Synthesis of aldehyde building blocks protected as acid labile N-boc N,O-acetals: Toward combinatorial solid phase synthesis of novel peptide isosteres

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 pr epared from 1,3-propanediol and 1,4-butanediol, respectively, via a short s eries of facile steps, in 70% overall yield in both cases. For the synthese s 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 w as found to cleanly and rapidly yield the aldehyde under strong acidic cond itions or, if desired, slower under less harsh conditions. As a demonstrati on of the use of the building blocks, one building block was coupled to a s olid support and, after unmasking of the aldehyde, submitted to three diffe rent types of nucleophilic reactions (Pictet-Spengler condensation, reducti ve amination, Horner-Wadsworth-Emmons olefination) followed by further chem ical modification, and the identity of the structures were verified after c leavage from the resin.