The retro-aldol reaction at residue 8 of R106-1 produced a chemical handle, in the form of a sarcosine residue, that was amenable to classical aldol alkylation conditions. In vitro assay of several new hydroxylated analogs have shown that L isomers exhibit more potent antifungal activity than D isomers. However, all analogs exhibited a significant decrease in activity against Cryptococcus neoformans. By contrast, structural modifications to R106 were tolerated by some Candida spp., but the potency of activity was diminished as compared to that of the natural product R106-1. The full structure-activity relationship of the new R106 analogs has provided important information about the steric and electronic requirements of binding to target receptors. Furthermore, comparison of the structural differences between R106-1 and other derivatives, suggested that the potential for hydrogen bonding (at residue 8) was a key structural feature that was required to maintain activity against Cryptococcus neoformans.