Total Synthesis and Complete Stereochemical Assignment of Amphirionin‐5, a Potent Natural Osteoblasts Proliferator

Amphirionin‐5, derived from dinoflagellates of the genus Amphidinium , exhibits a unique biological activity whereby trace amounts can lead to potent proliferation of osteoblasts, making it a promising candidate for regenerative therapy of bone and treatment of osteoporosis. However, the relative configuration of amphirionin‐5 has only been partially determined. Herein, the total synthesis of amphirionin‐5 is undertaken to establish its overall stereochemistry. Synthesized C16‐C28 model with the proposed relative configuration of C19‐C23 shows significant discrepancies between its NMR spectroscopic data around C19 and those of the corresponding substructures of the natural amphirionin‐5, suggesting of necessity for reconsideration of the relative configuration of C19. Two further 19 S ‐type C11‐C28 models are synthesized, and detailed NMR analysis reveals that the 13 C NMR of (19 S ,26 R )‐C11‐C28 models show the best agreement with those in the corresponding substructure of the natural product; thus, the relative configurations from C19 to C26 of amphirionin‐5 are proposed as 19 S *, 20 S *, 23 S *, and 26 R *. Coupling of the C1‐C16 segment, synthesized from an optically active α ‐silyloxy pentanolide as a common intermediate, and the (19 S ,26 R )‐C17‐C28 segment is achieved under intermolecular Stetter reaction conditions, enabling the convergent total synthesis of the candidate diastereomer of amphirionin‐5. Ultimately, the overall stereochemistry of amphirionin‐5 is fully assigned.