Stereoselective, nitro-Mannich/lactamisation cascades for the direct synthesis of heavily decorated 5-nitropiperidin-2-ones and related heterocycles

Jakubec, Pavol; Cockfield, Dane M.; Helliwell, Madeleine; Raftery, James; Dixon, Darren J.

doi:10.3762/bjoc.8.64

Cited by 34 publications

(15 citation statements)

References 113 publications

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“…Piperidines rank as the most prominent N-heterocyclic pharmacophore in current drugs on the market, appearing in~55% of all FDA-approved drugs containing at least one N-heterocycle, as well as in numerous bioactive natural products 3 . Convergent methods that unite multiple reactive fragments, particularly hetero-[4+2] cycloadditions, deliver substituted dehydropiperidines in enantioenriched form [21][22][23][24][25][26][27][28][29][30][31] ; however, critical substrate and/or catalyst control over regio-and stereoselectivity is challenging and often results in narrow scope. Traditional preparations of stereodefined piperidines using intramolecular S N 2-type reactions require selective installation of functional groups prior to ring closure, resulting in lower efficiency, modularity, and step economy as the desired target's complexity increases 3 .…”

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confidence: 99%

Intermolecular [3+3] ring expansion of aziridines to dehydropiperi-dines through the intermediacy of aziridinium ylides

et al. 2020

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The importance of N-heterocycles in drugs has stimulated diverse methods for their efficient syntheses. Methods that introduce significant stereochemical complexity are attractive for identifying new bioactive amine chemical space. Here, we report a [3 + 3] ring expansion of bicyclic aziridines and rhodium-bound vinyl carbenes to form complex dehydropiperidines in a highly stereocontrolled rearrangement. Mechanistic studies and DFT computations indicate that the reaction proceeds through formation of a vinyl aziridinium ylide; this reactive intermediate undergoes a pseudo-[1,4]-sigmatropic rearrangement to directly furnish heterocyclic products with net retention at the new CC bond. In combination with asymmetric silver-catalyzed aziridination, enantioenriched scaffolds with up to three contiguous stereocenters are rapidly delivered. The mild reaction conditions, functional group tolerance, and high stereospecificity of this method are well-suited for appending piperidine motifs to natural product and complex molecules. Ultimately, our work establishes the value of underutilized aziridinium ylides as key intermediates for converting small, strained rings to larger N-heterocycles.

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confidence: 99%

Intermolecular [3+3] ring expansion of aziridines to dehydropiperi-dines through the intermediacy of aziridinium ylides

et al. 2020

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“…Reactions of 4-nitrobutanoates ( 11 , 12 ) with ammonium acetate and a range of aldehydes afforded trans -5-nitropiperin-2-ones ( 13 – 16 ) in good yields and modest to excellent diastereoselectivity (Scheme 2 ). 14 Reduction of the nitro group with nickel boride, Boc protection of the resulting amines ( 17 – 20 ), and Buchwald–Hartwig couplings with bromide 4 gave a series of C4/C5/C6-substituted compounds ( 21 – 24 ), which were tested against BRD9 for potency and BRD4(1) for selectivity by DSF (see Table S1). All of the compounds showed selectivity for BRD9 over BRD4(1); however, lactam 24 (R 1 =H, R 2 =Ph) was considered to be the most promising compound for further development owing to its potency and the opportunity for further optimization.…”

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LP99: Discovery and Synthesis of the First Selective BRD7/9 Bromodomain Inhibitor

et al. 2015

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The bromodomain-containing proteins BRD9 and BRD7 are part of the human SWI/SNF chromatin-remodeling complexes BAF and PBAF. To date, no selective inhibitor for BRD7/9 has been reported despite its potential value as a biological tool or as a lead for future therapeutics. The quinolone-fused lactam LP99 is now reported as the first potent and selective inhibitor of the BRD7 and BRD9 bromodomains. Development of LP99 from a fragment hit was expedited through balancing structure-based inhibitor design and biophysical characterization against tractable chemical synthesis: Complexity-building nitro-Mannich/lactamization cascade processes allowed for early structure–activity relationship studies whereas an enantioselective organocatalytic nitro-Mannich reaction enabled the synthesis of the lead scaffold in enantioenriched form and on scale. This epigenetic probe was shown to inhibit the association of BRD7 and BRD9 to acetylated histones in vitro and in cells. Moreover, LP99 was used to demonstrate that BRD7/9 plays a role in regulating pro-inflammatory cytokine secretion.

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“…Paroxetine was white amorphous powder and named as 3-{(benzo [1,3]dioxol-5-yloxy)methyl}-4-(4-fluorophenyl)-1-(phenylsulfonyl)piperidine. The stereochemistry of the paroxetine was designed by the comparison of 1 H NMR coupling constant and also the 13 C NMR signals with the literature 15 .…”

Section: Resultsmentioning

confidence: 99%

Synthesis, Spectral and Enzyme Inhibition Studies on N-Aralkyl/ Aryl Sulfonated Derivatives of Commercially Available Paroxetine

Siddiqa¹,

Aziz-Ur-Rehman²,

Abbasi³

et al. 2014

Asian J. Chem.

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Paroxetine has potential inhibition and selectivity for 5-hydroxytryptamine (5-HTT, serotonin) uptake, having lessened tendency to execute the fallouts ordinarily associated with a tricyclic antidepressant 1-3 . The metabolic pathway of paroxetine was studied using [ 14 C]-labeled paroxetine and revealed (3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine as one of the metabolites, which seems to be an attractive intermediate for the preparation of paroxetine 2 . Paroxetine is used during the treatment of depression, obsessive compulsive disorder and panic disorder. Paroxetine is an enantiomerically pure (-)-trans-3,4-disubstituted piperidine and because of its biological grandness, various enantiocontrolled syntheses have been divulged 3 .Sulfonamides are pharmacologically significant compounds and largely used as carbonic anhydrase inhibitors; anticancer, antiinflammatory, antiviral agents; antimicrobial drugs, insulinreleasing sulfonamides; saluretics, antihydrod agents, antitumor drugs etc. These are the widely used as antibacterial agents because of their low cost, less toxicity and extraordinary activity 4-8 .Lipoxygenase (LOX, EC 1.13.11.12) belonging to a class of non-haem iron possessing dioxygenases, are widely occupied In the current work, a facile and environmentally benign series of N-aralkyl/aryl sulfonyl paroxetine 3a-n was synthesized and screened against lipoxygenase enzyme. These were geared up by the coupling of paroxetine (1) with different aralkyl/aryl sulfonyl chlorides, 2a-n, under dynamic pH control in aqueous basic media to form various N-substituted paroxetine (3a-l). The synthesized compounds were characterized by spectral data like IR, 1 H NMR, 13 C NMR and EI-MS. The bioactivity of all the synthesized compounds was evaluated against lipoxygenase (LOX) enzyme. Only six synthesized compounds showed moderate activity but all others remained inactive against lipoxygenase enzyme as it was evident from their IC50 values, relative to the standard used.

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Stereoselective, nitro-Mannich/lactamisation cascades for the direct synthesis of heavily decorated 5-nitropiperidin-2-ones and related heterocycles

Cited by 34 publications

References 113 publications

Intermolecular [3+3] ring expansion of aziridines to dehydropiperi-dines through the intermediacy of aziridinium ylides

Intermolecular [3+3] ring expansion of aziridines to dehydropiperi-dines through the intermediacy of aziridinium ylides

LP99: Discovery and Synthesis of the First Selective BRD7/9 Bromodomain Inhibitor

Synthesis, Spectral and Enzyme Inhibition Studies on N-Aralkyl/ Aryl Sulfonated Derivatives of Commercially Available Paroxetine

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