Total Synthesis of <i>ent</i>-Pregnanolone Sulfate and Its Biological Investigation at the NMDA Receptor

Kapras, Vojtěch; Vyklický, Vojtěch; Budêšínský, Miloś; Císařová, I.; Vyklický, Ladislav; Chodounská, Hana; Jahn, Ullrich

doi:10.1021/acs.orglett.7b03838

Cited by 19 publications

(14 citation statements)

References 40 publications

(57 reference statements)

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“…Several features of the solid‐state structures are noteworthy (Table ). The bond lengths of the C4−OTMP unit vary over a rather small range of 0.01 Å (atom numbering of X‐ray structures in Figure ) and are somewhat shorter than those in comparable simpler cyclic α‐carbonyl‐substituted alkoxyamines (cyclic ketones 1.454 Å, esters 1.435 Å) but are longer than those of α‐amino‐substituted alkoxyamines. Surprisingly, the C3−N2 distance varies and is, except for trans ‐ 3 , longer than in the corresponding cis isomers, whereas the C1−N1 bond lengths do not differ very much in both isomers.…”

Section: Resultsmentioning

confidence: 99%

Unique Stereoselective Homolytic C−O Bond Activation in Diketopiperazine‐Derived Alkoxyamines by Adjacent Amide Pyramidalization

Amatov

Jangra

Pohl

et al. 2018

Chemistry A European J

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Simple monocyclic diketopiperazine (DKP)-derived alkoxyamines exhibit unprecedented activation of a remote C-O bond for homolysis by amide distortion. The combination of strain-release-driven amide planarization and the persistent radical effect (PRE) enables a unique, irreversible, and quantitative trans→cis isomerization under much milder conditions than typically observed for such homolysis-limited reactions. This isomerization is shown to be general and independent of the steric and electronic nature of both the amino acid side chains and the substituents at the DKP nitrogen atoms. Homolysis rate constants are determined, and they significantly differ for both the labile trans diastereomers and the stable cis diastereomers. To reveal the factors influencing this unusual process, structural features of the kinetic trans diastereomers and thermodynamic cis diastereomers are investigated in the solid state and in solution. X-ray crystallographic analysis and computational studies indicate substantial distortion of the amide bond from planarity in the trans-alkoxyamines, and this is believed to be the cause for the facile and quantitative isomerization. Thus, these amino-acid-derived alkoxyamines are the first examples that exhibit a large thermodynamic preference for one diastereomer over the other upon thermal homolysis, and this allows controlled switching of configurations and configurational cycling.

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Section: Resultsmentioning

confidence: 99%

Unique Stereoselective Homolytic C−O Bond Activation in Diketopiperazine‐Derived Alkoxyamines by Adjacent Amide Pyramidalization

Amatov

Jangra

Pohl

et al. 2018

Chemistry A European J

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“…NMR studies revealed the formation preferentially of imidazolidinone intermediate 95 starting from triketone 66, while that of the enamine derivative 97 started from triketone 65, imidazolidinone intermediate 96 being present only in the initial stage of the reaction (Figure 8); this evidence underlines the different behaviour of triketones 65 and 66 during the reaction. More recently, in 2018 Jahn et al reported the total synthesis of ent-pregnanolone sulfate starting from (R)-1, obtained in excellent yield and selectivity (94% yield, 95% ee) in neat conditions at room temperature for 3 days, using prolinamide C-42 (5 mol%), which proved to be the best available catalyst for the preparation of this compound [80].…”

Section: Prolinamides and Prolinthioamidesmentioning

confidence: 99%

Organocatalyst Design for the Stereoselective Annulation towards Bicyclic Diketones and Analogues

et al. 2022

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The Wieland–Miescher ketone, Hajos–Parrish–Eder–Sauer–Wiechert ketone, and their analogues are bicyclic diketones essential as building blocks for the synthesis of several natural and bioactive molecules. For this reason, since 1971, when Hajos and Parrish and Eder, Sauer, and Wiechert reported the stereoselective synthesis of these compounds promoted by L-proline, numerous methodologies and organocatalysts have been studied over the years with the aim of identifying increasingly efficient asymmetrical syntheses of these bicyclic ketones. This review will outline the methodological and stereochemical features of the organocatalytic stereoselective synthesis of these bicyclic scaffolds based on the different organocatalysts employed from 1971 until today. Particular emphasis will be given to the structural features of the catalysts and to the reaction conditions.

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“…The Jahn group also used this approach in their synthesis and biological evaluation of ent -pregnanolone sulfate ( 149 , Scheme 16C). 47 They prepared TEMPO-adduct 145 in 12 steps prior to targeting the final cyclization of the steroid core employing the PRE. Thermolysis of 145 established the desired equilibrium, and the desired 5- exo-trig reaction occurred to afford 148 .…”

Section: Harnessing the Persistent Radical Tempo For The Synthesis Ofmentioning

confidence: 99%

Radicals in natural product synthesis

et al. 2018

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Free radical intermediates have intrigued chemists since their discovery, and an ever-increasing appreciation for their unique reactivity has resulted in the widespread utilization of these species throughout the field of chemical synthesis. This is most evident from the recent surge in the application of intermolecular radical reactions that feature in complex molecule syntheses. This tutorial review will discuss the diverse methods utilized for radical generation and reactivity to form critical bonds in natural product total synthesis. In particular, stabilized (e.g. benzyl) and persistent (e.g. TEMPO) radicals will be the primary focus.

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Total Synthesis of ent-Pregnanolone Sulfate and Its Biological Investigation at the NMDA Receptor

Cited by 19 publications

References 40 publications

Unique Stereoselective Homolytic C−O Bond Activation in Diketopiperazine‐Derived Alkoxyamines by Adjacent Amide Pyramidalization

Unique Stereoselective Homolytic C−O Bond Activation in Diketopiperazine‐Derived Alkoxyamines by Adjacent Amide Pyramidalization

Organocatalyst Design for the Stereoselective Annulation towards Bicyclic Diketones and Analogues

Radicals in natural product synthesis

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