SCHEME 1. Access to Diamino Alcohols 1
Analogues of Key Precursors of Aspartyl
Protease Inhibitors: Synthesis of
Trifluoromethyl Amino Epoxides
Nguyen Thi Ngoc Tam, Guillaume Magueur,
Miche`le Oure´vitch, Benoit Crousse,
Jean-Pierre Be´gue´, and Danie`le Bonnet-Delpon*
BioCIS-CNRS, Centre d’Etudes Pharmaceutiques,
rue J.B. Cle´ment, Chaˆtenay-Malabry 92296 Cedex, France
are versatile intermediates for the synthesis of a variety
of highly functionalized compounds (Scheme 1).4
Received August 23, 2004
The need still exists to find new protease inhibitors to
improve selectivity toward homologous proteases, fight
against problems associated with the development of
drug-resistant strains, and limit secondary effects.
While structural diversity can be easily introduced
through combinatorial libraries based on core units 1, a
modulation of the central unit has still to be explored.
Considering that strategies using specific properties
of fluorine have resulted in the production of effective
biomedical tools or drugs for numerous therapeutic
targets,5 the design of new inhibitors based upon a
fluorinated hydroxyethylamine scaffold could be of ben-
efit. Fluorinated amino acids6 and peptidomimetic units5b,7
can exhibit attractive features: a higher resistance to
oxidative8 and proteolytic degradation,9 a better bioavail-
ability, conformational restrictions on the peptide chain,
and modification of binding properties through modula-
tion of the pKa of adjacent functionalities.10 These specific
properties have been largely exploited for the design of
fluorine-containing protease inhibitors.11
The synthesis of the title compound is described through
original and tailored synthetic protocols. The addition of
vinylmagnesium bromide to CF3-N-aryl and N-alkyl aldi-
mines was efficient and did not require an activating
N-substituent. The resultant CF3-allylamines were con-
verted in an efficient and completely stereoselective route
to syn CF3-epoxides 3 via formation of bromhydrins 8. The
same sequence performed from the aldimine substituted
with the methyl ether of the (R)-phenylglycinol provided the
homochiral (R,R)-amino epoxide (de >98%). This study has
allowed access to the novel racemic and homochiral triflu-
oromethyl â-amino epoxides, analogues of key precursors of
various HIV protease inhibitors.
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Introduction
Peptidomimetic binding units 1a or 1b where R is a
benzyl or an isopropyl group are present in most HIV-1
protease inhibitors used in advanced clinical trials or in
tritherapies1 and in inhibitors of other proteases such as
cathepsin D2 and plasmepsins.3
Both types of diamino alcohols 1 can be easily accessed
from a common precursor, the amino epoxides 2, which
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Kukhar, V. P., Soloshonok, V. A., Eds.; Wiley: Chichester, 1994. (b)
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Future Directions; Ramachandran, P. V., Ed.; ACS Symposium Series
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10.1021/jo0485233 CCC: $30.25 © 2005 American Chemical Society
Published on Web 12/10/2004
J. Org. Chem. 2005, 70, 699-702
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