Enantioselective Preparation of β²-Amino Acid Derivatives for β-Peptide Synthesis

Abstract

β-Amino acids with a single side chain in the α-position (β 2 -aminoacids or H-β 2 -aminoacids or H-β 2 hXaa(PG)-OH; i.e., homo-aminoacids with proteinogenic side chains) have turned out to be importantcomponents in β-peptides. They contribute to unique secondarystructures, they are required for mimicking the structure and theactivity of β-turn-forming α-peptides, and theycan be used for protecting α-peptides against attack byaminopeptidases. In contrast to β 3 hXaa(PG)-OH; i.e., homo-aminoacids with proteinogenic side chains) have turned out to be importantcomponents in β-peptides. They contribute to unique secondarystructures, they are required for mimicking the structure and theactivity of β-turn-forming α-peptides, and theycan be used for protecting α-peptides against attack byaminopeptidases. In contrast to β 3 -homo-aminoacids, the β 2 -homo-aminoacids, the β 2 -isomers cannot be obtainedsimply by enantiospecific homologation of the (natural) α-aminoacids, but have to be prepared by enantioselective reactions orsequences of transformations, which are presented herein. The variouspreparative methods are ordered according to the bond at the stereogeniccenter, which is formed in the stereoselective step, with the fourstrategic bonds being the C(2)-C(3) backbone bond, theC(2)-side-chain bond, the C(2)-H bond, and theC(1)-C(2) bond between the carboxylate and the α-carbon.In the most frequently employed methods, a chiral auxiliary groupis attached at the carboxyl C(1) atom or at the nitrogen in the3-position, but there are also a number of enantioselective catalyticprocesses, including the hydrogenation of suitable acrylates. Thealternative of stereoselective synthesis, namely resolution of racemicmixtures (for instance by biocatalysis), is also discussed. A criticalcomparison of the various methods and strategies is presented. Forthe peptide chemist, a list is included with the Cbz-, Boc-, andFmoc-protected β 2 -isomers cannot be obtainedsimply by enantiospecific homologation of the (natural) α-aminoacids, but have to be prepared by enantioselective reactions orsequences of transformations, which are presented herein. The variouspreparative methods are ordered according to the bond at the stereogeniccenter, which is formed in the stereoselective step, with the fourstrategic bonds being the C(2)-C(3) backbone bond, theC(2)-side-chain bond, the C(2)-H bond, and theC(1)-C(2) bond between the carboxylate and the α-carbon.In the most frequently employed methods, a chiral auxiliary groupis attached at the carboxyl C(1) atom or at the nitrogen in the3-position, but there are also a number of enantioselective catalyticprocesses, including the hydrogenation of suitable acrylates. Thealternative of stereoselective synthesis, namely resolution of racemicmixtures (for instance by biocatalysis), is also discussed. A criticalcomparison of the various methods and strategies is presented. Forthe peptide chemist, a list is included with the Cbz-, Boc-, andFmoc-protected β 2 -amino acid building blocks,ready for peptide coupling. In addition, the search strategy fornonracemic β 2 -amino acid building blocks,ready for peptide coupling. In addition, the search strategy fornonracemic β 2 -amino acids and theirprecursors from the databases is described in detail. 1 Introduction 2 Why β 2 -amino acids and theirprecursors from the databases is described in detail. 1 Introduction 2 Why β 2 -Amino Acids? 3 Literature Search 4 Retrosynthetic Analysis 5 β 2 -Amino Acids? 3 Literature Search 4 Retrosynthetic Analysis 5 β 2 -Amino Acids by Formationof the C(2)-C(3) Bond 5.1 Is There a Stereospecific Route from α-Amino Acids? 5.2 Chiral Auxiliaries and Catalysts for C(2)-C(3)Bond -Formation 6 β 2 -Amino Acids by Formationof the C(2)-C(3) Bond 5.1 Is There a Stereospecific Route from α-Amino Acids? 5.2 Chiral Auxiliaries and Catalysts for C(2)-C(3)Bond -Formation 6 β 2 -Amino Acids by Formationof the C(2)-R Bond 6.1 α-Alkylations of Chiral Enolates Derived from β-AminopropanoicAcid 6.2 C(2)-R Bond Formation by Nucleophilic Additionand Substitution 7 β 2 -Amino Acids by Formationof the C(2)-R Bond 6.1 α-Alkylations of Chiral Enolates Derived from β-AminopropanoicAcid 6.2 C(2)-R Bond Formation by Nucleophilic Additionand Substitution 7 β 2 -Amino Acids by StereoselectiveFormation of the C(2)-H Bond 7.1 Protonation of Enols or Enolates Derived from 3-AminopropanoicAcid 7.2 Enantioselective Hydrogenation of Acrylates and Nitro-olefinswith Formation of β 2 -Amino Acids by StereoselectiveFormation of the C(2)-H Bond 7.1 Protonation of Enols or Enolates Derived from 3-AminopropanoicAcid 7.2 Enantioselective Hydrogenation of Acrylates and Nitro-olefinswith Formation of β 2 -Amino Acid Derivatives 8 Preparation of β 2 -Amino Acid Derivatives 8 Preparation of β 2 -Amino Acidswith Formation of the -Strategic C(1)-C(2) Bond 9 β 2 -Amino Acidswith Formation of the -Strategic C(1)-C(2) Bond 9 β 2 -Amino Acids by Resolution? 10 Detailed Search Strategy 11 Conclusions and a Table with β 2 -Amino Acids by Resolution? 10 Detailed Search Strategy 11 Conclusions and a Table with β 2 -AminoAcid Building Blocks for Peptide Synthesis