Meetings by month

January

22/01/2016

Wouter's paper

Effects of Active-Site Modification and Quaternary Structure on the Regioselectivity of Catechol-O-Methyltransferase

Dr. Brian J. C. Law, Dr. Matthew R. Bennett, Dr. Mark L. Thompson, Dr. Colin Levy, Dr. Sarah A. Shepherd, Prof. David Leys, Prof. Jason Micklefield

Graphical abstract

wouter2201

Catechol-O-methyltransferase (COMT), an important therapeutic target in the treatment of Parkinson's disease, is also being developed for biocatalytic processes, including vanillin production, although lack of regioselectivity has precluded its more widespread application. By using structural and mechanistic information, regiocomplementary COMT variants were engineered that deliver either meta- or para-methylated catechols. X-ray crystallography further revealed how the active-site residues and quaternary structure govern regioselectivity. Finally, analogues of AdoMet are accepted by the regiocomplementary COMT mutants and can be used to prepare alkylated catechols, including ethyl vanillin.

Thomas's paper

Pentafulvene for the Synthesis of Complex Natural Products: Total Syntheses of (±)-Pallambins A and B

Christian Ebner, Prof. Dr. Erick M. Carreira

Graphical abstract

thomas

The first total syntheses of pallambins A and B are enabled by the use of pentafulvene in an unprecedented Diels–Alder reaction. After elaboration of the adduct through chemoselective cyclopropanation, strategic C[BOND]H insertion affords the dense tetracyclic core of the natural products. 1,3-Dipolar cycloaddition and palladium(II)-catalyzed alkoxycarbonylation were leveraged for the construction of the hexacyclic scaffold en route to both natural products.

Cleo's paper

Transition-metal free reactions of boronic acids: cascade addition – ring-opening of furans towards functionalized γ-ketoaldehydesS. Roscalesa and A. G. Csákÿ

Graphical abstract

cleo

We describe the first ring-opening of furfuryl alcohols with boronic acids to afford functionalized γ-ketoaldehydes. The transformation builds a new C–C bond at the original C-4 of the starting furan, and tolerates ring-substitution at C-3 and C-4 positions. The reaction takes place under metal-free conditions by promotion with tartaric acid.

James's paper

Practical Direct α-Arylation of Cyclopentanones by Palladium/Enamine Cooperative Catalysis

Yan Xu, Tianshun Su, Zhongxing Huang, Prof. Dr. Guangbin Dong

Graphical abstract

james

Direct arylation of cyclopentanones has been a long-standing challenge because of competitive self-aldol condensation and multiple arylations. Reported herein is a direct mono-α-C[BOND]H arylation of cyclopentanones with aryl bromides which is enabled by palladium/amine cooperative catalysis. This method is scalable and chemoselective with broad functional-group tolerance. Application to controlled sequential arylation of cyclopentanones has been also demonstrated.

29/01/2016

 

Richard's paper

Cinchona Alkaloid-Catalyzed Asymmetric Conjugate Additions: The Bifunctional Brønsted Acid–Hydrogen Bonding Model

Matthew N. Grayson and K. N. Houk

Graphical abstract

richardWynberg’s report from 1977 that natural cinchona alkaloids catalyze the asymmetric conjugate addition of aromatic thiols to cycloalkenones is a landmark discovery in hydrogen bonding organocatalysis. Wynberg proposed that this reaction proceeded via the formation of a thiolate-alkylammonium tight ion pair and activation of the enone electrophile by a hydrogen bond from the catalyst’s hydroxyl group. This reaction model provided the mechanistic basis for understanding Wynberg’s reaction and many other asymmetric transformations since. Our quantum mechanical calculations reveal a different model should be used to explain the results: the alkylammonium ion activates the enone by Brønsted acid catalysis, and the catalyst’s hydroxyl group orients the thiolate nucleophile. The new model rationalizes the stereoselective outcome of Wynberg’s reaction and provides a new, general model for asymmetric cinchona organocatalysis.

Christian's paper

Self-assembled nanospheres with multiple endohedral binding sites pre-organize catalysts and substrates for highly efficient reactions

Qi-Qiang Wang, Sergio Gonell, Stefan H. A. M. Leenders, Maximilian Dürr, Ivana Ivanović-Burmazović & Joost N. H. Reek

Graphical abstract

chris

Tuning reagent and catalyst concentrations is crucial in the development of efficient catalytic transformations. In enzyme-catalysed reactions the substrate is bound—often by multiple non-covalent interactions—in a well-defined pocket close to the active site of the enzyme; this pre-organization facilitates highly efficient transformations. Here we report an artificial system that co-encapsulates multiple catalysts and substrates within the confined space defined by an M12L24nanosphere that contains 24 endohedral guanidinium-binding sites. Cooperative binding means that sulfonate guests are bound much more strongly than carboxylates. This difference has been used to fix gold-based catalysts firmly, with the remaining binding sites left to pre-organize substrates. This strategy was applied to a Au(I)-catalysed cyclization of acetylenic acid to enol lactone in which the pre-organization resulted in much higher reaction rates. We also found that the encapsulated sulfonate-containing Au(I) catalysts did not convert neutral (acid) substrates, and so could have potential in the development of substrate-selective catalysis and base-triggered on/off switching of catalysis.

Nils's paper

The Enantioselective Dakin–West Reaction

Raffael C. Wende, Alexander Seitz, Dominik Niedek, Sören M. M. Schuler, Dr. Christine Hofmann, Dr. Jonathan Becker, Prof. Dr. Peter R. Schreiner

Graphical abstract

nilsHere we report the development of the first enantioselective Dakin–West reaction, yielding α-acetamido methylketones with up to 58 % ee with good yields. Two of the obtained products were recrystallized once to achieve up to 84 % ee. The employed methylimidazole-containing oligopeptides catalyze both the acetylation of the azlactone intermediate and the terminal enantioselective decarboxylative protonation. We propose a dispersion-controlled reaction path that determines the asymmetric reprotonation of the intermediate enolate after the decarboxylation.

February

05/02/2016

Hossay's paper

Enantioselective aldol reactions with masked fluoroacetates

Jakub Saadi & Helma Wennemers

Graphical abstract

hossayDespite the growing importance of organofluorines as pharmaceuticals and agrochemicals, the stereoselective introduction of fluorine into many prominent classes of natural products and chemotherapeutic agents is difficult. One long-standing unsolved challenge is the enantioselective aldol reaction of fluoroacetate to enable access to fluorinated analogues of medicinally relevant acetate-derived compounds, such as polyketides and statins. Herein we present fluoromalonic acid halfthioesters as biomimetic surrogates of fluoroacetate and demonstrate their use in highly stereoselective aldol reactions that proceed under mild organocatalytic conditions. We also show that the methodology can be extended to formal aldol reactions with fluoroacetaldehyde and consecutive aldol reactions. The synthetic utility of the fluorinated aldol products is illustrated by the synthesis of a fluorinated derivative of the top-selling drug atorvastatin. The results show the prospects of the method for the enantioselective introduction of fluoroacetate to access a wide variety of highly functionalized fluorinated compounds.

Thomas's paper

Aqueous Titanium Trichloride Promoted Reductive Cyclization of o-Nitrostyrenes to Indoles: Development and Application to the Synthesis of Rizatriptan and Aspidospermidine

Graphical abstract

tom

Treatment of o-nitrostyrenes with aqueous TiCl3 solution at room temperature afforded indoles through a formal reductive C(sp2)–H amination process. A range of functions such as halides (Cl, Br), carbonyl (ester, carbamate), cyano, hydroxy, and amino groups were tolerated. From β,β-disubstituted o-nitrostyrenes, 2,3-disubstituted indoles were formed by a domino reduction/cyclization/migration process. Mild conditions, simple experimental procedure, ready accessibility of the starting materials and good to excellent yields characterize the present transformation. The methodology was used as a key step in a concise synthesis of rizatriptan and a formal total synthesis of aspidospermidine.

12/02/2016

Cleo's paper

An Asymmetric Vinylogous Michael Cascade of Silyl Glyoximide, Vinyl Grignard, and Nitroalkenes via Long Range Stereoinduction

Gregory R. Boyce and Jeffrey S. Johnson

Graphical abstract

cleoA diastereoselective auxiliary-mediated vinylation/[1,2]-Brook rearrangement/vinylogous Michael cascade of silyl glyoximide, vinylmagnesium bromide, and nitroalkenes is described. The reaction occurs with complete regio- and diastereocontrol in good yield. The diastereoselectivity is induced by a rare instance of 1,7-chirality transfer that is hypothesized to arise from a trans-multihetero-decalin transition state.

Sean's paper

 Iterative reactions of transient boronic acids enable sequential C–C bond formation

Claudio Battilocchio, Florian Feist, Andreas Hafner, Meike Simon, Duc N. Tran, Daniel M. Allwood, David C. Blakemore & Steven V. Ley

 Graphical abstract

sean

The ability to form multiple carbon–carbon bonds in a controlled sequence and thus rapidly build molecular complexity in an iterative fashion is an important goal in modern chemical synthesis. In recent times, transition-metal-catalysed coupling reactions have dominated in the development of C–C bond forming processes. A desire to reduce the reliance on precious metals and a need to obtain products with very low levels of metal impurities has brought a renewed focus on metal-free coupling processes. Here, we report the in situ preparation of reactive allylic and benzylic boronic acids, obtained by reacting flow-generated diazo compounds with boronic acids, and their application in controlled iterative C–C bond forming reactions is described. Thus far we have shown the formation of up to three C–C bonds in a sequence including the final trapping of a reactive boronic acid species with an aldehyde to generate a range of new chemical structures.

Hossay's paper

Unique Steric Effect of Geminal Bis(silane) To Control the High Exo-selectivity in Intermolecular Diels–Alder Reaction

Zengjin Liu, Xinglong Lin, Na Yang, Zhishan Su, Changwei Hu, Peihong Xiao, Yanyang He, and Zhenlei Song

Graphical abstract

hoss

 The unique steric effect of geminal bis(silane) [(R3Si)2CH] allows an exo-selective intermolecular Diels–Alder reaction of geminal bis(silyl) dienes with α,β-unsaturated carbonyl compounds. The approach shows good generality to form orthotrans cyclohexenes in good yields with high exo-selectivity and high enantioselectivity in some asymmetric cases. The excellent exo-stereocontrol aptitude of (R3Si)2CH group is highlighted by comparing with R3SiCH2 and R3Si groups, which leads to endo-selectivity predominantly. The conformational analysis of dienes suggests that (R3Si)2CH group effectively shields both sides of the diene moiety, ensuring the desired exo-selectivity. Moreover, the geminal bis(silane) can be further functionalized to transform the resulting orthotrans cycloadducts into useful synthons, which makes the approach hold great potential for organic synthesis.

19/02/2016

 

S Richard's paper

Catalytic SN2′- and Enantioselective Allylic Substitution with a Diborylmethane Reagent and Application in Synthesis

Ying Shi, Prof. Amir H. Hoveyda

Graphical abstract

richardA catalytic method for the site- and enantioselective addition of commercially available di-B(pin)-methane to allylic phosphates is introduced (pin=pinacolato). Transformations may be facilitated by an NHC–Cu complex (NHC=N-heterocyclic carbene) and products obtained in 63–95 % yield, 88:12 to >98:2 SN2′/SN2 selectivity, and 85:15–99:1 enantiomeric ratio. The utility of the approach, entailing the involvement of different catalytic cross-coupling processes, is highlighted by its application to the formal synthesis of the cytotoxic natural product rhopaloic acid A.

Sean's paper

Palladium-catalysed transannular C–H functionalization of alicyclic amines

Joseph J. Topczewski, Pablo J. Cabrera, Noam I. Saper & Melanie S. Sanford

Graphical abstract

sean

Discovering pharmaceutical candidates is a resource-intensive enterprise that frequently requires the parallel synthesis of hundreds or even thousands of molecules. C–H bonds are present in almost all pharmaceutical agents. Consequently, the development of selective, rapid and efficient methods for converting these bonds into new chemical entities has the potential to streamline pharmaceutical development1, 2, 3, 4. Saturated nitrogen-containing heterocycles (alicyclic amines) feature prominently in pharmaceuticals, such as treatments for depression (paroxetine, amitifadine), diabetes (gliclazide), leukaemia (alvocidib), schizophrenia (risperidone, belaperidone), malaria (mefloquine) and nicotine addiction (cytisine, varenicline)5. However, existing methods for the C–H functionalization of saturated nitrogen heterocycles, particularly at sites remote to nitrogen, remain extremely limited6, 7. Here we report a transannular approach to selectively manipulate the C–H bonds of alicyclic amines at sites remote to nitrogen. Our reaction uses the boat conformation of the substrates to achieve palladium-catalysed amine-directed conversion of C–H bonds to C–C bonds on various alicyclic amine scaffolds. We demonstrate this approach by synthesizing new derivatives of several bioactive molecules, including varenicline.

T Richard's paper

Tandem Allylboration–Prins Reaction for the Rapid Construction of Substituted Tetrahydropyrans: Application to the Total Synthesis of (−)-Clavosolide A

Dr. Alba Millán, James R. Smith, Jack L.-Y. Chen, Prof. Dr. Varinder K. Aggarwal

Graphical abstract

richTetrahydropyrans are common motifs in natural products and have now been constructed with high stereocontrol through a three-component allylboration-Prins reaction sequence. This methodology has been applied to a concise (13 steps) and efficient (14 % overall yield) synthesis of the macrolide (−)-clavosolide A. The synthesis also features an early stage glycosidation reaction to introduce the xylose moiety and a lithiation-borylation reaction to attach the cyclopropyl-containing side chain.

26/02/2016

 

Lola and Richard's paper

Organocatalysis by Networks of Cooperative Hydrogen Bonds: Enantioselective Direct Mannich Addition to Preformed Arylideneureas

Dr. Victor J. Lillo, Javier Mansilla, Prof. Dr. José M. Saá

Graphical abstract

chris

The concept of noncovalent organocatalysis by means of networks of cooperative hydrogen bonds (NCHB organocatalysis) has been explored. Arylideneureas were chosen as ideal substrates because of their powerful donor–acceptor properties. We have examined their uncatalyzed, direct Mannich reaction with acetoacetates in comparison with that catalyzed by a number of salan derivatives capable of providing a network of cooperative hydrogen bonds. Catalyst D [(R,R)-N,N′-bis(salicyl)cyclohexane-1,2-diamine] was found to drive the above direct Mannich reaction in an enantioselective manner, thereby allowing the synthesis of several Biginelli dihydropyrimidinones with high enantioselectivity. DFT calculations (B3LYP-D-PCM/6-31+G*//B3LYP/6-31+G*) revealed that the NCHB organocatalyst lowers the energy barrier of the reaction. The NCHB organocatalysts appear to function as biomimetic catalysts.

Hossay's paper

Iron Catalyzed Highly Enantioselective Epoxidation of Cyclic Aliphatic Enones with Aqueous H2O2

Olaf Cussó, Marco Cianfanelli, Xavi Ribas, Robertus J. M. Klein Gebbink*, and Miquel Costas*

Graphical abstract

hosAn iron complex with a C1-symmetric tetradentate N-based ligand catalyzes the asymmetric epoxidation of cyclic enones and cyclohexene ketones with aqueous hydrogen peroxide, providing the corresponding epoxides in good to excellent yields and enantioselectivities (up to 99% yield, and 95% ee), under mild conditions and in short reaction times. Evidence is provided that reactions involve an electrophilic oxidant, and this element is employed in performing site selective epoxidation of enones containing two alkene sites.

Wouter's paper

Asymmetric copper-catalyzed C-N cross-couplings induced by visible light

Quirin M. Kainz, Carson D. Matier, Agnieszka Bartoszewicz, Susan L. Zultanski, Jonas C. Peters*, Gregory C. Fu*

Graphical abstract

wDespite a well-developed and growing body of work in copper catalysis, the potential of copper to serve as a photocatalyst remains underexplored. Here we describe a photoinduced copper-catalyzed method for coupling readily available racemic tertiary alkyl chloride electrophiles with amines to generate fully substituted stereocenters with high enantioselectivity. The reaction proceeds at –40°C under excitation by a blue light-emitting diode and benefits from the use of a single, Earth-abundant transition metal acting as both the photocatalyst and the source of asymmetric induction. An enantioconvergent mechanism transforms the racemic starting material into a single product enantiomer.

 

March

04/03/2016

Sean's paper

Enantiospecific Alkynylation of Alkylboronic Esters

Dr. Yahui Wang, Dr. Adam Noble, Dr. Eddie L. Myers, Prof. Dr. Varinder K. Aggarwal

Graphical abstract

hEnantioenriched secondary and tertiary alkyl pinacolboronic esters undergo enantiospecific deborylative alkynylation through a Zweifel-type alkenylation followed by a 1,2-elimination reaction. The process involves use of α-lithio vinyl bromide or vinyl carbamate species, for which application to Zweifel-type reactions has not previously been explored. The resulting functionalized 1,1-disubstituted alkenes undergo facile base-mediated elimination to generate terminal alkyne products in high yield and excellent levels of enantiospecificity over a wide range of pinacolboronic ester substrates. Furthermore, along with terminal alkynes, internal and silyl-protected alkynes can be formed by simply introducing a suitable carbon- or silicon-based electrophile after the base-mediated 1,2-elimination reaction.

James' papers

CuSO4‑Mediated Decarboxylative Difluoroacetamidation of α,β-Unsaturated Carboxylic Acids

Qiao Chen, Chao Wang, Jiawei Zhou, Yanan Wang, Zhaoqing Xu*, and Rui Wang*

Graphical abstract

jThe first example of decarboxylative difluoroacetamidation of α,β-unsaturated carboxylic acids by using difluoromethyl-substituted carbonyl compounds was disclosed. The procedure, which was mediated by low-cost and benign CuSO4, furnished a broad range of difluorinated alkenes in remarkable yields with only the E configuration in most of the cases. Moreover, the product could be smoothly transformed to the corresponding difluorofunctionalized ester and alcohol in high yields.

Synthesis of Aryldifluoroamides by Copper-Catalyzed Cross-Coupling

Sophie I. Arlow, Prof. John F. Hartwig

Graphical abstract

j2A copper-catalyzed coupling of aryl, heteroaryl, and vinyl iodides with α-silyldifluoroamides is reported. The reaction forms α,α-difluoro-α-aryl amides from electron-rich, electron-poor, and sterically hindered aryl iodides in high yield and tolerates a variety of functional groups. The aryldifluoroamide products can be transformed further to provide access to a diverse array of difluoroalkylarenes, including compounds of potential biological interest.

Hossay's paper

Scalable, Metal- and Additive-Free, Photoinduced Borylation of Haloarenes and Quaternary Arylammonium Salts

Adelphe M. Mfuh, John D. Doyle, Bhuwan Chhetri, Hadi D. Arman, and Oleg V. Larionov*

Graphical abstract

hWe report herein a simple, metal- and additive-free, photoinduced borylation of haloarenes, including electron-rich fluoroarenes, as well as arylammonium salts directly to boronic acids. This borylation method has a broad scope and functional group tolerance. We show that it can be further extended to boronic esters and carried out on gram scale as well as under flow conditions.

 

11/03/2016

Cleo's paper

Hydroxymethylation beyond Carbonylation: Enantioselective Iridium-Catalyzed Reductive Coupling of Formaldehyde with Allylic Acetates via Enantiotopic π-Facial Discrimination

Victoria J. Garza and Michael J. Krische*

Graphical abstract

cleo

Chiral iridium complexes modified by SEGPHOS catalyze the 2-propanol-mediated reductive coupling of branched allylic acetates 1a1o with formaldehyde to form primary homoallylic alcohols 2a2o with excellent control of regio- and enantioselectivity. These processes, which rely on enantiotopic π-facial discrimination of σ-allyliridium intermediates, represent the first examples of enantioselective formaldehyde C–C coupling beyond aldol addition.

Nils' paper

Stereoselective Construction of β-Mannopyranosides by Anomeric O-Alkylation: Synthesis of the Trisaccharide Core of N-linked Glycans

Hai Nguyen, Danyang Zhu, Prof. Dr. Xiaohua Li, Prof. Dr. Jianglong Zhu

Graphical abstract

nils

A new and efficient approach for direct and stereoselective synthesis of β-mannopyranosides by anomeric O-alkylation has been developed. This anomeric O-alkylation of mannopyranose-derived lactols is proposed to occur under synergistic control of a kinetic anomeric effect and metal chelation. The presence of a conformationally flexible C6 oxygen atom in the sugar-derived lactol donors is required for this anomeric O-alkylation to be efficient, probably because of its chelation with cesium ion. In contrast, the presence of a C2 oxygen atom plays a minor role. This glycosylation method has been successfully utilized for the synthesis of the trisaccharide core of complex N-linked glycans.

Kari's paper

Enantioselective Synthesis of Atropisomeric Vinyl Arene Compounds by Palladium Catalysis: A Carbene Strategy

Jia Feng, Bin Li, Yun He, Prof. Dr. Zhenhua Gu

Graphical abstract

kari

An efficient palladium-catalyzed asymmetric synthesis of axially chiral vinyl arenes from aryl bromides and hydrazones is reported. The products were easily oxidized to axially chiral biaryl compounds, and the phosphine oxides were readily reduced to phosphine ligands.

18/03/2016

Lola's paper

Copper-Catalyzed Intermolecular Hydroamination of Internal Alkynes with Anilines and Amines

Tomoki Ishikawa, Taro Sonehara, Maki Minakawa, and Motoi Kawatsura*

Graphical abstract

lolaThe copper-catalyzed regioselective intermolecular hydroamination of the aryl and trifluoromethyl group or electron-withdrawing group substituted internal alkynes with amines has been accomplished. The reaction was effectively catalyzed by the ligand-free Cu(OTf)2 and afforded the intended amine derivatives in good yields after treatment of NaBH3CN.

Nils' paper

The Catalytic Cross-Coupling of Unactivated Arenes

David R. Stuart, Keith Fagnou*

Graphical abstract

Nil

The industrially important coupling of aromatic compounds has generally required differential prefunctionalization of the arene coupling partners with a halide and an electropositive group. Here we report that palladium, in conjunction with a copper oxidant, can catalyze the cross-coupling of N-acetylindoles and benzenes in high yield and high regioselectivity across a range of indoles without recourse to activating groups. These reactions are completely selective for arene cross-coupling, with no products arising from indole or benzene homo-coupling detected by spectroscopic analysis. This efficient reactivity should be useful in the design of other oxidative arene cross-couplings as well.

 

 

 

April

15/04/2016

Unorthodox Interactions at Work

Yingjie Zhao, Yoann Cotelle, Naomi Sakai, and Stefan Matile*

Graphical abstract

wouter

This Perspective elaborates on the currently unfolding interest in integrating unorthodox non-covalent interactions into functional systems. Initial emphasis is on anion−π interactions at work, particularly in catalysis. Recent highlights are described in comparison to a coinciding renaissance of the more conventional, charge-inverted cation−π catalysis. Progress with these complementary aromatic systems is then compared to recent efforts to integrate halogen and chalcogen bonds, the unorthodox counterparts of hydrogen bonds, into functional systems. General focus is on catalysis, pertinent examples on self-assembly, transport, sensing, and templation are covered as well.

 James, Sean and Richard's paper

Catalytic Enantioselective Conversion of Epoxides to Thiiranes

Saihu Liao, Markus Leutzsch, Mattia Riccardo Monaco, and Benjamin List*

Graphical abstract

rjsA highly efficient and enantioselective Brønsted acid catalyzed conversion of epoxides to thiiranes has been developed. The reaction proceeds in a kinetic resolution, furnishing both epoxide and thiirane in high yields and enantiomeric purity. Heterodimer formation between the catalyst and sulfur donor affords an effective way to prevent catalyst decomposition and enables catalyst loadings as low as 0.01 mol %.

22/04/2016

Sean's paper

Synthesis of Furo[3,2-c]benzopyrans via an Intramolecular [4 + 2] Cycloaddition Reaction of o-Quinonemethides

Li-Ming Zhao*, Ai-Li Zhang, Hua-Shuai Gao, and Jie-Huan Zhang

Graphical abstract

seanAn intramolecular [4 + 2] cycloaddition reaction of o-quinonemethides generated from salicylaldehydes and α-prenylated alcohols is described. In the presence of a catalytic amount of benzenesulfonic acid (BSA), the reaction proceeded smoothly in EtOH to afford furo[3,2-c]benzopyrans through a three-bond forming process in moderate to excellent yields with high diastereoselectivity. This reaction provides a simple and straightforward protocol to efficiently construct furo[3,2-c]benzopyran skeletons. A possible mechanism involving hemiacetal formation/hetero-Diels–Alder reaction is proposed to rationalize the observed results.

Hossay's paper

 Asymmetric [3 + 2] Cycloaddition of Vinylcyclopropanes and α,β-Unsaturated Aldehydes by Synergistic Palladium and Organocatalysis

Kim Søholm Halskov, Line Næsborg, Fernando Tur, and Karl Anker Jørgensen*

Graphical abstract

hossayThe stereoselective [3 + 2] cycloaddition between vinylcyclopropanes and α,β-unsaturated aldehydes promoted by combined palladium and organocatalysis is disclosed. The unique synergistic catalytic system allows for the stereoselective formation of highly substituted cyclopentanes with up to four stereocenters in high yields and selectivities. Vinylcyclopropanes with two different geminal substituents facilitate the formation of cyclopentanes containing a quaternary stereocenter. Furthermore, the developed reaction performs well on gram scale, and a number of transformations are demonstrated.

29/04/2016

 

Nils' paper

Pre-transmetalation intermediates in the Suzuki-Miyaura reaction revealed: The missing link

Andy A. Thomas, Scott E. Denmark

Graphical abstract

NilsDespite the widespread application of Suzuki-Miyaura cross-coupling to forge carbon-carbon bonds, the structure of the reactive intermediates underlying the key transmetalation step from the boron reagent to the palladium catalyst remains uncertain. Here we report the use of low-temperature rapid injection nuclear magnetic resonance spectroscopy and kinetic studies to generate, observe, and characterize these previously elusive complexes. Specifically, this work establishes the identity of three different species containing palladium-oxygen-boron linkages, a tricoordinate boronic acid complex, and two tetracoordinate boronate complexes with 2:1 and 1:1 stoichiometry with respect to palladium. All of these species transfer their boron-bearing aryl groups to a coordinatively unsaturated palladium center in the critical transmetalation event.

Richard's paper

Difluorocarbene Addition to Alkenes and Alkynes in Continuous Flow

Pauline Rullière, Patrick Cyr, and André B. Charette

Graphical abstract

rixh

The first in-flow difluorocarbene generation and addition to alkenes and alkynes is reported. The application of continuous flow technology allowed for the controlled generation of difluorocarbene from TMSCF3 and a catalytic quantity of NaI. The in situ generated electrophilic carbene reacts smoothly with a broad range of alkenes and alkynes, allowing the synthesis of the corresponding difluorocyclopropanes and difluorocyclopropenes. The reaction is complete within a 10 min residence time at high reaction concentrations. With a production flow rate of 1 mmol/min, continuous flow chemistry enables scale up of this process in a green, atom-economic, and safe manner.

James' paper

Dimitri A. Khrakovsky, Prof. Dr. Chuanzhou Tao, Miles W. Johnson, Richard T. Thornbury, Sophia L. Shevick, Prof. Dr. F. Dean Toste

Enantioselective, Stereodivergent Hydroazidation and Hydroamination of Allenes Catalyzed by Acyclic Diaminocarbene (ADC) Gold(I) Complexes

Graphical abstract

james

The gold-catalyzed enantioselective hydroazidation and hydroamination reactions of allenes are presented herein. ADC gold(I) catalysts derived from BINAM were critical for achieving high levels of enantioselectivity in both transformations. The sense of enantioinduction is reversed for the two different nucleophiles, allowing access to both enantiomers of the corresponding allylic amines using the same catalyst enantiomer.

 

 

May

06/05/2016

Wouter's paper

Reversible, Short α-Peptide Assembly for Controlled Capture and Selective Release of Enantiomers

Xi Chen, Ying He, Yongju Kim*, and Myongsoo Lee*

Graphical abstract

wouterAlthough significant progress has been achieved with short peptide nanostructures, the construction of switchable membrane assemblies remains a great challenge. Here we report short α-peptide assemblies that undergo thermo-reversible switching between assembly and disassembly states, triggered by the conformational change of laterally grafted short peptides from a folded α-helix to a random coil conformation. The α-helical peptide based on two oligoether dendron side groups forms flat disks, while the peptide helix based on three dendron side groups forms hollow vesicles. The vesicular membrane can spontaneously capture a racemic mixture through the self-formation of vesicular containers upon heating and enantioselectively release the chiral guest molecule through preferential diffusion across the vesicular walls.

Christian's paper

Asymmetric catalytic formation of quaternary carbons by iminium ion trapping of radicals

John J. Murphy, David Bastida, Suva Paria, Maurizio Fagnoni & Paolo Melchiorre

Graphical abstract

chris

An important goal of modern organic chemistry is to develop new catalytic strategies for enantioselective carbon–carbon bond formation that can be used to generate quaternary stereogenic centres. Whereas considerable advances have been achieved by exploiting polar reactivity1, radical transformations have been far less successful2. This is despite the fact that open-shell intermediates are intrinsically primed for connecting structurally congested carbons, as their reactivity is only marginally affected by steric factors3. Here we show how the combination of photoredox4 and asymmetric organic catalysis5 enables enantioselective radical conjugate additions to β,β-disubstituted cyclic enones to obtain quaternary carbon stereocentres with high fidelity. Critical to our success was the design of a chiral organic catalyst, containing a redox-active carbazole moiety, that drives the formation of iminium ions and the stereoselective trapping of photochemically generated carbon-centred radicals by means of an electron-relay mechanism. We demonstrate the generality of this organocatalytic radical-trapping strategy with two sets of open-shell intermediates, formed through unrelated light-triggered pathways from readily available substrates and photoredox catalysts—this method represents the application of iminium ion activation6 (a successful catalytic strategy for enantioselective polar chemistry) within the realm of radical reactivity.

James' paper

One-Pot Synthesis of Benzene-Fused Medium-Ring Ketones: Gold Catalysis-Enabled Enolate Umpolung Reactivity

Zhou Xu†‡, Hongyi Chen†, Zhixun Wang†, Anguo Ying†∥, and Liming Zhang*

Graphical abstract

james

Enolate umpolung reactivities offer valuable and potentially unique alternatives over the enolate counterparts for the construction of ubiquitous carbonyl compounds. We disclose here that N-alkenoxypyridinium salts, generated readily upon gold-catalyzed additions of protonated pyridine N-oxide to C–C triple bonds of unactivated terminal alkynes, display versatile enolate umpolung chemistry upon heating and react with tethered arene nucleophiles in an SN2′ manner. In a synthetically efficient one-pot, two-step process, this chemistry enables expedient preparation of valuable benzo-fused seven-/eight-membered cyclic ketones, including those of O-/N-heterocycles, from easily accessible aryl-substituted linear alkyne substrates. The reaction yields can be up to 87%.

13/05/2016

Richard T's paper

Positioning a Carbon–Fluorine Bond over the π Cloud of an Aromatic Ring: A Different Type of Arene Activation

Maxwell Gargiulo Holl, Mark D. Struble, Prakhar Singal, Dr. Maxime A. Siegler, Prof. Thomas Lectka

Graphical abstract

richard

It is known that the fluoro group has only a small effect on the rates of electrophilic aromatic substitutions. Imagine instead a carbon–fluorine (C−F) bond positioned tightly over the π cloud of an aryl ring—such an orthogonal, noncovalent arrangement could instead stabilize a positively charged arene intermediate or transition state, giving rise to novel electrophilic aromatic substitution chemistry. Herein, we report the synthesis and study of molecule 1, containing a rigid C−F⋅⋅⋅Ar interaction that plays a prominent role in both its reaction chemistry and spectroscopy. For example, we established that the C−F⋅⋅⋅Ar interaction can bring about a >1500 fold increase in the relative rate of an aromatic nitration reaction, affording functionalization on the activated ring exclusively. Overall, these results establish fluoro as a through-space directing/activating group that complements the traditional role of fluorine as a slightly deactivating aryl substituent in nitrations.

Nils and James' paper

Manganese-Catalyzed Borylation of Unactivated Alkyl Chlorides

Thomas C. Atack and Silas P. Cook*

nils

The use of low-cost manganese(II) bromide (MnBr2) and tetramethylethylenediamine (TMEDA) catalyzes the cross coupling of (bis)pinacolatodiboron with a wide range of alkyl halides, demonstrating the first manganese-catalyzed coupling with alkyl electrophiles. This method allows access to primary, secondary, and tertiary boronic esters from the parent chlorides, which were previously inaccessible as coupling partners. The reaction proceeds in high yield with as little as 1000 ppm catalyst loading, while 5 mol % can provide high yields in as little as 30 min. Finally, radical-clock experiments revealed that at 0 °C direct borylation outcompetes alternative radical processes, thereby providing synthetically useful, temperature-controlled reaction outcomes.

Richard S's paper

Tandem Olefin Metathesis/Oxidative Cyclization: Synthesis of Tetrahydrofuran Diols from Simple Olefins

Peter K. Dornan, Daniel Lee, and Robert H. Grubbs*

Graphical abstract

rich sA tandem olefin metathesis/oxidative cyclization has been developed to synthesize 2,5-disubstituted tetrahydrofuran (THF) diols in a stereocontrolled fashion from simple olefin precursors. The ruthenium metathesis catalyst is converted into an oxidation catalyst in the second step and is thus responsible for both catalytic steps. The stereochemistry of the 1,5-diene intermediate can be controlled through the choice of catalyst and the type of metathesis conducted. This olefin stereochemistry then controls the THF diol stereochemistry through a highly stereospecific oxidative cyclization.

20/05/2016

Wouter's paper

Activity-Based Proteome Profiling Probes Based on Woodward's Reagent K with Distinct Target Selectivity

Dr. Yong Qian, Dr. Marc Schürmann, Dr. Petra Janning, Prof. Dr. Christian Hedberg, Prof. Dr. Herbert Waldmann

Graphical abstract

wouter

Woodward's reagent K (WRK) is a reactive heterocyclic compound that has been employed in protein chemistry to covalently and unspecifically label proteins at nucleophilic amino acids, notably at histidine and cysteine. We have developed a panel of WRK-derived activity-based probes and show that surprisingly and unexpectedly, these probes are fairly selective for a few proteins in the human proteome. The WRK-derived probes show unique reactivity towards the catalytic N-terminal proline in the macrophage migration inhibitory factor (MIF) and can be used to label and, if equipped with a fluorophore, to image MIF activities in living cells.

Lola's paper

The Reductive Cleavage Of Picolinic Amides

Daniel H. O’ Donovan, Claudia De Fusco, David R. Spring

Graphical abstract

lol

Treatment of picolinic amides with excess zinc in aqueous hydrochloric acid at room temperature affords the corresponding amines in good to excellent yields. The mild reactions conditions exhibit useful functional group tolerance and facilitate the application of the picolinic amide moiety as a protecting group which can be easily introduced and selectively removed.

Sean's paper

Cyclization of 4-Phenoxy-2-coumarins and 2-Pyrones via a Double C–H Activation

Katrina Mackey, Leticia M. Pardo, Aisling M. Prendergast, Marie-T. Nolan, Lorraine M. Bateman, and Gerard P. McGlacken*

Graphical abstract

sean

Aryl–heteroaryl coupling via double C–H activation is a powerful transformation that avoids the installation of activating groups. A double C–H activation of privileged biological scaffolds, 2-coumarins and 2-pyrones, is reported. Despite the rich chemistry of these molecular frameworks, the yields are very good. Excellent regioselectivity was achieved on the pyrones. This methodology was applied to the synthesis of flemichapparin C in three steps. Isotope effect experiments were carried out, and a mechanism is proposed.

James's paper

Silicon–Carbon Bond Formation via Nickel-Catalyzed Cross-Coupling of Silicon Nucleophiles with Unactivated Secondary and Tertiary Alkyl Electrophiles

Crystal K. Chu, Yufan Liang, and Gregory C. Fu*

Graphical abstract

 

 

 

 

 

A wide array of cross-coupling methods for the formation of C–C bonds from unactivated alkyl electrophiles have been described in recent years. In contrast, progress in the development of methods for the construction of C–heteroatom bonds has lagged; for example, there have been no reports of metal-catalyzed cross-couplings of unactivated secondary or tertiary alkyl halides with silicon nucleophiles to form C–Si bonds. In this study, we address this challenge, establishing that a simple, commercially available nickel catalyst (NiBr2·diglyme) can achieve couplings of alkyl bromides with nucleophilic silicon reagents under unusually mild conditions (e.g., −20 °C); especially noteworthy is our ability to employ unactivated tertiary alkyl halides as electrophilic coupling partners, which is still relatively uncommon in the field of cross-coupling chemistry. Stereochemical, relative reactivity, and radical-trap studies are consistent with a homolytic pathway for C–X bond cleavage.

27/05/2016

Hossay's paper

Organocatalytic Redox Isomerization of Electron-Deficient Allylic Alcohols: Synthesis of 1,4-Ketoaldehydes

Keshab Mondal, Buddhadeb Mondal, and Subhas Chandra Pan*

Graphical abstract

An organocatalytic redox isomerization strategy has been developed for the synthesis of 1,4-ketoaldehydes. DABCO was found to be the best catalyst for the isomerization of γ-hydroxy enones. With 20 mol % of DABCO as catalyst and DMSO as the solvent high yields have been achieved for different 1,4-ketoaldehydes.

Nils' paper

Morita–Baylis–Hillman Reaction of α,β-Unsaturated Ketones with Allylic Acetates by the Combination of Transition-Metal Catalysis and Organomediation

Ya-Qiong Li†, Hai-Jun Wang‡, and Zhi-Zhen Huang*†

Graphical abstract

Abstract Image

An intermolecular Morita–Baylis–Hillman (MBH) reaction of α,β-unsaturated ketones with allylic acetates under the catalysis of 10 mol % of tetrakis(triphenylphosphine)palladium(0) and mediation of tributylphosphine has been developed in the presence of acetic acid, affording the desired α-coupling products. The MBH reaction has the advantages of good tolerance to many functional groups, excellent regioselectivity and E-stereoselectivity, and moderate to good yields.

 

 

 

 


 

 

June

03/06/2016

Thomas's paper

[3 + 2]-Cycloadditions of Azomethine Imines and Ynolates

Sarah E. Winterton and Joseph M. Ready*

Graphical abstract

Abstract Image


A novel [3 + 2]-cycloaddition between azomethine imines and lithium ynolates is described to sdsdddddddyyynthesize bicyclic pyrazolidinones. These bicyclic pyrazolidinones are versatile intermediates to form β-amino acids and monocyclic pyrazolidinones. High diastereoselectivity and stereospecificity allow access to optically active products.

10/06/2016

Hossay's paper

One-Pot Amide Bond Formation from Aldehydes and Amines via a Photoorganocatalytic Activation of Aldehydes

Giorgos N. Papadopoulos and Christoforos G. Kokotos*

Graphical abstract

Abstract Image

A mild, one-pot, and environmentally friendly synthesis of amides from aldehydes and amines is described. Initially, a photoorganocatalytic reaction of aldehydes with di-isopropyl azodicarboxylate leads to an intermediate carbonyl imide, which can react with a variety of amines to afford the desired amides. The initial visible light-mediated activation of a variety of monosubstituted or disubstituted aldehydes is usually fast, occurring in a few hours. Following the photocatalytic reaction, addition of the primary amine at room temperature or the secondary amine at elevated temperatures leads to the corresponding amide from moderate to excellent yields without epimerization. This methodology was applied in the synthesis of Moclobemide, a drug against depression and social anxiety.

Lola's paper

Nickel-Catalyzed Reductive Cross-Coupling of Benzyl Chlorides with Aryl Chlorides/Fluorides: A One-Pot Synthesis of Diarylmethanes

Jie Zhang, Gusheng Lu, Jin Xu, Hongmei Sun*, and Qi Shen

Graphical abstract

Abstract Image

The first nickel-catalyzed, magnesium-mediated reductive cross-coupling between benzyl chlorides and aryl chlorides or fluorides is reported. A variety of diarylmethanes can be prepared in good to excellent yields in a one-pot manner using easy-to-access mixed PPh3/NHC Ni(II) complexes of Ni(PPh3)(NHC)Br2 (NHC = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene, IPr, 1a; 1,3-di-tert-butylimidazol-2-ylidene, ItBu, 1b) as catalyst precursors. Activation of polychloroarenes or chemoselective cross-coupling based on the difference in catalytic activity between 1a and 1b is used to construct oligo-diarylmethane motifs.

Nils's paper

3-Butenyloxycarbonyl as a new hydroxyl protecting group in carbohydrate synthesis

Nana Zeng†, Youhong Niu†, Xin-Shan Ye

Graphical abstract

Image for unlabelled figure

3-Butenyloxycarbonyl (Bloc) has been identified as a new hydroxyl protecting group, which can be introduced under mild conditions in high yields and selectively removed by OsO4/NaIO4/2,6-lutidine in CH3CN–H2O without affecting most commonly-used protecting groups. Moreover, this new protecting group is inert under glycosylation conditions.

17/06/2016

Sean's paper

Modular, Catalytic Enantioselective Construction of Quaternary Carbon Stereocenters by Sequential Cross-Coupling Reactions

Bowman Potter, Emma K. Edelstein, and James P. Morken*

Graphical abstract

Abstract Image

 

 

 

 

The catalytic Suzuki–Miyaura cross-coupling with chiral γ,γ-disubstituted allylboronates in the presence of RuPhos ligand occurs with high regioselectivity and enantiospecificity, furnishing nonracemic compounds with quaternary centers. Mechanistic experiments suggest that the reaction occurs by transmetalation with allyl migration, followed by rapid reductive elimination.

Wouter's paper

Integrin-Targeting Knottin Peptide–Drug Conjugates Are Potent Inhibitors of Tumor Cell Proliferation

Nick Cox, James R. Kintzing,Mark Smith, Gerald A. Grant, Prof. Jennifer R. Cochran

Graphical abstract

Figure 1.

Antibody–drug conjugates (ADCs) offer increased efficacy and reduced toxicity compared to systemic chemotherapy. Less attention has been paid to peptide–drug delivery, which has the potential for increased tumor penetration and facile synthesis. We report a knottin peptide–drug conjugate (KDC) and demonstrate that it can selectively deliver gemcitabine to malignant cells expressing tumor-associated integrins. This KDC binds to tumor cells with low-nanomolar affinity, is internalized by an integrin-mediated process, releases its payload intracellularly, and is a highly potent inhibitor of brain, breast, ovarian, and pancreatic cancer cell lines. Notably, these features enable this KDC to bypass a gemcitabine-resistance mechanism found in pancreatic cancer cells. This work expands the therapeutic relevance of knottin peptides to include targeted drug delivery, and further motivates efforts to expand the drug-conjugate toolkit to include non-antibody protein scaffolds.

Richard S paper

The Methylene Alkoxy Carbamate Self-Immolative Unit: Utilization for the Targeted Delivery of Alcohol-Containing Payloads with Antibody–Drug Conjugates

Dr. Robert V. Kolakowski, Karl T. Haelsig, Kim K. Emmerton, Chris I. Leiske, Jamie B. Miyamoto, Julia H. Cochran, Dr. Robert P. Lyon, Dr. Peter D. Senter, Dr. Scott C. Jeffrey

Graphical abstract

Figure 1.

A strategy for the conjugation of alcohol-containing payloads to antibodies has been developed and involves the methylene alkoxy carbamate (MAC) self-immolative unit. A series of MAC β-glucuronide model constructs were prepared to evaluate stability and enzymatic release, and the results demonstrated high stability at physiological pH in a substitution-dependent manner. All the MAC model compounds efficiently released alcohol drug surrogates under the action of β-glucuronidase. To assess the MAC technology for ADCs, the potent microtubule-disrupting agent auristatin E (AE) was incorporated through the norephedrine alcohol. Conjugation of the MAC β-glucuronide AE drug linker to the anti-CD30 antibody cAC10, and an IgG control antibody, gave potent and immunologically specific activities in vitro and in vivo. These studies validate the MAC self-immolative unit for alcohol-containing payloads within ADCs, a class that has not been widely exploited.

24/06/2016

James' paper

Access to P-Stereogenic Phosphinates via N-Heterocyclic Carbene-Catalyzed Desymmetrization of Bisphenols

Zhijian Huang, Xuan Huang, Baosheng Li, Chengli Mou, Song Yang, Bao-An Song, and Yonggui Robin Chi

Graphical abstract

Abstract Image

 

 

 

A carbene-catalyzed desymmetrization of prochiral bisphenol compounds bearing remote P-stereogenic centers is disclosed. The catalytic reactions can be performed on gram scales with 1 mol % N-heterocyclic carbene (NHC) catalyst, providing efficient access to enantiomerically enriched P-stereogenic phosphinates. The chiral phosphinates prepared with our method can find widespread applications as asymmetric organic catalysts and ligands.

Nils' paper

Discovery of a Long-Range Perlin Effect in a Conformationally Constrained Oxocane

Ellen Berry†, Gabriel dos Passos Gomes‡, Alex MacLean§, Justin R. Martin∥, and Paul A. Wiget

Graphical abstract

Abstract Image

Herein, we present the crystal structure, NMR J analysis, and conformational and natural bond order analyses of tricyclic oxocane (1), resulting in the discovery of a long-range Perlin effect at C4 and C5. The normal Perlin effect (NPE) of Δ1JC–H = 18.38 Hz at C5 is the largest to date for a nonanomeric methylene due to an unprecedented through-space n → σ* stabilizing interaction. The NPE at C4 where Δ1JC–H = 6.91 Hz is nearly double those found in cyclohexanone.

Sean's paper

Silyl Radical Activation of Alkyl Halides in Metallaphotoredox Catalysis: A Unique Pathway for Cross-Electrophile Coupling

Patricia Zhang, Chi “Chip” Le, and David W. C. MacMillan*

Graphical abstract

Abstract Image

A strategy for cross-electrophile coupling has been developed via the merger of photoredox and transition metal catalysis. In this report, we demonstrate the use of commercially available tris(trimethylsilyl)silane with metallaphotoredox catalysis to efficiently couple alkyl bromides with aryl or heteroaryl bromides in excellent yields. We hypothesize that a photocatalytically generated silyl radical species can perform halogen-atom abstraction to activate alkyl halides as nucleophilic cross-coupling partners. This protocol allows the use of mild yet robust conditions to construct Csp3–Csp2 bonds generically via a unique cross-coupling pathway.

 

 

July

08/07/2016

Richard S' paper

Controlling Asymmetric Remote and Cascade 1,3-Dipolar Cycloaddition Reactions by Organocatalysis

Pernille H. Poulsen, Stefania Vergura, Alicia Monleón, Danny Kaare Bech Jørgensen, and Karl Anker Jørgensen*

Graphical abstract

Abstract Image

The regio- and stereoselective control of cycloaddition reactions to polyconjugated systems has been demonstrated by applying asymmetric organocatalysis. Reaction of 2,4-dienals with nitrones allows for a highly regio- and stereoselective 1,3-dipolar cycloaddition in the presence of an aminocatalyst. The first cycloaddition on the remote olefin can be followed either by a cascade reaction or by other selective reactions of the remaining olefin. The chiral products are obtained in good to high yields and excellent diastereo- and enantioselectivities. The remote selective concept has been extended to 2,4,6-trienals by means of a novel enantioselective triple cascade 1,3-dipolar cycloaddition reaction. The formation of chiral poly 1,3-amino alcohols is also demonstrated.

Shijia's paper

Benzofulvenes in Trienamine Catalysis: Stereoselective Spiroindene Synthesis

Bjarke S. Donslund, Rune Pagh Nielsen, Sofie M. N. Mønsted, Prof. Karl Anker Jørgensen

Graphical abstract

Scheme 1.

The asymmetric formation of spiroindenes containing up to four contiguous stereocenters from the reaction of benzofulvenes with 2,4-dienals through trienamine catalysis is described. The benzofulvene core was found to be an excellent starting point for the synthesis of interesting spiroindenes through a formal cycloaddition pathway. The reaction was mediated by a diphenylprolinol silyl ether catalyst, and a diverse array of spiroindenes were obtained in high yields with excellent stereoselectivity. An attractive feature of the developed system is the possibility to diversify the product scaffold significantly by further manipulation of the chiral spiroindenes. Thus, three intramolecular ring-closing reactions following the organocatalytic step resulted in highly complex polycyclic systems.

Christian's paper

Catalytic, asymmetric difluorination of alkenes to generate difluoromethylated stereocenters


Steven M. Banik, Jonathan William Medley, Eric N. Jacobsen*

Graphical abstract

Difluoromethyl groups possess specific steric and electronic properties that invite their use as chemically inert surrogates of alcohols, thiols, and other polar functional groups important in a wide assortment of molecular recognition processes. We report here a method for the catalytic, asymmetric, migratory geminal difluorination of β-substituted styrenes to access a variety of products bearing difluoromethylated tertiary or quaternary stereocenters. The reaction uses commercially available reagents (m-chloroperbenzoic acid and hydrogen fluoride pyridine) and a simple chiral aryl iodide catalyst and is carried out readily on a gram scale. Substituent effects and temperature-dependent variations in enantioselectivity suggest that cation-π interactions play an important role in stereodifferentiation by the catalyst.

 

15/07/2016

Hossay's paper

Asymmetric Conjugate Addition of Organoboron Reagents to Common Enones Using Copper Catalysts

Chunlin Wu†, Guizhou Yue‡, Christian Duc-Trieu Nielsen†, Kai Xu†, Hajime Hirao*†, and Jianrong (Steve) Zhou*†

Graphical abstract

Abstract Image

Copper complexes of phosphoramidites efficiently catalyzed asymmetric addition of arylboron reagents to acyclic enones. Importantly, rare 1,4-insertion of arylcopper(I) was identified which led directly to O-bound copper enolates. The new mechanism is fundamentally different from classical oxidative addition/reductive elimination of organocopper(I) on enones.

Wouter's paper

Selective Metal-Site-Guided Arylation of Proteins

Jens Willwacher, Ritu Raj, Shabaz Mohammed, and Benjamin G. Davis*

Graphical abstract

Abstract Image

 

 

 

 

 

 

 

We describe palladium-mediated S-arylation that exploits natural metal-binding motifs to ensure high site selectivity for a proximal reactive residue. This allows the chemical identification not only of proteins that bind metals but also the environment of the metal-binding site itself through proteomic analysis of arylation sites. The transformation is easy to perform under standard conditions, does not require the isolation of a reactive Ar–Pd complex, is broad in scope, and is applicable in cell lysates as well as to covalent inhibition/modulation of metal-dependent enzymatic activity.

22/07/2016

Christian's paper

Role of Silver Salts in Palladium-Catalyzed Arene and Heteroarene C–H Functionalization Reactions

Monica D. Lotz†, Nicole M. Camasso†, Allan J. Canty*‡, and Melanie S. Sanford*†

Graphical abstract

Abstract Image

Silver carboxylate salts are widely used as additives in palladium-catalyzed C–H functionalization reactions. However, the role of these silver additives is often not fully understood. This paper describes an investigation of the role of AgOPiv in the stoichiometric activation of C6F5H at a well-defined PdII complex as well as in the PdII-catalyzed oxidative dimerization of 2-alkylthiophenes. Both in situ NMR spectroscopy and H/D exchange studies of the reactions of C6F5H implicate a role for AgOPiv in the C–H cleavage event, generating Ag–C6F5 as an intermediate. The catalytic studies show similar trends despite the different conditions and substrates, suggesting that AgOPiv promotes a similar metalation of the thiophene in the catalytic transformations. This proposal is supported by DFT calculations, which show energetically feasible pathways for concerted metalation–deprotonation of both 2-methylthiophene and pentafluorobenzene at [Ag(OPiv)]2. These studies suggest that initial metalation of C–H substrates at AgI carboxylates should be considered as a plausible pathway in C–H functionalization reactions involving mixtures of Ag and Pd salts.

Wouter's paper

Fluorescence probes to detect lipid-derived radicals

Ken-ichi Yamada, Fumiya Mito, Yuta Matsuoka, Satsuki Ide, Kazushige Shikimachi, Ayano Fujiki, Daiki Kusakabe, Yuma Ishida, Masataka Enoki, Arisa Tada, Miyuki Ariyoshi, Toshihide Yamasaki & Mayumi Yamato

Graphical abstract

Spectroscopic responses and selectivity for lipid radicals.

Lipids and their metabolites are easily oxidized in chain reactions initiated by lipid radicals, forming lipid peroxidation products that include the electrophiles 4-hydroxynonenal and malondialdehyde. These markers can bind cellular macromolecules, causing inflammation, apoptosis and other damage. Methods to detect and neutralize the initiating radicals would provide insights into disease mechanisms and new therapeutic approaches. We describe the first high-sensitivity, specific fluorescence probe for lipid radicals, 2,2,6-trimethyl-4-(4-nitrobenzo[1,2,5]oxadiazol-7-ylamino)-6-pentylpiperidine-1-oxyl (NBD-Pen). NBD-Pen directly detected lipid radicals in living cells by turn-on fluorescence. In a rat model of hepatic carcinoma induced by diethylnitrosamine (DEN), NBD-Pen detected lipid radical generation within 1 h of DEN administration. The lipid radical scavenging moiety of NBD-Pen decreased inflammation, apoptosis and oxidative stress markers at 24 h after DEN, and liver tumor development at 12 weeks. Thus, we have developed a novel fluorescence probe that provides imaging information about lipid radical generation and potential therapeutic benefits in vivo.

 

August

05/08/2016

Christian's paper

Remote-Stereocontrol in Dienamine Catalysis: Z-Dienamine Preferences and Electrophile–Catalyst Interaction Revealed by NMR and Computational Studies

Andreas Seegerer†, Johnny Hioe†, Michael M. Hammer†, Fabio Morana†, Patrick J. W. Fuchs‡, and Ruth M. Gschwind*†

Graphical abstract

Abstract Image

Catalysis with remote-stereocontrol provides special challenges in design and comprehension. One famous example is the dienamine catalysis, for which high ee values are reported despite insufficient shielding of the second double bond. Especially for dienamines with variable Z/E-ratios of the second double bond, no correlations to the ee values are found. Therefore, the structures, thermodynamics, and kinetics of dienamine intermediates in SN-type reactions are investigated. The NMR studies show that the preferred dienamine conformation provides an effective shielding if large electrophiles are used. Calculations at SCS-MP2/CBS-level of theory and experimental data of the dienamine formation show kinetic preference for the Z-isomer of the second double bond and a slow isomerization toward the thermodynamically preferred E-isomer. Modulations of the rate-determining step, by variation of the concentration of the electrophile, allow the conversion of dienamines to be observed. With electrophiles, a faster reaction of Z- than of E-isomers is observed experimentally. Calculations corroborate these results by correlating ee values of three catalysts with the kinetics of the electrophilic attack and reveal the significance of CH−π and stacking interactions in the transition states. Thus, for the first time a comprehensive understanding of the remote stereocontrol in γ-functionalization reactions of dienamines and an explanation to the “Z/E-dilemma” are presented. The combination of bulky catalyst subsystems and large electrophiles provides a shielding of one face and causes different reactivities of E/Z-dienamines in nucleophilic attacks from the other face. Kinetic preferences for the formation of Z-dienamines and their unfavorable thermodynamics support high ee values.

Hossay's paper

Synthesis of Functionalized Pyridines via a Regioselective Oxazoline Promoted C−H Amidation Reaction

Tracy M. M. Maiden,† Stephen Swanson,‡ Panayiotis A. Procopiou,‡ and Joseph P. A. Harrity*

Graphical abstract

Abstract Image

The first Rh-catalyzed C–H amidation of pyridines is reported. The incorporation of a substituent at the C2 position both is crucial to the success of this transformation and provides considerable scope for further elaboration of the resulting products. Among these compounds, 2-chloropyridines allow access to a selection of intermediates including a versatile azaquinazoline scaffold.

12/08/2016

 

Lola's paper

Richard T. Thornbury, Prof. Dr. F. Dean Toste

Graphical abstract
Scheme 2.
 
 
 
 
 
 
 
 
 
 
The palladium-catalyzed defluorinative coupling of 1-aryl-2,2-difluoroalkenes with boronic acids is described. Broad functional-group tolerance arises from a redox-neutral process by a palladium(II) active species which is proposed to undergo a β-fluoride elimination to afford the products. The monofluorostilbene products were formed with excellent diastereoselectivity (≥50:1) in all cases, and it is critical, as traditional chromatographic techniques often fail to separate monofluoroalkene isomers. As a demonstration of this method's unique combination of reactivity and functional-group tolerance, a Gleevec® analogue, using a monofluorostilbene as an amide isostere, was synthesized.
 
Kleo's paper
 

Selective Synthesis of Six Products from a Single Indolyl α-Diazocarbonyl Precursor

Michael J. James, Prof. Peter O'Brien, Prof. Richard J. K. Taylor, Dr. William P. Unsworth

Graphical abstract

Figure 1.

 

 

 

 

 

 

Indolyl α-diazocarbonyls can be selectively cyclized to give six distinct products through the careful choice of catalyst and reaction conditions. A range of catalysts were used, including complexes of RhII, PdII, and CuII, as well as SiO2, to promote diazo decomposition and subsequent cyclization/rearrangement through a range of mechanistic pathways.

Oner's paper

Pericyclic Cascade toward Isochromenes: Application to the Synthesis of Alkaloid Benzosimuline

Martín J. Riveira*, Agustina La-Venia, and Mirta P. Mischne

Graphical abstract

Abstract Image

The synthesis of biologically active alkaloid benzosimuline, isolated from the shrub Zanthoxylum simulans, is reported. Key transformation involves an oxa-6π electrocyclic ring-opening/hetero-Diels–Alder pericyclic cascade. Although the last aromatization step proved to be cumbersome, this work unfolds a unique route to access interesting molecules from simple precursors

 

 

September

02/09/2016

Richard's paper

Targeted Delivery and Sustained Antitumor Activity of Triptolide through Glucose Conjugation

Dr. Qing-Li He, Dr. Il Minn, Dr. Qiaoling Wang, Dr. Peng Xu, Dr. Sarah A. Head, Emmanuel Datan, Prof. Biao Yu, Prof. Martin G. Pomper, Prof. Jun O. Liu

Graphical abstract

Figure 1.

Triptolide, a key ingredient from the traditional Chinese medicinal plant thunder god vine, which has been used to treat inflammation and autoimmune diseases for centuries, has been shown to be an irreversible inhibitor of the XPB subunit of the transcription factor TFIIH and initiation of RNA polymerase II mediated transcription. The clinical development of triptolide over the past two decades has been limited by its toxicity and low water solubility. Herein, we report the development of a glucose conjugate of triptolide, named glutriptolide, which was intended to target tumor cells overexpressing glucose transporters selectively. Glutriptolide did not inhibit XPB activity in vitro but demonstrated significantly higher cytotoxicity against tumor cells over normal cells with greater water solubility than triptolide. Furthermore, it exhibited remarkable tumor control in vivo, which is likely due to sustained stepwise release of active triptolide within cancer cells. These findings indicate that glutriptolide may serve as a promising lead for developing a new mechanistic class of anticancer drugs.

Lola's paper

Copper-Mediated Oxidative Fluorination of Aryl Stannanes with Fluoride

Raymond F. Gamache†, Christopher Waldmann‡, and Jennifer M. Murphy*‡

Graphical abstract

Abstract Image

 

 

 

 

A regiospecific method for the oxidative fluorination of aryl stannanes using tetrabutylammonium triphenyldifluorosilicate (TBAT) and copper(II) triflate is described. This reaction is robust, uses readily available reagents, and proceeds via a stepwise protocol under mild conditions (60 °C, 3.2 h). Broad functional group tolerance, including arenes containing protic and nucleophilic groups, is demonstrated.

Hossay's paper

Synthesis of 1,3-Substituted Cyclobutanes by Allenoate-Alkene [2 + 2] Cycloaddition

Michael L. Conner and M. Kevin Brown*

Graphical abstract

Abstract Image

A method for the [2 + 2] cycloaddition of terminal alkenes with allenoates is presented. This process allows for the rapid synthesis of 1,3-substituted cyclobutanes in high yield under simple and robust reaction conditions.

16/09/2016

Onur's paper

Copper-catalyzed N-thioetherification of sulfoximines using disulfides

Hui Zhu,a Jin-Tao Yu*a and Jiang Cheng*

Graphical abstract

onur

 

 

A novel copper-catalyzed N-thioetherification of sulfoximines under mild reaction conditions was developed. In this procedure, the N–S bond formation was achieved using readily available disulfides as the sulfur source.

Christian's paper

Sequential catalysis: exploiting a single rhodium(I) catalyst to promote an alkyne hydroacylation–aryl boronic acid conjugate addition sequence

Maitane Fernández,a Matthias Castainga and Michael C. Willis*a

Graphical abstract

chris

We demonstrate that a single Rh(I) complex can promote two mechanistically distinct C–C bond-forming reactions – alkyne hydroacylation and aryl boronic acid conjugate addition – to deliver substituted ketone products from the controlled assembly of three readily available fragments. This is a rare example of a Rh(I)/Rh(III) cycle and a redox neutral Rh(I) cycle being promoted by a single catalyst. The process is broad in scope, allowing significant variation of all three reaction components. Incorporation of an enantiomerically pure bis-phosphine ligand renders the process enantioselective. Superior levels of enantioselectivity (up to >99% ee) can be achieved from using a two catalyst system, whereby two Rh(I) complexes, one incorporating an achiral bis-phosphine ligand and the second a chiral diene ligand, are introduced at the start of the reaction sequence.

23/09/2016

Wouter's paper

Tunable Probes with Direct Fluorescence Signals for the Constitutive and Immunoproteasome

Dr. Christian Dubiella, Dr. Haissi Cui, Prof. Dr. Michael Groll

Graphical abstract

Figure 1.

Electrophiles are commonly used for the inhibition of proteases. Notably, inhibitors of the proteasome, a central determinant of cellular survival and a target of several FDA-approved drugs, are mainly characterized by the reactivity of their electrophilic head groups. We aimed to tune the inhibitory strength of peptidic sulfonate esters by varying the leaving groups. Indeed, proteasome inhibition correlated well with the pKa of the leaving group. The use of fluorophores as leaving groups enabled us to design probes that release a stoichiometric fluorescence signal upon reaction, thereby directly linking proteasome inactivation to the readout. This principle could be applicable to other sulfonyl fluoride based inhibitors and allows the design of sensitive probes for enzymatic studies.

Christian's paper

Site-selective C–H arylation of primary aliphatic amines enabled by a catalytic transient directing group

Yongbing Liu & Haibo Ge

Graphical abstract

Transition-metal-catalysed C–H functionalization of alkylamines.

Transition-metal-catalysed direct C–H bond functionalization of aliphatic amines is of great importance in organic and medicinal chemistry research. Several methods have been developed for the direct sp3 C–H functionalization of secondary and tertiary aliphatic amines, but site-selective functionalization of primary aliphatic amines in remote positions remains a challenge. Here, we report the direct, highly site-selective γ-arylation of primary alkylamines via a palladium-catalysed C–H bond functionalization process on unactivated sp3 carbons. Using glyoxylic acid as an inexpensive, catalytic and transient directing group, a wide array of γ-arylated primary alkylamines were prepared without any protection or deprotection steps. This approach provides straightforward access to important structural motifs in organic and medicinal chemistry without the need for pre-functionalized substrates or stoichiometric directing groups and is demonstrated here in the synthesis of analogues of the immunomodulatory drug fingolimod directly from commercially available 2-amino-2-propylpropane-1,3-diol.

 

30/09/2016

Onur's paper

An efficient construction of N,N-bicyclic pyrazolidinones comprising enaminonitriles via asymmetric [3+2] cycloaddition

Manjunatha Vishwanath,a Koilpitchai Sivamuthuramana and Venkitasamy Kesavan*a

Graphical abstract

Graphical abstract: An efficient construction of N,N-bicyclic pyrazolidinones comprising enaminonitriles via asymmetric [3+2] cycloaddition

 

 

 

 

The first thiourea catalysed asymmetric [3+2] cycloaddition reaction between azomethine imines and malanonitriles was developed. Using this novel synthetic strategy, hybrid molecules containing N,N-bicyclic pyrazolidinones fused with enaminonitriles were synthesized in good yields with excellent enantioselectivities (up to 98% ee).

Wouter's paper

Autocatalytic, bistable, oscillatory networks of biologically relevant organic reactions

Sergey N. Semenov, Lewis J. Kraft, Alar Ainla, Mengxia Zhao, Mostafa Baghbanzadeh, Victoria E. Campbell, Kyungtae Kang, Jerome M. Fox & George M. Whitesides

Graphical abstract

Overview of the network of organic reactions.

Networks of organic chemical reactions are important in life and probably played a central part in its origin1, 2, 3. Network dynamics regulate cell division4, 5, 6, circadian rhythms7, nerve impulses8 and chemotaxis9, and guide the development of organisms10. Although out-of-equilibrium networks of chemical reactions have the potential to display emergent network dynamics11 such as spontaneous pattern formation, bistability and periodic oscillations12, 13, 14, the principles that enable networks of organic reactions to develop complex behaviours are incompletely understood. Here we describe a network of biologically relevant organic reactions (amide formation, thiolate–thioester exchange, thiolate–disulfide interchange and conjugate addition) that displays bistability and oscillations in the concentrations of organic thiols and amides. Oscillations arise from the interaction between three subcomponents of the network: an autocatalytic cycle that generates thiols and amides from thioesters and dialkyl disulfides; a trigger that controls autocatalytic growth; and inhibitory processes that remove activating thiol species that are produced during the autocatalytic cycle. In contrast to previous studies that have demonstrated oscillations and bistability using highly evolved biomolecules (enzymes15 and DNA16, 17) or inorganic molecules of questionable biochemical relevance (for example, those used in Belousov–Zhabotinskii-type reactions)18, 19, the organic molecules we use are relevant to metabolism and similar to those that might have existed on the early Earth. By using small organic molecules to build a network of organic reactions with autocatalytic, bistable and oscillatory behaviour, we identify principles that explain the ways in which dynamic networks relevant to life could have developed. Modifications of this network will clarify the influence of molecular structure on the dynamics of reaction networks, and may enable the design of biomimetic networks and of synthetic self-regulating and evolving chemical systems.

Hossay's paper

Diastereoselective Cobalt-Mediated Cross-Couplings of Cycloalkyl Iodides with Alkynyl or (Hetero)Aryl Grignard Reagents

Jeffrey M. Hammann†, Diana Haas†, Carl-Phillip Tüllmann, Konstantin Karaghiosoff, and Paul Knochel*

Graphical abstract

Abstract Image

 

 

 

 

 

A highly diastereoselective cross-coupling of variously substituted cycloalkyl iodides with alkynyl and (hetero)aryl Grignard reagents using cobalt(II) chloride has been successfully developed. With the THF-soluble CoCl2·LiCl and the inexpensive ortho-phenanthroline derivative, neocuproine, as a ligand, diastereomeric ratios of up to 99:1 were achieved. A range of functional groups are tolerated in the Grignard reagent (e.g., CF3, Piv, CN, OPiv, NMe2, CO2NEt2, SF5, OTBS).

October

14/10/2016

Jay's paper

gem-Disubstituent Effect:  Theoretical Basis and Synthetic Applications

Michael E. Jung * and Grazia Piizzi *

Graphical abstract

NONE AVAILABLE

21/10/2016

Wouter's paper

Exploring the Binding Proteins of Glycolipids with Bifunctional Chemical Probes

Xiaohui Liu, Ting Dong, Yu Zhou, Prof. Dr. Niu Huang, Prof. Dr. Xiaoguang Lei

Graphical abstract

Figure 1.

 

 

 

 

 

 

 

Glycolipids are important structural components of biological membranes and perform crucial functions in living systems, including signaling transduction and interaction with extracellular environment. However, the mechanistic exploration of glycolipids in vivo is challenging because they are not genetically encoded. Herein, we designed and synthesized a series of bifunctional monogalactosyldiacylglycerol (MGDG) probes as a model by introducing diazirine and terminal alkyne moieties on an aliphatic chain. In combination with proteome profiling and molecular modeling, we have demonstrated that MGDG alleviates inflammation by antagonizing TLR4.

Enantioselective Formation of All-Carbon Quaternary Centers via C–H Functionalization of Methanol: Iridium-Catalyzed Diene Hydrohydroxymethylation

Khoa D. Nguyen, Daniel Herkommer, and Michael J. Krische*

Graphical abstract

Abstract Image

The first catalytic enantioselective C–C couplings of methanol (>30 × 106 tons/year) are reported. Insertion of 2-substituted dienes into the methanol C–H bond occurs in a regioselective manner to form all-carbon quaternary centers with excellent levels of enantioselectivity using an iridium–PhanePhos catalyst. Mechanistic studies corroborate a Curtin–Hammett scenario in which methanol dehydrogenation triggers rapid, reversible diene hydrometalation en route to regioisomeric allyliridium–formaldehyde pairs, yet single constitutional isomers are formed.

Beyond Thermodynamic Acidity: A Perspective on the Complex-Induced Proximity Effect (CIPE) in Deprotonation Reactions†
Marna C. Whisler Dr., Stephen MacNeil Dr., Victor Snieckus Prof. Dr., Peter Beak Prof. Dr.

Graphical abstract

Scheme 1.

The concept of the complex-induced proximity effect (CIPE) in deprotonations is helpful in elucidating the mechanisms involved in carbanion chemistry and in planning organic syntheses. In this Review, the consequences of complexation of organolithium bases to functional groups of the substrates before the proton-transfer step are discussed. Experimental data from kinetic measurements and isotope-labeling experiments as well as the results of calculations in many cases point to a prelithiation complex as a reaction intermediate. Some examples from natural products synthesis illustrate how this concept can be used to obtain intermediates in a regio- or stereoselective manner. Of particular interest is the functionalization of positions that are remote from the coordination group.

28/10/2016

Hossay's paper

Enantioselective, Catalytic Fluorolactonization Reactions with a Nucleophilic Fluoride Source

Eric M. Woerly, Steven M. Banik, and Eric N. Jacobsen*

Graphical abstract

Abstract Image

The enantioselective synthesis of 4-fluoroisochromanones via chiral aryl iodide-catalyzed fluorolactonization is reported. This methodology uses HF-pyridine as a nucleophilic fluoride source with a peracid stoichiometric oxidant and provides access to lactones containing fluorine-bearing stereogenic centers in high enantio- and diastereoselectivity. The regioselectivity observed in these lactonization reactions is complementary to that obtained with established asymmetric electrophilic fluorination protocols.

Christian's  paper

An artificial metalloenzyme with the kinetics of native enzymes

P. Dydio1,2,*, H. M. Key1,2,*, A. Nazarenko1, J. Y.-E. Rha1, V. Seyedkazemi1, D. S. Clark3,4, J. F. Hartwig

Graphical abstract

Natural enzymes contain highly evolved active sites that lead to fast rates and high selectivities. Although artificial metalloenzymes have been developed that catalyze abiological transformations with high stereoselectivity, the activities of these artificial enzymes are much lower than those of natural enzymes. Here, we report a reconstituted artificial metalloenzyme containing an iridium porphyrin that exhibits kinetic parameters similar to those of natural enzymes. In particular, variants of the P450 enzyme CYP119 containing iridium in place of iron catalyze insertions of carbenes into C–H bonds with up to 98% enantiomeric excess, 35,000 turnovers, and 2550 hours−1turnover frequency. This activity leads to intramolecular carbene insertions into unactivated C–H bonds and intermolecular carbene insertions into C–H bonds. These results lift the restrictions on merging chemical catalysis and biocatalysis to create highly active, productive, and selective metalloenzymes for abiological reactions.

 

 

November

04/11/2016

Christine's paper

Synthesis of Pyrrolidines and Pyrrolizidines with α-Pseudoquaternary Centers by Copper-Catalyzed Condensation of α-Diazodicarbonyl Compounds and Aryl γ-Lactams

Dr. Sébastien Goudedranche, Dr. Céline Besnard, Léo Egger, Prof. Jérôme Lacour

Graphical abstract

Scheme 1.

N-aryl γ-lactams react intermolecularly with acceptor–acceptor diazo reagents, usually dicarbonyl compounds, in a copper-catalyzed process to yield functionalized pyrrolidines with α-pseudoquaternary centers. As 1,2-acyl or -phosphoryl migration is preferred, single regioisomers are obtained. Furthermore, in the presence of a Lewis acid, subsequent Friedel–Crafts reactions yield tricyclic pyrrolizidines in excellent yields (90–96 %) and diastereoselectivities (up to >20:1).

Lola's paper

Dioxygen-Promoted Pd-Catalyzed Aminocarbonylation of Organoboronic Acids with Amines and CO: A Direct Approach to Tertiary Amides

Long Ren†, Xinwei Li†, and Ning Jiao

Graphical abstract

Abstract Image

 

 

 

 

A direct approach from organoboronic acids and amines to tertiary amides via Pd-catalyzed aerobic aminocarbonylation has been developed. The presence of O2 significantly promotes the efficiency of this transformation. This method uses commercially available organoboronic acids and cheap CO and O2 (1 atm), which renders amides an easy synthesis with broad substrate scope and high functional group tolerance.

Youssef's paper

Alternatives for Conventional Alkane Solvents

Mary L. Harrell, Thomas Malinski, Coralys Torres-López, Kimberly Gonzalez, Jakkrit Suriboot, and David E. Bergbreiter

Graphical abstract

Abstract Image

The studies described in this paper show that hydrocarbon oligomers are alternatives for low molecular weight alkane solvents. These oligomeric solvents are nontoxic, nonvolatile, and recyclable alternatives to heptane in thermomorphic solvent mixtures that use a polar solvent such as methanol, aqueous ethanol, or DMF or in biphasic mixtures that use acetonitrile. Regardless of which polar solvent is used, hydrocarbon oligomers like poly(α-olefin)s (PAOs) exhibit very low leaching into the polar phase. UV–visible spectroscopy studies show that these solvents have the solubility properties of heptane. For example, PAOs dissolve heptane soluble dyes and quantitatively separate them from polar phases in thermomorphic solvent mixtures. PAOs either as pure solvents or as additives in heptane act as antileaching agents, decreasing the already low leaching of such dyes into a polar phase in heptane/polar solvent mixtures. These oligomeric hydrocarbon solvents were also compared to heptane in studies of azo dye isomerization. The results show that thermal isomerization of an azo dye occurs at the same rate in heptane and a PAO. Further studies of carboxylic acid promoted dye isomerization in heptane and a PAO show that low molecular weight and oligomeric carboxylic acids are kinetically equivalent at accelerating this isomerization. The results suggest that these and other hydrocarbon oligomers behave as solvents like their low molecular weight nonpolar hydrocarbon solvents and that they can be substituted successfully for conventional solvents like heptane.

11/11/2016

Youssef's paper

Metal-Free Aromatic Carbon–Phosphorus Bond Formation via a Sandmeyer-Type Reaction

Shuai Wang, Di Qiu, Fanyang Mo, Yan Zhang, and Jianbo Wang*

Graphical abstract

Abstract Image

An efficient metal-free phosphorylation process based on a Sandmeyer-type transformation with arylamines as the starting materials is developed. The transformation proceeds smoothly at room temperature without the exclusion of moisture or air. This phosphorylation reaction tolerates a wide range of functional groups and affords the phosphorylation products in moderate to good yields, thus providing a valuable method for the formation of aromatic carbon–phosphorus bonds.

 Lola's paper

Palladium-Triggered Chemical Rescue of Intracellular Proteins via Genetically Encoded Allene-Caged Tyrosine

Jie Wang†§, Siqi Zheng§, Yanjun Liu§, Zhaoyue Zhang§, Zhi Lin§, Jiaofeng Li§, Gong Zhang†§, Xin Wang†‡, Jie Li§, and Peng R. Chen*§‡

Graphical abstract

Abstract Image

Chemical de-caging has emerged as an attractive strategy for gain-of-function study of proteins via small-molecule reagents. The previously reported chemical de-caging reactions have been largely centered on liberating the side chain of lysine on a given protein. Herein, we developed an allene-based caging moiety and the corresponding palladium de-caging reagents for chemical rescue of tyrosine (Tyr) activity on intracellular proteins. This bioorthogonal de-caging pair has been successfully applied to unmask enzymatic Tyr sites (e.g., Y671 on Taqpolymerase and Y728 on Anthrax lethal factor) as well as the post-translational Tyr modification site (Y416 on Src kinase) in vitro and in living cells. Our strategy provides a general platform for chemical rescue of Tyr-dependent protein activity inside cells.

Christian's papers

Amide-directed photoredox-catalysed C–C bond formation at unactivated sp3 C–H bonds

John C. K. Chu & Tomislav Rovis

Graphical abstract

Selectivity issues with C–H bond functionalization.

Carbon–carbon (C–C) bond formation is paramount in the synthesis of biologically relevant molecules, modern synthetic materials and commodity chemicals such as fuels and lubricants. Traditionally, the presence of a functional group is required at the site of C–C bond formation. Strategies that allow C–C bond formation at inert carbon–hydrogen (C–H) bonds enable access to molecules that would otherwise be inaccessible and the development of more efficient syntheses of complex molecules1, 2. Here we report a method for the formation of C–C bonds by directed cleavage of traditionally non-reactive C–H bonds and their subsequent coupling with readily available alkenes. Our methodology allows for amide-directed selective C–C bond formation at unactivated sp3 C–H bonds in molecules that contain many such bonds that are seemingly indistinguishable. Selectivity arises through a relayed photoredox-catalysed oxidation of a nitrogen–hydrogen bond. We anticipate that our findings will serve as a starting point for functionalization at inert C–H bonds through a strategy involving hydrogen-atom transfer.

Catalytic alkylation of remote C–H bonds enabled by proton-coupled electron transfer

Gilbert J. Choi, Qilei Zhu, David C. Miller, Carol J. Gu & Robert R. Knowles

Graphical abstract

Design and development of a catalytic amidyl-mediated C–H alkylation.

Despite advances in hydrogen atom transfer (HAT) catalysis1, 2, 3, 4, 5, there are currently no molecular HAT catalysts that are capable of homolysing the strong nitrogen–hydrogen (N–H) bonds of N-alkyl amides. The motivation to develop amide homolysis protocols stems from the utility of the resultant amidyl radicals, which are involved in various synthetically useful transformations, including olefin amination6, 7, 8, 9, 10, 11 and directed carbon–hydrogen (C–H) bond functionalization12, 13, 14, 15, 16. In the latter process—a subset of the classical Hofmann–Löffler–Freytag reaction—amidyl radicals remove hydrogen atoms from unactivated aliphatic C–H bonds17, 18, 19, 20, 21. Although powerful, these transformations typically require oxidative N-prefunctionalization of the amide starting materials to achieve efficient amidyl generation. Moreover, because these N-activating groups are often incorporated into the final products, these methods are generally not amenable to the direct construction of carbon–carbon (C–C) bonds. Here we report an approach that overcomes these limitations by homolysing the N–H bonds of N-alkyl amides via proton-coupled electron transfer. In this protocol, an excited-state iridium photocatalyst and a weak phosphate base cooperatively serve to remove both a proton and an electron from an amide substrate in a concerted elementary step. The resultant amidyl radical intermediates are shown to promote subsequent C–H abstraction and radical alkylation steps. This C–H alkylation represents a catalytic variant of the Hofmann–Löffler–Freytag reaction, using simple, unfunctionalized amides to direct the formation of new C–C bonds. Given the prevalence of amides in pharmaceuticals and natural products, we anticipate that this method will simplify the synthesis and structural elaboration of amine-containing targets. Moreover, this study demonstrates that concerted proton-coupled electron transfer can enable homolytic activation of common organic functional groups that are energetically inaccessible using traditional HAT-based approaches.

18/11/2016

Lola's paper

Direct Evidence of a Dinuclear Copper Intermediate in Cu(I)-Catalyzed Azide-Alkyne Cycloadditions

B. T. Worrell, J. A. Malik, V. V. Fokin*

Graphical abstract

 

 

 

 

 

 

 

 

Copper(I)-catalyzed azide-alkyne cycloaddition has become a commonly employed method for the synthesis of complex molecular architectures under challenging conditions. Despite the widespread use of copper-catalyzed cycloaddition reactions, the mechanism of these processes has remained difficult to establish due to the involvement of multiple equilibria between several reactive intermediates. Real-time monitoring of a representative cycloaddition process via heat-flow reaction calorimetry revealed that monomeric copper acetylide complexes are not reactive toward organic azides unless an exogenous copper catalyst is added. Furthermore, crossover experiments with an isotopically enriched exogenous copper source illustrated the stepwise nature of the carbon–nitrogen bond-forming events and the equivalence of the two copper atoms within the cycloaddition steps.

Wouter's paper

Chemoenzymatic Labeling of Proteins for Imaging in Bacterial Cells

Samuel H. Ho and David A. Tirrell*

Graphical abstract

Abstract Image

 

 

 

Reliable methods to determine the subcellular localization of bacterial proteins are needed for the study of prokaryotic cell biology. We describe here a simple and general technique for imaging of bacterial proteins in situ by fluorescence microscopy. The method uses the eukaryotic enzyme N-myristoyltransferase to modify the N-terminus of the protein of interest with an azido fatty acid. Subsequent strain-promoted azide–alkyne cycloaddition allows conjugation of dyes and imaging of tagged proteins by confocal fluorescence microscopy. We demonstrate the method by labeling the chemotaxis proteins Tar and CheA and the cell division proteins FtsZ and FtsA in Escherichia coli. We observe distinct spatial patterns for each of these proteins in both fixed and live cells. The method should prove broadly useful for protein imaging in bacteria.

Youssef's paper

Total Synthesis of (+)-Cytosporolide A via a Biomimetic Hetero-Diels–Alder Reaction

Ken-ichi Takao*, Shuji Noguchi, Shu Sakamoto, Mizuki Kimura, Keisuke Yoshida, and Kin-ichi Tadano

Graphical abstract

Abstract Image

 

 

 

 

The first total synthesis of (+)-cytosporolide A was achieved by a biomimetic hetero-Diels–Alder reaction of (−)-fuscoatrol A with o-quinone methide generated from (+)-CJ-12,373. The dienophile, highly oxygenated caryophyllene sesquiterpenoid (−)-fuscoatrol A, was synthesized from the synthetic intermediate in our previous total synthesis of (+)-pestalotiopsin A. The o-quinone methide precursor, isochroman carboxylic acid (+)-CJ-12,373, was synthesized through a Kolbe–Schmitt reaction and an oxa-Pictet–Spengler reaction. The hetero-Diels–Alder reaction of these two compounds proceeded with complete chemo-, regio-, and stereoselectivity to produce the complicated pentacyclic ring system of the cytosporolide skeleton. This total synthesis unambiguously demonstrates that natural cytosporolide A has the structure previously suggested.

25/11/2016

Christine's paper

Stereoselective Synthesis of α-Fluoro-γ-nitro Thioesters under Organocatalytic Conditions

Elena Cosimi, Jakub Saadi, and Helma Wennemers*

Graphical abstract

Abstract Image

 

 

 

 

Fluorinated monothiomalonates (F-MTMs) were used as building blocks for the stereoselective synthesis of organofluorine compounds. We present conjugate addition reactions between F-MTMs with nitroolefins that proceed under mild organocatalytic conditions and provide access to α-fluoro-γ-nitro thioesters with adjacent tetrasubstituted and tertiary stereogenic centers. Only 1 mol % of a cinchona alkaloid–urea catalyst is necessary to obtain the addition products in excellent yields and stereoselectivities. The methodology allowed for the straightforward synthesis of a fluorinated analogue of the PAR-2 agonist AC-264613.

Lola's paper

Target discovery in small-molecule cell-based screens by in situ proteome reactivity profiling

Michael J Evans, Alan Saghatelian, Erik J Sorensen & Benjamin F Cravatt

Graphical abstract

Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com

Chemical genomics aims to discover small molecules that affect biological processes through the perturbation of protein function1, 2. However, determining the protein targets of bioactive compounds remains a formidable challenge3. We address this problem here through the creation of a natural product–inspired small-molecule library bearing protein-reactive elements. Cell-based screening identified a compound, MJE3, that inhibits breast cancer cell proliferation. In situ proteome reactivity profiling revealed that MJE3, but not other library members, covalently labeled the glycolytic enzyme phosphoglycerate mutase 1 (PGAM1), resulting in enzyme inhibition. Interestingly, MJE3 labeling and inhibition of PGAM1 were observed exclusively in intact cells. These results support the hypothesis that cancer cells depend on glycolysis for viability and promote PGAM1 as a potential therapeutic target. More generally, the incorporation of protein-reactive compounds into chemical genomics screens offers a means to discover targets of bioactive small molecules in living systems, thereby enabling downstream mechanistic investigations.

 

December

02/12/2016

Lola's paper

An in Situ Generated Palladium on Aluminum Oxide: Applications in Gram-Scale Matsuda–Heck Reactions

Simon Pape†, Lauryna Daukšaitė†, Sandra Lucks†, Xiaoting Gu‡, and Heiko Brunner

Graphical abstract

Abstract Image

 

 

 

 

 

In situ generated palladium on aluminum oxide provides an active catalytic system for Matsuda-Heck reactions in gram-scale. The novel catalyst proceeded through a significantly higher catalytic activity compared to the classical Pd/C system. Based on the high catalytic activity the first α,β,β-triarylation of methyl acrylate in good yields could be provided in one-step.

Richard's paper

Carbon Cationic Relay via Superelectrophiles: Synthesis of Spiro-diazafluorenes

Dongqing Lin†§, Ying Wei†§, Changjin Ou‡, Hao Huang†, Linghai Xie*†, Lei Tang†, and Wei Huang*

Graphical abstract

Abstract Image

 

Superelectrophilic-initiated carbon cationic relay reactions of diazafluorenones with phenols were developed to provide strategically novel and atom-economic access to spirodiazafluorenes via tandem Friedel–Crafts reaction, nucleophilic addition, and intramolecular cyclization sequences. A range of spirodiazafluorenes that are difficult to synthesize with traditional protocols has been constructed successfully in middle to high yields using this method.

Wouter's paper

Directed evolution of cytochrome c for carbon–silicon bond formation: Bringing silicon to life

S. B. Jennifer Kan, Russell D. Lewis, Kai Chen, Frances H. Arnold*

Graphical abstract

 

Enzymes that catalyze carbon–silicon bond formation are unknown in nature, despite the natural abundance of both elements. Such enzymes would expand the catalytic repertoire of biology, enabling living systems to access chemical space previously only open to synthetic chemistry. We have discovered that heme proteins catalyze the formation of organosilicon compounds under physiological conditions via carbene insertion into silicon–hydrogen bonds. The reaction proceeds both in vitro and in vivo, accommodating a broad range of substrates with high chemo- and enantioselectivity. Using directed evolution, we enhanced the catalytic function of cytochrome c from Rhodothermus marinus to achieve more than 15-fold higher turnover than state-of-the-art synthetic catalysts. This carbon–silicon bond-forming biocatalyst offers an environmentally friendly and highly efficient route to producing enantiopure organosilicon molecules.

09/12/2016

Christian's paper

A general, modular method for the catalytic asymmetric synthesis of alkylboronate esters

Jens Schmidt, Junwon Choi, Albert Tianxiang Liu, Martin Slusarczyk, Gregory C. Fu

Graphical abstract

Alkylboron compounds are an important family of target molecules, serving as useful intermediates, as well as end points, in fields such as pharmaceutical science and organic chemistry. Facile transformation of carbon-boron bonds into a wide variety of carbon-X bonds (where X is, for example, carbon, nitrogen, oxygen, or a halogen), with stereochemical fidelity, renders the generation of enantioenriched alkylboronate esters a powerful tool in synthesis. Here we report the use of a chiral nickel catalyst to achieve stereoconvergent alkyl-alkyl couplings of readily available racemic α-haloboronates with organozinc reagents under mild conditions. We demonstrate that this method provides straightforward access to a diverse array of enantioenriched alkylboronate esters, in which boron is bound to a stereogenic carbon, and we highlight the utility of these compounds in synthesis.

Richard's paper

Nickel-Catalyzed CO2 Rearrangement of Enol Metal Carbonates for the Efficient Synthesis of β-Ketocarboxylic Acids

Ryo Ninokata, Tatsuya Yamahira, Dr. Gen Onodera, Prof. Dr. Masanari Kimura

Graphical abstract

Scheme 1

 

4-Methylene-1,3-dioxolan-2-ones underwent oxidative addition of a Ni0 catalyst in the presence of Me2Al(OMe), followed by a coupling reaction with alkynes, to form δ,ϵ-unsaturated β-ketocarboxylic acids with high regio- and stereoselectivity. The reaction proceeds by [1,3] rearrangement of an enol metal carbonate intermediate and the formal reinsertion of CO2.

Wouter's paper

Generation of influenza A viruses as live but replication-incompetent virus vaccines

Longlong Si*, Huan Xu*, Xueying Zhou, Ziwei Zhang, Zhenyu Tian, Yan Wang, Yiming Wu, Bo Zhang, Zhenlan Niu, Chuanling Zhang, Ge Fu, Sulong Xiao, Qing Xia, Lihe Zhang, Demin Zhou

Graphical abstract

The conversion of life-threatening viruses into live but avirulent vaccines represents a revolution in vaccinology. In a proof-of-principle study, we expanded the genetic code of the genome of influenza A virus via a transgenic cell line containing orthogonal translation machinery. This generated premature termination codon (PTC)–harboring viruses that exerted full infectivity but were replication-incompetent in conventional cells. Genome-wide optimization of the sites for incorporation of multiple PTCs resulted in highly reproductive and genetically stable progeny viruses in transgenic cells. In mouse, ferret, and guinea pig models, vaccination with PTC viruses elicited robust humoral, mucosal, and T cell–mediated immunity against antigenically distinct influenza viruses and even neutralized existing infecting strains. The methods presented here may become a general approach for generating live virus vaccines that can be adapted to almost any virus.

16/12/2016

Christian's paper

An iron-catalysed C–C bond-forming spirocyclization cascade providing sustainable access to new 3D heterocyclic frameworks

Kirsty Adams, Anthony K. Ball, James Birkett, Lee Brown, Ben Chappell, Duncan M. Gill, P. K. Tony Lo, Nathan J. Patmore, Craig. R. Rice, James Ryan, Piotr Raubo & Joseph B. Sweeney

Graphical abstract

Synthesis of spirocyclic bis-heterocycles that are the cores of natural products.

Heterocyclic architectures offer powerful creative possibilities to a range of chemistry end-users. This is particularly true of heterocycles containing a high proportion of sp3-carbon atoms, which confer precise spatial definition upon chemical probes, drug substances, chiral monomers and the like. Nonetheless, simple catalytic routes to new heterocyclic cores are infrequently reported, and methods making use of biomass-accessible starting materials are also rare. Here, we demonstrate a new method allowing rapid entry to spirocyclic bis-heterocycles, in which inexpensive iron(III) catalysts mediate a highly stereoselective C–C bond-forming cyclization cascade reaction using (2-halo)aryl ethers and amines constructed using feedstock chemicals readily available from plant sources. Fe(acac)3 mediates the deiodinative cyclization of (2-halo)aryloxy furfuranyl ethers, followed by capture of the intermediate metal species by Grignard reagents, to deliver spirocycles containing two asymmetric centres. The reactions offer potential entry to key structural motifs present in bioactive natural products.

Christine's paper

Regioselective Hydrohydroxyalkylation of Styrene with Primary Alcohols or Aldehydes via Ruthenium-Catalyzed C−C Bond Forming Transfer Hydrogenation

Hongde Xiao, Gang Wang, Prof. Michael J. Krische

Graphical abstract

Figure 1

 

Transfer hydrogenative coupling of styrene with primary alcohols using the precatalyst HClRu(CO)(PCy3)2 modified by AgOTf or HBF4 delivers branched or linear adducts from benzylic or aliphatic alcohols, respectively. Related 2-propanol mediated reductive couplings also are described.