Application of the Ester Enolate Claisen Rearrangement in the Synthesis of Amino Acids Containing Quaternary Carbon Centers

Abstract

Ester enolate Claisen rearrangement of highly substituted amino acid allylic esters 4 allows for the synthesis of sterically demanding amino acids 5 with beta-quaternary carbon centers. Because of enolate fixation by chelation, the rearrangement occurs in a highly diastereoselective fashion. The methodology is suitable not only for glycine derivatives but also for allylic esters of various amino acids. In this case amino acids with two vicinal quaternary carbon centers are created. With unsymmetrically substituted allylic esters like 4k-n the rearrangement proceeds with a high degree of diastereoselectivity.

Recent advancements in the homoallylamine chemistry

“…Then, Barlett and co-workers investigated the diastereoselectivity of this process [56]. Nowadays, this methodology has been applied successfully for diastereoselective synthesis of other amino acids with β-quaternary carbon centers (Kazmaier's method) [57][58][59]. The rearrangement of amino acid allylic esters occurs in a high diastereoselective fashion due to enolate fixation by chelation.…”

“…Deprotonation of N-protected amino acid allylic esters 33a with LDA at -78 °C and subsequent addition of a metal salt (ZnCl 2 , AlMeCl 2 , MgCl 2 , Al(Oi-Pr) 3 ) presumably results in the formation of chelated metal enolate, which undergoes rearrangement affording unsaturated amino acids 34 with two vicinal quaternary carbon centers [59] (Scheme 13). In general best results are obtained with zinc chloride and methylaluminum dichloride.…”

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].…”

Chelated Enolates of Amino Acid Esters − New and Efficient Nucleophiles for Isomerization-Free, Stereoselective Palladium-Catalyzed Allylic Substitutions

“…The anti products, however, cannot be obtained as easily from the corresponding (Z)-esters. [19] Scheme 2. Chelate Claisen rearrangement of glycine allyl esters For that reason, we wanted to ascertain whether the anti products might be accessible through palladium-catalyzed allylic alkylation.…”