The stereoselective α-alkylation of chiral β-hydroxy esters and some applications thereof

Fráter, Georg; Müller, Urs; Günther, Wulf

doi:10.1016/s0040-4020(01)82413-3

Cited by 264 publications

(92 citation statements)

References 35 publications

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“…75 Para evitar alquilação em C5, o grupo sulfinila em 115 e 116 foi reduzido a sulfeto por tratamento com TiCl 3 76 (85%) e o produto resultante, tratado com LDA levando à formação do diânion que, após adição de MeI, forneceu 117, juntamente com o diastereoisômero em uma proporção de 4:1 (75%).…”

Section: Síntese Do Enantiômero Do Intermediáriounclassified

Sínteses totais das crocacinas A, C e D: novos antibióticos isolados de Chondromyces crocatus e Chondromyces pediculatus

Oliveira¹,

Dias²,

Rosso³

2008

Quím. Nova

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Section: Síntese Do Enantiômero Do Intermediáriounclassified

Sínteses totais das crocacinas A, C e D: novos antibióticos isolados de Chondromyces crocatus e Chondromyces pediculatus

Oliveira¹,

Dias²,

Rosso³

2008

Quím. Nova

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“…adding the larger alkyl group before methylation, proceeds with poor selectivity and produces inseparable mixtures of 2R,3R-anti and 2R,3S-syn analogues. [16][17] The difficulty in obtaining the syn product by reversing the alkylation sequence warrants an alternate synthetic route. In order to access the novel 2S,3R diastereomer, we envisaged inverting the stereochemistry of the fragment through oxidation, followed by diastereoselective reduction.…”

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confidence: 99%

“…The FraterSeebach method of alkylating chiral β-hydroxy esters was used to install the methyl and various alkyl groups onto 3 with excellent diastereoselectivity. 17 The addition of two equivalents of strong base generates a di-anion which forms a six-membered ring chelate. 17 The stereoconfiguration of the secondary alcohol directs the electrophilic addition from the less hindered face, thereby yielding the anti product with a consistently high diastereomeric ratio (dr; as measured by NMR of the crude sample).…”

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confidence: 99%

“…17 The addition of two equivalents of strong base generates a di-anion which forms a six-membered ring chelate. 17 The stereoconfiguration of the secondary alcohol directs the electrophilic addition from the less hindered face, thereby yielding the anti product with a consistently high diastereomeric ratio (dr; as measured by NMR of the crude sample). Swern oxidation was used to afford the prochiral ketone 6a in good yield, which was subsequently reduced to the R-alcohol 7a.…”

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confidence: 99%

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Stereochemical modification of geminal dialkyl substituents on pantothenamides alters antimicrobial activity

Hoegl¹,

Darabi²,

Tran³

et al. 2014

Bioorganic & Medicinal Chemistry Letters

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Pantothenamides are N-substituted pantothenate derivatives which are known to exert antimicrobial activity through interference with coenzyme A (CoA) biosynthesis or downstream CoA-utilizing proteins. A previous report has shown that replacement of the ProR methyl group of the benchmark N-pentylpantothenamide with an allyl group (R-anti configuration) yielded one of the most potent antibacterial pantothenamides reported so far (MIC of 3.2 μM for both sensitive and resistant Staphylococcus aureus). We describe herein a synthetic route for accessing the corresponding R-syn diastereomer using a key diastereoselective reduction with Baker's yeast, and report on the scope of this reaction for modified systems. Interestingly, whilst the R-anti diastereomer is the only one to show antibacterial activity, the R-syn isomer proved to be significantly more potent against the malaria parasite (IC 50 of 2.4 ± 0.2 μM). Our research underlines the striking influence that stereochemistry has on the biological activity of pantothenamides, and may find utility in the study of various CoA-utilizing systems. Keywordspantothenamides; antibacterial; antiplasmodial; baker's yeast; coenzyme A Infectious diseases remain a major contributing factor to worldwide mortality. Moreover, the development of antimicrobial resistance is raising significant concerns about the increasingly limited efficacy of currently available treatments. 1 There have been considerable efforts towards discovering and characterising novel therapeutic targets for antimicrobial drugs. One such target which has emerged as a promising point-of-attack is

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“…28 The reaction seemed to proceed through the Li-chelated six-membered transition state, in which the bulky t-butyl ester group prevents access of the electrophile from the upper side as shown in Scheme 2. 29 Hydrogenation of 18 afforded 19, and subsequently its methyl ester moiety was selectively hydrolyzed with LiOH in aqueous THF, followed by ring-closing reaction with PyBOP 30 to afford the β-lactone 20 (unit D, Pg = t-Bu). The relative stereochemistry of 20 was determined by NOE experiments (Figure 6-a).…”

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Design and synthesis of the stabilized analogs of belactosin A with the unnatural cis-cyclopropane structure

et al. 2013

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The belactosin A analog 2a, having the unnatural cis-cyclopropane structure instead of the trans-cyclopropane structure in belactosin A, is a much more potent proteasome inhibitor than belactosin A. However, its cell growth inhibitory effect is rather lower than that expected from its remarkable proteasome inhibitory effect, probably due to its instability under cellular conditions. We hypothesized that the instability of 2a was due to its chemical and enzymatic hydrolysis of the strained β-lactone moiety. Thus, to increase the stability of 2a by chemical modification, its analogs with a sterically more hindered β-lactone moiety and/or cyclopropylic strain-based conformational restriction were designed and synthesized, resulting in the identification of a stabilized analog 6a as a proteasome inhibitor with cell growth inhibitory effects. Our findings suggest that the chemical and biological stability of 2a is significantly affected by the steric hindrance around its β-lactone carbonyl moiety and the conformational flexibility of the molecule.

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The stereoselective α-alkylation of chiral β-hydroxy esters and some applications thereof

Cited by 264 publications

References 35 publications

Sínteses totais das crocacinas A, C e D: novos antibióticos isolados de Chondromyces crocatus e Chondromyces pediculatus

Sínteses totais das crocacinas A, C e D: novos antibióticos isolados de Chondromyces crocatus e Chondromyces pediculatus

Stereochemical modification of geminal dialkyl substituents on pantothenamides alters antimicrobial activity

Design and synthesis of the stabilized analogs of belactosin A with the unnatural cis-cyclopropane structure

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