Mannich-Type Reactions of Nitrones, Oximes, and Hydrazones

Merino, Pedro; Tejero, Tomás

doi:10.1055/s-0030-1260979

Cited by 35 publications

(18 citation statements)

References 77 publications

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“…On the basis of our previous findings with MeMgBr, BF 3 •Et 2 O was chosen as the Lewis acid for inverting the stereoselectivity of the addition. 22 The addition of different Grignard reagents RMgBr (R = octyl, undecyl, dodecyl, tridecyl) to nitrone 6 was initially investigated in THF as a solvent at −78°C for 2 h without BF 3 . 23 The corresponding hydroxylamines were obtained as a mixture of two diastereoisomers 7 and 8 with good isolated yields (from 57% to 70%).…”

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confidence: 99%

Stereoselective Synthesis of C-2 Alkylated Trihydroxypiperidines: Novel Pharmacological Chaperones for Gaucher Disease

Clemente

Matassini

Goti

et al. 2019

ACS Med. Chem. Lett.

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Pharmacological chaperones (PCs) are small molecules that bind and stabilize enzymes. They can rescue the enzymatic activity of misfolded or deficient enzymes when they are used at subinhibitory concentration, thus with minimal side effects. Pharmacological Chaperone Therapy (PCT) is an emerging treatment for many lysosomal storage disorders (LSDs) including Gaucher disease, the most common, which is characterized by a deficiency in the GCase enzyme. We report herein a straightforward synthetic strategy to afford C-2 substituted trihydroxypiperidines with different alkyl chains starting from low cost D-mannose. Stereoselective Grignard reagent addition onto a key nitrone intermediate in the presence or absence of a suitable Lewis acid afforded both epimers of the target compounds, after a final reductive amination-ring closure step. We show that the shift of the alkyl chain from the endocyclic nitrogen to the C-2 position leads to a considerable increase in chaperoning efficacy, affording a new compound (4a) able to induce a remarkable 1.9-fold maximal increase in GCase activity.

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confidence: 99%

Stereoselective Synthesis of C-2 Alkylated Trihydroxypiperidines: Novel Pharmacological Chaperones for Gaucher Disease

Clemente

Matassini

Goti

et al. 2019

ACS Med. Chem. Lett.

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“…The 2,4-diphenyl-3-azabicyclo[3.3.1]nonan-9-ones were synthesized by the Mannich reaction [ 46 – 49 ]. As shown in Scheme 1 ; 1 and 2 were synthesized using ammonium acetate, benzaldehyde, and acetone or 2-butanone (4:4:1), respectively [ 50 – 52 ].…”

Section: Resultsmentioning

confidence: 99%

Investigation of the role of stereoelectronic effects in the conformation of piperidones by NMR spectroscopy and X-ray diffraction

Garcías-Morales¹,

Ortegón-Reyna²,

Ariza‐Castolo³

2015

Beilstein J. Org. Chem.

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SummaryThis paper reports the synthesis of a series of piperidones 1–8 by the Mannich reaction and analysis of their structures and conformations in solution by NMR and mass spectrometry. The six-membered rings in 2,4,6,8-tetraphenyl-3,7-diazabicyclo[3.3.1]nonan-9-ones, compounds 1 and 2, adopt a chair–boat conformation, while those in 2,4-diphenyl-3-azabicyclo[3.3.1]nonan-9-ones, compounds 3–8, adopt a chair–chair conformation because of stereoelectronic effects. These stereoelectronic effects were analyzed by the 1 J C–H coupling constants, which were measured in the 13C satellites of the 1H NMR spectra obtained with the hetero-dqf pulse sequence. In the solid state, these stereoelectronic effects were investigated by measurement of X-ray diffraction data, the molecular geometry (torsional bond angles and bond distances), and inter- and intramolecular interactions, and by natural bond orbital analysis, which was performed using density functional theory at the ωB97XD/6311++G(d,p) level. We found that one of the main factors influencing the conformational stability of 3–8 is the interaction between the lone-pair electrons of nitrogen and the antibonding sigma orbital of C(7)–Heq (nN→σ*C–H(7)eq), a type of hyperconjugative interaction.

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“…The addition of enolates to nitrones has been recently reviewed [77] and the reader is referred to such a report for publications prior to 2011. Very recently, the mechanism of the Mannich reactions with nitrones has been elucidated [78] and it is observed a change of mechanism from stepwise to concerted (actually, one kinetic step but two stages) on passing from α-substituted enolates (derived from esters and ketones) to α-unsubstituted enolates (derived from aldehydes).…”

Section: Enolates (Mannich-type Reactions) and Related Compoundsmentioning

confidence: 99%

“…[9] In 2000 we reviewed, for the first time, the use of chiral non-racemic nitrones in the preparation of enantiomerically pure hydroxylamines through nucleophilic additions [10] and later, we presented some of our own results in the field [11] including Mannich-type reactions [12] and application to the construction of nitrogenated heterocycles. [13] Thus, it is not intended to cover all aspects of stereoselective nucleophilic additions to nitrones but will restrict itself to the most recent studies.…”

Section: Introductionmentioning

confidence: 99%

Recent Advances in the Preparation of Enantiomerically Pure Hydroxylamines from Nitrones

Matute¹,

García‐Viñuales²,

Hayes³

et al. 2016

COS

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This review covers the recent advances in the synthesis of enantiomerically pure hydroxylamines employing nitrones as starting materials. Nucleophilic additions of organometallic reagents to nitrones are the most common way for introducing a hydroxyamino group into carbon skeletons with the concomitant formation of a new carbon-carbon bond. Addition of carbanions derived from enolates, cyanide or fluorinated derivatives allow the preparation of complex structures. Radical additions and, in particular samarium diiodide-mediated reductive coupling of nitrones with carbonyl compounds and α,β-unsaturated esters have also been considered. All these approaches provide efficient methods of preparation of enantiomerically pure hydroxylamienes that are valuable synthetic intermediates. KeywordsHydroxylamines; Nitrones; Organometallics; Mannich; Reductive coupling 2 Graphical Abstract 3

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Mannich-Type Reactions of Nitrones, Oximes, and Hydrazones

Cited by 35 publications

References 77 publications

Stereoselective Synthesis of C-2 Alkylated Trihydroxypiperidines: Novel Pharmacological Chaperones for Gaucher Disease

Stereoselective Synthesis of C-2 Alkylated Trihydroxypiperidines: Novel Pharmacological Chaperones for Gaucher Disease

Investigation of the role of stereoelectronic effects in the conformation of piperidones by NMR spectroscopy and X-ray diffraction

Recent Advances in the Preparation of Enantiomerically Pure Hydroxylamines from Nitrones

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