Enantioselective Mannich‐Type Reactions to Construct Trifluoromethylthio‐Containing Tetrasubstituted Carbon Stereocenters <i>via</i> Asymmetric Dual‐Reagent Catalysis

Xu, Lijun; Wang, Hongyu; Zheng, Changwu; Zhao, Gang

doi:10.1002/adsc.201700321

Cited by 37 publications

(5 citation statements)

References 76 publications

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“…To a solution of CH 2 Cl 2 (5 mL) and 2-(diphenylphosphino)ethylamine (1.8 mmol, 418.2 mg), phenyl isothiocyanate (2.0 mmol, 244 µL) was added. The reaction was carried out at room temperature during 18 h. After that, the solvent was evaporated and the product was purified by column chromatography (SiO 2 , hexane:AcOEt, 7:3), obtaining the final product T2 as a white solid in 85% yield [71]. 1 To a solution of T2 (0.05 mmol, 18.2 mg) in CH 2 Cl 2 (8 mL), [Ag(OTf)(PPh 3 )] (0.05 mmol, 25.9 mg) was added.…”

Section: Synthesis Of Thiourea T2mentioning

confidence: 99%

Synthesis of New Thiourea-Metal Complexes with Promising Anticancer Properties

et al. 2021

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In this work, two thiourea ligands bearing a phosphine group in one arm and in the other a phenyl group (T2) or 3,5-di-CF3 substituted phenyl ring (T1) have been prepared and their coordination to Au and Ag has been studied. A different behavior is observed for gold complexes, a linear geometry with coordination only to the phosphorus atom or an equilibrium between the linear and three-coordinated species is present, whereas for silver complexes the coordination of the ligand as P^S chelate is found. The thiourea ligands and their complexes were explored against different cancer cell lines (HeLa, A549, and Jurkat). The thiourea ligands do not exhibit relevant cytotoxicity in the tested cell lines and the coordination of a metal triggers excellent cytotoxic values in all cases. In general, data showed that gold complexes are more cytotoxic than the silver compounds with T1, in particular the complexes [AuT1(PPh3)]OTf, the bis(thiourea) [Au(T1)2]OTf and the gold-thiolate species [Au(SR)T1]. In contrast, with T2 better results are obtained with silver species [AgT1(PPh3)]OTf and the [Ag(T1)2]OTf. The role played by the ancillary ligand bound to the metal is important since it strongly affects the cytotoxic activity, being the bis(thiourea) complex the most active species. This study demonstrates that metal complexes derived from thiourea can be biologically active and these compounds are promising leads for further development as potential anticancer agents.

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Section: Synthesis Of Thiourea T2mentioning

confidence: 99%

Synthesis of New Thiourea-Metal Complexes with Promising Anticancer Properties

et al. 2021

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“…Despite the fact that significant advances have been achieved for the synthesis of achiral SCF 3 -containing molecules, the stereospecific introduction of the SCF 3 group into target molecules has remained an unmet challenge. ,, Remarkable progress was made in 2013 when Rueping and Shen simultaneously and independently disclosed natural Cinchona alkaloid catalyzed asymmetric electrophilic trifluoromethylthiolation of β-keto esters. They utilized similar Cinchona alkaloid catalysts but used different electrophilic SCF 3 sources.…”

Section: Introductionmentioning

confidence: 99%

Mechanism and Origins of Stereoinduction in Natural Cinchona Alkaloid Catalyzed Asymmetric Electrophilic Trifluoromethylthiolation of β-Keto Esters with N-Trifluoromethylthiophthalimide as Electrophilic SCF₃ Source

Xue

Cheng

2017

ACS Catal.

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The trifluoromethylthio (SCF3) group enjoys a privileged role in the field of drug discovery because its incorporation into a drug molecule often leads to significantly improved pharmacokinetics and efficacy. In spite of its prime importance in drug discovery, the stereospecific introduction of the SCF3 group into target molecules has remained an unmet challenge. A major breakthrough was made in 2013 when Rueping and Shen simultaneously and independently disclosed natural Cinchona alkaloid catalyzed asymmetric electrophilic trifluoromethylthiolation of β-keto esters. However, two key issues remain obscure. (a) What is the preferred mode of catalysis? (b) How is asymmetric induction accomplished? Here we report an in-depth computational exploration into the mechanism and origin of stereoinduction in Cinchona alkaloid catalyzed trifluoromethylthiolation of β-keto esters with N-trifluoromethylthiophthalimide as electrophilic SCF3 source. Three mechanistic possibilities, i.e., (a) the transfer-trifluoromethylthiolation, (b) the Wynberg ion pair-hydrogen bonding model, and (c) the Houk–Grayson bifunctional Brønsted acid-hydrogen bonding model, were evaluated with density functional theory (B3LYP-D3 and M06-2X functionals). Our calculations suggest that, in contrast to Cinchona alkaloid catalyzed conjugate additions, the most preferred mode for the title reaction is not the Houk–Grayson bifunctional Brønsted acid-hydrogen bonding model but instead the Wynberg ion pair-hydrogen bonding model, wherein the SCF3 transfer proceeds via an SN2-like mechanism. Consequently, although the Houk–Grayson bifunctional Brønsted acid–hydrogen bonding model has recently been demonstrated to be a general mechanistic model for Cinchona alkaloid catalyzed asymmetric Michael additions, this catalysis mode cannot be simply extended to an asymmetric SN2-type of reaction. The predicted enantioselectivities based on the Wynberg ion pair-hydrogen bonding model are in good agreement with experimental data, lending strong support to the plausibility of this mode of catalysis. Noncovalent interaction (NCI) analysis of the stereocontrolling transition state structures reveals that the enantioselectivity is mainly induced by the concerted action of multiple weak noncovalent substrate–catalyst interactions, such as C–H···O, C–H···S, C–H···π, and π···π interactions. Not only has this contribution provided insights into the mechanistic model and principles of stereocontrol by Cinchona alkaloids but also it should offer help in the future design of catalysts and asymmetric electrophilic trifluoromethylthiolation reactions.

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“…Meanwhile, a building block approach is also a powerful and practical method to construct a chiral carbon center bearing the SCF 3 group [11] . Zhao group has developed the chiral BA‐catalyzed enantioselective Mannich‐type reaction of SCF 3 ‐substituted benzylic cyanide as the starting building block (Scheme 1e) [11c] . Despite the aforementioned certain efforts, there still remains structural limitations in the synthesis of chiral SCF 3 ‐containing compounds, and expansion of their chemical space is highly desired.…”

Section: Methodsmentioning

confidence: 99%

Asymmetric Synthesis of SCF₃‐Substituted Alkylboronates by Copper‐Catalyzed Hydroboration of 1‐Trifluoromethylthioalkenes

Kojima,

Nishii,

Hirano

2024

Angew Chem Int Ed

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A synthetic method for preparation of optically active trifluoromethylthio (SCF3) compounds by a copper‐catalyzed regio‐ and enantioselective hydroboration of 1‐trifluoromethylthioalkenes with H–Bpin has been developed. The enantioselective hydrocupration of an in situ generated CuH species and subsequent boration reaction generate a chiral SCF3‐contaning alkylboronate, of which Bpin moiety can be further transformed to deliver various optically active SCF3 molecules. Computational studies suggest that the SCF3 group successfully controls the regioselectivity in the reaction.

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Enantioselective Mannich‐Type Reactions to Construct Trifluoromethylthio‐Containing Tetrasubstituted Carbon Stereocenters via Asymmetric Dual‐Reagent Catalysis

Cited by 37 publications

References 76 publications

Synthesis of New Thiourea-Metal Complexes with Promising Anticancer Properties

Synthesis of New Thiourea-Metal Complexes with Promising Anticancer Properties

Mechanism and Origins of Stereoinduction in Natural Cinchona Alkaloid Catalyzed Asymmetric Electrophilic Trifluoromethylthiolation of β-Keto Esters with N-Trifluoromethylthiophthalimide as Electrophilic SCF₃ Source

Asymmetric Synthesis of SCF₃‐Substituted Alkylboronates by Copper‐Catalyzed Hydroboration of 1‐Trifluoromethylthioalkenes

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Enantioselective Mannich‐Type Reactions to Construct Trifluoromethylthio‐Containing Tetrasubstituted Carbon Stereocenters via Asymmetric Dual‐Reagent Catalysis

Cited by 37 publications

References 76 publications

Synthesis of New Thiourea-Metal Complexes with Promising Anticancer Properties

Synthesis of New Thiourea-Metal Complexes with Promising Anticancer Properties

Mechanism and Origins of Stereoinduction in Natural Cinchona Alkaloid Catalyzed Asymmetric Electrophilic Trifluoromethylthiolation of β-Keto Esters with N-Trifluoromethylthiophthalimide as Electrophilic SCF3 Source

Asymmetric Synthesis of SCF3‐Substituted Alkylboronates by Copper‐Catalyzed Hydroboration of 1‐Trifluoromethylthioalkenes

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Product

Resources

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Mechanism and Origins of Stereoinduction in Natural Cinchona Alkaloid Catalyzed Asymmetric Electrophilic Trifluoromethylthiolation of β-Keto Esters with N-Trifluoromethylthiophthalimide as Electrophilic SCF₃ Source

Asymmetric Synthesis of SCF₃‐Substituted Alkylboronates by Copper‐Catalyzed Hydroboration of 1‐Trifluoromethylthioalkenes