Direct asymmetric syntheses of chiral aldehydes and ketones via N-acyl chiral auxiliary derivatives including chiral Weinreb amide equivalents

Davies, Stephen G.; Fletcher, Ai M.; Thomson, James E.

doi:10.1039/c3cc45463k

Cited by 30 publications

(6 citation statements)

References 192 publications

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“…The divergent functional group manipulation of enantio-enriched product 6 allowed for easy access to β-amino acid derivatives with an α-F-α-CF 3 tetra-substituted stereogenic center (Scheme ). 7-Azaindoline amide behaved similarly to Weinreb amides; arylation and hydride reduction of 6p using PhMgBr and LiAlH 4 gave corresponding ketone 7 and aldehyde 8 , respectively, without any overarylation or overreduction. Acidic hydrolysis of the 7-azaindoline amide smoothly proceeded with 6 N aqueous HCl at 60 °C with a concomitant removal of the Boc group, furnishing free β-amino acid hydrochloride 9 .…”

Section: Resultsmentioning

confidence: 99%

Direct Catalytic Asymmetric Mannich-Type Reaction of α- and β-Fluorinated Amides

et al. 2015

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The last two decades have witnessed the emergence of direct enolization protocols providing atom-economical and operationally simple methods to use enolates for stereoselective C-C bond-forming reactions, eliminating the inherent drawback of the preformation of enolates using stoichiometric amounts of reagents. In its infancy, direct enolization relied heavily on the intrinsic acidity of the latent enolates, and the reaction scope was limited to readily enolizable ketones and aldehydes. Recent advances in this field enabled the exploitation of carboxylic acid derivatives for direct enolization, offering expeditious access to synthetically versatile chiral building blocks. Despite the growing demand for enantioenriched fluorine-containing small molecules, α- and β-fluorinated carbonyl compounds have been neglected in direct enolization chemistry because of the competing and dominating defluorination pathway. Herein we present a comprehensive study on direct and highly stereoselective Mannich-type reactions of α- and β-fluorine-functionalized 7-azaindoline amides that rely on a soft Lewis acid/hard Brønsted base cooperative catalytic system to guarantee an efficient enolization while suppressing undesired defluorination. This protocol contributes to provide a series of fluorinated analogs of enantioenriched β-amino acids for medicinal chemistry.

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Section: Resultsmentioning

confidence: 99%

Direct Catalytic Asymmetric Mannich-Type Reaction of α- and β-Fluorinated Amides

et al. 2015

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“…The appropriateness which thestructural diversity can be made in combing the aryl remains provided most related to the improvement protocol. Furthermore, the intermediates (26)(27)(28)(29)…”

Section: Scheme 4 Palladium-catalyzed Preparation Of Weinreb Amides From Boronic Acids and N-methyl-n-methoxycarbamoyl Chloridementioning

confidence: 99%

Recent Developments in Weinreb Synthesis and Their Applications

Khalid

Mohammed

Kalo³

2019

Orient. J. Chem

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N-methoxy-N-methyl amides or Weinreb amides are worthy embranchment of amide group and their rich functional groups in organic synthesis become a strong else unfeasible conversion. Weinreb amides are produced as an intermediate product of the reaction of carboxylic acids, acid chloride or esters with organometallic reagents, which was first uncovered in 1981. The direct conversion of carboxylic acids or acid chlorides or esters to ketones or aldehydes using organometallic reagents do not lead in high yields, because the intermediate ketones are still highly reactive toward the organometallic reagent. However, after derivatization to the corresponding Weinreb Amide, reaction with organometallics does give the desired ketones, as the initial adduct is stabilized and doesn't undergo further reactions. A nucleophilic addition to the Weinreb amides results in a unique and stable five-membered cyclic tetrahedral intermediate which protects the over-addition, leading to a selective conversion.

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“…We have now identified the title compound, Fernholz Weinreb amide (I), as a new key intermediate to the Fernholz aldehyde, reducing the number of steps in the stereoselective synthesis. The O-TBDMS-protected Weinreb amide (I) may be used to prepare (II) using DIBALH, transferred to ketones with Grignard reagents or used for other synthetic transformations (Sivaraman et al, 2009;Davies et al, 2013).…”

Section: Chemical Contextmentioning

confidence: 99%

Crystal structure of (S)-2-[(3S,8S,9S,10R,13S,14S,17R)-3-hydroxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-N-methoxy-N-methylpropanamide (Fernholz Weinreb amide)

et al. 2015

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Direct asymmetric syntheses of chiral aldehydes and ketones via N-acyl chiral auxiliary derivatives including chiral Weinreb amide equivalents

Cited by 30 publications

References 192 publications

Direct Catalytic Asymmetric Mannich-Type Reaction of α- and β-Fluorinated Amides

Direct Catalytic Asymmetric Mannich-Type Reaction of α- and β-Fluorinated Amides

Recent Developments in Weinreb Synthesis and Their Applications

Crystal structure of (S)-2-[(3S,8S,9S,10R,13S,14S,17R)-3-hydroxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-N-methoxy-N-methylpropanamide (Fernholz Weinreb amide)

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