Journal
ORGANIC PROCESS RESEARCH & DEVELOPMENT
Volume 25, Issue 1, Pages 98-107Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.oprd.0c00436
Keywords
eldecalcitol; C-2-symmetric; C-H hydroxylation; Sharpless epoxidation; triflate alkylation
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Funding
- Advanced Technology Center (ATC) Program [10048257]
- Ministry of Trade, Industry, and Energy of Korea
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The industrial-scale synthesis of eldecalcitol involves a series of reactions including selective protecting group manipulation, palladium-catalyzed cyclization, and C-H hydroxylation to provide the highly crystalline product.
Industrial-scale synthesis of eldecalcitol is described. AA highly diastereoselective epoxidation of p-methoxybenzyl (PMB) protected dienol at room temperature provides the key epoxide intermediate with a secondary hydroxyl group, which is alkylated with a triflate to set up all of the subunits at the C-1, C-2, and C-3 positions of the A-ring fragment. Selective protecting group manipulation followed by palladium-catalyzed cyclization then provides the A-ring synthon. The C/D-ring fragment is obtained by (1) direct C-H hydroxylation of Grundman's ketone using in situ prepared trifluoropropanone dioxirane and (2) protection. Finally, the coupling of the A-ring with the C/D-ring fragment, global deprotection, and recrystallization provide the highly crystalline eldecalcitol.
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