title: Synthesis of aldehyde building blocks protected as acid labile N-Boc N,O-acetals: toward combinatorial solid phase synthesis of novel peptide isosteres.
abstract: The synthesis of (RS)-3'-tert-butoxycarbonyl-perhydro-1', 3'-oxazine-2'-yl acetic acid and the syntheses of the simple and C-2 substituted 3'-tert-butoxycarbonyl-perhydro-1',3'-oxazine-2'(RS)-yl propionic acids from simple starting materials are presented. The simple compounds were prepared from 1,3-propanediol and 1, 4-butanediol, respectively, via a short series of facile steps, in 70% overall yield in both cases. For the syntheses of the C-2 substituted compounds of the longer homologue, (RS)-3'-tert-butoxycarbonyl-perhydro-1',3'-oxazine-2'-yl propionic acid, a malonic ester route was selected, thus allowing easy incorporation of various side chains. The stability of the novel aldehyde protection group, the N-Boc N,O-acetal moiety, under various acidic conditions was investigated, and it was found to cleanly and rapidly yield the aldehyde under strong acidic conditions or, if desired, slower under less harsh conditions. As a demonstration of the use of the building blocks, one building block was coupled to a solid support and, after unmasking of the aldehyde, submitted to three different types of nucleophilic reactions (Pictet-Spengler condensation, reductive amination, Horner-Wadsworth-Emmons olefination) followed by further chemical modification, and the identity of the structures were verified after cleavage from the resin.
authors.affiliation: Center for Solid Phase Organic Combinatorial Chemistry, Department of Chemistry, Carlsberg Laboratory, Gamle Carlsberg Vej 10, DK-2500 Valby, Denmark.
authors.forename: T
authors.initials: T
authors.lastname: Groth
authors.forename: M
authors.initials: M
authors.lastname: Meldal
mesh_terms: D000080:Acetals / Q000737:chemistry*; D000447:Aldehydes / Q000138:chemical synthesis* / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D020650:Combinatorial Chemistry Techniques; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D007202:Indicators and Reagents; D010084:Oxidation-Reduction; D010455:Peptides / Q000737:chemistry*; D012997:Solvents
chemical_list: D000080:Acetals; D000447:Aldehydes; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D010455:Peptides; D012997:Solvents