Enantioselective Preparation of <i>β</i>²‐Amino Acids with Aspartate, Glutamate, Asparagine, and Glutamine Side Chains

Abstract

Abstract ( S )‐ β 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→FmocNH, CO 2 H→CO 2 NH 2 →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 β 2 hAsn and of a β 2 hGln derivative were determined by HPLC on a Chiralcel column to be 99.7 : 0.3 and &gt;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)!