dd, 1H, J¼2.9, 2.9 Hz), 2.94e2.90 (m, 1H);
4.21 (s, 2H), 3.77 (s, 3H), 3.72e3.49 (m, 2H); 13C NMR (CDCl3,
d ppm)
13C NMR (CDCl3,
d
ppm) 174.9, 145.2, 129.3, 128.6, 126.2, 73.9, 67.5,
169.6, 159.5, 156.6, 147.7, 145.0, 135.1, 133.6, 132.4, 131.7, 131.2, 129.8,
126.1,124.3,118.9,118.0,117.6, 68.6, 64.1, 55.2, 51.8, 50.4, 47.8; IR (thin
film, cmꢁ1) 3345, 3063, 2963, 1791, 1600, 1555, 1528, 1103; MS (ESþ)
calculated for C24H27N3O9S, [MþH]þ 534.1, found [MþH]þ 534.1.
62.0; IR (KBr, cmꢁ1) 3314, 3068, 1732.
The enantiomeric N-trityl-(R)-serine (R-13) was also prepared in
a similar manner from (R)-serine.
4.2.1.13. N-Triphenylmethyl-(S)-serine allyl ester (14). N-Triphe-
nylmethyl-(S)-serine (0.30 g, 0.87 mmol) was converted to its
caesium salt by dissolving it in dry methanol (3.0 ml) containing
Cs2CO3 (0.15 g, 0.45 mmol) under a nitrogen atmosphere. After
removing the solvent in vacuo, the salt produced was re-dissolved
in DMF (0.6 ml) and the resulting mixture was treated with allyl
bromide (0.10 ml, 0.90 mmol). The solution was left stirring for
a further 18 h at ambient temperature, after which the DMF was
removed in vacuo. The mixture was then re-dissolved in ethyl ac-
etate (3 ml) and washed with citric acid solution (1ꢂ10 ml, 5% aq w/
v). The aqueous layers were combined and extracted with ethyl
acetate (2ꢂ10 ml), and the organic layers were combined and
washed with water (12ꢂ10 ml). The organic layer was dried over
anhydrous magnesium sulfate and the solvent was removed in
vacuo producing a brown oil (0.30 g, 90%). Rf 0.73, hexaneeethyl
4.2.1.15. 2-(S)-Allyloxycarbonylamino-3-(4-methoxy-benzyla-
mino)-propionic acid allyl ester (16). Thiophenol (0.6 ml, 0.6 mmol)
was dissolved in DMF (2 ml) and treated with K2CO3 (0.20 g,
1.6 mmol) in water (1 ml), which was then stirred at 0 ꢀC for 10 min.
Compound 15 (0.10 g, 0.53 mmol) was dissolved in DMF (1 ml) and
added to the thiophenol mixture and stirred overnight at room
temperature under a nitrogen atmosphere. Ethyl acetate (10 ml)
was added and the mixture washed with water (2 x 10 ml), dried
over magnesium sulfate and concentrated in vacuo giving a yellow
oil. Purification by flash column chromatography on silica gel in
DCMediethyl ether (2:1) removed the yellow fraction. Meth-
anoleDCM (5:95) was then added to give 16 as a light brown oil
(0.15 g, 80%). Rf 0.37, DCMediethyl ether (2:1) (stain ninhydrin,
yellow spot); 1H NMR (CDCl3,
d
ppm) 7.20 (d, 2H, J¼8.4 Hz), 6.85 (d,
2H, J¼8.7 Hz), 5.95e5.82 (m, 2H), 5.72 (d, 1H, J¼6.3 Hz), 5.34e5.23
acetate (2:1); 1H NMR (CDCl3,
d
ppm) 7.50 (dd, 6H, J¼8.4, 5.3 Hz),
(m, 4H), 4.64e4.56 (m, 4H), 4.44e4.41 (m, 1H), 3.80 (s, 2H), 3.79 (s,
7.25e7.22 (m, 9H), 5.70e5.67 (m, 1H), 5.18 (dd, 1H, J¼1.5, 1.3 Hz),
5.13 (dd, 1H, J¼1.5, 1.5 Hz), 4.19e4.17 (m, 1H), 4.09e4.00 (m, 1H),
3.72 (dd, 1H, J¼6.6, 6.4 Hz), 3.54 (dd, 2H, J¼4.2, 3.9 Hz); 13C NMR
3H), 3.72 (dd, 2H, J¼4.5, 3.3 Hz). 13C NMR (CDCl3,
d ppm) 166.1,
159.7, 155.9, 146.7, 131.2, 128.9, 119.5, 67.9, 55.3, 52.8, 51.2, 48.7. IR
(thin film, cmꢁ1) 3311, 3030, 2876, 1720, 1666, 1489; MS (ESþ)
calculated for C18H24N2O5, [Mþ1] 649.2, found [Mþ1] 649.2.
(CDCl3, d ppm) 173.1, 145.1, 131.6, 128.7, 127.9, 126.6, 118.4, 71.0, 65.7,
64.9, 57.8; IR (thin film, cmꢁ1) 3477, 3068, 2960, 1740, 1635.
The enantiomeric R-14 was also prepared in a similar manner
from N-trityl-(R)-serine.
4.2.1.16. 2-(S)-Allyloxycarbonylamino-3-{(4-methoxy-benzyl)-[2-
(S)-methoxycarbonyl-2-(toluene-4-sulfonylamino)-ethyl]-amino}-
Please cite this article in press as: O’Brien, K.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.06.011

K. O’Brien et al. / Tetrahedron xxx (2014) 1e11
9
propionic acid allyl ester (17). Aziridine 2a (0.65 g, 0.28 mmol) and
J¼6.0 Hz). 13C NMR (CDCl3,
d
ppm) 169.2, 60.9, 54.9, 52.1, 19.2. IR
DAP 16 (0.10 g, 0.28 mmol) were dissolved in dry DCM (5 ml) and
stirred at room temperature, under a nitrogen atmosphere, for
20 min. Freshly distilled BF3$OEt2 (0.01 ml, 0.1 mmol) was then
added and the mixture was stirred at 40 ꢀC for 24 h. The mixture was
then diluted with DCM (10 ml) and washed with saturated aqueous
NaHCO3 solution (10 ml) and water (10 ml), dried over magnesium
sulfate, and then the solvent was removed in vacuo giving a brown
residue. Purification by preparative TLC in petroleum ethereethyl
acetate (2:1) gave 17 as a clear oil (48 mg, 30%). Rf 0.26, petroleum
(KBr, cmꢁ1) 3407, 2967, 1745.
N-trityl-(L)-threonine methyl ester was synthesised using a simi-
lar method to that used to synthesise 14, except (
ester hydrochloride (0.54 g, 3.2 mmol) was used, to yield a white
solid (0.98 g, 82%).8 Rf: 0.50 petroleum ethereethyl acetate (2:1). 1H
L)-threonine methyl
NMR (CDCl3,
d ppm) 7.49 (m, 6H), 7.31e7.14 (m, 9H), 3.78 (m, 1H),
3.38 (d, 1H J¼3.5 Hz), 3.15 (s, 3H), 1.22 (d, 3H J¼6.3 Hz). 13C NMR
(CDCl3, d ppm) 173.7, 145.4, 128.9, 127.9, 126.6, 69.7, 62.5, 53.4, 51.7,
18.9. IR (KBr, cmꢁ1) 3481, 3055, 2978, 1732, 1592.
ethereethyl aceatate (2:1); 1H NMR (CDCl3,
d ppm) 7.74 (d, 2H,
J¼8.2 Hz), 7.30 (d, 2H, J¼8.0 Hz), 7.20 (d, 2H, J¼5.3 Hz), 6.65 (d, 2H,
J¼6.3 Hz), 5.99e5.82 (m, 2H), 5.73 (s, 1H, J¼17.4 Hz), 5.50 (d, 1H,
J¼12.9 Hz), 5.35e5.23 (m, 4H), 4.60(dd, 4H, J¼5.6, 5.5 Hz), 4.44e4.36
(m, 2H), 3.97 (dd, 2H, J¼4.2, 3.6 Hz), 3.88 (d, 2H, J¼3.6 Hz), 3.80 (s,
3H) 3.73 (d, 2H, J¼3.6 Hz), 2.96 (s, 3H), 2.42 (s, 3H); MS (ESþ) cal-
culated for C29H37N3O9S, [MþH]þ 604.3, found [MþH]þ 604.3.
4.2.1.20. N-Triphenylmethyl-(
)-threonine was synthesised using a similar method to that used
to synthesise N-triphenylmethyl-(S)-serine (13), except -threonine
(1.13 g, 9.5 mmol) was used to yield a white solid (2.02 g, 59%). 1H
L
)-threonine. N-Triphenylmethyl-
(L
L
NMR (CDCl3,
d
ppm) 7.40 (d, 6H, J¼6.0 Hz), 7.28e7.15 (m, 9H), 3.91
(m, 1H), 3.52 (dd, 1H, J¼5.9, 5.8 Hz), 1.19 (d, 3H, J¼5.6 Hz); 13C NMR
(CDCl3, d ppm) 174.6, 145.2, 128.6, 127.7, 126.6, 70.6, 60.5, 54.8, 18.3;
4.2.1.17. (2R)-Methyl 2-(((S)-3-methoxy-2-(4-nitrophenylsulfo
namido)-3-oxopropyl)(4-methoxybenzyl)amino)-3S-(4-methylphenyl
sulfonamido) propanoate (18). Compound 18 was synthesised us-
ing a similar method to that used to synthesise 8, except the
protected Dap 5a and aziridine 2a were used. The crude product
was purified using preparatory TLC on silica gel (petroleum
ethereethyl acetate 4:1) to yield 18 as a pale yellow oil (0.08 g,
47%). Rf: 0.29 petroleum ethereethyl acetate (1:1); 1H NMR (CDCl3,
IR (KBr, cmꢁ1) 3341, 3082, 2977, 1737.
4.2.1.21. N-Triphenylmethyl-(
nylmethyl-( )-threonine allyl ester was synthesised using a similar
method to that used to synthesise N-trityl-( )-serine methyl ester,
except N-triphenylmethyl-( )-threonine (0.31 g, 0.87 mmol) was
used to yield a brown oil (0.31 g, 90%). Rf: 0.60 petroleum ether-
eethyl acetate (2:1); 1H NMR (CDCl3,
ppm) 7.49 (m, 6H), 7.28e7.12
L
)-threonine allyl ester. N-Triphe-
L
L
L
d
d
ppm) 8.33 (d, 2H, J¼8.9 Hz), 8.00 (d, 2H, J¼8.7 Hz), 7.69 (d, 2H,
(m, 9H), 5.63 (m, 1H), 5.16 (m, 2H), 4.06 (m, 1H), 3.82 (m, 2H), 3.40
J¼8.0 Hz), 7.28 (d, 2H, J¼8.1 Hz), 7.08 (d, 2H, J¼8.4 Hz), 6.84 (d, 2H,
J¼8.4 Hz), 3.98 (t, 1H, J¼6.5 Hz), 3.81 (s, 3H), 3.73 (s, 3H), 3.65 (d,
1H, J¼13.0 Hz), 3.55 (d, 1H, J¼12.9 Hz), 3.50 (s, 3H), 3.46 (m, 1H),
3.23 (m, 1H), 3.09 (m, 2H), 3.00 (m, 1H), 2.42 (s, 3H); 13C NMR
(d, 1H J¼7.3 Hz), 1.22 (d, 3H J¼6.1 Hz); 13C NMR (CDCl3,
d ppm)
173.0, 145.5, 131.6, 129.0, 127.9, 126.7, 118.8, 70.8, 69.8, 62.5, 53.5,
19.0; IR (thin film, cmꢁ1) 3446, 3058, 2931, 1732, 1674.
(CDCl3,
d
ppm) 170.9, 170.7, 159.3, 150.1, 145.5, 143.6, 136.6, 130.4,
4.2.1.22. (2S,3R)-Methyl-1-(trityl)-aziridine-2-carboxylic
methyl ester (20a). Compound 20a was synthesised using a similar
method to that used to synthesise 1a, except N-trityl-( )-threonine
acid
129.7, 128.4, 127.0, 124.2, 114.1, 62.7, 55.3, 55.3, 55.2, 54.5, 52.4,
52.1, 41.4, 21.5; IR (thin film, cmꢁ1) 3391, 3078, 2962, 1745, 1732,
1529, 1391, 1249, 1141.
L
methyl ester (2.06 g, 5.5 mmol) was used, to yield a cloudy oil
(1.79 g, 91%). Rf: 0.82 petroleum ethereethyl acetate (2:1); 1H NMR
4.2.1.18. (2R)-Methyl 3-(((S)-1-allyloxy-3-(4-methylphenyl
sulfonamido)-1-oxopropan-2-yl)(4-methoxybenzyl)amino)-2-(4-
nitrophenylsulfonamido) propanoate (19). Compound 19 was syn-
thesised using a similar method to that used to synthesise 18,
except the protected Dap 5a and aziridine 2b were used. The crude
product was purified using preparatory TLC on silica gel (petroleum
ethereethyl acetate 4:1) to yield 19 as a pale yellow oil (0.07 g,
39%). Rf: 0.24 petroleum ethereethyl acetate (1:1); 1H NMR (CDCl3,
(CDCl3, d ppm) 7.53 (m, 6H), 7.28e7.13 (m, 9H), 3.67 (s, 3H),1.90 (dd,
1H, J¼3.8, 3.7 Hz), 1.66 (m, 1H), 1.36 (d, 3H, J¼6.2 Hz); 13C NMR
(CDCl3,
d ppm) 170.8, 144.2, 129.5, 127.7, 127.0, 75.1, 51.9, 36.1, 35.0,
13.4; IR (thin film, cmꢁ1) 3069, 2947, 1739.
4.2.1.23. (2S,3R)-Methyl-1-trityl-aziridine-2-carboxylic acid allyl
ester (20b). Compound 20b was synthesised using a similar
method to that used to synthesise 1b, except N-triphenylmethyl-
d
ppm) 8.32 (d, 2H, J¼8.8 Hz), 8.00 (d, 2H, J¼8.8 Hz), 7.68 (d, 2H,
(
L
)-threonine allyl ester (2.07 g, 5.16 mmol) was used to yield 20b as
a yellow oil (1.72 g, 87%). Rf: 0.90 petroleum ethereethyl acetate
(2:1); 1H NMR (CDCl3,
ppm) 7.45 (m, 6H), 7.31e7.19 (m, 9H), 5.88
J¼8.7 Hz), 7.27 (d, 2H, J¼8.6 Hz), 7.11 (d, 2H, J¼8.7 Hz). 6.84 (d, 2H,
J¼8.7 Hz), 5.66 (m, 1H), 5.20 (m, 3H), 4.35 (d, 2H, J¼6.0 Hz), 3.97
(t, 1H), 3.81 (s, 3H), 3.72 (s, 3H), 3.66 (d, 1H, J¼13.5 Hz), 3.57 (d, 1H,
J¼13.5 Hz), 3.46 (m, 1H), 3.25 (m, 1H), 3.10e2.98 (m, 3H), 2.41 (s,
d
(m, 1H), 5.24 (m, 2H), 4.59 (m, 2H), 1.84 (d, 1H J¼6.5 Hz), 1.55 (m,
1H), 1.27 (d, 3H J¼5.5 Hz); 13C NMR (CDCl3)
d ppm; 170.0, 143.9,
3H); 13C NMR (CDCl3,
d
ppm) 170.9, 170.0, 159.3, 150.1, 145.5, 143.5,
132.2, 129.4, 128.3, 126.6, 118.5, 82.0, 65.4, 36.0, 35.0, 13.4; IR (thin
136.7, 130.6, 130.5, 129.7, 128.5, 127.0, 124.3, 120.0, 114.1, 66.8, 62.8,
55.5, 55.4, 55.3, 54.6, 52.1, 41.5, 21.5; IR (thin film, cmꢁ1) 3376, 3065,
2963, 1751, 1732, 1684, 1524, 1391, 1247.
film, cmꢁ1) 3080, 2975, 1742, 1641.
4.2.1.24. (2S,3R)-Methyl-1-(p-tosyl)-aziridine-2-carboxylic acid
methyl ester (21a). Compound 21a was synthesised using a similar
method to that used to synthesise 2a, except 20a (2.07 g, 5.8 mmol)
was used to yield a clear oil (1.26 g, 81%). Rf: 0.47 petroleum
4.2.1.19. (
)-Threonine methyl ester hydrochloride.8 A 250 ml 3-
L
necked round-bottom flask was equipped with a condenser,
a dropping funnel and a rubber septum. The condenser was fitted
with a calcium chloride drying tube. The dropping funnel was
charged with acetyl chloride (23.0 ml, 0.33 mol). The flask was filled
with 75 mls of methanol and cooled to 0 ꢀC in an ice bath under
ethereethyl acetate (2:1); 1H NMR (CDCl3,
d ppm) 7.85 (d, 2H,
J¼8.4 Hz), 7.35 (d, 2H, J¼8.3 Hz), 3.73 (s, 3H), 3.39 (d, 1H, J¼7.5 Hz),
3.10 (m, 1H), 2.44 (s, 3H), 1.32 (d, 3H, J¼5.6 Hz); 13C NMR (CDCl3,
d
ppm) 166.2, 145.0, 136.6, 129.8, 128.0, 53.0, 41.4, 40.1, 21.6, 12.4; IR
nitrogen. The acetyl chloride is added dropwise over 5 min before
L-
(thin film, cmꢁ1) 3072, 2979, 1741, 1214.
threonine (13.58 g, 0.11 mol) was added before heating to reflux
temperature. After 2 h the solvent is removed in vacuo to yield
a white fluffy solid (18.75 g, 97%), which was used without further
4.2.1.25. (2S,3R)-Methyl-1-(p-nosyl)-aziridine-2-carboxylic acid
methyl ester (21b). Compound 21b was synthesised using a similar
method to that used to synthesise 2b, except 20a (2.07 g, 5.8 mmol)
was used to yield a yellow oil (1.39 g, 80%). Rf: 0.51 petroleum
purification. 1H NMR (CDCl3,
d
ppm) 4.12 (d, 1H, J¼5.8 Hz), 3.87 (d,
1H, J¼5.8 Hz), 3.78 (dd, 1H, J¼5.3, 5.2 Hz), 3.67 (s, 3H), 1.21 (d, 3H,
Please cite this article in press as: O’Brien, K.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.06.011

10
K. O’Brien et al. / Tetrahedron xxx (2014) 1e11
20
ethereethyl acetate (2:1); 1H NMR (CDCl3,
d
ppm) 8.35 (d, 2H,
42%); Rf: 0.45 petroleum ethereethyl acetate (1:1); [
1.0 in CHCl3); 1H NMR (CDCl3,
a
]
D
þ7.10ꢀ (c
J¼8.8 Hz), 8.14 (d, 2H, J¼8.8 Hz), 3.68 (s, 3H), 3.44 (d, 1H, J¼7.5 Hz),
d
ppm) 8.32 (d, 2H, J¼8.7 Hz), 8.03 (d,
3.18 (m, 1H), 1.21 (d, 3H, J¼5.7 Hz); 13C NMR (CDCl3,
d
ppm) 165.6,
2H, J¼8.7 Hz), 7.13 (d, 2H, J¼8.4 Hz), 6.83 (d, 2H, J¼8.5 Hz), 3.88 (d,
1H, J¼3.2 Hz), 3.78 (s, 3H), 3.65 (d, 2H, J¼12.6 Hz), 3.49 (d, 1H,
J¼12.7 Hz), 3.47 (s, 3H), 3.18 (m, 1H), 1.17 (d, 2H, J¼5.6 Hz); 13C NMR
150.8, 145.4, 129.2, 124.4, 52.8, 42.2, 40.7, 12.4; IR (thin film, cmꢁ1
)
3080, 2967, 1747, 1540, 1379, 1276.
(CDCl3,
d ppm) 170.8, 158.9, 149.9, 145.9, 131.0, 129.4, 128.4, 124.6,
4.2.1.26. (2S,3R)-Methyl-1-(p-nitrobenzyloxycarbony)-aziridine-
2-carboxylic acid methyl ester (21c). Compound 21c was synthesised
using a similar method to that used to synthesise 2c, except 20a
(2.07 g, 5.8 mmol) was used to yield a yellow oil (1.33 g, 78%). Rf:
113.8, 60.2, 55.3, 53.8, 52.6, 50.6, 18.0; IR (thin film, cmꢁ1) 3352,
3066, 2967, 1741, 1521, 1386, 1191; HRMS (ESþ) calculated for
C
19H24N3O7S, [MþH]þ 438.1329, found [MþH]þ 438.1330.
0.45 petroleum ethereethyl acetate (2:1); 1H NMR (CDCl3,
d
ppm)
4.2.1.32. (2R,3S)-Methyl 2-(4-methoxybenzylamino)-3-(4-
8.08 (d, 2H, J¼8.8 Hz), 7.44 (d, 2H, J¼8.8 Hz), 5.12 (d, 2H, J¼3.1 Hz),
methylphenylsulfonamido) butanoate (24a). Rf: 0.29 petroleum
3.67 (s, 3H), 3.18 (d, 1H, J¼6.7 Hz), 2.78 (m, 1H), 1.27 (d, 3H,
ethereethyl acetate (1:1); 1H NMR (CDCl3,
d
ppm) 7.64 (d, 2H,
J¼5.6 Hz); 13C NMR (CDCl3,
d
ppm) 171.4, 161.2, 147.6, 143.9, 129.2,
J¼8.4 Hz), 7.20 (d, 2H, J¼8.4 Hz), 7.10 (d, 2H, J¼8.6 Hz), 6.78 (d, 2H,
J¼8.6 Hz), 3.73 (s, 3H), 3.65e3.50 (dd, 2H, J¼12.6, 12.6 Hz), 3.56 (s,
3H), 3.50 (d, 1H, J¼12.6 Hz), 3.43 (m, 1H), 3.01 (d, 1H, J¼5.1 Hz), 2.33
123.4, 66.8, 53.6, 39.8, 39.0, 12.6; IR (thin film, cmꢁ1) 3065, 2981,
1744, 1680, 1528, 1397, 1212.
(s, 3H), 1.02 (d, 3H, J¼6.5 Hz). 13C NMR (CDCl3,
d ppm) 172.8, 158.9,
4.2.1.27. (2S,3R)-Methyl-1-(p-tosyl)-aziridine-2-carboxylic acid
allyl ester (22a). Compound 22a was synthesised using a similar
method to that used to synthesise 3a, except 20b (2.07 g, 5.4 mmol)
was used to yield a clear oil (1.34 g, 84%). Rf: 0.47 petroleum
143.3, 137.5, 130.7, 129.6, 129.6, 127.2, 113.8, 64.2, 55.3, 52.4, 52.0,
51.5, 21.5, 17.6; IR (thin film, cmꢁ1) 3365, 3089, 2982, 1738, 1194,
1133.
ethereethyl acetate (2:1); 1H NMR (CDCl3,
d
ppm) 7.85 (d, 2H,
4.2.1.33. (2S,3R)-Allyl 3-(4-methoxybenzylamino)-2-(4-
J¼8.8 Hz), 7.35 (d, 2H, J¼8.8 Hz), 5.88 (m, 1H), 5.22 (m, 2H), 4.65 (d,
methylphenylsulfonamido) butanoate (25a). Pale yellow oil (0.09 g,
20
2H, J¼6.0 Hz), 3.39 (d, 1H, J¼6.6 Hz), 3.10 (m, 1H), 2.44 (s, 3H), 1.32
42%); Rf: 0.2 petroleum ethereethyl acetate (1:1); [
a
]
þ21.83ꢀ (c
D
(d, 3H, J¼5.8 Hz); 13C NMR (CDCl3,
d
ppm) 166.2, 145.0, 136.6, 131.1,
1.0 in CHCl3); 1H NMR (CDCl3,
d
ppm) 7.72 (d, 2H, J¼8.3 Hz), 7.27 (d,
129.8, 128.0, 119.0, 66.5, 41.4, 40.1, 21.6, 12.4; IR (thin film, cmꢁ1
)
2H, J¼8.3 Hz), 7.15 (d, 2H, J¼8.4 Hz), 6.83 (d, 2H, J¼8.4 Hz), 5.66 (m,
1H), 5.16 (m, 2H), 4.38e4.25 (dd, 2H, J¼6.0, 6.0 Hz), 3.82 (d, 1H,
J¼3.6 Hz), 3.78 (s, 3H), 3.71 (d, 1H, J¼13.2 Hz), 3.54 (d, 1H,
J¼13.2 Hz), 3.12 (m, 1H), 2.40 (s, 3H), 1.15 (d, 3H, J¼6.5 Hz); 13C NMR
3090, 2992, 1740, 1621, 1220.
4.2.1.28. (2S,3R)-Methyl-1-(p-nosyl)-aziridine-2-carboxylic acid
allyl ester (22b). Compound 22b was synthesised using a similar
method to that used to synthesise 3b, except 20b (2.07 g, 5.4 mmol)
was used to yield a yellow oil (1.35 g, 77%). Rf: 0.54 petroleum
(CDCl3,
d ppm) 170.3, 158.7, 143.5, 136.7, 131.7, 131.1, 129.6, 129.3,
127.2, 119.0, 113.7, 66.1, 60.1, 55.2, 54.0, 50.3, 21.5, 17.5; IR (thin film,
cmꢁ1) 3346, 3081, 2962, 1744, 1612, 1201, 1152; HRMS (ESþ) cal-
ethereethyl acetate (2:1); 1H NMR (CDCl3,
d
ppm) 8.35 (d, 2H,
culated for
433.1796.
C
22H29N2O5S, [MþH]þ 433.1792, found [MþH]þ
J¼9.0 Hz), 8.14 (d, 2H, J¼8.9 Hz), 5.86 (m 1H), 5.26 (m, 2H), 4.57 (d, 2H,
J¼5.8 Hz), 3.48 (d,1H, J¼7.5Hz), 3.20(m,1H),1.29 (d, 3HJ¼5.7 Hz);13
C
NMR (CDCl3,
d
ppm) 164.8,150.8,143.5,130.9,129.2,124.4,119.5, 66.5,
4.2.1.34. (2S,3R)-Allyl 3-(4-methoxybenzylamino)-2-(4-
nitrophenylsulfonamido) butanoate (25b). Pale yellow oil (0.1 g,
42.0, 40.7,12.3; IR (thin film, cmꢁ1) 3077, 2954,1742,1538,1371,1242.
43%); Rf: 0.41 petroleum ethereethyl acetate (1:1); [
a
]
20 þ12.37ꢀ (c
D
4.2.1.29. (2S,3R)-Methyl-1-(p-nitrobenzyloxycarbony)-aziridine-
2-carboxylic acid allyl ester (22c). Compound 22c was synthesised
using a similar method to that used to synthesise 3c, except 20b
(2.07 g, 5.4 mmol) was used to yield a yellow oil (1.29 g, 75%). Rf:
1.0 in CHCl3); 1H NMR (CDCl3,
d
ppm) 8.31 (d, 2H, J¼8.8 Hz), 8.01 (d,
2H, J¼8.8 Hz), 7.12 (d, 2H, J¼8.5 Hz), 6.84 (d, 2H, J¼8.5 Hz), 5.63 (m,
1H), 5.18 (m, 2H) 4.42 (dd, 1H, J¼12.8, 6.1 Hz), 4.30 (dd, 1H, J¼12.7,
6.1 Hz), 3.88 (d, 1H, J¼4.6 Hz), 3.78 (s, 3H), 3.68 (d, 1H, J¼12.8 Hz),
3.51 (d, 1H, J¼12.8 Hz), 3.21 (m, 1H), 1.19 (d, 3H, J¼6.3 Hz); 13C NMR
0.42 petroleum ethereethyl acetate (2:1); 1H NMR (CDCl3,
d ppm)
8.25 (d, 2H, J¼8.8 Hz), 7.55 (d, 2H, J¼8.8 Hz), 5.90 (m, 1H), 5.38e5.19
(CDCl3, d ppm) 170.1, 158.8, 149.9, 145.9, 131.6, 130.0, 129.2, 128.4,
(m, 4H), 4.70 (d, 2H, J¼5.8 Hz), 3.23 (d, 1H, J¼6.7 Hz), 2.88 (m, 1H),
124.6, 119.5, 113.8, 66.4, 60.3, 55.2, 53.9, 50.8, 18.2; IR (thin film,
cmꢁ1) 3397, 3069, 2981, 1738, 1612, 1557, 1379, 1176; HRMS (ESþ)
calculated for C21H26N3O7S, [MþH]þ 464.1486, found [MþH]þ
464.1504.
1.39 (d, 3H, J¼5.6 Hz); 13C NMR (CDCl3,
d ppm) 166.6, 161.1, 147.8,
142.4, 131.3, 128.5, 123.8, 119.2, 66.9, 66.2, 39.9, 39.1, 12.7; IR (thin
film, cmꢁ1) 3068, 2982, 1741, 1681, 1640, 1209.
DAPs 23a, 24a, 23b, 24b, 25aec and 26 were prepared by ring-
opening of 3-methyl aziridines with p-methoxybenzylamine using
the general procedure used to prepare DAPs 4aec and 6c.
4.2.1.35. (2S,3R)-Allyl 3-(4-methoxybenzylamino)-2-((4-
nitrobenzyloxy)carbonylamino) butanoate (25c). Pale yellow oil
20
(0.09 g, 39%); Rf: 0.50 petroleum ethereethyl acetate (1:1); [a]
D
4.2.1.30. (2S,3R)-Methyl 3-(4-methoxybenzylamino)-2-(4-
methylphenylsulfonamido) butanoate (23a). Cloudy oil (0.08 g,
þ29.62ꢀ (c 1.0 in CHCl3); 1H NMR (CDCl3,
d ppm) 8.19 (d, 2H
J¼8.8 Hz), 7.51 (d, 2H J¼8.8 Hz), 7.17 (d, 2H J¼8.9 Hz), 6.85 (d, 2H,
J¼8.8 Hz), 6.08 (s (br), 1H), 5.90 (m, 1H), 5.36e5.25 (m, 2H), 4.80 (s,
2H), 4.64 (d, 2H, J¼6.0 Hz), 4.27 (pseudo t, 2H, J¼4.3 Hz), 3.79 (s,
3H), 3.24 (d, 1H J¼7.2 Hz), 2.78 (m, 1H), 1.29 (d, 3H J¼5.6 Hz); 13C
41%); Rf: 0.18 petroleum ethereethyl acetate (1:1); [
a
]
20 þ16.55ꢀ (c
D
1.0 in CHCl3); 1H NMR (CDCl3,
d
ppm) 7.71 (d, 2H, J¼8.1 Hz), 7.28 (d,
2H, J¼8.0 Hz), 7.13 (d, 2H, J¼8.4Hz), 6.82(d, 2H, J¼8.4 Hz), 3.81(d,1H,
J¼3.6 Hz), 3.80 (s, 3H), 3.68 (d,1H, J¼12.8 Hz), 3.55 (d,1H, J¼12.8 Hz),
3.45 (s, 3H), 3.09 (m,1H), 2.41 (s, 3H),1.13 (d, 3H, J¼6.2 Hz); 13C NMR
NMR (CDCl3,
d ppm) 167.8, 163.1, 159.0, 148.5, 147.5, 131.4, 129.8,
129.2,126.9,123.6,119.1,114.0, 66.2, 63.8, 55.3, 44.4, 40.5, 39.4,13.0;
IR (thin film, cmꢁ1) 3380, 3071, 2980, 1742, 1666, 1206; HRMS:
(ESþ) calculated for C23H28N3O7, calculated [MþH]þ 458.1943,
found [MþH]þ 458.1922.
(CDCl3,
d ppm) 171.1, 158.7, 143.5, 136.7, 131.8, 129.5, 129.3, 127.2,
113.7, 60.4, 55.2, 53.9, 52.3, 50.3, 21.5, 17.6; IR (thin film, cmꢁ1) 3411,
3077, 2977, 1733, 1213, 1126; HRMS (ESþ) calculated for
C
20H27N2O5S, [MþH]þ 407.1635, found [MþH]þ 407.1628.
4.2.1.36. (2R,3S)-Allyl
phenylsulfonamido) butanoate (26b). Rf: 0.52 petroleum ether-
eethyl acetate (1:1). 1H NMR (CDCl3,
ppm) 8.28 (d, 2H, J¼8.8 Hz),
2-(4-methoxybenzylamino)-3-(4-nitro-
4.2.1.31. (2S,3R)-Methyl 3-(4-methoxybenzylamino)-2-(4-
nitrophenylsulfonamido) butanoate (23b). Pale yellow oil (0.09 g,
d
Please cite this article in press as: O’Brien, K.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.06.011

K. O’Brien et al. / Tetrahedron xxx (2014) 1e11
11
2. (a) Taylor, C.; De Silva, S.-T. J. Org. Chem. 2011, 76, 5703e5711; (b) Taylor, C.;
Wang, W. Tetrahedron 2007, 63, 9033e9047; (c) Boschin, G.; D’Agostina, A.;
Arnoldi, A. Food Chem. 2002, 78, 325e331; (d) Friedman, M. J. Agric. Food Chem.
1999, 47, 1295e1319.
7.96 (d, 2H, J¼8.7 Hz), 7.07 (d, 2H, J¼8.4 Hz), 6.80 (d, 2H, J¼8.4 Hz),
5.63 (m, 1H), 5.18 (m, 2H), 4.26 (dd, 2H, J¼6.2, 6.1 Hz), 3.80 (s, 3H),
3.72 (d, 1H, J¼12.9 Hz), 3.58 (d, 1H, J¼12.9 Hz), 3.28 (m, 1H), 2.98 (d,
1H, J¼7.4 Hz), 1.07 (d, 2H, J¼5.8 Hz). 13C NMR (CDCl3,
d ppm) 172.8,
3. (a) Arnison, P. G.; Bibb, M. J.; Bierbaum, G.; Bowers, A. A.; Bugni, T. S.; Bulaj, G.;
Camarero, J. A.; Campopiano, D. J.; Challis, G. L.; Clardy, J.; Cotter, P. D.; Craik, D.
J.; Dawson, M.; Dittmann, E.; Donadio, S.; Dorrestein, P. C.; Entian, K.-D.;
158.8, 149.9, 147.6, 131.5, 130.9, 129.0, 128.5, 124.1, 119.2, 113.8, 66.5,
63.8, 55.2, 52.9, 51.1, 18.1. IR (thin film, cmꢁ1) 3368, 3068, 2979,
1739, 1622, 1552, 1378, 1165.
€
Fischbach, M. A.; Garavelli, J. S.; Goransson, U.; Gruber, C. W.; Haft, D. H.;
Hemscheidt, T. K.; Hertweck, C.; Hill, C.; Horswill, A. R.; Jaspars, M.; Kelly, W. L.;
Klinman, J. P.; Kuipers, O. P.; Link, A. J.; Liu, W.; Marahiel, M. A.; Mitchell, D. A.;
€
Moll, G. N.; Moore, B. S.; Muller, R.; Nair, S. K.; Nes, I. F.; Norris, G. E.; Olivera, B.
Acknowledgements
M.; Onaka, H.; Patchett, M. L.; Piel, J.; Reaney, M. J. T.; Rebuffat, S.; Ross, R. P.;
Sahl, H.-G.; Schmidt, E. W.; Selsted, M. E.; Severinov, K.; Shen, B.; Sivonen, K.;
€
Smith, L.; Stein, T.; Sussmuth, R. D.; Tagg, J. R.; Tang, G.-L.; Truman, A. W.;
We are grateful to Strand I of the Irish Government’s National
Development Plan Technological Sector Research Program for
funding (Grant PP07/TA07) for K.O’B and the Higher Education
Authority’s Programme for Research in Third-Level Institutions IV
Vederas, J. C.; Walsh, C. T.; Walton, J. D.; Wenzel, S. C.; Willey, J. M.; Van der
Donk, W. Nat. Prod. Rep. 2013, 30, 108e160; (b) Knerr, P. J.; Van der Donk, W. A.
Annu. Rev. Biochem. 2012, 81, 479e505.
4. Tabor, A. Org. Biomol. Chem. 2011, 9, 7606e7628.
5. (a) Ross, A. C.; McKinnie, S. M. K.; Vederas, J. C. J. Am. Chem. Soc. 2012, 134,
2008e2011; (b) Liu, H.; Pattabiraman, V. R.; Vederas, J. C. Org. Lett. 2009, 11,
5574e5577; (c) Liu, H.; Pattabiraman, V.; Vederas, J. Org. Lett. 2007, 9,
4211e4214.
ꢀ
for funding for K.o P and K.O’B.
Supplementary data
ꢀ
6. O’Brien, K.; o Proinsias, K.; Kelleher, F. Tetrahedron Lett. 2013, 54, 2395e2397.
ꢀ
7. (a) Perez, M.; Pleixats, R. Tetrahedron 1995, 51, 8355e8362; (b) Paulus, T.;
Supplementary data related to this article can be found at
http://dx.doi.org/10.1016/j.tet.2014.06.011.
Riemer, C.; Beck-Sickinger, A. G.; Henle, T.; Klostermeyer, H. Eur. Food Res.
Technol. 2006, 222, 242e249; (c) Kim, B. M.; So, S. M. Tetrahedron Lett. 1999, 40,
7687e7690.
8. Willems, J. G. H.; Hersmis, M. C.; de Gelder, R.; Smits, J. M. M.; Hammink, J. B.;
Dommerholt, F. J.; Thijs, L.; Zwanenburg, B. J. Chem. Soc., Perkin Trans. 1 1997,
963e967.
References and notes
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Mimics In Modern Supramolecular Chemistry: Strategies for Macrocycle Synthesis;
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Germany, 2008.
9. O’Brien, K.; Kelleher, F. Tetrahedron Lett. 2013, 54, 6627e6630.
ꢀ
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11. Nakajima, K.; Oda, H.; Okawa, K. Bull. Chem. Soc. Jpn. 1983, 56, 520e522.
Please cite this article in press as: O’Brien, K.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.06.011