Preparation of Protected β 2 ‐ and β 3 ‐Homocysteine, β 2 ‐ and β 3 ‐Homohistidine, and β 2 ‐Homoserine for Solid‐Phase Syntheses

• Published in: Helvetica chimica acta Vol. 87; no. 12; pp. 3131 - 3159
• Main Authors: Lelais, Gérald, Micuch, Peter, Josien‐Lefebvre, Delphine, Rossi, Francesco, Seebach, Dieter
• Format: Journal Article
• Language: English
• Published: 01.12.2004
• ISSN: 0018-019X; 1522-2675
• DOI: 10.1002/hlca.200490280

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 β ‐peptides consisting of amino acids with proteinogenic side chains, we needed to have reliable preparative access to the title compounds. The two β 3 ‐homoamino 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 β 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→O t Bu etherification (for β 2 hSer; Schemes 5 and 6 ), OH→STrt replacement (for β 2 hCys; Scheme 7 ), and CH 2 OH→CH 2 N 3 →CH 2 NH 2 transformations (for β 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 H‐ and 13 C‐NMR spectroscopy, mass spectrometry, elemental analyses, and (in some cases) by X‐ray crystal‐structure analysis.