Meetings by month

January

06/01/2017

Christine's paper

Extension of Pd-Mediated One-Pot Ketone Synthesis to Macrocyclization: Application to a New Convergent Synthesis of Eribulin

Jung Hwa Lee, Zhanjie Li†, Ayumi Osawa, and Yoshito Kishi*

Graphical abstract

Abstract Image

Recently reported Pd-mediated one-pot ketone synthesis from an unactivated alkyl bromide and a thioester has been extended to a macrocyclic ketone synthesis. In situ generation of alkylzinc halide via single electron transfer (SET), using NbCpCl4 and CrCl3, was the key for the success of macrocyclization. A new convergent synthesis of eribulin has been achieved, using (1) catalytic asymmetric Ni/Cr-mediated coupling to form the C19–C20 bond, (2) base-induced cyclization to form the methylenetetrahydrofuran ring, and (3) Pd-mediated one-pot ketone synthesis to form the macrocyclic ketone.

Ololade's paper

Visible-Light-Induced Acetalization of Aldehydes with Alcohols

Hong Yi†§, Linbin Niu†§, Shengchun Wang†, Tianyi Liu†, Atul K. Singh†, and Aiwen Lei*†‡

Graphical abstract

Abstract Image

 

 

 

In this work, we have achieved a simple and general method for acetalization of aldehydes by means of a photochemical reaction under low-energy visible light irradiation. A broad range of aromatic, heteroaromatic, and aliphatic aldehydes have been protected under neutral conditions in good to excellent yields using a catalytic amount of Eosin Y as the photocatalyst. Our visible light mediated acetalization strategies are successful for more challenging acid-sensitive aldehydes and sterically hindered aldehydes. Notably, this protocol is chemoselective to aldehydes, while ketones remain intact.

13/01/2017

Christian's paper

 
Yongho ParkKaid C. HarperNadine KuhlEugene E. KwanRichard Y. LiuEric N. Jacobsen
 
Graphical abstract
 
Carbohydrates are involved in nearly all aspects of biochemistry, but their complex chemical structures present long-standing practical challenges to their synthesis. In particular, stereochemical outcomes in glycosylation reactions are highly dependent on the steric and electronic properties of coupling partners; thus, carbohydrate synthesis is not easily predictable. Here we report the discovery of a macrocyclic bis-thiourea derivative that catalyzes stereospecific invertive substitution pathways of glycosyl chlorides. The utility of the catalyst is demonstrated in the synthesis of trans-1,2-, cis-1,2-, and 2-deoxy-β-glycosides. Mechanistic studies are consistent with a cooperative mechanism in which an electrophile and a nucleophile are simultaneously activated to effect a stereospecific substitution reaction.
 
Wouter's paper
 

Chemoenzymatic Approach for the Preparation of Asymmetric Bi-, Tri-, and Tetra-Antennary N-Glycans from a Common Precursor

Ivan A. Gagarinov†, Tiehai Li, Javier Sastre Toraño†, Tomislav Caval, Apoorva D. Srivastava, John A. W. Kruijtzer, Albert J. R. Heck, and Geert-Jan Boons

Graphical abstract
Abstract Image
 

 

 

 

 

 

 

Progress in glycoscience is hampered by a lack of well-defined complex oligosaccharide standards that are needed to fabricate the next generation of microarrays, to develop analytical protocols to determine exact structures of isolated glycans, and to elucidate pathways of glycan biosynthesis. We describe here a chemoenzymatic methodology that makes it possible, for the first time, to prepare any bi-, tri-, and tetra-antennary asymmetric N-glycan from a single precursor. It is based on the chemical synthesis of a tetra-antennary glycan that has N-acetylglucosamine (GlcNAc), N-acetyllactosamine (LacNAc), and unnatural Galα(1,4)-GlcNAc and Manβ(1,4)-GlcNAc appendages. Mammalian glycosyltransferases recognize only the terminal LacNAc moiety as a substrate, and thus this structure can be uniquely extended. Next, the β-GlcNAc terminating antenna can be converted into LacNAc by galactosylation and can then be enzymatically modified into a complex structure. The unnatural α-Gal and β-Man terminating antennae can sequentially be decaged by an appropriate glycosidase to liberate a terminal β-GlcNAc moiety, which can be converted into LacNAc and then elaborated by a panel of glycosyltransferases. Asymmetric bi- and triantennary glycans could be obtained by removal of a terminal β-GlcNAc moiety by treatment with β-N-acetylglucosaminidase and selective extension of the other arms. The power of the methodology is demonstrated by the preparation of an asymmetric tetra-antennary N-glycan found in human breast carcinoma tissue, which represents the most complex N-glycan ever synthesized. Multistage mass spectrometry of the two isomeric triantennary glycans uncovered unique fragment ions that will facilitate identification of exact structures of glycans in biological samples.

Richard's paper

Rapid Asymmetric Synthesis of Disubstituted Allenes by Coupling of Flow-Generated Diazo Compounds and Propargylated Amines

Jian-Siang Poh, Szabolcs Makai, Timo von Keutz, Dr. Duc N. Tran, Dr. Claudio Battilocchio, Dr. Patrick Pasau, Prof. Steven V. Ley

Graphical abstract

Scheme 1.

 

 

 

 

 

 

 

 

We report herein the asymmetric coupling of flow-generated unstabilized diazo compounds and propargylated amine derivatives, using a new pyridinebis(imidazoline) ligand, a copper catalyst and base. The reaction proceeds rapidly, generating chiral allenes in 10–20 minutes with high enantioselectivity (89–98 % de/ee), moderate yields and a wide functional group tolerance.

Richards paper

Room-Temperature Coupling/Decarboxylation Reaction of α-Oxocarboxylates with α-Bromoketones: Solvent-Controlled Regioselectivity for 1,2- and 1,3-Diketones

Zhen He†, Xiaotian Qi‡, Zhijie She†, Yinsong Zhao†, Shiqing Li†, Junbin Tang†, Ge Gao*† , Yu Lan*‡, and Jingsong You

Graphical abstract

Abstract Image

 

 

 

 

 

A transition-metal-free and room-temperature coupling/decarboxylation reaction between α-oxocarboxylates and α-bromoketones is reported herein. It represents the first mild and regioselective synthesis of either 1,2- or 1,3-diketones from the same starting materials. Notably, the regioselectivity is simply controlled by solvents. The preliminary experimental data and DFT calculations suggest sequential Darzens-type coupling, alkaline hydrolysis, KOH-promoted oxirane opening and decarboxylation in one pot. This method is efficient for the synthesis of α,β-epoxy-γ-butyrolactone and curcuminoids.

Lola's paper

Asymmetric Catalysis of the Carbonyl-Amine Condensation: Kinetic Resolution of Primary Amines

Sayantani Das, Nilanjana Majumdar, Chandra Kanta De, Dipti Sankar Kundu, Arno Döhring, Anika Garczynski, and Benjamin List

Graphical abstract

Abstract Image

 

 

 

 

 

 

A Brønsted acid catalyzed kinetic resolution of primary amines is described that is based on the condensation between an amine and a carbonyl compound. 1,3-Diketones react with racemic α-branched amines to furnish the corresponding enantioenriched enaminone and recovered starting material. Good to excellent enantioselectivity was observed with both aromatic and aliphatic primary amines. This process represents the first small-molecule catalyzed kinetic resolution of aliphatic amines.

Christine's paper

Frustrated Lewis Acid/Brønsted Base Catalysts for Direct Enantioselective α-Amination of Carbonyl Compounds

Ming Shang, Xiaoxu Wang, Seung Moh Koo, Jennifer Youn, Jessica Z. Chan, Wenzhi Yao, Brian T. Hastings, and Masayuki Wasa

Graphical abstract

Abstract Image

 

 

 

 

 

A method for enantioselective direct α-amination reaction catalyzed by a sterically “frustrated” Lewis acid/Brønsted base complex is disclosed. Cooperative functioning of the Lewis acid and Brønsted base components gives rise to in situ enolate generation from monocarbonyl compounds. Subsequent reaction with hydrogen-bond activated dialkyl azodicarboxylates delivers α-aminocarbonyl compounds in high enantiomeric purity.

27/01/2017

Christian's paper

Cobalt-Catalyzed Enantio- and Diastereoselective Intramolecular Hydroacylation of Trisubstituted Alkenes

Dr. Junfeng Yang, Dr. Alice Rérat, Yang Jie Lim, Dr. Corinne Gosmini, Prof. Naohiko Yoshikai

Graphical abstract

Scheme 1

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Enantio- and diastereoselective synthesis of trans-2,3-disubstituted indanones is achieved by intramolecular hydroacylation of 2-alkenylbenzaldehydes bearing trisubstituted alkenyl groups under cobalt-chiral diphosphine catalysis. Notably, a high level of enantioselectivity is induced regardless of the stereochemistry (E/Z ratio) of the alkenyl group of the starting material. Deuterium-labeling experiments shed light on the productive reaction pathways of the E- and Z-isomers.

Youssef's paper

Oxidative Entry into the Illicium Sesquiterpenes: Enantiospecific Synthesis of (+)-Pseudoanisatin

Kevin Hung§, Matthew L. Condakes§, Takahiro Morikawa, and Thomas J. Maimone

Graphical abstract

Abstract Image

Illicium sesquiterpenes have been the subject of numerous synthetic efforts due to their ornate and highly oxidized structures as well as significant biological activities. Herein we report the first chemical synthesis of (+)-pseudoanisatin from the abundant feedstock chemical cedrol (∼$50 USD/kg) in 12 steps using extensive site-selective C(sp3)–H bond functionalization. Significantly, this work represents a novel oxidative strategic template for future approaches to these natural products and their analogs.

February

03/02/2017

Youssef's paper

Catalytic Asymmetric Bromocyclization of Polyenes

Ramesh C. Samanta* and Hisashi Yamamoto*

Graphical abstract

Abstract Image

 

 

 

 

 

 

The first catalytic asymmetric bromonium ion-induced polyene cyclization has been achieved by using a chiral BINOL-derived thiophosphoramide catalyst and 1,3-dibromo-5,5-dimethylhydantoin as an electrophilic bromine source. Bromocyclization products are obtained in high yields, with good enantiomeric ratios and high diastereoselectivity, and are abundantly found as scaffolds in natural products.

Adrian's paper

Cobalt-catalysed C–H carbonylative cyclisation of aliphatic amides

Patrick Williamson, Alicia Galvána and Matthew J. Gaunt

Graphical abstract

Graphical abstract: Cobalt-catalysed C–H carbonylative cyclisation of aliphatic amides

A cobalt-catalysed C–H carbonylation of aliphatic carboxamide derivatives is described, employing commercially available Co(II)-salts in the presence of a silver oxidant. This operationally simple process utilises an atmospheric pressure of CO and generates a range of substituted succinimide products bearing diverse functional groups that can be successfully accessed via this methodology.

Pol's paper

Water-Enabled Catalytic Asymmetric Michael Reactions of Unreactive Nitroalkenes: One-Pot Synthesis of Chiral GABA-Analogs with All-Carbon Quaternary Stereogenic Centers

Jae Hun Sim, Prof. Choong Eui Song

Graphical abstract

Figure 1.

Water enables new catalytic reactions for otherwise unreactive substrate systems. Under the “on water” reaction conditions, extremely unreactive β,β-disubstituted nitroalkenes smoothly underwent enantioselective Michael addition reactions with dithiomalonates using a chiral squaramide catalyst, affording both enantiomers of highly enantioenriched Michael adducts with all-carbon-substituted quaternary centers. The developed “on water” protocol was successfully applied for the scalable one-pot syntheses of chiral GABA analogs with all-carbon quaternary stereogenic centers at the β-position, which might show highly interesting pharmaceutical properties.

Christian's paper

Unique physicochemical and catalytic properties dictated by the B3NO2 ring system

Hidetoshi Noda, Makoto Furutachi, Yasuko Asada, Masakatsu Shibasaki & Naoya Kumagai

Graphical abstract

Chemical space for six-membered heterocycles composed of B, C, N and O atoms and the structure of DATBs.

The expansion of molecular diversity beyond what nature can produce is a fundamental objective in chemical sciences. Despite the rich chemistry of boron-containing heterocycles, the 1,3-dioxa-5-aza-2,4,6-triborinane (DATB) ring system, which is characterized by a six-membered B3NO2 core, remains elusive. Here, we report the synthesis of m-terphenyl-templated DATB derivatives, displaying high stability and peculiar Lewis acidity arising from the three suitably arranged boron atoms. We identify a particular utility for DATB in the dehydrative amidation of carboxylic acids and amines, a reaction of high academic and industrial importance. The three boron sites are proposed to engage in substrate assembly, lowering the entropic cost of the transition state, in contrast with the operative mechanism of previously reported catalysts and amide coupling reagents. The distinct mechanistic pathway dictated by the DATB core will advance not only such amidations, but also other reactions driven by multisite activation.

10/02/2017

Wouter's paper

Chemical Stabilization of Unnatural Nucleotide Triphosphates for the in Vivo Expansion of the Genetic Alphabet

Aaron W. Feldman, Vivian T. Dien, and Floyd E. Romesberg

Graphical abstsract

Abstract Image

 

We have developed an unnatural base pair (UBP) and a semisynthetic organism (SSO) that imports the constituent unnatural nucleoside triphosphates and uses them to replicate DNA containing the UBP. However, propagation of the UBP is at least in part limited by the stability of the unnatural triphosphates, which are degraded by cellular and secreted phosphatases. To circumvent this problem, we now report the synthesis and evaluation of unnatural triphosphates with their β,γ-bridging oxygen replaced with a difluoromethylene moiety, yielding dNaMTPCF2and dTPT3TPCF2. We find that although dNaMTPCF2 cannot support in vivo replication, likely due to poor polymerase recognition, dTPT3TPCF2 can, and moreover, its increased stability can contribute to increased UBP retention. The data demonstrate the promise of this chemical approach to SSO optimization, and suggest that other modifications should be sought that confer phosphatase resistance without interfering with polymerase recognition.

Richard's paper

Pd-Catalyzed Conversion of Aryl Iodides to Sulfonyl Fluorides Using SO2 Surrogate DABSO and Selectfluor

Ariana L. Tribby†, Ismeraí Rodríguez†, Shamira Shariffudin‡, and Nicholas D. Ball

Graphical abstsract

Abstract Image

A one-pot Pd-catalyzed conversion of aryl iodide to aryl sulfonyl fluorides using DABSO and selectfluor has been developed generating aryl sulfonyl fluorides in good to excellent yields. The reaction results in the generation of electronically and sterically diverse sulfonyl fluorides. Additionally, sulfonyl fluorides can be converted to aryl sulfonamides and sulfonic esters using Cs2CO3 under mild conditions.

Christian's paper

The development and mechanistic investigation of a palladium-catalyzed 1,3-arylfluorination of chromenes

Richard T. Thornbury,a Vaneet Saini,b Talita de A. Fernandes,ac Celine B. Santiago,d Eric P. A. Talbot,ab Matthew S. Sigman,d Jeffrey M. McKennab and F. Dean Toste

Graphical abstsract

Graphical abstract: The development and mechanistic investigation of a palladium-catalyzed 1,3-arylfluorination of chromenes

 

 

 

 

 

A mild palladium-catalyzed ligand-controlled regioselective 1,3-arylfluorination of 2[H]-chromenes has been developed. The products with a syn-1,3 substitution pattern were obtained with high enantiomeric excess using a PyrOx ligand, wherein the utility of these pyranyl-fluorides was further demonstrated through their participation in a diastereoselective C–C bond forming reaction. Ligand dependent divergent formation of both the 1,3- and 1,2- alkene difunctionalization products was observed. The nature of this bifurcation was investigated through experimental studies in combination with computational and statistical analysis tools. Ultimately, the site selectivity was found to rely on ligand denticity and metal electrophilicity, the electronics of the boronic acid, and the donor ability of the directing group in the substrate.

 

17/02/2017

Richard's paper

Visible Light Copper Photoredox-Catalyzed Aerobic Oxidative Coupling of Phenols and Terminal Alkynes: Regioselective Synthesis of Functionalized Ketones via C≡C Triple Bond Cleavage

Arunachalam Sagadevan, Vaibhav Pramod Charpe, Ayyakkannu Ragupathi, and Kuo Chu Hwang

Graphical abstract

Abstract Image

Direct oxidative coupling of phenols and terminal alkynes was achieved at room temperature by a visible-light-mediated copper-catalyzed photoredox process. This method allows regioselective synthesis of hydroxyl-functionalized aryl and alkyl ketones from simple phenols and phenylacetylene via C≡C triple bond cleavage. 47 examples were presented. From a synthetic perspective, this protocol offers an efficient synthetic route for the preparation of pharmaceutical drugs, such as pitofenone and fenofibrate.

Lukas's paper

Chemoselective Acylation of Primary Amines and Amides with Potassium Acyltrifluoroborates under Acidic Conditions

Alberto Osuna Gálvez, Cédric P. Schaack, Hidetoshi Noda, and Jeffrey W. Bode*

Graphical abstract

Abstract Image

Current methods for constructing amide bonds join amines and carboxylic acids by dehydrative couplings—processes that usually require organic solvents, expensive and often dangerous coupling reagents, and masking other functional groups. Here we describe an amide formation using primary amines and potassium acyltrifluoroborates promoted by simple chlorinating agents that proceeds rapidly in water. The reaction is fast at acidic pH and tolerates alcohols, carboxylic acids, and even secondary amines in the substrates. It is applicable to the functionalization of primary amides, sulfonamides, and other N-functional groups that typically resist classical acylations and can be applied to late-stage functionalizations.

Christian's paper

Light-Driven Enantioselective Organocatalytic β-Benzylation of Enals

Dr. Luca Dell'Amico, Dr. Victor M. Fernández-Alvarez, Prof. Dr. Feliu Maseras, Prof. Dr. Paolo Melchiorre

Graphical abstract

Figure 1.

A photochemical organocatalytic strategy for the direct enantioselective β-benzylation of α,β-unsaturated aldehydes is reported. The chemistry capitalizes upon the light-triggered enolization of 2-alkyl-benzophenones to afford hydroxy-o-quinodinomethanes. These fleeting intermediates are stereoselectively intercepted by chiral iminium ions, transiently formed upon condensation of a secondary amine catalyst with enals. Density functional theory (DFT) studies provided an explanation for why the reaction proceeds through an unconventional Michael-type addition manifold, instead of a classical cycloaddition mechanism and subsequent ring-opening.

24/02/2017

Wouter's paper

Azido and Tetrazolo 1,2,4,5-Tetrazine N-Oxides

Dr. David E. Chavez, Dr. Damon A. Parrish, Dr. Lauren Mitchell, Dr. Greg H. Imler

Graphical abstract

Figure 1.

 

This study presents the synthesis and characterization of the oxidation products of 3,6-diazido-1,2,4,5-tetrazine (1) and 6-amino-[1,5-b]tetrazolo-1,2,4,5-tetrazine (2). 3,6-Diazido-1,2,4,5-tetrazine-1,4-dioxide was produced from oxidation with peroxytrifluoroacetic acid, and more effectively using hypofluorous acid, and 2 can be oxidized to two different products, 6-amino-[1,5-b]tetrazolo-1,2,4,5-tetrazine mono-N-oxide and di-N-oxide. These N-oxide compounds display promising performance properties as energetic materials.

Lukas's paper

Catalytic Asymmetric Intramolecular [4+2] Cycloaddition of In Situ Generated ortho-Quinone Methides

Dr. Youwei Xie, Prof. Dr. Benjamin List

Graphical abstract

Figure 1.

 

 

 

 

 

Herein, we describe the first catalytic asymmetric intramolecular [4+2] cycloaddition of in situ generated ortho-quinone methides. In the presence of a confined chiral imidodiphosphoric acid catalyst, various salicylaldehydes react with dienyl alcohols to give transient ortho-quinone methide intermediates, which undergo an intramolecular [4+2] cycloaddition to provide highly functionalized furanochromanes and pyranochromanes in excellent diastereoselectivity and enantioselectivity.

Pol's paper

Highly Regio- and Enantioselective Vicinal Dihalogenation of Allyl Amides

Bardia Soltanzadeh†, Arvind Jaganathan‡, Yi Yi†, Hajoon Yi†, Richard J. Staples†, and Babak Borhan

Graphical abstract

Abstract Image

 

We report a highly regio-, diastereo- and enantioselective vicinal dihalogenation of allyl amides. E- and Z-alkenes with both aryl and alkyl substituents were compatible with this chemistry. This is the result of exquisite catalyst controlled regioselectivity enabling use of electronically unbiased substrates. The reaction employs commercially available catalysts and halenium sources along with cheap inorganic halide salts to affect this transformation. A preliminary effort to extend this chemistry to heterodihalogenation is also presented.

March

03/03/2017

Adrian's paper

Construction of a visible light-driven hydrocarboxylation cycle of alkenes by the combined use of Rh(I) and photoredox catalysts

Kei Murata,a Nobutsugu Numasawa,a Katsuya Shimomaki,a Jun Takayaa and Nobuharu Iwasawa*a

Graphical abstract

Graphical abstract: Construction of a visible light-driven hydrocarboxylation cycle of alkenes by the combined use of Rh(i) and photoredox catalysts

A visible light driven catalytic cycle for hydrocarboxylation of alkenes with CO2 was established using a combination of a Rh(I) complex as a carboxylation catalyst and [Ru(bpy)3]2+ (bpy = 2,2′- bipyridyl) as a photoredox catalyst. Two key steps, the generation of Rh(I) hydride species and nucleophilic addition of π-benzyl Rh(I) species to CO2, were found to be mediated by light.

Christian's paper

Radical-polar crossover reactions of vinylboron ate complexes

Marvin Kischkewitz1, Kazuhiro Okamoto2, Christian Mück-Lichtenfeld1, Armido Studer

Graphical abstract

Vinyl boronic esters are valuable substrates for Suzuki-Miyaura cross-coupling reactions. However, boron-substituted alkenes have drawn little attention as radical acceptors, and the radical chemistry of vinylboron ate complexes is underexplored. We show here that carbon radicals add efficiently to vinylboron ate complexes and that their adduct radical anions undergo radical-polar crossover: A 1,2-alkyl/aryl shift from boron to the α-carbon sp2 center provides secondary or tertiary alkyl boronic esters. In contrast to the Suzuki-Miyaura coupling, a transition metal is not required, and two carbon-carbon bonds are formed. The valuable boronic ester moiety remains in the product and can be used in follow-up chemistry, enlarging the chemical space of the method. The cascade uses commercial starting materials and provides access to perfluoroalkylated alcohols, γ-lactones, γ-hydroxy alkylnitriles, and compounds bearing quaternary carbon centers.

 

10/03/2017

Lola's paper

Tf2NH-Catalyzed Formal [3 + 2] Cycloaddition of Ynamides with Dioxazoles: A Metal-Free Approach to Polysubstituted 4-Aminooxazoles

Yingying Zhao†‡§, Yancheng Hu†§, Chunxiang Wang†, Xincheng Li*†, and Boshun Wan

Graphical abstract

Abstract Image

An unprecedented Tf2NH-catalyzed formal [3 + 2] cycloaddition of ynamides with dioxazoles was developed to construct various polysubstituted 4-aminooxazoles. This approach features a metal-free catalytic bimolecular assembly of oxazole motifs, a low-cost catalyst, exceptionally mild reaction conditions, a very short reaction time, a broad substrate scope, and high efficiency. This metal-free protocol may find applications in pharmaceutical-oriented synthesis.

17/03/2017

Wouter's paper

Application of Methyl Bisphosphine-Ligated Palladium Complexes for Low Pressure N-11C-Acetylation of Peptides

Thomas L. Andersen, Dr. Patrik Nordeman, Heidi F. Christoffersen, Dr. Hélène Audrain, Prof. Dr. Gunnar Antoni, Prof. Dr. Troels Skrydstrup

Graphical abstract

Scheme 1.

A mild and effective method is described for 11C-labeling of peptides selectively at the N-terminal nitrogen or at internal lysine positions. The presented method relies on the use of specific biphosphine palladium–methyl complexes and their high reactivity towards amino-carbonylation of amine groups in the presence [11C]carbon monoxide. The protocol facilitates the production of native N-11C-acetylated peptides, without any structural modifications and has been applied to a selection of bioactive peptides.

Hossay's paper

Catalytic Asymmetric Diamination of Styrenes

Kilian Muñiz*†‡ , Laura Barreiro†§, R. Martín Romero†§, and Claudio Martínez

Graphical abstract

Abstract Image

 

 

 

 

 

 

An enantioselective catalytic vicinal diamination of styrenes is reported, which proceeds under entirely intermolecular reaction control. It relies on a chirally modified aryliodine(I) catalyst and proceeds within an iodine(I/III) manifold with conventional 3-chloroperbenzoic acid as a terminal oxidant. An environmentally benign solvent combination not only adds to the attractiveness of the process but also slows down the rate of the undesired background reaction. A total of 30 examples are presented, which consistently provide high enantiomeric excesses in the range 91–98%.

Pol's paper

Metal-Free Intermolecular Aminoarylation of Alkynes

Pauline T. G. Rabet, Scott Boyd, Prof. Michael F. Greaney

Graphical abstract

Scheme 1.

A metal-free aminoarylation of internal alkynes is described, yielding tetrasubstituted enaminoates. The transformation proceeds in good to excellent yields through a tandem conjugate addition/Smiles rearrangement involving aryl and heteroaryl sulfonamides. Substrate scope is very broad under simple, user-friendly conditions, and the reaction can be used to easily access biologically active phenethylamine derivatives.

 

24/03/2017

Pol's paper 

Photosensitizer-Free, Gold-Catalyzed C–C Cross-Coupling of Boronic Acids and Diazonium Salts Enabled by Visible Light

Sina Witzel, Jin Xie, Matthias Rudolph, A. Stephen K. Hashmi

Graphical abstract

Scheme 1.

The first photosensitizer-free visible light-driven, gold-catalyzed C–C cross-couplings of arylboronic acids and aryldiazonium salts are reported. The reactions can be conducted under very mild conditions, using a catalytic amount of tris(4-trifluoromethyl)phosphinegold(I) chloride [(4-CF3-C6H4)3PAuCl] with methanol as the solvent allowing an alternative access to a variety of substituted biaryls in moderate to excellent yields with broad functional group tolerance.

Wouter's paper

Chlorodifluoromethane-triggered formation of difluoromethylated arenes catalysed by palladium

Zhang Feng, Qiao-Qiao Min, Xia-Ping Fu, Lun An & Xingang Zhang

Graphical abstract

A catalytic approach to difluoromethylated arenes using ClCF2H.

 

 

 

 

 

Difluoromethylated aromatic compounds are of increasing importance in pharmaceuticals, agrochemicals and materials. Chlorodifluoromethane (ClCF2H), an inexpensive, abundant and widely used industrial raw material, represents the ideal and most straightforward difluoromethylating reagent, but introduction of the difluoromethyl group (CF2H) from ClCF2H into aromatics has not been reported. Here, we describe a direct palladium-catalysed difluoromethylation method for coupling ClCF2H with arylboronic acids and esters to generate difluoromethylated arenes with high efficiency. The reaction exhibits a remarkably broad substrate scope, including heteroarylboronic acids, and was used for difluoromethylation of a range of pharmaceuticals and biologically active compounds. Preliminary mechanistic studies revealed that a palladium difluorocarbene intermediate is involved in the reaction. Although numerous metal–difluorocarbene complexes have been prepared, the catalytic synthesis of difluoromethylated or difluoromethylenated compounds involving metal–difluorocarbene complexes has not received much attention. This new reaction therefore also opens the door to understand metal–difluorocarbene complex catalysed reactions.

31/03/2017

Adrian‘s paper

Copper-catalyzed direct alkylation of heteroarenes

Cédric Theunissen,a Jianjun Wanga and Gwilherm Evano

Graphical abstract

Graphical abstract: Copper-catalyzed direct alkylation of heteroarenes

An efficient and broadly applicable process is reported for the direct alkylation of C–H bonds in heteroarenes, privileged scaffolds in many areas of science. This reaction is based on the copper-catalyzed addition of alkyl radicals generated from activated secondary and tertiary alkyl bromides to a wide range of arenes, including furans, thiophenes, pyrroles, and their benzo-fused derivatives, as well as coumarins and quinolinones.

Wouter’s paper

Ligand-Promoted meta-C−H Functionalization of Benzylamines

Dr. Peng Wang, Marcus E. Farmer, Prof. Dr. Jin-Quan Yu

Graphical abstract

Scheme 1.

 

 

 

 

 

 

Meta-C−H functionalization of benzylamines has been developed using a PdII/transient mediator strategy. Using 2-pyridone ligands and 2-carbomethoxynorbornene (NBE-CO2Me) as the mediator, arylation, amination, and chlorination of benzylamines are realized. This protocol features a broad substrate scope and is compatible with heterocylic coupling partners. Moreover, the loading of the Pd can be lowered to 2.5 mol % by using the optimal ligand.

Christian’ paper

Remote site-selective C–H activation directed by a catalytic bifunctional template

Zhipeng Zhang, Keita Tanaka & Jin-Quan Yu

Graphical abstract


Design of a cooperative bimetallic approach for remote, site-selective C–H activation.

 

 

 

In chemical syntheses, the activation of carbon–hydrogen (C–H) bonds converts them directly into carbon–carbon or carbon–heteroatom bonds without requiring any prior functionalization. C–H activation can thus substantially reduce the number of steps involved in a synthesis. A single specific C–H bond in a substrate can be activated by using a ‘directing’ (usually a functional) group to obtain the desired product selectively1, 2, 3, 4, 5. The applicability of such a C–H activation reaction can be severely curtailed by the distance of the C–H bond in question from the directing group, and by the shape of the substrate, but several approaches have been developed to overcome these limitations6, 7, 8, 9, 10, 11, 12. In one such approach, an understanding of the distal and geometric relationships between the functional groups and C–H bonds of a substrate has been exploited to achieve meta-selective C–H activation by using a covalently attached, U-shaped template13, 14, 15, 16, 17. However, stoichiometric installation of this template has not been feasible in the absence of an appropriate functional group on which to attach it. Here we report the design of a catalytic, bifunctional nitrile template that binds a heterocyclic substrate via a reversible coordination instead of a covalent linkage. The two metal centres coordinated to this template have different roles: one reversibly anchors substrates near the catalyst, and the other cleaves remote C–H bonds. Using this strategy, we demonstrate remote, site-selective C–H olefination of heterocyclic substrates that do not have the necessary functional groups for covalently attaching templates.

April

15/04/2016

Wouter's paper

Catalytic Coupling between Unactivated Aliphatic C–H Bonds and Alkynes via a Metal–Hydride Pathway

Yan Xu†‡, Michael C. Young‡, and Guangbin Dong

Graphical abstract

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We report a Rh(I)-catalyzed site-selective coupling between ketone β-C(sp3)–H bonds and aliphatic alkynes using an in situ-installed directing group. Upon hydrogenation or hydration, various β-alkylation or β-aldol products of the ketones are obtained with broad functional group tolerance. Mechanistic investigations support the involvement of a Rh–H intermediate through oxidative addition of Rh(I) into the β-C–H bonds. Thus, to the best of our knowledge, this transformation represents the first example of catalytic couplings between unsaturated hydrocarbons and unactivated aliphatic C–H bonds via a metal–hydride pathway.

Lola's paper

Potassium bromide catalyzed N-S bond formation via oxidative dehydrogenation

Tian-Qun Yua, 1, Yong-Sheng Houa, 1, Yi Jianga, 1, Wen-Xuan Xua, 1, Tao Shia, Xia Wua, Jin-Chao Zhanga, Dian Hea, , , Zhen Wang

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N-substituted benzo[d]isothiazol-3(2H)-ones are a family of compounds with extremely important application. Recently, we have developed a new green pathway to synthesize these compounds via potassium bromide-catalyzed intramolecular oxidative dehydrogenative cyclization. This reaction has high functional group tolerance and affords excellent yield even in gram scale.

Pol's paper

Mechanism and Origins of Stereoselectivity in the Cinchona Thiourea- and Squaramide-Catalyzed Asymmetric Michael Addition of Nitroalkanes to Enones

Matthew N. Grayson

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We report density functional theory calculations that examine the mechanism and origins of stereoselectivity of Soós’ landmark discovery from 2005 that cinchona thioureas catalyze the asymmetric Michael addition of nitroalkanes to enones. We show that the electrophile is activated by the catalyst’s protonated amine and that the nucleophile binds to the thiourea moiety by hydrogen bonding. These results lead to the correction of published mechanistic work which did not consider this activation mode. We have also investigated the corresponding cinchona squaramide-catalyzed reaction and found that it proceeds by the same mechanism despite the differences in the geometry of the two catalysts’ hydrogen-bond-donating groups, which demonstrates the generality of this mechanistic model.

 

May

05/05/2017

Wouter's paper

Remote carboxylation of halogenated aliphatic hydrocarbons with carbon dioxide

Francisco Juliá-Hernández, Toni Moragas, Josep Cornella & Ruben Martin

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Switchable site-selective catalytic carboxylation at remote sp3 C–H sites.

Catalytic carbon–carbon bond formation has enabled the streamlining of synthetic routes when assembling complex molecules1. It is particularly important when incorporating saturated hydrocarbons, which are common motifs in petrochemicals and biologically relevant molecules. However, cross-coupling methods that involve alkyl electrophiles result in catalytic bond formation only at specific and previously functionalized sites2. Here we describe a catalytic method that is capable of promoting carboxylation reactions at remote and unfunctionalized aliphatic sites with carbon dioxide at atmospheric pressure. The reaction occurs via selective migration of the catalyst along the hydrocarbon side-chain3 with excellent regio- and chemoselectivity, representing a remarkable reactivity relay when compared with classical cross-coupling reactions. Our results demonstrate that site-selectivity can be switched and controlled, enabling the functionalization of less-reactive positions in the presence of a priori more reactive ones. Furthermore, we show that raw materials obtained in bulk from petroleum processing, such as alkanes and unrefined mixtures of olefins, can be used as substrates. This offers an opportunity to integrate a catalytic platform en route to valuable fatty acids by transforming petroleum-derived feedstocks directly4.

Lola's paper

Multiple Approaches to the In Situ Generation of Anhydrous Tetraalkylammonium Fluoride Salts for SNAr Fluorination Reactions

Megan A. Cismesia†, Sarah J. Ryan†, Douglas C. Bland‡, and Melanie S. Sanford*

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This article focuses on the development of practical approaches to the in situ generation of anhydrous fluoride salts for applications in nucleophilic aromatic substitution (SNAr) reactions. We report herein that a variety of combinations of inexpensive nucleophiles (e.g., tetraalkylammonium cyanide and phenoxide salts) and fluorine-containing electrophiles (e.g., acid fluoride, fluoroformate, benzenesulfonyl fluoride, and aryl fluorosulfonate derivatives) are effective for this transformation. Ultimately, we demonstrate that the combination of tetramethylammonium 2,6-dimethylphenoxide and sulfuryl fluoride (SO2F2) serves as a particularly practical route to anhydrous tetramethylammonium fluoride. This procedure is applied to the SNAr fluorination of a range of electron-deficient aryl and heteroaryl chlorides as well as nitroarenes.

Richard's paper

Atroposelective Synthesis of Axially Chiral Biaryls by Palladium-Catalyzed Asymmetric C−H Olefination Enabled by a Transient Chiral Auxiliary

Qi-Jun Yao, Shuo Zhang, Bei-Bei Zhan, Prof. Dr. Bing-Feng Shi

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Atroposelective synthesis of axially chiral biaryls by palladium-catalyzed C−H olefination, using tert-leucine as an inexpensive, catalytic, and transient chiral auxiliary, has been realized. This strategy provides a highly efficient and straightforward access to a broad range of enantioenriched biaryls in good yields (up to 98 %) with excellent enantioselectivities (95 to >99 % ee). Kinetic resolution of trisubstituted biaryls bearing sterically more demanding substituents is also operative, thus furnishing the optically active olefinated products with excellent selectivity (95 to >99 % ee, s-factor up to 600).

12/05/2017

Youssef's paper

Synthesis of Anthropomorphic Molecules:  The NanoPutians

Stephanie H. Chanteau and James M. Tour

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Described here are the synthetic details en route to an array of 2-nm-tall anthropomorphic molecules in monomeric, dimeric, and polymeric form. These anthropomorphic figures are called, as a class, NanoPutians. Using tools of chemical synthesis, the ultimate in designed miniaturization can be attained while preparing the most widely recognized structures:  those that resemble humans.

Adrian's paper

Pyridine sulfinates as general nucleophilic coupling partners in palladium-catalyzed cross-coupling reactions with aryl halides

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Graphical abstract: Pyridine sulfinates as general nucleophilic coupling partners in palladium-catalyzed cross-coupling reactions with aryl halides

 

 

 

Pyridine rings are ubiquitous in drug molecules; however, the pre-eminent reaction used to form carbon–carbon bonds in the pharmaceutical industry, the Suzuki–Miyaura cross-coupling reaction, often fails when applied to these structures. This phenomenon is most pronounced in 2-substituted pyridines, and results from the difficulty in preparing, the poor stability of, and low efficiency in reactions of pyridine-2-boronates. We demonstrate that by replacing these boronates with pyridine-2-sulfinates, a cross-coupling process of unrivalled scope and utility is realized. The corresponding 3- and 4-substituted pyridine variants are also efficient coupling partners. In addition, we apply these sulfinates in a library format to the preparation of medicinally relevant derivatives of the drugs varenicline (Chantix) and mepyramine (Anthisan).

Pol's paper

A Highly Stereoselective Synthesis of Tetrahydrofurans

Johannes Appun, Dr. Michael Boomhoff, Patrick Hoffmeyer, Isa Kallweit, Maik Pahl, Prof. Dr. Detlev Belder, Prof. Dr. Christoph Schneider

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The development of a direct and highly stereoselective synthesis of 2,3,5-substituted tetrahydrofurans has been accomplished through a combination of batch- and microchip-MS-experiments. This sequential transformation comprises a Lewis acid-mediated reaction of bis(silyl) dienediolate 1 and a broad range of aldehydes, furnishing products with three new σ-bonds and three stereogenic centers in a one-pot process with typically good yields and excellent stereoselectivity. Key steps which have been elucidated primarily with microchip-MS-experiments include a vinylogous aldol reaction and a Prins-type cyclization. Furthermore, a titanium BINOL complex is a powerful chiral catalyst for this process. The products were further converted into bi- and tricylic products by carbonyl–ene reactions, proceeding with excellent yields and diastereoselectivity.

19/05/2017

Pol's paper

Meta-C‒H Arylation and Alkylation of Benzylsulfonamide Enabled by a Pd(II)/Isoquinoline Catalyst

Jin-Quan Yu, Guolin Cheng, Peng Wang

No graphical abstract available yet

Palladium(II)-catalyzed meta-C‒H arylation and alkylation of benzylsulfonamide using 2-carbomethoxynorbornene (NBE-CO2Me) as a transient mediator are realized using a newly developed electron-deficient directing group and isoquinoline as a ligand. This protocol features broad substrate scope and good functional group tolerance. The meta-substituted benyzlsulfonamide can be readily transformed to sodium sulfonate, sulfonate ester, sulfonamide, as well as styrenes via Julia-type olefination. The unique impact of the isoquinoline ligand underscores the importance of subtle matching between ligands and the directing groups.

Richard's paper

One-Step Annulative π-Extension of Alkynes with Dibenzosiloles or Dibenzogermoles by Palladium/o-chloranil Catalysis

Dr. Kyohei Ozaki, Keiichiro Murai, Wataru Matsuoka, Dr. Katsuaki Kawasumi, Dr. Hideto Ito, Prof. Dr. Kenichiro Itami

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Reliable and short synthetic routes to polycyclic aromatic hydrocarbons and nanographenes are important in materials science. Herein, we report an efficient one-step annulative π-extension reaction of alkynes that provides access to diarylphenanthrenes and related nanographene precursors. In the presence of a cationic palladium/o-chloranil catalyst system and dibenzosiloles or dibenzogermoles as π-extending agents, a variety of diarylacetylenes are transformed successfully into 9,10-diarylphenanthrenes in a single step with good functional-group tolerance. Furthermore, double π-extension reactions of 1,4-bis(phenylethynyl)benzene and diphenyl-1,3-butadiyne are demonstrated, affording oligoarylene products, which show potential for application in the synthesis of larger polycyclic aromatic hydrocarbons and nanographenes.