Studies on the Synthesis of Vitamin D Analogs with Aromatic D-Ring

Abstract

Herein, we describe our studies on the synthesis of 1α,25-dihydroxyvitamin D 3 analogs possessing a benzene ring replacing the natural 5-membered D-ring by the Wittig-Horner and dienyne approaches. A key feature is the synthesis of a Cr(CO) 3 -complexed previtamin D derivative that enables the construction of vitamin D analogs with aromatic D-ring through a thermal [1,7]-H sigmatropic shift. This study establishes the basis for the design of new vitamin D analogs containing aromatic D-ring, complexed or uncomplexed to Cr(CO) 3 type moieties for specific molecular recognition and drug research and development.

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

“…of up to 50 mg of vitamin D analog requires the use of an excess of the phosphine oxide 17; (b) low yield obtained in the formation of the triene unit with alkylketones substituted at C11; [43] (b) unsuitable for the synthesis of analogs of 1,25D 3 with alkyl substituents at C-6 [43] or aromatic D-ring; [44,45] (c) long multistep synthesis of phosphine oxides modified at the Aring. [46] The first example of palladium-catalyzed cyclization to vitamin D A-ring synthons for the Wittig-Horner approach was carried out in Shimizu's laboratory (Scheme 2).…”

“…[70][71][72][73][74][75][76][77][78][79][80] The relative high temperature (reflux in triethyl amine-toluene) required for the Pd(0)-catalyzed alkylative cyclization is unsuitable for the formation of vitamin D analogs that undergo thermal equilibration to the previtamin D form such as 6-methyl-25hydroxyvitamin D 3 , [43,81] and aromatic-D-ring analogs. [44,45]…”

“…[43] This Pd-catalyzed ring-closure/Suzuki-Miyaura strategy (Approach I, Scheme 1) indeed circumvents the problems associated with previous synthetic approaches providing a general method for the small-scale preparation of a wide variety of 1,25D 3 analogs in high yield, in protic medium, under mild conditions, in a practical, economical, and reproducible fashion, including 1,25D 3 analogs that show tendency to equilibrate with the corresponding previtamins or that cannot be obtained by the Wittig-Horner method. [44,45] The scope of this approach is illustrated by the efficient construction of the triene moieties of the natural hormone 1,25D 3 [43] and the highly active and non-calcemic analog 79 [92] (Scheme 14). Alkenyl bromide 20d was prepared from ketone 16d in 80% yield.…”

“…[43,111,112,116,[123][124][125][126][127][128][129][130][131][132][133][134][135][136][137][138][139][140][141] This synthetic route has the following advantages: (1) the easy and short preparation of the A-ring-enyne synthons (bottom fragment); and (2) the easy preparation of the enol triflates (upper fragment) from the corresponding ketones. The main disadvantages are: (1) the overhydrogenation during Lindlar partial hydrogenation of the triple bond; (2) the low yield on vitamin D when thermal isomerization favors the previtamin D intermediate (for example 6-methyl-1,25D 3 analogs, [44] and aromatic-D-ring-1,25D 3 analogs; [45,46] and (3) the instability of the vitamin D compound under the thermal isomerization of the previtamin D form.…”

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

“…Both the Pd(0)-catalyzed cyclization/Suzuki–Miyaura cross-coupling approach and the dienyne approach allowed access to this type of compounds. However, the vitamin D triene system of 2a unexpectedly equilibrated to a large extent at room temperature to the previtamin D form 2b via [1,7]-H sigmatropic shift. ,, This drawback led us to explore the synthesis of a series of 1,25D 3 analogues that lack the C-ring and possess an aromatic D-ring. PG-136 (Figure ) is an example of this new class of highly active and noncalcemic 1,25D 3 analogues …”