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Organic Chemistry Highlights

Total Synthesis

Monday, December 4, 2023
Douglass F. Taber
University of Delaware

The Chen/Wang Synthesis of Retigeranic Acid

Retigeranic acid (3), isolated from the Western Himalayas lichen Lobaria retigera, presents a variety of intriguing architectural challenges. Xiaoming Chen and Shao-Hua Wang of Lanzhou University devised a concise route to 3 based on the H-atom transfer cyclization of the diene 1 to the ketone 2 (J. Am. Chem. Soc. 2023, 145, 13549. DOI: 10.1021/jacs.3c04850).

The starting material for the convergent assembly of 1 was the β-keto ester 4, readily prepared from pulegone. Alkylation with the bromide 5 followed by demethoxycarbonylation led to the cyclopentanone 6. One carbon homologation followed by modified Conia cyclization completed the synthesis of the aldehyde 7.

The other cyclic quaternary center of 1 was constructed by Sharpless asymmetric epoxidation of geraniol 8 followed by protection and Lewis acid-mediated pinacol rearrangement to give 9. The corresponding enone 10 was cyclized to the ketone 11. Following the House precedent established decades ago, intramolecular alkylation of the derived bromide proceeded smoothly, leading to the triflate 13. Coupling with the aldehyde 7 completed the assembly of the ketone 1.

The conversion of 1 to 2 presumably proceeded by H atom addition to the exo methylene, leading to the free radical 14. Further cyclization then gave 2.

The ketone 2 had the wrong relative configuration at C-2, and was a mixture of epimers at C-12. Addition of the lithium acetylide 15 followed by dehydration and Au-catalyzed conversion of the alkyne to the ketone delivered the diene 16. Oxidative cleavage to the corresponding carboxylic acid followed by selective hydrogenation completed the synthesis of retigeranic acid (3).

Five weeks earlier, Hanfeng Ding of Zhejiang University published an alternative route to retigeranic acid (3) (J. Am. Chem. Soc. 2023, 145, 11927. DOI: 10.1021/jacs.3c03178). It is instructive to compare and contrast these two approaches.

D. F. Taber, Org. Chem. Highlights 2023, December 4.