Synthesis of Resveratrol and Its Analogs, Phase-Transfer Catalyzed Asymmetric Glycolate Aldol Reaction, and Total Synthesis of 8,9-Methylamido-Geldanamycin

• Main Author: Liu, Jing
• Format: Others
• Published: BYU ScholarsArchive 2007
• Subjects: resveratrol; phase-transfer catalysts; aldol; Geldanamycin; decarbonylative Heck reaction.; Biochemistry; Chemistry
• Online Access: https://scholarsarchive.byu.edu/etd/1415; https://scholarsarchive.byu.edu/cgi/viewcontent.cgi?article=2414&context=etd

The phytoalexin resveratrol and its acetyl analogs have been made using a decarbonylative Heck reaction. The acid chloride derived from 3,5-dihydroxybenzoic acid was coupled with suitable protected 4-hydroxystyrene in the presence of palladium acetate and N,N-bis-(2,6-diisopropylphenyl)-4,5-dihydro imidazolium chloride to give the substituted stilbene in good yield as the key step. Human HL-60 cell assays showed the 4'-acetyl resveratrol variant improved activity (ED50 17 μM) relative to resveratrol (24 μM). Cinchona phase-transfer catalysts (PTC) were developed for glycolate aldol reactions to give differentially protected 1,2-diol products. Silyl enol ether of diphenylmethoxy-2,5-dimethoxyacetophenone reacted to generate benzhydryl-protected products. O-Allyl trifluorobenzyl cinchonium hydrodifluoride (20 mol %) catalyzed the addition of the silyl enol ether to benzaldehyde to give aldol product as a single syn-product in 76% yield and 80% ee. Recrystallization enriched the product to 95% ee, and a Baeyer-Villiger reaction transformed the product into useful ester intermediates. A novel unnatural product, 8,9-Methylamido-Geldanamycin, has been designed and synthesized. Using a convergent route, the total synthesis of the molecule involved only 27 longest linear steps. New synthesis methodologies, including auxiliary controlled asymmetric anti-glycolate aldol, syn-norephedrine aldol, and selective p-quinone formation, were used.