A Stereoselective entry into functionalized 1,2-diamines by zinc-mediated homologation of α-aminoacids

Article abstract of DOI:10.1021/ol0708020

A general, stereoselective synthsis of 4,5-disubstituted imidazolidines-2-ones from α-aminoacids has been developed: the key steps are a Biaise reaction of bromoacetate on α-aminonitriles and further reduction. Although reduction with sodium cyanoborohydride afforded a mixture of cis and trans isomers 6a-e with moderate to good stereoselectivity, reduction with sodium in liquid ammonia gave the trans isomers 8a-e with complete stereoselectivity. Acidic hydrolysis of the urea gave 4-amino-pyrrolidinones, which can be precursors to β,γ-diaminoacids or 3-aminopyrrolidines.

Full text of DOI:10.1021/ol0708020

ORGANIC
LETTERS
2007
Vol. 9, No. 13
2521-2524
A Stereoselective Entry into
Functionalized 1,2-Diamines by
Zinc-Mediated Homologation of
r
-Aminoacids
Cam Thuy Hoang, Vale´rie Alezra, Re´gis Guillot,† and Cyrille Kouklovsky*
Laboratoire de Chimie des Proce´de´s et Substances Naturelles, Institut de Chimie
Mole´culaire et des Mate´riaux d’Orsay (UMR CNRS n°8182), Baˆtiment 410, UniVersite´
de Paris-Sud 11, F-91405 Orsay, France
cykouklo@icmo.u-psud.fr
Received April 4, 2007
ABSTRACT
A general, stereoselective synthesis of 4,5-disubstituted imidazolidines-2-ones from
Blaise reaction of bromoacetate on -aminonitriles and further reduction. Although reduction with sodium cyanoborohydride afforded a mixture
of cis and trans isomers 6a e with moderate to good stereoselectivity, reduction with sodium in liquid ammonia gave the trans isomers 8a−e
r-aminoacids has been developed: the key steps are a
r
−
with complete stereoselectivity. Acidic hydrolysis of the urea gave 4-amino-pyrrolidinones, which can be precursors to
3-aminopyrrolidines.
â,γ-diaminoacids or
Stereochemically defined 1,2-diamines are valuable building
blocks in organic synthesis as they can be used as metal
ligands, organic catalysts, and precursors to biologically
relevant compounds, such as nonproteinogenic aminoacids,
or alkaloids.1 In a study related to the synthesis of statin
analogues, we planned to prepare enantiomerically pure â,γ-
diaminoacids, which belong to the 1,2-diamine family, in a
convergent manner by homologation of R-aminoacids. â,γ-
Diaminoacids are new type of aminoacid that have been the
subject of growing interest, owing to their capacity to modify
biological properties in small peptides.2,3 Furthermore, cy-
clization of these aminoacids gives rise to 4-aminopyrroli-
dinone, thus providing an entry into the 3-aminopyrrolidine
family of alkaloids4 (Figure 1).
In this communication, we wish to report a general,
convergent, and stereoselective approach to syn- or anti-â,γ-
diaminoacids from optically active R-aminoacids by zinc-
mediated homologation with the Blaise reaction, followed
by reduction.
The Blaise reaction is a variant of the Reformatsky reaction
with nitriles as substrates and has been described as a method
for the synthesis of â-ketoesters from nitriles.5 Zinc-mediated
condensation of R-bromoesters onto nitriles affords an
(4) Synthetic approaches to enantiomerically pure 3-aminopyrrolidines:
Davies, S. G.; Garner, A. C.; Goddard, E. C.; Kruchinin, D.; Roberts, P.
M.; Rodriguez-Solla, H.; Smith, A. D. Chem. Commun. 2006, 2664 and
references cited therein. See also: (a) Jean, L.; Rouden, J.; Maddaluno, J.;
Lasne, M.-C. J. Org. Chem. 2004, 69, 8893. (b) Huang, P. Q.; Wang, S.
L.; Ye, J. L.; Ruan, Y. P.; Huang, Y. Q.; Zheng, H.; Goa, J. X. Tetrahedron
1998, 54, 12547.
(5) (a) Blaise, E. C.R. Hebd. Se´ances Acad. Sci. 1901, 132, 478. (b)
Kagan, H. B.; Suen, Y. H. Bull. Soc. Chim. Fr. 1966, 1819. (c) For a recent
review concerning the Reformatsky and Blaise reactions in synthesis:
Ocampo, R.; Dolbier, W. R., Jr. Tetrahedron 2004, 60, 9325.
† To whom correspondance concerning X-ray crystallography should be
addressed. E-mail: regisguillot@icmo.u-psud.fr.
(1) For a review on the chemistry of 1,2-diamines: Lucet, D.; Le Gall,
T.; Mioskowski, C. Angew. Chem., Int. Ed. 1998, 37, 2580.
(2) (a) Schostarez, H. J. J. Org. Chem. 1988, 53, 3628. (b) Thaisrivongs,
S.; Schostarez, H. J.; Pals, D. T.; Turner, S. R. J. Med. Chem. 1987, 30,
1837.
(3) Synthetic approaches to â,γ-diaminoacids: Yoo, D.; Kwon, S.; Kim,
Y. G. Tetrahedron: Asymmetry 2005, 16, 3762 and references cited therein.
10.1021/ol0708020 CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/02/2007

Table 1. Synthesis of N,N-Diprotected R-Aminonitriles
Figure 1. â,γ-Diaminoacids and corresponding pyrrolidine deriva-
tives.
iminozincate intermediate, which is then hydrolyzed in an
acidic medium to the corresponding â-ketoester. An impor-
tant modification of the Blaise reaction was developed by
Kishi and co-workers who reported that hydrolysis of the
reaction medium with concentrated potassium carbonate
afforded an enaminoester.6 Therefore, it was anticipated that
this reaction, followed by reduction of the enaminoester,
could be applied to the synthesis of â-aminoacids. This
strategy has been applied to the synthesis of â-lactams7 and
more recently to the synthesis of carbohydrate-derived
â-aminoacids.8,9 Our approach to the synthesis of 4-ami-
nopyrrolidinones and â,γ-diaminoacids relies on a similar
strategy that involves the preparation of R-aminonitriles from
R-aminoacids, Blaise reaction, and subsequent reduction of
the enaminoester (Figure 2).
entry
R1
yield of 2 (%)
yield of 3 (%)
eea (%)
a
b
c
Me
iPr
iBu
Bn
46
45
43
55
93
84
89
91
>99
99
>99
>99
d
a
Determined by HPLC.
L-R-aminoacids 1a-d (Table 1). Additionally, the known
N-Cbz L-proline11 2e was prepared according to known
methods. Initial attempts to perform the Blaise reaction on
aminonitriles 2a-d resulted in low yields and complex
mixtures of products. It appeared that the presence of a
secondary amino group was deleterious to the reaction,
probably due to competitive deprotonation and alkylation.
Therefore, a second protection of the nitrogen atom as a
benzyl ether was envisaged. Thus, deprotonation of R-ami-
nonitriles 2a-d (NaH, DMF) and addition onto a solution
of benzyl iodide gave the R-aminonitriles 3a-d in good
yields without racemization, as determined by HPLC. These
special conditions were used to avoid racemization, as
observed using standard benzylation conditions.
The Blaise reaction on aminonitriles 2e and 3a-d was
accomplished by treatment with excess tert-butyl bromoac-
etate in the presence of zinc (activated with 1,2-dibromoet-
hane) in refluxing THF, followed by quenching with 50%
aqueous potassium carbonate. However, the expected enami-
noesters 4a-e were obtained as minor products,12 the major
being the 2-imidazolidinone derivatives 5a-e (Scheme 1).
These compounds result from intramolecular reaction of the
intermediate iminozincate onto the benzyl carbamate. Actu-
ally, it was possible to transform the acyclic enaminoesters
4a-e into the cyclic derivatives 5a-e by treatment with
NaH. This was routinely achieved after extraction to obtain
pure 5a-e.
Figure 2. General approach to â,γ-diaminoacids and related
γ-lactams.
N-Benzyloxycarbonyl aminonitriles 2a-d were prepared
Conditions for the Blaise reaction allow the products to
be obtained in good yields. No substitution of the nitrile
group by the enolate was observed. Moreover, all the
enaminoesters 5a-e were obtained as single diastereomers
without any racemization, as determined by chiral HPLC.
as pure enantiomers10 in three steps from the corresponding
(6) Hannick, S. M.; Kishi, Y. J. Org. Chem. 1983, 48, 3833.
(7) (a) Mauduit, M.; Kouklovsky, C.; Langlois, Y.; Riche, C. Org. Lett.
2000, 2, 1053. (b) Mauduit, M.; Kouklovsky, C.; Langlois, Y. Eur. J. Org.
Chem. 2000, 1595.
(8) Dondoni, A.; Massi, A.; Minghini, E. Synlett 2006, 539.
(9) Blaise reaction with cyanohydrins: Syed, J.; Forster, S.; Effenberger,
F. Tetrahedron: Asymmetry 1998, 9, 805.
(10) The whole synthetic sequence was performed on both racemic and
enantiomerically pure material for each amino acid. The enantiomeric purity
of each intermediate was checked by HPLC on a chiral column.
(11) Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J. B.; Ley,
S. V. Org. Biomol. Chem. 2005, 3, 84.
(12) Compounds 4a-e were obtained as single diastereomers as always
observed for the Blaise reaction: Lee, A. S.-Y.; Cheng, R.-Y.; Pan, O.-G.
Tetrahedron Lett. 1997, 38, 443.
2522
Org. Lett., Vol. 9, No. 13, 2007

configuration of 6b was determined to be 1,2-cis by X-ray
crystallography after removal of the benzyl group on nitrogen
to give 7b (Figure 3). The cis selective reduction of valine
Scheme 1. Blaise Reaction of Protected R-Aminonitriles
The reduction of imidazolines 5a-e was carried out under
three different conditions: hydrogenation, hydride, or dis-
solving metal reductions. Hydrogenation at ambient pressure
resulted in migration of the exocyclic double bond into the
imidazolidone ring, thus inducing complete racemization. In
contrast, low-temperature reduction with sodium cyanoboro-
hydride in acidic medium gave good yields of the reduced
compounds 6a-e without loss of enantiomeric purity.
Reduction of the valine derivative 5b gave 6b as a single
diastereomer (Table 2, entry b), whereas reduction of other
substrates gave a mixture of stereomers.13 The relative
Figure 3. X-ray crystal of compound 7b.
derivative 5b is believed to proceed via an acyliminium
species, in which the hydride attacks on the opposite face to
the R1 substituent (si face, Table 2).
Reduction under dissolving metal conditions14 was next
attempted; treatment of cyclic enaminoesters 5a-e with
sodium in THF/ammonia15 gave a mixture of reduced
products consisting of the reduced ester, the corresponding
carboxylic acid, and the primary alcohol.16 For easier
characterization, the crude mixture was treated with refluxing
NaOH solution to give a mixture of the carboxylic acid 8a-d
and primary alcohol 9a-d (Table 2). Importantly, both
compounds were always obtained as single diastereomers.
Reoxidation of primary alcohols 9a-d (PDC, DMF) gave
carboxylic acids 8a-d with the same relative configuration,
thus proving that the reduction is totally diastereoselective.
Table 2. Diastereoselective Reduction of 5a-e with Sodium
Cyanoborohydride
1
A comparison between H and 13C NMR spectra of com-
pound 8b and the acid obtained after saponification of ester
6b showed that the relative configuration obtained by
reduction with Na/NH3 was different from that obtained by
cyanoborohydride reduction. To explain this stereoselectivity,
we suggest that the reaction proceeds first via a radical anion
intermediate which adopts the trans configuration owing to
the stabilization of the SOMO orbital by the neighboring
entry
substrate
yield (%)
cis/transa
(13) Tetrabutylammonium cyanoborohydride or sodium triacetoxyboro-
hydride did not improve the stereoselectivity.
(14) Reviews: (a) Venturello, P.; Barbero, M. Science of Synthesis; Georg
Thieme Verlag: Stuttgart, 2005; Vol. 8b, p 881. (b) Caine, D. Org. React.
(New York) 1976, 23, 1.
(15) To the best of our knowledge, there is only one example of reduction
of an enaminoester derivative under Birch conditions: Schlessinger, R. H.;
Iwanowicz, E. J.; Springer, J. P. J. Org. Chem. 1986, 51, 3070.
(16) The presence of alcohol 9a-d must be due to traces of moisture in
the reaction medium.
a
b
c
d
e
5a
5b
5c
5d
5e
74
84
55
55
67
1.6:1
>99:1
1:2
1:1.5
1:2
a
1
Ratio determined by H NMR analysis of the crude product.
Org. Lett., Vol. 9, No. 13, 2007
2523

Scheme 2. Synthesis of 4-Amino-pyrrolidinones 10b and 11b
Table 3. Reduction of Enamines 5a-d under Dissolving Metal
Conditions
Hydrolysis of the imidazolidine-2-one 7b was accom-
plished by treatment with 3 N HCl at 90 °C, giving lactam
10b as a single product after purification on Dowex resin.
Alternatively, the N-benzylated γ-lactam 11b could be
obtained from 6b by omitting the hydrogenolysis step
(Scheme 2).
In conclusion, we have described a general and stereose-
lective entry into new functionalized 1,2-diamines from
R-aminoacids using a chemoselective zinc-mediated homolo-
gation of R-aminonitriles, followed by a stereoselective
reduction. The 4-aminopyrrolidinones obtained after hydro-
lytic cleavage of ureas might be transformed into â,γ-
diaminoacids by saponification or into 3-aminopyrrolidines
by reduction. These applications, as well as the total synthesis
of structurally related natural products, are currently under
study.
entry
substrate
yield of 8 (%)
yield of 9 (%)
de (%)
1
2
3
4
5
5a
5b
5c
5d
5e
52
50
47
50
44a
27
23
15
18
-
>99
>99
>99
>99
>99
Acknowledgment. We thank the CNRS for providing a
doctoral grant to C.T.H., D. Gori and M.-T. Adeline (ICSN,
Gif-sur-Yvette, France) for HPLC analysis, and CNRS and
Ministe`re de la Recherche et de l’Enseignement Supe´rieur
for financial support.
a
Compound 8e was isolated as its methyl ester.
C-C bond.17 Further electron transfer gives an anionic
intermediate which is protonated by ammonia from the â
face (re face) to give 1,2-trans-imidazolidinone18 (Table 3).
Supporting Information Available: Experimental pro-
cedures and analytical and spectral characterization for all
new compounds, including a CIF file with X-ray data for
compound 7b. This material is available free of charge via
the Internet at http://pubs.acs.org.
(17) For a discussion about the stereoselectivity of the Birch reduction:
Pradhan, S. K. Tetrahedron 1986, 42, 6351.
(18) Similarity between H and 13C NMR spectra of compounds 8a-e
1
and minor isomers for compounds 6a and 6e allowed cis/trans assignment
for each isomer in compounds 6a-e (see Supporting Information for details).
OL0708020
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Org. Lett., Vol. 9, No. 13, 2007