Thiophene backbone amide linkers, a new class of easily prepared and highly acid-labile linkers for solid-phase synthesis.
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 widely used. Here we present a new class of highly acid-labile backbone amide linkers (BAL handles) based on 3,4-ethylenedioxythiophene (EDOT), which we have termed T-BAL. These thiophene linkers are synthesized in three convenient steps from commercially available EDOT. In the linker design, the spacer was introduced to the EDOT core either via a carbon-carbon bond or via a thioether linkage. Introduction of the spacer via a C-C bond was performed by a chemoselective Negishi coupling without transient protection of the aldehyde group to provide the T-BAL1 handle. Introduction via a thioether linkage was performed by a facile nucleophilic aromatic substitution between the brominated EDOT aldehyde and unprotected mercapto acids to provide T-BAL2 and T-BAL3 handles. The minimal use of protecting groups gave the corresponding linker molecules in few synthetic steps and in good yields. After anchoring of the linker to a polymeric support, introduction of the first amino acid was achieved by reductive amination, giving a secondary amine. A following acylation of the secondary amine with a symmetrical amino 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 either low 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 aqueous acetic acid. Tert-butyl based protecting groups, tert-butyl esters, tert-butyl ethers, and Boc groups, as well as dimethyl acetals were relatively stable to these mild conditions for release of the peptides.
Jessing
Mikkel
M
Department of Chemistry, University of Copenhagen, Universitetsparken 5, DK-2100 Copenhagen, Denmark.
Brandt
Malene
M
Jensen
Knud J
KJ
Christensen
Jørn B
JB
Boas
Ulrik
U
D000577:Amides / Q000737:chemistry*; D002625:Chemistry, Organic / Q000379:methods*; D004151:Dipeptides / Q000737:chemistry; D004743:Enkephalin, Leucine / Q000737:chemistry; D010455:Peptides / Q000138:chemical synthesis*; D013876:Thiophenes / Q000737:chemistry*
D000577:Amides; D004151:Dipeptides; D010455:Peptides; D013876:Thiophenes; D004743:Enkephalin, Leucine