Synthesis of deuterium labeled NMDA receptor inhibitor – 20-Oxo-5β-[9,12,12- 2H 3]pregnan-3α-yl- l-glutamyl 1-ester

[Display omitted] ► Synthesis of the deuterated inhibitor of NMDA receptor. ► Efficient method for introduction of three deuterium atoms into positions 9 and 12 of steroid skeleton. ► Deoxygenation of 11-hydroxy substituent via the Barton–McCombie reaction. 20-Oxo-5β-[9,12,12- 2H 3]pregnan-3α-yl- l-...

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Bibliographic Details
Published in:Steroids 2012-02, Vol.77 (3), p.282-287
Main Authors: Kapras, Vojtech, Slavickova, Alena, Stastna, Eva, Vyklicky, Ladislav, Vales, Karel, Chodounska, Hana
Format: Article
Language:English
Subjects:
Biological and medical sciences
Chromatography, Thin Layer
Deuterium - chemistry
Deuterium labeling
Fundamental and applied biological sciences. Psychology
Glutamates - chemistry
Hydroxyprogesterones - chemistry
Isotope Labeling - methods
Magnetic Resonance Spectroscopy
Molecular Structure
Neuroprotection
NMDA receptor
Oxidation-Reduction
Pregnanolone - analogs & derivatives
Pregnanolone - chemical synthesis
Pregnanolone - chemistry
Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors
Solvents - chemistry
Vertebrates: endocrinology
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Summary:[Display omitted] ► Synthesis of the deuterated inhibitor of NMDA receptor. ► Efficient method for introduction of three deuterium atoms into positions 9 and 12 of steroid skeleton. ► Deoxygenation of 11-hydroxy substituent via the Barton–McCombie reaction. 20-Oxo-5β-[9,12,12- 2H 3]pregnan-3α-yl- l-glutamyl 1-ester 11 was synthesized as an internal standard for quantification of a neuroprotective NMDA receptor ligand, 20-oxo-5β-pregnan-3α-yl- l-glutamyl 1-ester 18 and its metabolites, in plasma and tissue. 11α-Hydroxy-progesterone ( 1) was reduced under basic conditions to yield the corresponding 5β-steroid. Protection of the 3- and 20-oxo groups and oxidation of the 11α-hydroxy group was then followed by a deuterium exchange, conducted under basic conditions using deuterated methanol. Next, the carbonyl moiety at C-11 was reduced and the 11α-hydroxyl group removed through utilization of the Barton–McCombie reaction. Subsequent deprotection of the 3- and 20-acetals and stereoselective reduction of the 3-oxo group gave the desired trideuterated pregnanolone ( 8). This was coupled with protected glutamic acid, which was then deprotected to yield [9,12,12- 2H 3]-pregnanolone glutamate ( 11) with >99% isotopic purity.
ISSN:0039-128X
1878-5867
DOI:10.1016/j.steroids.2011.12.019