Total synthesis of biselide A

Abstract

A total synthesis of the marine macrolide biselide A is described that relies on an enantiomerically enriched α-chloroaldehyde as the sole chiral building block. Several strategies to construct the macrocycle are presented including a macrocyclic Reformatsky reaction that ultimately provides access to the natural product in a longest linear sequence of 18 steps. Biological testing of synthetic biselide A suggests this macrolide disrupts cell division through a mechanism related to the regulation of microtubule cytoskeleton organization. Overall, this concise synthesis and insight gained into the mechanism of action should inspire medicinal chemistry efforts directed at structurally related anticancer marine macrolides.

Fig. 1. Representative examples of haterumalide (1–3, 5 and 6) and biselide (6 and 7) natural products.

Fig. 2. Previous syntheses of haterumalide and biselide natural products and a chlorohydrin-based strategy for the synthesis of biselide A (7). LLS = longest linear sequence.

Scheme 1. Multigram synthesis of α-chloroaldehyde 24.

Scheme 2. A relay ring closing metathesis strategy for biselide A.

Scheme 3. Synthesis of the tetrahydrofurans 52 and 53.

Scheme 4. Synthesis of the seco acids 62 and 63.

Scheme 5. Synthesis of the bromoacetate 77.

Scheme 6. Completion of the synthesis of biselide A (7).

Fig. 3. Cell Painting results for biselide A (7). (A) Cell Painting fingerprints for dilution series of biselide A. Yellow = positive deviation from control values, blue = negative deviation from control values. Comparison of Cell Painting fingerprints for active biselide A concentrations and representative related reference compounds. (B) Original Cell Painting images including control and biselide A (top row), representative TargetMol compounds with related MOAs (middle row) and TargetMol compounds with other, unrelated MOAs (bottom row). Images are composite images from all fluorescence channels.