Synthesis of Bacillamide B–D and Neobacillamide A Alkaloids, and Their Antipodes: Unambiguous Assignment of Absolute Configurations and Direction of Optical Rotations

The increasing occurrence of algal blooms in aquatic ecosystems has heightened interest in bacillamide alkaloids owing to their pronounced algicidal activity. A critical review of the literature revealed several inconsistencies and contradictions regarding the absolute configurations and optical rotations of both naturally occurring and synthetically prepared bacillamides. To clarify these discrepancies, we developed a new enantioselective synthesis of bacillamides B–D, neobacillamide A, and their respective antipodes, starting from the enantiomers of 2‐(1‐hydroxyethyl)thiazole. This approach enables the efficient and stereocontrolled preparation of all target compounds, along with their enantiomers. Importantly, single‐crystal X‐ray diffraction analysis of the picrate salt of (–)‐bacillamide D and its antipode in conjunction with their synthetic relationships, allowed an unambiguous assignment of absolute configuration. The absolute configurations and directions of optical rotation were reliably established for the entire series of bacillamides and their enantiomers. Chiral HPLC methods were also developed to determine the enantiomeric excess of the alkaloids and their counterparts. Our results correct previous stereochemical misassignments and establish a definitive correlation between structure, chirality, and optical rotation for this class of bioactive natural products. The clarified stereochemical framework provides a solid foundation for understanding structure–activity relationships and for the rational design of analogues with enhanced biological efficacy.