Amino Acid-Based Synthesis of
Trifluoromethylalkene Dipeptide Isosteres by
Alcohol-Assisted Nucleophilic
Trifluoromethylation and
Organozinc-Copper-Mediated SN2′ Alkylation
Kazuya Kobayashi, Tetsuo Narumi, Shinya Oishi,
Hiroaki Ohno, and Nobutaka Fujii*
FIGURE 1. Structures of native peptide bond and corresponding
alkene-type isosteres. Xaa, Yaa ) amino acid side chains.
Graduate School of Pharmaceutical Sciences, Kyoto
synthesis and functional evaluation of EADIs.3 We found that
the simple alkene unit is not always sufficient as a peptide
mimetic partially because of a smaller dipole moment than that
of the native peptide bond (EADI: 0.1 D; native peptide bond:
3.6 D; Figure 1).4
UniVersity, Sakyo-ku, Kyoto 606-8501, Japan
ReceiVed March 13, 2009
We turned our attention to fluoroalkene and trifluoromethy-
lalkene dipeptide isosteres (FADI and CF3-ADI, respectively).
These isosteres can be considered to be more ideal peptide bond
mimetics because a carbonyl oxygen of the peptide bond is
replaced by a highly electronegative fluorine atom or trifluoro-
methyl group: induced polarization of the C-X bond by these
substituents contributes to have a closer dipole moment to a
native peptide bond (FADI: 1.4 D; CF3-ADI: 2.3 D).4 The
potential character of these substituents as hydrogen bond
acceptors can also be expected.5 Whereas we and others have
reported diastereoselective synthetic methodologies for FADIs
as well as their applications to biologically active peptides,6
only a few examples of a diastereoselective synthesis and
functional evaluation of CF3-ADI have been reported to date.4,7
We recently developed an efficient stereoselective methodology
for the preparation of optically pure Xaa-Gly-type CF3-ADI
utilizing palladium-catalyzed carbonylation.8 Our next subject
is the synthesis of Xaa-Yaa CF3-ADIs, which requires the
stereoselective introduction of the R-alkyl group.
A novel synthetic approach to Xaa-Yaa-type (Z)-trifluorom-
ethylalkene dipeptide isostere (CF3-ADI) has been developed.
Starting from readily available L-phenylalanine and L-alanine,
several CF3-ADIs were obtained through nucleophilic trif-
luoromethylation of γ-keto esters and SN2′ alkylation of
trifluoromethylated mesylates. The influence of a trifluoro-
methyl group on the diastereoselectivity of the SN2′ reaction
is also discussed.
Replacement of native hydrolyzable peptide bonds with
nonhydrolyzable mimetics is one of the most promising ap-
proaches toward overcoming the major drawbacks of peptides,
including poor bioavailability and short physiological half-lives
due to rapid proteolysis.1 Among the known isosteric units, the
(E)-alkene-type dipeptide isostere (EADI), designed on the basis
of the planar structure of the parent peptide bond in its resonance
structure, is well-known as a potential trans-peptide bond-
equivalent.2 We have been engaged in the stereoselective
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10.1021/jo9005602 CCC: $40.75 2009 American Chemical Society
Published on Web 05/15/2009