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Varinder K Aggarwal - One of the best experts on this subject based on the ideXlab platform.
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α-Sulfinyl Benzoates as Precursors to Li and Mg Carbenoids for the Stereoselective Iterative Homologation of Boronic Esters.
Journal of the American Chemical Society, 2017Co-Authors: Giorgia Casoni, Matthew Burns, Murat Kucukdisli, James M. Fordham, Eddie L. Myers, Varinder K AggarwalAbstract:The stereoselective reagent-controlled Homologation of boronic esters is one of a small number of iteratable synthetic transformations that if automated could form the basis of a veritable molecule-making machine. Recently, α-stannyl triisopropylbenzoates and α-sulfinyl chlorides have emerged as useful building blocks for the iterative Homologation of boronic esters. However, α-stannyl benzoates need to be prepared using stoichiometric amounts of the (+)- or (−)-enantiomer of the scarcely available and expensive diamine sparteine; also, these building blocks, together with the byproducts that are generated during Homologation, are perceived as being toxic. On the other hand, α-sulfinyl chlorides are difficult to prepare with high levels of enantiopurity and are prone to undergo deleterious acid–base side-reactions under the reaction conditions for Homologation, leading to low stereospecificity. Here, we show that the use of a hybrid of these two building blocks, namely, α-sulfinyl triisopropylbenzoates, l...
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α‑Sulfinyl Benzoates as Precursors to Li and Mg Carbenoids for the Stereoselective Iterative Homologation of Boronic Esters
2017Co-Authors: Giorgia Casoni, Matthew Burns, Murat Kucukdisli, James M. Fordham, Eddie L. Myers, Varinder K AggarwalAbstract:The stereoselective reagent-controlled Homologation of boronic esters is one of a small number of iteratable synthetic transformations that if automated could form the basis of a veritable molecule-making machine. Recently, α-stannyl triisopropylbenzoates and α-sulfinyl chlorides have emerged as useful building blocks for the iterative Homologation of boronic esters. However, α-stannyl benzoates need to be prepared using stoichiometric amounts of the (+)- or (−)-enantiomer of the scarcely available and expensive diamine sparteine; also, these building blocks, together with the byproducts that are generated during Homologation, are perceived as being toxic. On the other hand, α-sulfinyl chlorides are difficult to prepare with high levels of enantiopurity and are prone to undergo deleterious acid–base side-reactions under the reaction conditions for Homologation, leading to low stereospecificity. Here, we show that the use of a hybrid of these two building blocks, namely, α-sulfinyl triisopropylbenzoates, largely overcomes the above drawbacks. Through either the sulfinylation of α-magnesiated benzoates with either enantiomer of Andersen’s readily available menthol-derived sulfinate or the α-alkylation of enantiopure S-chiral α-sulfinyl benzoates, we have prepared a range of highly enantiopure mono- and disubstituted α-sulfinyl benzoates, some bearing sensitive functional groups. Barbier-type reaction conditions have been developed that allow these building blocks to be converted into lithium (t-BuLi) and magnesium (i-PrMgCl·LiCl) carbenoids in the presence of boronic esters, thus allowing efficient and highly stereospecific Homologation. The use of magnesium carbenoids allows carbon chains to be grown with the incorporation of sensitive functional groups, such as alkyl/aryl halides, azides, and esters. The use of lithium carbenoids, which are less sensitive to steric hindrance, allows sterically encumbered carbon–carbon bonds to be forged. We have also shown that these building blocks can be used consecutively in three- and four-step iterative Homologation processes, without intervening column chromatography, to give contiguously substituted carbon chains with very high levels of enantio- and diastereoselectivity
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stereocontrolled synthesis of 1 5 stereogenic centers through three carbon Homologation of boronic esters
ChemInform, 2015Co-Authors: Phillip J. Unsworth, Daniele Leonori, Varinder K AggarwalAbstract:An efficient procedure for the three-carbon Homologation of pinacol boronic esters (I) is developed.
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Stereocontrolled Synthesis of 1,5‐Stereogenic Centers Through Three‐Carbon Homologation of Boronic Esters.
ChemInform, 2015Co-Authors: Phillip J. Unsworth, Daniele Leonori, Varinder K AggarwalAbstract:An efficient procedure for the three-carbon Homologation of pinacol boronic esters (I) is developed.
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Toward Ideality: The Synthesis of (+)-Kalkitoxin and (+)-Hydroxyphthioceranic Acid by Assembly-Line Synthesis
Journal of the American Chemical Society, 2015Co-Authors: Sebastien Balieu, Gayle E. Hallett, Matthew Burns, Teerawut Bootwicha, John Studley, Varinder K AggarwalAbstract:The iterative Homologation of boronic esters using chiral lithiated benzoate esters and chloromethyllithium has been applied to the highly efficient syntheses of two natural products, (+)-kalkitoxin and (+)-hydroxyphthioceranic acid. The chiral lithiated benzoate esters (>99% ee) were generated from the corresponding stannanes, which themselves were prepared by Hoppe–Beak deprotonation of ethyl 2,4,6-triisopropyl-benzoate with s-BuLi in the presence of (+)- or (−)-sparteine and trapping with Me3SnCl followed by recrystallization. In addition, it was found that purification between several Homologations could be avoided, substantially increasing both chemical and manpower efficiency. In the case of (+)-kalkitoxin, six iterative Homologations were conducted on commercially available p-MeOC6H4CH2Bpin to build up the core of the molecule before the C–B bond was converted into the desired C–N bond, without purification of intermediates. In the case of (+)-hydroxyphthioceranic acid, 16 iterative Homologations w...
Vittorio Pace - One of the best experts on this subject based on the ideXlab platform.
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Straightforward chemoselective access to unsymmetrical dithioacetals through a thiosulfonate Homologation-nucleophilic substitution sequence
Chemical communications (Cambridge England), 2020Co-Authors: Laura Ielo, Wolfgang Holzer, Veronica Pillari, Natalie Gajic, Vittorio PaceAbstract:A sequential C1-Homologation-nucleophilic substitution tactic is presented for the preparation of rare unsymmetrical dithioacetals. The judicious selection of thiosulfonates as convenient sulfur electrophilic sources - upon the Homologation event conducted on an intermediate α-halothioether - guarantees the release of the non-reactive sulfonate group, thus enabling the subsequent nucleophilic displacement with an external added thiol [(hetero)aromatic and/or aliphatic]. Uniform high yields and excellent chemocontrol were deduced during the extensive scope study, thus documenting the versatility of the direct technique for the preparation of these unique and manipulable materials.
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The synthetic versatility of the Tiffeneau–Demjanov chemistry in Homologation tactics
Monatshefte für Chemie - Chemical Monthly, 2019Co-Authors: Stefan M. Kohlbacher, Vivien-sandra Ionasz, Laura Ielo, Vittorio PaceAbstract:The Tiffeneau–Demjanov rearrangement can be regarded as an interesting alternative to the more common semi-pinacol transposition. It is usually employed for ring extension but, under specific conditions, it can also be used for ring contraction. Compared to other techniques, such as the Demjanov rearrangement or Homologations with diazo compounds, the Tiffeneau–Demjanov pathway presents attractive features including high yielding and selective processes. Ring enlargements follow very strict and simple rules, such as the movement of the less substituted carbon and retention of the configuration. The rearrangement process is mainly affected by steric factors, due to presence of neighbouring groups, rather than electronic ones. The ring contraction may be achieved positioning the amine within the ring, thus achieving a high level of control. Unfortunately, applications of the reaction in modern Homologation chemistry are rare; therefore, the aim of the review is re-proposing to the synthetic community the versatility of this venerable reaction and thus, spurring its employment for tackling challenging Homologations processes. Graphic abstract
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direct and chemoselective synthesis of tertiary difluoroketones via weinreb amide Homologation with a chf2 carbene equivalent
Organic Letters, 2019Co-Authors: Margherita Miele, Andrea Citarella, Nicola Micale, Wolfgang Holzer, Vittorio PaceAbstract:The Homologation of Weinreb amides into difluoromethylketones with a formal nucleophilic CHF2 transfer agent is reported. Activating TMSCHF2 with potassium tert-amylate enables a convenient access to the difluorinated Homologation reagent, which adds to the acylating partners. The high chemoselectivity showcased in the presence of variously multifunctionalized Weinreb amides, jointly with uniformly high yields, enables the strategy of general applicability without requiring any stabilization element for the putative carbanion.
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telescoped divergent chemoselective c1 and c1 c1 Homologation of imine surrogates access to quaternary chloro and halomethyl trifluoromethyl aziridines
Angewandte Chemie, 2019Co-Authors: Laura Ielo, Wolfgang Holzer, Saad Touqeer, Alexander Roller, Thierry Langer, Vittorio PaceAbstract:A conceptually novel, high-yielding, mono- or bis-Homologation was realized with lithium halocarbenoids and enables the one-step, fully chemocontrolled assembly of a new class of quaternary trifluoromethyl aziridines. Trifluoroacetimidoyl chlorides (TFAICs) act as convenient electrophilic platforms, enabling the addition of either one or two homologating elements by simply controlling the stoichiometry of the process. Mechanistic studies highlighted that the Homologation event, carried out with two different carbenoids (LiCH2 Cl and LiCH2 F), leads to fluoromethyl analogues in which the first nucleophile is employed for constructing the cycle and the second for decorating the resulting molecular architecture.
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A practical guide for using lithium halocarbenoids in Homologation reactions
Monatshefte für Chemie - Chemical Monthly, 2018Co-Authors: Serena Monticelli, Laura Castoldi, Marta Rui, Giada Missere, Vittorio PaceAbstract:Lithium halocarbenoids are versatile reagents for accomplishing Homologation processes. The fast α-elimination they suffer has been considered an important limitation for their extensive use. Herein, we present a series of practical considerations for an effective employment in the Homologation of selected carbon electrophiles. Graphical abstract
Sung Keon Namgoong - One of the best experts on this subject based on the ideXlab platform.
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trimethyl borate magnesium halide complex induced one pot Homologation reactions of isoquinoline with dialkyl tmp zincate
Tetrahedron Letters, 2012Co-Authors: Sung Keon NamgoongAbstract:Abstract Novel one-pot Homologation reactions of isoquinoline with lithium dialkyl-TMP-zincate⋅2MgBrCl/trimethyl borate are described. 1-Alkylisoquinolines ( 2 , 3A , 4A, 5A , 6 , and 7 ) and 1-alkyl-3,4-dihydroisoquinolines ( 3B , 4B , and 5B ) are easily prepared under the presented reaction conditions. The role of the B(OMe) 3 /MgBrCl complex is examined in these Homologation reactions. The specific reaction mechanisms, including 1,2-migration of the alkyl ligands from 1-isoquinolylzincates, are proposed. The migratory aptitudes of ligands of 1-isoquinolylzincates are also discussed.
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Trimethyl borate/magnesium halide complex-induced one-pot Homologation reactions of isoquinoline with dialkyl-TMP-zincate
Tetrahedron Letters, 2012Co-Authors: Sung Keon NamgoongAbstract:Abstract Novel one-pot Homologation reactions of isoquinoline with lithium dialkyl-TMP-zincate⋅2MgBrCl/trimethyl borate are described. 1-Alkylisoquinolines ( 2 , 3A , 4A, 5A , 6 , and 7 ) and 1-alkyl-3,4-dihydroisoquinolines ( 3B , 4B , and 5B ) are easily prepared under the presented reaction conditions. The role of the B(OMe) 3 /MgBrCl complex is examined in these Homologation reactions. The specific reaction mechanisms, including 1,2-migration of the alkyl ligands from 1-isoquinolylzincates, are proposed. The migratory aptitudes of ligands of 1-isoquinolylzincates are also discussed.
Matthew Burns - One of the best experts on this subject based on the ideXlab platform.
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α-Sulfinyl Benzoates as Precursors to Li and Mg Carbenoids for the Stereoselective Iterative Homologation of Boronic Esters.
Journal of the American Chemical Society, 2017Co-Authors: Giorgia Casoni, Matthew Burns, Murat Kucukdisli, James M. Fordham, Eddie L. Myers, Varinder K AggarwalAbstract:The stereoselective reagent-controlled Homologation of boronic esters is one of a small number of iteratable synthetic transformations that if automated could form the basis of a veritable molecule-making machine. Recently, α-stannyl triisopropylbenzoates and α-sulfinyl chlorides have emerged as useful building blocks for the iterative Homologation of boronic esters. However, α-stannyl benzoates need to be prepared using stoichiometric amounts of the (+)- or (−)-enantiomer of the scarcely available and expensive diamine sparteine; also, these building blocks, together with the byproducts that are generated during Homologation, are perceived as being toxic. On the other hand, α-sulfinyl chlorides are difficult to prepare with high levels of enantiopurity and are prone to undergo deleterious acid–base side-reactions under the reaction conditions for Homologation, leading to low stereospecificity. Here, we show that the use of a hybrid of these two building blocks, namely, α-sulfinyl triisopropylbenzoates, l...
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α‑Sulfinyl Benzoates as Precursors to Li and Mg Carbenoids for the Stereoselective Iterative Homologation of Boronic Esters
2017Co-Authors: Giorgia Casoni, Matthew Burns, Murat Kucukdisli, James M. Fordham, Eddie L. Myers, Varinder K AggarwalAbstract:The stereoselective reagent-controlled Homologation of boronic esters is one of a small number of iteratable synthetic transformations that if automated could form the basis of a veritable molecule-making machine. Recently, α-stannyl triisopropylbenzoates and α-sulfinyl chlorides have emerged as useful building blocks for the iterative Homologation of boronic esters. However, α-stannyl benzoates need to be prepared using stoichiometric amounts of the (+)- or (−)-enantiomer of the scarcely available and expensive diamine sparteine; also, these building blocks, together with the byproducts that are generated during Homologation, are perceived as being toxic. On the other hand, α-sulfinyl chlorides are difficult to prepare with high levels of enantiopurity and are prone to undergo deleterious acid–base side-reactions under the reaction conditions for Homologation, leading to low stereospecificity. Here, we show that the use of a hybrid of these two building blocks, namely, α-sulfinyl triisopropylbenzoates, largely overcomes the above drawbacks. Through either the sulfinylation of α-magnesiated benzoates with either enantiomer of Andersen’s readily available menthol-derived sulfinate or the α-alkylation of enantiopure S-chiral α-sulfinyl benzoates, we have prepared a range of highly enantiopure mono- and disubstituted α-sulfinyl benzoates, some bearing sensitive functional groups. Barbier-type reaction conditions have been developed that allow these building blocks to be converted into lithium (t-BuLi) and magnesium (i-PrMgCl·LiCl) carbenoids in the presence of boronic esters, thus allowing efficient and highly stereospecific Homologation. The use of magnesium carbenoids allows carbon chains to be grown with the incorporation of sensitive functional groups, such as alkyl/aryl halides, azides, and esters. The use of lithium carbenoids, which are less sensitive to steric hindrance, allows sterically encumbered carbon–carbon bonds to be forged. We have also shown that these building blocks can be used consecutively in three- and four-step iterative Homologation processes, without intervening column chromatography, to give contiguously substituted carbon chains with very high levels of enantio- and diastereoselectivity
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Toward Ideality: The Synthesis of (+)-Kalkitoxin and (+)-Hydroxyphthioceranic Acid by Assembly-Line Synthesis
Journal of the American Chemical Society, 2015Co-Authors: Sebastien Balieu, Gayle E. Hallett, Matthew Burns, Teerawut Bootwicha, John Studley, Varinder K AggarwalAbstract:The iterative Homologation of boronic esters using chiral lithiated benzoate esters and chloromethyllithium has been applied to the highly efficient syntheses of two natural products, (+)-kalkitoxin and (+)-hydroxyphthioceranic acid. The chiral lithiated benzoate esters (>99% ee) were generated from the corresponding stannanes, which themselves were prepared by Hoppe–Beak deprotonation of ethyl 2,4,6-triisopropyl-benzoate with s-BuLi in the presence of (+)- or (−)-sparteine and trapping with Me3SnCl followed by recrystallization. In addition, it was found that purification between several Homologations could be avoided, substantially increasing both chemical and manpower efficiency. In the case of (+)-kalkitoxin, six iterative Homologations were conducted on commercially available p-MeOC6H4CH2Bpin to build up the core of the molecule before the C–B bond was converted into the desired C–N bond, without purification of intermediates. In the case of (+)-hydroxyphthioceranic acid, 16 iterative Homologations w...
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toward ideality the synthesis of kalkitoxin and hydroxyphthioceranic acid by assembly line synthesis
Journal of the American Chemical Society, 2015Co-Authors: Sebastien Balieu, Gayle E. Hallett, Matthew Burns, Teerawut Bootwicha, John Studley, Varinder K AggarwalAbstract:The iterative Homologation of boronic esters using chiral lithiated benzoate esters and chloromethyllithium has been applied to the highly efficient syntheses of two natural products, (+)-kalkitoxin and (+)-hydroxyphthioceranic acid. The chiral lithiated benzoate esters (>99% ee) were generated from the corresponding stannanes, which themselves were prepared by Hoppe–Beak deprotonation of ethyl 2,4,6-triisopropyl-benzoate with s-BuLi in the presence of (+)- or (−)-sparteine and trapping with Me3SnCl followed by recrystallization. In addition, it was found that purification between several Homologations could be avoided, substantially increasing both chemical and manpower efficiency. In the case of (+)-kalkitoxin, six iterative Homologations were conducted on commercially available p-MeOC6H4CH2Bpin to build up the core of the molecule before the C–B bond was converted into the desired C–N bond, without purification of intermediates. In the case of (+)-hydroxyphthioceranic acid, 16 iterative Homologations w...
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Toward Ideality: The Synthesis of (+)-Kalkitoxin and (+)-Hydroxyphthioceranic Acid by Assembly-Line Synthesis
Journal of the American Chemical Society, 2015Co-Authors: Sebastien Balieu, Gayle E. Hallett, Matthew Burns, Teerawut Bootwicha, John Studley, And Varinder K. AggarwalAbstract:The iterative Homologation of boronic esters using chiral lithiated benzoate esters and chloromethyllithium has been applied to the highly efficient syntheses of two natural products, (+)-kalkitoxin and (+)-hydroxyphthioceranic acid. The chiral lithiated benzoate esters (>99% ee) were generated from the corresponding stannanes, which themselves were prepared by Hoppe–Beak deprotonation of ethyl 2,4,6-triisopropyl-benzoate with s-BuLi in the presence of (+)- or (−)-sparteine and trapping with Me3SnCl followed by recrystallization. In addition, it was found that purification between several Homologations could be avoided, substantially increasing both chemical and manpower efficiency. In the case of (+)-kalkitoxin, six iterative Homologations were conducted on commercially available p-MeOC6H4CH2Bpin to build up the core of the molecule before the C–B bond was converted into the desired C–N bond, without purification of intermediates. In the case of (+)-hydroxyphthioceranic acid, 16 iterative Homologations were conducted on p-MeOC6H4Bpin with only four intermediate purifications before oxidation of the C–B bond to the desired alcohol. The stereocontrolled and efficient syntheses of these complex molecules highlight the power of iterative chemical synthesis using boronic esters.
Wolfgang Holzer - One of the best experts on this subject based on the ideXlab platform.
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Straightforward chemoselective access to unsymmetrical dithioacetals through a thiosulfonate Homologation-nucleophilic substitution sequence
Chemical communications (Cambridge England), 2020Co-Authors: Laura Ielo, Wolfgang Holzer, Veronica Pillari, Natalie Gajic, Vittorio PaceAbstract:A sequential C1-Homologation-nucleophilic substitution tactic is presented for the preparation of rare unsymmetrical dithioacetals. The judicious selection of thiosulfonates as convenient sulfur electrophilic sources - upon the Homologation event conducted on an intermediate α-halothioether - guarantees the release of the non-reactive sulfonate group, thus enabling the subsequent nucleophilic displacement with an external added thiol [(hetero)aromatic and/or aliphatic]. Uniform high yields and excellent chemocontrol were deduced during the extensive scope study, thus documenting the versatility of the direct technique for the preparation of these unique and manipulable materials.
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direct and chemoselective synthesis of tertiary difluoroketones via weinreb amide Homologation with a chf2 carbene equivalent
Organic Letters, 2019Co-Authors: Margherita Miele, Andrea Citarella, Nicola Micale, Wolfgang Holzer, Vittorio PaceAbstract:The Homologation of Weinreb amides into difluoromethylketones with a formal nucleophilic CHF2 transfer agent is reported. Activating TMSCHF2 with potassium tert-amylate enables a convenient access to the difluorinated Homologation reagent, which adds to the acylating partners. The high chemoselectivity showcased in the presence of variously multifunctionalized Weinreb amides, jointly with uniformly high yields, enables the strategy of general applicability without requiring any stabilization element for the putative carbanion.
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telescoped divergent chemoselective c1 and c1 c1 Homologation of imine surrogates access to quaternary chloro and halomethyl trifluoromethyl aziridines
Angewandte Chemie, 2019Co-Authors: Laura Ielo, Wolfgang Holzer, Saad Touqeer, Alexander Roller, Thierry Langer, Vittorio PaceAbstract:A conceptually novel, high-yielding, mono- or bis-Homologation was realized with lithium halocarbenoids and enables the one-step, fully chemocontrolled assembly of a new class of quaternary trifluoromethyl aziridines. Trifluoroacetimidoyl chlorides (TFAICs) act as convenient electrophilic platforms, enabling the addition of either one or two homologating elements by simply controlling the stoichiometry of the process. Mechanistic studies highlighted that the Homologation event, carried out with two different carbenoids (LiCH2 Cl and LiCH2 F), leads to fluoromethyl analogues in which the first nucleophile is employed for constructing the cycle and the second for decorating the resulting molecular architecture.
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chemoselective synthesis of n substituted α amino α chloro ketones via chloromethylation of glycine derived weinreb amides
Advanced Synthesis & Catalysis, 2013Co-Authors: Vittorio Pace, Wolfgang Holzer, Guido Verniest, Andres R Alcantara, Norbert De KimpeAbstract:Functionalized α-arylamino-α′-chloro ketones are obtained in high yield via a straightforward Homologation reaction of Weinreb amides derived from N-arylglycines using in situ generated chloromethyllithium. The use of the Weinreb amides is essential and allows the chemoselective Homologation of N-aryl-N-substituted glycine analogues, a transformation which is not possible using similar glycine esters. The procedure is promising for the large-scale preparation of α-amino-α′-chloropropanones, which are valuable precursors for a variety of bioactive compounds.
