Article
Chemistry, Multidisciplinary
Maria Sanchez-Rosello, Marcos Escolano, Daniel Gavina, Carlos del Pozo
Summary: The asymmetric intramolecular aza-Michael reaction (IMAMR) is a convenient strategy for generating heterocycles with nitrogen-substituted stereocenters, finding widespread applications in the total synthesis of alkaloids and biologically relevant compounds. Recent developments in asymmetric versions of IMAMR mainly involve the use of organocatalysts, such as chiral imidazolidinones and diaryl prolinol derivatives. The use of N-sulfinyl imines with dual roles has also emerged as a versatile mode for performing the asymmetric IMAMR.
Article
Chemistry, Multidisciplinary
Jeff K. Kerkovius, Andrea Stegner, Aneta Turlik, Pik Hoi Lam, Kendall N. Houk, Sarah E. Reisman
Summary: (+)-Matrine and (+)-isomatrine, tetracyclic alkaloids derived from Sophora flavescens, are synthesized through a biosynthetic pathway involving (-)-lysine and the intermediacy of Delta 1-piperidine. A new dearomative annulation reaction using pyridine as a stable surrogate for Delta 1-piperidine allows for the efficient synthesis of matrine alkaloids. Isomatrine, synthesized in four steps from inexpensive commercially available chemicals, serves as the precursor to other lupin alkaloids.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Chemistry, Applied
Fabian Scharinger, Matthias Weil, Michael Schnuerch, Katharina Bica-Schroeder
Summary: We introduce a simple method for the synthesis of chiral diazabicycloalkanes in a single reaction step. This method is applicable to a wide range of enals and has high functional group tolerance.
ADVANCED SYNTHESIS & CATALYSIS
(2023)
Article
Chemistry, Applied
Laura A. Bryant, Kenneth Shankland, Hannah E. Straker, Callum D. Johnston, Nicholas R. Lees, Alexander J. A. Cobb
Summary: The article describes a rare organocatalytic intramolecular cyclization of resorcinols with a high enantioselectivity using a specific organocatalyst. The obtained bicyclic resorcinols show excellent utility in the synthesis of cannabinoid-like compounds, and exhibit anticonvulsant activity.
ADVANCED SYNTHESIS & CATALYSIS
(2021)
Article
Biochemistry & Molecular Biology
Zoran Glasovac, Luka Baresic, Davor Margetic
Summary: The reaction mechanism of guanidinium chlorides with dimethyl acetylenedicarboxylate in a aza-Michael addition reaction/intramolecular cyclization was investigated using DFT M06-2X and B3LYP computational approaches. The energies of the products were compared with experimental data or product ratios obtained from other methods. The diversity of the products was explained by the formation of different tautomers upon deprotonation. The initial nucleophilic addition was found to be the most energetically demanding step, and the overall reaction was exergonic due to methanol elimination during cyclization.
Article
Chemistry, Organic
Zhao-Fei Zhang, Zhong-Hua Gao, Chun-Lin Zhang, Song Ye
Summary: The intramolecular aza-Michael addition of alkyl amines to α,β-unsaturated carboxylic acids catalyzed by N-heterocyclic carbenes has been successfully achieved, allowing for the synthesis of pyrrolidine and piperidine derivatives. The use of chiral NHC catalysts demonstrated promising enantioselectivities up to 55% ee. Further chemical transformations of the products provided carboxylic acids, alcohols, and unprotected amines.
Review
Chemistry, Organic
Marcos Escolano, Daniel Gavina, Javier Torres, Santiago Diaz-Oltra, Carlos del Pozo
Summary: The organocatalytic enantioselective desymmetrization reaction via intramolecular (hetero)Michael addition is an effective strategy for creating complex carbo- and heterocycles with multiple stereocenters in a simple manner. The main challenge lies in the design and synthesis of the starting materials.
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
(2021)
Article
Chemistry, Applied
Andrea Guerrero-Corella, Miguel A. Valle-Amores, Alberto Fraile, Jose Aleman
Summary: An asymmetric organocatalytic aza-Michael addition reaction of ketimines to nitroolefins is described, utilizing 2-hydroxybenzophenone imine to improve the enantioselective addition of N-centered nucleophiles to nitroalkenes. The versatility of the process is demonstrated under both batch and flow conditions, resulting in the synthesis of a wide variety of nitroamine derivatives with excellent yields and enantioselectivities. Additionally, this methodology was successfully applied to the formal synthesis of VNI, a drug-like scaffold for the treatment of Chagas disease.
ADVANCED SYNTHESIS & CATALYSIS
(2021)
Article
Chemistry, Organic
Deniz Tozendemir, Cihangir Tanyeli
Summary: Cinchona alkaloid-derived organocatalysts have been widely utilized in asymmetric transformations, resulting in products with high enantiopurity. A bifunctional quinine-derived sulfonamide organocatalyst was developed for catalyzing the asymmetric sulfa-Michael reaction, achieving high enantioselectivity with low catalyst loading. The enriched sulfa-Michael addition products were successfully oxidized to obtain the corresponding sulfones.
BEILSTEIN JOURNAL OF ORGANIC CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Wai Fung Cheng, Shiqiang Ma, Yin Tung Lai, Yuen Tsz Cheung, Kornkamon Akkarasereenon, Yiqin Zhou, Rongbiao Tong
Summary: An intramolecular aza-Prins cyclization of aza-Achmatowicz rearrangement products was developed using bismuth tribromide as both an efficient Lewis acid and a bromide nucleophile source. This approach enables the construction of highly functionalized 9-azabicyclo[3.3.1]nonanes, which are valuable building blocks for alkaloid natural products and drug molecules. The application of this method to the total synthesis of six indole alkaloids demonstrates its significant synthetic utility.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Physical
Fangfang Guo, Jiean Chen, Yong Huang
Summary: Recently, chiral N-heterocyclic carbenes (NHCs) have been established as powerful catalysts for enantioselective bond-forming processes via noncovalent interactions. A bifunctional NHC with an embedded hydrogen-bonding motif has been reported in this study, showing remarkable tolerance of various Michael acceptors in an asymmetric aza-conjugate addition reaction, with catalytic efficiency far exceeding that of the benchmark tertiary amine-thiourea scaffold.
Review
Chemistry, Applied
Alexander Yu. Rulev
Summary: The 1,4-conjugated addition of nitrogen centered nucleophiles to electron-deficient alkenes is a significant and widely used reaction. Previous protocols mainly focused on strong Michael donors, but recent studies have shown the increasing popularity of weak nitrogen nucleophiles in conjugate addition. The use of more efficient catalyst systems has achieved impressive progress in this area. This review critically analyzes the results obtained in reactions of weak nucleophiles with electron-deficient alkenes over the past twelve years.
ADVANCED SYNTHESIS & CATALYSIS
(2023)
Article
Chemistry, Multidisciplinary
Subhankar Biswas, Siddhartha K. Purkayastha, Ankur K. Guha, Subhas Chandra Pan
Summary: An asymmetric Michael addition/hydroarylation reaction sequence, catalyzed by a squaramide and a combination of silver and gold salts, has been developed to synthesize cyclic aza-spirooxindole derivatives in high yields and enantioselectivities. Computational study was also performed.
CHEMICAL COMMUNICATIONS
(2023)
Article
Chemistry, Multidisciplinary
Xiu-Ning Hu, Dong-Ping Wu, Ye-Peng Xu, Pei-Qiang Huang
Summary: The first organocatalytic asymmetric synthesis of an advanced intermediate of (+)-sarain A was achieved by combining organocatalytic asymmetric Michael addition reaction and a nitrogen-to-carbon chirality transfer. This method allows for the construction of three chiral centers and chemoselective reduction of a key lactam intermediate, providing a tricyclic intermediate with all necessary functionalities for further elaboration into (+)-sarain A.
CHEMISTRY-A EUROPEAN JOURNAL
(2021)
Review
Chemistry, Organic
Pratibha Sharma, Raakhi Gupta, Raj K. Bansal
Summary: The article reviews the literature on asymmetric aza-MR of amines and amides catalyzed by organocatalysts in the past 10 years. Studies show that both types of organocatalysts, whether through non-covalent interactions or through covalent bond formation, play important roles in this reaction.
BEILSTEIN JOURNAL OF ORGANIC CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Tamara Topala, Alejandro Pascual-Alvarez, M. Angeles Moldes-Tolosa, Andreea Bodoki, Alfonso Castineiras, Javier Torres, Carlos del Pozo, Joaquin Borras, Gloria Alzuet-Pina
JOURNAL OF INORGANIC BIOCHEMISTRY
(2020)
Article
Chemistry, Organic
Kazuki Hirano, Takuya Saito, Yamato Fujihira, Daniel M. Sedgwick, Santos Fustero, Norio Shibata
JOURNAL OF ORGANIC CHEMISTRY
(2020)
Review
Chemistry, Organic
Jorge Escorihuela, Daniel M. Sedgwick, Alberto Llobat, Mercedes Medio-Simon, Pablo Barrio, Santos Fustero
BEILSTEIN JOURNAL OF ORGANIC CHEMISTRY
(2020)
Article
Chemistry, Organic
Marcos Escolano, Javier Torres Fernandez, Fernando Rabasa-Alcaniz, Maria Sanchez-Rosello, Carlos del Pozo
Review
Chemistry, Multidisciplinary
Jianlin Han, Lorand Kiss, Haibo Mei, Attila Mario Remete, Maja Ponikvar-Svet, Daniel Mark Sedgwick, Raquel Roman, Santos Fustero, Hiroki Moriwaki, Vadim A. Soloshonok
Summary: This comprehensive review focuses on the effects of fluoride ions and organofluorine compounds on human health and the environment, as well as related topics including the reasons for the advancement of fluorine-containing pharmaceuticals and agrochemicals, metabolism of fluorinated drugs, withdrawn fluorinated drugs, natural sources of fluorine compounds in the environment, sources of fluoride intake, and biomarkers of fluoride exposure.
Article
Chemistry, Organic
Yamato Fujihira, Kazuki Hirano, Makoto Ono, Hideyuki Mimura, Takumi Kagawa, Daniel M. Sedgwick, Santos Fustero, Norio Shibata
Summary: A simple protocol using potassium bases with triglyme or tetraglyme as solvents can safely yield pentafluoroethylation products. Encapsulation of the K cation by glymes inhibits its contact with reactive anionic pentafluoroethyl counterions, preventing their transformation into explosive tetrafluoroethylene. The generation of sterically demanding K(G3)(2) and K(G4)(2) cations serves as an effective reservoir for unstable pentafluoroethyl anions.
JOURNAL OF ORGANIC CHEMISTRY
(2021)
Article
Chemistry, Organic
Alberto Llobat, Jorge Escorihuela, Santos Fustero, Mercedes Medio-Simon
Summary: In this study, homopropargyl amines and chiral homoallenyl amines were successfully synthesized by the addition of propargylmagnesium bromide to fluorinated aromatic sulfinyl imines. The choice of coordinating or noncoordinating solvents was found to have a significant impact on the diastereoselectivity outcomes. DFT calculations were used to rationalize the regio- and diastereoselectivities observed experimentally.
Review
Chemistry, Applied
Shintaro Kawamura, Pablo Barrio, Santos Fustero, Jorge Escorihuela, Jianlin Han, Vadim A. Soloshonok, Mikiko Sodeoka
Summary: The difunctionalizative trifluoromethylation of unsaturated C-C bonds is a highly useful and efficient method for synthesizing trifluoromethyl compounds. This review focuses on reactions that simultaneously form C-heteroatom and C-H bonds, providing useful CF3 group-containing building blocks. The comprehensive survey categorizes reactions into those that are synthetically mature and those with room for further development.
ADVANCED SYNTHESIS & CATALYSIS
(2023)
Article
Chemistry, Multidisciplinary
Jorge Escorihuela, Santos Fustero
Summary: The chemistry of fluorinated compounds has grown significantly in recent decades due to the diverse properties they possess. Among them, fluorinated chiral imines, especially the Ellman's imines, are crucial in the synthesis of enantioenriched carbocycles and heterocycles with exceptional biological and synthetic properties. This personal account highlights the important findings of our research group in the past two decades, focusing on asymmetric tandem reactions, particularly the intramolecular aza-Michael reaction, diversity oriented synthesis, asymmetric tandem reactions involving a p-tolylsulfinyl group, cycloaddition processes, and the use of fluorinated chiral N-sulfinyl imines and their derivatives as starting materials for enyne compounds in Pauson-Khand reactions, [2+2+2]-cycloadditions, and metathesis reactions.
Article
Chemistry, Organic
Marcos Escolano, Daniel Gavina, Santiago Diaz-Oltra, Maria Sanchez-Rosello, Carlos del Pozo
Summary: The enantioselective synthesis of fluorinated indolizidinone derivatives is achieved through an intramolecular aza-Michael reaction, followed by dimethyltitanocene methylenation and ring closing metathesis (RCM). The final products contain a fluorine-containing tetrasubstituted double bond generated by the RCM reaction, demonstrating high challenge. The synthetic sequence exhibits excellent enantioselectivities with acceptable overall yields.
Article
Chemistry, Multidisciplinary
Christian Cristobal, Daniel Gavina, Ines Alonso, Maria Ribagorda, Juan C. Carretero, Carlos del Pozo, Javier Adrio
Summary: An enantioselective synthesis of polycyclic fluorinated pyrrolidines has been achieved by Cu-catalyzed intramolecular 1,3-dipolar cycloaddition. The method enables the formation of desired products with high yields and up to 99% enantiomeric excess, indicating the excellent activating role of fluoroalkyl substituents in this transformation.
CHEMICAL COMMUNICATIONS
(2022)
Article
Chemistry, Organic
Alberto Llobat, Jorge Escorihuela, Carmen Ramirez de Arellano, Santos Fustero, Mercedes Medio-Simon
Summary: This study describes the preparation of merged symmetrical tetrahydroisoquinolines with central chirality through a rhodium-catalyzed intramolecular [2 + 2 + 2] cycloaddition. The results demonstrate that linear triynes lacking a 3-atom tether can efficiently undergo cyclisation. Additional substitution at the benzene rings can be achieved by employing substituted triynes at the terminal triple bonds, leading to more complex tetrahydroisoquinolines.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2022)
Article
Chemistry, Organic
Javier Torres, Marcos Escolano, Gloria Alzuet-Pina, Maria Sanchez-Rosello, Carlos del Pozo
Summary: A new methodology has been developed to access the quinolizidine skeleton asymmetrically, involving two consecutive intramolecular aza-Michael reactions of sulfinyl amines with bis-enone moieties. The method, which has excellent yields and diastereocontrol, was successfully applied to the total synthesis of alkaloids lasubine I and myrtine.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Alvaro Sanz-Vidal, Daniel Gavina, Lia Sotorrios, Enrique Gomez-Bengoa, Fernando Lopez Ortiz, Maria Sanchez-Rosello, Carlos del Pozo
Summary: This novel synthesis strategy for polycyclic trifluoromethyl arenes involves a DBU-promoted tandem cycloaromatization reaction, resulting in a metal-free and air-tolerant process. It enables the synthesis of these compounds from readily available starting materials under mild reaction conditions.
CHEMICAL COMMUNICATIONS
(2021)
Article
Chemistry, Multidisciplinary
Marcos Escolano, Marta Guerola, Javier Torres, Daniel Gavina, Gloria Alzuet-Pina, Maria Sanchez-Rosello, Carlos del Pozo
CHEMICAL COMMUNICATIONS
(2020)
Article
Chemistry, Organic
Fuying Zhu, Yamei Lin
Summary: In this study, a low-metal iron-supported catalyst (Fe20/NC-Mg) was reported for the efficient synthesis of quinoxaline compounds, using water as a solvent and without additional bases. The synergistic effect of FeNx site and Mg (OH)2 nanorods in the catalyst played a key role in achieving high yields (82-91%) in 16 examples. The gram-level synthesis and reusability of the catalysts after four cycles demonstrated its industrial application potential.
Article
Chemistry, Organic
Mikhail Kozlov, Alexey Tyurin, Andrey Dmitrenok, Vyacheslav Rusak, Aleksander Fedorov, Igor Zavarzin, Yulia Volkova
Summary: This study presents a novel and practical synthesis method for phosphorus-substituted 1,3,4-thiadiazolines using phosphorylthioformic acid hydrazides and ketones. The protocol demonstrates operational simplicity, availability of reagents, and tolerance towards different functional groups.
Article
Chemistry, Organic
Jisna Jose, Thomas Mathew
Summary: 2-Cyclopentenone and its derivatives are highly esteemed synthetic intermediates with exceptional utility in organic synthesis. They are favored structural motifs in numerous pharmaceutical drugs and natural products, highlighting their significance. The review discusses the various methods used to synthesize cyclopentenones from 2016 to 2023.
