Computational, ReactIR-, and NMR-spectroscopic investigations on the chiral formyl anion equivalent N-(alpha-lithiomethylthiomethyl)-4-isopropyl-5,5-diphenyloxazolidin-2-one and related compounds.

The 4-isopropyl-3-methylthiomethyl-5,5-diphenyloxazolidin-2-one is readily lithiated in THF on the exocyclic CH2 group (1 --> 2) to give a synthetically useful chiral nucleophilic formylating reagent. We have now studied the lithiation reaction by ReactIR spectroscopy and the structure of the organolithium reagent by computational methods and by NMR-spectroscopic measurements. The lithiation is complete at -78 degrees C within 90 seconds, and it is accompanied by a decrease of the C=O wavenumber by 50 cm(-1). The NMR data (collected in [D8]THF) give no evidence for 13C,6Li coupling or for aggregation; from DPFGSE-ROE spectra the single diastereoisomer of the lithium compound 2 seen in the NMR spectra (NMR-spectroscopic measurements from -105 to -20 degrees C) is assigned like configuration; the 13C=O signal of the oxazolidinone undergoes a 7 ppm downfield shift upon lithiation (1 --> 2); line-shape analyses of the signals from the diastereotopic CH2 and CMe2 protons in lithiated 4,4-dimethyl-3-methylthiomethyloxazolidin-2-one (model compound 7) reveal a deltaH(double dagger) of 8.9 +/- 0.2 kcal mol(-1) for enantiomerization. The theoretical calculations provide an energy-minimum structure for the lithium compound 2 with coordination of the carbonyl oxygen to lithium, with an antiperiplanar arrangement of the C,Li and S,CH3 bonds, and with relative like configuration of the two stereocenters--in perfect agreement with the conclusions from the IR- and NMR-spectroscopic measurements!

The outstanding biological stability of beta- and gamma-peptides toward proteolytic enzymes: an in vitro investigation with fifteen peptidases.

A series of 36 linear and cyclic beta- and gamma-peptides consisting of as few as two, and as many as 15 residues, was offered as substrates to 15 commercially available proteases of bacterial, fungal, and eukaryotic origin, including a beta-lactamase and amidases, as well as most vigorous, nonspecific proteases, such as the 20S proteasome from human erythrocytes. For comparison, an alpha-eicosapeptide and standard substrates of the proteolytic enzymes were included in the investigation. Under conditions of complete cleavage of the alpha-peptide within 15 min the beta- and gamma-peptides were stable for at least 48 h. Inhibition studies with seven beta- and gamma-peptides and alpha-chymotrypsin show that the residual enzyme activity toward succinyl-Ala-Ala-Pro-Phe-p-nitroanilide is unchanged within experimental error after incubation for 15 min with the peptide analogues. Thus, beta- and gamma-peptides with proteinogenic side chains, that is, consisting of the singly or doubly homologated natural alpha-amino acids (one or two CH(2) groups inserted in the backbone of each residue), are completely stable to common proteases, without inhibiting their normal activity (as demonstrated for alpha-chymotrypsin). This proteolytic stability of peptides built of homologated amino acids is a prerequisite for their potential use as drugs.