Aldol Condensation of Evans Chiral Enolates with Acetophenones. Its Application to the Stereoselective Synthesis of Homochiral Antifungal Agents

Bartrolí, Javier; Turmo, Enric; Belloc, Jordi; Forn, J.

doi:10.1021/jo00115a014

Cited by 38 publications

(31 citation statements)

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“…Rate studies delineate why the stereochemistries of the additions in Scheme 1 are insensitive to aggregation. Our work sheds light on why everything mattered for Singer et al 5a …”

Section: Introductionmentioning

confidence: 75%

“…There is also an oddly high proportion of additions to ketones , 5 which are widely believed to be poor substrates owing to the tendency of hindered aldolates to undergo retroaldol additions. 6 Singer et al 5a at Pfizer developed a plant-scale synthesis exploiting the addition in eq 2. We consulted Singer about the details, and he noted emphatically and with a noticeable grimace, “ everything mattered.” …”

Section: Introductionmentioning

confidence: 99%

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Structure–Reactivity Relationships in Lithiated Evans Enolates: Influence of Aggregation and Solvation on the Stereochemistry and Mechanism of Aldol Additions

2015

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Aldol additions to isobutyraldehyde and cyclohexanone with lithium enolates derived from acylated oxazolidinones (Evans enolates) are described. Previously characterized trisolvated dimeric enolates undergo rapid addition to isobutyraldehyde to give a 12:1 syn:syn selectivity in high yield along with small amounts of one anti isomer. The efficacy of the addition depends critically on aging effects and the reaction quench. Unsolvated tetrameric enolates that form on warming the solutions are unreactive toward isobutyraldehyde and undergo retroaldol reaction under forcing conditions. Additions to cyclohexanone are relatively slow but form a single isomeric adduct in >80% yield. The ketone-derived aldolates are robust. All attempts to control stereoselectivity by controlling aggregation failed. Rate studies of addition to cyclohexanone trace the lack of aggregation-dependent selectivities to a monomer-based mechanism. The synthetic implications and possible utility of lithium enolates in Evans aldol additions are discussed.

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“…Rate studies delineate why the stereochemistries of the additions in Scheme 1 are insensitive to aggregation. Our work sheds light on why everything mattered for Singer et al 5a …”

Section: Introductionmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Structure–Reactivity Relationships in Lithiated Evans Enolates: Influence of Aggregation and Solvation on the Stereochemistry and Mechanism of Aldol Additions

2015

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“…2 One might surmise that lithiated Evans enolates would be central to the plotline, 3 but they reside between the more reactive sodium enolates used in alkylations 4 and the more selective transition metal and boron enolates used for aldol additions. 5 Nonetheless, there are a handful of lithium-based Evans aldol additions, and surprisingly, many are additions to ketones 6 rather than aldehydes. 7 …”

Section: Introductionmentioning

confidence: 99%

Lithium Amino Alkoxide–Evans Enolate Mixed Aggregates: Aldol Addition with Matched and Mismatched Stereocontrol

et al. 2018

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Building on structural and mechanistic studies of lithiated enolates derived from acylated oxazolidinones (Evans enolates) and chiral lithiated amino alkoxides, we found that amino alkoxides amplify the enantioselectivity of aldol additions. The pairing of enantiomeric series affords matched and mismatched stereoselectivities. The structures of mixed tetramers showing 2:2 and 3:1 (alkoxide-rich) stoichiometries are determined spectroscopically. Rate and computational studies provide a viable mechanistic and stereochemical model based on the direct reaction of the 3:1 mixed tetramers, but they raise unanswered questions for the 2:2 mixed aggregates.

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“…(C12H15FN4O) C, H, N. (16). The compound was obtained by adaptation of our previous published procedure: 14 …”

Section: Methodsmentioning

confidence: 99%

“…Optically active amines 11-14 and 16 were synthesized using Evans chiral oxazolidinones, following our reported methodology. 14 The heterocyclecarboxylic acids 17-28 were obtained by slight modifications of published procedures 15-25 as summarized in Scheme 2, or they were commercially available. Pyrimidones II were prepared from I (D ) H, B ) NH 2 ) by heating with formamidine acetate in DMF.…”

Section: Chemistrymentioning

confidence: 99%

New Azole Antifungals. 2. Synthesis and Antifungal Activity of Heterocyclecarboxamide Derivatives of 3-Amino-2-aryl-1-azolyl-2-butanol

et al. 1998

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A series of 92 azole antifungals containing an amido alcohol unit was synthesized. The nature and substitution of the amide portion was systematically modified in search of improved antifungal activity, especially against filamentous fungi. The compounds were tested in vitro against a variety of clinically important pathogens and in vivo (po) in a murine candidosis model. Thiazole and thiophene carboxamides carrying both a substituted phenyl ring and a small alkyl group were best suited for activity against filamentous fungi. In a subset of these compounds, the amide portion was conformationally locked by means of a pyrimidone ring and it was proven that only an orthogonal orientation of the phenyl ring yields bioactive products. A tendency to display long plasma elimination half-lives was observed in both series. Two compounds, 74 and 107, representative of the open and cyclic amides, respectively, were chosen for further studies, based on their excellent activity in in vivo murine models of candidosis and aspergillosis. This work describes the SARs found within this series. The next paper displays the results obtained in a related series of compounds, the quinazolinones.

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Aldol Condensation of Evans Chiral Enolates with Acetophenones. Its Application to the Stereoselective Synthesis of Homochiral Antifungal Agents

Cited by 38 publications

References 1 publication

Structure–Reactivity Relationships in Lithiated Evans Enolates: Influence of Aggregation and Solvation on the Stereochemistry and Mechanism of Aldol Additions

Structure–Reactivity Relationships in Lithiated Evans Enolates: Influence of Aggregation and Solvation on the Stereochemistry and Mechanism of Aldol Additions

Lithium Amino Alkoxide–Evans Enolate Mixed Aggregates: Aldol Addition with Matched and Mismatched Stereocontrol

New Azole Antifungals. 2. Synthesis and Antifungal Activity of Heterocyclecarboxamide Derivatives of 3-Amino-2-aryl-1-azolyl-2-butanol

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