A Reverse Approach to the Total Synthesis of Halichondrin B.

A new strategy is described for the total synthesis of halichondrin B featuring reversal of the sequential construction of a number of its cyclic ethers from the classical approach by instead forming C-O bonds first followed by C-C bond formation. Employing the Nicholas reaction to generate linear ethers as precursors for the total synthesis of halichondrin B and other members of the halichondrin and eribulin families of compounds, this novel approach provides new opportunities for the development of improved syntheses of these complex and valuable compounds. In this Article, we report the syntheses of defined fragments I, MN, EFG, and A. Fragments I and MN were then coupled and elaborated to advanced intermediate IJKLMN, which was joined with fragment EFG to afford, after appropriate elaboration and macrolactonization, the more advanced polycyclic intermediate EFGHIJKLMN. Elaboration of the latter and coupling with fragment A followed by further functionalization completed the total synthesis of halichondrin B through a short and convergent pathway.

Total Synthesis of (+)-Strongylophorines 2 and 9.

The first enantioselective total syntheses of highly complex hexacyclic meroterpenoids STR-2 and -9 (strongylophorine (STR)) are reported. Key elements of the synthetic route include the use of Robinson-type annulation reaction to construct the tricyclic terpenoid building block and a highly efficient PIDA-mediated 1,3-diaxial sp3 C-H activation to incorporate the requisite δ-lactone moiety. This route also enables the determination of absolute configuration of the synthesized natural products.

Enantioselective Total Synthesis and Assignment of the Absolute Configuration of the Meroterpenoid (+)-Taondiol.

The first enantioselective total synthesis of (+)-taondiol, a pentacyclic marine meroterpenoid, has been achieved, which in addition to confirming the structure also established the absolute configuration of the natural product. The notable points in the synthetic route are synthesis of a highly functionalized tricyclic diterpenoid moiety starting from an enantiopure Wieland-Miescher ketone derivative in concise manner via Robinson-type annulation and an elegant hydrogen atom transfer olefin reduction followed by Lewis acid-catalyzed Friedel-Crafts reaction for one-pot C-C and C-O bond formations resulting in construction of the pentacyclic meroterpenoid skeleton.

Biomimetic Enantioselective Total Synthesis of (-)-Petromindole.

The first enantioselective total synthesis of (-)-petromindole, an architecturally distinct congener of indole diterpene family, has been achieved. Key features of this synthetic route include the scalable and concise synthesis of tricyclic allylic alcohol from enantiopure Wieland-Mischer ketone derivative, and TMSOTf-mediated, highly efficient biomimetic C-4 cyclization of indole derivative for the rapid construction of a hexacyclic skeleton of petromindole.

Biomimetic Enantioselective Total Synthesis of (-)-Mycoleptodiscin A.

Biomimetic total synthesis of (-)-mycoleptodiscin A (1) was achieved starting from the enantiopure key intermediate, which was prepared by Friedel-Crafts reaction between 7-methoxyindole and chiral primary allylic alcohol. The crucial step in this synthesis was an intramolecular Friedel-Crafts reaction at C-4 of the indole derivative driven by the EDG/EWG within a compound that was rationally designed to prevent the cyclization reaction at the C-2 positon of indole, thereby successfully providing the complete carbon framework of 1. This intramolecular Friedel-Crafts reaction at C-4 of indole derivative could be applied for the synthesis of other C-4-substituted indole alkaloid natural products.