A unique semisynthetic pathway has been used as a route to novel R106 derivatives. R106-sarcosine, 2, was discovered to be a key intermediate to obtain these derivatives using classical aldol alkylation conditions. Surprisingly, the site of alkylation on 2 was found to be conformationally hindered which yielded both the D and L isomers of R106-1 (aureobasidin A), 1, and other new R106 derivatives. The scope of the alkylation was found to be highly dependent upon the reactivity potential of the electrophile. Semiempirical calculations on R106-1 and 8-(N-methylthrenonine)aureobasidin A, 7, were performed to investigate the thermodynamic stabilities of the D and L isomers. By contrast to stable conformations observed by two X-ray crystal structures of aureobasidins, the calculations indicated that the D isomers were significantly more stable. Furthermore, model semiempirical calculations to probe facial selecitivty were consistent with results obtained experimentally.