Klaus Burger

Synthetic strategies to alpha-trifluoromethyl and alpha-difluoromethyl substituted alpha-amino acids.

The combination of the unique physical and chemical properties of fluorine with proteinogenic amino acids represents a new approach to the design of biologically active compounds including peptides with improved pharmacological parameters. Therefore, the development of routine synthetic methods which enable the effective and selective introduction of fluorine into the desired amino acids from readily available starting materials is of significant synthetic importance. The scope of this critical review is to summarize the most frequently employed strategies for the synthesis of alpha-difluoromethyl and alpha-trifluoromethyl substituted alpha-amino acids (114 references).

Fluoro Heterocycles with Five-Membered Rings

Publisher Summary This chapter deals with the chemistry of five-membered ring fluorinated heterocycles. Fluorine and perfluoroalkyl groups positioned strategically in target molecules can considerably modify the chemical properties, biological activity, and selectivity. Fluoro-containing compounds play a significant role in medicinal and agricultural chemistry, as well as in material science. A number of fluoro and perfluoroalkyl-substituted pharmaceuticals, agrochemicals, dyes, and polymers are largely commercialized. Important differences in chemical reactivity of fluorinated compounds are based on the difference in: (1) carbon–fluorine, (2) carbon–hydrogen bond energy, and (3) electronegativity between fluorine and hydrogen. It is observed that fluorine introduced into biologically active molecules can block metabolism. There are two fundamentally different strategies, by which fluorine and perfluoroalkyl groups can be introduced into target molecules: (1) direct introduction that occurs by direct substitution of hydrogen by fluorine and perfluoroalkyl groups in a late step of the reaction sequence, and (2) introduction of fluorine and perfluoroalkyl groups by the application of fluorine-containing building blocks, derived from the readily available starting materials.

Proteolytically stable peptides by incorporation of α-Tfm amino acids

A series of model peptides containing α‐trifluoromethyl‐substituted amino acids in five different positions relative to the predominant cleavage site of the serine protease α‐chymotrypsin was synthesized by solution methods to investigate the influence of α‐Tfm substitution on the proteolytic stability of peptides. Proteolysis studies demonstrated absolute stability of peptides substituted in the P1 position and still considerable proteolytic stability for peptides substituted at the P2 and P′2 positions compared with the corresponding unsubstituted model peptide. Comparison with peptides containing the fluorine‐free disubstituted amino acid α‐aminoisobutyric acid allowed to separate electronic from steric effects. Furthermore, the absolute configuration of the α‐Tfm‐substituted amino acid was found to exert considerable effects on the proteolytic stability, especially in P′1 substituted peptides. Investigations of this phenomenon using empirical force field calculations revealed that in the (S,R,S)‐diasteromer the steric constraints exhibited by the α‐Tfm group can be outweighed by an advantageous interaction of the fluorine atoms with the serine side chain of the enzyme. In contrast, a favourable interaction between substrate and enzyme is impossible for the (S,S,S)‐diastereomer.

Evidence of Complete Hydrophobic Coating of Bombesin by Trifluoroethanol in Aqueous Solution: An NMR Spectroscopic and Molecular Dynamics Study

Bombesin is a tetradecapeptide that possesses a random coil structure in pure water. In the presence of 30 % (v/v) 2,2,2-trifluoroethanol (TFE), it adopts a partial helical conformation involving the C-terminal amino acids 6-14. This conformational change, known as the TFE effect, is studied here in terms of the solvation state of the peptide at different TFE concentrations by means of intermolecular homo- and heteronuclear NOE measurements. When an aqueous solution of bombesin is titrated with TFE, a continual decrease in the water/peptide interactions and a concomitant increase in the TFE/peptide interactions is observed, and at 30 % (v/v) TFE no homonuclear NOEs between water and the peptide can be detected. The conformational transition of the bombesin molecule is thus accompanied by a complete surface covering with TFE. A parallel molecular dynamics (MD) study of the peptide in aqueous solution with the single-point charge (SPC) water model and in a 30 % (v/v) TFE/water mixture with a recently developed TFE model has also been performed. The 10 ns simulations were in agreement with the experimental data. The calculations indicate stabilisation of the alpha-helix in the H(2)O/TFE mixture, in contrast to the situation in pure water, and clustering of the TFE molecules around the peptide.

Synthesis of α-trifluoromethyl substituted α-amino acid derivatives from methyl 3,3,3-trifluoro-2-diazopropionate

Abstract New derivatives 2–7 of α-trifluoromethyl substituted amino acids are synthesized via tranformation of ammonium ylides formed on reaction of methyl 3,3,3-trifluoro-2-diazopropionate with amines and amides, respectively.

Incorporation of α-trifluoromethyl substituted α-amino acids into C-and N-terminal position of peptides and peptide mimetics using multicomponent reactions

Abstract Methodology for incorporation of α-trifluoromethyl substituted amino acids into the C-and N-terminal position of peptides and peptide mimetics via multicomponent reactions of the Passerini and Ugi type is described.

The Molecular Structure of Some Transition-Metal Complexes with 1,2,3,4-Tetrazole-5-thiolate Anions

The molecular structures of nine transition metal tetrazolethiolates have been determined by X-ray structure determinations. The ligand is invariably coordinated through its sulfur atom to the metal center [M = PdII, CuI, AgI, AuI, AuIII, and Hg]. The M−S−C bond angles vary considerably, but this cannot be correlated with variations in the C−S bond lengths. Intermolecular association occurs for Ph3PAu(SCN4Me) via Au−S contacts, leading to dimeric strands in the solid state. The copper compound (Ph3P)3Cu4(SCN4Me)4 (5), possesses a rather asymmetric structure: one Cu atom is tricoordinated by 3 sulfur atoms, the other three are tetracoordinated by P and N as well as by S atoms.

An Efficient Approach to the Family of 4-Substituted Pipecolic Acids. Syntheses of 4-Oxo, cis-4-Hydroxy-, and trans-4-Hydroxy-L-pipecolic Acids from L-Aspartic Acid

Abstract Syntheses of 4-oxo-, cis -4-hydroxy-, and trans -4-hydroxy-L-pipecolic acids from L-aspartic acid using hexafluoroacetone as protecting reagent are described. Combination of a Stille cross-coupling reaction with subsequent Lewis acid catalyzed intramolecular Michael addition provides 4-oxo-L-pipecolic acid 5 or trans -6-methyl-4-oxo-L-pipecolic acid. Borohydride reduction of the protected 4-oxo-L-pipecolic acid derivative gives the corresponding cis -4-hydroxy-L-pipecolic acid 8 . The trans isomer 10 is obtained in good yield via Mitsunobu inversion.

Peptide modification by introduction of α-trifluoromethyl α-amino acids via 4-trifluoromethyl-1,3-oxazolidin-2,5-diones☆

Abstract α-Trifluoromethyl substituted α-amino acids can be introduced into the N-terminal position of peptides on carboxyl group activation via Leuchs anhydrides.

Über das synthesepotential trifluormethyl-substituierter Zinn-Heterocyclen

Zusammenfassung 4,4-Bis(trifluormethyl)-substituierte Heterodiene des Typs (F 3 C) 2) CN-C(R 1 )=X (X = O, S, NR 2 ) reagleren mit zweiwertigen Zinnverbindungen [Zinn(II)-chlorid, Stannocen etc.] nach dem Schema der [4+1] - Cycloaddition. Durch den Cycloadditionsprozeβ erfolgt eine Umpolung des Kohlenstoffatoms, das die beiden Trifluormethylgruppen tragt. Dies ist Voraussetzung fur eine kontrollerte, stufenweise Fluorid-Eliminierung aus einer der beiden Trifluormethylgruppen. Trifluormethyl-substituierte Zinn-Heterocyclen sind damit wertvolle Bausteine fur die Synthese fluor- und trifluormethyl-substituierter organischer Verbindungen.