SCHEME 1
Asym m etr ic Syn th esis of â-Am in o Ester s by
Aza -Mich a el Rea ction of r,â-Un sa tu r a ted
Am id es Usin g (S,S)-(+)-P seu d oep h ed r in e a s
Ch ir a l Au xilia r y
J uan Etxebarria, J ose L. Vicario, Dolores Badia,* and
Luisa Carrillo
Departamento de Qu´ımica Orga´nica II, Facultad de Ciencia
y Tecnologı´a, Universidad del Pa´ıs Vasco/ Euskal Herriko
Unibertsitatea, P.O. Box 644, E-48080, Bilbao, Spain
qopbaurm@lg.ehu.es
Received December 4, 2003
Abstr a ct: Chiral nonracemic â-amino esters were prepared
in good yields and enantioselectivities using the diastereo-
selective conjugate addition of nitrogen nucleophiles to R,â-
unsaturated amides derived from (S,S)-(+)-pseudoephedrine
as the key step. In this way, several â-amino amide adducts
were prepared using different conjugate acceptors and two
different lithium benzylamides as nucleophiles. These ad-
ducts were easily converted in only one step, into the final,
highly enantioenriched â-amino esters
iary in the conjugate addition reaction of nitrogen nu-
cleophiles to R,â-unsaturated amides derived from this
amino alcohol. It is particularly important to remark that
only a limited number of examples can be found in the
literature in which chiral auxiliaries have been used
directly attached to the carbonyl moiety of the acceptor
in asymmetric aza-Michael reactions.3-5 The main reason
for this is that the chiral information remains located
too far away from the position in which the new stereo-
center is going to be formed. In fact, the systems that
have been tested with good results in this particular case
have resulted in extremely hindered substrates3 or func-
tionalized moieties that can interact with the conjugate
system, either at the carbonyl group4 or at the CdC
double bond (for example by π-stacking interactions),5
thus reaching a rigid, well-organized intermediate. There-
fore, we wish to report herein the first example in which
a reagent derived from (S,S)-(+)-pseudoephedrine has
been employed as chiral electrophile,6 showing that this
amino alcohol is able to exert a very effective remote
stereochemical control in the asymmetric conjugate ad-
dition of nitrogen nucleophiles.
Amides 1a -e (Scheme 1) were easily prepared by
N-acylation of commercially available (S,S)-(+)-pseu-
doephedrine with the corresponding acyl chlorides,2i some
of which are also commercially available and the others
can be prepared without difficulty from the corresponding
R,â-unsaturated carboxylic acids. With these amides in
hand, we proceeded to perform a preliminary survey of
possible nitrogen nucleophiles to be used in the asym-
metric conjugate addition, using amide 1a (R1 ) Me) as
The asymmetric conjugate addition is regarded as one
of the most powerful tools for the formation of C-C or
C-X bonds that allows the preparation of chiral com-
pounds in a stereocontrolled fashion.1 A particularly in-
teresting version of this reaction is the conjugate addition
of nitrogen nucleophiles to R,â-unsaturated carbonyl
compounds, the so-called aza-Michael reaction, which
represents one of the most attractive procedures for the
asymmetric synthesis of â-amino carbonyl derivatives.
On the other hand, the commercially available, cheap
reagent pseudoephedrine has provided excellent results
as a chiral auxiliary in several C-C and C-X bond-
forming reactions in which, in all cases reported, amides
derived from this amino alcohol have been employed as
nucleophiles via their corresponding enolates.2 Additional
advantages of the use of this auxiliary are related to the
unique reactivity of the amide function present in the
obtained adducts, which allows the preparation of a wide
range of other interesting chiral building blocks.
With all these precedents in mind, we decided to check
the ability of (S,S)-(+)-pseudoephedrine as chiral auxil-
* Corresponding author.
(1) Reviews: (a) Krause, N.; Hoffmann-Ro¨der, A. Synthesis 2001,
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d’Angelo, J .; Desmaele, D.; Dumas, F.; Guingant, A. Tetrahedron:
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(2) (a) Vicario, J . L.; Bad´ıa, D.; Rodr´ıguez, M.; Carrillo, L. Tetrahe-
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(6) (S,S)-(+)-Pseudoephedrine has previously been used as auxiliary
in Michael reactions, but in these cases, the corresponding amide
enolates were employed as chiral nucleophiles (see refs 2b and 2f).
10.1021/jo0357768 CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/14/2004
2588
J . Org. Chem. 2004, 69, 2588-2590