Synthetic Studies toward Bacillaene and Analogues

Abstract

Thirty years after its first isolation, bacillaene, a polyketide and polyene antibiotic initially discovered in <em>Bacillus subtilis</em>, remains a subject of ongoing research. While significant contributions to the study of this natural product have come from the fields of biochemistry and molecular biology, no contributions were reported from the field of synthetic organic chemistry. <br/> Despite its intriguing structure, the synthesis of bacillaene is severely hampered due to its highly labile molecular architecture. <br/> In this work, the great challenge of developing a total synthesis of the natural product bacillaene and a simplified analogue was pursued. It features improved syntheses of bimetallic linchpin reagents, iterative cross-coupling strategies and investigations into isomerization processes. Furthermore, the purification and isolation of unstable polyenes is described in detail. Additionally, a valuable method for monitoring polyene iteration via UV-vis shift analyses was developed. <br/> The synthesis of the hexaene core of bacillaene was achieved with excellent geometrical purity and subsequently compared to the authentic natural product. A first bacillaene analogue was successfully synthesized, however its final isolation and characterization was not achieved. <br/> Additionally, methods for the synthesis of the enamide sidechain were explored. The Peterson olefination method for enamide formation, as described by <em>Fürstner</em>, was successfully implemented on a test system. Finally, based on the insights gained from this work, a synthetic strategy is proposed that might enable a future total synthesis of the natural product bacillaene.