UPS on Weinreb resin: A facile solid-phase route to aldehyde and ketone derivatives of "unnatural" amino acids and peptides

The solid-phase synthesis of "unnatural" amino aldehydes, amino ketones, pe ptide aldehydes, and peptide ketones was accomplished from commercially ava ilable resin in a series of room temperature reactions. The initial step in volved addition of an "unnatural" side chain to the N-terminus of a benzoph enone imine-activated Weinreb resin-bound amino acid or peptide derivative. The alkylated imine was hydrolyzed, and the amine was converted to the Boc -, Cbz-, or naphthoyl derivative. The resin-bound substrate was then cleave d with DIBAL-H or a Grignard reagent to give the amino aldehyde, amino keto ne, peptide aldehyde, or peptide ketone products. Twenty-four reactions wer e carried out simultaneously using a "Billboard" reaction apparatus to give products in 27-87% (59% average) isolated yield.