Synthesis of β^2,2-Amino Acids by Stereoselective Alkylation of Isoserine Derivatives Followed by Nucleophilic Ring Opening of Quaternary Sulfamidates

Abstract

Chiral bicyclic N,O -acetal isoserine derivatives have been synthesized by an acid-catalyzed tandem N , O -acetalization/intramolecular transcarbamoylation reaction between conveniently protected l -isoserine and 2,2,3,3-tetramethoxybutane. The delicate balance of the steric interactions between the different functional groups on each possible diastereoisomer controls their thermodynamic stability and hence the experimental product distribution. These chiral isoserine derivatives undergo diastereoselective alkylation at the α position, proceeding with either retention or inversion of the configuration depending on the relative configuration of the stereocenters. Quantum mechanical calculations revealed that a concave-face alkylation is favored due to smaller torsional and steric interactions at the bicyclic scaffold. This synthetic methodology gives access to chiral β 2,2 -amino acids, attractive compounds bearing a quaternary stereocenter at the α position with applications in peptidomimetic and medicinal chemistry. Thus, enantiopure α-alkylisoserine derivatives were produced upon acidic hydrolysis of these alkylated scaffolds. In addition, α-benzylisoserine was readily transformed into a five-membered ring cyclic sulfamidate, which was ring opened regioselectively with representative nucleophiles to yield other types of enantiopure β 2,2 -amino acids such as α-benzyl-α-heterofunctionalized-β-alanines and α-benzylnorlanthionine derivatives.

Modular synthesis of congested β2,2-amino acids via the merger of photocatalysis and oxidative functionalisations

“…1). These include multi-step sequences, such as alkylation followed by Curtius rearrangement, 3 nitrile reductions, 4 reductive aminations; 5,6 or the Arndt–Eistert homologation. 7 The most common way to prepare β-amino acids is through Mannich addition reactions, which are limited to certain reactive electrophiles ( e.g.…”