Synthesis of 2‐Ethyl‐19‐nor Analogs of 1α,25‐Dihydroxyvitamin D₃

Abstract

The synthesis of two new A‐ring precursors, useful for the convergent assembly of 2α‐ethyl and 2β‐ethyl derivatives of 19‐nor‐1α,25‐dihydroxyvitamin D3, is described. These building blocks were prepared in 14 steps from quinic acid, which led to a new and practical synthesis of 2α‐ethyl‐14‐epi‐19‐nor‐20‐epi‐23‐yne‐1,25(OH)2D3, an analog that shows a remarkably low calcemic effect in mice, while retaining the ability to promote cell differentiation and to inhibit cell proliferation in a number of human cancer cell lines.

O,O-Silyl Group Migrations in Quinic Acid Derivatives: An Opportunity for Divergent Synthesis

“…Gladly, the Dess–Martin periodinane oxidation of 3a gave ketone in an excellent 98% yield, which was further transformed into exocyclic alkene 7 using Tebbe’s reagent (Scheme ). The olefination took place despite the congestion around the secondary alcohol caused by the TBDPS groups, similar to the reported olefination of the TBDMS-protected quinic acid ester derivative …”

“…The olefination took place despite the congestion around the secondary alcohol caused by the TBDPS groups, similar to the reported olefination of the TBDMS-protected quinic acid ester derivative. 26 We envisioned that the syntheses of the family of natural products 6 could be easily achieved by selective epoxide opening of key intermediate 10 with an organometallic reagent derived from the corresponding fatty acid, after deoxygenation of 3a (Scheme 4a). To avoid regio-and diastereoselective issues in the opening of a cyclic siloxonium ion, we decided to proceed with the Barton−McCombie deoxygenation of 3a instead of using the previously explored borane-catalyzed deoxygenation with hydrosilanes.…”

A Predictive Model for the Pd‐Catalyzed Site‐Selective Oxidation of Diols

“…Next, we applied the model to predict the site‐selectivity in the oxidation of quinic acid ( 42 ) (Scheme 5b) [33–35] . This polyol contains three secondary hydroxy groups that have a cis and a trans relation, as well as a tertiary alcohol.…”

“…[27] Next, we applied the model to predict the site-selectivity in the oxidation of quinic acid (42) (Scheme 5b). [33][34][35] This polyol contains three secondary hydroxy groups that have a cis and a trans relation, as well as a tertiary alcohol. According to our model, the C4À OH in quinic acid (see Scheme 5b for numbering) is deactivated because of the vicinal axial C3À OH.…”

Design, Synthesis, Biological Activity, and Structural Analysis of Novel Des-C-Ring and Aromatic-D-Ring Analogues of 1α,25-Dihydroxyvitamin D3

“…The ligand–VDR complex then interacts with the retinoid X receptor to form a heterodimer, which binds, with the assistance of cofactors, to specific regions of the DNA to induce the formation of proteins, which are responsible for a wide range of biological functions including the regulation of mineral homeostasis, cell differentiation-proliferation, apoptosis, and the immune system. − Despite the wide range of biological activities, the clinical applications of the hormone 1,25D 3 have been limited due to its collateral hypercalcemic effects . This problem has sparked interest in the development of less hypercalcemic and more selective 1,25D 3 analogues for the treatment of hyperproliferative diseases, and a few synthetic noncalcemic analogues are already being successfully used in the treatment of psoriasis. − Most of the 1,25D 3 analogues developed to date are modified in the side chain and A-ring, but only a few having structural alterations in the C-ring and/or D-ring have been developed due to synthetic difficulties. − Biological studies on 1,25D 3 analogues that lack the D-ring, − C-ring, ,− the bicyclic CD-ring, − or are modified on the C- or D-rings ,− show that the native CD-core is not mandatory for biological activity and its alteration can reduce the calcemic activity.…”