The Asymmetric Chelate-Claisen Rearrangement as a Key Step in the Syntheses of Non-Proteinogenic Amino Acids

Abstract

Allylic esters of TFA-protected amino acids undergo asymmetric Claisen rearrangements in the presence of cinchona alkaloids, giving rise to g,d-unsaturated amino acids in a highly stereoselective fashion. The products are useful precursors for the short and efficient synthesis of more complex compounds such as substituted 4-hydroxyornithines and iminosugars. Starting from the unsaturated amino acids, iodolactonization, bicylization and opening of the lactone ring with nucleophiles such as amino acids or peptides provide hydroxyproline derivatives directly incorporated into peptides.

Claisen rearrangements based on vinyl fluorides

“…Most importantly, from the synthetic point of view, there were developed plenty of variants of this type of rearrangement. By way of example, the Carroll [6,7], the Johnson [8], the Eschenmoser [9,10] (including the Overman variant [11,12]), the Reformatsky [13,14], the ester enolate [15][16][17], and the Ireland-Claisen rearrangements [18][19][20] should be mentioned as some of the synthetically most useful variants regularly applied with non-fluorinated compounds.…”

Synthesis of Unnatural/Nonproteinogenic α‐Amino Acids

“…The approach also allows for a,a-disubstituted amino acids to be accessed [96]. The use of a Claisen rearrangement illustrates the power of this reaction class (Scheme 12.22) [97,98].…”

Synthesis of γ-fluoro-α-amino acids by Claisen rearrangement

“…As the configuration of the enolate is determined by chelation and the chair-like transition state is preferred, the stereochemistry of the major products can be predicted [50][51][52]. Many applications of this reaction for the stereoselective synthesis of g,d-unsaturated a-amino acids have been described [53][54][55][56][57][58][59][60][61][62][63]. Moreover, this reaction has been used for the introduction of unsaturated side chains into peptides [50,60,[62][63][64][65] and for the synthesis of other pharmacologically relevant molecules [66][67][68].…”

“…Many applications of this reaction for the stereoselective synthesis of g,d-unsaturated a-amino acids have been described [53][54][55][56][57][58][59][60][61][62][63]. Moreover, this reaction has been used for the introduction of unsaturated side chains into peptides [50,60,[62][63][64][65] and for the synthesis of other pharmacologically relevant molecules [66][67][68]. Furthermore, asymmetric variants applying optically active allylic esters [51,52,62,[65][66][67] or enantiopure ligands at the metal ion [69,70] have been developed.…”