Aziridines derived from amino acids as synthons in pseudopeptide synthesis

Article abstract of DOI:10.1016/j.tet.2006.02.003

The reactivity of the Z-protected aziridine derived from aspartic acid has been studied with various N- and O-nucleophiles. The optimized reaction conditions allow quick and easy access to 1, 2-diamines or amino alcohols. In the case of opening with N-nuc

Full text of DOI:10.1016/j.tet.2006.02.003

Tetrahedron 62 (2006) 3509–3516
Aziridines derived from amino acids as synthons
in pseudopeptide synthesis
*
Laidong Song, Vincent Servajean and Josiane Thierry
Institut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
Received 10 January 2006; accepted 1 February 2006
Abstract—The reactivity of the Z-protected aziridine derived from aspartic acid has been studied with various N- and O-nucleophiles. The
optimized reaction conditions allow quick and easy access to 1, 2-diamines or amino alcohols. In the case of opening with N-nucleophiles,
very good regioselectivity was observed. Use of an a-amino ester as the nucleophile yielded a methyleneamino pseudodipeptide.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
the two other surrogates are scarce as there is no general
methodology for their synthesis. In principle, these three
pseudopeptides could be obtained from a common
precursor, namely an aziridine, which could be opened by
amino acids or peptide esters or analogues (a-hydroxy or
a-thio esters) as shown in Scheme 1. A preliminary report
exploring the reactivity of the aziridine derived from an
aspartic acid derivative with amines has shown the
feasability of this approach with respect to the methylene-
amino analogue.5
During the course of our ongoing study concerning the
tetrapeptide Ac-Ser-Asp-Lys-Pro-OH extracted from bone
marrow,1 we were interested in preparing various
analogues, which would be stable towards proteolysis.2 A
common approach to achieve this goal is to replace the
hydrolyzable peptide bond by a surrogate bond.3 Among
the number of possibilities reported in the literature, the
methyleneamino, methyleneoxy and methylenethio pseudo-
peptides have retained our attention. Of the three, only the
former has been extensively used since a fully described
methology is available for its preparation.4 Examples of
Aziridines as reactive intermediates have drawn conside-
rable interest in the last decade.6 They can be opened by
HO2C
O
O
CO2H
H
N
H
N
N
H
N
O
O
OH
NH2
O
HO2C
R3
S
R1O
O
S
+
X
CO2R4
HX
N
N
H
R2
NH2
methyleneamino X = NH
methyleneoxy X = O
methylenethio X = S
Scheme 1. Preparation of pseudodipeptides through opening of an aziridine by an a-amino, a-hydroxy or a-thio ester.
Keywords: Methyleneamino pseudopeptide; Z-Substituted aziridine opening; Microwaves; b-Amino alcohols; b-Amino acids.
*
Corresponding author. Fax: C33 1 69 07 72 47; e-mail: josiane.thierry@icsn.cnrs-gif.fr
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.02.003

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L. Song et al. / Tetrahedron 62 (2006) 3509–3516
a variety of amine, alcohol, thiol or carbon nucleophiles.
Their reactivity depends greatly on the nature of the
substituent on the nitrogen. Thus, N-sulfonylaziridines
react very readily with nucleophiles.7 Using the chiral
pool, optically active aziridines can be easily obtained from
a-amino alcohols and many reports deal with aziridines
derived from serine. There are, however, fewer papers
dealing with aziridines derived from other amino acids.8
Our purpose was to prepare derivatives, which could be
used directly for peptide synthesis from amino acids having
common protecting groups such as t-butyl and benzyl via
the use of aziridines (Scheme 1).
along with some tertiary amine 5 resulting from the attack of
secondary amine 3 on aziridine 2 as shown in Table 1
(entries 1, 3, 4). In order to avoid the formation of 5, we used
an excess of nucleophile (3 equiv) in the following
reactions.
Microwave-assisted organic synthesis has proven very
efficient in shortening reaction times and increasing yields
of sluggish reactions.11 We used microwave irradiation to
accelerate the reaction of 2 with amines and sealed tubes,
which allowed reaction temperatures higher than the solvent
or reagent boiling points. The screening of other reactions
conditions (different solvents (toluene, THF) or catalysts
(Yb(OTf)3,12 MgClO4, LiBF4, Sc(OTf)313) did not provide
any benefit. However, the amount of LiClO4 could be
reduced to 0.5 equiv without reduction of yield whereas the
use of 0.2 equiv decreased the rate of the reaction. Finally,
the best reaction conditions were found to be 3 equiv of
We first addressed the question of the reactivity of
N-benzyloxycarbonyl protected aziridines by studying
aziridine 2 obtained from Z-Asp(OBut)-ol. This molecule
bearing a tert-butyl ester on the side chain was reacted with
various N-nucleophiles after screening of different mild
reaction conditions. The reaction of 2 with oxygenated and
sulfur nucleophiles was studied afterwards.
†
nucleophile in acetonitrile at 100 8C with 0.5 equiv LiClO4
as catalyst in sealed tubes under microwave irradiation
(Method B).
The aziridine opening reaction with simple amines (Table 1,
entries 1–8) displayed very good regioselectivity except for
benzylhydroxylamine (entry 5) where 3 and 4 were obtained
in a ratio of 4:1, respectively. In all cases, the attack took
place on the less substituted carbon. In some cases (entries 7
and 8), no product 4 resulting from attack at C-2 was
isolated. Microwave activation gave satisfactory results
considerably increasing the rate of the reactions (entries 1
and 2 and entries 3 and 4) while giving better yields. The
reactions were generally completed within 1 h (entries 4,
7–8). The tertiary amine 5 was not obtained when a larger
excess of nucleophile (3 equiv) was used (entries 7 and 8).
2. Results
2.1. Preparation of aziridine 2
Aziridine 2 was synthesized from the amino alcohol Z-L-
Asp(OBut)-ol 1.9 This alcohol, obtained from commercial
Z-L-Asp(OBut)-OH was treated either under Mitsunobu
conditions (PPh3, DEAD, THF) or with methanesulfonyl
chloride in the presence of diisopropylethylamine
(Scheme 2).8 Only the Mitsunobu reaction yielded aziridine
2. The mesylation of alcohol 1 followed by reflux with
DIPEA gave the chloride 7 as the sole product. This chloride
resisted further treatment with various bases (K2CO3,
KHCO3, NaHSO3, AgO, KF, NaH), which gave either no
reaction or decomposition.
The 1, 2-diamino compounds 3 and 4 are valuable synthetic
intermediates as their various protecting groups may be
selectively cleaved before further elaboration.
CO2But
OH
CO2But
Cl
2.2.2. Opening of 2 with other N-nucleophiles and amino
acid esters (entries 9–11). When 2 was treated with the free
bases of glycine tert-butyl ester or lysine methyl ester, 3 was
obtained in good yield as the only regioisomer in the case of
the latter (entry 10) whereas a slight amount of 4 could be
isolated in the case of the former nucleophile (entry 9).
a
ZHN
ZHN
1
X
7
CO2But
b
2
3
Treatment of 2 with NaN3 (2 equiv) in CH3CN/H2O yielded
only one regioisomer 3, along with some elimination
product 6 (29%) (entry 11).
N
Z
2
Scheme 2. Synthesis of aziridine 2 (a): MsCl, DIPEA, THF, reflux, 20 h,
90%; (b): PPh3, DEAD, THF, 0 8C, 30 min, rt, 18 h, 60–90%.
2.3. Ring opening of aziridine 2 with O-nucleophiles
2.2. Ring opening of aziridine 2 with N-nucleophiles
2.3.1. With alcohols (Scheme 3). Whereas, a wealth of
catalysts is known to promote the opening of aziridines with
N-nucleophiles, there are only a few described for their
opening with O-nucleophiles, namely Lewis acids.6 The
most widely used catalyst is boron trifluoride etherate
(BF3$OEt2), though Yb(OTf)3 and Sn(OTf)2 have also
been reported for cases in which the alcohol nucleophile is
used as the solvent. More recently, CAN7b has been used to
catalyze the opening of tosyl aziridines also when using the
alcohol as the solvent.
2.2.1. With simple amines. We first applied conditions
taken from the literature.10 All the reactions were run in
refluxing acetonitrile with 1.2 equiv of nucleophile and
1 equiv of LiClO4† (Method A, entries 1, 3, 5). Most of the
reactions were completed in 22–29 h and were quite
regioselective yielding an approximately 1:10 ratio of 4:3
14
15
† Lithium perchlorate in organic solvents is a potential explosive hazard. It
must be handled in small amounts and with appropriate care.

L. Song et al. / Tetrahedron 62 (2006) 3509–3516
3511
Table 1. Reaction of 2 with N-nucleophiles
CO2But
RNH2
N
R
ZHN
ZHN
ButO2C
RHN
ZHN
+
N
NHR
NHZ
+
+
ButO2C
CO2But
ButO2C
CO2But
LiClO4
Z
NHZ
2
3
4
5
6
Entry
Nucleophile (equiv)
Methoda
Time (h)
Yield (3C4) (%)b
Ratio 4:3
Yield 5 (%)b
1
2
3
4
5
6
7
8
PhCH2NH2 (1.1)
PhCH2NH2 (3)
A
B
A
Ac
A
A
B
B
B
A
B
22
0.5
29
2
22
8 days
0.5
0.3
1
60
85
60
70
76
67
82
88
80
82
47
1:11
1:14
1:11
1:8
3
CH2]CH–CH2–NH2 (1.5)
CH2]CH–CH2–NH2 (1.5)
PhCH2–ONH2 (1.2)
PhCH2OCONHNH2 (2.4)
(OEt)2CHCH2NH2 (3)
p-MeO–PhCH2NH2 (3)
H2NCH2CO2But (3)
H-Lys(Boc)-OMe (1.2)
NaN3 (2)
6
10
1:4
1:14
2
5
d
d
9
10
11
1:26
d
18
1.1
d,e
a
4
Method A: aziridine 2 (0.3 mmol), amine (1.2 equiv) and LiClO (1 equiv) in refluxing acetonitrile (1.5 mL). Method B: aziridine 2 (0.2 mmol), amine
(3 equiv) and LiClO4 (0.5 equiv) in acetonitrile (1 mL) in sealed tubes under microwave irradiation TZ100 8C, power: 40 W.
b Yields of purified products.
c Same conditions as entry 3, except that the reaction mixture in sealed tubes was subjected to microwave irradiation TZ80 8C, power: 40 W.
d No product 4 was isolated.
e Elimination product 6: 29%.
(Scheme 4), the two regioisomers 8b and 9b were obtained
CO2But
in 56% yield and in a 1.5:1 ratio. Keeping in mind our goal
of preparing methyleneoxypseudodipeptides, we also used
as nucleophile the benzyl ester of (2S)-6-(tert-butylcarbox-
ylamino)-2-hydroxy-hexanoic acid 10 obtained through
nitrous deamination of L-lysine followed by protection of
the amino and carboxylic functions with the corresponding
protecting groups (Scheme 5).16 Using the same conditions
as described above, no product corresponding to the
expected mass could be isolated. Numerous attempts to
improve these reaction conditions by varying the ratios of
the reagents or the reaction temperature consistently gave
the same results, that is, a reaction mixture the mass and
NMR spectra of which indicated the loss of a t-butyl group.
Careful HPLC analysis indicated a 7:3 ratio of two products
and allowed the isolation of sufficient amounts for their
identification. 2D NMR analysis established their structures
as being two regioisomers 11 (major) and 12 (minor) as
shown in Scheme 5. Although the Boc group is known to
react in an intramolecular fashion with aziridines,19 there is
no literature precedence for such an intermolecular reaction
to the best of our knowledge.
ZHN
RO
ButO2C
OR
NHZ
ROH
+
ButO2C
N
BF3.OEt2
Z
2
8
9
Scheme 3. Ring opening of 2 with alcohols.
2.3.1.1. Reaction of 2 with benzyl alcohol. A first
experiment run with 2 equiv of benzyl alcohol and 0.5 equiv
of BF3$OEt2 catalyst at 0 8C for 1 h and at room temperature
overnight provided a 46% yield of 8a and 9a in a 1:1 ratio. A
additional experiment run at K30 8C with only 0.1 equiv of
BF3$OEt2 improved the yield (74%) while giving the same
ratio of regioisomers. Different sets of conditions were then
investigated aiming to achieve better regioselectivity in
favor of 8. The use of bentonite yielded modest overall
yields (40%) of 8a and 9a in a 1:1 ratio for reactions run at
130 8C in toluene or 100 8C without solvent under
microwave activation. Montmorillonite KSF or K10 were
not useful as catalysts either at room temperature in CH2Cl2
or in refluxing CH3CN. Silica gel under solvent free
conditions was totally inefficient.
2.3.2. With acetic acid.17 The opening of aziridine 2 with
AcOH (5 equiv) at room temperature for 24 h yielded two
compounds 8c and 9c, which could not be easily separated
on silica gel. Acetylation of the alcohol 1 with acetic
anhydride and DMAP allowed identification of 8c in the
2.3.1.2. With secondary alcohols. We then used methyl
lactate as a model of an a-hydroxy ester nucleophile. In
the presence of BF3$OEt2 (0.2 equiv) as the catalyst
CO2But
ZHN
RO
OR
NHZ
ROH
+
ButO2C
ButO2C
N
BF3.OEt2
Z
2
8a R = CH2Ph
9a R = CH2Ph
8b R= CH3CHCO2Me
Scheme 4. Ring opening of 2 with primary and secondary alcohols.
9b R = CH3CHCO2Me

3512
L. Song et al. / Tetrahedron 62 (2006) 3509–3516
NHBoc
BocHN
NH2
ref.16
CO2H
L-Lys
NHBoc
CO2But
NHZ
CO2But
X
+
S
+
S
S
S
ZHN
S
O
CO2Bzl
CO2Bzl
10
H2N
O
HO
S
BzlO2C
N
CO2But
Z
2
CO2But
H
ZHN
H
O
N
CO2Bzl
OH
O
N
CO2Bzl
OH
ZHN
ButO2C
O
O
11
12
Scheme 5. Opening of 2 with (2S)-2-hydroxy 6-amino hexanoic acid derivative 10.
CO2But
NHZ
CO2But
CO2But
RT, 24 h
+
AcOH
+
AcO
ZHN
N
OAc
Z
2
8c
9c
Scheme 6. Opening of 2 with acetic acid.
HPLC chromatogram of the mixture. The reaction gave the
two regioisomers 8c and 9c in 81% yield and 3:1 ratio
(Scheme 6).
transformations. The opening of 2 with the methyl ester of
H-Lys(Boc)-OMe (entry 10, Table 1) provided the
methyleneaminopseudopeptide
Z-Asp(OBut)J[CH2-
NH]Lys(Boc)-OMe with a good yield and excellent
regioselectivity thereby affording a new route to this kind
of compound. Treatment of 2 with alcohol in presence of
boron trifluoride etherate gave mixtures of regioisomers
whereas the use of a thiol as nucleophile gave only the
product of C-3 attack. The synthesized compounds are
presently being explored as building blocks in pseudopep-
tide synthesis.
2.4. Ring opening of aziridine 2 with S-nucleophiles
There are several reports of such a reaction.7a,18,19 One
describes the opening of a Z-protected serine-derived
aziridine with various thiols used in large excess.18a The
reaction, catalyzed by boron trifluoride etherate, required
severals days to reach completion and was very regioselec-
tive. Crotti et al.18b used thiophenol (3 equiv) under metal
assisted (LiClO4) or basic (Et3N) conditions in aprotic
(CH3CN) or protic (MeOH) solvents to open activated
bicyclic tosyl aziridines. They also observed very good
regioselectivity as did Dauban et al.18c in their study of a Ac
or Z-protected bicyclic aziridine.
3. Experimental
3.1. General
Protected amino acids are from Novabiochem (VWR) and
Senn Chemicals. L-Lysine was purchased from Sigma.
Commercially available reagents were used as received.
Solvents were dried on dry basic alumina prior to use.
Analytical TLC was conducted on Merck 60F-254 silica gel
on precoated aluminum sheets; compounds were visualized
with UV-light or with ninhydrine.
CO2But
ZHN
SCH2Ph
PhCH2SH
ButO2C
N
Et3N
Z
2
13
Scheme 7. Opening of 2 with benzyl mercaptan.
Flash column chromatography was performed using Merck
silica gel 60 (40–63 m). Infrared spectra were recorded on a
Perkin–Elmer Spectrum BX instrument. Optical rotations
were measured on a Jasco polarimeter using a cell of 1 dm-
length path. Mass spectra were obtained using LCT
Micromass (low and high resolution ESC) spectrometer.
1H and 13C NMR spectra were recorded in CDCl3 on a
AM300, AVANCE 300 Bruker 300 MHz. Chemical shifts
are expressed in ppm referenced to the peak of CDCl3,
defined at dZ77.1 (13C). Microanalyses were performed by
the analytical laboratory in Gif. HPLC analysis was
performed on a Waters apparatus consisting of Alliance
gradient controller, an automatic 717 injector, a multi-
wavelength UV detector and a chromatogram analyser.
Analyses were carried out on a C18-Symmetry column
Thus, 2 was treated with benzyl mercaptan under the
conditions described by Maligres7a and Crotti.18b The best
results were obtained under basic conditions with Et3N
(5 equiv) in methanol and benzylmercaptan (3 equiv) at
room temperature or Et3N (0.2 equiv) in THF and
benzylmercaptan (1.05 equiv) at 30 8C. In both cases, the
thioether 13 was obtained after 5 days in 65% yield as a
single regioisomer (Scheme 7).
The present study shows that benzyloxycarbamate-pro-
tected aziridines, although less activated than tosylazir-
idines, are sufficiently reactive to be easily and
regioselectively opened by N-nucleophiles giving 1,
2-diamino compounds suitably protected for further

L. Song et al. / Tetrahedron 62 (2006) 3509–3516
3513
(5 m, 4.6!250 mm). The eluent was a mixture of H2O and
acetonitrile both containing 0.1% trifluoroacetic acid at a
1 mL/min flow rate. The mass spectrometer connected to the
HPLC apparatus was a Waters Micromass ZQ with an ESI
probe. The microwave oven was a Discovere monomodal
apparatus from CEM mWaves (Orsay, France). Experi-
mental parameters were: power: 40 W, temperature: 100 8C.
by the nucleophile (0.45 mmol or as described in Table 1)
were added to the solution. The reaction mixture was
refluxed (except in the case of entry 4 where it was heated at
50 8C) and monitored by TLC. At the end of the reaction
period, the mixture was diluted with CH2Cl2 and washed
with water. The organic layer was washed with brine and
dried over Na2SO4. The crude product was purified by silica
gel column chromatography.
3.1.1. (2R)-2-tert-Butoxycarbonylmethyl-aziridine-1-
carboxylic acid benzyl ester 2. To a solution of
triphenylphosphine (2.62 g, 10 mmol) in THF (25 mL)
cooled in an ice-water bath was added DEAD (1.6 mL,
10 mmol) over 30 min. A solution of Z-Asp(OBut)-ol9b
(1.55 g, 5 mmol) in THF (12.5 mL) was added dropwise
over 1 h at the same temperature. After 1 h at 0 8C, the
reaction mixture was stirred at room temperature for 19 h.
After evaporation of the solvents, the residue was taken up in
CH2Cl2 and separated by column chromatography on silica
gel. Elution with CH2Cl2 gave 0.667 g of pure aziridine and
further elution with CH2Cl2–MeOH (99/1) gave 0.468 g of a
less pure fraction, which was further purified on a silica gel
column with heptane–EtOAc (85/15) yielding 0.344 g of
pure product as a clear oil. Overall yield: 69%. Rf 0.53
(heptane/EtOAc, 7:3); Rf 0.67 (CH2Cl2/ether, 95:5).
Method B. Aziridine 2 (0.2 mmol) was dissolved in
acetonitrile (1 mL) in a heavy-walled tube. LiClO4
(10 mg, 0.1 mmol) followed by the nucleophile
(0.6 mmol) were added to the solution. The tube was sealed
with a teflon cap. The reaction mixture was submitted to
microwave irradiation at TZ100 8C and PZ40 W under
magnetic stirring for at least 20 min in the Discover
microwave apparatus. The reaction was monitored by
TLC. The reaction mixture was diluted with CH2Cl2 and
washed with water. The organic layer was washed with
brine and dried with Na2SO4. Alternatively, the reaction
mixture was evaporated under vacuum. In both cases, the
crude product was purified by silica gel column
chromatography.
3.2.1. With benzylamine (Method A).
[a]D C23.7 (c 0.76, MeOH). MS (EI): m/z 292 (MC%), 236
(MC%K56), 192 (MC%K100), 107, 91, 57. 1H NMR
(300 MHz): 1.43 (s, 9H), 2.08 (d, JZ3.6 Hz, 1H), 2.27
(dd, JZ6.6, 16 Hz, 1H), 2.43 (d, JZ6 Hz, 1H), 2.58 (dd,
JZ6, 16 Hz, 1H), 2.80 (M, 1H), 5.14 (S, 2H), 7.35 (s, 5H);
13C NMR (75 MHz): d 28.14, 31.57, 34.16, 38.88, 68.32,
81.30, 128.29, 128.41, 128.63, 135.82, 163.06, 169.74.
Anal. Calcd for C16H21NO4 C, 65.96, H, 7.27, N, 4.81.
Found: C, 66.09, H, 7.17, N, 4.69.
3.2.1.1. (3S)-tert-Butyl-4-benzylamino-3-benzyloxy-
carbonylamino-butyrate 3a. Yield: 55%, Rf 0.17
(EtOAc/heptane, 4:6). H NMR (300 MHz): 1.43 (s, 9H),
1
1.51 (br s, 1H), 2.50 (m, 2H), 2.75 (m, 2H), 3.79 (s, 2H),
4.10 (m, 1H), 5.12 (s, 2H), 5.48 (m, 1H), 7.31, 7.36 (s, 10H);
13C NMR (75 MHz): 28.0, 38.4, 48.2, 51.8, 53.7, 66.6, 81.1,
127.0, 128.1, 128.4, 128.5, 136.5, 140.1, 155.9, 170.8. MS:
MHC: 399, MHCK56: 243; HRMS Found: C23H31N2O4
399.2272; calcd: 399. 2284; IR (neat): 3330, 2976, 1721,
1249, 1156, 741.
3.1.2. (3S)- tert-Butyl-3-benzyloxycarbonylamino-4-
chloro-butyrate 7. Z-L-Asp(OBut)-ol 19b (3.21 g,
10 mmol) was dissolved in THF (20 mL), DMAP (25 mg,
0.2 mmol) and DIPEA (4 mL, 23 mmol) were added, the
mixture was cooled to K20 8C and then CH3SO2Cl (1 mL,
12 mmol) was added dropwise. The resulting suspension
was warmed gradually to room temperature and then
refluxed at 90 8C for 20 h. The mixture was cooled to
room temperature; EtOAc (30 mL) and NaCl solution
(20 mL) were added; the organic phase was isolated, dried
over Na2SO4 and evaporated under vacuum to leave a syrup,
which was purified by chromatography (EtOAc/pentane,
1:8–1:4) to give 2.61 g (90%) of the chloride derivative Rf
3.2.1.2. 3(R)-3-Benzylamino-4-benzyloxycarbonyl-
amino-butyric acid-tert-butyl ester 4a. Yield: 5%, Rf
0.30 (EtOAc/heptane, 4:6). H NMR (300 MHz): 1.45 (s,
9H), 1.75 (br s, 1H), 2.42 (d, 2H), 3.14 (m, 1H), 3.26 (m,
1H), 3.35 (m, 1H), 3.80 (s, 2H), 5.12 (s, 2H), 5.31 (m, 1H),
7.32, 7.38 (s, 10H); 13C NMR: 28.1, 38.3, 43.4, 50.9, 53.9,
66.7, 67.0, 81.1, 127.1, 128.2, 128.5, 128.6, 136.4, 139.9,
156.3, 171.2. MS: MNaC: 421, MHC: 399, MHCK56: 343;
HRMS C23H31N2O4Na. Found: 421.2096; calcd: 421.2103.
1
3.2.2. With allylamine (Method B).
3.2.2.1. (3S)-tert-Butyl-4-allylamino-3-benzyloxy-
carbonylamino-butyrate 3b. Yield: 62%. [a]D K5 (c
0.9, CHCl3). 1H NMR (300 MHz): 1.43 (s, 9H), 1.67 (br s,
1H), 2.51 (m, 2H), 2.73 (m, 2H), 3.25 (br s, 2H), 4.06 (m,
1H), 5.10 (br sCm, 4H), 5.50 (m, 1H), 5.86 (m, 1H), 7.37 (s,
5H); 13C NMR (75 MHz): 28.0, 38.4, 48.2, 51.6, 52.1, 66.6,
81.1, 116.1, 128.0, 128.3, 128.5, 128.6, 136.5, 155.8, 170.8.
IR (neat): 3338, 2978, 1722, 1537, 1253, 1158, 1054, 919,
919, 738, 697. MS: MNaC: 371, MHC: 349, MHCK56:
293; HRMS C19H29N2O4. Found: 349.2132; calcd:
349.2127.
1
0.51 (EtOAc/heptane, 1:2). [a]D K2.2 (c 1.1, CHCl3). H
NMR (300 MHz): 1.38 (s, 9H), 2.28–2.37 (q, 1H), 2.63–
2.69 (q, 1H), 4.05–4.10 (q, 1H), 4.26–4.36 (m, 1H), 4.47–
4.53 (t, 1H), 5.15 (s, 2H), 7.25–7.33 (m, 5H); 13C NMR
(75 MHz): 28.1, 42.1, 60.2, 72.3, 73.8, 81.0, 128.1, 128.4,
135.2, 163.1, 170.4. IR (neat) 3325, 2977, 1697, 1529, 1367,
1246, 1149, 1043, 955, 840, 737. MS (ES): m/z 350
(MNaC), 294 (MNaCK56); HRMS C16H22ClNO4Na.
Found: 350. 1126; calcd: 350.1135.
3.2. General procedure for opening of 2 with
N-nucleophiles
3.2.2.2. (3R)-tert-Butyl-3-allylamino-4-benzyloxy-
carbonylamino-butyrate 4b. Yield: 8%, Rf 0.54 (EtOAc/
heptane, 4:6). H NMR (300 MHz): 1.43 (s, 9H), 2.39 (d,
1
Method A. Aziridine 2 (0.3 mmol) was dissolved in
acetonitrile (1.5 mL). LiClO4 (31 mg, 0.3 mmol) followed
2H), 2.96–3.40 (m, 4H), 5.03–5.31 (br sCm, 5H), 5.85

3514
L. Song et al. / Tetrahedron 62 (2006) 3509–3516
(m, 1H), 7.37 (s, 5H); 13C NMR (75 MHz): 28.1, 38.3, 41.3,
49.3, 53.7, 66.7, 81.1, 116.5, 128.1, 128.5, 136.5, 157,
171.2. MS: MNaC: 371, MHC: 349, MHCK56:293; IR
(neat): 3338, 1722.
451.2217; calcd: 451.2209; IR (neat): 3335, 2977, 2836,
1723, 1611, 1513, 1247, 1157, 1037, 843, 739.
3.2.7. With glycine tert-butyl ester (Method B).
3.2.7.1. (3S)-tert-Butyl-3-benzyloxycarbonylamino-4-
(tert-butoxycarbonylmethyl-amino)-butyrate 3g. Yield:
77%, Rf 0.23 (EtOAc/heptane, 3:1). [a]D C5.7 (c 1.9,
CHCl3). 1H NMR (300 MHz): 1.4 (s, 9H), 1.43 (s, 9H), 2.48
(m, 2H), 2.76 (m, 2H), 3.35 (AB s, 2H, JZ17 Hz), 4.03 (m,
1H), 5.11 (s, 2H), 5.50 (br, 1H), 7.36 (m, 5H); 13C NMR
(75 MHz): 28.0, 28.1, 38.3, 48.3, 51.6, 52.0, 66.6, 81.0,
81.2, 128.0, 128.4, 136.6, 155.9, 170.7, 171.6. MS (m/z):
445 (MNaC), 423 (MHC), 389 (MNaCKtBu), 367
(MHCKtBu), 311 (MNaCKZ); HRMS C22H34N2O6Na.
Found: 445.2351; calcd: 445.2315; IR (neat): 3338, 2978,
1728, 1530, 1368, 1247, 1157, 1054, 846, 752.
3.2.3. With O-benzylhydroxylamine (Method A).
3.2.3.1. (3S)-tert-Butyl-4-benzyloxyamino-3-benzyloxy-
carbonylamino-butyrate 3c. Yield: 60%, Rf 0.25 (EtOAc/
heptane, 3:7). [a]D C18 (c 1.1, CHCl3). 1H NMR: 1.43 (s,
9H), 2.56 (d, 2H), 3.08 (m, 2H), 4.20 (m, 1H), 4.69 (s, 2H),
5.11 (s, 2H), 5.47 (m, 1H), 5.74 (br s, 1H), 7.34, 7.37 (s,
10H); 13C NMR (75 MHz): 28.0, 38.1, 46.9, 54.3, 66.6,
76.1, 81.1, 128.0, 128.1, 128.4, 128.5, 136.5, 137.5,
155.8, 170.7. MS: MKC: 453, MNaC: 437, MHC: 415,
MNaCK56: 381, MHCK56: 359; HRMS (ES)
C23H30N2O5Na. Found: 437.2028; calcd: 437.2052
3.2.8. With sodium azide (Method B).
3.2.3.2. (3R)-3-Benzyloxyamino-4-benzyloxycarbonyl-
amino-butyric acid-tert-butyl ester 4c. Yield: 16%. H
1
3.2.8.1. (3S)-tert-Butyl-4-azido-3-benzyloxycarbonyl-
amino-butyrate 3h. Yield: 47%, Rf 0.41 (EtOAc/heptane,
1:2). [a]D K3.0 (c 1.2, CHCl3). 1H NMR (300 MHz): 1.45
(s, 9H), 2.54 (d, 2H), 3.51 (m, 2H), 4.16 (m, 1H), 5.13 (s,
2H), 5.45 (m, 1H), 7.38 (br s, 5H); 13C NMR (75 MHz):
28.0, 37.2, 47.9, 53.7, 66.9, 81.7, 128.1, 128.2, 128.5, 136.2,
155.6, 170.1. MS (m/z): 357 (MNaC), 301 (MNaCK56);
HRMS C16H22N4O4Na. Found: 357.1549; calcd: 357.1539;
IR (neat): 3328, 2979, 2103, 1727, 1532, 1454, 1368, 1255,
1157, 1055, 961, 843, 738.
NMR (300 MHz): 1.43 (s, 9H), 2.34 (m, 1H), 2.46 (m, 1H),
3.21 (m, 1H), 3.33 (m, 1H), 4.55 (s, 2H), 4.96 (br s, 1H),
5.10 (s, 2H), 6.04 (br s, 1H), 7.36, 7.37 (s, 10H); 13C NMR
(75 MHz): 28.1, 35.2, 42.2, 56.9, 66.7, 76.6, 81.1, 128.0,
128.1, 128.4, 128.5, 128.6, 136.5, 137.6, 155.8, 171.1. MS:
MKC: 453, MNaC: 437, MHC: 415, MNaCK56: 381,
MHCK56: 359.
3.2.4. With N-benzyloxycarbonylhydrazine (Method A).
3.2.4.1. 3(S)-4-(N-Benzyloxycarbonyl-hydrazino)-3-
benzyloxycarbonylamino-butyric acid-tert-butyl ester
3d. Yield: 63%, Rf 0.25 (EtOAc/heptane, 4:6). [a]D C53
(c 1, CHCl3). 1H NMR (300 MHz): 1.42 (s, 9H), 2.32–2.61
(dd, 2H), 2.75–3.06 (m, 2H), 4.12 (m, 2H), 5.13 (m, 5H),
5.52 (m, 1H), 6.83 (m, 1H), 7.37 (10H); 13C NMR
(75 MHz): 28.1, 38.0, 46.3, 54.1, 54.6, 66.8, 67.0, 81.3,
128.0, 128.1, 128.2, 128.3, 128.4, 128.5, 136.1, 136.4,
156.6, 157.2, 170.7; HRMS (ES) C24H31N3O6Na. Found:
480.2134; calcd: 480.2111.
3.2.9. With H-Lys(Boc)-OMe (Method B).
3.2.9.1. (2S)-Methyl-2-(2-benzyloxycarbonylamino-3-
tert-butoxycarbonyl-propylamino)-6-tert-butoxycarbon-
ylamino hexanoate 3i. Yield: 83%, Rf 0.23 (EtOAc/
heptane, 4:6); Rf 0.28 (CH2Cl2/MeOH, 98:2). 1H NMR
(300 MHz): 1.46 (s, 9H), 1.47 (s, 9H), 2.37 (d, 2H, JZ
6.3 Hz), 3.08 (m, 1H), 3.25 (m, 2H), 3.33 (s, 2H), 5.12 (s,
2H), 5.49 (m, 1H), 7.35 (m, 5H); 13C NMR (75 MHz): 28.0,
38.8, 43.5, 49.1, 54.5, 66.6, 81.0, 81.4, 128.1, 128.5, 136.6,
156.6, 170.7, 171.6. IR (neat): 3342, 2975, 2928, 1728,
1530, 1366, 1236, 1145, 843, 751. MS (m/z): 574 (MNaC),
552 (MHC); HRMS C28H46N3O8Na. Found: 552.3286;
calcd: 552.3285.
3.2.5. With 2,2-diethoxyethylamine (Method B).
3.2.5.1. (3S)-tert-Butyl-3-benzyloxycarbonylamino-4-
(2,2-diethoxy-ethylamino)-butyrate 3e. Yield: 82%, Rf
1
0.22 (EtOAc/heptane, 3:1). [a]D C2.2 (c 1.3, CHCl3). H
3.3. General procedure for opening of aziridine 2 with
O-nucleophiles.
NMR (300 MHz): 1.22 (t, 6H, JZ7.1 Hz), 1.43 (s, 9H), 2.49
(m, 2H), 2.76 (m, 4H), 3.53 (m, 2H), 3.68 (m, 2H), 4.08 (m,
1H), 4.54 (t, 1H), 5.10 (s, 2H), 5.45 (br, 1H), 7.34 (m, 5H);
13C NMR (75 MHz): 15.4, 28.0, 38.3, 48.3, 52.1, 52.3, 62.3,
66.6, 81.01, 102.0, 128.0, 128.5, 136.6, 155.9, 170.7. MS
(m/z): 425.2 (MHC); IR (neat): 3332, 2976, 2930, 1725,
1530, 1455, 1368, 1250, 1157, 1061, 844, 738
3.3.1. With benzyl alcohol. BF3$OEt2 (6 mL, 0.1 equiv)
was added to a solution of 2 (146 mg, 0.5 mmol) and benzyl
alcohol (104 mL, 2 equiv) in dry CHCl3 (6 mL) cooled to
K30 8C. After 3 h 30 min stirring at this temperature, the
reaction mixture was diluted with CH2Cl2 and washed with
a 5% NaHCO3 solution. The organic layer was then washed
with H2O, brine and dried on Na2SO4. Evaporation under
reduced pressure yielded an oil (217 mg) containing 8a, 9a
and benzyl alcohol, which was separated on a silica gel
column. Elution with heptane/EtOAc 8:2 gave pure 8a
(19 mg), a mixture of 8a and 9a (107 mg) and pure 9a
(27 mg). Overall yield: 74%.
3.2.6. With p-methoxybenzylamine (Method B).
3.2.6.1. (3S)-tert-Butyl-3-benzyloxycarbonylamino-4-
(4-methoxy-benzylamino)-butyrate 3f. Yield: 88%, Rf
1
0.31 (EtOAc/heptane, 5:2). [a]D K0.6 (c 1.5, CHCl3). H
NMR (300 MHz): 1.43 (s, 9H), 2.50 (m, 2H), 2.74 (m, 2H),
3.74 (s, 2H), 3.82 (s, 3H), 4.09 (m, 1H), 5.11 (s, 2H), 5.44
(br, 1H), 6.79 (d, 2H, JZ8.6 Hz), 7.15 (d, 2H, JZ8.6 Hz),
7.38 (m, 5H); 13C NMR (75 MHz): 28.0, 38.4, 48.1, 51.7,
53.1, 55.2, 66.6, 81.0, 113.8, 128.0, 128.5, 129.2, 132.3,
136.6, 155.9, 158.7, 170.8. MS (m/z): 451 (MNaC), 429
(MHC), 373 (MHCK56); HRMS C24H31N2O5Na. Found:
3.3.1.1. (3S)-tert-Butyl-3-benzyloxycarbonylamino-4-
benzyloxy-butyrate 8a. Rf 0.53 (heptane/EtOAc, 7:3). [a]D
K8 (c 1.1, MeOH).1H NMR (300 MHz): 1.38 (s, 9H), 2.53
(d, 2H, JZ6.3 Hz), 3.51 (m, 2H), 4.19 (m, 1H), 4.48 (s, 2H),
5.07 (s, 2H), 5.38 (br d, 1H), 7.32 (br s, 10H); 13C NMR

L. Song et al. / Tetrahedron 62 (2006) 3509–3516
3515
(75 MHz): 28.1, 37.5, 48.1, 66.8, 71.1 73.3, 81.1, 127.8,
127.7, 128.5, 128.2, 128.6, 136.6, 138.0, 155.8, 170.7. MS
(m/z): 438 (MKC), 422 (MNaC), 366 (MNaCK56), 266
(MHCK134); IR (neat): 3335, 2977, 1732, 1538, 738, 697.
NaHCO3 solution. The organic layer was then washed with
H2O, brine and dried on Na2SO4. Evaporation under
reduced pressure yielded an oil (207 mg). The residue was
purified by flash chromatography with heptane–EtOAc (7/3)
to remove excess 10. Elution with methanol and evaporation
of methanol fractions gave a mixture of 11 and 12 (79 mg)
as a transparent oil, which could only be separated by
HPLC. Analysis of the mixture showed a 7:3 ratio of 11 and
12. Elution on a C18-symmetry column was isocratic with a
mixture of H2O and acetonitrile (1/1) both containing 0.1%
trifluoroacetic acid at a 1 mL/min flow rate. tR (11)Z
23.0 min, tR (12)Z24.1 min.
3.3.1.2. (3S)-tert-Butyl-3-benzyloxy-4-benzyloxy-
carbonylamino-butyrate 9a. Rf 0.45 (heptane/EtOAc,
7:3). [a]D C1 (c 1.1, MeOH). H NMR (300 MHz): 1.41
1
(s, 9H), 2.50 (AB s, 2H, JZ6.3 Hz), 3.25 (m, 1H), 3.39 (m,
1H), 3.94 (m, 1H), 4.58 (AB s, 2H, JZ11 Hz), 5.05 (s, 3H),
7.31 (br s, 10H); 13C NMR (75 MHz): 28.2, 39.0, 43.9, 66.8,
72.0 75.1, 81.1, 127.9, 128.2, 128.6, 136.6, 138.1, 156.6,
170.4. MS (m/z): 438 (MKC), 422 (MNaC), 400 (MHC),
366 (MNaCK56), 344 (MHCK56), 266 (MHCK134); IR
(neat): 3343, 2976, 1718, 1540, 737, 697.
Chromatography under the same conditions provided each
compound as a pure sample (2 mg) allowing 2D NMR
analysis. Both compounds had an identical ESI mass
spectum corresponding to MNaCK56: 595.
3.3.2. With (S)-methyl lactate. To a cold solution of
BF3$OEt2 (9 mL, 0.2 equiv) in CHCl3 (0.4 mL) was added
methyl lactate (72 mL, 2 equiv) followed by a solution of 2
(111 mg, 0.4 mmol) in CHCl3 (1.2 mL). After 1 h stirring in
the ice bath, the reaction mixture was diluted with CH2Cl2
and washed with a 5% NaHCO3 solution. The organic layer
was then washed with H2O, brine and dried on Na2SO4.
Evaporation under reduced pressure yielded an oil (157 mg)
containing 8b and 9b. MS-HPLC analysis of the crude
product indicated that the 2 regioisomers were present (tRZ
11.79 and 12.35 min) in a 1.5–1 ratio. The analysis was
performed on a Waters Symmetry column. The eluent was a
gradient of H2O and acetonitrile both containing 0.1% TFA
starting from 35% acetonitrile to 100% over 20 min at a
1 mL/min flow rate.
Compound 11. 13C NMR (100 MHz) in DMSO-d6: 21.9,
28.0, 29.4, 33.7, 38.4, 40.7, 44.3, 66.8, 67.3, 70.2, 81.2,
128.1, 124.4, 128.5, 128.6, 128.7, 135.1, 136.4, 155.7,
156.5, 155.7, 169.2, 174.9.
3.4. Opening of 2 with benzyl mercaptan.
3.4.1. (2S)-tert-Butyl 3-(benzyloxycarbonylamino)-
4-(benzylthio) butyrate propanoate 13. (a) Benzyl
mercaptan (37 mL, 1.05 equiv) was added to a solution of
aziridine 2 (87 mg, 0.3 mmol) and Et3N (8 mL, 0.2 equiv) in
THF (0.3 mL). The reaction was run under argon for 5 days
at 30 8C. The reaction mixture was diluted with ether and
the organic phase was washed with water, brine and dried on
Na2SO4. Evaporation under reduced pressure yielded an oil
(121 mg). The residue was purified by flash chromatography
with heptane–EtOAc (8/2) to give 13 (81 mg) as an oil.
3.3.3. With acetic acid. Acetic acid (86 mL, 5 equiv) was
added to a solution of aziridine 2 (87 mg, 0.3 mmol) in
CH2Cl2 (0.9 mL). The solution was stirred under argon
during 24 h. The reaction mixture was diluted with CH2Cl2
and washed with a 5% NaHCO3 solution. The organic layer
was washed with H2O, brine and dried on Na2SO4.
Evaporation under reduced pressure afforded 102 mg of a
yellow oil. The crude product was separated by flash
chromatography. Elution with heptane/EtOAc 75/25 did not
allow separation of the two regioisomers and gave 95 mg of
(b) Benzylmercaptan (105 mL, 3 equiv) was added to a
solution of aziridine 2 (87 mg, 0.3 mmol) and Et3N (208 mL,
5 equiv) in methanol (0.3 mL). The reaction was run under
argon for 5 days at room temperature. The reaction mixture
was diluted with ether and the organic phase was washed
with water, brine and dried on Na2SO4. Evaporation under
reduced pressure yielded an oil (176 mg). The residue was
purified by flash chromatography with heptane–EtOAc (8/2)
to give 13 (82 mg).
1
a mixture of 8c and 9c. H NMR analysis showed a of 3:1
ratio of 8c:9c. A second flash chromatography using
petroleum ether–acetone (9:1) gave pure 8c (8 mg) and a
mixture of 8c and 9c.
Rf 0.53 (EtOAc/heptane, 3:7). [a]D C10.8 (c 1.6, CHCl3).
1H NMR (300 MHz): 1.43 (s, 9H), 2.49–2.69 (m, 4H), 4.74
(br s, 2H), 4.14 (m, 1H), 5.12 (s, 2H), 5.42 (1H), 7.36 (m,
10H); 13C NMR (75 MHz): 28.0, 35.4, 36.5, 38.6, 47.6,
66.7, 81.3, 127.1, 128.0, 128.1, 128.5, 128.9, 136.5, 138.0,
155.6, 170.5. MS (m/z): 438 (MNaC), 382 (MNaCK56);
HRMS C23H29NO4NaS. Found: 438.1675; calcd: 438.1715.
3.3.3.1. (3S)-4-Acetoxy-3-benzyloxycarbonylamino-
butyric acid tert-butyl ester 8c. Rf 0.31 (EtOAc/heptane,
3:7). H NMR (300 MHz): 1.43 (s, 9H), 2.05 (s, 3H), 2.52
1
(d, JZ5.9 Hz, 2H), 4.15 (m, 2H), 4.28 (m, 1H), 5.11 (s, 2H),
5.41 (d, JZ9 Hz, 1H), 7.35 (s, 5H); 13C NMR (75 MHz):
20.7, 28.0, 37.1, 47.2, 65.1, 66.8, 81.5, 127.1, 128.1, 128.5,
136.3, 155.3, 155.6, 170.0, 170.7. MS (m/z): 390 (MKC),
374 (MNaC), 318 (MNaCK56).
Acknowledgements
3.3.4. With benzyl (2S)-6-(tert-butyloxycarbonyl-
amino)-2-hydroxy-hexanoate 10. BF3$OEt2 (52 mL,
0.2 equiv) in dry CHCl3 (0.2 mL) was added to a solution
of 2 (65 mg, 0.22 mmol) and alcohol 10 (151 mg, 2 equiv)
in dry CHCl3 (0.6 mL) cooled to 0 8C. After 15 min stirring
at this temperature and 4 h at room temperature, the reaction
mixture was diluted with CH2Cl2 and washed with a 5%
The authors thank M.-T. Adeline and V. Pavlosky for
isolation of regioisomers 11 and 12 and various analytical
analyses. They also are grateful to M.-T. Martin for
determination of structures of 11 and 12 by NMR and to
Drs. R. Dodd and P. Dauban for careful reading of the
manuscript.

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L. Song et al. / Tetrahedron 62 (2006) 3509–3516
9. (a) Amino acids and Peptides are Abbreviated and Designated
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