Synthesis of N-Alkyl-N-hydroxyguanidines: A Comparative Study Using Different Protecting Group Strategies

Representing a prime example of the interesting structures found in natural products, the N-alkyl-N-hydroxyguanidine moiety has so far only found limited attention in synthetic organic chemistry. Our studies on Streptomyces-produced muraymycin nucleoside antibiotics have led to a systematic investigation of the synthetic access to the N-hydroxyguanidine-functionalized lipid structure of biologically potent A-series muraymycins. A protecting-group-free approach has been proven to be superior to a strategy employing highly reactive urethane-protected guanidinylation reagents, particularly due to the unexpected instability of fully protected N-alkyl-N-hydroxyguanidines. The protecting-group-free method has been used for the synthesis of other N-alkyl-N-hydroxyguanidine derivatives, namely the antibiotic N(5)-hydroxy-L-arginine. These synthetic results will enable the elucidation of the properties and biological significance of the N-alkyl-N-hydroxyguanidine functionality.