Total synthesis of 1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3 (ED-71)

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

“…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. 25 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%). 26 Nevertheless, the use of equimolar amounts of tert-butyl hydroperoxide in this route presents a potential safety hazard.…”

“…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.…”

“…In 2020, Deng et al proposed an efficient approach for constructing the A-ring using epoxide 2b (obtained by d -mannitol, five steps, 19.8% yield) as the starting material. 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%) .…”

Large-Scale Synthesis of Eldecalcitol

“…Among them, eldecalcitol ( 1 ) has achieved prominent commercial success for the treatment of osteoporosis in Japan and has shown superior activity in lowering the risk of fracture and in increasing the bone mineral density over alfacalcidol. , In this context, extensive efforts have been made to devise an efficient synthesis of eldecalcitol. − These could be categorized into two main strategies: (1) the late-stage photoisomerization of a fully functionalized 7-dehydrocholesterol derivative (Figure , Route 1) and (2) the coupling reaction of the A- and the C/D-ring precursors (Routes 2 and 3). The former strategy was developed by Chugai Pharmaceutical, commencing from lithocholic acid, and is now used in the commercial process .…”

“…This feature necessitates preparative HPLC purification (Route 1). The latter strategy was developed using either a coupling of the A-ring synthon via the Horner–Wittig reaction (Route 2) or the transition-metal catalyzed cyclization of the A-ring ene-yne fragment with the appropriate C/D-ring-containing synthon (Route 3). , These routes also suffered from low yields in the final cyclization and coupling reactions, respectively. Herein, we disclose a highly practical preparation of the A and C/D-ring fragments and their subsequent manipulation toward eldecalcitol.…”