ChemInform Abstract: Synthesis of Conformationally Constrained α‐Amino Acid Derivatives Containing Bicyclo[2.2.2] Unit via the Diels—Alder and Suzuki—Miyaura Cross‐Coupling Reactions as Key Steps.

Abstract

Conformationally constrained α-amino acid (AAA) derivatives 1,2 play a significant role in designing peptidomimetics and peptide modifications. Constrained AAAs such as 2-aminoisobutyric acid (Aib) 1 is found to be useful in the peptide design, when it incorporates into the peptide; the resulting peptides adopt α-helical or β-sheet conformation. To design various peptidomimetics and peptide catalysts, these racemic or meso constrained AAAs are important because when they are coupled with optically pure proteinogenic AAA, two diastereoisomers are formed which can be easily separated by conventional methods. Various synthetic methodologies have been developed where the Diels–Alder (DA) reaction is a useful tool to prepare bicyclic AAA derivatives 3 . These bicyclic AAAs 1b such as 2a,b are prepared by the Bucherer–Bergs reaction or Strecker synthesis. Highly constrained bicyclic AAA derivative (e.g. 3a) (Ref 4a) has been synthesized by the DA reaction of methyl 2-acetamidoacrylate 11 and the anthracene 10. It is worth mentioning that, this strategy is useful to design non-steroidal biologically relevant molecules 4b-i . There-fore, a systematic investigation has been undertaken to design the synthesis of bicyclo[2.2.2]octane related AAA derivatives. Later, this strategy has been extended to 9-substituted anthracene derivatives to generate the substituted bicyclic constrained AAA derivatives 3b (Ref 5) by a regioselective DA reaction (Figure 1).