A Stereospecific Synthesis of 24(S)-Hydroxyvitamin D₂, a Prodrug for 1α,24(S)-Dihydroxyvitamin D₂

Abstract

This contribution describes the first stereospecific synthesis of 24(S)-hydroxyvitamin D2 (1), a metabolite of vitamin D2. This metabolite acts as a prodrug for 1α,24(S)-dihydroxyvitamin D2 (2), which is under development for treatment of various diseases characterized by cellular hyperproliferation. The key step of the synthesis involves the Wittig−Horner olefination of (S)-2,3-dimethyl-2-triethysilyloxybutyraldehyde (17) and a vitamin D2 phosphine oxide derivative (22). The synthesis of the requisite aldehyde started with the commercially available l-(+)-valine and was completed in seven steps. The vitamin D2 phosphine oxide derivative was synthesized in seven steps starting from vitamin D2.

Synthesis of the C10–C24‐Bis‐Spiroacetal Core of 13‐Desmethyl Spirolide C Based on a Sila‐Stetter‐Acetalization Process

“…The alkylation occurred with high diastereocontrol, leading to 22 in 82 % yield as a single stereoisomer with the relative configuration as shown 17. Dioxolanone ring‐opening under basic conditions,21 followed by coupling of the resulting carboxylic acid with the N ‐methyl‐ N ‐methoxy amine led to the Weinreb amide 23 22. Protection of the tertiary hydroxy group in 23 followed by addition of a vinyl Grignard reagent finally led to the desired enone 8 in 11 steps (longest linear sequence) and 21 % overall yield from ( R )‐aspartic acid.…”

Synthesis of 24(28)-Methylene-1α-Hydroxyvitamin D3, a Novel Vitamin D3 Analogue

“…23 113 °C). SO 2 -Cycloadduct of 3(S)-(tert-but yldimethylsilyloxy)-9, 10-secoergosta-5, 7(E), 10(19), 22(E)-tetraene 15 (8): A solution compound 7 (57.96 g, 126 mmol) in dichloromethane (300 mL) was treated with imidazole (11.15 g, 164 mmol) and TBDMS chloride (22.78 g, 151 mmol) at room temperature. The reaction mixture was stirred under N 2 at room temperature overnight.…”

“…At the beginning of our research work, anthracene was used as catalyst, 15 the reaction was uncomplete and the yield was only about 50%. While 9-acetyl anthracene was introduced, 22 the reaction was improved with the yield up to 90% and the crude 18 could be used directly in next step. The desired product 1 was then obtained by removing the TBS protecting group of compound 18 using tetrabutylammonium fluoride in THF.…”

Purification and biochemical characterisation of a novel glutamate decarboxylase from rice bran

“…Diese Synthesevorschrift wurde bei Roche zur Herstellung von 100 g Calcitriol 3 angewendet 41. Eine ähnliche Route, die als geeignet zur Produktion in größerem Maßstab eingestuft wurde, wurde zur stereospezifischen Synthese von 24( S )‐Hydroxyvitamin D 2 ( 11 ) genutzt 42. Unter Verwendung des gleichen SO 2 ‐Addukts 9 im 200‐g‐Maßstab wurde der Wirkstoff in g‐Mengen erhalten (Schema ).…”