Selective cleavage of carbamate protecting groups from aziridines with otera's catalyst

Article abstract of DOI:10.1071/CH13464

Otera's distannoxane catalyst was found to promote the cleavage of carbamate groups from N-protected aziridines. This method enables the chemoselective cleavage of an aziridinyl N-carbobenzyloxy (Cbz) group in the presence of other N-Cbz groups. The selec

Full text of DOI:10.1071/CH13464

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem. 2014, 67, 411–415
Full Paper
http://dx.doi.org/10.1071/CH13464
Selective Cleavage of Carbamate Protecting Groups
from Aziridines with Otera’s Catalyst
A
A
A
A B
,
Shan Sun, Ilaria Tirotta, Nicholas Zia, and Craig A. Hutton
A
School of Chemistry and Bio21 Molecular Science and Biotechnology Institute,
The University of Melbourne, Melbourne, Vic. 3010, Australia.
Corresponding author. Email: chutton@unimelb.edu.au
B
Otera’s distannoxane catalyst was found to promote the cleavage of carbamate groups from N-protected aziridines. This
method enables the chemoselective cleavage of an aziridinyl N-carbobenzyloxy (Cbz) group in the presence of other
N-Cbz groups. The selectivity is due to the longer, weaker N–C bond of aziridinyl carbamates, as inferred through IR and
crystallographic analyses.
Manuscript received: 3 September 2013.
Manuscript accepted: 16 October 2013.
Published online: 11 November 2013.
Introduction
groups. Cleavage of the methyl carbamate (Moc) group of 3c
was successful, generating unprotected aziridine 4 (albeit in low
isolated yield[4]; Scheme 2). However, the tert-butyloxycarbonyl
(Boc)-protected compound 3b underwent only transesterifi-
cation to 5b, with no Boc cleavage occurring. Presumably,
sterically hindered carbamates are less prone to cleavage, in
line with Otera’s findings that sterically hindered esters are not
effectively transesterified under such conditions.[2b]
Acyclic carbamates were next investigated. Upon treatment
of the Boc/Moc-protected diaminobutane 6 with Otera’s catalyst
and benzyl alcohol in toluene, no reaction was observed.
Similarly, when differentially protected diaminopimelate
derivative 7a was treated under identical conditions no carba-
mate cleavage was observed, only transesterification of the
methyl ester to the corresponding benzyl ester 7b. Further, the
carbamate-protected anilines 8a–c were also unreactive under
these conditions. Thus, it is apparent that the cleavage of
carbamate groups under these conditions does not extend to
acyclic systems (Chart 1).
With the conclusion that acyclic carbamate systems were
not reactive towards Otera’s catalyst, cyclic systems were
explored. Cbz-proline benzyl ester 9 was unreactive to standard
conditions, and similarly the Cbz-azetidine-2-carboxylate
methyl ester 10a did not undergo carbamate cleavage, only
transesterification to 10b (Chart 2).
Given the apparent selectivity for cleavage of aziridine-
based carbamate groups, we sought to exploit this selectivity
through the chemoselective removal of one of the two
Cbz-protecting groups in dipeptide 14. Dipeptide 14 was pre-
pared from N-tritylaziridine carboxylate 11. Hydrolysis of
N-tritylaziridine carboxylate 11[5] gave the corresponding acid,
which was coupled to Ne-Cbz lysine methyl ester to give
dipeptide 13. Trityl deprotection and Cbz-reprotection gave
dipeptide 14. Treatment of aziridine-containing dipeptide 14
with Otera’s catalyst under the standard transesterification/
deprotection conditions yielded the singly Cbz-deprotected,
transesterified dipeptide 15 (Scheme 3), highlighting the
Protecting group chemistry is central to virtually all facets of
organic synthesis, and is of prime importance in peptide
chemistry where orthogonal protecting groups are crucial to
chemoselective reactions at numerous amine and carboxylate
functional groups. Carbamate protection of amines is extremely
versatile due to the variety of carbamate groups that have
been developed and the consequent ability to selectively cleave
these protecting groups under a range of conditions,[1] leaving
other groups such as amides intact. The cleavage of carbamate
protecting groups is normally determined by the nature of the
O-alkyl group as the O–C bond is generally the initial bond
cleaved during deprotection. Herein we describe the selective
removal of carbamates based instead on the nature of the N-alkyl
group. Specifically, we demonstrate that aziridinyl-based car-
bamates are uniquely susceptible to cleavage with Otera’s
catalyst.
Otera and co-workers showed that 1,3-disubstituted tetra-
organodistannoxanes 1 are efficient transesterification cata-
lysts.[2] Several of these distannoxanes have been made
commercially available at times, and are collectively referred
to as Otera’s catalyst. These species are actually pre-catalysts,
being converted to the active catalyst 2 in presence of the alcohol
involved in the transesterification reaction (Scheme 1).
During the course of our studies on aziridine ring-opening
reactions[3] we were surprised to find that treatment of Cbz-
protected aziridine-2-carboxylate methyl ester 3a with benzyl
alcohol in the presence of Otera’s catalyst not only resulted in
transesterification to the benzyl ester, but also the cleavage of
the Cbz group, generating aziridine 4. Benzyl carbonate was
isolated as a by-product, confirming that benzyl alcohol attacks
the carbamate carbonyl group, displacing the aziridine. We
therefore set out to explore the scope and limitations of carba-
mate deprotection reactions with Otera’s catalyst.
Initial studies focussed on treatment of several carbamate-
protected aziridine-2-carboxylates to investigate whether this
reaction was general across a variety of carbamate protecting
Journal compilation Ó CSIRO 2014
www.publish.csiro.au/journals/ajc

412
S. Sun et al.
109.58, which results in the nitrogen lone pair possessing more
‘s’-character and being less delocalized into the carbonyl group;
such changes in the hybridization of the aziridinyl nitrogen
render the –CO2R part of the carbamate more ‘ester-like’.
Analysis of the IR spectra of these and related carbamate-
protected heterocycles reveals distinct differences between
aziridinyl and other carbamates. While carbamates typically
ϭ
ϭ
1
2
Scheme 1. Conversion of Otera’s (pre)catalyst into active catalyst.
show carbonyl IR absorbances at ,1700 cmꢀ1 [6–8]
,
sponding IR absorbances for the aziridinyl carbamates 3a–c and
the corre-
others[9,10] occur at 1720–1735 cmꢀ1 closer to a typical ester
,
’
C¼O absorbance.[11] Further, an inspection of the Cambridge
Structural Database (CSD) reveals a related effect where the
N–C(O) bond of aziridinyl-carbamates is significantly longer
than those of other carbamates. The N–C(O) bond of carbamate-
ϩ
a
b
c
ϭ
3
4
5
ϭ
ϭ
˚
˚
protected aziridines is on average 1.40 A (16 hits), whereas
˚
non-aziridinyl compounds average ,1.34 A (azetidines, 1.33 A
˚
˚
Scheme 2. Treatment of carbamate-protected aziridines with Otera’s
(13 hits); pyrrolidines, 1.34 A (620 hits); piperidines, 1.34 A
(304 hits).[12] The longer, weaker aziridinyl N–C(O) bonds are
consequently more prone to cleavage under the described
reaction conditions.
catalyst.
6
Conclusion
7a
7b
ϭ
In conclusion, we have unearthed a novel method for the
selective deprotection of aziridines. We demonstrate that
Otera’s catalyst is able to perform a chemoselective transfor-
mation at aziridinyl-carbamate. Using this method two Cbz-
protecting groups in a single molecule can be differentiated and
made ‘orthogonal’ when one is on an aziridinyl nitrogen. The
use of Otera’s catalyst to cleave carbamates is unprecedented.
ϭ
8
Chart 1.
Experimental
(S)-N-Benzyloxycarbonyl aziridine-2-carboxylate
methyl ester 3a
10a
10b
ϭ
9
ϭ
N-Trityl aziridine-2-carboxylate methyl ester[5] (1.00 g,
2.92 mmol) was dissolved in a solution of methanol (5 mL) and
chloroform (5 mL), and the solution was cooled to 08C. Tri-
fluoroacetic acid (4 mL) was added and the resulting solution
was stirred for 3 h. The solvent was removed under vacuum,
and dried azeotropically with the addition of diethyl ether. The
dried material was dissolved in dichloromethane (20 mL)
and cooled to 08C. Triethylamine (2 mL) and a 50 % benzyl
chloroformate solution in toluene (1.2 mL, 3.5 mmol) were
added, and the resulting solution was warmed to room temper-
ature and stirred for 16 h. The solution was then evaporated
under vacuum, and the crude residue was purified by flash
chromatography (10–20 % ethyl acetate/hexanes) to yield the
title compound as a pale amber oil (305 mg, 44 % yield). nmax
(neat)/cmꢀ1 2957, 1729, 1441, 1379, 1323, 1294, 1224, 1192,
1025, 753, 699. dH (500 MHz, CDCl3) 7.37–7.33 (m, 5H), 5.17–
5.11 (m, 2H), 3.70 (s, 3H), 3.10 (dd, J 5.5, 3.0, 1H), 2.59 (dd,
J 3.0, 1.5, 1H), 2.47 (dd, J 5.5, 1.5, 1H). Data in accordance with
literature values.[9,13]
Chart 2.
11
12
13
’
15
14
(S)-N-tert-Butoxycarbonyl aziridine-2-carboxylate
methyl ester 3b
Scheme 3. Chemoselective cleavage of aziridinyl-Cbz group.
N-Trityl aziridine-2-carboxylate methyl ester[5] (1.00 g,
2.92 mmol) was dissolved in a solution of methanol (5 mL) and
chloroform (5 mL), and the solution was cooled to 08C. Tri-
fluoroacetic acid (4 mL) was added and the resulting solution
was stirred for 3 h. The solvent was removed under vacuum,
and dried azeotropically with the addition of diethyl ether. The
dried material was dissolved in dichloromethane (20 mL) and
chemoselective cleavage of carbamate protecting groups based
on the nature of the nitrogen.
We postulate that the chemoselectivity for cleavage of
aziridinyl-based carbamate groups is due to the highly strained
nature of the three-membered ring. Aziridines possess bond
angles of ,608, much lower than a tetrahedral bond angle of

Deprotection of Aziridine Carbamates with Otera’s Catalyst
413
cooled to 08C. Triethylamine (2 mL) and di-tert-butyl dicar-
bonate (764 mg, 3.5 mmol) were added, and the resulting
solution was warmed to room temperature and stirred for 16 h.
The solution was then evaporated under vacuum, and the
crude residue was purified by flash chromatography (10–20 %
ethyl acetate/hexanes) to yield the title compound as a pale
amber oil (411 mg, 70 % yield); nmax (neat)/cmꢀ1 2980, 1745,
1722, 1440, 1392, 1369, 1327, 1306, 1233, 1203, 1150, 1087,
1021, 968, 852, 800. dH (600 MHz, CDCl3) 3.63 (s, 3H), 2.89
(dd, J 5.3, 3.1, 1H), 2.37 (dd, J 3.1, 1.3, 1H), 2.27 (dd, J 5.3, 1.3,
1H), 1.31 (s, 9H); dC (150 MHz, CDCl3) 168.7, 159.4, 81.8,
52.3, 34.6, 31.1, 27.7. Data in accordance with literature
values.[14]
1-tert-Butoxycarbonylamino-4-
methoxycarbonylaminobutane 6
To a solution of 1,4-diaminobutane (4.03 g, 45.7 mmol) in
dichloromethane (60 mL) at 08C was added a solution of
di-tert-butyl dicarbonate (1.00 g, 4.58 mmol) in dichloro-
methane (20 mL) dropwise over 2 h, whereupon the solution was
brought to room temperature and stirred for 20 h. The solution
was washed with water (30 mL), brine (30 mL), dried (magne-
sium sulfate), and reduced under vacuum. The crude residue was
purified by flash chromatography to yield N-Boc-diaminobutane
as a yellow powder (0.815 g, 95 % yield); dH (400 MHz, CDCl3)
4.70 (br s, 1H), 3.11 (m, 2H), 2.73 (m, 2H), 1.81 (m, 2H), 1.46
(m, 2H), 1.43 (s, 9H). m/z (ESI-MS) 189.1659; [MþH]þ
requires 189.1598.[15]
(S)-N-Methoxycarbonyl aziridine-2-carboxylate
methyl ester 3c
To
a solution of N-Boc-1,4-diaminobutane (0.500 g,
2.66 mmol) and pyridine (0.26 mL, 3.2 mmol) in dichloro-
methane (20 mL) at 08C was added methyl chloroformate
(0.27 mL, 3.5 mmol). The solution was stirred overnight,
quenched with ice/water (20 mL), and the organic phase was
washed with water (3 ꢁ 20 mL), brine (20 mL), dried (magne-
sium sulfate), and reduced under vacuum. The crude residue
was purified by flash chromatography to afford the title com-
pound as an off-white powder (0.20 g, 30 % yield), mp 85–878C.
dH (400 MHz, CDCl3) 4.84 (br s, 1H), 4.61 (br s, 1H), 3.77
(s, 3H), 3.17 (br s, 1H), 3.11 (m, 2H), 1.49 (m, 2H), 1.46 (m, 2H),
1.44 (s, 9H). dC (100 MHz, CDCl3) 157.3, 156.2, 79.1, 52.0,
40.7, 40.2, 28.4, 27.4, 27.3. m/z (ESI-MS) 247.1653; [MþH]þ
requires 247.1652.
N-Trityl aziridine-2-carboxylate methyl ester[5] (1.06 g,
3.09 mmol) was dissolved in a solution of methanol (5 mL)
and chloroform (5 mL), and the solution was cooled to 08C.
Trifluoroacetic acid (4 mL) was added and the resulting
solution was stirred for 3 h. The solvent was removed under
vacuum, and dried azeotropically with the addition of
diethyl ether. The dried material was dissolved in dichlor-
omethane (20 mL) and cooled to 08C. Triethylamine (2 mL)
and methyl chloroformate (290 mL, 3.7 mmol) were added,
and the resulting solution was warmed to room temperature
and stirred for 16 h. The solution was then evaporated under
vacuum, and the crude residue was purified by flash chroma-
tography (10–25 % ethyl acetate/hexanes) to yield the title
compound as a pale amber oil (158 mg, 32 % yield); nmax (neat)/
cmꢀ1 2923, 1735, 1464, 1378, 772. dH (600 MHz, CDCl3) 3.72
(s, 3H), 3.68 (s, 3H), 3.04 (dd, J 5.4, 3.2, 1H), 2.49 (dd, J 3.2, 1.3,
1H), 2.42 (dd, J 5.4, 1.3, 1H). dC (150 MHz, CDCl3) 168.7,
161.4, 53.8, 52.7, 34.7, 31.3. Data in accordance with literature
values.[9]
2-tert-Butoxycarbonylamino-6-
methoxycarbonylaminopimelic acid
1-tert-butyl 7-methyl diester 7a
To N-Cbz glycine methyl ester a-dimethyl phosphonate[16]
(235 mg, 0.710 mmol) and DBU (100 mL, 0.68 mmol) in
dichloromethane (4.5 mL) was added a solution of N-diBoc
L-glutamate semialdehyde tert-butyl ester[17] (250 mg,
0.645 mmol) in dichloromethane (4.5 mL). The solution was
stirred for 3 h, and then reduced under vacuum. The crude
residue was purified by flash chromatography (10–20 % ethyl
acetate/hexanes) to yield the corresponding alkene as a yellow
oil (215 mg, 56 % yield). To the alkene (165 mg, 0.278 mmol)
was added a solution of trifluoroacetic acid (64 mL, 0.835 mmol)
in dichloromethane (1 mL), and the resulting solution was stir-
red for 3 h. The solution was washed with a solution of sodium
carbonate (89 mg, 0.84 mmol) in water (1 mL), and the organic
phase was dried (magnesium sulfate), and reduced under vac-
uum to yield the corresponding singly Boc-protected compound
(134 mg, 98 % yield). This alkene (134 mg, 0.27 mmol) was
dissolved in methanol, then Pd(OH)2/C (13 mg) was added. The
mixture was stirred under a hydrogen atmosphere for 16 h, fil-
tered over Celite, and reduced under vacuum to yield 2-tert-
butoxycarbonylamino-6-aminopimelic acid 1-tert-butyl ester
7-methyl ester (as a mixture of diastereomers). The residue was
dissolved in dichloromethane (2 mL) and cooled to 08C.
Pyridine (29 mL, 0.35 mmol) and methyl chloroformate (25 mL,
0.33 mmol) were added and the resulting solution was stirred for
30 min at 08C. The solution was then warmed to room temper-
ature and then continued to stir 16 h. The solvent was removed
under vacuum and the residue was diluted with dichloromethane
(20 mL) and washed with water (3 ꢁ 10 mL), brine (10 mL),
dried(magnesiumsulfate), andevaporated. Thecrude residuewas
purified by flash chromatography (20 % ethyl acetate/hexanes)
(S)-Aziridine-2-carboxylate benzyl ester 4
From 3a: To (S)-N-benzyloxycarbonyl aziridine-2-carboxylate
methyl ester 3a (103 mg, 0.44 mmol) and Otera’s catalyst
(50 mg, 0.044 mmol) in toluene (2 mL) was added benzyl
alcohol (450 mL, 4.4 mmol), and the solution was heated at
1008C overnight. The solution was diluted with ethyl acetate
(20 mL) and extracted with 1 M hydrochloric acid solution
(20 mL). The aqueous phase was basified with saturated
sodium bicarbonate solution (10 mL), and extracted with ethyl
acetate (20 mL). The organic phase was dried (magnesium
sulfate) and reduced under vacuum to yield the title compound
as a yellow oil (15 mg, 19 % yield).[4] dH (500 MHz, CDCl3)
7.41–7.28 (m, 5H), 5.23–5.17 (m, 2H), 2.57 (br s, 1H), 2.04
1
(d, J 3.5, 1H), 1.88 (br s, 1H). H NMR data in accordance
with literature values.[10]
From 3c: To (S)-N-methoxycarbonyl aziridine-2-carboxylate
methyl ester 3c (70 mg, 0.44 mmol) and Otera’s catalyst
(50 mg, 0.044 mmol) in toluene (2 mL) was added benzyl alco-
hol (450 mL, 4.4 mmol), and the solution was heated at 1008C
overnight. The solution was diluted with ethyl acetate (20 mL)
and extracted with 1 M hydrochloric acid solution (20 mL).
The aqueous phase was basified with saturated sodium bicar-
bonate solution (10 mL), and extracted with ethyl acetate
(20 mL). The organic phase was dried (magnesium sulfate)
and reduced under vacuum to yield the title compound as a
yellow oil (8 mg, 10 % yield).[4]

414
S. Sun et al.
to yield the title compound as a pale yellow oil (60 mg, 53 %
yield over two steps). dH (500 MHz, CDCl3) 5.29 (m, 1H), 5.05
(m, 1H), 4.33 (m, 1H), 4.12 (m, 1H), 1.83–1.58 (m, 6H), 1.45 (s,
9H), 1.44 (s, 9H). m/z (ESI-MS) 419.2383; [MþH]þ requires
419.2388.
N-Benzyloxycarbonyl aziridine-2-carboxyl-
(Ne-benzyloxycarbonyl)lysine methyl ester 14
N-Trityl aziridine-2-carboxylate methyl ester[4] (500 mg,
1.46 mmol) was dissolved in a mixture of tetrahydrofuran
(15 mL) and water (2 mL) at 08C. Aqueous 1 M sodium
hydroxide (20 mL) was added, followed by aqueous 1 M lithium
hydroxide (10 mL) and the mixture was stirred for 2 h. The
mixture was diluted with dichloromethane (50 mL) and 15 %
w/v aqueous citric acid (40 mL), and the organic phase was
further washed with citric acid solution (3 ꢁ 20 mL). The
combined aqueous phases were extracted with dichloromethane
(3 ꢁ 30 mL), and the combined organic phases were then
dried (magnesium sulfate) and reduced under vacuum, giving
N-tritylaziridine-2-carboxylate (quantitative). N-Tritylaziridine-
2-carboxylate (500 mg, 1.52 mmol) was added to dimethylfor-
mamide (10 mL), followed by addition of diisopropylethylamine
(2.8 mL, 15 mmol) and (benzotriazol-1-yloxy)tripyrrolidino-
phosphonium hexafluorophosphate (1.58 mg, 3.04 mmol).
After standing for 15 min, lysine derivative 12[20] (503 mg,
3.04 mmol) was added, and the solution was stirred for 16 h. The
solution was diluted with dichloromethane (40 mL), washed
with water (5 ꢁ 30 mL), dried (magnesium sulfate), and reduced
under vacuum. The crude residue was purified by flash chro-
matography (20–35 % ethyl acetate/hexanes) to yield dipeptide
13 (0.46 g, 50 % yield).
A 50 % v/v solution of trifluoroacetic acid/dichloromethane
(0.2 mL) was added to a solution of dipeptide 13 (53 mg,
88 mmol) in 50 % v/v methanol/dichloromethane at 08C. After
stirring for 20 min, additional 50 % v/v trifluoroacetic acid/
dichloromethane (0.2 mL) was added, and the solution stirred
for a further 20 min. The solvent was then removed azeotro-
pically with methanol under vacuum and the residue was
redissolved in dichloromethane (2.5 mL). Upon cooling, triethy-
lamine (40 mL, 0.26 mmol) and 50 % benzyl chloroformate/
toluene (45 mL, 0.13 mmol) were added to the solution, which
was then warmed to room temperature and stirred overnight.
The solvent was removed under vacuum, and the crude residue
was purified by flash chromatography (30–60 % ethyl acetate/
hexanes) to yield the title compound as a yellow oil (30 mg, 68 %
yield). dH (500 MHz, CDCl3) 7.36–7.25 (m, 10H), 6.79 (d, J 7.5,
1H), 5.18–5.08 (m, 4H), 4.85 (m, 1H), 4.55 (m, 1H), 3.73 (s, 3H),
3.15 (m, 2H), 3.06 (dd, J 5.0, 2.5, 1H), 2.51 (d, J 5.5, 1H), 2.38
(d, J 1.0, 1H), 1.82 (m, 1H), 1.67 (m, 1H), 1.47 (m, 2H), 1.27
(m, 2H). dC (125 MHz, CDCl3) 172.4, 167.2, 161.3, 156.7,
136.7, 135.4, 128.8, 128.7, 128.7, 128.6, 128.3, 69.0, 66.8,
52.7, 51.9, 40.6, 37.1, 32.2, 32.0, 29.5, 22.3. m/z (ESI-MS)
520.2051; [MþH]þ requires 520.2054.
2-tert-Butoxycarbonylamino-6-
methoxycarbonylaminopimelic acid
1-tert-butyl 7-benzyl diester 7b
To 7a (7.0 mg, 17 mmol) and Otera’s catalyst (2.0 mg, 2 mmol) in
toluene (0.4 mL) was added benzyl alcohol (18 mL, 0.17 mmol),
and the solution was heated at 1008C for 40 h. The solvent was
removed under a stream of nitrogen and the residue was purified
by flash chromatography (15 % ethyl acetate/hexanes) to
yield the title compound as an pale oil (6.0 mg, 71 % yield).
dH (600 MHz, CDCl3) 7.39–7.33 (m, 5H), 5.31 (m, 1H), 5.17
(m, 2H), 5.03 (m, 1H), 4.38 (m, 1H), 4.12 (m, 1H), 3.67 (s, 3H),
1.91–1.52 (m, 6H), 1.44 (s, 18H). m/z (ESI-MS) 495.2692;
[MþH]þ requires 495.2701.
N-Benzyloxycarbonyl azetidine-2-carboxylate
methyl ester 10a
To a solution of N-Boc azetidine-2-carboxylate (1.00 g,
4.98 mmol) in methanol (10 mL) and benzene (15 mL) was
added dropwise 2.0 M (trimethylsilyl)diazomethane solution in
hexanes (4 mL, 8 mmol). Water (,10 mL) was added and the
mixture was stirred for 1 h. The solvent was removed under
vacuum to quantitatively yield N-Boc azetidine-2-carboxylate
methyl ester. To the methyl ester (300 mg, 1.40 mmol) in
dichloromethane (5 mL) was added trifluoroacetic acid (1 mL),
and the resulting solution was stirred for 1 h. The solvent was
azeotropically removed with dichloromethane under vacuum to
yield the amine product. The residue was redissolved in anhy-
drous dichloromethane (5 mL), followed by the addition of
triethylamine (1 mL). Upon cooling to 08C, a 50 % benzyl
chloroformate/toluene solution was added, and the solution was
stirred overnight. The solvent was then removed and the crude
residue was purified by flash chromatography (15–35 % ethyl
acetate/hexanes) to yield the title compound as a pale yellow
oil (277 mg, 80 % yield). dH (600 MHz, CDCl3) 7.32–7.26
(m, 5H), 5.12–5.04 (m, 2H), 4.67 (m, 1H), 4.06 (m, 1H), 3.93
(m, 1H), 3.68 (s, 3H), 2.52 (m, 1H), 2.19 (m, 1H). dC (150 MHz,
CDCl3) 171.6, 155.8, 136.5, 128.5, 128.1, 128.0, 66.9, 60.4,
52.3, 47.7, 20.8. 1H and 13C NMR data in accordance with lit-
erature values.[18]
N-Benzyloxycarbonyl azetidine-2-carboxylate
benzyl ester 10b
Aziridine-2-carboxyl-(Ne-benzyloxycarbonyl)lysine
benzyl ester 15
To N-Cbz azetidine methyl ester 10a (45 mg, 0.18 mmol) and
Otera’s catalyst (20 mg, 0.018 mmol) in toluene (1 mL) was
added benzyl alcohol (190 mL, 1.8 mmol), and the solution
was heated at 1008C overnight. The solution was diluted with
ethyl acetate (20 mL) and this was washed with 10 % sodium
bicarbonate solution (3 ꢁ 10 mL). The organic phase was
dried (magnesium sulfate) and reduced under vacuum to yield
the title compound as a pale oil (15 mg, 25 % yield) conta-
minated with benzyl alcohol. nmax (neat)/cmꢀ1 2955, 1743,
1705, 1408, 1347, 1286, 1207, 1125, 1064, 1024, 970, 917, 755,
738, 698. dH (600 MHz, CDCl3) 7.37–7.35 (m, 10H), 5.16 (br
s, 2H), 5.07 (br s, 2H), 4.74 (m, 1H), 4.10 (m, 1H), 3.97 (m, 1H),
2.56 (m, 1H), 2.22 (m, 1H). Data in accordance with literature
values.[19]
To dipeptide 14 (34 mg, 68 mmol) and Otera’s catalyst (8 mg,
7 mmol) in toluene (2 mL) was added benzyl alcohol (75 mL,
0.69 mmol), and the solution was heated at 1008C for 28 h. The
solvent was removed under a stream of nitrogen and the residue
was purified by flash chromatography (0–10 % methanol/
dichloromethane) to yield the title compound as a pale yellow oil
(5.0 mg, 17 % yield). [4]; dH (400 MHz, CDCl3) 7.36–7.31
(m, 10H), 5.18–5.04 (m, 4H), 4.48–4.42 (m, 1H), 3.12–3.01
(m, 2H), 1.90–1.63 (m, 3H), 1.52–1.25 (m, 6H). dC (100 MHz,
CDCl3) 173.3, 158.9, 129.6, 129.6, 129.5, 129.4, 129.3, 128.9,
128.8, 67.9, 67.4, 54.0, 41.4, 32.1, 30.7, 30.4, 26.2, 23.9. m/z
(ESI-MS) 440.2176; [MþH]þ requires 440.2180. Purification

Deprotection of Aziridine Carbamates with Otera’s Catalyst
415
also yielded the transesterifed product (benzyl ester of 14) as
an oil (1.0 mg, 3 % yield). dH (500 MHz, CDCl3) 7.38–7.30
(m, 15H), 6.78 (d, J 7.6, 1H), 5.21–5.07 (m, 6H), 4.75 (m, 1H),
4.59 (m, 1H), 3.11–3.08 (m, 2H), 3.06 (dd, J 6.4, 3.3, 1H), 2.50
(d, J 6.4, 1H), 2.38 (d, J 2.9, 1H), 1.86–1.80 (m, 2H), 1.67–1.18
(m, 4H). m/z (ESI-MS) 574.2556; [MþH]þ requires 574.2548.
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NMR spectra for compounds 3–5, 7, 10, 13–15 are available on
the Journal’s website.
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