Despite the promise of amide bond isosteres for improving the resistance toward degradation by exoproteases by several orders of magnitude, the use of nonhydrolyzable substitutes for the amide group has often led to disappointing decreases in biological activity. 1 The frequent lack of success with ground-state amide bond mimetics stands in contrast to the very promising use of hydroxyethylene protease inhibitors as mimics of the tetrahedral intermediate in amide bond hydrolysis. 2 Nonetheless, the development of effective amide bond isosteres holds considerable promise as a stepping stone toward the rational design of small molecule analogues of bioactive oligo-and polypeptides. Analogues such as thiomethylene and aminomethylene isosteres, however, exchange the conformationally restricted amide function with highly flexible single bonds. Disubstituted (E)-alkene isosteres 1 provide a better fit for the C i -(R)-C i+1 (R) distance (3.8 Å) but are inadequate mimetics of the electrostatic potential surface as well as the backbone φ,ψ-dihedral angles. Gellman and co-workers designed the tetrasubstituted (E)-alkene Gly-Gly dipeptide mimetic 2 to induce conformational rigidification and promote -hairpin formation. 3 More recently, Hoffman and co-workers reported the use of gauche pentane interactions for the design of -hairpin analogue 3. 4 We were interested in exploring the use of trisubstituted (E)-alkene isosteres such as 4 as -turn mimetics. A combination of A 1,3 -and A 1,2 -strain leads to considerable restrictions in φ,ψ-dihedral angles in these substrates, and the Ramachandran plot of the methylalkene isostere of alanine is closely related to the parent amino acid. 5 In contrast, the disubstituted (E)-alkene analogue is conformationally much more flexible. Even greater steric restrictions are observed for a trifluoromethylated derivative 5 where only ca. 15% of the Ramachandran plot area remains within 15 kJ/mol of the energy minimum. Methylalkene moieties are abundant in terpenes and polypropionate natural products and have indeed been shown to serve as surrogates of backbone amide functions in enzymeinhibitor complexes. 6The mimicry of the electronic properties of the amide bond represents perhaps the most challenging parameter for effective isostere design. Electrostatically, the (trifluoromethyl)alkene represents a better match of the amide bond than any other common alkene isostere ( Figure 1).Efficient synthetic approaches toward diastereomerically and enantiomerically pure alkene peptide isosteres are under intense investigation. 8 A particularly promising convergent pathway utilizes the S N 2′-addition of cuprate reagents to alkenyl aziridines and allylic mesylates. 9 The former approach has also been applied to solid-phase synthesis. 10 We have now extended these methods toward a general synthesis of methyl-and (trifluoromethyl)alkene isosteres and, for the first time, systematically compared the solid state conformations of these peptide mimetics.Swern oxidation of the epoxy alcohol 6, obtained in...
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