Thiophene Backbone Amide Linkers, a New Class of Easily Prepared and Highly Acid-Labile Linkers for Solid-Phase Synthesis
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Solid-phase synthesis is of tremendous importance for small-molecule and biopolymer synthesis. Linkers(handles) that release amide-containing products after completion of solid-phase synthesis are widelyused. Here we present a new class of highly acid-labile backbone amide linkers (BAL handles) based on3,4-ethylenedioxythiophene (EDOT), which we have termed T-BAL. These thiophene linkers aresynthesized in three convenient steps from commercially available EDOT. In the linker design, the spacerwas introduced to the EDOT core either via a carbon-carbon bond or via a thioether linkage. Introductionof the spacer via a C-C bond was performed by a chemoselective Negishi coupling without transientprotection of the aldehyde group to provide the T-BAL1 handle. Introduction via a thioether linkage wasperformed by a facile nucleophilic aromatic substitution between the brominated EDOT aldehyde andunprotected mercapto acids to provide T-BAL2 and T-BAL3 handles. The minimal use of protectinggroups gave the corresponding linker molecules in few synthetic steps and in good yields. After anchoringof the linker to a polymeric support, introduction of the first amino acid was achieved by reductiveamination, giving a secondary amine. A following acylation of the secondary amine with a symmetricalamino acid anhydride resulted in a backbone amide linkage between the handle and the growing substrate(e.g., peptide chain). After solid-phase synthesis, the substrates could be released from the resin by eitherlow acid conditions using 1% TFA in CH2Cl2 or high acid conditions such as 50% TFA in CH2Cl2.Peptide thioesters could be released from the T-BAL1 handle under very mild conditions using aqueousacetic acid. Tert-butyl based protecting groups, tert-butyl esters, tert-butyl ethers, and Boc groups, aswell as dimethyl acetals were relatively stable to these mild conditions for release of the peptides.

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