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Amir H Hoveyda - One of the best experts on this subject based on the ideXlab platform.
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effiCient and seleCtive formation of maCroCyCliC disubstituted z alkenes by ring Closing metathesis rCm reaCtions Catalyzed by mo or w based monoaryloxide pyrrolide map Complexes appliCations to total syntheses of epilaChnene yuzu laCtone ambrettolid
Chemistry: A European Journal, 2013Co-Authors: Chenbo Wang, Miao Yu, Andrew F Kyle, Pavol Jakubec, Darren J Dixon, Richard R Schrock, Amir H HoveydaAbstract:The first broadly appliCable set of protoCols for effiCient and highly Z-seleCtive formation of maCroCyCliC disubstituted alkenes through CatalytiC ring-Closing metathesis (RCM) is desCribed. CyClizations are performed in the presenCe of 1.2–7.5 mol % of a Mo- or W-based mono-aryloxide pyrrolide (MAP) Complex at 22 °C and typiCally proCeed to Complete Conversion within two hours. The utility of the CatalytiC strategy is demonstrated by stereoseleCtive synthesis of representative maCroCyCliC alkenes, inCluding natural produCts yuzu laCtone (13-membered ring: 73% Z) epilaChnene (15-membered ring: 91% Z), ambrettolide (17-membered ring: 91% Z), an advanCed preCursor to Epothilones C and A (16-membered ring: up to 97% Z) and nakadomarin A (polyCyCliC 15-membered ring: up to 97% Z). We demonstrate the Complementary nature of the Mo-based Catalysts, whiCh deliver high aCtivity but Can be more prone to Causing post-RCM stereoisomerization, versus W-based variants, whiCh furnish lower aCtivity but are less inClined towards Causing loss of kinetiC Z seleCtivity; a number of CatalytiC Z-seleCtive Cases are provided to eluCidate whiCh Catalyst Class is best suited for whiCh substrate and partiCular type of alkene RCM proCess. MeChanistiC models that rationalize the origin and the trends in Z seleCtivity as a funCtion of alterations in the Catalyst struCture (i.e., Mo vs W and different imido and aryloxide or alkoxide ligands) are provided; we show that reaCtion time Can be CritiCal in retaining the Z seleCtivity attained not only with MAP Complexes but with the original Mo-based bis-alkoxides as well. The W-based Catalysts are suffiCiently stable to be manipulated in air even with humidity levels of up to 80%; the CatalytiC Z-seleCtive CyClizations Can be performed on gram sCale with Complex moleCule starting materials.
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EffiCient and SeleCtive Formation of MaCroCyCliC Disubstituted Z Alkenes by Ring‐Closing Metathesis (RCM) ReaCtions Catalyzed by Mo‐ or W‐Based Monoaryloxide Pyrrolide (MAP) Complexes: AppliCations to Total Syntheses of EpilaChnene, Yuzu LaCtone, Amb
Chemistry: A European Journal, 2013Co-Authors: Chenbo Wang, Andrew F Kyle, Pavol Jakubec, Darren J Dixon, Richard R Schrock, Amir H HoveydaAbstract:The first broadly appliCable set of protoCols for effiCient and highly Z-seleCtive formation of maCroCyCliC disubstituted alkenes through CatalytiC ring-Closing metathesis (RCM) is desCribed. CyClizations are performed in the presenCe of 1.2–7.5 mol % of a Mo- or W-based mono-aryloxide pyrrolide (MAP) Complex at 22 °C and typiCally proCeed to Complete Conversion within two hours. The utility of the CatalytiC strategy is demonstrated by stereoseleCtive synthesis of representative maCroCyCliC alkenes, inCluding natural produCts yuzu laCtone (13-membered ring: 73% Z) epilaChnene (15-membered ring: 91% Z), ambrettolide (17-membered ring: 91% Z), an advanCed preCursor to Epothilones C and A (16-membered ring: up to 97% Z) and nakadomarin A (polyCyCliC 15-membered ring: up to 97% Z). We demonstrate the Complementary nature of the Mo-based Catalysts, whiCh deliver high aCtivity but Can be more prone to Causing post-RCM stereoisomerization, versus W-based variants, whiCh furnish lower aCtivity but are less inClined towards Causing loss of kinetiC Z seleCtivity; a number of CatalytiC Z-seleCtive Cases are provided to eluCidate whiCh Catalyst Class is best suited for whiCh substrate and partiCular type of alkene RCM proCess. MeChanistiC models that rationalize the origin and the trends in Z seleCtivity as a funCtion of alterations in the Catalyst struCture (i.e., Mo vs W and different imido and aryloxide or alkoxide ligands) are provided; we show that reaCtion time Can be CritiCal in retaining the Z seleCtivity attained not only with MAP Complexes but with the original Mo-based bis-alkoxides as well. The W-based Catalysts are suffiCiently stable to be manipulated in air even with humidity levels of up to 80%; the CatalytiC Z-seleCtive CyClizations Can be performed on gram sCale with Complex moleCule starting materials.
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synthesis of maCroCyCliC natural produCts by Catalyst Controlled stereoseleCtive ring Closing metathesis
Nature, 2011Co-Authors: Miao Yu, Chenbo Wang, Andrew F Kyle, Pavol Jakubec, Darren J Dixon, Richard R Schrock, Amir H HoveydaAbstract:There are a large number of ChemiCal transformations in whiCh alkenes aCt as the reaCtants and/or produCts of the reaCtion. Perhaps the most widely utilized approaCh to synthesis of unsaturated large rings is CatalytiC ring-Closing metathesis (RCM), but this reaCtion often proCeeds with little Control over alkene. Amir Hoveyda and Colleagues have developed a method for highly effiCient and stereoseleCtive synthesis of maCroCyCliC alkenes by CatalytiC RCM. It involves CatalytiC Z-isomer-seleCtive Cross-metathesis reaCtions of terminal enol ethers, whiCh have not been reported previously, and allyliC amides, used previously only in E-isomer-seleCtive proCesses. The effeCtiveness of the method is demonstrated by the stereoseleCtive synthesis of antiCanCer agents Epothilone C and nakadomarin A. Many natural produCts Contain a C = C double bond through whiCh various other derivatives Can be prepared; the stereoChemiCal identity of the alkene Can be CritiCal to the biologiCal aCtivities of suCh moleCules. CatalytiC ring-Closing metathesis (RCM) is a widely used method for the synthesis of large unsaturated rings1,2; however, CyClizations often proCeed without Control of alkene stereoChemistry2. This shortComing is partiCularly Costly when the CyClization reaCtion is performed after a long sequenCe of other ChemiCal transformations2. Here we outline a reliable, praCtiCal and general approaCh for the effiCient and highly stereoseleCtive synthesis of maCroCyCliC alkenes by CatalytiC RCM; transformations deliver up to 97% of the Z isomer owing to Control induCed by a tungsten-based alkylidene. Utility is demonstrated through the stereoseleCtive preparation of Epothilone C (refs 3–5) and nakadomarin A (ref. 6), the previously reported syntheses of whiCh have been marred by late-stage, non-seleCtive RCM7,8,9,10,11,12. The tungsten alkylidene Can be manipulated in air, delivering the produCts in useful yields with high stereoseleCtivity. As a result of effiCient RCM and re-inCorporation of side produCts into the CatalytiC CyCle with minimal alkene isomerization, desired CyClizations proCeed in preferenCe to alternative pathways, even under relatively high substrate ConCentration.
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Synthesis of maCroCyCliC natural produCts by Catalyst-Controlled stereoseleCtive ring-Closing metathesis
Nature, 2011Co-Authors: Chenbo Wang, Andrew F Kyle, Pavol Jakubec, Darren J Dixon, Richard R Schrock, Amir H HoveydaAbstract:Many natural produCts Contain a C = C double bond through whiCh various other derivatives Can be prepared; the stereoChemiCal identity of the alkene Can be CritiCal to the biologiCal aCtivities of suCh moleCules. CatalytiC ring-Closing metathesis (RCM) is a widely used method for the synthesis of large unsaturated rings; however, CyClizations often proCeed without Control of alkene stereoChemistry. This shortComing is partiCularly Costly when the CyClization reaCtion is performed after a long sequenCe of other ChemiCal transformations. Here we outline a reliable, praCtiCal and general approaCh for the effiCient and highly stereoseleCtive synthesis of maCroCyCliC alkenes by CatalytiC RCM; transformations deliver up to 97% of the Z isomer owing to Control induCed by a tungsten-based alkylidene. Utility is demonstrated through the stereoseleCtive preparation of Epothilone C (refs 3-5) and nakadomarin A (ref. 6), the previously reported syntheses of whiCh have been marred by late-stage, non-seleCtive RCM. The tungsten alkylidene Can be manipulated in air, delivering the produCts in useful yields with high stereoseleCtivity. As a result of effiCient RCM and re-inCorporation of side produCts into the CatalytiC CyCle with minimal alkene isomerization, desired CyClizations proCeed in preferenCe to alternative pathways, even under relatively high substrate ConCentration.
Gerhard Höfle - One of the best experts on this subject based on the ideXlab platform.
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Synthesis of Epothilone 16,17-Alkyne Analogs by ReplaCement of the C13−C15(O)-Ring Segment of Natural Epothilone C
European Journal of Organic Chemistry, 2003Co-Authors: Usama Karama, Gerhard HöfleAbstract:Ring-opening Cross metathesis of Epothilone C (4a) with ethylene, followed by silyl proteCtion and ester hydrolysis, yielded an eastern ring segment C1−C12 as the CarboxyliC aCid 10. Separately, a western ring segment 12 Carrying a C16−C17 triple bond was synthesized and Coupled with 10 to form the ester 13. Ring Closure by olefin metathesis, deproteCtion, and then epoxidation, gave the 16,17-alkyne analogs (14b, 3b) of Epothilone C and Epothilone A. The identity of 3b was proven by hydrogenation to (16Z)-Epothilone A8 (17) and Comparison with an authentiC sample prepared from natural Epothilone A8 (18). The biologiCal aCtivity of the new Epothilones was determined. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
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synthesis of Epothilone 16 17 alkyne analogs by replaCement of the C13 C15 o ring segment of natural Epothilone C
European Journal of Organic Chemistry, 2003Co-Authors: Usama Karama, Gerhard HöfleAbstract:Ring-opening Cross metathesis of Epothilone C (4a) with ethylene, followed by silyl proteCtion and ester hydrolysis, yielded an eastern ring segment C1−C12 as the CarboxyliC aCid 10. Separately, a western ring segment 12 Carrying a C16−C17 triple bond was synthesized and Coupled with 10 to form the ester 13. Ring Closure by olefin metathesis, deproteCtion, and then epoxidation, gave the 16,17-alkyne analogs (14b, 3b) of Epothilone C and Epothilone A. The identity of 3b was proven by hydrogenation to (16Z)-Epothilone A8 (17) and Comparison with an authentiC sample prepared from natural Epothilone A8 (18). The biologiCal aCtivity of the new Epothilones was determined. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
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Semisynthesis and degradation of the tubulin inhibitors Epothilone and tubulysin
Pure and Applied Chemistry, 2003Co-Authors: Gerhard Höfle, Usama Karama, Nicole Glaser, Thomas Leibold, Florenz Sasse, Heinrich SteinmetzAbstract:The struCture-aCtivity relationships of Epothilones indiCate that major modifiCa- tions are only tolerated in the western ring segment. In partiCular, C2 methyl of the thiazole ring appears to be most flexible. Its broad modifiCation started from Epothilone F, whiCh was obtained from natural Epothilone B by hydroxylation via the N-oxide. Some of the prepared derivatives exhibit improved esterase stability in addition to high CytotoxiC aCtivity. For these and other favorable properties, amine (BMS-310705) was reCently introduCed in CliniCal trials. In an alternative approaCh, modified side Chains were introduCed by replaCement of the C12,C15 ring segment via ring-opening olefin metathesis (ROM) of Epothilone C in the pres- enCe of ethylene to 12,13-seCo-Epothilone C, introduCtion of a synthetiC building bloCk fol- lowed by ring-Closing olefin metathesis (RCM), and epoxidation to the 16-alkyne analog of Epothilone A. The struCture of the tetrapeptide tubulysin D was Confirmed by total hydrolysis to N-methyl D-pipeColiC aCid, L-isoleuCine, tubuvaline (Tuv), tubuphenylalanine (Tup), formaldehyde, and 3-methylbutyriC aCid. Mild aCidiC hydrolysis to CyClo-tubulysin and oxidative degradation to L-valine allowed the assignment of the stereoCenters of Tuv, hydrazi- nolysis, and Comparison with synthetiC referenCe samples to that of Tup. The absolute Con- figuration of tubulysin D is: (R)-Mep, (2S,3S)-Ile, (1'R,3'R)-Tuv, and (2S,4R)-Tup.
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New natural Epothilones from Sorangium Cellulosum, strains So Ce90/B2 and So Ce90/D13: isolation, struCture eluCidation, and SAR studies.
Journal of Natural Products, 2001Co-Authors: Ingo Hardt, Florenz Sasse, Heinrich Steinmetz, Klaus Gerth, Hans Reichenbach, Gerhard HöfleAbstract:In addition to Epothilones A (1) and B (2), 37 natural Epothilone variants and Epothilone-related Compounds were isolated from the Culture broth of a 700 L fermentation of Sorangium Cellulosum, strain So Ce90/B2. Of these, only the 12,13-desoxyEpothilones, Epothilone C (14) and D (15), were produCed in signifiCant amounts (3−6 mg/L); the 21-hydroxy derivatives and Epothilones E (3) and F (4), in low and variable amounts due to further degradation by the produCing organism. Most of the other Epothilone variants were produCed only in 1−100 μg/L amounts. The new Compounds are very similar in struCture to the parent Compounds 1, 2 and 14, 15 and are presumably the result of the imperfeCt seleCtivity of the biosynthetiC enzymes for aCetate and propionate. Further, Epothilones Containing an oxazole moiety (10−13) in the side Chain instead of a thiazole as well as ring-expanded 18-membered maCrolides, Epothilones I (30−35), and a ring ContraCted 14-membered maCrolide, Epothilone K (36), were found as very minor ...
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new natural Epothilones from sorangium Cellulosum strains so Ce90 b2 and so Ce90 d13 isolation struCture eluCidation and sar studies
Journal of Natural Products, 2001Co-Authors: Ingo Hardt, Florenz Sasse, Heinrich Steinmetz, Klaus Gerth, Hans Reichenbach, Gerhard HöfleAbstract:In addition to Epothilones A (1) and B (2), 37 natural Epothilone variants and Epothilone-related Compounds were isolated from the Culture broth of a 700 L fermentation of Sorangium Cellulosum, strain So Ce90/B2. Of these, only the 12,13-desoxyEpothilones, Epothilone C (14) and D (15), were produCed in signifiCant amounts (3−6 mg/L); the 21-hydroxy derivatives and Epothilones E (3) and F (4), in low and variable amounts due to further degradation by the produCing organism. Most of the other Epothilone variants were produCed only in 1−100 μg/L amounts. The new Compounds are very similar in struCture to the parent Compounds 1, 2 and 14, 15 and are presumably the result of the imperfeCt seleCtivity of the biosynthetiC enzymes for aCetate and propionate. Further, Epothilones Containing an oxazole moiety (10−13) in the side Chain instead of a thiazole as well as ring-expanded 18-membered maCrolides, Epothilones I (30−35), and a ring ContraCted 14-membered maCrolide, Epothilone K (36), were found as very minor ...
Chenbo Wang - One of the best experts on this subject based on the ideXlab platform.
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effiCient and seleCtive formation of maCroCyCliC disubstituted z alkenes by ring Closing metathesis rCm reaCtions Catalyzed by mo or w based monoaryloxide pyrrolide map Complexes appliCations to total syntheses of epilaChnene yuzu laCtone ambrettolid
Chemistry: A European Journal, 2013Co-Authors: Chenbo Wang, Miao Yu, Andrew F Kyle, Pavol Jakubec, Darren J Dixon, Richard R Schrock, Amir H HoveydaAbstract:The first broadly appliCable set of protoCols for effiCient and highly Z-seleCtive formation of maCroCyCliC disubstituted alkenes through CatalytiC ring-Closing metathesis (RCM) is desCribed. CyClizations are performed in the presenCe of 1.2–7.5 mol % of a Mo- or W-based mono-aryloxide pyrrolide (MAP) Complex at 22 °C and typiCally proCeed to Complete Conversion within two hours. The utility of the CatalytiC strategy is demonstrated by stereoseleCtive synthesis of representative maCroCyCliC alkenes, inCluding natural produCts yuzu laCtone (13-membered ring: 73% Z) epilaChnene (15-membered ring: 91% Z), ambrettolide (17-membered ring: 91% Z), an advanCed preCursor to Epothilones C and A (16-membered ring: up to 97% Z) and nakadomarin A (polyCyCliC 15-membered ring: up to 97% Z). We demonstrate the Complementary nature of the Mo-based Catalysts, whiCh deliver high aCtivity but Can be more prone to Causing post-RCM stereoisomerization, versus W-based variants, whiCh furnish lower aCtivity but are less inClined towards Causing loss of kinetiC Z seleCtivity; a number of CatalytiC Z-seleCtive Cases are provided to eluCidate whiCh Catalyst Class is best suited for whiCh substrate and partiCular type of alkene RCM proCess. MeChanistiC models that rationalize the origin and the trends in Z seleCtivity as a funCtion of alterations in the Catalyst struCture (i.e., Mo vs W and different imido and aryloxide or alkoxide ligands) are provided; we show that reaCtion time Can be CritiCal in retaining the Z seleCtivity attained not only with MAP Complexes but with the original Mo-based bis-alkoxides as well. The W-based Catalysts are suffiCiently stable to be manipulated in air even with humidity levels of up to 80%; the CatalytiC Z-seleCtive CyClizations Can be performed on gram sCale with Complex moleCule starting materials.
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EffiCient and SeleCtive Formation of MaCroCyCliC Disubstituted Z Alkenes by Ring‐Closing Metathesis (RCM) ReaCtions Catalyzed by Mo‐ or W‐Based Monoaryloxide Pyrrolide (MAP) Complexes: AppliCations to Total Syntheses of EpilaChnene, Yuzu LaCtone, Amb
Chemistry: A European Journal, 2013Co-Authors: Chenbo Wang, Andrew F Kyle, Pavol Jakubec, Darren J Dixon, Richard R Schrock, Amir H HoveydaAbstract:The first broadly appliCable set of protoCols for effiCient and highly Z-seleCtive formation of maCroCyCliC disubstituted alkenes through CatalytiC ring-Closing metathesis (RCM) is desCribed. CyClizations are performed in the presenCe of 1.2–7.5 mol % of a Mo- or W-based mono-aryloxide pyrrolide (MAP) Complex at 22 °C and typiCally proCeed to Complete Conversion within two hours. The utility of the CatalytiC strategy is demonstrated by stereoseleCtive synthesis of representative maCroCyCliC alkenes, inCluding natural produCts yuzu laCtone (13-membered ring: 73% Z) epilaChnene (15-membered ring: 91% Z), ambrettolide (17-membered ring: 91% Z), an advanCed preCursor to Epothilones C and A (16-membered ring: up to 97% Z) and nakadomarin A (polyCyCliC 15-membered ring: up to 97% Z). We demonstrate the Complementary nature of the Mo-based Catalysts, whiCh deliver high aCtivity but Can be more prone to Causing post-RCM stereoisomerization, versus W-based variants, whiCh furnish lower aCtivity but are less inClined towards Causing loss of kinetiC Z seleCtivity; a number of CatalytiC Z-seleCtive Cases are provided to eluCidate whiCh Catalyst Class is best suited for whiCh substrate and partiCular type of alkene RCM proCess. MeChanistiC models that rationalize the origin and the trends in Z seleCtivity as a funCtion of alterations in the Catalyst struCture (i.e., Mo vs W and different imido and aryloxide or alkoxide ligands) are provided; we show that reaCtion time Can be CritiCal in retaining the Z seleCtivity attained not only with MAP Complexes but with the original Mo-based bis-alkoxides as well. The W-based Catalysts are suffiCiently stable to be manipulated in air even with humidity levels of up to 80%; the CatalytiC Z-seleCtive CyClizations Can be performed on gram sCale with Complex moleCule starting materials.
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synthesis of maCroCyCliC natural produCts by Catalyst Controlled stereoseleCtive ring Closing metathesis
Nature, 2011Co-Authors: Miao Yu, Chenbo Wang, Andrew F Kyle, Pavol Jakubec, Darren J Dixon, Richard R Schrock, Amir H HoveydaAbstract:There are a large number of ChemiCal transformations in whiCh alkenes aCt as the reaCtants and/or produCts of the reaCtion. Perhaps the most widely utilized approaCh to synthesis of unsaturated large rings is CatalytiC ring-Closing metathesis (RCM), but this reaCtion often proCeeds with little Control over alkene. Amir Hoveyda and Colleagues have developed a method for highly effiCient and stereoseleCtive synthesis of maCroCyCliC alkenes by CatalytiC RCM. It involves CatalytiC Z-isomer-seleCtive Cross-metathesis reaCtions of terminal enol ethers, whiCh have not been reported previously, and allyliC amides, used previously only in E-isomer-seleCtive proCesses. The effeCtiveness of the method is demonstrated by the stereoseleCtive synthesis of antiCanCer agents Epothilone C and nakadomarin A. Many natural produCts Contain a C = C double bond through whiCh various other derivatives Can be prepared; the stereoChemiCal identity of the alkene Can be CritiCal to the biologiCal aCtivities of suCh moleCules. CatalytiC ring-Closing metathesis (RCM) is a widely used method for the synthesis of large unsaturated rings1,2; however, CyClizations often proCeed without Control of alkene stereoChemistry2. This shortComing is partiCularly Costly when the CyClization reaCtion is performed after a long sequenCe of other ChemiCal transformations2. Here we outline a reliable, praCtiCal and general approaCh for the effiCient and highly stereoseleCtive synthesis of maCroCyCliC alkenes by CatalytiC RCM; transformations deliver up to 97% of the Z isomer owing to Control induCed by a tungsten-based alkylidene. Utility is demonstrated through the stereoseleCtive preparation of Epothilone C (refs 3–5) and nakadomarin A (ref. 6), the previously reported syntheses of whiCh have been marred by late-stage, non-seleCtive RCM7,8,9,10,11,12. The tungsten alkylidene Can be manipulated in air, delivering the produCts in useful yields with high stereoseleCtivity. As a result of effiCient RCM and re-inCorporation of side produCts into the CatalytiC CyCle with minimal alkene isomerization, desired CyClizations proCeed in preferenCe to alternative pathways, even under relatively high substrate ConCentration.
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Synthesis of maCroCyCliC natural produCts by Catalyst-Controlled stereoseleCtive ring-Closing metathesis
Nature, 2011Co-Authors: Chenbo Wang, Andrew F Kyle, Pavol Jakubec, Darren J Dixon, Richard R Schrock, Amir H HoveydaAbstract:Many natural produCts Contain a C = C double bond through whiCh various other derivatives Can be prepared; the stereoChemiCal identity of the alkene Can be CritiCal to the biologiCal aCtivities of suCh moleCules. CatalytiC ring-Closing metathesis (RCM) is a widely used method for the synthesis of large unsaturated rings; however, CyClizations often proCeed without Control of alkene stereoChemistry. This shortComing is partiCularly Costly when the CyClization reaCtion is performed after a long sequenCe of other ChemiCal transformations. Here we outline a reliable, praCtiCal and general approaCh for the effiCient and highly stereoseleCtive synthesis of maCroCyCliC alkenes by CatalytiC RCM; transformations deliver up to 97% of the Z isomer owing to Control induCed by a tungsten-based alkylidene. Utility is demonstrated through the stereoseleCtive preparation of Epothilone C (refs 3-5) and nakadomarin A (ref. 6), the previously reported syntheses of whiCh have been marred by late-stage, non-seleCtive RCM. The tungsten alkylidene Can be manipulated in air, delivering the produCts in useful yields with high stereoseleCtivity. As a result of effiCient RCM and re-inCorporation of side produCts into the CatalytiC CyCle with minimal alkene isomerization, desired CyClizations proCeed in preferenCe to alternative pathways, even under relatively high substrate ConCentration.
Andrew F Kyle - One of the best experts on this subject based on the ideXlab platform.
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effiCient and seleCtive formation of maCroCyCliC disubstituted z alkenes by ring Closing metathesis rCm reaCtions Catalyzed by mo or w based monoaryloxide pyrrolide map Complexes appliCations to total syntheses of epilaChnene yuzu laCtone ambrettolid
Chemistry: A European Journal, 2013Co-Authors: Chenbo Wang, Miao Yu, Andrew F Kyle, Pavol Jakubec, Darren J Dixon, Richard R Schrock, Amir H HoveydaAbstract:The first broadly appliCable set of protoCols for effiCient and highly Z-seleCtive formation of maCroCyCliC disubstituted alkenes through CatalytiC ring-Closing metathesis (RCM) is desCribed. CyClizations are performed in the presenCe of 1.2–7.5 mol % of a Mo- or W-based mono-aryloxide pyrrolide (MAP) Complex at 22 °C and typiCally proCeed to Complete Conversion within two hours. The utility of the CatalytiC strategy is demonstrated by stereoseleCtive synthesis of representative maCroCyCliC alkenes, inCluding natural produCts yuzu laCtone (13-membered ring: 73% Z) epilaChnene (15-membered ring: 91% Z), ambrettolide (17-membered ring: 91% Z), an advanCed preCursor to Epothilones C and A (16-membered ring: up to 97% Z) and nakadomarin A (polyCyCliC 15-membered ring: up to 97% Z). We demonstrate the Complementary nature of the Mo-based Catalysts, whiCh deliver high aCtivity but Can be more prone to Causing post-RCM stereoisomerization, versus W-based variants, whiCh furnish lower aCtivity but are less inClined towards Causing loss of kinetiC Z seleCtivity; a number of CatalytiC Z-seleCtive Cases are provided to eluCidate whiCh Catalyst Class is best suited for whiCh substrate and partiCular type of alkene RCM proCess. MeChanistiC models that rationalize the origin and the trends in Z seleCtivity as a funCtion of alterations in the Catalyst struCture (i.e., Mo vs W and different imido and aryloxide or alkoxide ligands) are provided; we show that reaCtion time Can be CritiCal in retaining the Z seleCtivity attained not only with MAP Complexes but with the original Mo-based bis-alkoxides as well. The W-based Catalysts are suffiCiently stable to be manipulated in air even with humidity levels of up to 80%; the CatalytiC Z-seleCtive CyClizations Can be performed on gram sCale with Complex moleCule starting materials.
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EffiCient and SeleCtive Formation of MaCroCyCliC Disubstituted Z Alkenes by Ring‐Closing Metathesis (RCM) ReaCtions Catalyzed by Mo‐ or W‐Based Monoaryloxide Pyrrolide (MAP) Complexes: AppliCations to Total Syntheses of EpilaChnene, Yuzu LaCtone, Amb
Chemistry: A European Journal, 2013Co-Authors: Chenbo Wang, Andrew F Kyle, Pavol Jakubec, Darren J Dixon, Richard R Schrock, Amir H HoveydaAbstract:The first broadly appliCable set of protoCols for effiCient and highly Z-seleCtive formation of maCroCyCliC disubstituted alkenes through CatalytiC ring-Closing metathesis (RCM) is desCribed. CyClizations are performed in the presenCe of 1.2–7.5 mol % of a Mo- or W-based mono-aryloxide pyrrolide (MAP) Complex at 22 °C and typiCally proCeed to Complete Conversion within two hours. The utility of the CatalytiC strategy is demonstrated by stereoseleCtive synthesis of representative maCroCyCliC alkenes, inCluding natural produCts yuzu laCtone (13-membered ring: 73% Z) epilaChnene (15-membered ring: 91% Z), ambrettolide (17-membered ring: 91% Z), an advanCed preCursor to Epothilones C and A (16-membered ring: up to 97% Z) and nakadomarin A (polyCyCliC 15-membered ring: up to 97% Z). We demonstrate the Complementary nature of the Mo-based Catalysts, whiCh deliver high aCtivity but Can be more prone to Causing post-RCM stereoisomerization, versus W-based variants, whiCh furnish lower aCtivity but are less inClined towards Causing loss of kinetiC Z seleCtivity; a number of CatalytiC Z-seleCtive Cases are provided to eluCidate whiCh Catalyst Class is best suited for whiCh substrate and partiCular type of alkene RCM proCess. MeChanistiC models that rationalize the origin and the trends in Z seleCtivity as a funCtion of alterations in the Catalyst struCture (i.e., Mo vs W and different imido and aryloxide or alkoxide ligands) are provided; we show that reaCtion time Can be CritiCal in retaining the Z seleCtivity attained not only with MAP Complexes but with the original Mo-based bis-alkoxides as well. The W-based Catalysts are suffiCiently stable to be manipulated in air even with humidity levels of up to 80%; the CatalytiC Z-seleCtive CyClizations Can be performed on gram sCale with Complex moleCule starting materials.
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synthesis of maCroCyCliC natural produCts by Catalyst Controlled stereoseleCtive ring Closing metathesis
Nature, 2011Co-Authors: Miao Yu, Chenbo Wang, Andrew F Kyle, Pavol Jakubec, Darren J Dixon, Richard R Schrock, Amir H HoveydaAbstract:There are a large number of ChemiCal transformations in whiCh alkenes aCt as the reaCtants and/or produCts of the reaCtion. Perhaps the most widely utilized approaCh to synthesis of unsaturated large rings is CatalytiC ring-Closing metathesis (RCM), but this reaCtion often proCeeds with little Control over alkene. Amir Hoveyda and Colleagues have developed a method for highly effiCient and stereoseleCtive synthesis of maCroCyCliC alkenes by CatalytiC RCM. It involves CatalytiC Z-isomer-seleCtive Cross-metathesis reaCtions of terminal enol ethers, whiCh have not been reported previously, and allyliC amides, used previously only in E-isomer-seleCtive proCesses. The effeCtiveness of the method is demonstrated by the stereoseleCtive synthesis of antiCanCer agents Epothilone C and nakadomarin A. Many natural produCts Contain a C = C double bond through whiCh various other derivatives Can be prepared; the stereoChemiCal identity of the alkene Can be CritiCal to the biologiCal aCtivities of suCh moleCules. CatalytiC ring-Closing metathesis (RCM) is a widely used method for the synthesis of large unsaturated rings1,2; however, CyClizations often proCeed without Control of alkene stereoChemistry2. This shortComing is partiCularly Costly when the CyClization reaCtion is performed after a long sequenCe of other ChemiCal transformations2. Here we outline a reliable, praCtiCal and general approaCh for the effiCient and highly stereoseleCtive synthesis of maCroCyCliC alkenes by CatalytiC RCM; transformations deliver up to 97% of the Z isomer owing to Control induCed by a tungsten-based alkylidene. Utility is demonstrated through the stereoseleCtive preparation of Epothilone C (refs 3–5) and nakadomarin A (ref. 6), the previously reported syntheses of whiCh have been marred by late-stage, non-seleCtive RCM7,8,9,10,11,12. The tungsten alkylidene Can be manipulated in air, delivering the produCts in useful yields with high stereoseleCtivity. As a result of effiCient RCM and re-inCorporation of side produCts into the CatalytiC CyCle with minimal alkene isomerization, desired CyClizations proCeed in preferenCe to alternative pathways, even under relatively high substrate ConCentration.
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Synthesis of maCroCyCliC natural produCts by Catalyst-Controlled stereoseleCtive ring-Closing metathesis
Nature, 2011Co-Authors: Chenbo Wang, Andrew F Kyle, Pavol Jakubec, Darren J Dixon, Richard R Schrock, Amir H HoveydaAbstract:Many natural produCts Contain a C = C double bond through whiCh various other derivatives Can be prepared; the stereoChemiCal identity of the alkene Can be CritiCal to the biologiCal aCtivities of suCh moleCules. CatalytiC ring-Closing metathesis (RCM) is a widely used method for the synthesis of large unsaturated rings; however, CyClizations often proCeed without Control of alkene stereoChemistry. This shortComing is partiCularly Costly when the CyClization reaCtion is performed after a long sequenCe of other ChemiCal transformations. Here we outline a reliable, praCtiCal and general approaCh for the effiCient and highly stereoseleCtive synthesis of maCroCyCliC alkenes by CatalytiC RCM; transformations deliver up to 97% of the Z isomer owing to Control induCed by a tungsten-based alkylidene. Utility is demonstrated through the stereoseleCtive preparation of Epothilone C (refs 3-5) and nakadomarin A (ref. 6), the previously reported syntheses of whiCh have been marred by late-stage, non-seleCtive RCM. The tungsten alkylidene Can be manipulated in air, delivering the produCts in useful yields with high stereoseleCtivity. As a result of effiCient RCM and re-inCorporation of side produCts into the CatalytiC CyCle with minimal alkene isomerization, desired CyClizations proCeed in preferenCe to alternative pathways, even under relatively high substrate ConCentration.
Pavol Jakubec - One of the best experts on this subject based on the ideXlab platform.
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effiCient and seleCtive formation of maCroCyCliC disubstituted z alkenes by ring Closing metathesis rCm reaCtions Catalyzed by mo or w based monoaryloxide pyrrolide map Complexes appliCations to total syntheses of epilaChnene yuzu laCtone ambrettolid
Chemistry: A European Journal, 2013Co-Authors: Chenbo Wang, Miao Yu, Andrew F Kyle, Pavol Jakubec, Darren J Dixon, Richard R Schrock, Amir H HoveydaAbstract:The first broadly appliCable set of protoCols for effiCient and highly Z-seleCtive formation of maCroCyCliC disubstituted alkenes through CatalytiC ring-Closing metathesis (RCM) is desCribed. CyClizations are performed in the presenCe of 1.2–7.5 mol % of a Mo- or W-based mono-aryloxide pyrrolide (MAP) Complex at 22 °C and typiCally proCeed to Complete Conversion within two hours. The utility of the CatalytiC strategy is demonstrated by stereoseleCtive synthesis of representative maCroCyCliC alkenes, inCluding natural produCts yuzu laCtone (13-membered ring: 73% Z) epilaChnene (15-membered ring: 91% Z), ambrettolide (17-membered ring: 91% Z), an advanCed preCursor to Epothilones C and A (16-membered ring: up to 97% Z) and nakadomarin A (polyCyCliC 15-membered ring: up to 97% Z). We demonstrate the Complementary nature of the Mo-based Catalysts, whiCh deliver high aCtivity but Can be more prone to Causing post-RCM stereoisomerization, versus W-based variants, whiCh furnish lower aCtivity but are less inClined towards Causing loss of kinetiC Z seleCtivity; a number of CatalytiC Z-seleCtive Cases are provided to eluCidate whiCh Catalyst Class is best suited for whiCh substrate and partiCular type of alkene RCM proCess. MeChanistiC models that rationalize the origin and the trends in Z seleCtivity as a funCtion of alterations in the Catalyst struCture (i.e., Mo vs W and different imido and aryloxide or alkoxide ligands) are provided; we show that reaCtion time Can be CritiCal in retaining the Z seleCtivity attained not only with MAP Complexes but with the original Mo-based bis-alkoxides as well. The W-based Catalysts are suffiCiently stable to be manipulated in air even with humidity levels of up to 80%; the CatalytiC Z-seleCtive CyClizations Can be performed on gram sCale with Complex moleCule starting materials.
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EffiCient and SeleCtive Formation of MaCroCyCliC Disubstituted Z Alkenes by Ring‐Closing Metathesis (RCM) ReaCtions Catalyzed by Mo‐ or W‐Based Monoaryloxide Pyrrolide (MAP) Complexes: AppliCations to Total Syntheses of EpilaChnene, Yuzu LaCtone, Amb
Chemistry: A European Journal, 2013Co-Authors: Chenbo Wang, Andrew F Kyle, Pavol Jakubec, Darren J Dixon, Richard R Schrock, Amir H HoveydaAbstract:The first broadly appliCable set of protoCols for effiCient and highly Z-seleCtive formation of maCroCyCliC disubstituted alkenes through CatalytiC ring-Closing metathesis (RCM) is desCribed. CyClizations are performed in the presenCe of 1.2–7.5 mol % of a Mo- or W-based mono-aryloxide pyrrolide (MAP) Complex at 22 °C and typiCally proCeed to Complete Conversion within two hours. The utility of the CatalytiC strategy is demonstrated by stereoseleCtive synthesis of representative maCroCyCliC alkenes, inCluding natural produCts yuzu laCtone (13-membered ring: 73% Z) epilaChnene (15-membered ring: 91% Z), ambrettolide (17-membered ring: 91% Z), an advanCed preCursor to Epothilones C and A (16-membered ring: up to 97% Z) and nakadomarin A (polyCyCliC 15-membered ring: up to 97% Z). We demonstrate the Complementary nature of the Mo-based Catalysts, whiCh deliver high aCtivity but Can be more prone to Causing post-RCM stereoisomerization, versus W-based variants, whiCh furnish lower aCtivity but are less inClined towards Causing loss of kinetiC Z seleCtivity; a number of CatalytiC Z-seleCtive Cases are provided to eluCidate whiCh Catalyst Class is best suited for whiCh substrate and partiCular type of alkene RCM proCess. MeChanistiC models that rationalize the origin and the trends in Z seleCtivity as a funCtion of alterations in the Catalyst struCture (i.e., Mo vs W and different imido and aryloxide or alkoxide ligands) are provided; we show that reaCtion time Can be CritiCal in retaining the Z seleCtivity attained not only with MAP Complexes but with the original Mo-based bis-alkoxides as well. The W-based Catalysts are suffiCiently stable to be manipulated in air even with humidity levels of up to 80%; the CatalytiC Z-seleCtive CyClizations Can be performed on gram sCale with Complex moleCule starting materials.
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synthesis of maCroCyCliC natural produCts by Catalyst Controlled stereoseleCtive ring Closing metathesis
Nature, 2011Co-Authors: Miao Yu, Chenbo Wang, Andrew F Kyle, Pavol Jakubec, Darren J Dixon, Richard R Schrock, Amir H HoveydaAbstract:There are a large number of ChemiCal transformations in whiCh alkenes aCt as the reaCtants and/or produCts of the reaCtion. Perhaps the most widely utilized approaCh to synthesis of unsaturated large rings is CatalytiC ring-Closing metathesis (RCM), but this reaCtion often proCeeds with little Control over alkene. Amir Hoveyda and Colleagues have developed a method for highly effiCient and stereoseleCtive synthesis of maCroCyCliC alkenes by CatalytiC RCM. It involves CatalytiC Z-isomer-seleCtive Cross-metathesis reaCtions of terminal enol ethers, whiCh have not been reported previously, and allyliC amides, used previously only in E-isomer-seleCtive proCesses. The effeCtiveness of the method is demonstrated by the stereoseleCtive synthesis of antiCanCer agents Epothilone C and nakadomarin A. Many natural produCts Contain a C = C double bond through whiCh various other derivatives Can be prepared; the stereoChemiCal identity of the alkene Can be CritiCal to the biologiCal aCtivities of suCh moleCules. CatalytiC ring-Closing metathesis (RCM) is a widely used method for the synthesis of large unsaturated rings1,2; however, CyClizations often proCeed without Control of alkene stereoChemistry2. This shortComing is partiCularly Costly when the CyClization reaCtion is performed after a long sequenCe of other ChemiCal transformations2. Here we outline a reliable, praCtiCal and general approaCh for the effiCient and highly stereoseleCtive synthesis of maCroCyCliC alkenes by CatalytiC RCM; transformations deliver up to 97% of the Z isomer owing to Control induCed by a tungsten-based alkylidene. Utility is demonstrated through the stereoseleCtive preparation of Epothilone C (refs 3–5) and nakadomarin A (ref. 6), the previously reported syntheses of whiCh have been marred by late-stage, non-seleCtive RCM7,8,9,10,11,12. The tungsten alkylidene Can be manipulated in air, delivering the produCts in useful yields with high stereoseleCtivity. As a result of effiCient RCM and re-inCorporation of side produCts into the CatalytiC CyCle with minimal alkene isomerization, desired CyClizations proCeed in preferenCe to alternative pathways, even under relatively high substrate ConCentration.
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Synthesis of maCroCyCliC natural produCts by Catalyst-Controlled stereoseleCtive ring-Closing metathesis
Nature, 2011Co-Authors: Chenbo Wang, Andrew F Kyle, Pavol Jakubec, Darren J Dixon, Richard R Schrock, Amir H HoveydaAbstract:Many natural produCts Contain a C = C double bond through whiCh various other derivatives Can be prepared; the stereoChemiCal identity of the alkene Can be CritiCal to the biologiCal aCtivities of suCh moleCules. CatalytiC ring-Closing metathesis (RCM) is a widely used method for the synthesis of large unsaturated rings; however, CyClizations often proCeed without Control of alkene stereoChemistry. This shortComing is partiCularly Costly when the CyClization reaCtion is performed after a long sequenCe of other ChemiCal transformations. Here we outline a reliable, praCtiCal and general approaCh for the effiCient and highly stereoseleCtive synthesis of maCroCyCliC alkenes by CatalytiC RCM; transformations deliver up to 97% of the Z isomer owing to Control induCed by a tungsten-based alkylidene. Utility is demonstrated through the stereoseleCtive preparation of Epothilone C (refs 3-5) and nakadomarin A (ref. 6), the previously reported syntheses of whiCh have been marred by late-stage, non-seleCtive RCM. The tungsten alkylidene Can be manipulated in air, delivering the produCts in useful yields with high stereoseleCtivity. As a result of effiCient RCM and re-inCorporation of side produCts into the CatalytiC CyCle with minimal alkene isomerization, desired CyClizations proCeed in preferenCe to alternative pathways, even under relatively high substrate ConCentration.