Daniel Obrecht

A novel synthesis of (R)- and (S)-α-alkylated aspartic and glutamic acids: α-alkylated aspartic succinimides as new type of β-turn type II and II′ mimetics

Abstract A novel and efficient synthesis of optically pure ( R )- and ( S )-α-methyl glutamic acid ( 1 ), ( R )- and ( S )-α-methyl aspartic acid ( 2a ) and ( R )- and ( S )-α-isobutyl aspartic acid ( 2b ) using L-phenylalanine cyclohexylamide 4 as chiral auxiliary is described. Crystal structures show that the ( R )- and ( S )-α-methyl glutamic acid derivatives ( S,S )- 5 and ( R,S )- 6 adopt β-turn type I geometries, whereas the corresponding aspartimide derivatives ( R,S )- 12a,b form a β-turn type II and ( S,S )- 11a a β-turn type II′. These findings suggest, that the succinimide derivatives of ( R )- and ( S )-α-alkyl aspartic acids can serve as building blocks to stabilise β-turns of type II (or II′) in peptides depending on their absolute configuration.

A new general three component solution-phase synthesis of 2-amino-1,3-thiazole and 2,4-diamino-1,3-thiazole combinatorial libraries

Abstract A general procedure for the solution-phase synthesis of amino-1,3-thiazole libraries 9 and 10 is described. Their preparation is based on the condensation of amidines 1 and thiouronium salts 2 with isothiocyanates 3 , affording amidino–thioureas and thioureido-thioureas of types 4 and 5 . Subsequent treatment with α-bromo ketones 6 led to the S -alkylated intermediate, which yielded 1,3-thiazoles of types 9 and 10 via a base-catalysed ring closure process ( Scheme 1 ) Download high-res image (102KB) Download full-size image Scheme 1 . . In addition, this methodology tolerates a diverse range of functionality without recourse to protection.

A novel access to 2,4-substituted quinolines from acetylenic ketones

Abstract 2, 4-Substituted quinolines of type 7 and 8 were synthesized starting from 2-amino thiophenol and acetylenic acetals 5 to yield various substituted benzo[b][1, 4] thiazepine intermediates of type 6 . Subsequent sulfur extrusion in refluxing toluene led to 2, 4-substituted quinoline acetals 7 , which were transformed into the corresponding 2-substituted quinoline-4-carbaldehydes 8 in good to excellent yields.

Design and synthesis of novel nonpolar host peptides for the determination of the 310- and α-helix compatibilities of α-amino acid buildig blocks: An assessment of α,α-disubstituted glycines

The present work describes three novel nonpolar host peptide sequences that provide a ready assessment of the 310‐ and α‐helix compatibilities of natural and unnatural amino acids at different positions of small‐ to medium‐size peptides. The unpolar peptides containing Ala, Aib, and a C‐terminal p‐iodoanilide group were designed in such a way that the peptides could be rapidly assembled in a modular fashion, were highly soluble in solvent mixtures of triflouroethanol and H2O for CD‐ and two‐dimensional (2D) nmr spectroscopic analyses, and showed excellent crystallinity suited for x‐ray structure analysis. To validate our approach we synthesized 9‐mer peptides 79a–96 (Table IV), 12‐mer peptides 99–110c (Table V), and 10‐mer peptides 120a–125d and 129–133 (Table VI and Scheme 8) incorporating a series of optically pure cyclic and open‐chain (R)‐ and (S)‐α,α‐disubstituted glycines 1–10 (Figure 2). These amino acids are known to significantly modulate the conformations of small peptides.

Monitoring solid phase synthesis by infrared spectroscopic techniques

The paper describes the use of attenuated total reflection fourier transform-infrared (ATR FT-IR) microspectroscopic techniques for the verification of the structure of chemical compounds synthesised on polystyrene beads in combinatorial chemistry. A six step reaction sequence is characterised completely by infrared (IR) spectroscopic investigations of single beads. Incomplete reactions or the occurrence of side products are clearly indicated. Quantitative information can be extracted with high precision using absorption bands of the polymer matrix as internal standard. Compared to other IR techniques, the ATR micro IR technique shows clear advantages with respect to sensitivity and resolution. The technique has the potential to be used for the characterisation of single beads in split and combined synthesis techniques.

Applications of Parallel Synthesis to Lead Optimization

Parallel synthesis of focused compound libraries for hit confirmation and lead optimization are certainly important drivers for shortening the lead discovery phase in the pharmaceutical and crop protection industries. In this article we show with permission of Roche and Syngenta three real case studies where Polyphor synthesized focused libraries for lead validation and optimization using high-throughput parallel synthesis and purification techniques. The three examples differ significantly in the synthetic strategies which were employed as well as in the chemical complexity of the final products. A multigeneration approach towards insecticidal triazines, the application of a sequential three-component reaction towards insecticidal and fungicidal thiazoles and finally a multistep synthesis approach of advanced building blocks followed by a two-step final derivatization towards novel antiviral N-hydroxy-indolin-2-ones are presented. In all cases 100-200 analogues were synthesized using parallel synthesis in solution followed by purification of the final products by parallel flash or high-throughput (unattended) HPLC (coupled to MS) within four months. Promising biological results were obtained in all three cases.