A Common C2 -Symmetric 2,2'-Biphenol Building Block and its Application in the Synthesis of (+)-di-epi-Gonytolide A.

A variety of biaryl polyketides exhibit remarkable bioactivities. However, their synthetic accessibility is often challenging. Herein, the enantioselective preparation and synthetic application of an axially chiral 2,2'-biphenol building block is outlined that represents a common motif of these intriguing natural products. Based on the highly regioselective and scalable bromination of a phenol precursor, a coupling process by Lipshutz cuprate oxidation was developed. A copper-mediated deracemization strategy proved to be superior to derivatization or kinetic resolution approaches. Key steps in the overall building block synthesis were rationalized through DFT studies. Utilizing the 2,2'-biphenol, a highly diastereoselective five step synthesis of formerly unknown (+)-di-epi-gonytolide A was developed, thus showcasing the building block's general potential for the synthesis of natural products and their derivatives. En route, the first enantioselective construction of a chromone dimer intermediate was established.

Application of Cyclic Diaryliodonium Salts in the Synthesis of Axially Chiral Natural Product Analogues.

The application of cyclic diaryliodonium salts in the synthesis of bioactive natural product analogues was demonstrated. Axially chiral biaryls were obtained via the enantioselective ring opening of cyclic diaryliodonium salts. Regioselective borylation was key in accessing both enantiomers of a biphenol key intermediate in eight steps overall. 8,8″-Amino biflavones were synthesized, their bioactivity profiled, and the eutomer identified. The structure-activity relationship was probed.

Modular Approach for the Synthesis and Bioactivity Profiling of 8,8'-Biflavones.

In this work, we report the scalable and modular synthesis of a library of 55 monomeric and dimeric flavonoids including 14 8,8'-biflavones. The sterically demanding tetra-ortho-substituted axis of an acetophenone dimer key intermediate was constructed in a regioselective manner using Fe-mediated oxidative coupling. This step was systematically optimized and performed on up to multigram scale. The biological activities of this compound library were evaluated, including cytotoxicity against healthy and malignant human cell lines, antimicrobial activity against the apicomplexan parasite Toxoplasma gondii, and antioxidant capacity. A marked increase in activity for the 8,8'-dimeric structures compared to that of their monomeric counterparts was observed. Several biflavones were identified with high selectivity indices (low cytotoxicity and high antiprotozoal activity), showing that this class of natural products may serve as lead structures for further investigations.