γ-Turn Mimicry with Benzodiazepinones and Pyrrolobenzodiazepinones Synthesized from a Common Amino Ketone Intermediate.

To investigate diazepinone analogues as γ-turn mimics, seven 1,4-benzodiazepin-2-ones 6 and fourteen pyrrolo[1,2-d][1,4]benzodiazepin-6-ones 4 and 5 were synthesized from 1-(2-aminophenyl)pent-4-en-1-one (7). Acylation of aniline 7 with N-Boc-amino acids, olefin oxidation, Boc removal, and intramolecular Paal-Knorr condensation gave 4 and 5. Alternatively, Boc removal prior to oxidation gave benzodiazepinones 6, which were converted to 4 by ozonolysis and cyclization. Comparison of dihedral angle values for the amino acid component from X-ray analyses of 4g, 5f, and 6f and related diazepinones has catalogued the manner by which ring substituents affect the component's ability to mimic the central residues of γ-turns.

Synthesis of protected 2-pyrrolylalanine for peptide chemistry and examination of its influence on prolyl amide isomer equilibrium.

Protected enantiopure 2-pyrrolylalanine was synthesized for application in peptide science as an electron-rich arylalanine (histidine) analog with π-donor capability. (2S)-N-(Boc)-N'-(Phenylsulfonyl)-, (2S)-N,N'-bis-(phenylsulfonyl)-, and (2S)-N,N'-bis-(Boc)-3-(2-pyrrolyl)alanines (10, 3, and 14, respectively) were made in 13-17% overall yields and six to seven steps from oxazolidine ß-methyl ester 4. Homoallylic ketone 5 was prepared by a copper-catalyzed cascade addition of vinylmagnesium bromide to ester 4 and converted to pyrrolyl amino alcohol 7 by olefin oxidation and Paal-Knorr condensation. Protecting group shuffle and oxidation of the primary alcohol enabled the synthesis of pyrrolylalanines. The bis-Boc analog 14 proved useful in peptide chemistry and was employed to make N-acetyl-pyrrolylalaninyl-proline N''-methylamide 25. A study of the influence of the pyrrole moiety on the prolyl amide isomer equilibrium of 25 using (1)H NMR spectroscopy in chloroform, DMSO, and water demonstrated that the pyrrolylalanine peptide exhibited behavior and conformations different from those of other arylalanine analogs.

Synthesis of a new pi-deficient phenylalanine derivative from a common 1,4-diketone intermediate and study of the influence of aromatic density on prolyl amide isomer population.

Enantiopure (2S)-N-(Boc)-3-(6-methylpyridazinyl)alanine (14) has been synthesized to serve as a phenylalanine analog lacking significant pi-donor capability. Two approaches were developed to furnish the target compound from L-aspartic acid as chiral educt in respectively six and nine steps and 13% and 12% yields. In both routes, a key homoallylic ketone intermediate was synthesized by a copper-catalyzed cascade addition of vinylmagnesium bromide to a carboxylic ester. Dipeptide models Ac-Xaa-Pro-NHMe (21a-c) were prepared and the relative populations of prolyl cis- and trans-amide isomers were measured in chloroform, dimethylsulfoxide, and water by proton NMR spectroscopy in order to assess the significance of the electron density of the neighboring aromatic residue on the prolyl amide geometry.

Three-step solution-phase combinatorial access to 1,2-disubstituted and 1,2,5-trisubstituted pyrroles from carboxylic esters.

An efficient diversity-oriented strategy has been developed for the solution-phase parallel synthesis of di- and trisubstituted pyrrole libraries. Methyl esters 1 were effectively converted to 1,2-di- and 1,2,5-trisubstituted pyrroles 5 and 6 in three steps. Treatment of ester 1 with vinylmagnesium bromide in the presence of copper (I) cyanide yielded the corresponding homoallylic ketone 2, which was subjected to ozonolysis or Tsuji-Wacker oxidation to yield the respective cyclization precursors 3 and 4 after aqueous workup. Compounds 3 and 4 were condensed without further purification with a primary amine to afford the desired 1,2-di- or 1,2,5-trisubstituted pyrroles 5 and 6 in good yield and purity.