Synthesis of methyleneaminodipeptides via ring opening of a 2-(t-butoxycarbonylmethyl)aziridine derivative

Article abstract of DOI:10.1016/j.tetlet.2003.11.047

The reactivity of 2-(t-butoxycarbonylmethyl)aziridine-1-carboxylic acid benzyl ester has been studied with various N-nucleophiles. The ring-opening reaction was always regioselective, the nucleophile attacking preferentially the less hindered carbon of th

Full text of DOI:10.1016/j.tetlet.2003.11.047

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 821–823
Synthesis of methyleneaminodipeptides via ring opening of a
2
-(t-butoxycarbonylmethyl)aziridine derivative
*
Josiane Thierry and Vincent Servajean
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France
Received 22 August 2003; revised 30 October 2003; accepted 7 November 2003
Abstract—The reactivity of 2-(t-butoxycarbonylmethyl)aziridine-1-carboxylic acid benzyl ester has been studied with various
N-nucleophiles. The ring-opening reaction was always regioselective, the nucleophile attacking preferentially the less hindered
carbon of the aziridine. The reaction was used to prepare a methyleneamino pseudodipeptide using the a-amine of a lysine ester.
Ó 2003 Elsevier Ltd. All rights reserved.
During the course of our program on the synthesis of
1
analogues of the tetrapeptide AcSDKP, an inhibitor of
CO Bu
t
ZHN
t
RHN
2
NHR
NHZ
RNH
2
+
t
Bu O
2
C
Bu O C
2
the hematopoietic stem cells, we had to prepare
pseudopeptides of the methyleneoxy and methylene-
amino types. To reach this goal, we envisioned using a
single intermediate, which could yield both types of
pseudopeptides, and that the aziridine derived from the
b-amino alcohol Asp-ol could be such an intermediate.
N
1
2a R = PhCH
2
3aR = PhCH
2
Z
b
c
d
e
CH
PhCH O
PhCH
Lys(Boc)-OMe
2
=CHCH
2
b
c
d
e
CH
PhCH 2
PhCH OCONH
Lys(Boc)-OMe
2 2
=CHCH
2
O
2
OCONH
2
Scheme 1. Ring-opening reactions of aziridine 1 with N-nucleophiles.
Aziridines have recently attracted considerable attention
2
in synthesis, as they are reactive intermediates, which
But
But
CO
2
But
CO
CO
2
CO
2
can be opened with a variety of nucleophiles such
as amines, alcohols, thiols or carbanionic species.
Although most reports deal with activated aziridines,
mainly sulfonamides, we considered using a carbamate-
protected aziridine as the required synthon. The reac-
tivity of the aziridine 1 has been explored with simple
a
b
OH
ZHN
2
H
ZHN
N
Z
Z= PhCH OCO
1
2
Scheme 2. Synthesis of aziridine 1 (a) (i): isobutyl chloroformate,
N-methylmorpholine, )15 °C, (ii): NaBH , H O, )10 °C; (b) PPh
DEAD, THF, 30 min, 0 °C, 18 h, rt, 60–90% for two steps.
4
2
3
,
amines and with the
OMe (Scheme 1).
L-lysine derivative H-L-Lys(Boc)-
The results of the reaction of 1 with various amines
5
The aziridine 1 was obtained from the amino alcohol
t
according to the conditions reported in the literature
are recorded in Table 1.
Z-
Z-
L
-Asp(OBu )-ol, itself derived from the amino acid
t
3
L
-Asp(OBu )-OH, in 90% yield by way of a Mits-
4
unobu reaction (Scheme 2).
All the reactions were run in acetonitrile with 1.2 equiv
of nucleophile and 1 equiv of LiClO , (except for entry
4
d, where 2.4 equiv of benzylcarbazate were used), at
80 °C (except for entry b where the reaction was run at
Keywords: Pseudopeptides methyleneamino; Aziridine opening; Micro-
waves; Lithium perchlorate; Solvent-free reaction.
Note: Lithium perchlorate in organic solvents is a potential explosive
hazard. It must be handled in small amounts and with appropriate
care.
*
Corresponding author. Tel.: +1-69-823126; fax: +1-69-07-7247;
e-mail: josiane.thierry@icsn.cnrs-gif.fr
0
040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.047

822
J. Thierry, V. Servajean / Tetrahedron Letters 45 (2004) 821–823
Table 1. Reactivity of 1 towards N-nucleophiles
CO
2
But
ZHN
t
RHN
Bu O C
ZHN
Bu O C
R
NHR
RNH
2
NHZ
N
+
+
Bu O
2
C
t
t
CO But
2
N
LiClO
4
2
2
Z
NHZ
1
2
3
4
a
a
Entry
R
Reaction time (h)
Yield 2 + 3 (%)
Ratio 3:2
Yield 4 (%)
a
b
c
d
e
PhCH
2
22
29
60
60
1:11
1:11
1:4
3
b
CH
2
@CH–CH
2
6
PhCH
PhCH
2
O
OCONH
-Lys(Boc)-OMe
22
8 days
18
61
63
83
––
––
5
2
1:14
c
––
L
a
b
c
Isolated yield of purified products. Yields have not been optimized.
Aziridine 1 (6%) was recovered.
3e was not isolated.
4
by silica gel flash chromatography were characterized
by IR, H NMR, C NMR, and mass spectroscopy.
5 °C). The compounds obtained through purification
secondary amine 2 on 1 and their formation could be
avoided by using an excess of the original amine
nucleophile.
1
13
6
All the reactions were slow and gave satisfactory yields.
The regioselectivity was in most cases high yielding a
large excess of 2, the regioisomer resulting from the
attack of the nucleophile on the least substituted carbon.
The best yield was obtained with the lysine derivative
The aziridine 1 was also treated with benzylamine
(1.2 equiv) in THF in the presence of Yb(OTf)
3
(0.1 equiv) at 45 °C according to the conditions reported
by Meguro et al. The reaction was rather slow (65 h)
7
and yielded a mixture of regioisomers (72%) in a ratio
(3a:2a) of 1:8 along with a 12% yield of 4a.
(
entry e). This reaction yielded compound 2e (Z-
t
L
-
2
Asp(OBu )W(CH NH)-L-Lys(Boc)-OMe), methylene-
amino pseudodipeptide, which can be further elongated
as the protecting groups are orthogonal. The 1,2-di-
amines 2a–d are interesting synthetic intermediates as
they are b-amino acids substituted at C-4.
In order to achieve improved regioselectivity, the use
of a solid support was considered. In another set of
experiments, aziridine 1 was treated with 1.1 equiv of
benzylamine on different solid supports: alumina (acti-
vated or unactivated), silica gel, or Bentonite under
solvent-free conditions (Table 2). The reaction was run
in most cases at room temperature.
Small amounts of compounds 4a, 4b, and 4e were iso-
lated. They are formed by the attack of the respective
Table 2. Ring-opening of 1 under solvent-free conditions with benzylamine
O
O
O
OBut
OBut
OBut
Benzylamine (1.1 eq.)
2
PhH CHN
N
Z
ZHN
NHZ
3a
R.T.
2
NHCH Ph
2
a
a
b
Entry
Support
Conditions
9 d
2.7 d, rt, MW, 3 h
Yield 2a + 3a (%)
Ratio 3a:2a
c
c
1
2
3
4
5
6
7
Activated alumina
Activated alumina
Alumina
53
34
60
46
46
55
1:9
d
e
––
6.6 d
8.6 d
1:11
1:5
Silica gel
Silica gel
e
4.8 d, rt, MW, 3 h
8.6 d
1:2.4
d
Bentonite
Bentonite
––
1:11
e
f
MW, 1 h
60
a
Support (600 mg/mmol): Alumina for chromatography (70–230 mesh) from Merck; Silica gel for chromatography (230–400 mesh) from Merck;
Bentonite from Aldrich. Aziridine 1 was dispersed on the solid support along with benzylamine (1.1 equiv). The products were extracted from the
2 2
solid support by triturating the solid with CH Cl /MeOH 80/20.
b
c
Isolated yield of purified products. Yields have not been optimized.
Neutral alumina was activated by heating in an oven at 550 °C for 18 h.
Product 3a was not isolated.
d
e
Microwave experiments were conducted in sealed tubes with a monomodal apparatus: Discover from CEM l Waves (Orsay, France). Experiment
parameters were: power: 40 W, temperature: 80 °C.
f
4a (4%) was also isolated.

J. Thierry, V. Servajean / Tetrahedron Letters 45 (2004) 821–823
823
All the reactions proceeded very slowly, taking several
days to reach completion. The use of activated alumina
yielded a mixture of regioisomers 2a and 3a (53%).
Unactivated alumina gave a comparable yield and a
similar ratio of 2a and 3a (entries 1 and 3). Activation
of the reaction with microwaves for 3 h resulted in a
lower yield but only 2a was obtained (entry 2). The
same phenomenon was not observed when the reaction
mixture was exposed on silica gel to microwaves since
the same overall yield of 2a and 3a was obtained.
However, it is noteworthy that the ratio of 3a:2a was
significantly different (entries 4 and 5). Bentonite seems
to be the most appropriate support; the reaction was
considerably faster when exposed to microwaves while
the same yield of regioisomers and a good regioselec-
tivity in favor of 2a was obtained in both cases (entries
The solvent-free reaction of 1 with benzylamine on
Bentonite under microwave activation gave the same
results as the classical reaction but in a much shorter
time and represents a significant improvement in the
procedure.
References and notes
1. Gaudron, S.; Adeline, M.-T.; Potier, P.; Thierry, J.
J. Med. Chem. 1997, 40, 3963–3968.
2
. (a) McCoull, W.; Davis, F. A. Synthesis 2000, 1347–1365;
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Chemistry; Springer Verlag: Berlin, Heidelberg, 2001; Vol.
(
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16, pp 93–124; (c) Sweeney, J. B. Chem. Soc. Rev. 2002, 31,
247–258.
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and 7).
3
J. Tetrahedron Lett. 1991, 32, 923–926.
4. Mitsunobu, O. Synthesis 1981, 1–28.
5. Anaya de Parrodi, C.; Vasquez, V.; Quintero, L.; Juaristi, E.
Synth. Commun. 2001, 31, 3295–3302.
The ring-opening reaction of aziridine 1 with different
N-nucleophiles demonstrates good regioselectivity, the
major regioisomer resulting from the attack on the
secondary carbon. The compounds obtained through
this reaction are valuable polyfunctionalized intermedi-
6
7
. Lake, F.; Moberg, C. Eur. J. Org. Chem. 2002, 3179–3188.
. Meguro, M.; Asao, N.; Yamamoto, Y. Tetrahedron Lett.
1994, 35, 7395–7398.
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ates. Some of them (2a–b, 2e, 3a–b) may be further
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Ed. 1998, 37, 2580–2627.
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J.; Atras, B.; Lever, A. F. Nature (London) 1982, 299, 555–
transformed as they are orthogonally protected. We
have presented here a new route to methyleneamino
pseudopeptides, which represents a valid alternative to
9
the existing methology. The conditions are mild enough
to be applied to most a-amino esters or highly func-
tionalized amines as nucleophiles.
5
57; (b) Martinez, J.; Bali, J.-P.; Rodriguez, M.; Castro, B.;
Magous, R.; Laur, J.; Lignon, M.-F. J. Med. Chem. 1985,
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