Convergent and stereospecific synthesis of molecules containing alpha-functionalized guanidiniums via alpha-guanidino acids.

To introduce chirality and functional groups adjacent to guanidiniums to modulate specificity and affinity in recognition, N,N'-bis(Boc)-alpha-guanidino acids were synthesized from alpha-amino acid methyl esters. Protected alpha-guanidino acids coupled to cyclohexylamine and trans-1,4-diaminocyclohexane in good yield and with retention of stereochemistry. Boc deprotection was conducted under mild acidic conditions (0.5 M HCl/EtOAc) to minimize epimerization. The deprotected guanidinium is configurationally stable under more acidic conditions. This approach represents a practical, convergent, stereospecific methodology to introduce chiral alpha-substituted guanidinium groups into molecules.