The ortho backbone amide linker (o-BAL) is an easily prepared and highly acid-labile handle for solid-phase synthesis.
The tris(alkoxy)benzyl backbone amide linker (BAL) has found widespread application in solid-phase synthesis. The key intermediate for preparation of para BAL (p-BAL) is 2,6-dimethoxy-4-hydroxybenzaldehyde; several reports on its synthesis have appeared. However, the ortho analogue of the handle (o-BAL) has successfully been used by us for the synthesis of C-terminal-modified peptides, oligosaccharides, and substituted anilines. Here, we present a new and convenient synthesis of the key intermediate for o-BAL, 4,6-dimethoxy-2-hydroxybenzaldehyde, by a highly regioselective demethylation with BBr3, followed by purification through steam distillation. Cleavage studies of Leu-enkephalin anchored to either o-BAL or p-BAL handles revealed that both handles were surprisingly acid-labile and released the peptide with dilute TFA (5% and even 1% TFA in CH2Cl2). This useful property allowed the synthesis of fully protected Leu-enkephalin. The very convenient synthesis of 4,6-dimethoxy-2-hydroxybenzaldehyde combined with the benign properties of the o-BAL handle may make it the preferred regioisomer.
Boas
Ulrik
U
Department of Chemistry, University of Copenhagen, Universitetsparken 5, DK-2100 Copenhagen, Denmark.
Brask
Jesper
J
Christensen
Jørn B
JB
Jensen
Knud J
KJ
D000143:Acids / Q000494:pharmacology; D000577:Amides / Q000737:chemistry; D000586:Amination; D001547:Benzaldehydes / Q000138:chemical synthesis* / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D003432:Cross-Linking Reagents / Q000138:chemical synthesis* / Q000737:chemistry; D004743:Enkephalin, Leucine / Q000737:chemistry; D006868:Hydrolysis
D000143:Acids; D000577:Amides; D001547:Benzaldehydes; D003432:Cross-Linking Reagents; D004743:Enkephalin, Leucine; C071066:2,4-dimethoxybenzaldehyde