A general approach for the synthesis of 5-substituted-4-amino-pyrrolidin-2-ones and 5-substituted-4-amino-3-pyrrolin-2-ones

Article abstract of DOI:10.1016/j.tetlet.2009.03.003

Short stereoselective syntheses of both 5-substituted-4-amino-pyrrolidin-2-ones and 5-substituted-4-amino-3-pyrrolin-2-ones from natural α-amino acids are described.

Full text of DOI:10.1016/j.tetlet.2009.03.003

Tetrahedron Letters 50 (2009) 2402–2404
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A general approach for the synthesis of 5-substituted-4-amino-pyrrolidin-2-
ones and 5-substituted-4-amino-3-pyrrolin-2-ones
a
a
b
Sergio Pinheiro a, , Ronaldo C. da Silva Júnior , Acácio Silva de Souza , José Walkimar de M. Carneiro ,
*
Estela M. F. Muri c, O. A. C. Antunes d
a Departamento de Química Orgânica, Instituto de Química, Universidade Federal Fluminense, Outeiro de S. João Batista s/n Centro 24020-141, Niterói, RJ, Brazil
b Departamento de Química Geral e Inorgânica, Instituto de Química, Universidade Federal Fluminense, RJ, Brazil
c Faculdade de Farmácia, Universidade Federal Fluminense, RJ, Brazil
d Instituto de Química, Universidade Federal do Rio de Janeiro, CT, Bloco A 641, 21941-970 Rio de Janeiro, RJ, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Short stereoselective syntheses of both 5-substituted-4-amino-pyrrolidin-2-ones and 5-substituted-4-
Received 26 January 2009
Revised 28 February 2009
Accepted 2 March 2009
Available online 6 March 2009
amino-3-pyrrolin-2-ones from natural
a
-amino acids are described.
Ó 2009 Elsevier Ltd. All rights reserved.
Cyclic diamino acids derivatives like 4-amino-pyrrolidin-2-ones
and 4-amino-3-pyrrolin-2-ones are recognized to be of biological
importance ( Fig. 1). Indeed, 4-amino-pyrrolidin-2-ones are de-
scribed as peptidomimetics,1 as structural sub-units of natural
lin-2-one 2 and the benzotiazepine 3 have, respectively, herbi-
cidal9 and antibacterial activities.11
products,2 as useful precursors of
c
-lactam bridged dipeptides,3
and in the structures of renin-inhibiting peptides.4 In addition, 4-
amino-pyrrolidin-2-ones are important intermediates for the syn-
theses of 3-aminopyrrolidines, which are ubiquitous systems
found in natural products as alkaloids and in a diverse number of
compounds displaying an impressive range of biological activities.5
Also, 3-aminopyrrolidines were recently employed as useful
organocatalysts in asymmetric Mannich reactions.6 Furthermore,
4-amino-pyrrolidin-2-ones provide an excellent synthetic entry
H2N
H2N
O
4
4
R
O
R
O
R
O
5
N
H
5
N
H
N
H
4-aminopyrrolidin-2-ones 4-aminopyrrolin-2-ones tetramic acids
Figure 1. 4-amino-pyrrolidin-2-ones and 4-amino-3-pyrrolin-2-ones.
into b,c-diaminoacids, that have been subject of growing interest
due to their biological properties.7,8
MeHN
MeO
Cl
Although natural products containing the 4-amino-3-pyrrolin-
2-one unit (b-amino-unsaturated lactams) are unknown, to the
best of our knowledge, some compounds of this class have been
of interest due to their biological properties as herbicidal,9 for
the treatment of epilepsy, anxiety, and tension,10 as antibacterial11
or hypoglycemic,12 and as dipeptide analogues.13
H2N
HO
HO2C
R
H
N
O
N
H
O
N
Bn
Some examples are shown in Figure 2. While lactams 1 are sub-
units of antifungal and cytotoxic natural cyclic hexapeptides
microsclerodermins,2 the highly active antipsychotic agent nemo-
napride has been commercialized under its racemic form.14 Pep-
tides containing 3-amino-deoxystatine have better renin
inhibitory activities than those derived from statine,8 which is a
component of the aspartyl protease inhibitor pepstatin. The pyrro-
1
(+)-nemonapride
H2N Ph
R = H, OH
Cl
NH2
S
CO2H
N
H
O
N
NH2
(3S, 4S)-3-aminodeoxystatine
O
N
H
3
2
* Corresponding author. Tel.: +55 21 26292369; fax: +55 21 26292129.
E-mail address: spinuff@gmail.com (S. Pinheiro).
Figure 2. Some biologically active b-amino lactams.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.003

S. Pinheiro et al. / Tetrahedron Letters 50 (2009) 2402–2404
2403
In spite of the growing interest in both 4-amino-pyrrolidin-2-
O
HON
R
H2N
R
H2N
R
i
ii
ones and 4-amino-3-pyrrolin-2-ones, few routes have been de-
scribed to the stereoselective syntheses of these kind of com-
pounds. Indeed, the few methods reported for the synthesis of 4-
amino-3-pyrrolin-2-ones suffer from the lack of generality and in-
clude nucleophilic substitution of tetramic acids derivatives by
amines,10,12,13 ring closure from azadienes,15 ring expansion of azi-
rines,16 Dieckmann cyclization,17 and conjugate addition of azide
to an unsaturated lactam followed by treatment with trifluoroace-
tic acid,18 among other methods.19
Typical routes to 5-substituted-4-amino-pyrrolidin-2-ones
described so far include alkyl radical addition-cyclization of oxime
ethers,20 the Beckmann rearrangement of oximes,21 the intramolec-
ularrearrangementof b-lactams,22 and conjugate addition of amines
to both enoates23 and to bicyclic pyrrolidin-2-ones (unsaturated
lactams).5c,24 More recently, a multistep asymmetric synthesis of
iii
R
O
O
O
O
N
Boc
N
Boc
N
Boc
N
Boc
4a-e
7a-e
6a-e
6a: 96%
6b: 85%
6c: 98%
6d: 92%
6e: 87%
5a-e
4a and 7a: R = i-Bu
4b and 7b: R = Bn
4c and 7c: R = Me
4d and 7d: R = s-Bu
5a: 91%
5b: 90%
5c: 85%
5d: 89%
5e: 87%
4e and 7e: R = (CH2)2SMe
Scheme 2. Reagents and conditions: (i) NH2OHÁHCl, NaHCO3, Na2SO4, CH2Cl2, rt,
48 h; (ii) MoO3, NaBH4, MeOH, rt, 6 h; (iii) NaBH3CN, HOAc, rt, 2 h.
anti-5-isopropyl-4-amino-pyrrolidin-2-ones from
a-amino acids
The stereochemical assignments of the newly created stereo-
genic centers in 5a–e were made on the basis of nOe NMR spectra
and the proposed absolute configurations are in agreement with
the products from reduction of 4a–e described in the literature.26
For example, starting from H4 of 2b, a significant nOe was observed
with H5 (9.7%), which implies a syn relationship between the sub-
stituents in positions 4 and 5. Next, based on the preparation of
dipeptide analogues derived from 4-alkylamino-pyrrolin-2-ones
from tetramic acids and protected amino acids,13 we turned atten-
tion to synthesize 5-substituted-4-amino-3-pyrrolin-2-ones 6a–e
from tetramic acids (Scheme 2). Reactions of 4a–e with hydroxyl-
amine furnished the corresponding oximes 7a–e (as mixtures of E-
and Z-isomers)30 as yellow oils in quantitative yields and high
purities. The subsequent reactions of 7a–e with NaBH4 in the pres-
was described.25 Although tetramic acids can be considered as
attractive starting materials for the stereoselective syntheses of
5-substituted-4-amino-3-pyrrolidin-2-ones, Tønder and co-work-
ers reported that the direct reductive amination of tetramic acids
with amino acids failed to reach these heterocyclic compounds.13
In fact, they had to employ a stepwise procedure comprising enam-
ine formation from tetramic acids and protected amino acids
followed by hydrogenation to prepare peptide derivatives of syn-5-
alkyl-4-amino-pyrrolidin-2-ones.
Herein we are pleasant to report a procedure for reductive ami-
nation of tetramic acids with ammonium hydroxide/NaBH3CN as
well as an approach based on reduction of oximes for the stereo-
controlled syntheses of syn-5-substituted-4-amino-pyrrolidin-2-
ones and 5-substituted-4-amino-3-pyrrolin-2-ones from natural
31
ence of MoO3 led to good yields of the corresponding imines,
a-amino acids.
which are in equilibrium with the 5-substituted-4-amino-3-pyrro-
lin-2-ones 6a–e.15 Also, in these cases the compounds 6a–e were
sufficiently pure to be used in the next step without further puri-
fication. Upon reduction with NaBH3CN in HOAc, the pyrrolin-2-
ones 6a–e produced the corresponding lactams 5a–e in good yields
and high purity.32
In conclusion, although both methods disclosed in this Letter
are limited to producing primary amines, they allowed an easy
production of 5-substituted-4-amino-pyrrolidin-2-ones and 5-
The known tetramic acids 4a–e were easily prepared in multi-
gram scales and high overall yields without further purificationfrom
N-protected natural a-amino acids using the Meldrum’s acid con-
densation method, as already described (Scheme 1).26 Attempts to
perform one-pot direct reductive amination of 4a using NaBH3CN
in AcONH4 or aniline,27 NaBH3CN/ZnCl2/piperidine,28 and NaB-
29
H(OAc)3/AcONH4 failed to produce the 4-amino-pyrrolidin-2-
one 5a, suggesting a slow formation of the imine intermediate from
ammonia and more substituted amines in a similar situation to that
described by Tønder and co-workers.13a This way, we employed an
alternative stepwise protocol based on imine formation followed
by in situ reduction to convert easily 4a–e into 5-substituted-4-ami-
no-pyrrolidin-2-ones 5a–e. These products were obtained as color-
less oils in acceptable yields and with total control of the
stereoselectivity, after purification by flash chromatography on
silica gel. All the spectral data of 5a–e are in agreement with the
literature for both closely related 5-substituted-4-hydroxy-pyrroli-
din-2-ones26b and 4-alkylamino-pyrrolidin-2-ones.13b
substituted-4-amino-3-pyrrolin-2-ones from different natural
a-
amino acids using simple protocols. The latter compounds were
easily converted in the former by reduction with NaBH3CN.
Acknowledgments
The authors acknowledge FAPERJ, CAPES, CNPq, and FINEP, Bra-
zilian Financing Agencies, for financial support.
Supplementary data
O
H2N
R
Supplementary data (experimental procedures, characteriza-
tion data, 1H and 13C NMR for all new compounds) associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2009.03.003.
R
CO2H
NH2
i
ii
R
O
O
N
Boc
N
Boc
4a-e
5a-e
References and notes
a: R = i-Bu
b: R = Bn
c: R = Me
d: R = s-Bu
4a: 80%
4b: 75%
4c: 75%
4d: 75%
5a: 47%
5b: 51%
5c: 49%
5d: 47%
5e: 42%
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