Rapid and efficient synthesis of peptides containing α,α-dialkylamino acids employing KOBt

Abstract

Several Fmoc-a,a-dialkylamino acids and their acid chlorides have been prepared, isolated and characterised. The synthesis of peptides containing sterically hindered dialkylamino acids has been accomplished using acid chloride/KOBt in dichloromethane. The yields as well as the purity of the peptides were satisfactory.

Amino acid chlorides: a journey from instability and racemization toward broader utility in organic synthesis including peptides and their mimetics

“…227 Fmoc-amino acid chloride/KOBt protocol has also been extended for preparing peptides containing α,α-dialkylamino acids including Ac 5 c, Ac 6 c, Ac 7 c, Dbg, and Dpg. 76 Also, microwaves assisted zinc dust mediated coupling involving highly hindered α,α-dialkylamino acids and cyclic as well as acyclic α,α-dialkylamino acids has lead to their assembly in good yields of 79-90%. 228 Preparation of hindered peptides possessing up to four successive diphenylglycine or Aib residues was accomplished by using azido acid chloride method.…”

“…133 After coupling the azide Also Fmoc-amino acid chloride/KOBt protocol has been utilized for the synthesis of peptides containing α,α-dialkyl amino acids as well as N-methyl amino acids (tables 12,13). 76 The protocol, as indicated by 1 H NMR studies, was reported to be free from racemization. Fmoc-Ala-MeVal-OMe 72 161 3 Fmoc-Ala-MeIle-OMe 98 161 4 Bts-Leu-MeVal-O t Bu Na 2 CO 3 /CH 2 Cl 2 , rt 95 111 5 Fmoc-Ala-D-MePhe-Ala-OMe aq.…”

“…166 As a base does not mediate the coupling, 5(4H)-oxazolone 66 formation is circumvented. 76,149,150,167 The undesired product, KCl is formed out as a solid which is removed by filtration. Similarly, a combination of Fmoc-amino…”

“…Several Fmoc-N-methylamino acid chlorides, Fmoc-dialkylamino acid chlorides were also reported by employing SOCl 2 method at room temperature in moderate to good yields. 76 All these compounds were obtained as solids and were shelf stable under anhydrous conditions.…”