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 intr...

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Bibliographic Details
Published in:Chemistry : a European journal 2023-06, Vol.29 (34), p.e202300941-n/a
Main Authors: Greb, Julian, Drennhaus, Till, Klischan, Moritz K. T., Schroeder, Zachary W., Frey, Wolfgang, Pietruszka, Jörg
Format: Article
Language:English
Subjects:
atropisomerism
Bromination
building block
Chemistry
Construction
density functional calculations
Enantiomers
Natural products
Oxidation
Phenols
Polyketides
Stereoselectivity
Synthesis
total synthesis
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Summary: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. An axially chiral biphenol with a common biaryl polyketide motif was investigated. The versatile building block was made accessible by a streamlined synthesis featuring an efficient coupling procedure as well as a DFT‐rationalized starting material bromination and thermodynamically controlled deracemization process. An application was demonstrated in a concise and highly‐diastereoselective synthesis of (+)‐di‐epi‐gonytolide A.
ISSN:0947-6539
1521-3765
DOI:10.1002/chem.202300941