Accelerated Submonomer Solid-Phase Synthesis of Peptoids Incorporating Multiple Substituted N-Aryl Glycine Monomers.
N-Aryl glycines are a chemically diverse class of peptoid monomers that have strong structure-inducing propensities. Yet their use has been limited due to the sluggish reactivity of the weakly nucleophilic aniline submonomers. Here, we report up to a 76-fold rate acceleration of the displacement reaction using aniline submonomers in solid-phase peptoid synthesis. This is achieved by adding halophilic silver salts to the displacement reaction, facilitating bromide abstraction and AgBr precipitation. Mechanistic insight derived from analysis of a series of 15 substituted anilines reveals that the silver-mediated reaction proceeds through a transition state that has considerably less positive charge buildup on the incoming nucleophile and an enhanced leaving group. This straightforward enhancement to the submonomer method enables the rapid room temperature synthesis of a wide variety of N-aryl glycine-rich peptoid oligomers, possessing both electron-withdrawing and -donating substituents, in good yields.
The Molecular Foundry, Lawrence Berkeley National Laboratory , 1 Cyclotron Road, Berkeley, California 94720, United States.
Caroline
C
Proulx
The Molecular Foundry, Lawrence Berkeley National Laboratory , 1 Cyclotron Road, Berkeley, California 94720, United States.
Stan
S
Yoo
The Molecular Foundry, Lawrence Berkeley National Laboratory , 1 Cyclotron Road, Berkeley, California 94720, United States.
Michael D
MD
Connolly
The Molecular Foundry, Lawrence Berkeley National Laboratory , 1 Cyclotron Road, Berkeley, California 94720, United States.
Ronald N
RN
Zuckermann
D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry*; D046911:Macromolecular Substances / Q000737:chemistry*; D008958:Models, Molecular; D034444:Peptoids / Q000138:chemical synthesis* / Q000737:chemistry; D060327:Solid-Phase Synthesis Techniques / Q000379:methods
D046911:Macromolecular Substances; D034444:Peptoids; D005998:Glycine