Chiral aminal templates 6. Diastereoselectivity of hydrazo-ne alkylation. Asymmetric synthesis of α-amino-aldehydes

Glyoxal is efficiently transformed into the chiral animals bearing the hydrazone functionality 2a and 2b. These compounds react under complete diastereocontrol with various organolithium reagents, affording chiral hydrazines 3 -9. Reduction with Raney nickel leads to aminal protected a-aminoaldehydes, which, in turn, are easily hydrolyzed to the free chiral aldehydes (after tBoc protection of the amine)

Ultrasound assisted cleavage of hydrazines by Raney nickel

The reductive N-N cleavage of N-substituted N',N'-dimethylhydrazines to give primary amines by Raney nickel/hydrogen is conveniently performed under atmospheric pressure of hydrogen by sonication of the reaction vessel in a simple ultrasound cleaner. Sterically hindered hydrazines are also cleaved and no racemization or debenzylation is observed

Straightforward Synthesis of Novel Enantiopure α‑Trifluoromethylated Azetidine 2‑Carboxylic Acid and Homoserines

The straightforward syntheses of enantiopure (2<i>R</i>)-2-trifluoro­methyl-2-carboxy­azetidine and (<i>R</i>)- and (<i>S</i>)-trifluoro­methyl­homo­serines are reported. The key step is a Strecker-type reaction on a common chiral CF₃-containing bicyclic oxazolidine intermediate obtained by a condensation reaction of (<i>R</i>)-phenylglycinol and ethyl-4,4,4-trifluoro­aceto­acetate (ETFAA)

Trifluoromethylthiolation of tryptophan and tyrosine derivatives

The incorporation of fluorinated groups into peptides significantly affects their biophysical properties. We report herein the synthesis of Fmoc-protected trifluoromethylthiolated tyrosine (CF$_3$S-Tyr) and tryptophan (CF$_3$S-Trp) analogues on a gram scale (77–93% yield) and demonstrate their use as highly hydrophobic fluorinated building blocks for peptide chemistry. The developed methodology was successfully applied to the late-stage regioselective trifluoromethylthiolation of Trp residues in short peptides (66–80% yield) and the synthesis of various CF$_3$S-analogues of biologically active monoamines. To prove the concept, Fmoc-(CF$_3$S)Tyr and -Trp were incorporated into the endomorphin-1 chain (EM-1) and into model tripeptides by solid-phase peptide synthesis. A remarkable enhancement of the local hydrophobicity of the trifluoromethylthiolated peptides was quantified by the chromatographic hydrophobicity index determination method, demonstrating the high potential of CF$_3$S-containing amino acids for the rational design of bioactive peptides