Solution phase structures of enantiopure and racemic lithium N-benzyl-N-(α-methylbenzyl)amide in THF: low temperature 6Li and 15N NMR spectroscopic studies

Tdw., Claridge; Davies, Stephen G.; Kruchinin, Dennis; Odell, Barbara; Roberts, Paul M.; Russell, Angela J.; Thomson, James E.; Toms, Steven M.

doi:10.1016/j.tetasy.2013.07.001

Cited by 6 publications

(6 citation statements)

References 60 publications

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“…With the chiral amine 6 in hand, the asymmetric synthesis of target ( R )‐cinacalcet was studied (Scheme ). Amine ( R )‐ 6 was condensed with the acyl chloride derived from acid 7 to furnish ( R )‐ N ‐(1‐(1‐naphthalenyl) ethyl)‐3‐(3‐trifluoromethylphenyl) propanamide 8 (87% ee, 93% yield over two steps) . The enatiomeric purity of amide ( R )‐ 8 was upgraded to 99% ee via slow recrystallization from n ‐hexane and ethyl acetate.…”

Section: Resultssupporting

confidence: 80%

“…The crude acid was treated with oxalyl chloride followed by ammonium hydroxide to furnish ( R )‐2‐(1‐naphthalenyl) propanamide 5 (81% yield, over 3 steps) . Hoffman‐type rearrangement of amide ( R )‐ 5 , triggered by treatment with bis‐(trifluoroacetoxy)iodobenzene, afforded ( R )‐1‐(1‐naphthalenyl)ethanamine 6 with 87% ee in 81% yield …”

Section: Resultsmentioning

confidence: 99%

“…26 Hoffman-type rearrangement of amide (R)-5, triggered by treatment with bis-(trifluoroacetoxy)iodobenzene, afforded (R)-1-(1-naphthalenyl)ethanamine 6 with 87% ee in 81% yield. 27,28 With the chiral amine 6 in hand, the asymmetric synthesis of target (R)-cinacalcet was studied (Scheme 3). Amine (R)-6 was condensed with the acyl chloride derived from acid 7 to furnish (R)-N-(1-(1-naphthalenyl) ethyl)-3-(3-trifluoromethylphenyl) propanamide 8 (87% ee, 93% yield over two steps).…”

Section: Synthesis Of (R)-cinacalcetmentioning

confidence: 99%

“…Amine (R)-6 was condensed with the acyl chloride derived from acid 7 to furnish (R)-N-(1-(1-naphthalenyl) ethyl)-3-(3-trifluoromethylphenyl) propanamide 8 (87% ee, 93% yield over two steps). 29,30 The enatiomeric purity of amide (R)-8 was upgraded to 99% ee via slow recrystallization from n-hexane and ethyl acetate. Finally, reduction of the amide (R)-8 with LiAlH 4 converted it to the target (R)-cinacalcet with 99% ee in 92% yield.…”

Section: Synthesis Of (R)-cinacalcetmentioning

confidence: 99%

See 3 more Smart Citations

Enantioselective synthesis of (R)‐Cinacalcet via cobalt‐catalysed asymmetric Negishi cross‐coupling

et al. 2019

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A novel enantioselective synthesis of (R)‐cinacalcet with 99% enantiomeric excesses (ee) has been achieved. The main strategies of the approach include a gram‐scale cobalt‐catalysed asymmetric cross‐coupling of racemic ester with arylzinc reagent, Hoffman‐type rearrangement of acidamide, the amidation of chiral amine, and improving the ee of chiral amide from 87% to 99% via recrystallization.

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Section: Resultssupporting

confidence: 80%

Section: Resultsmentioning

confidence: 99%

Section: Synthesis Of (R)-cinacalcetmentioning

confidence: 99%

Section: Synthesis Of (R)-cinacalcetmentioning

confidence: 99%

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Enantioselective synthesis of (R)‐Cinacalcet via cobalt‐catalysed asymmetric Negishi cross‐coupling

et al. 2019

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“…Lithium amides 2 – typically exist as dimers in ethereal solutions (Scheme ), but they have to deaggregate to monomers 23 – via open dimers 22 – to undergo reasonably fast conjugate addition, as shown by Collum et al in a recent study . Catalytic amounts of lithium chloride promote deaggregation of 2 – and faster conjugate addition to unsaturated esters 1 , as demonstrated here for methyl ester 1d and sorbate 1e , which undergo the conjugate addition significantly less efficiently in the absence of LiCl (cf.…”

Section: Discussionmentioning

confidence: 52%

N,2,3,4‐Tetrasubstituted Pyrrolidines through Tandem Lithium Amide Conjugate Addition/Radical Cyclization/Oxygenation Reactions

et al. 2016

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Enantioselective syntheses of densely functionalized pyrrolidines deriving their chirality from (R)‐1‐(phenyl)ethylamine are reported. Allylic amines and β‐substituted‐α,β‐unsaturated esters are used as the building blocks in this one‐pot reaction. Single electron transfer (SET) oxidation served to merge the reactivities of anionic enolate and radical intermediates. Ferrocenium hexafluorophosphate, which is easy to prepare, store and handle, was applied as SET oxidant and persistent free radical TEMPO served as the oxygenating agent introducing a protected hydroxy function, which proved to be beneficial for further derivatization. Exclusive 2,3‐trans and up to 6:1 3,4‐cis/trans diastereoselectivities were achieved in the targeted tetrasubstituted pyrrolidines.

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To be or not to be butterfly: New mechanistic insights in the Aza‐Michael asymmetric addition of lithium (R)‐N‐benzyl‐N‐(α‐methylbenzyl)amide

2014

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The asymmetric Aza-Michael addition of homochiral lithium benzylamides to α,β-unsaturated esters represents an extended protocol to obtain enantioenriched β-amino esters. An exhaustive mechanistic revision of the originally proposed mechanism is reported, developing a quantum mechanics/molecular mechanics protocol for the asymmetric Aza-Michael reaction of homochiral lithium benzylamides. Explicit and implicit solvent schemes were considered, together with a proper account of long-range dispersion forces, evaluated through a density functional theory benchmark of different functionals. Theoretical results showed that the diastereoselectivity is mainly controlled by the N-α-methylbenzyl moiety placing, deriving a Si/Re 99:1 diastereoselective ratio, in good agreement with reported experimental results. The main transition state geometries are two transition state conformers in a "V-stacked" orientation of the amide's phenyl rings, differing in the tetrahydrofuran molecule arrangement coordinated to the metal center. Extensive conformational sampling and quantum-level refinement give reasonable good speed/accuracy results, allowing this protocol to be extended to other similar Aza-Michael reaction systems.

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Solution phase structures of enantiopure and racemic lithium N-benzyl-N-(α-methylbenzyl)amide in THF: low temperature 6Li and 15N NMR spectroscopic studies

Cited by 6 publications

References 60 publications

Enantioselective synthesis of (R)‐Cinacalcet via cobalt‐catalysed asymmetric Negishi cross‐coupling

Enantioselective synthesis of (R)‐Cinacalcet via cobalt‐catalysed asymmetric Negishi cross‐coupling

N,2,3,4‐Tetrasubstituted Pyrrolidines through Tandem Lithium Amide Conjugate Addition/Radical Cyclization/Oxygenation Reactions

To be or not to be butterfly: New mechanistic insights in the Aza‐Michael asymmetric addition of lithium (R)‐N‐benzyl‐N‐(α‐methylbenzyl)amide

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