Synthesis of the First 24-Aminovitamin D3 Derivatives by Diastereoselective Conjugate Addition to a Chiral Methyleneoxazolidinone in Aqueous Media

Abstract

S y n t h e s i s o f t h e f i r s t 2 4 -A m i n o v i t a m i n D 3 D e r i v a t i v e sAbstract: The synthesis of the first 24-aminovitamin D 3 derivatives is reported. A stereoselective convergent synthetic approach was employed to prepare 24(S)-benzoylamino-25-hydroxyvitamin D 3 and 24(S)-benzoylamino-1a,25-dihydroxyvitamin D 3 in six steps from iodide 2 in 34% and 42% overall yields, respectively. The key step in the synthesis is a novel diastereoselective ultrasonically induced conjugate addition, promoted by the zinc-copper couple, of iodide 2 to methyleneoxazolidinone 4 in aqueous media. The conjugate vitamin D triene system was constructed using the Lythgoe approach.Vitamin D 3 (1a, Figure 1), through its major active metabolites 1a,25-dihydroxyvitamin D 3 [1a,25-(OH) 2 -D 3 , 1b, calcitriol] and 24(R),25-dihydroxyvitamin D 3 [24(R),25-(OH) 2 -D 3 , 1c, secalciferol], exhibits a wide range of biological functions. 1 Besides the regulation of calcium and phosphorus homeostasis, vitamin D 3 participates in cellular proliferation and differentiation processes as well as in some functions related to the immune system. However, its utility as a drug in the treatment of tumors and skin diseases is limited since effective doses provoke undesirable calcemic side effects. 1a For this reason, the search for vitamin D 3 analogues with selective biological function -i.e. a low calcemic effect and high activity as a cellular differentiation agent -has been extensively pursued in the last two decades. 2 The numerous analogues of vitamin D 3 synthesized to date has allowed the establishment of some structure-activity relationships (SAR). These relationships show that the side chain plays a crucial role and that small structural modifications have dramatic effects on the biological activity. 3 Indeed, the most important analogues of vitamin D in terms of therapeutic utility are those containing a modified side chain. 4 We report here the stereoselective synthesis of the first 24-aminovitamin D analogues (1d).Bearing in mind the influence of the hydroxyl groups at C-24 or C-25 on both the binding to the vitamin D receptor (VDR) and the associated biological responses, 3 we considered that the replacement of one of these groups by another polar unit, particularly an amino group or derivative thereof, could give rise to novel analogues with a modified affinity for the VDR and hence different biological activity. The amino group is a very important group in drug development but, despite the large number of modifications that have been made in the vitamin D 3 side chain, the synthesis of amino analogues of vitamin D 3 has not been reported previously.As part of our program devoted to the synthesis of vitamin D analogs and metabolites, as well as to the rational understanding of related biological functions, we recently discovered 5 that 24,25-(OH) 2 -D 3 active metabolites such as secalciferol can be synthesized by employing a diastereoselective conjugate addition in aqueous media 6 of iodide 2 to Seebach's dioxolanone 3....

Stereoselective convergent synthesis of 24-substituted metabolites and analogues of vitamin D

“…When the reaction was performed with the dioxolanone enantiomer (−)-6, under the same experimental conditions, the conjugate addition product 10 was obtained in similar yield (74%) and stereoselectivity [cis:trans ratio of 13:1, 86% de, major diastereomer: (24S)]. This result proves that the stereoselectivity of the reaction is independent of the chirality of the iodide and that a remarkable, highly diastereoselective protonation of the enolate in aqueous media occurs [20,21]. On the other hand, ultrasonically induced conjugate addition of iodide 8 to methyleneoxazolidinone (−)-7, promoted by a zinc-copper couple in aqueous ethanol, afforded oxazolidinone 11 as a cis:trans mixture of diastereomers in a 4.9:1 ratio [66% de, major diastereomer: (24S)] and 74% yield.…”

“…A stereoselective Wittig-Horner reaction between ketone 23 and the anion of phosphine oxide 4, generated by treatment with n-BuLi at low temperature, afforded the protected vitamin D analogue 24 (80%). Deprotection with TBAF gave the first amino derivative of vitamin D 3 , 24S-benzoylamino-25-hydroxyvitamin D 3 (26), in 96% yield (6 steps from iodide 8, 36% overall yield) [21].…”

“…Wittig-Horner reaction of ketone 23 with the anion of 1␣-hydroxylated phosphine oxide 5 gave the protected vitamin 25 in 95% yield. Deprotection with TBAF gave the desired vitamin analogue, 24S-benzoylamino-1␣,25-dihydroxyvitamin D 3 (27), in 6 steps and 45% overall yield from iodide 8 [21].…”

The Centennial Collection of VDR Ligands: Metabolites, Analogs, Hybrids and Non-Secosteroidal Ligands

“…1α,25-Dihydroxy-21-(3-hydroxy-3-methylbutyl)vitamin D 3 (435, Gemini) [171] has emerged as the lead compound with superior gene transcription activity and tumor-cell-line inhibition. Figure 11 (2001Figure 11 ( -2002 [183][184][185][186][187][188][189][190][191][192][193][194][195][196]. 1α,25-(OH) 2 -16-ene-20-epi-23-yne-3-epi-D 3 (493), 1α,25(OH) 2 -16-ene-23-yne-hexafluoro-3-epi-D 3 (494), and 1α,25(OH) 2 -16-ene-3-epi-D 3 (495) are potent inducers of apoptosis of HL-60 cells.…”

Diastereoselective Conjugate Addition to Chiral α,β‐Unsaturated Carbonyl Systems in Aqueous Media: An Enantioselective Entry to α‐ and γ‐Hydroxy Acids and α‐Amino Acids

“…In particular, our group soon found applications for this methodology in the synthesis of vitamin D metabolites and analogues 11. Later, we applied this methodology for the stereoselective synthesis of 24‐hydroxyvitamin D metabolites12 and 24‐aminovitamin D derivatives 13. In a recent communication,14 we reported the diastereoselective ultrasonically induced zinc–copper conjugate addition of achiral iodides to chiral α,β‐unsaturated systems in aqueous media.…”