Large-Scale Synthesis of Eldecalcitol

Abstract

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.

Dioxiranes: a half-century journey

“…In 2021, Shin and co-workers reported the industrial-scale synthesis of eldecalcitol ( 567 ), a vitamin D3-analog used in the treatment of osteoporosis. 330 The 23-step synthesis with an overall yield of 0.42% involved dioxirane-mediated C–H oxidation. Vitamin D3 ( 564 ) was converted into Grundman's ketone 565 via ozonolysis, then treatment with in situ generated 10 selectively hydroxylated a tertiary C–H bond to give alcohol 566 (Scheme 127).…”

Process Development of Tacalcitol

“…Flash chromatography (silica gel, hexanes/EA = 40:1) afforded the desired olefin 20 (59 g, 87%) as a pale yellow to colorless oil. 1 (1R,3aR,4S,7aR)-1-((2R,5S,E)-5-(Benzyloxy)-6-methylhept-3-en-2-yl)-7a-methyloctahydro-1H-inden-4-ol (21). To a solution of protected alcohol 20 (59 g, 0.12 mol) in THF (43 mL), TBAF (183 mL, 0.18 mol) was added and the reaction mixture heated at 60 °C for 4−5 h. Upon completion of the reaction, as monitored by the TLC analysis (hexanes/ EtOAc = 5:1), the reaction mixture was cooled to room temperature and quenched by the addition of H 2 O (250 mL).…”

“…15 These routes however risk low asymmetric induction during the key diastereoselective isopropylation step. 21 In our ongoing investigations into the synthesis of vitamin D analogues 22 including 1, we were particularly drawn to the route published by Fall and co-workers, who have utilized a modified Julia olefination reaction to functionalize the C/D ring containing sulfone 6 (Route 3). 19 This approach, however, is significantly limited by the reported low yield in the modified Julia reaction.…”

Novel, Practical, and Scalable Approach for the Synthesis of Eldecalcitol

“…Various strategies have been reported for the synthesis of A-ring phosphine oxide (Figure ), which serves as a key synthon in another synthetic route. − In 1993, Takahashi and Nakazawa reported a method for constructing the A-ring fragment using epoxide 2a . However, in 2015, Zhao and Liu discovered a problem with Takahashi’s strategy: during the key Michael addition reaction, the silane protecting group in the substrate rearranged, resulting in an incorrect structure for the final product.…”

“…This method utilizes d -mannitol as a chiral source to directly establish the C-1 and C-2 stereocenters of the A-ring and constructs the C-3 stereocenter through Sharpless asymmetric epoxidation . In 2022, Shin et al optimized the reaction conditions of Sharpless asymmetric epoxidation to obtain epoxide 2c with high optical purity (97.9%) and yield (85%) . Nevertheless, the use of equimolar amounts of tert -butyl hydroperoxide in this route presents a potential safety hazard.…”