Stereoselective Convergent Synthesis of 24,25-Dihydroxyvitamin D3 Metabolites: A Practical Approach

Abstract

New 4‐substituted acyloxyproline derivatives with different hydrophobic properties of the acyl group were easily synthesized and used as catalysts in the direct asymmetric aldol reaction between cyclic ketones (cyclohexanone and cyclopentanone) and several substituted benzaldehydes. Reactions were carried out using water, this being the best reaction medium examined. Screening of these catalysts showed that compounds bearing the most hydrophobic acyl chains [4‐phenylbutanoate and 4‐(pyren‐1‐yl)butanoate] provided better results. The latter catalysts were successfully used in only 2 mol% at room temperature without additives to give aldol products in excellent stereoselectivities. These results demonstrate that derivatization of the proline moiety with the proper simple hydrophobic substituent in the 4‐position can furnish highly active and stereoselective catalysts without the need of additional chiral backbones in the molecule. Finally, an explanation of the observed stereoselectivities in the presence of water is provided.

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.…”

“…Protection of the 24,25-diol unit as a ketal with acetone and subsequent oxidation of the hydroxyl group at the C-8 position afforded the ketones 16 or 17. A Wittig-Horner reaction between ketones 16-17 and the anion of the phosphine oxide of 4, which contained the vitamin D ring A, generated by treatment with n-BuLi at low temperature, followed by treatment with TBAF and the cationic resin AG ® 50W-X4 afforded, in 7 steps from iodide 8, the 24R,25-(OH) 2 -D 3 (1c, secalciferol) in 32% overall yield, and 24S,25-(OH) 2 -D 3 (1d) in 38% overall yield [20].…”

“…This is an active metabolite that is generated in vivo from calcitriol, in vitro from secalciferol and has preferential biological action in the transport of calcium in the intestine [22]. A Wittig-Horner reaction between ketone 16 and the anion of the 1␣-hydroxylated phosphine oxide 5 [23], generated at low temperature with n-BuLi, followed by deprotection with TBAF and treatment with the resin AG ® 50W-X4 yielded the desired metabolite 1␣,24R,25-(OH) 3 -D 3 (1e) in 40% overall yield from 8 [20].…”

Synthesis of Low Abundant Vitamin D Metabolites and Assaying Their Distribution in Human Serum by Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) as a New Tool for Diagnosis and Risk Prediction of Vitamin DRelated Diseases

“…To employ an A-ring diphenylphosphine oxide such as 26 is favourable, if no further substituents except a C-3 OH group and a C-10 exo-methylene group in the A-ring are needed, as it is already present in vitamin D 2 (13). As example for an efficient application of this strategy, the synthesis of 24,25(OH) 2 D 3 (6) and its deuterated counterpart (d-6), their 3-epi-analogs (9/d-9) and 1α-analogs (5/d-5), is shown in Scheme 3 [37]. Here, diol 23 is converted to its corresponding iodide, which is coupled with enone 27 (obtained in a few routine steps from (R)-(-)-lactic acid using a zinc-copper-catalyzed reaction mediated by ultrasound, leading to 28.…”

Stereoselective synthesis of C24-hydroxylated vitamin D3 analogs: A practical and expeditius route to calcipotriol

“…Most of the many approaches to the synthesis of 24-hydroxylated metabolites and analogs of vitamin D 3 have involved linear routes and chromatographic separation of complex mixtures of diastereoisomers [4]. Only recently have convergent and stereoselective approaches been developed [5,6]. We describe here an efficient synthesis of calcipotriol (2) [7] that illustrates a new approach to C24-hydroxylated vitamin D side chains.…”