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2018 Volume 76 Issue 11
2018, 76(11): 817-818
doi: 10.6023/A1811E001
Abstract:
2018, 76(11): 825-830
doi: 10.6023/A18060233
Abstract:
Recent developments in the field of asymmetric α-functionalization of arylacetic acids and derivatives by combining chiral Lewis base and transition-metal catalyst are summarized. The unique character of Lewis bases, specifically, chiral benzotetramisole derivatives, plays a crucial role in these innovative strategies.
Recent developments in the field of asymmetric α-functionalization of arylacetic acids and derivatives by combining chiral Lewis base and transition-metal catalyst are summarized. The unique character of Lewis bases, specifically, chiral benzotetramisole derivatives, plays a crucial role in these innovative strategies.
2018, 76(11): 831-837
doi: 10.6023/A18060232
Abstract:
Recently, N-heterocyclic carbene (NHC) catalysis has achieved significant achievement in the field of cooperative catalysis. With the combination of other established catalysis modes (e.g., Lewis acid, Brønsted acid/base, hydrogen-bond donor), great improvement has been made in the enhancement of reactivity and stereoselectivity, and this strategy has emerged as a powerful instrument in organic synthesis to construct complex molecules. However, owing to the strong propensity of NHCs to bind to transition metals, the development of cooperative catalysis of NHCs and transition metals remains a longstanding and challenging work. At present, some important progress has been made in the combination of NHCs with palladium, copper and ruthenium, and the coordination of NHCs and transition metals can be controlled by the modulation of ligand and alkalinity in reaction system, which not only avoiding the deactivation of the catalysts, but also improving the reaction activity efficiently. This strategy has also been used in the asymmetric construction of bioactive molecular scaffolds. In this perspective, the achievements on NHC and transition metals cooperative catalysis will be discussed.
Recently, N-heterocyclic carbene (NHC) catalysis has achieved significant achievement in the field of cooperative catalysis. With the combination of other established catalysis modes (e.g., Lewis acid, Brønsted acid/base, hydrogen-bond donor), great improvement has been made in the enhancement of reactivity and stereoselectivity, and this strategy has emerged as a powerful instrument in organic synthesis to construct complex molecules. However, owing to the strong propensity of NHCs to bind to transition metals, the development of cooperative catalysis of NHCs and transition metals remains a longstanding and challenging work. At present, some important progress has been made in the combination of NHCs with palladium, copper and ruthenium, and the coordination of NHCs and transition metals can be controlled by the modulation of ligand and alkalinity in reaction system, which not only avoiding the deactivation of the catalysts, but also improving the reaction activity efficiently. This strategy has also been used in the asymmetric construction of bioactive molecular scaffolds. In this perspective, the achievements on NHC and transition metals cooperative catalysis will be discussed.
2018, 76(11): 838-849
doi: 10.6023/A18060237
Abstract:
Transition metal catalysis is one of the most important tools to accurately forge chemical bonds in modern organic synthesis. Organocatalysis, a biomimetic catalysis usually with metal-free small organic molecules, is a relatively young research area that started to flourish at the beginning of this century. Catalytic allylic substitutions are a kind of versatile reactions in organic chemistry; the combination of transition metal catalysis and organocatalysis in these reactions not only significantly expands the scope of nucleophiles, but also helps to resolve the stereocontrol issues. This paper will summarize the advance in the field of catalytic asymmetric allylic substitutions through synergetic transition metal-and organocatalysis. According to the source of chirality, these advances will be classified to three types. The first type is the catalytic asymmetric allylic substitutions induced by chiral transition metal catalysts. For these reactions, chiral ligands, including phosphine ligands and hybrid P, N ligands, have been used to achieve the high enantioselectivity. The non-chiral organocatalysts, such as pyrrolidine, Brønsted acids and boron reagents, were only used to activate the nucleophile or assist the generation of π-allyl metal intermediates. The second type is the catalytic asymmetric allylic substitutions induced by chiral organocatalysts. For the reaction of this type, various chiral organocatalysts, including chiral amines, chiral ureas and others, not only activate the substrates, but also control the enantioselectivity of allylic substitutions well through covalent and non-covalent bonds. Non-chiral ligands were only used to improve the catalytic capacity of transition metals. The last type is the catalytic asymmetric allylic substitutions induced by both of chiral transition metal catalysts and chiral organocatalyst. This strategy can not only realize the excellent stereo-control, but also achieve the challenging diastereo-diversity, if there exist continuous chiral centers. Overall, the joint utilization of transition metals and organocatalysts can achieve many significant asymmetric allylic substitutions that were previously difficult to realize through single transition metal catalysis. Meanwhile, the mechanism of representative transformations will be briefly introduced and at last, the prospective in this area will be given, such as simpler allylic sources and greener catalyst system.
Transition metal catalysis is one of the most important tools to accurately forge chemical bonds in modern organic synthesis. Organocatalysis, a biomimetic catalysis usually with metal-free small organic molecules, is a relatively young research area that started to flourish at the beginning of this century. Catalytic allylic substitutions are a kind of versatile reactions in organic chemistry; the combination of transition metal catalysis and organocatalysis in these reactions not only significantly expands the scope of nucleophiles, but also helps to resolve the stereocontrol issues. This paper will summarize the advance in the field of catalytic asymmetric allylic substitutions through synergetic transition metal-and organocatalysis. According to the source of chirality, these advances will be classified to three types. The first type is the catalytic asymmetric allylic substitutions induced by chiral transition metal catalysts. For these reactions, chiral ligands, including phosphine ligands and hybrid P, N ligands, have been used to achieve the high enantioselectivity. The non-chiral organocatalysts, such as pyrrolidine, Brønsted acids and boron reagents, were only used to activate the nucleophile or assist the generation of π-allyl metal intermediates. The second type is the catalytic asymmetric allylic substitutions induced by chiral organocatalysts. For the reaction of this type, various chiral organocatalysts, including chiral amines, chiral ureas and others, not only activate the substrates, but also control the enantioselectivity of allylic substitutions well through covalent and non-covalent bonds. Non-chiral ligands were only used to improve the catalytic capacity of transition metals. The last type is the catalytic asymmetric allylic substitutions induced by both of chiral transition metal catalysts and chiral organocatalyst. This strategy can not only realize the excellent stereo-control, but also achieve the challenging diastereo-diversity, if there exist continuous chiral centers. Overall, the joint utilization of transition metals and organocatalysts can achieve many significant asymmetric allylic substitutions that were previously difficult to realize through single transition metal catalysis. Meanwhile, the mechanism of representative transformations will be briefly introduced and at last, the prospective in this area will be given, such as simpler allylic sources and greener catalyst system.
2018, 76(11): 850-856
doi: 10.6023/A18060244
Abstract:
The combination of N-heterocyclic carbenes (NHCs) and Lewis acids (LA) have been occasionally employed in asymmetric annulation reactions. However, synergistic effect of LA on NHC-mediated reactions remains scarce. Herein, we demonstrate that by switching LA co-catalysts, two distinct active species, homoenolate and acyl azolium, can be accessed from the same set of substrates. NHC-catalyzed enantioselective hydroesterification is one of the most straightforward strategies to prepare β-chiral esters. Despite recent advances for this redox-neutral transformation, obtaining high enantioselectivity and yield remains challenging. We recently reported synergistic catalysis, combining an achiral NHC and a chiral phosphoric acid, enables highly enantioselective hydrothioesterification and hydroesterification of enals. However, both stereoselectivity and yield for hydroesterification are far from ideal. Specifically, sluggish reactions, accompanied with ee's in mid-80% are often obtained. Additionally, competing pathways for E/Z isomerization and oxidative esterification of enal are serious for a number of substrates. In order to address this issue, we propose a new cooperative catalytic system, consisting of a NHC, a LA and a proton-shuttling agent, might accelerate the pivotal asymmetric β-protonation process. We suspect that the choice of LA might provide complementary reaction pathways from the same enal substrates. Starting from β-alkyl cinnamaldehydes, highly enantioselective hydroesterification is accomplished via asymmetric β-protonation enabled by a magnesium co-catalyst. In sharp contrast, the same homoenolate intermediate can undergo aerobic oxidation, via single electron transfer (SET), in the presence of a ruthenium co-catalyst. Control experiments show distinct rate difference between the E-and Z-isomers of enal. Substrates with Z-configuration react significantly slower under the standard reactions. E/Z isomerization is also slow. Photoirradiation was applied to address the challenging issue of isomeric enals and both high yield and ee are obtained using start materials as E/Z mixtures. General procedure for the asymmetric β-protonation is as following:NHC pre-catalyst (0.01 mmol), MgCl2 (0.01 mmol), DABCO (0.12 mmol), 4 Å MS (100 mg), alcohol (0.6 mmol) and enal substrate (0.1 mmol) were dissolved in toluene (1.0 mL). The resulted mixture was stirred at room temperature under Ar atmosphere for 15 h. Upon complete consumption of the enal, the mixture was concentrated and purified by flash column chromatography. For the aerobic oxidation, the reaction proceeded with RuCl3 (0.01 mmol) under O2 atmosphere.
The combination of N-heterocyclic carbenes (NHCs) and Lewis acids (LA) have been occasionally employed in asymmetric annulation reactions. However, synergistic effect of LA on NHC-mediated reactions remains scarce. Herein, we demonstrate that by switching LA co-catalysts, two distinct active species, homoenolate and acyl azolium, can be accessed from the same set of substrates. NHC-catalyzed enantioselective hydroesterification is one of the most straightforward strategies to prepare β-chiral esters. Despite recent advances for this redox-neutral transformation, obtaining high enantioselectivity and yield remains challenging. We recently reported synergistic catalysis, combining an achiral NHC and a chiral phosphoric acid, enables highly enantioselective hydrothioesterification and hydroesterification of enals. However, both stereoselectivity and yield for hydroesterification are far from ideal. Specifically, sluggish reactions, accompanied with ee's in mid-80% are often obtained. Additionally, competing pathways for E/Z isomerization and oxidative esterification of enal are serious for a number of substrates. In order to address this issue, we propose a new cooperative catalytic system, consisting of a NHC, a LA and a proton-shuttling agent, might accelerate the pivotal asymmetric β-protonation process. We suspect that the choice of LA might provide complementary reaction pathways from the same enal substrates. Starting from β-alkyl cinnamaldehydes, highly enantioselective hydroesterification is accomplished via asymmetric β-protonation enabled by a magnesium co-catalyst. In sharp contrast, the same homoenolate intermediate can undergo aerobic oxidation, via single electron transfer (SET), in the presence of a ruthenium co-catalyst. Control experiments show distinct rate difference between the E-and Z-isomers of enal. Substrates with Z-configuration react significantly slower under the standard reactions. E/Z isomerization is also slow. Photoirradiation was applied to address the challenging issue of isomeric enals and both high yield and ee are obtained using start materials as E/Z mixtures. General procedure for the asymmetric β-protonation is as following:NHC pre-catalyst (0.01 mmol), MgCl2 (0.01 mmol), DABCO (0.12 mmol), 4 Å MS (100 mg), alcohol (0.6 mmol) and enal substrate (0.1 mmol) were dissolved in toluene (1.0 mL). The resulted mixture was stirred at room temperature under Ar atmosphere for 15 h. Upon complete consumption of the enal, the mixture was concentrated and purified by flash column chromatography. For the aerobic oxidation, the reaction proceeded with RuCl3 (0.01 mmol) under O2 atmosphere.
2018, 76(11): 857-861
doi: 10.6023/A18060235
Abstract:
In the recent decade, the palladium-catalyzed allylic C-H alkylation reaction of simple alkenes has been well-established as an efficient and atom-economical synthetic alternative for the fine chemical synthesis without the requirement of any prefunctionalization, in comparison with the conventional procedures. We recently established a highly enantioselective α-allylation reaction of enolizable aldehydes with terminal alkenes by using a ternary catalyst system, including palladium, amine, and chiral Brønsted acid, wherein the chiral anion controls the enantioselectivity. Although this protocol provides allylic alkylation products with high levels of enantioselectivity of up to 90% ee, the extension of the optimal conditions to a 1, 4-diene led to a very low regioslectivity. In the presence of a palladium complex, an oxidant and a chiral phosphoric acid, the 1, 4-diene could be smoothly oxidized and principally generated two regiomeric π-vinylallyl-palladium phosphate intermediates, either of which led to different products. Therefore, the simultaneous control of regio-and stereoselectivities in the allylic C-H alkylation reaction of aldehydes with 1, 4-dienes would pose additional challenge in comparison with a similar reaction of allylarenes. Herein, we will report an asymmetric α-allylation of enolizable aldehydes with a wide range of 1, 4-dienes enabled by cooperative catalysis of a palladium complex, amine, and a chiral Brønsted acid. The presence of 6 mol% Pd(OAc)2, 24 mol% P(4-MeOC6H4)3, 6 mol% chiral phosphoric acid (R)-TRIP, 80 mol% cumylamine and 1.50 equivalents of 2, 6-dimethylbenzoquinone enabled (E)-penta-1, 4-dien-1-ylbenzene (1a) to smoothly undergo the asymmetric allylic C-H alkylation reaction with 2-phenylpropanal (2a), giving rise to the desired α-allylated aldehyde 3a in a 77% isolated yield, 11:1 regioselectivity, 20:1 E/Z and 93% ee. Under the optimal conditions, the generality for enolizable aldehydes was investigated and revealed that 2-aryl propinonaldehydes bearing either electron-donating or electron-withdrawing substituent at the para-(3b~3f) or meta-(3g~3i) position of the phenyl moiety were nicely tolerated, giving rise to the desired allylation products in moderate to good yields with excellent regio-, E/Z-and enantioselectivities. Moreover, 2-naphthyl propinonaldehyde was also able to participate in the asymmetric allylic C-H alkylation reaction, providing the allylation product (3j) with 73% yield, 10:1 regioselectivity, 12:1 E/Z and 91% ee. The examination of 1, 4-dienes found that this protocol tolerated a wide scope of aryl and alkyl substituted 1, 4-dienes, which showed broad adaptability for the facile construction of a broad spectrum of chiral α-quaternary carbonyl compounds. In addition to the terminal aryl-substituted 1, 4-dienes (3k~3q), different substitution patterns were allowed to offer excellent enantioselectivities ranging from 92% ee to 95% ee. Interestingly, this protocol was also amenable to a long chain aliphatic substituent. Although a terminal phenyl (3r) group showed detrimental effect on the regio-and E/Z-selectivities, while the ester (3s), chloride (3t), ether (3u) and cyclohexyl (3v) groups were nicely compatible with the protocol, affording the products with satisfactory results in terms of yields, regio-and stereoselectivities.
In the recent decade, the palladium-catalyzed allylic C-H alkylation reaction of simple alkenes has been well-established as an efficient and atom-economical synthetic alternative for the fine chemical synthesis without the requirement of any prefunctionalization, in comparison with the conventional procedures. We recently established a highly enantioselective α-allylation reaction of enolizable aldehydes with terminal alkenes by using a ternary catalyst system, including palladium, amine, and chiral Brønsted acid, wherein the chiral anion controls the enantioselectivity. Although this protocol provides allylic alkylation products with high levels of enantioselectivity of up to 90% ee, the extension of the optimal conditions to a 1, 4-diene led to a very low regioslectivity. In the presence of a palladium complex, an oxidant and a chiral phosphoric acid, the 1, 4-diene could be smoothly oxidized and principally generated two regiomeric π-vinylallyl-palladium phosphate intermediates, either of which led to different products. Therefore, the simultaneous control of regio-and stereoselectivities in the allylic C-H alkylation reaction of aldehydes with 1, 4-dienes would pose additional challenge in comparison with a similar reaction of allylarenes. Herein, we will report an asymmetric α-allylation of enolizable aldehydes with a wide range of 1, 4-dienes enabled by cooperative catalysis of a palladium complex, amine, and a chiral Brønsted acid. The presence of 6 mol% Pd(OAc)2, 24 mol% P(4-MeOC6H4)3, 6 mol% chiral phosphoric acid (R)-TRIP, 80 mol% cumylamine and 1.50 equivalents of 2, 6-dimethylbenzoquinone enabled (E)-penta-1, 4-dien-1-ylbenzene (1a) to smoothly undergo the asymmetric allylic C-H alkylation reaction with 2-phenylpropanal (2a), giving rise to the desired α-allylated aldehyde 3a in a 77% isolated yield, 11:1 regioselectivity, 20:1 E/Z and 93% ee. Under the optimal conditions, the generality for enolizable aldehydes was investigated and revealed that 2-aryl propinonaldehydes bearing either electron-donating or electron-withdrawing substituent at the para-(3b~3f) or meta-(3g~3i) position of the phenyl moiety were nicely tolerated, giving rise to the desired allylation products in moderate to good yields with excellent regio-, E/Z-and enantioselectivities. Moreover, 2-naphthyl propinonaldehyde was also able to participate in the asymmetric allylic C-H alkylation reaction, providing the allylation product (3j) with 73% yield, 10:1 regioselectivity, 12:1 E/Z and 91% ee. The examination of 1, 4-dienes found that this protocol tolerated a wide scope of aryl and alkyl substituted 1, 4-dienes, which showed broad adaptability for the facile construction of a broad spectrum of chiral α-quaternary carbonyl compounds. In addition to the terminal aryl-substituted 1, 4-dienes (3k~3q), different substitution patterns were allowed to offer excellent enantioselectivities ranging from 92% ee to 95% ee. Interestingly, this protocol was also amenable to a long chain aliphatic substituent. Although a terminal phenyl (3r) group showed detrimental effect on the regio-and E/Z-selectivities, while the ester (3s), chloride (3t), ether (3u) and cyclohexyl (3v) groups were nicely compatible with the protocol, affording the products with satisfactory results in terms of yields, regio-and stereoselectivities.
2018, 76(11): 862-868
doi: 10.6023/A18060238
Abstract:
We report an asymmetric tandem reaction realized by sequential Au(I)/chiral bifunctional tertiary amine catalysis. A tandem olefination/asymmetric cyclization reaction is developed, allowing facile synthesis of quaternary spirocyclic oxindoles in good yields and stereoselectivities from N-Ac protected diazooxindoles 1, monofluorinated enol silyl ethers 2 and 2-tosylaminochalcone 4. The initial cross coupling reaction of diazooxindole and fluorinated enol silyl ethers, catalyzed by 3.0 mol% IPrAuBF4, readily afforded 3-alkenyloxindoles for the subsequent Michael/Michael addition of 2-tosylaminochalcone catalyzed by 5.0~10.0 mol% chiral bifunctional tertiary amine-squaramide C1. The tandem reaction was performed by the following general procedure. Under an atmosphere of N2, to an oven-dried Schlenk tube were added IPrAuCl (6.0 mg, 0.0099 mmol, 3.3 mol%) and AgBF4 (1.8 mg, 0.0090 mmol, 3.0 mol%), followed by anhydrous CH2Cl2 (1.0 mL). The resulting mixture was stirred at 25℃ for 0.5 h and then cooled down to 0℃. After ethers 2 (1.5 equiv.) was added in one-portion, a solution of diazooxindoles 1 in 1.5 mL of CH2Cl2 was added slowly by a syringe pump in 20 minutes. The reaction was stirred at 0℃ till full consumption of 1 by TLC analysis. After the successive addition of C1 and 4 (1.1 equiv.), the reaction was warmed to 25℃ and stirred till full consumption of 3, and the mixture was directly subjected to the column chromatography by using petroleum ether/dichloromethane (1/2.5, V/V) as the eluent to give the desired spirocyclic oxindoles 5. The diastereoselectivities of 5 (>20:1) were determined by 1H NMR analysis of the crude reaction mixture. The key step of this tandem sequence is the cross coupling reaction of monofluorinated enol silyl ethers and donor-acceptor diazo reagents. We further examined the substrates scope of acyclic aryl diazoacetates and fluorinated enol silyl ethers by using 1.0 mol% IPrAuSbF6 as catalyst, providing a new method for the efficient synthesis of trisubstituted alkenes.
We report an asymmetric tandem reaction realized by sequential Au(I)/chiral bifunctional tertiary amine catalysis. A tandem olefination/asymmetric cyclization reaction is developed, allowing facile synthesis of quaternary spirocyclic oxindoles in good yields and stereoselectivities from N-Ac protected diazooxindoles 1, monofluorinated enol silyl ethers 2 and 2-tosylaminochalcone 4. The initial cross coupling reaction of diazooxindole and fluorinated enol silyl ethers, catalyzed by 3.0 mol% IPrAuBF4, readily afforded 3-alkenyloxindoles for the subsequent Michael/Michael addition of 2-tosylaminochalcone catalyzed by 5.0~10.0 mol% chiral bifunctional tertiary amine-squaramide C1. The tandem reaction was performed by the following general procedure. Under an atmosphere of N2, to an oven-dried Schlenk tube were added IPrAuCl (6.0 mg, 0.0099 mmol, 3.3 mol%) and AgBF4 (1.8 mg, 0.0090 mmol, 3.0 mol%), followed by anhydrous CH2Cl2 (1.0 mL). The resulting mixture was stirred at 25℃ for 0.5 h and then cooled down to 0℃. After ethers 2 (1.5 equiv.) was added in one-portion, a solution of diazooxindoles 1 in 1.5 mL of CH2Cl2 was added slowly by a syringe pump in 20 minutes. The reaction was stirred at 0℃ till full consumption of 1 by TLC analysis. After the successive addition of C1 and 4 (1.1 equiv.), the reaction was warmed to 25℃ and stirred till full consumption of 3, and the mixture was directly subjected to the column chromatography by using petroleum ether/dichloromethane (1/2.5, V/V) as the eluent to give the desired spirocyclic oxindoles 5. The diastereoselectivities of 5 (>20:1) were determined by 1H NMR analysis of the crude reaction mixture. The key step of this tandem sequence is the cross coupling reaction of monofluorinated enol silyl ethers and donor-acceptor diazo reagents. We further examined the substrates scope of acyclic aryl diazoacetates and fluorinated enol silyl ethers by using 1.0 mol% IPrAuSbF6 as catalyst, providing a new method for the efficient synthesis of trisubstituted alkenes.
2018, 76(11): 869-873
doi: 10.6023/A18060227
Abstract:
Compared with indium(Ⅲ), indium(I) has both vacant p-orbitals and an electron lone pair, showing distinctive catalytic behaviors. However, chiral indium(I) catalysis has been rarely reported. Previously, we have developed asymmetric binary acid catalysis with indium(Ⅲ) and chiral phosphoric acid for a number of enantioselective transformations. Asymmetric binary-acid catalysis in[4+2] cycloaddition of β, γ-unsaturated α-keto esters with different olefins have been reported by our groups over the past five years. In 2013, we developed exo-selective and enantioselective[4+2] cycloaddition of simple industrial feedstock olefins, such as propene and isobutene, styrene and so on, catalyzed by In(BArF)3/1a. However, the reaction with electron-rich olefins, such as 4-methoxylstyrene did not work very well by indium(Ⅲ) catalysis due to uncontrolled polymerization side pathway. Very recently, we developed a new binary acid system InCl/1a, which could catalyze enantioselective[4+2] annulation of β, γ-unsaturated α-keto esters with much more electron-rich alkoxyallenes. In this study, we reported that the binary acid InCl and 1a was an effective and exo-selective catalyst for the[4+2] cycloaddition of simple olefins. In the presence of InCl (10 mol%) and chiral phosphoric acid 1a (10 mol%), the reaction occurred smoothly to afford the desired cycloadducts in moderate to good yields (20%~93%), with excellent diastereoselectivity (>95:5, exo/endo) and enantioselectivity (up to 99% ee) under the room temperature in CHCl3. Different olefins, such as styrenes 2, ring-strained norbornene 5a, norbornadiene 5b, and cyclopentadiene dimer 5c all worked well with excellent stereoselectivity under the optimal reaction conditions. More importantly, when 4-methoxylstyrene is used, the reaction can proceeded smoothly to afford[4+2] adduct 4k in 70% yield and good stereoselectivity (>95:5 dr, and 88% ee). The typical procedure for asymmetric[4+2] cycloaddition is as follows:To a dry reaction tube was added chiral phosphoric acid 1a (0.005 mmol, 5 mol%), InCl (0.005 mmol, 5 mol%), 4 MS (10 mg), 3 (0.1 mmol), then CHCl3 (0.5 mL) and 2 or 5 (0.5 mmol) was added to the mixture. The mixture was stirred for 24 h at room temperature. The mixture was purified by column chromatography to give the desired cycloaddition products 4 or 6.
Compared with indium(Ⅲ), indium(I) has both vacant p-orbitals and an electron lone pair, showing distinctive catalytic behaviors. However, chiral indium(I) catalysis has been rarely reported. Previously, we have developed asymmetric binary acid catalysis with indium(Ⅲ) and chiral phosphoric acid for a number of enantioselective transformations. Asymmetric binary-acid catalysis in[4+2] cycloaddition of β, γ-unsaturated α-keto esters with different olefins have been reported by our groups over the past five years. In 2013, we developed exo-selective and enantioselective[4+2] cycloaddition of simple industrial feedstock olefins, such as propene and isobutene, styrene and so on, catalyzed by In(BArF)3/1a. However, the reaction with electron-rich olefins, such as 4-methoxylstyrene did not work very well by indium(Ⅲ) catalysis due to uncontrolled polymerization side pathway. Very recently, we developed a new binary acid system InCl/1a, which could catalyze enantioselective[4+2] annulation of β, γ-unsaturated α-keto esters with much more electron-rich alkoxyallenes. In this study, we reported that the binary acid InCl and 1a was an effective and exo-selective catalyst for the[4+2] cycloaddition of simple olefins. In the presence of InCl (10 mol%) and chiral phosphoric acid 1a (10 mol%), the reaction occurred smoothly to afford the desired cycloadducts in moderate to good yields (20%~93%), with excellent diastereoselectivity (>95:5, exo/endo) and enantioselectivity (up to 99% ee) under the room temperature in CHCl3. Different olefins, such as styrenes 2, ring-strained norbornene 5a, norbornadiene 5b, and cyclopentadiene dimer 5c all worked well with excellent stereoselectivity under the optimal reaction conditions. More importantly, when 4-methoxylstyrene is used, the reaction can proceeded smoothly to afford[4+2] adduct 4k in 70% yield and good stereoselectivity (>95:5 dr, and 88% ee). The typical procedure for asymmetric[4+2] cycloaddition is as follows:To a dry reaction tube was added chiral phosphoric acid 1a (0.005 mmol, 5 mol%), InCl (0.005 mmol, 5 mol%), 4 MS (10 mg), 3 (0.1 mmol), then CHCl3 (0.5 mL) and 2 or 5 (0.5 mmol) was added to the mixture. The mixture was stirred for 24 h at room temperature. The mixture was purified by column chromatography to give the desired cycloaddition products 4 or 6.
2018, 76(11): 874-877
doi: 10.6023/A18070291
Abstract:
Chiral tertiary alcohols are ubiquitous in medicinally relevant agents and biologically active natural products. Although some catalytic asymmetric approaches for the synthesis of chiral tertiary alcohols have been reported, the development of efficient methods for enantioselective construction of tertiary alcohols is still highly appealing. Most recently, we have developed Pd-catalyzed asymmetric decarboxylative cycloaddition of vinylethylene carbonates (VECs) with formaldehyde to construct tertiary alcohol derivatives. The reaction was catalyzed by the chiral palladium complex with a chiral phosphoramidite to afford methylene acetal protected tertiary vinylglycols in high efficiency. Since the pioneer works by Gong and Takemoto respectively for the allylic substitution under cooperative catalysis of palladium complex and chiral phase-transfer catalyst, the asymmetric allylic substitution synergistically catalyzed by transition metal and organocatalyst has recently attracted a great deal of attention. However, there have been no reports on the combination of transition-metal and squaramide for the allylic alkylation. In this communication, we will report the asymmetric decarboxylative cycloaddition of VECs with formaldehyde under cooperative catalytic system of achiral palladium complex and chiral squaramide. With combination of palladium complex in situ generated from Pd2(dba)3·CHCl3 (2.5 mol%) and achiral phosphine ligand L4 (10 mol%) and chiral squaramide OC2 (25 mol%) as cooperative catalysts, the reaction of VECs with paraformaldehyde (10 equiv.) proceeded smoothly to give desired tertiary alcohol derivatives in good yields (51%~65%) with moderate enantioselectivities (62%~79% ee). The reaction conditions are also suitable for the reaction of VEC with electronic deficient arylaldehydes to afford desired products in high yields with good enantioselectivities, although the catalytic system is less effective for the control of the diastereoselectivities. Although the enantioselectivity of the reaction is not significantly high, we firstly demonstrated that the chiral induction for the cycloaddition reaction could be achieved under the cooperative catalytic system of achiral palladium complex and chiral squaramide. The detail reaction mechanism and stereochemical outcome are currently underway, and will be reported in due course.
Chiral tertiary alcohols are ubiquitous in medicinally relevant agents and biologically active natural products. Although some catalytic asymmetric approaches for the synthesis of chiral tertiary alcohols have been reported, the development of efficient methods for enantioselective construction of tertiary alcohols is still highly appealing. Most recently, we have developed Pd-catalyzed asymmetric decarboxylative cycloaddition of vinylethylene carbonates (VECs) with formaldehyde to construct tertiary alcohol derivatives. The reaction was catalyzed by the chiral palladium complex with a chiral phosphoramidite to afford methylene acetal protected tertiary vinylglycols in high efficiency. Since the pioneer works by Gong and Takemoto respectively for the allylic substitution under cooperative catalysis of palladium complex and chiral phase-transfer catalyst, the asymmetric allylic substitution synergistically catalyzed by transition metal and organocatalyst has recently attracted a great deal of attention. However, there have been no reports on the combination of transition-metal and squaramide for the allylic alkylation. In this communication, we will report the asymmetric decarboxylative cycloaddition of VECs with formaldehyde under cooperative catalytic system of achiral palladium complex and chiral squaramide. With combination of palladium complex in situ generated from Pd2(dba)3·CHCl3 (2.5 mol%) and achiral phosphine ligand L4 (10 mol%) and chiral squaramide OC2 (25 mol%) as cooperative catalysts, the reaction of VECs with paraformaldehyde (10 equiv.) proceeded smoothly to give desired tertiary alcohol derivatives in good yields (51%~65%) with moderate enantioselectivities (62%~79% ee). The reaction conditions are also suitable for the reaction of VEC with electronic deficient arylaldehydes to afford desired products in high yields with good enantioselectivities, although the catalytic system is less effective for the control of the diastereoselectivities. Although the enantioselectivity of the reaction is not significantly high, we firstly demonstrated that the chiral induction for the cycloaddition reaction could be achieved under the cooperative catalytic system of achiral palladium complex and chiral squaramide. The detail reaction mechanism and stereochemical outcome are currently underway, and will be reported in due course.
2018, 76(11): 878-882
doi: 10.6023/A18100413
Abstract:
Enantioenriched pyrrolidines bearing a β-aryl group and an α-quaternary carbon stereocenter are important structural motifs in many natural products and pharmaceuticals, and their enantioselective synthesis has thus received extensive attention over the last several decades. Nonetheless, so far as we know, asymmetric aminoarylation of alkenes to access such targets has only been independently reported by Wolfe and Liu using palladium catalysis involving a key aminopalladation step, and thus, general and practical methodologies towards a variety of chiral pyrrolidines are still in demand and highly desirable. As part of our ongoing interest in radical-initiated difunctionalization reactions of alkenes based on Cu(I)/chiral phosphoric acid (CPA) catalysis, we sought to develop a mechanistically distinct and complementary approach for this asymmetric palladium(Ⅱ)-catalyzed aminoarylation of alkenes. Herein we describe our efforts toward the development of the efficient asymmetric radical-initiated aminoarylation of alkenes with aryldiazonium salts enabled by Cu(I)/CPA catalysis. A general procedure for the aminoarylation of alkenes with aryldiazonium salts is as follows:under argon, an oven-dried resealable Schlenk tube equipped with a magnetic stir bar was charged with urea substrate 1 (0.1 mmol, 1.0 equiv.), CuI (1.9 mg, 0.01 mmol, 10 mol%), CPA[(S)-A1 (9.3 mg, 0.015 mmol, 15 mol%], aryldiazonium salts 2 (0.12 mmol, 1.2 equiv.), Na3PO4 (19.7 mg, 0.12 mmol, 1.2 equiv.) and isopropyl acetate(1.0 mL) at 32℃ and the sealed tube was then stirred under the same conditions. Upon completion (monitored by thin-layer chromatography), the reaction mixture was directly purified by silica gel chromatography[eluent:V(petroleum ether):V(EtOAc)=100:0 to 3:1] to afford the desired product 3. The enantiometric excess of product was determined by chiral high-performance liquid chromatography (HPLC) analysis. A broad scope of substrates worked well under this standard conditions to afford enantioenriched pyrrolidines in good yield with good to excellent enantioselectivity. A series of control experiments were conducted to determine the reaction mechanism as a radical process and a possible mechanism was proposed.
Enantioenriched pyrrolidines bearing a β-aryl group and an α-quaternary carbon stereocenter are important structural motifs in many natural products and pharmaceuticals, and their enantioselective synthesis has thus received extensive attention over the last several decades. Nonetheless, so far as we know, asymmetric aminoarylation of alkenes to access such targets has only been independently reported by Wolfe and Liu using palladium catalysis involving a key aminopalladation step, and thus, general and practical methodologies towards a variety of chiral pyrrolidines are still in demand and highly desirable. As part of our ongoing interest in radical-initiated difunctionalization reactions of alkenes based on Cu(I)/chiral phosphoric acid (CPA) catalysis, we sought to develop a mechanistically distinct and complementary approach for this asymmetric palladium(Ⅱ)-catalyzed aminoarylation of alkenes. Herein we describe our efforts toward the development of the efficient asymmetric radical-initiated aminoarylation of alkenes with aryldiazonium salts enabled by Cu(I)/CPA catalysis. A general procedure for the aminoarylation of alkenes with aryldiazonium salts is as follows:under argon, an oven-dried resealable Schlenk tube equipped with a magnetic stir bar was charged with urea substrate 1 (0.1 mmol, 1.0 equiv.), CuI (1.9 mg, 0.01 mmol, 10 mol%), CPA[(S)-A1 (9.3 mg, 0.015 mmol, 15 mol%], aryldiazonium salts 2 (0.12 mmol, 1.2 equiv.), Na3PO4 (19.7 mg, 0.12 mmol, 1.2 equiv.) and isopropyl acetate(1.0 mL) at 32℃ and the sealed tube was then stirred under the same conditions. Upon completion (monitored by thin-layer chromatography), the reaction mixture was directly purified by silica gel chromatography[eluent:V(petroleum ether):V(EtOAc)=100:0 to 3:1] to afford the desired product 3. The enantiometric excess of product was determined by chiral high-performance liquid chromatography (HPLC) analysis. A broad scope of substrates worked well under this standard conditions to afford enantioenriched pyrrolidines in good yield with good to excellent enantioselectivity. A series of control experiments were conducted to determine the reaction mechanism as a radical process and a possible mechanism was proposed.
2018, 76(11): 883-889
doi: 10.6023/A18060234
Abstract:
Transition-metal-catalyzed asymmetric insertion of carbene into O-H bonds is a straightforward method for the synthesis of chiral alcohols and their derivatives. In recent years, a variety of chiral catalysts have been developed to achieve high enantioselective insertions of metal carbenes derived from α-diazoesters into O-H bonds of alcohols, phenols, carboxylic acids, and even water. However, there are few successful examples of the asymmetric O-H bond insertion using α-diazoketones as carbene precursors. In this paper, we report the first asymmetric O-H insertion of α-diazoketones with alcohols co-catalyzed by achiral dirhodium complexes and chiral spiro phosphoric acids. The reaction has high yields and high enantioselectivity (up to 95% ee). The present O-H bond insertion reaction provides an efficient method for the synthesis of very useful chiral α-alkoxy ketones, which are easily transformed to corresponding 1, 2-diol derivatives with excellent diastereoselectivity. The density functional theory (DFT) calculation was performed to study the mechanism of the reaction. It is found that the chiral spiro phosphoric acid can promote the proton transfer process of enol intermediates generated from rhodium carbene and alcohol like chiral proton-transfer shuttle and realize enantioselectivity control accordingly. Water are likely to participate in this proton transfer step and has a remarkable effect on the enantiocontrol of the reaction. A typical procedure for the enantioselective O-H bond insertion of α-diazoketones is as follows. Powered Rh2(TPA)4 (2.9 mg, 0.002 mmol, 1 mol%) and chiral spiro phosphoric acid (R)-1k (3.3 mg, 0.004 mmol, 2 mol%) were introduced into an oven-dried Schlenk tube in an argon-filled glovebox. After CHCl3 (2 mL) was injected into the Schlenk tube, the solution was stirred at 25℃ under the argon atmosphere. A solution of benzyl alcohol (21.6 mg, 0.2 mmol) and 1-diazo-1-phenylpropan-2-one (2a, 33.8 mg, 0.21 mmol) in 1 mL of CHCl3 were then introduced into the Schlenk tube containing catalysts. The resulting mixture was stirred at 25℃ until the diazo compound 2a disappeared. After concentration in vacuo, the residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, V:V=15:1) to give (-)-1-(benzyloxy)-1-phenyl-propan-2-one (4a, 43.2 mg, 0.18 mmol, 90% yield) as a colorless oil.
Transition-metal-catalyzed asymmetric insertion of carbene into O-H bonds is a straightforward method for the synthesis of chiral alcohols and their derivatives. In recent years, a variety of chiral catalysts have been developed to achieve high enantioselective insertions of metal carbenes derived from α-diazoesters into O-H bonds of alcohols, phenols, carboxylic acids, and even water. However, there are few successful examples of the asymmetric O-H bond insertion using α-diazoketones as carbene precursors. In this paper, we report the first asymmetric O-H insertion of α-diazoketones with alcohols co-catalyzed by achiral dirhodium complexes and chiral spiro phosphoric acids. The reaction has high yields and high enantioselectivity (up to 95% ee). The present O-H bond insertion reaction provides an efficient method for the synthesis of very useful chiral α-alkoxy ketones, which are easily transformed to corresponding 1, 2-diol derivatives with excellent diastereoselectivity. The density functional theory (DFT) calculation was performed to study the mechanism of the reaction. It is found that the chiral spiro phosphoric acid can promote the proton transfer process of enol intermediates generated from rhodium carbene and alcohol like chiral proton-transfer shuttle and realize enantioselectivity control accordingly. Water are likely to participate in this proton transfer step and has a remarkable effect on the enantiocontrol of the reaction. A typical procedure for the enantioselective O-H bond insertion of α-diazoketones is as follows. Powered Rh2(TPA)4 (2.9 mg, 0.002 mmol, 1 mol%) and chiral spiro phosphoric acid (R)-1k (3.3 mg, 0.004 mmol, 2 mol%) were introduced into an oven-dried Schlenk tube in an argon-filled glovebox. After CHCl3 (2 mL) was injected into the Schlenk tube, the solution was stirred at 25℃ under the argon atmosphere. A solution of benzyl alcohol (21.6 mg, 0.2 mmol) and 1-diazo-1-phenylpropan-2-one (2a, 33.8 mg, 0.21 mmol) in 1 mL of CHCl3 were then introduced into the Schlenk tube containing catalysts. The resulting mixture was stirred at 25℃ until the diazo compound 2a disappeared. After concentration in vacuo, the residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, V:V=15:1) to give (-)-1-(benzyloxy)-1-phenyl-propan-2-one (4a, 43.2 mg, 0.18 mmol, 90% yield) as a colorless oil.
2018, 76(11): 890-894
doi: 10.6023/A18060224
Abstract:
Allylic alkylation first pioneered by Tsuji in 1965 and, later adapted by Trost in 1973 with the introduction of phosphine ligands represents one of the straightforward and powerful synthetic tool for new carbon-carbon formation, especially the direct asymmetric allylic alkylation (AAA) has been widely utilized in the synthesis of natural products and pharmaceutical molecules. Conventionally, AAA reactions involve activated allylic alcohol derivatives, such as carbonates, amines, acetates, and halides, which require an equivalent strong base to react with the acidic by-product and inevitably results in stoichiometric waste. From the viewpoint of environmental and atom economy, the direct use of allylic alcohol instead its derivatives is much more practical by virtue of only water being formed as a byproduct. However, one of the challenges existed in such transformations is the poor reactivity of allylic alcohol. In 2006, a breakthrough was first made by Trost group, by using stoichiometric amounts of borane as the critical promoter in the direct AAA reaction of indoles with allylic alcohols. Afterwards, List, Gong, and Zhang reported independently the significant achievements applying aldehyde, pyrazol-5-ones, and ketones as nucleophiles, respectively. In 2004, our group enclosed the Brønsted acid accelerated Pd-catalyzed direct asymmetric allylic alkylation of azlactones with simple allylic alcohols. On the other hand, triphenylamine (TPA) as a strong electron-donating and oxidative stable molecule has been extensively utilized in the new organic electroluminescent materials, special dye synthesis and organic solar cells. Considering the impressive fluorescence emission ability of TPA and basing on these pioneering works, we reasoned that the direct connection of the TPA substructure with amino acid molecules could give rise to the fluorescence emission compounds. Thus, we report here the first installation of the non-natural amino acid derivatives bearing TPA core skeleton via Pd-catalyzed direct AAA reaction and the desired products were obtained with excellent yields (68%~95%) and enantioselectivities (90%~97% ee). The optimized reaction condition is as following:To a dried Schlenk tube were added activated 5 MS (100 mg), Pd2(dba)3 (4.0 mol%), L3 (10.0 mol%), solvent toluene (1.0 mL), and was stirred at 60℃ for 20 min. Then the reaction mixture was cooled down to room temperature, azlactones 1 (0.2 mmol), allylic alcohol 2 (0.3 mmol) and benzoic acid (10.0 mol%) in toluene (1.0 mL) was added and continue to stir at 60℃ for 20 h until the reaction was complete (monitored by TLC). The solvent was then removed under vacuum and the residue was purified by flash chromatography on silica gel to afford the desired product.
Allylic alkylation first pioneered by Tsuji in 1965 and, later adapted by Trost in 1973 with the introduction of phosphine ligands represents one of the straightforward and powerful synthetic tool for new carbon-carbon formation, especially the direct asymmetric allylic alkylation (AAA) has been widely utilized in the synthesis of natural products and pharmaceutical molecules. Conventionally, AAA reactions involve activated allylic alcohol derivatives, such as carbonates, amines, acetates, and halides, which require an equivalent strong base to react with the acidic by-product and inevitably results in stoichiometric waste. From the viewpoint of environmental and atom economy, the direct use of allylic alcohol instead its derivatives is much more practical by virtue of only water being formed as a byproduct. However, one of the challenges existed in such transformations is the poor reactivity of allylic alcohol. In 2006, a breakthrough was first made by Trost group, by using stoichiometric amounts of borane as the critical promoter in the direct AAA reaction of indoles with allylic alcohols. Afterwards, List, Gong, and Zhang reported independently the significant achievements applying aldehyde, pyrazol-5-ones, and ketones as nucleophiles, respectively. In 2004, our group enclosed the Brønsted acid accelerated Pd-catalyzed direct asymmetric allylic alkylation of azlactones with simple allylic alcohols. On the other hand, triphenylamine (TPA) as a strong electron-donating and oxidative stable molecule has been extensively utilized in the new organic electroluminescent materials, special dye synthesis and organic solar cells. Considering the impressive fluorescence emission ability of TPA and basing on these pioneering works, we reasoned that the direct connection of the TPA substructure with amino acid molecules could give rise to the fluorescence emission compounds. Thus, we report here the first installation of the non-natural amino acid derivatives bearing TPA core skeleton via Pd-catalyzed direct AAA reaction and the desired products were obtained with excellent yields (68%~95%) and enantioselectivities (90%~97% ee). The optimized reaction condition is as following:To a dried Schlenk tube were added activated 5 MS (100 mg), Pd2(dba)3 (4.0 mol%), L3 (10.0 mol%), solvent toluene (1.0 mL), and was stirred at 60℃ for 20 min. Then the reaction mixture was cooled down to room temperature, azlactones 1 (0.2 mmol), allylic alcohol 2 (0.3 mmol) and benzoic acid (10.0 mol%) in toluene (1.0 mL) was added and continue to stir at 60℃ for 20 h until the reaction was complete (monitored by TLC). The solvent was then removed under vacuum and the residue was purified by flash chromatography on silica gel to afford the desired product.
2018, 76(11): 895-900
doi: 10.6023/A18060228
Abstract:
Sulfonamide is a key structural unit of several groups of vitally synthetic drugs that have been extensively used as antimicrobials, antiretroviral drugs and anticancer agents. In particular, enantiomerically pure sulfonamides represent a rapidly-increasing important substance in new drug discovery due to their unique pharmacological properties. Thus, developing asymmetric synthetic methods involving rapid and highly efficient construction of these compounds is extremely important and highly demanded for medicinal chemists. In our laboratory, we have reported a serial of asymmetric multicomponent reactions via trapping reactive ammonium ylides generated from amines and diazo compounds in the presence of transition metal complexes and chiral phosphoric acids. In this work, an asymmetric three-component reaction of sulfonamides, diazo compounds and imines cooperatively catalyzed by Rh2(OAc)4 and chiral phosphoric acids was reported. This Rh2(OAc)4 and chiral phosphoric acids cooperatively catalyzed three-component reaction of sulfonamides, diazo compounds and imines accomplished with satisfying yields (up to 85%), high diastereoselectivity (>20:1) and excellent enantioselectivity (up to 99% ee), thus providing a rapid access to synthesize enantiomerically enriched sulfonamides bearing two adjacent chiral carbons. Furthermore, this newly developed three-component reaction was carried out on a gram-scale with a lower catalyst loading and without impacting the yield, diastereoselectivity and enantioselectivity. Finally, we explored the further transformation of obtained three-component reaction products:1) treatment of 5aaa with LiAlH4 under 0℃ in THF for 8.0 h gave the corresponding alcohol derivative 6 in 82% yield without changing the diastereoselectivity and enantioselectivity (0.20 mmol scale); 2) treatment of 5aaa with triphosgene and triethylamine under 0℃ in DCM for 1.0 h, gave five-membered heterocyclic sulfoximine derivative 7 bearing three adjacent chiral atoms (2 carbons and 1 sulfur) in 80% yield with perfect diastereoselectivity (>20:1) and remained enantioselectivity (0.20 mmol scale).
Sulfonamide is a key structural unit of several groups of vitally synthetic drugs that have been extensively used as antimicrobials, antiretroviral drugs and anticancer agents. In particular, enantiomerically pure sulfonamides represent a rapidly-increasing important substance in new drug discovery due to their unique pharmacological properties. Thus, developing asymmetric synthetic methods involving rapid and highly efficient construction of these compounds is extremely important and highly demanded for medicinal chemists. In our laboratory, we have reported a serial of asymmetric multicomponent reactions via trapping reactive ammonium ylides generated from amines and diazo compounds in the presence of transition metal complexes and chiral phosphoric acids. In this work, an asymmetric three-component reaction of sulfonamides, diazo compounds and imines cooperatively catalyzed by Rh2(OAc)4 and chiral phosphoric acids was reported. This Rh2(OAc)4 and chiral phosphoric acids cooperatively catalyzed three-component reaction of sulfonamides, diazo compounds and imines accomplished with satisfying yields (up to 85%), high diastereoselectivity (>20:1) and excellent enantioselectivity (up to 99% ee), thus providing a rapid access to synthesize enantiomerically enriched sulfonamides bearing two adjacent chiral carbons. Furthermore, this newly developed three-component reaction was carried out on a gram-scale with a lower catalyst loading and without impacting the yield, diastereoselectivity and enantioselectivity. Finally, we explored the further transformation of obtained three-component reaction products:1) treatment of 5aaa with LiAlH4 under 0℃ in THF for 8.0 h gave the corresponding alcohol derivative 6 in 82% yield without changing the diastereoselectivity and enantioselectivity (0.20 mmol scale); 2) treatment of 5aaa with triphosgene and triethylamine under 0℃ in DCM for 1.0 h, gave five-membered heterocyclic sulfoximine derivative 7 bearing three adjacent chiral atoms (2 carbons and 1 sulfur) in 80% yield with perfect diastereoselectivity (>20:1) and remained enantioselectivity (0.20 mmol scale).
