Organometallic Chemistry

Development of a Highly Selective Plasmodium falciparum Proteasome Inhibitor with Anti‐malaria Activity in Humanized Mice

2021-03-11T20:00:00.001+05:30

Development of a Highly Selective Plasmodium falciparum Proteasome Inhibitor with Anti‐malaria Activity in Humanized Mice

Plasmodium falciparum proteasome (Pf20S) inhibitors are active against Plasmodium at multiple stages—erythrocytic, gametocyte, liver, and gamete activation stages—indicating that selective Pf20S inhibitors possess the potential to be therapeutic, prophylactic, and transmission‐blocking antimalarials. Starting from a reported compound, we developed a noncovalent, macrocyclic peptide inhibitor of the malarial proteasome with high species selectivity and improved pharmacokinetic properties. The compound demonstrates specific, time‐dependent inhibition of the β5 subunit of the Pf20S, kills artemisinin‐sensitive and artemisinin‐resistant P. falciparum isolates in vitro and reduces parasitemia in humanized, P. falciparum‐infected mice.

A short de novo synthesis of nucleoside analogs

2020-08-07T10:47:00.005+05:30

A short de novo synthesis of nucleoside analogs

BY MICHAEL MEANWELL, STEVEN M. SILVERMAN, JOHANNES LEHMANN, BHARANISHASHANK ADLURI, YANG WANG, RYAN COHEN, LOUIS-CHARLES CAMPEAU, ROBERT BRITTON

Nucleoside analogs are commonly used in the treatment of cancer and viral infections. Their syntheses benefit from decades of research but are often protracted, unamenable to diversification, and reliant on a limited pool of chiral carbohydrate starting materials. We present a process for rapidly constructing nucleoside analogs from simple achiral materials. Using only proline catalysis, heteroaryl-substituted acetaldehydes are fluorinated and then directly engaged in enantioselective aldol reactions in a one-pot reaction. A subsequent intramolecular fluoride displacement reaction provides a functionalized nucleoside analog. The versatility of this process is highlighted in multigram syntheses of D- or L-nucleoside analogs, locked nucleic acids, iminonucleosides, and C2′- and C4′-modified nucleoside analogs. This de novo synthesis creates opportunities for the preparation of diversity libraries and will support efforts in both drug discovery and development.

A photochemical dehydrogenative strategy for aniline synthesis

2020-08-06T17:58:00.003+05:30

A photochemical dehydrogenative strategy for aniline synthesis

Shashikant U. Dighe

, Fabio Juliá

, Alberto Luridiana

, James J. Douglas

& Daniele Leonori

A dual cobalt and photocatalysis system provides a way to assemble anilines from cyclohexanones and amines by progressively dehydrating the intermediate imine.

Photoenzymatic enantioselective intermolecular radical hydroalkylation

2020-08-06T17:51:00.005+05:30

Photoenzymatic enantioselective intermolecular radical hydroalkylation

Xiaoqiang Huang , Binju Wang, Yajie Wang, Guangde Jiang, Jianqiang Feng & Huimin Zhao

A transformation in which an ‘ene’ reductase catalyses the visible-light-induced intermolecular radical hydroalkylation of alkenes gives carbonyl compounds with a remote stereocentre in high yield and enantioselectivity.

Chemo‐ and Enantioselective Oxidative α‐Azidation of Carbonyl Compounds

2020-08-06T17:45:00.001+05:30

Chemo‐ and Enantioselective Oxidative α‐Azidation of Carbonyl Compounds

High‐performance hypoiodite catalysis was developed for the chemoselective oxidative or decarboxylative oxidative α‐azidation of 1,3‐dicarbonyl compounds (see scheme). By this method, the late‐stage azidation of complex molecules with NaN3 and hydrogen peroxide as the azide source and oxidant, respectively, was possible under extremely mild conditions.

Palladium(II)‐Catalyzed Enantioselective Azidation of Unactivated Alkenes

2020-08-05T16:40:00.007+05:30

Palladium(II)‐Catalyzed Enantioselective Azidation of Unactivated Alkenes

A Pd‐catalyzed enantioselective intramolecular aminoazidation of unactivated alkenes using readily accessible 1‐azido‐1,2‐benziodoxol‐3(1H )‐one (ABX) as an azidating agent was established. This reaction affords a wide variety of structurally diverse 3‐N3‐substituted piperidines in good yields with excellent enantioselectivity, proceeds under mild reaction conditions, and features good functional‐group compatibility.

Synthesis, Characterization, and Reactivity of a Hypervalent‐Iodine‐Based Nitrooxylating Reagent

2020-08-05T16:39:00.001+05:30

Synthesis, Characterization, and Reactivity of a Hypervalent‐Iodine‐Based Nitrooxylating Reagent

Organic nitrate esters were synthesized through the use of a hypervalent‐iodine‐based nitrooxylating reagent. Its versatile reactivity under various reaction conditions is demonstrated in the synthesis of nitrooxylated β‐keto esters, 1,3‐diketones, malonates, and oxindoles under mild conditions.

Cobalt‐Catalyzed C8‐Dienylation of Quinoline‐N‐Oxides

2020-08-05T16:37:00.000+05:30

Cobalt‐Catalyzed C8‐Dienylation of Quinoline‐N‐Oxides

Rahul K. Shukla
Akshay M. Nair
Salman Khan
Prof. Chandra M. R. Volla
CoIII‐catalyzed site‐selective C8−H activation of quinoline N‐oxides is demonstrated, engaging allenes as dienylation partners under relatively mild reaction conditions. The combination of a carbonate leaving group on the allene and 30 mol % of a NaF additive was found to be crucial for the dienylation reaction with a broad range of quinoline N‐oxides and allenes, including late‐stage functionalizations. Mechanistic studies provide key insights into the reaction mechanism.

Review:The importance of synthetic chemistry in the pharmaceutical industry

2019-01-18T17:39:00.000+05:30

Science

The importance of synthetic chemistry in the pharmaceutical industry

BY KEVIN R. CAMPOS, PAUL J. COLEMAN, JUAN C. ALVAREZ, SPENCER D. DREHER, ROBERT M. GARBACCIO, NICHOLAS K. TERRETT, RICHARD D. TILLYER, MATTHEW D. TRUPPO, EMMA R. PARMEE

Chemical synthesis plays a key role in pharmaceutical research and development. Campos et al. review some of the advantages that have come from recent innovations in synthetic methods. In particular, they highlight small-molecule catalysts stimulated by visible light, enzymes engineered for versatility beyond their intrinsic function, and bio-orthogonal reactions to selectively modify proteins for conjugation. High-throughput techniques are also poised to accelerate methods optimization from small-scale discovery to large-scale production, and complementary machine-learning approaches are just coming into focus.

Concise total syntheses of (–)-jorunnamycin A and (–)-jorumycin enabled by asymmetric catalysis

2019-01-18T17:36:00.001+05:30

Science

Concise total syntheses of (–)-jorunnamycin A and (–)-jorumycin enabled by asymmetric catalysis

BY ERIC R. WELIN, AURAPAT NGAMNITHIPORN, MAX KLATTE, GUILLAUME LAPOINTE, GERIT M. POTOTSCHNIG, MARTINA S. J. MCDERMOTT, DYLAN CONKLIN, CHRISTOPHER D. GILMORE, PAMELA M. TADROSS, CHRISTOPHER K. HALEY, KENJI NEGORO, EMIL GLIBSTRUP, CHRISTIAN U. GRÜNANGER, KEVIN M. ALLAN, SCOTT C. VIRGIL, DENNIS J. SLAMON, BRIAN M. STOLTZ

SCIENCE18 JAN 2019 : 270-275

A route to two marine natural products distinct from the biosynthesis enables structural diversification for drug discovery.

Jorumycin is a structurally complex, pentacyclic organic compound produced by a marine mollusk. The success of a similar compound, trabectedin, in treating certain types of cancer has focused attention on exploring jorumycin's pharmaceutical properties. Welin et al.developed a succinct route to synthesizing jorumycin and the closely related jorunnamycin A that deliberately diverges from the putative biosynthetic pathway underlying prior chemical syntheses. This route, which hinges on a carefully optimized asymmetric catalytic hydrogenation, can be easily modified to introduce unnatural structural diversity for functional optimization in further drug discovery research.

Divergent Synthesis of Natural Derivatives of (+)‐Saxitoxin Including 11‐Saxitoxinethanoic Acid

2019-01-10T22:19:00.001+05:30

Angewchem
Divergent Synthesis of Natural Derivatives of (+)‐Saxitoxin Including 11‐Saxitoxinethanoic Acid
Dr. James R. Walker, Dr. Jeffrey E. Merit, Dr. Rhiannon Thomas‐Tran, Doris T. Y. Tang, Prof. J. Du Bois

[2,3]=4 toxins: A synthetic strategy that enables access to four naturally occurring guanidinium toxins, namely saxitoxin, decarbamoyl saxitoxin, C13‐acetoxy saxitoxin, and C11‐saxitoxinethanoic acid, is detailed. Highlights of this work include an unusual Mislow–Evans rearrangement and a late‐stage Stille ketene acetal cross‐coupling reaction.

Ynamide‐Mediated Thiopeptide Synthesis

2019-01-10T22:17:00.000+05:30

Angewchem

Ynamide‐Mediated Thiopeptide Synthesis
Jinhua Yang, Changliu Wang, Silin Xu, Prof. Dr. Junfeng Zhao

Effective to the backbone: In an ynamide‐mediated two‐step procedure for thiopeptide bond formation, readily available monothiocarboxylic acids served as thioacyl donors. The appropriate balance between the activity and stability of α‐thioacyloxyenamide intermediates formed by the addition of the monothiocarboxylic acid to the ynamide enabled them to act as effective thioacylating reagents.

Palladium‐Catalyzed Intermolecular [4+1] Spiroannulation by C(sp3)−H Activation and Naphthol Dearomatization

2019-01-10T22:15:00.000+05:30

Angewchem

Palladium‐Catalyzed Intermolecular [4+1] Spiroannulation by C(sp3)−H Activation and Naphthol Dearomatization
Bojun Tan, Lu Bai, Pin Ding, Jingjing Liu, Yaoyu Wang, Prof. Dr. Xinjun Luan

Two types of halides: A palladium‐catalyzed [4+1] spiroannulation of two types of aryl halides has been developed for the rapid construction of a new class of spirocycles. This intermolecular domino process was realized through a sequence of C(sp³)−H cleavage, unsymmetrical biaryl coupling, and naphthol dearomatization.

Carbonylation of Alkyl Radicals Derived from Organosilicates through Visible‐Light Photoredox Catalysis

2019-01-10T22:12:00.002+05:30

Angewchem

Carbonylation of Alkyl Radicals Derived from Organosilicates through Visible‐Light Photoredox Catalysis
Alex Cartier, Etienne Levernier, Dr. Vincent Corcé, Prof. Takahide Fukuyama, Dr. Anne‐Lise Dhimane, Dr. Cyril Ollivier, Prof. Ilhyong Ryu, Prof. Louis Fensterbank

Advocating a regime change: Primary, secondary, and tertiary alkyl radicals, formed by the photocatalyzed oxidation of organosilicates, underwent three‐component reactions with carbon monoxide (CO) and radical acceptors to provide unsymmetrical ketones (see scheme). The concept of radical carbonylation under a photooxidative regime and metal‐free conditions has significant potential more generally for photocatalytic carbonylation reactions.

Oxidative Addition to Palladium(0) Made Easy through Photoexcited‐State Metal Catalysis: Experiment and Computation

2019-01-10T22:09:00.004+05:30

Angewchem

Oxidative Addition to Palladium(0) Made Easy through Photoexcited‐State Metal Catalysis: Experiment and Computation
Dr. Rajesh Kancherla, Dr. Krishnamoorthy Muralirajan, Dr. Bholanath Maity, Chen Zhu, Patricia E. Krach, Prof. Dr. Luigi Cavallo, Prof. Dr. Magnus Rueping

Excited‐state palladium catalyzed decarboxylative alkylation of α,β‐unsaturated acids is achieved by a barrierless approach under visible light irradiation at room temperature with good stereoselectivity. Detailed DFT calculations with experimental evidence suggests a neutral decarboxylative pathway.

Late‐Stage Peptide Diversification through Cobalt‐Catalyzed C−H Activation: Sequential Multicatalysis for Stapled Peptides

2019-01-10T22:06:00.000+05:30

Angewchem

Late‐Stage Peptide Diversification through Cobalt‐Catalyzed C−H Activation: Sequential Multicatalysis for Stapled Peptides
Dr. Mélanie M. Lorion, Nikolaos Kaplaneris, Dr. Jongwoo Son, Dr. Rositha Kuniyil, Prof. Dr. Lutz Ackermann

C−H activation meets metathesis: Bioorthogonal C−H activation of peptides was accomplished by using air‐and moisture‐stable catalysts based on Earth‐abundant cobalt. This reaction set the stage for the combination of C−H functionalization and olefin metathesis to construct complex cyclic peptides.

Rapid Construction of Structurally Diverse Quinolizidines, Indolizidines, and Their Analogues via Ruthenium‐Catalyzed Asymmetric Cascade Hydrogenation/Reductive Amination

2019-01-10T22:03:00.002+05:30

Angewchem

Rapid Construction of Structurally Diverse Quinolizidines, Indolizidines, and Their Analogues via Ruthenium‐Catalyzed Asymmetric Cascade Hydrogenation/Reductive Amination
Ya Chen, Yan‐Mei He, Shanshan Zhang, Tingting Miao, Prof. Dr. Qing‐Hua Fan

Cascade reaction: A rapid construction of enantioenriched benzo‐fused quinolizidines, indolizidines, and their analogues by ruthenium‐catalyzed asymmetric cascade hydrogenation/reductive amination of quinolinyl‐ and quinoxalinyl‐containing ketones is described. A range of chiral benzo‐fused aliphatic N‐heterocyclic compounds were obtained in good yields with excellent enantio‐ and diastereoselectivities (up to >99 % ee, >20:1 dr).

A Concise Total Synthesis of (±)‐Vibralactone

2019-01-10T22:00:00.001+05:30

Angewchem

A Concise Total Synthesis of (±)‐Vibralactone
Sepand K. Nistanaki, Luke A. Boralsky, Roy D. Pan, Prof. Dr. Hosea M. Nelson

Bringing the housane down: The five‐step synthesis of (±)‐vibralactone, a biologically active terpenoid natural product, is described. This is the shortest total synthesis of (±)‐vibralactone reported to date.

The Combination of Benzaldehyde and Nickel‐Catalyzed Photoredox C(sp3)−H Alkylation/Arylation

2019-01-10T21:57:00.000+05:30

Angewchem

The Combination of Benzaldehyde and Nickel‐Catalyzed Photoredox C(sp3)−H Alkylation/Arylation
M. Sc. Lumin Zhang, M. Sc. Xiaojia Si, M. Sc. Yangyang Yang, M. Sc. Marc Zimmer, M. Sc. Sina Witzel, Dr. Kohei Sekine, Dr. Matthias Rudolph, Prof. Dr. A. Stephen K. Hashmi

A combined approach: A simple and general strategy involving the combination of a photo‐organocatalyst (benzaldehyde) and a transition‐metal catalyst (nickel) has been developed for the highly selective photoredox C(sp³)−H alkylation/arylation of ethers. A selective late‐stage modification of (−)‐ambroxide has also been conducted to demonstrate the applicability of the method.

Access to All‐Carbon Spirocycles through a Carbene and Thiourea Cocatalytic Desymmetrization Cascade Reaction

2019-01-10T21:51:00.002+05:30

Angewchem

Access to All‐Carbon Spirocycles through a Carbene and Thiourea Cocatalytic Desymmetrization Cascade Reaction
Shitian Zhuo, Tingshun Zhu, Liejin Zhou, Chengli Mou, Huifang Chai, Yunpeng Lu, Lutai Pan, Zhichao Jin, Prof. Dr. Yonggui Robin Chi

Harmony between cats: Dual carbene and thiourea catalysis enabled rapid asymmetric access to spirocyclic compounds by a desymmetrization process (see scheme). The presence of the thiourea cocatalyst was essential for this carbene‐catalyzed enantioselective synthesis of all‐carbon spirocycles to proceed. The reaction products can be readily transformed into sophisticated multicyclic molecules and chiral ligands.

Chiral Sulfide Catalysis for Desymmetrizing Enantioselective Chlorination

2019-01-10T21:48:00.000+05:30

Angewchem

Chiral Sulfide Catalysis for Desymmetrizing Enantioselective Chlorination
Qingxiang Cao, Jie Luo, Prof. Dr. Xiaodan Zhao

A chiral sulfide catalyzed the desymmetrizing enantioselective chlorination of various aryl‐tethered diolefins and diaryl‐tethered olefins to afford teralins and tricyclic hexahydrophenalene derivatives, respectively, bearing multiple stereogenic centers. In contrast, the tertiary amine catalyst (DHQD)₂PHAL led to a diastereomeric product. The products could be transformed into diverse compounds such as spiro‐N‐heterocycles.

Catalyst‐Controlled 1,2‐ and 1,1‐Arylboration of α‐Alkyl Alkenyl Arenes

2019-01-10T21:45:00.000+05:30

Angewchem

Catalyst‐Controlled 1,2‐ and 1,1‐Arylboration of α‐Alkyl Alkenyl Arenes
Allison M. Bergmann, Stanna K. Dorn, Kevin B. Smith, Kaitlyn M. Logan Prof. M. Kevin Brown

Two methods are reported for the 1,2‐ and 1,1‐arylboration of α‐methyl vinyl arenes. In the case of 1,2‐arylboration, the formation of a quaternary center occurred through a rare cross‐coupling reaction of a tertiary organometallic complex. 1,1‐Arylboration was enabled by catalyst optimization and occurred through a β‐hydride elimination/reinsertion cascade. Enantioselective variants of both processes are presented as well as mechanistic investigations.

Palladium‐Catalyzed Divergent Cyclopropanation by Regioselective Solvent‐Driven C(sp3)−H Bond Activation

2018-10-26T11:58:00.000+05:30

Angewchem

Palladium‐Catalyzed Divergent Cyclopropanation by Regioselective Solvent‐Driven C(sp3)−H Bond Activation

Da Sol Chung, Jae Sung Lee, Ho Ryu, Dr. Jiyong Park, Hyunjoong Kim, Joo Hyun Lee, Dr. U Bin Kim, Prof. Dr. Won Koo Lee, Prof. Dr. Mu‐Hyun Baik, Prof. Dr. Sang‐gi Lee

A tandem palladium‐catalyzed Heck/regioselective C(sp3)−H activation reaction for the divergent synthesis of spiro‐ and fused‐cyclopropanated indolines from N‐methallylated 2‐bromoarylamides. The regioselectivity of the C−H bond activation in the σ‐alkylPdII intermediate is controlled by the solvent used.

Total Synthesis of an Atropisomer of the Schisandra Triterpenoid Schiglautone A

2018-10-26T11:54:00.005+05:30

Angewchem

Total Synthesis of an Atropisomer of the Schisandra Triterpenoid Schiglautone A

Binjie Ma, Yifan Zhao, Dr. Chi He, Prof. Dr. Hanfeng Ding

A diastereoselective approach for the total synthesis of an unusual atropisomer of the Schisandra triterpenoid (±)‐schiglautone A is described. The efficient synthetic strategy features three key transformations: 1) two sequential titanium(III)‐catalyzed radical cyclization/homologation reactions to construct the trans‐fused [6,7] bicycle as well as install the quaternary carbons at C10 and C14 with the desired stereochemistry; 2) a Claisen rearrangement followed by a ring‐closing metathesis to forge the strained nine‐membered ring; and 3) a substrate‐controlled Michael addition to enable the introduction of the C17 side‐chain with good diastereoselectivity.

Synthesis of Functionalized Cyclopropanes from Carboxylic Acids by a Radical Addition–Polar Cyclization Cascade

2018-10-26T11:49:00.002+05:30

Angewchem

Synthesis of Functionalized Cyclopropanes from Carboxylic Acids by a Radical Addition–Polar Cyclization Cascade

Dr. Chao Shu, Riccardo S. Mega Björn, J. Andreassen, Dr. Adam Noble, Prof. Dr. Varinder K. Aggarwal

The development of a photoredox‐catalyzed decarboxylative radical addition–polar cyclization cascade approach to functionalized cyclopropanes. Reductive termination of radical–polar crossover reactions between aliphatic carboxylic acids and electron‐deficient alkenes yielded carbanion intermediates that were intercepted in intramolecular alkylations with alkyl chlorides appended to the alkene substrate.