Formal Desymmetrization of the Diastereotopic Chains in Gemini Calcitriol Derivatives with Two Different Side Chains at C‐20

Abstract

Derivatives of calcitriol with two equal side chains emanating at C‐20, also known as gemini, have emerged as interesting compounds, either as instruments for assessing the steric requirements of the vitamin D receptor or as drug candidates. We now describe the syntheses of gemini analogs where the two side chains differ from each other. While retaining the 2‐hydroxy‐2‐methylpentyl moiety, common to both calcitriol and gemini, as one chain, we replaced the other with a 1,1,1‐trifluoro‐2‐hydroxy‐2‐(trifluoromethyl)‐3‐pentynyl group. The features comprising this chain modification are commonly regarded to improve toxicity profiles and drug performance. The resulting epimeric pairs with a new stereogenic center at C‐20 were resolved and the absolute configurations assigned. The side‐chain desymmetrization protocols described herein serve as a basis for additional synthesis activity in this area. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

Calcitriol derivatives with two different side-chains at C-20. Part 4: Further chain modifications that alter VDR-dependent monocytic differentiation potency in human leukemia cells

“…The key intermediate 2 prepared from alkene 1 has been described, 17 A Simmons-Smith reaction of 2(Scheme 1) produced 3 stereospecifically in excellent yield.…”

“…11,12 The discovery that 20-epi vitamin D analogs can exhibit higher potencies 13,14 engendered the synthesis of Gemini, distinguished by two identical side chains emanating at C-20. 15,16 In a second generation of Gemini compounds, chain-modifications aimed at metabolic retardation and enhanced differentiation were introduced stereoselectively 17,18 and their effects evaluated. 19,20 Increased anti-proliferative activities of 20-desmethyl-20-cyclopropyl-cholecalciferol analogs have also been reported, 21 and an additional modification in the form of an unsaturated chain containing terminal trifluoromethyl groups and a 19-nor A-ring 22 has demonstrated enhanced transcriptional activity while maintaining low hypercalcemia-induction potential when compared to 1,25D.…”

Colon cancer and solar ultraviolet B radiation and prevention and treatment of colon cancer in mice with vitamin D and its Gemini analogs

“…6B) [33]. The importance of a spacer in the form of the C,Dring moiety was underscored when it was demonstrated that a hormone analog, featuring a direct connection of the Aring to the side-chain assembly via the 5,7-diene linkage, did not bind to the VDR [34]. Upon introducing a distinct five-membered ring, the E-ring, at carbons 13, 17, and 20, the analog did bind to the VDR and exhibited 1,25(OH) 2 D 3 -like properties, but with only 10% of the affinity compared to 1,25(OH) 2 D 3 (Fig.…”

Calcitriol derivatives with two different side chains at C-20

“…This task was achieved by the addition of borane to the diastereotopic face of the alkene moiety in 5 [9,10]. Completion of the hydroboration protocol provided the pair of epmeric dihydroxyalkanes 6 and 7 that was easily separated by chromatography (Scheme 1).…”

“…Completion of the hydroboration protocol provided the pair of epmeric dihydroxyalkanes 6 and 7 that was easily separated by chromatography (Scheme 1). The absolute configuration of these alkenols is based on a crystallographic analysis [10]. A sequence of steps converted these diols to ketones of the type 9a and 9b.…”