Convergent total synthesis of (+)-calcipotriol: A scalable, modular approach to vitamin D analogs

Abstract

Significance Vitamin D (VitD), a group of secosteroids, has proved to be an essential molecule in supporting overall human health. Structurally, modification at C20 has led to the discovery of novel analogs with a wide range of biological targets. Among them, calcipotriol (Daivonex; LEO Pharma) has been a proven clinical drug for the treatment of psoriasis, an autoimmune skin disease. This work relates to an improved process for the preparation of intermediates useful for the preparation of a range of VitD derivatives, including calcipotriol, and to processes for preparation of calcipotriol. Strategic bond disconnections enable de novo syntheses of both A- and CD-rings not wedded to semisynthesis.

Synthesis of the indeno[1,2-b]indole core of janthitrem B

“…The method was later used by Baran and coworkers in their synthesis of (+)-calcipotriol. 23 However, when we applied these conditions to indole 14 , we obtained an intractable product mixture.…”

Pd(0)‐Catalyzed‐Mediated Synthesis of Vitamin D Compounds

“…The Convergent Wittig‐Horner Approach ( E ) developed by Lythgoe [21] and improved by the Hoffman‐La Roche group (Nutley), [40] features direct formation of the vitamin D triene system by coupling the lithium anion of phosphine oxide 17 (A‐ring) to a Grundmann's type ketone 16 (CD‐side chain fragment) under mild conditions. The most useful CD‐fragment is the Inhoffen‐Lythgoe diol that can be prepared by degradation of vitamin D 2 , [41] although related and versatile bicyclic CD‐fragments have been obtained by total synthesis [42] . The commercial availability of phosphine oxide 17 makes this approach the method of choice to synthesize 1,25D 3 ‐analogs modified at the side chain.…”

Desymmetrization of Cyclohexadienones Containing a Quaternary γ-Carbon Atom by Conjugate Addition of Boron Nucleophiles

“…Initially, we tested Baran’s protocol in the model reaction of cyclohexadienone 1a and boron reagent 2a to give 3aa (Table ), but no desired product was obtained (not shown). We then started with a systematic optimization of the reaction conditions (Table ; see the Supporting Information for the detailed optimization data).…”

“…Of note, Ito and co-workers also realized a γ-selective allylic displacement of an allylic acylal, which furnished the product with borylation in the neopentylic position with 55% ee . In 2022, Baran and co-workers reported a convergent total synthesis of (+)-calcipotriol in which a key precursor was prepared by a desymmetrizing, copper-catalyzed 1,4-addition of a boron nucleophile to cyclohexadienone derivatives with a protected tertiary alcohol in the γ-position (Scheme C) …”

“…A bisborylation would be even more intriguing, as a structurally relative simple cyclohexadienone 1 would be converted into a cyclohexanone derivative with three adjacent stereogenic carbon atoms at C3, C4, and C5 in a highly congested environment. The bisborylation of 1 was, indeed, achieved in 90% yield by increasing the amount of B 2 (pin) 2 ( 2a ) to 3.0 equiv in the standard procedure with L4 , but the diastereomeric ratio was poor (dr = 3:1 for anti - 4aaa ); we find it interesting that Baran and co-workers did not mention the formation of any bisborylated product with 3.0 equiv of B 2 (pin) 2 (see Scheme C) . Almost the same result was obtained with the racemic QuinoxP* ligand rac - L4 (91% yield, dr = 2:1).…”