Published on Web 09/16/2009
Aza-ꢀ3-cyclopeptides: A New Way of Controlling Nitrogen
Chirality
Cle´mence Mocquet,† Arnaud Salau¨n,† Paul Claudon,‡ Barbara Le Grel,†
Michel Potel,† Gilles Guichard,‡ Brigitte Jamart-Gre´goire,†,§ and Philippe Le Grel*,†
ICMV and CSM, UMR CNRS 6226, UniVersite´ de Rennes I, 263 aVenue du Ge´ne´ral Leclerc
35042 Rennes Cedex, France, CNRS, Institut de Biologie Mole´culaire et Cellulaire, Laboratoire
d’Immunologie et Chimie The´rapeutiques, 15 rue Descartes, 67000 Strasbourg, France, and
UMR CNRS-INPL 7568, B.P. 451, 54001 Nancy, France
Received July 13, 2009; E-mail: Philippe.legrel@univ-rennes1.fr
Abstract: Sixteen and 24 membered aza-ꢀ3-peptidic macrocycles containing a R-hydrazinoacid or a ꢀ3-
aminoacid were synthesized. The conformation of these pseudopeptides was determined by using NH chemical
shift analysis, NH extinction, VT-NMR experiments, and X-ray diffraction. The study shows that a stable
conformation is retained between 223 and 413 K. The latter is characterized by an uninterrupted internal H-bond
network and a syndiotactic arrangement of the asymmetric centers. It means that the presence of the optically
pure residue acts as a conformational lock to select a single enantiomer through the cyclization by controlling
the absolute configuration of all the nitrogen atoms. To our knowledge, this represents the first example of a
dynamic enantioselection process involving several centers prone to pyramidal inversion. These results give a
new impulsion to the control of nitrogen chirality, which remained limited to small cycles for 60 years.
Introduction
has been extended to slightly larger rings, mostly cyclic hydrazine
like 1,2-diazetidines,9 1,3,4-oxadiazolidines10 and diazabicyclo-
In contrast to its homologues down in the column of the periodic
table, the sp3 nitrogen atom undergoes fast pyramidal inversion
which makes challenging to resolve racemic compounds where
chirality relies on this element. Very few molecules make excep-
tions to this fundamental physical rule. As far back as in the 1940s,
slow NPI was predicted to occur for a nitrogen atom inside a three-
membered ring in relation with the additional angular strain brought
by the trigonal transition state.1 This led, after two decades of
efforts, to the demonstration of slow NPI in N-alkyl aziridines.2 It
was later expected that the inversion barrier should be further
enhanced by connecting the nitrogen atom to another element
bearing an unshared pair, partly due to electronic repulsion during
the inversion process.3 By combining these structural features, the
magnitude of the barrier to NPI becomes high enough to allow
the isolation of invertomers of N-halogenoaziridines,4 alkoxyaziri-
dines,5 diaziridines,6 oxaziridines,7 and triaziridine.8 The concept
heptane,11 to some 1,2-oxazolidines,12 and even acyclic di-
alkoxyamines13 and trialkoxyamines.14 On the whole, slow NPI
remained for 60 years the quasi-exclusive prerogative of small
cyclic compounds.
Recently, we discovered that aza-ꢀ3-cyclopeptidic macro-
cycles with 16 or 24 bonds undergo strikingly slow backbone
reversal, with energy barriers in the range of 75-80 kJ/mol.15
The backbone of these pseudopeptides contains exclusively
hydrazide linkages. This amide surrogate sustain a cooperative
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† Universite´ de Rennes I.
‡ Laboratoire d’Immunologie et Chimie The´rapeutiques.
§ UMR CNRS-INPL.
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9
10.1021/ja9058074 CCC: $40.75 2009 American Chemical Society
J. AM. CHEM. SOC. 2009, 131, 14521–14525 14521