Preparation of Protected β²‐ and β³‐Homocysteine, β²‐ and β³‐Homohistidine, and β²‐Homoserine for Solid‐Phase Syntheses

Abstract

The Ser, Cys, and His side chains play decisive roles in the syntheses, structures, and functions of proteins and enzymes. For our structural and biomedical investigations of b-peptides consisting of amino acids with proteinogenic side chains, we needed to have reliable preparative access to the title compounds. The two b 3homoamino acid derivatives were obtained by Arndt ± Eistert methodology from Boc-His(Ts)-OH and Fmoc-Cys(PMB)-OH (Schemes 2 ± 4), with the side-chain functional groups reactivities requiring special precautions. The b 2 -homoamino acids were prepared with the help of the chiral oxazolidinone auxiliary DIOZ by diastereoselective aldol additions of suitable Ti-enolates to formaldehyde (generated in situ from trioxane) and subsequent functional-group manipulations. These include OH 3 O t Bu etherification (for b 2 hSer; Schemes 5 and 6), OH 3 STrt replacement (for b 2 hCys; Scheme 7), and CH 2 OH 3 CH 2 N 3 3 CH 2 NH 2 transformations (for b 2 hHis; Schemes 9 ± 11). Including protection/deprotection/re-protection reactions, it takes up to ten steps to obtain the enantiomerically pure target compounds from commercial precursors. Unsuccessful approaches, pitfalls, and optimization procedures are also discussed. The final products and the intermediate compounds are fully characterized by retention times (t R ), melting points, optical rotations, HPLC on chiral columns, IR, 1 Hand 13 C-NMR spectroscopy, mass spectrometry, elemental analyses, and (in some cases) by X-ray crystalstructure analysis.

Synthesis and in Vitro and in Vivo Characterization of Highly β1-Selective β-Adrenoceptor Partial Agonists

“…40 Phthalimide protection of 34 was effected through a solvent-free method, by heating directly with phthalic anhydride to give acid 35 , 41 which was converted to the corresponding acyl azide with the aid of diphenylphosphoryl azide in the presence of TEA; careful reflux of this intermediate promoted Curtius rearrangement to the isocyanate. The isocyanate solution was divided into two equal portions, prior to addition of either 2- or 3-aminophenol, producing protected intermediates 36a and 36b .…”

Conformationally Constrained Histidines in the Design of Peptidomimetics: Strategies for the χ-Space Control

“…[80] using the Arndt-Eistert homologation from Fmoc-His(τ-BOM)-OH, Fmoc-His(τ-Tr)-OH, Boc-His(τ-Bn)-OH, Boc-His(π-Bn)-OH, and Boc-His(τ-BOM)-OH were unsuccessful. Only Ts-protected histidines reacted with CH 2 N 2 to form the corresponding diazo ketones, probably due to the strong electron-withdrawing effect of the tosylate, which renders the 1 H -imidazolyl- N -atom less nucleophilic.…”

“…Retrosynthetic analysis for the preparation of the Fmoc-β 2 hHis(Tr)-OH via alkylation, Mannich-Type reaction and aldol addition of chiral acyloxazolidinones [80]. …”

“…Further transformation towards the formation of β 2 -homo-histidine derivatives led to the formation of compound 95 [80]. …”

Azurin–Poly(N‐isopropylacrylamide) Conjugates by Site‐Directed Mutagenesis and their Thermosensitive Behavior in Electron‐Transfer Processes

“…Radical bromination (Br 2 , hn, CCl 4 ) of 4-ethylbenzonitrile gave 1, which was converted to alkoxyamine 2 by using a known procedure. [5] Reduction of 2 with lithium aluminum hydride (LAH) and subsequent coupling with trityl-protected imidazole propionic acid 4 [13] gave radical initiator 5 after deprotection. Nitroxide-mediated polymerization was conducted in C 6 D 6 with 0.5-2 mol % 5 at 125 8C in sealed tubes.…”