S)-b 2 -Homoamino acids with the side chains of Asp, Glu, Asn, and Gln have been prepared and suitably protected (N-Fmoc, CO 2 t Bu, CONHTrt) for solid-phase peptide syntheses. The key steps of the syntheses are: N-acylation of 5,5-diphenyl-4-isopropyl-1,3-oxazolidin-2-one (DIOZ) with succinic and glutaric anhydrides (Scheme 2), alkylation of the corresponding Li-enolates with benzyl iodoacetate and Curtius degradation (Scheme 4), and removal of the chiral auxiliary (Scheme 5). In addition, numerous functional-group manipulations (CO 2 H > CO 2 t Bu, CO 2 Bn > CO 2 H, CbzNH 3 FmocNH, CO 2 H 3 CO 2 NH 2 3 CONHTrt; Schemes 2, 4, 5, and 6) were necessary, in order to arrive at the four target structures. The configurational assignments were confirmed by X-ray crystal-structure determinations (Scheme 2 and Fig. 3). The enantiomeric purities of a b 2 hAsn and of a b 2 hGln derivative were determined by HPLC on a Chiralcel column to be 99.7 : 0.3 and > 99 : 1, respectively (Fig. 4). Notably, it took up to twelve steps to prepare a suitably protected trifunctional product with a single stereogenic center (overall yield of 10% from DIOZ and succinic anhydride)! Part of the Master Thesis (Diplomarbeit) of S. K., ETH-Z¸rich, 2003. 5 ) With the exceptions of Fmoc-b 3 hHis(Trt)-OH and Fmoc-b 3 hCys(Trt)-OH, all −proteinogenic× b 3 -amino acids, which can be prepared by ArndtÀEistert homologation of the corresponding a-amino acids, are commercially available.compounds for their use in solid-phase b-peptide synthesis is the Fmoc protection of the b-amino group, and the t Bu or Trt protecting group on the side chains. Thus, we thought that 3-acyl-DIOZ derivatives of succinic and glutaric acids could serve as precursors for the corresponding b 2 -homoaspartic and b 2 -homoglutamic acids, respectively. The amino functionality would be introduced either by a diastereoselectiveMannich-type reaction (cf. bond 1 in Fig. 1) or by a carbalkoxymethylation, followed by Curtius degradation (connections 1 2 in Fig. 1), to give the desired amino acid skeleton, which could be further elaborated by protecting-group exchange (Scheme 1).
Scheme 1. Retrosynthetic Analysis for the Preparation of the b 2 -Amino Acids with Asx and Glx Side ChainsHelvetica Chimica Acta ± Vol. 87 (2004) 1547 Fig. 2. Target b 2 -amino acid derivatives Scheme 2. Nucleophilic Ring Opening of the Succinic and Glutaric Anhydrides ( 3 1 and 2), N-Acylation of (R)-DIOZ to Form the Acyloxazolidinones 3 and 4, Respectively, and X-Ray-Crystal Structure of 3Helvetica Chimica Acta ± Vol. 87 (2004) 1548 7 ) The reaction was rather messy and the formation of polymerization products were observed.
