First synthesis of a beta(2)-homoamino acid by enantioselective catalysis.

Article abstract of DOI:10.1021/ol027252k

The enantioselective conjugate addition of diethylzinc to the activated nitroolefin methyl 3-nitropropenoate is efficiently catalyzed by copper(I) complexes with BINOL-based enantiopure phosphoramidite ligands. The nitroolefin moiety acts as the predomina

Full text of DOI:10.1021/ol027252k

ORGANIC
LETTERS
2
2003
Vol. 5, No. 1
First Synthesis of a â -Homoamino Acid
7
9-80
by Enantioselective Catalysis
Audrius Rimkus and Norbert Sewald*
Faculty of Chemistry, UniVersity of Bielefeld, PO Box 10 01 31,
D-33501 Bielefeld, Germany
norbert.sewald@uni-bielefeld.de
Received November 8, 2002
ABSTRACT
The enantioselective conjugate addition of diethylzinc to the activated nitroolefin methyl 3-nitropropenoate is efficiently catalyzed by copper(I)
complexes with BINOL-based enantiopure phosphoramidite ligands. The nitroolefin moiety acts as the predominant Michael acceptor, giving
rise to the unambiguous formation of 2-alkyl-3-nitro-propanoates. Moderate to excellent enantioselectivities and high chemical yields are
2
obtained. The product can easily be transformed into a â -homoamino acid.
The conjugate addition of carbon nucleophiles to R,â-
unsaturated compounds belongs to the classical carbon-
carbon bond forming strategies. The versatility of this
In recent years several ligands have been utilized in the
enantioselective conjugate addition of diorganozinc com-
1
7
pounds to nitroolefins. 3-Nitropropenoates are ideally suited
2
reaction type is due to the wide variety of donors (organo-
metallic reagents, Michael donors, other carbanions) and
as precursors of â -homoamino acids as the side chain R
2
may be introduced by conjugate addition of R Zn. Herein
2
acceptors (R,â-unsaturated reagents) that can be employed.
we describe an enantioselective conjugate addition of dieth-
ylzinc to the activated nitroolefin methyl 3-nitropropenoate8
2 catalyzed by BINOL-based enantiopure copper(I)/phos-
phoramidite complexes (Scheme 1). The synthesis of cata-
lysts of this type and their application in conjugate additions
of dialkylzinc compounds to various enones have been first
In particular, the use of dialkylzinc reagents has been
extremely successful in the development of highly enantio-
2
b,3
selective catalytic conjugate additions in recent years.
4
The addition of nucleophiles to nitroolefins represents a
convenient access to nitroalkanes that are versatile intermedi-
ates in organic synthesis. The nitro functionality can be easily
transformed into an amine, an oxime, a ketone, or a
carboxylic acid, etc., providing a wide range of synthetically
9
reported by Feringa et al. The influence of the nature of
the copper salt on the stereoselectivity of conjugate additions
has been recently investigated by us and Alexakis et al.10
5
2
interesting compounds. Among these, â -homoamino acids
side chain at C , amino group at C ) are of special interest,
R
â
(
(
5) (a) Barrett, A. G. M.; Grabowski, G. Chem. ReV. 1986, 86, 751-
7
2
62. (b) Kabalka, G. W.; Varma, R. S. Org. Prep. Proced. Int. 1987, 19,
83-328. (b) Perekalin, V. V.; Lipina, E. S.; Berestovitskaya, V. M.;
Efremov, D. A. Nitroalkenes, Conjugated Nitrocompounds; John Wiley &
as the corresponding â-peptides adopt novel and unique
6
folding patterns. Syntheses of this class of compounds
employing asymmetric catalysis have not yet been described.
Sons: New York, 1994.
(
6) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. ReV. 2001,
(
1) Jung, M. E. ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, 1991; Vol. 4, pp 1-67.
2) (a) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
101, 3219-3232.
(7) (a) Sewald, N.; Wendisch, V. Tetrahedron: Asymmetry 1998, 9,
1341-1344. (b) Alexakis, A.; Benhaim, C. Org. Lett. 2000, 2, 2579-2581.
(c) Versleijen, J. P. G.; van Leusen, A. M.; Feringa, B. L. Tetrahedron
Lett. 1999, 40, 5803-5806. (d) Ongeri, S.; Piarulli, U.; Jackson, R. F. W.;
Gennari, C. Eur. J. Org. Chem. 2001, 803-807. (e) Luchaco-Cullis, C. A.;
Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 8192-8193.
(8) For synthesis of nitroolefins, see also: (a) Shin, C.; Yamaura, M.;
Inui, E.; Ishida, Y.; Yoshimura, J. Bull. Chem. Soc. Jpn. 1978, 51, 2618-
2621. (b) Shechter, H.; Conrad, F. J. Am. Chem. Soc. 1953, 75, 5610-
5613. (c) Piet, J. C.; Le Hetet, G.; Cailleux, P.; Benhaoua, H.; Carri e´ , R.
Bull. Soc. Chim. Belg. 1996, 105, 33-44.
(
Pergamon Press: Oxford, 1992. (b) Krause, N.; Hoffmann-R o¨ der, A.
Synthesis 2001, 171-196.
(
3) (a) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346-353. (b) Sibi, M.
P.; Manyem, S. Tetrahedron 2000, 56, 8033-8061.
(4) (a) Seebach, D.; Colvin, E. W.; Lehr, F.; Weller, T. Chimia 1979,
3
3, 1-18. (b) Ono, N. The Nitro Group in Organic Synthesis; Wiley-
VCH: New York, 2001. (c) Berner, O. M.; Tedeschi, L.; Enders, D. Eur.
J. Org. Chem. 2002, 1877-1894. (d) Rimkus, A.; Sewald, N. Org. Lett.
2
002, 4, 3289-3291.
1
0.1021/ol027252k CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/10/2002

Scheme 1. Synthesis of Phosphoramidites L1 and L2
Table 1. Enantioselective Copper(I)-Catalyzed Conjugate
Addition of Diethylzinc to Methyl 3-Nitropropenoate 2
a
entry
ligand
solvent
T, °C
ee, %
isomer
1
2
3
4
5
6
7
8
9
(M,S,S)-L1
(M,S,S)-L1
(P,S,S)-L1
(M,S,S)-L1
(M,S,S)-L1
(M,S,S)-L1
(P,R,R)-L2
(M,R,R)-L2
(P,R,R)-L2
(M,R,R)-L2
(P,R,R)-L2
(M,R,R)-L2
toluene
toluene
toluene
ether
ether
THF
toluene
toluene
ether
ether
ether
-50
-30
-30
-30
-78
-30
-30
-30
-30
-30
-78
-78
10
28
12
68
77
16
67
52
73
12
92
15
(+)
(+)
(-)
(+)
(+)
(-)
(+)
(+)
(+)
(-)
(+)
(+)
1
1
1
0
1b
2b
ether
a
Isolated yields of 3 range from 70% to 94%. b 0.5 mol % Cu(OTf)2
and 1.0 mol % ligand.
by the tert.-butyloxycarbonyl group (Boc), and subsequently
2
saponified to give the â -homoamino acid 4 (Scheme 2).
We used copper(II) triflate as the source of copper(I), because
it is easy to handle and reduced in situ by diethyl zinc.
The synthesis of phosphoramidites L1 and L2 was
performed following a modified procedure originally de-
scribed by Feringa et al. Starting from phosphorus trichloride,
enantiomerically pure bis(phenylethyl)amine 1 and racemic
BINOL or its 3,3′-dimethyl derivative (Scheme 1) are
reacted, followed by chromatographic resolution of the
diastereomeric phosphoramidites.1 Alternatively, enantio-
merically pure BINOL may be employed. The 3,3′-dimethyl
derivative of BINOL was synthesized according to Wood-
ward’s method.12
2
Scheme 2. Synthesis of the Boc-Protected â -Homoamino
Acid 4
1
In conclusion, we found that diethylzinc can be efficiently
added to the activated nitroolefin methyl 3-nitropropenoate
We found that the copper(I)-catalyzed conjugate addition
of diethylzinc to methyl 3-nitropropenoate 2 proceeds with
varying enantioselectivity, depending on ligand, solvent, and
reaction conditions employed. Substrate and catalyst con-
centrations also influence the enantioselectivity.7 The best
results are obtained with ligand (P,R,R)-L2 in diethyl ether
at -78 °C, which provides 3 in 94% yield and 92% ee (Table
2
. The reaction is catalyzed by BINOL-based enantiopure
phosphoramidite/copper complexes and provides nitro pre-
cursors of â -homoamino acids. Enantioselectivities up to
9
The nitroolefin moiety acts as the predominant Michael
acceptor, giving rise to the unambiguous formation of
2
2% ee and chemical yields up to 94% have been obtained.
b
2-alkyl-3-nitro-propanoate 3. These experiments clearly show
1, entry 11). Enantioselectivity drops to 15% ee when the
that 3-nitropropenoate 2 is ideally suited as a valuable
precursor in the catalytic asymmetric synthesis of â -
homoamino acids. Different side chains may be introduced
via conjugate addition of organozinc reagents.
diastereomeric ligand (M,R,R)-L2 is used under these reac-
tion conditions (Table 1, entry 12). Even less than 0.5 mol
2
%
of copper(II) and 1.0 mol % of chiral phosphoramidite L
are sufficient for very fast and clean reaction at -78 °C.
The â-nitroester 3 can easily be reduced by catalytic
transfer hydrogenation using ammonium formate, protected
Acknowledgment. The authors gratefully acknowledge
support from Konrad Adenauer Foundation and University
of Bielefeld (Ph.D. grants to A.R.) and Fonds der Chemi-
schen Industrie.
(9) (a) de Vries, A. H. M.; Meetsma, A.; Feringa, B. L. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 2374-2376. (b) Feringa, B. L.; Pineschi, M.; Arnold,
L. A.; Imbos, R.; de Vries, A. H. M. Angew. Chem., Int. Ed. Engl. 1997,
Supporting Information Available: Experimental pro-
cedures and listings of physical and spectroscopic data of
the synthesized compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
3
6, 2620-2623.
10) (a) Wendisch, V.; Sewald, N. Tetrahedron: Asymmetry 1997, 8,
253-1257. (b) Alexakis, A.; Benhaim, C.; Rosset, S.; Humam, M. J. Am.
(
1
Chem. Soc. 2002, 124, 5262-5263.
(11) See Supporting Information for details.
(12) Dennis, M. R.; Woodward, S. J. Chem. Soc., Perkin Trans. 1 1998,
1
081-1085.
OL027252K
80
Org. Lett., Vol. 5, No. 1, 2003