Asymmetric Synthesis of New Chiral Cyclic Ketols

Renouf, Philippe; Poirier, Jean‐Marie; Duhamel, Pierre

doi:10.1021/jo980344w

Cited by 6 publications

(3 citation statements)

References 11 publications

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“…The consistency of this observation is evident for each example as shown in Table 1 28,30 . The selectivity concerning products 17 and 18 was determined by analysis of the 1 H and 19 F NMR spectra of (R)-α-methoxy-α-(trifluoromethyl)phenyl acetic acid (MTPA) 29,31,32 The chemical shift of the singlet of the methyl group at C-2 position was significantly different for each diastereomeric MTPA derivative and was clearly observed in the 1 H NMR spectrum. The same was true for the CF 3 signals for each MTPA ester which were separated in the 19 F NMR spectrum.…”

Section: Methodsmentioning

confidence: 99%

Synthesis of bicyclic oxepanes: an enantioselective approach to the western part of Shaagrockol C

2013

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Section: Methodsmentioning

confidence: 99%

Synthesis of bicyclic oxepanes: an enantioselective approach to the western part of Shaagrockol C

2013

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“…Interestingly, ketal-opened product 3 was also formed in 12% yield, suggesting that Pd-catalyzed enantioselective formation of the quaternary stereocenter of 4 from 1 may be in competition with ketal-ring opening. Exposure of 1 to our standard decarboxylative alkylation conditions (Pd 2 dba 3 and ( S )- t -BuPHOX in THF at 25 °C)7 resulted in formation of 4 8 in 62% yield. Allyl ketone 4 required derivatization to ene-dione 5 via Ru-catalyzed metathesis9 with methyl acrylate and Grubbs' 2 nd generation catalyst 6 in order to determine the enantiomeric excess of the product from the asymmetric alkylation reaction.…”

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confidence: 96%

High-Throughput Screening of the Asymmetric Decarboxylative Alkylation Reaction of Enolate-Stabilized Enol Carbonates

McDougal¹,

Virgil²,

Stoltz³

2010

Synlett

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The use of high-throughput screening allowed for the optimization of reaction conditions for the palladium-catalyzed asymmetric decarboxylative alkylation reaction of enolate-stabilized enol carbonates. Changing to a non-polar reaction solvent and to an electron-deficient PHOX derivative as ligand from our standard reaction conditions improved the enantioselectivity for the alkylation of a ketal-protected,1,3-diketone-derived enol carbonate from 28% ee to 84% ee. Similar improvements in enantioselectivity were seen for a β-keto-ester derived-and an α-phenyl cyclohexanone-derived enol carbonate.Keywords asymmetric catalysis; high-throughput screening; palladium; ligands; solvent effect New methods for the construction of highly substituted carbocycles with defined stereochemistry are important for the synthesis of natural products and pharmaceutical agents. 1 Although automation is well-established within the pharmaceutical industry for the rapid synthesis of new chemical entities, identification of biological activity via screening, and process optimization, 2 less work has been performed within the academic community utilizing automation. 3 Similarly, the identification of efficient catalysts and their associated optimized reaction conditions, which cannot usually be predicted, often necessitates high-throughput methods to perform the required time-and labor-intensive screening. 4 Herein we report the optimization of the Pd-catalyzed, asymmetric decarboxylative alkylation 5 of enolate-stabilized enol carbonates for the synthesis of all-carbon quaternary stereocenters through automated high-throughput screening of reaction conditions. Enol carbonate 1, derived from 2-methyl cyclohexa-1,3-dione, was selected as our substrate for the asymmetric Pd-catalyzed decarboxylative alkylation reaction (Scheme 1). Enol carbonate 1 was synthesized from known mono-ketal 2 6 via deprotonation with NaH in THF at 60 °C and trapping of the resulting thermodynamic enolate with allyl chloroformate in 69% yield. Interestingly, ketal-opened product 3 was also formed in 12% yield, suggesting that Pdcatalyzed enantioselective formation of the quaternary stereocenter of 4 from 1 may be in competition with ketal-ring opening. Exposure of 1 to our standard decarboxylative alkylation conditions (Pd 2 dba 3 and (S)-t-BuPHOX in THF at 25 °C) 7 resulted in formation of 4 8 in 62% yield. Allyl ketone 4 required derivatization to ene-dione 5 via Ru-catalyzed metathesis 9 with methyl acrylate and Grubbs' 2 nd generation catalyst 6 in order to determine the enantiomeric excess of the product from the asymmetric alkylation reaction. Chiral HPLC analysis of 5 showed that the desired quaternary stereocenter-containing product was formed in a poor 28% ee under our standard reaction conditions.In order to obtain ketone 4 with high levels of enantioselectivity, we conducted highthroughput, parallel screening to determine the required catalyst and reaction conditions. Experiments were conducted in 1 mL vials within 96-well microtiter plates usin...

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“…Enantiomerically pure ketol 6 could be prepared by microorganism asymmetric reduction of the corresponding prochiral diketone 5, 8 or by enzymatic hydrolysis of prochiral dienol diacetate of 5 developed recently by Renouf et al 9 Though baker's yeast mediated asymmetric reduction of ketones has been widely used to obtain chiral building blocks since it is cheap, versatile, and easy to perform, 10 baker's yeast reduction of 5 provided a nearly equivalent mixture of diastereomeric ketols 6 and 7. 8 However, the highly reductive fungus, Geotrichum sp., 11 could reduce the diketone 5 more efficiently to give the ketols 6 and 7 in the ratio of 83:17 (Scheme 1).…”

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First Stereoselective Synthesis of the Versatile Chiral Building Block (7aR)-5,6-Dihydro-7a-methyl-1H-indene-2,7(4H,7aH)-dione

魏志良¹,

李祖义²,

林国强³

2000

Synthesis

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A versatile chiral building block (7aR)-5,6-dihydro-7a-methyl-1H-indene-2,7(4H,7aH)-dione (4) was firstly enantiomerically synthesized from the microbial transformation ketol product 6 in 61.3% overall yield and over 96% ee.Enantiomerically pure bicyclic enones 1-4 may constitute useful building blocks for elaboration of synthetic strategies in the field of steroids, terpenes and related molecules. 1-4 The enantiomerically enriched forms of Wieland-Miescher ketone 1 and Hajos-Parrish ketone 2 could be efficiently prepared by asymmetric cyclization of their prochiral precursors, 2-methyl-2-(3-oxobutyl)-1,3-cyclohexanedione and 2-methyl-2-(3-oxobutyl)-1,3-cyclopentanedione, respectively, by the use of prolineenamine 2 or catalytic antibody. 3 However, ring construction of the fused cyclopentenones 3 and 4 from their corresponding 1,3-cycloalkanedione derivatives using the standard aldol condition is quite difficult. 4 Though optically active 3 has been asymmetrically synthesized by Trost 5 and Brooks, 6 preparation of the enantiomerically enriched form of 4 has not been reported so far, to our knowledge. 7 In this paper, we present the first enantioselective synthesis of the versatile building block 4 from the ketol 6.Enantiomerically pure ketol 6 could be prepared by microorganism asymmetric reduction of the corresponding prochiral diketone 5, 8 or by enzymatic hydrolysis of prochiral dienol diacetate of 5 developed recently by Renouf et al. 9 Though baker's yeast mediated asymmetric reduction of ketones has been widely used to obtain chiral building blocks since it is cheap, versatile, and easy to perform, 10 baker's yeast reduction of 5 provided a nearly equivalent mixture of diastereomeric ketols 6 and 7. 8 However, the highly reductive fungus, Geotrichum sp., 11 could reduce the diketone 5 more efficiently to give the ketols 6 and 7 in the ratio of 83:17 (Scheme 1). Scheme 1Because the two diastereomeric ketols 6 and 7 could not be separated efficiently by silica gel chromatography, the mixture obtained from microbial reduction of 5 was converted to the corresponding acetals 8 and 9, which could be separated efficiently by chromatography. After treatment with 3 M HCl, compounds 8 and 9 were converted to ketols 6 and 7 in nearly optically pure forms, respectively (Scheme 2).Reagents and conditions: i) Cat. p-TsOH, HOCH 2 CH 2 OH, CH(OEt) 3 ; ii) 3 M HCl. Scheme 2Considering that the hydroxy group would interfere with the subsequent transformations, it was efficiently protected as the tert-butyldimethylsilyl ether 10. Wacker oxidation of the olefin provided the corresponding dione 11 with good yield (83%). Cyclization and dehydration of diDownloaded by: University of North Carolina -Chapel Hill. Copyrighted material.

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Asymmetric Synthesis of New Chiral Cyclic Ketols

Cited by 6 publications

References 11 publications

Synthesis of bicyclic oxepanes: an enantioselective approach to the western part of Shaagrockol C

Synthesis of bicyclic oxepanes: an enantioselective approach to the western part of Shaagrockol C

High-Throughput Screening of the Asymmetric Decarboxylative Alkylation Reaction of Enolate-Stabilized Enol Carbonates

First Stereoselective Synthesis of the Versatile Chiral Building Block (7aR)-5,6-Dihydro-7a-methyl-1H-indene-2,7(4H,7aH)-dione

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