Meetings by month
The activation mode of a rotaxane-based organocatalyst with both secondary amine and squaramide catalytic units can be switched with acid or base. The macrocycle blocks whichever of the catalytic sites it is positioned over. The switchable rotaxane catalyst generates different products from a mixture of three building blocks according to the location of the macrocyclic ring in the rotaxane.
Elvis J. M. Maduli, Steven J. Edeson, Stephen Swanson, Panayiotis A. Procopiou and Joseph P. A. Harrity
A Cu-promoted cyclization of 2-nitrophenyl iodoacetylenes provides a direct route to a range of 2-iodoisatogens. These compounds represent useful intermediates for the late-stage elaboration of the C–I bond to furnish isatins and a range of alternative heterocyclic products.
Narayanaganesh Balasubramanian, Tanmay Mandal and Gregory R. Cook
The general and efficient palladium-catalyzed indium-mediated allylation of chiral hydrazones was accomplished with excellent yield (72–92%) and diastereoselectivity (up to 99:1). The development of this reaction and the substrate scope are described. The conversion was found to be proportional to the phosphine concentration, which provided insight into the mechanism and competing pathways of the redox transmetalation process.
Oleksandr O. Kovalenko, Alexey Volkov and Hans Adolfsson
Diethylzinc (Et2Zn) can be used as an efficient and chemoselective catalyst for the reduction of tertiary amides under mild reaction conditions employing cost-effective polymeric silane (PMHS) as the hydride source. Crucial for the catalytic activity was the addition of a substoichiometric amount of lithium chloride to the reaction mixture. A series of amides containing different additional functional groups were reduced to their corresponding amines, and the products were isolated in good-to-excellent yields.
Charlotte E. Allen, Peter R. Curran, Andrew S. Brearley, Valerie Boissel, Lilya Sviridenko, Neil J. Press,Jeffrey P. Stonehouse and Alan Armstrong
A kinetic template-guided tethering (KTGT) strategy has been developed for the site-directed discovery of fragments that bind to defined protein surfaces, where acrylamide-modified fragments can be irreversibly captured in a protein-templated conjugate addition reaction. Herein, an efficient and facile method is reported for the preparation of acrylamide libraries from a diverse range of amine fragments using a solid-supported quaternary amine base.
Amay J. Bandodkar, Wenzhao Jia, Ceren Yardımcı, Xuan Wang, Julian Ramirez and Joseph Wang
We present a proof-of-concept demonstration of an all-printed temporary tattoo-based glucose sensor for noninvasive glycemic monitoring. The sensor represents the first example of an easy-to-wear flexible tattoo-based epidermal diagnostic device combining reverse iontophoretic extraction of interstitial glucose and an enzyme-based amperometric biosensor. In-vitro studies reveal the tattoo sensor’s linear response toward physiologically relevant glucose levels with negligible interferences from common coexisting electroactive species. The iontophoretic-biosensing tattoo platform is reduced to practice by applying the device on human subjects an d moni toring variations in glycemic levels due to food consumption. Correlation of the sensor response with that of a commercial glucose meter underscores the promise of the tattoo sensor to detect glucose levels in a noninvasive fashion. Control on-body experiments demonstrate the importance of the reverse iontophoresis operation and validate the sensor specificity. This preliminary investigation indicates that the tattoo-based iontophoresis-sensor platform holds considerable promise for efficient diabetes management and can be extended toward noninvasive monitoring of other physiologically relevant analytes present in the interstitial fluid.
Kim Søholm Halskov, Florian Kniep, Vibeke Henriette Lauridsen, Eva Høgh Iversen, Bjarke Skyum Donslund and Karl Anker Jørgensen
A novel organocatalytic activation mode of cyclopropanes is presented. The reaction concept is based on a design in which a reactive donor–acceptor cyclopropane intermediate is generated by in situ condensation of cyclopropylacetaldehydes with an aminocatalyst. The mechanism of this enamine-based activation of cyclopropylacetaldehydes is investigated by the application of a combined computational and experimental approach. The activation can be traced to a favorable orbital interaction between the π–orbital of the enamine and the σ*C–C orbital of the cyclopropyl ring. Furthermore, the synthetic potential of the developed system has been evaluated. By the application of a chiral secondary amine catalyst, the organocatalytically activated cyclopropanes show an unexpected and highly stereoselective formation of cyclobutanes, functionalizing at the usually inert sites of the donor–acceptor cyclopropane. By the application of 3-olefinic oxindoles and benzofuranone, biologically relevant spirocyclobutaneoxindoles and spirocyclobutanebenzofuranone can be obtained in good yields, high diastereomeric ratios, and excellent enantiomeric excesses. The mechanism of the reaction is discussed and two mechanistic proposals are presented.
Wouter's & Lola's paper
Olaf Cussó, Xavi Ribas, Julio Lloret-Fillol and Miquel Costas
Highly enantioselective epoxidation of α-substituted styrenes with aqueous H2O2 is described by using a chiral iron complex as the catalyst and N-protected amino acids (AAs) as coligands. The amino acids synergistically cooperate with the iron center in promoting an efficient activation of H2O2 to catalyze epoxidation of this challenging class of substrates with good yields and stereoselectivities (up to 97 % ee) in short reaction times.
James and Alex 's paper
Markus Lindqvist, Katja Borre, Kirill Axenov,Bianka Kótai, Martin Nieger, Markku Leskelä,Imre Pápai and Timo Repo
We report the synthesis and reactivity of a chiral aminoborane displaying both rapid and reversible H2 activation. The catalyst shows exceptional reactivity in asymmetric hydrogenation of enamines and unhindered imines with stereoselectivities of up to 99% ee. DFT analysis of the reaction mechanism pointed to the importance of both repulsive steric and stabilizing intermolecular non-covalent forces in the stereodetermining hydride transfer step of the catalytic cycle.
Ji Hye Kim, Ilija Čorić, Chiara Palumbo and Benjamin List
A highly enantioselective kinetic resolution of diols via asymmetric acetalization has been achieved using a chiral confined imidodiphosphoric acid catalyst. The reaction is highly efficient for the resolution of tertiary alcohols, giving selectivity factors of up to >300. Remarkably, even in cases where the selectivity factors are only moderate, highly enantioenriched diols are obtained via a stereodivergent resolution to diastereomeric acetals.
Kate D. Otley and Jonathan A. Ellman
The development of a method for the Rh(III)-catalyzed direct vinylation of an aromatic C–H bond to give functionalized styrenes in good yield, using vinyl acetate as a convenient and inexpensive vinyl source, is reported. High functional group tolerance is demonstrated for electronically distinct arenes as well as different directing groups. Mechanistic investigation resulted in the characterization of a novel rhodium–metallacycle, which represents the first X-ray structure of a [1,2]-Rh(III)-alkenyl addition adduct.
Stephanie C.M. Dorn, Andrew K. Olsen, Rachel E. Kelemen, Ruja Shrestha and Daniel J. Weix
The direct, regioselective, and stereoselective arylation of activated alkynes with aryl iodides using a nickel catalyst and manganese reductant is described. The reaction conditions are mild (40 °C in MeOH, no acid or base) and an intermediate organomanganese reagent is unlikely. Functional groups tolerated include halides and pseudohalides, free and protected anilines, and a benzyl alcohol. Other activated alkynes including an amide and a ketone also reacted to form arylated products in good yields.
Long Chen, Yi Du, Xing-Ping Zeng, Tao-Da Shi, Feng Zhou and Jian Zhou
A one-pot tandem Wittig/conjugate reduction/Paal–Knorr reaction is reported for the synthesis of di- or trisubstituted furans. This novel sequence first demonstrates the possibility of successively recycling waste from upstream steps to catalyze downstream reactions.
Hong-Ping Deng, Dong Wang and Kálmán J. Szabó
Allylboronates undergo C–H allylation of unsubstituted or monosubstituted benzoquinone and naphthoquinone substrates. In the case of 2,5- or 2,6-disubstituted quinones addition involving the substituted carbon takes place. Allylation with stereodefined allylboronates occurs with retention of the configuration.
Harshkumar H. Patel and Matthew S. Sigman
We report a highly enantioselective intermolecular Heck reaction of alkenyl triflates and acyclic primary or racemic secondary alkenols. The mild reaction conditions permit installation of a wide range of alkenyl groups at positions β, γ, or δ to a carbonyl group in high enantioselectivity. The success of this reaction is attributed to the use of electron-withdrawing alkenyl triflates, which offer selective β-hydride elimination followed by migration of the catalyst through the alkyl chain to give the alkenylated carbonyl products. The synthetic utility of the process is demonstrated by a two-step modification of a reaction product to yield a tricyclic core structure, present in various natural products.
Janes and Olga's paper
Michael L. Conner , Yao Xu and M. Kevin Brown
Catalytic enantioselective [2 + 2] cycloadditions between allenoates and alkenes is disclosed. The method functions well for a variety of alkenes, and the products are generated with excellent levels of enantioselectivity. One of the most significant aspects of the present method is that unactivated alkenes are suitable substrates for this method, which is distinctly different from nearly all other catalytic enantioselective [2 + 2] cycloaddition methods.
Søren Kramer and Gregory C. Fu
Due in part to the common occurrence of five-membered nitrogen heterocycles in bioactive molecules, the discovery of methods for the enantioselective synthesis of such structures is a useful endeavor. Building on a single example by Tong of a phosphine-catalyzed [4 + 1] annulation of an amine with an allene that furnished an achiral dihydropyrrole in 22% yield, we have developed, with the aid of a new chiral spirophosphine catalyst, a method with increased utility, specifically, improved yield, enhanced scope (the use of γ-substituted allenes), and good ee. The enantioenriched dihydropyrrole products can be transformed into other interesting families of compounds with very good stereoselectivity.
Shihui Liu, Ying Hu, Pengfei Qian, Yanwei Hu, Guizhen Ao, Shaohua Chen, Shilei Zhang, Yinan Zhang
Dibenzoxazepine and its derivatives is considered the most well-known heterocycles that are ubiquitous in pharmaceuticals and agrochemicals. It has also been shown that even one of its prevalent synthetic precursor dibenzoxazepinone possesses a broad spectrum of biological activities, such as anti-HIV reverse transcriptase, antipsychotics, anti-biotics, and liver X receptor antagonist. The synthetic strategy to this precursor is mainly composed of a step-by-step procedure, in which the diaryl ether is firstly produced and then followed by an intramolecular ring closing reaction to form the amide bond, or vice versa (eq 1). The typical reactions in this procedure include amide coupling, nucleophilic aromatic substitution, and transition-metal coupling.
Chenfei Zhao and Daniel Seidel
Pyrrolidine and related amines undergo asymmetric A3 reactions in the presence of copper iodide and an easily accessible cocatalyst possessing both a carboxylic acid and a thiourea moiety. Propargylamines are obtained with up to 96% ee, and catalyst loadings can be as low as 1 mol %. Pyrrolidine-derived propargylamines, in the absence of directing grLola's [oups, can be transformed to the corresponding allenes without loss of enantiopurity.
Qiaobin Liang, Ping Xing ‡, Zuogang Huang, Jiajia Dong, K. Barry Sharpless, Xiaoxian Li and Biao Jiang
Aryl fluorosulfates were prepared by a simple method and employed as coupling partners in the Suzuki–Miyaura reaction. The cross-coupling reactions were performed in water under air at room temperature without ligands or additives such as surfactants or phase-transfer reagents and proceeded smoothly to give excellent yields. Aryl fluorosulfates could also be used as alternatives to halides or triflates in other coupling reactions.
Zhoutong Sun, Richard Lonsdale, Xu-Dong Kong, Jian-He Xu, Jiahai Zhou and Manfred T. Reetz
Directed evolution based on saturation mutagenesis at sites lining the binding pocket is a commonly practiced strategy for enhancing or inverting the stereoselectivity of enzymes for use in organic chemistry or biotechnology. However, as the number of residues in a randomization site increases to five or more, the screening effort for 95 % library coverage increases astronomically until it is no longer feasible. We propose the use of a single amino acid for saturation mutagenesis at superlarge randomization sites comprising 10 or more residues. When used to reshape the binding pocket of limonene epoxide hydrolase, this strategy, which drastically reduces the search space and thus the screening effort, resulted in R,R- and S,S-selective mutants for the hydrolytic desymmetrization of cyclohexene oxide and other epoxides. X-ray crystal structures and docking studies of the mutants unveiled the source of stereoselectivity and shed light on the mechanistic intricacies of this enzyme.
Interligand Interactions Dictate the Regioselectivity of trans-Hydrometalations and Related Reactions Catalyzed by [Cp*RuCl]. Hydrogen Bonding to a Chloride Ligand as a Steering Principle in Catalysis
Stephan M. Rummelt, Karin Radkowski, Dragoş-Adrian Roşca and Alois Fürstner
Reactions of internal alkynes with R3M–H (M = Si, Ge, Sn) follow an unconventional trans-addition mode in the presence of [Cp*Ru(MeCN)3]PF6 (1) as the catalyst; however, the regioselectivity is often poor with unsymmetrical substrates. This problem can be solved upon switching to a catalyst comprising a [Ru–Cl] bond, provided that the acetylene derivative carries a protic functional group. The R3M unit is then delivered with high selectivity to the alkyne-C atom proximal to this steering substituent. This directing effect originates from the ability of the polarized [Ru–Cl] bond to engage in hydrogen bonding with the protic substituent, which helps upload, activate, and lock the alkyne within the coordination sphere. An additional interligand contact of the chloride with the −MR3 center positions the incoming reagent in a matching orientation that translates into high regioselectivity. The proposed secondary interactions within the loaded catalyst are in line with a host of preparative and spectral data and with the structures of the novel ruthenium π-complexes 10 and 11 in the solid state. Moreover, the first X-ray structure of a [Ru(σ-stannane)] complex (12a) is presented, which indeed features peripheral Ru–Cl···MR3 contacts; this adduct also corroborates that alkyne trans-addition chemistry likely involves σ-complexes as reactive intermediates. Finally, it is discussed that interligand cooperativity might constitute a more general principle that extends to mechanistically distinct transformations. The presented data therefore make an interesting case for organometallic chemistry that provides inherently better results when applied to substrates containing unprotected rather than protected −OH, −NHR, or −COOH groups.
Jing Li , Jing Zhang , Haibo Tan , and David Zhigang Wang
Mild and direct C–H bond functionalizations and vinylations of tetrahydrofuran with alkynes have been accomplished through visible light photocatalysis, yielding a range of vinyl tetrahydrofurans under the synergistic actions of organic dye-type photocatalyst eosin Y, tert-butyl hydroperoxide (t-BuOOH), and a 45 W household lightbulb. A significant kinetic isotope effect (KIE) was recorded, which helps shed light on the mechanistic course.
Jennifer V. Obligacion , Jamie M. Neely , Aliza N. Yazdani , Iraklis Pappas , and Paul J. Chirik
A bis(imino)pyridine cobalt-catalyzed hydroboration of terminal alkynes with HBPin (Pin = pinacolate) with high yield and (Z)-selectivity for synthetically valuable vinylboronate esters is described. Deuterium labeling studies, stoichiometric experiments, and isolation of catalytically relevant intermediates support a mechanism involving selective insertion of an alkynylboronate ester into a Co–H bond, a pathway distinct from known precious metal catalysts where metal vinylidene intermediates have been proposed to account for the observed (Z) selectivity. The identity of the imine substituents dictates the relative rates of activation of the cobalt precatalyst with HBPin or the terminal alkyne and, as a consequence, is responsible for the stereochemical outcome of the catalytic reaction
Simon Breitler and Erick M. Carreira
The use of formaldehyde N,N-dialkylhydrazones as neutral C1-nucleophiles in the iridium-catalyzed substitution of allylic carbonates is described for two processes. Kinetic resolution or, alternatively, stereospecific substitution affords configurationally stable α,α-disubstituted aldehyde hydrazones in high enantiomeric excess and yield. This umpolung approach allows for the construction of optically active allylic nitriles and dithiolanes as well as branched α-aryl aldehydes. A catalyst-controlled reaction with Enders’ chiral hydrazone derivatives followed by diastereoselective nucleophilic addition to the hydrazone products constitutes a two-step stereodivergent synthesis of chiral amines.
Elizabeth H. Krenske, Sarah Lam, Jerome P. L. Ng, Brian Lo, Sze Kui Lam, Pauline Chiu and Kendall N. Houk
Silyl-triflate-catalyzed (4+3) cycloadditions of epoxy enolsilanes with dienes provide a mild and chemoselective synthetic route to seven-membered carbocycles. Epoxy enolsilanes containing a terminal enolsilane and a single stereocenter undergo cycloaddition with almost complete conservation of enantiomeric purity, a finding that argues against the involvement of oxyallyl cation intermediates which have been previously proposed for these types of reactions. Reported are theoretical and experimental investigations of the cycloaddition mechanism. The major enantiomers of the cycloadducts are derived from SN2-like reactions of the silylated epoxide with the diene, in which stereospecific ring opening and formation of the two new C-C bonds occur in a single step. Calculations predict, and experiments confirm, that the observed small losses of enantiomeric purity are traced to a triflate-mediated double SN2 cycloaddition pathway.
Michael W. Danneman , Ki Bum Hong and Jeffrey N. Johnston
Doubly intermolecular alkene diamination is achieved with electron-rich, terminal alkenes through the use of a hypervalent iodine (PhI(OAc)2) reagent, iodide, and electron-rich amines. Mono- and disubstituted amines combine with electron-rich alkenes, particularly o-hydroxystyrenes, to achieve the greatest level of generality. This operationally straightforward protocol, unreliant on conventional metal-based activation, is compatible with a broad range of functional groups.
Li Wang , Ravish K. Akhani and Sheryl L. Wiskur
The silylation-based kinetic resolution of trans 2-arylcyclohexanols was accomplished by employing a triaryl silyl chloride as the derivatizing reagent with a commercially available isothiourea catalyst. The methodology is selective for the trans diastereomer over the cis, which provides an opportunity to selectively derivatize one stereoisomer out of a mixture of four. By employing this technology, a facile, convenient method to form a highly enantiomerically enriched silylated alcohol was accomplished through a one-pot reduction–silylation sequence that started with a 2-aryl-substituted ketone.
Andrei Dragan, Tomasz M. Kubczyk, Julian H. Rowley, Stephen Sproules and Nicholas C. O. Tomkinson
Malonoyl peroxide 7, prepared in a single step from the commercially available diacid, is an effective reagent for the oxidation of aromatics. Reaction of an arene with peroxide 7 at room temperature leads to the corresponding protected phenol which can be unmasked by aminolysis. An ionic mechanism consistent with the experimental findings and supported by isotopic labeling, Hammett analysis, EPR investigations, and reactivity profile studies is proposed.
Courtney C. Roberts, Desirée M. Matías, Matthew J. Goldfogel and Simon J. Meek
The activation of carbodicarbene (CDC)–Rh(I) pincer complexes by secondary binding of metal salts is reported for the catalytic site-selective hydro-heteroarylation of dienes (up to 98% yield and >98:2 γ:α). Reactions are promoted by 5 mol % of a readily available tridentate (CDC)–Rh complex in the presence of an inexpensive lithium salt. The reaction is compatible with a variety of terminal and internal dienes and tolerant of ester, alkyl halide, and boronate ester functional groups. X-ray data and mechanistic experiments provide support for the role of the metal salts on catalyst activation and shed light on the reaction mechanism. The increased efficiency (120 to 22 °C) made available by catalytic amounts of metal salts to catalysts containing C(0) donors is a significant aspect of the disclosed studies.
Oleg V. Fedorov, Mikhail D. Kosobokov, Vitalij V. Levin, Marina I. Struchkova and Alexander D. Dilman
A method for the difluorohomologation of ketones accompanied by halogenation of a C–H bond is described. The reaction involves silylation, difluorocarbene addition using Me3SiCF2Br activated by a bromide ion, and halogenation of intermediate cyclopropanes with N-bromo- orN-iodosuccinimide. The whole process is performed without isolation of intermediates. The resulting α,α-difluoro-β-halo-substituted ketones can be readily converted into fluorine containing pyrazole derivatives and oxetanes.
Yamin Zhu, Mengdi Zhao, Wenkui Lu, Linyi Li and Zengming Shen
A novel approach to the Cu-catalyzed cyanation of simple arenes using acetonitrile as an attractive cyano source has been documented. The C–H functionalization of arenes without directing groups involves a sequential iodination/cyanation to give the desired aromatic nitriles in good yields. A highly efficient Cu/TEMPO system for acetonitrile C–CN bond cleavage has been discovered. TEMPO is used as a cheap oxidant and enables the reaction to be catalytic in copper. Moreover, TEMPOCH2CN 6 has been identified as the active cyanating agent and shows high reactivity for forming the −CN moiety.
Anne B. Neef, Lucile Pernot, Verena N. Schreier, Leonardo Scapozza and Nathan W. Luedtke
Pathogen-selective labeling was achieved by using the novel gemcitabine metabolite analogue 2′-deoxy-2′,2′-difluoro-5-ethynyluridine (dF-EdU) and click chemistry. Cells infected with Herpes Simplex Virus-1 (HSV-1), but not uninfected cells, exhibit nuclear stainin g u pon the addition of dF-EdU and a f luorescent azide. The incorporation of the dF-EdU into DNA depends on its phosphorylation by a herpes virus thymidine kinase (TK). Crystallographic analyses revealed how dF-EdU is well accommodated in the active site of HSV-1 TK, but steric clashes prevent dF-EdU from binding human TK. These results provide the first example of pathogen-enzyme-dependent incorporation and labeling of bioorthogonal functional groups in human cells..
Jinghan Gui, Chung-Mao Pan, Ying Jin, Tian Qin, Julian C. Lo, Bryan J. Lee, Steven H. Spergel, Michael E. Mertzman, William J. Pitts, Thomas E. La Cruz, Michael A. Schmidt, Nitin Darv,Swaminathan R. Natarajan and Phil S. Baran
The synthesis and functionalization of amines are fundamentally important in a vast range of chemical contexts. We present an amine synthesis that repurposes two simple feedstock building blocks: olefins and nitro(hetero)arenes. Using readily available reactants in an operationally simple procedure, the protocol smoothly yields secondary amines in a formal olefin hydroamination. Because of the presumed radical nature of the process, hindered amines can easily be accessed in a highly chemoselective transformation. A screen of more than 100 substrate combinations showcases tolerance of numerous unprotected functional groups such as alcohols, amines, and even boronic acids. This process is orthogonal to other aryl amine syntheses, such as the Buchwald-Hartwig, Ullmann, and classical amine-carbonyl reductive aminations, as it tolerates aryl halides and carbonyl compounds.
Masahiro Abo and Eranthie Weerapana
Cysteine residues are subject to diverse modifications, such as oxidation, nitrosation, and lipidation. The resulting loss in cysteine reactivity can be measured using electrophilic chemical probes, which importantly provide the stoichiometry of modification. An iodoacetamide (IA)-based chemical probe has been used to concurrently quantify reactivity changes in hundreds of cysteines within cell lysates. However, the cytotoxicity of the IA group precludes efficient live-cell labeling, which is important for preserving transient cysteine modifications. To overcome this limitation, a caged bromomethyl ketone (BK) electrophile was developed, which shows minimal cytotoxicity and provides spatial and temporal control of electrophile activation through irradiation. The caged-BK probe was utilized to monitor cysteine reactivity changes in A431 cells upon epidermal growth factor (EGF)-stimulated release of cellular reactive oxygen species. Decreased reactivity was observed for cysteines known to form sulfenic acids and redox-active disulfides. Importantly, the caged-BK platform provided the first quantification of intracellular disulfide bond formation upon EGF stimulation. In summary, the caged-BK probe is a powerful tool to identify reactivity changes associated with diverse cysteine modifications, including oxidation, metal chelation, and inhibitor binding, within a physiologically relevant context.
Dillon H. Miles , Joan Guasch , and F. Dean Toste
The enantioselective addition of anilines to azoalkenes was accomplished through the use of a chiral phosphoric acid catalyst. The resulting α-arylamino hydrazones were obtained in good yields and excellent enantioselectivities and provide access to enantioenriched α-arylamino ketones. A serendipitous kinetic resolution of racemic α-arylamino hydrazones is also described.
Hai T. Dao, Chao Li, Quentin Michaudel, Brad D. Maxwell and Phil S. Baran
A solution to the classic unsolved problem of olefin hydromethylation is presented. This highly chemoselective method can tolerate labile and reactive chemical functionalities and uses a simple set of reagents. An array of olefins, including mono-, di-, and trisubstituted olefins, are all smoothly hydromethylated. This mild protocol can be used to simplify the synthesis of a specific target or to directly “edit” complex natural products and other advanced materials. The method is also amenable to the simple installation of radioactive and stable labeled methyl groups.
Zhi Yang, Mingdong Zhong, Xiaoli Ma, Susmita De, Chakkittakandiyil Anusha, Pattiyil Parameswaran and Herbert W. Roesky
The reaction of [LAlH2] (L=HC(CMeNAr)2, Ar=2,6-iPr2C6H3) with MeOTf (Tf=SO2CF3) resulted in the formation of [LAlH(OTf)] (1) in high yield. The triflate substituent in 1 increases the positive charge at the aluminum center, which implies that 1 has a strong Lewis acidic character. The excellent catalytic activity of 1 for the hydroboration of organic compounds with carbonyl groups was investigated. Furthermore, it was shown that 1 effectively initiates the addition reaction of trimethylsilyl cyanide (TMSCN) to both aldehydes and ketones. Quantum mechanical calculations were carried out to explore the reaction mechanism.
Stephen A Davis, Benjamin M Vincent, Matthew M Endo, Luke Whitesell, Karen Marchillo, David R Andes, Susan Lindquist and Martin D Burke
Drugs that act more promiscuously provide fewer routes for the emergence of resistant mutants. This benefit, however, often comes at the cost of serious off-target and dose-limiting toxicities. The classic example is the antifungal amphotericin B (AmB), which has evaded resistance for more than half a century. We report markedly less toxic amphotericins that nevertheless evade resistance. They are scalably accessed in just three steps from the natural product, and they bind their target (the fungal sterol ergosterol) with far greater selectivity than AmB. Hence, they are less toxic and far more effective in a mouse model of systemic candidiasis. To our surprise, exhaustive efforts to select for mutants resistant to these more selective compounds revealed that they are just as impervious to resistance as AmB. Thus, highly selective cytocidal action and the evasion of resistance are not mutually exclusive, suggesting practical routes to the discovery of less toxic, resistance-evasive therapies.
Thomas P. Blaisdell and James P. Morken
A hydroxyl functional group positioned β to a pinacol boronate can serve to direct palladium-catalyzed cross-coupling reactions. This feature can be used to control the reaction site in multiply borylated substrates and can activate boronates for reaction that would otherwise be unreactive.
Srinivas Samala, Gajendra Singh, Ravi Kumar, Ravi Sankar Ampapathi and Bijoy Kundu
A one pot synthesis of 1H-benzo[g]indoles, tetrahydrobenzo[h]quinolines, and naphtho[1,2-b]azepines from 2-alkynyl benzaldehydes and cyclic amino acids is reported. The salient feature of the strategy involves formation of three new bonds (one C-N and two C-C bonds) by a metal-free decarboxylation/cyclization/one-carbon ring expansion sequence in one pot..
Fedor Romanov-Michailidis , Kassandra F. Sedillo , Jamie M. Neely , and Tomislav Rovis
α,β-Unsaturated oxime pivalates are proposed to undergo reversible C(sp2)–H insertion with cationic Rh(III) complexes to furnish five-membered metallacycles. In the presence of 1,1-disubstituted olefins, these species participate in irreversible migratory insertion to give, after reductive elimination, 2,3-dihydropyridine products in good yields. Catalytic hydrogenation can then be used to convert these molecules into piperidines, which are important structural components of numerous pharmaceuticals.
Nicholas A. White and Tomislav Rovis
An unprecedented N-heterocyclic carbene (NHC)-catalyzed annulation of enals to form 3,4-disubstituted cyclopentanones has been discovered. Aryl enals undergo dimerization in the presence of a single-electron oxidant to form C2 symmetric cyclopentanones. A cross-reaction has also been developed, allowing for the synthesis of differentially substituted cyclopentanones. Mechanistically, the reaction is thought to proceed through radical intermediates, further establishing the synthetic utility of this class of reactivity.
James C. Anderson *, Joshua P. Barham , and Christopher D. Rundell
Reductive cyclization of 2-iminonitrostyrenes (from the condensation of 2-aminostyrenes with an aldehyde and subsequent nitration of the alkene) using a bifunctional thiourea catalyst and tert-butyl-Hantzsch ester leads to an intramolecular conjugate hydride addition nitro-Mannich reaction to give the corresponding cis-2-aryl-3-nitrotetrahydroquinolines as single diastereoisomers in high yields and enantioselectivities.
Aaron C. Sather, Hong Geun Lee, James R. Colombe, Anni Zhang and Stephen L. Buchwald
Contemporary organic chemists employ a broad range of catalytic and stoichiometric methods to construct molecules for applications in the material sciences, and as pharmaceuticals agrochemicals, and sensors. The utility of a synthetic method may be greatly reduced if it relies on a glove box to enable the use of air- and moisture-sensitive reagents or catalysts. Furthermore, many synthetic chemistry laboratories have numerous containers of partially used reagents that have been spoiled by exposure to the ambient atmosphere. This is exceptionally wasteful from both an environmental and a cost perspective. Here we report an encapsulation method for stabilizing and storing air- and moisture-sensitive compounds. We demonstrate this approach in three contexts, by describing single-use capsules that contain all of the reagents (catalysts, ligands, and bases) necessary for the glove-box-free palladium-catalysed carbon–fluorine carbon–nitrogen, and carbon–carbon bond-forming reactions. This strategy should reduce the number of error-prone, tedious and time-consuming weighing procedures required for such syntheses and should be applicable to a wide range of reagents, catalysts, and substrate combinations.
Yoichiro Kuninobu, Haruka Ida, Mitsumi Nishi and Motomu Kanai
Regioselective C–H bond transformations are potentially the most efficient method for the synthesis of organic molecules. However, the presence of many C–H bonds in organic molecules and the high activation barrier for these reactions make these transformations difficult. Directing groups in the reaction substrate are often used to control regioselectivity, which has been especially successful for the ortho-selective functionalization of aromatic substrates. Here, we describe an iridium-catalysed meta-selective C–H borylation of aromatic compounds using a newly designed catalytic system. The bipyridine-derived ligand that binds iridium contains a pendant urea moiety. A secondary interaction between this urea and a hydrogen-bond acceptor in the substrate places the iridium in close proximity to the meta-C–H bond and thus controls the regioselectivity. 1H NMR studies and control experiments support the participation of hydrogen bonds in inducing regioselectivity. Reversible direction of the catalyst through hydrogen bonds is a versatile concept for regioselective C–H transformations.
Christopher C. Nawrat, Christopher R. Jamison, Yuriy Slutskyy, David W. C. MacMillan and Larry E. Overman
Alkyl oxalates are new bench-stable alcohol-activating groups for radical generation under visible light photoredox conditions. Using these precursors, the first net redox-neutral coupling of tertiary and secondary alcohols with electron-deficient alkenes is achieved.
Luca & James' paper
Rauful Alam, Tobias Vollgraff, Lars Eriksson and Kálmán J. Szabó
Allylboration of ketones with γ-disubstituted allylboronic acids is performed in the presence of chiral BINOL derivatives. The reaction is suitable for single-step creation of adjacent quaternary stereocenters with high selectivity. We show that, with an appropriate choice of the chiral catalyst and the stereoisomeric prenyl substrate, full control of the stereo- and enantioselectivity is possible in the reaction.
Christine Gally, Bettina M. Nestl and Bernhard Hauer
The asymmetric dihydroxylation of olefins is of special interest due to the facile transformation of the chiral diol products into valuable derivatives. Rieske non-heme iron oxygenases (ROs) represent promising biocatalysts for this reaction as they can be engineered to efficiently catalyze the selective mono- and dihydroxylation of various olefins. The introduction of a single point mutation improved selectivities (≥95 %) and conversions (>99 %) towards selected alkenes. By modifying the size of one active site amino acid side chain, we were able to modulate the regio- and stereoselectivity of these enzymes. For distinct substrates, mutants displayed altered regioselectivities or even favored opposite enantiomers compared to the wild-type ROs, offering a sustainable approach for the oxyfunctionalization of a wide variety of structurally different olefins.
Chi “Chip Le and David W. C. MacMillan
In this study we demonstrate that molecular fragments, which can be readily coupled via a simple, in situ RO—C═OR bond-forming reaction, can subsequently undergo metal insertion–decarboxylation–recombination to generate Csp2–Csp3 bonds when subjected to metallaphotoredox catalysis. In this embodiment the conversion of a wide variety of mixed anhydrides (formed in situ from carboxylic acids and acyl chlorides) to fragment-coupled ketones is accomplished in good to high yield. A three-step synthesis of the medicinal agent edivoxetine is also described using this new decarboxylation–recombination protocol.
Ying He, Zhenyu Yang, Richard T. Thornbury and F. Dean Toste
The development of an enantioselective palladium-catalyzed 1,1-fluoroarylation of unactivated aminoalkenes is described. The reaction uses arylboronic acids as the arene source and Selectfluor as the fluorine source to generate benzylic fluorides in good yields with excellent enantioselectivities. This transformation, likely proceeding through an oxidative Heck mechanism, affords 1,1-difunctionalized alkene products.
Ramona Pirwerdjan, Peter Becker and Carsten Bolm
N-Alkynylated sulfoximines undergo smooth transformations with benzoic acids and sulfonamides under mild conditions affording the corresponding hydroacyloxylation or hydroamination products. The transformations proceed in the absence of catalysts or additional reagents in short reaction times generating the products in excellent yields and very high stereoselectivities.
Rambabu N. Reddi, Pragati K. Prasad and Arumugam Sudala
A novel, N-heterocyclic carbene (NHC) catalyzed direct oxidative coupling of styrenes with aldehydes has been described for the synthesis of α,β-epoxy ketones in good yields. This unprecedented regioselective oxidative coupling employs NBS/DBU/DMSO (DBU=1,8-diazabicyclo [5.4. 0] undec-7-ene, DMSO=dimethylsulfoxide, NBS=N-bromosuccinimide) as an oxidative system at ambient conditions. Additionally, first NHC-catalyzed Darzens reaction of α-bromoketones and aldehydes under mild reaction conditions has also been described. Interestingly, mechanistic studies have revealed the preferred reactivity of NHC with alkene/α-bromoketone rather than aldehydes, thus proceeding via the ketodeoxy Breslow intermediate.
Yan Xu, Guobing Yan, Zhi Ren and Guangbin Dong
Site-selective C−H functionalization has emerged as an attractive tool for derivatizing complex synthetic intermediates, but its use for late-stage diversification is limited by the functional groups that can be introduced, especially at unactivated sp3-hybridized positions. To overcome this, we introduce a strategy that directly installs a sulfonyloxy group at a β-C−H bond of a masked alcohol and subsequently employs nucleophilic substitution reactions to prepare various derivatives. Hydroxyl groups are widely found in bioactive molecules and are thus readily available as synthetic handles. A directing group is easily added (and subsequently removed) from the alcohols such that a formal site-selective β-C−H sulfonyloxylation of these alcohols is achieved. Substitution reactions with carbon, nitrogen, oxygen and other nucleophiles then lead to diverse functionalizations that may help to streamline the synthesis of complex analogues for drug discovery.
Achim Link, Christian Fischer and Christof Sparr
A direct transformation of carboxylic acid esters into arenes with 1,5-bifunctional organomagnesium reagents is described. This efficient and practical method enables the one-step defunctionalization of various carboxylic acid esters to prepare benzene, anthracene, tetracene, and pentacene derivatives. A double nucleophilic addition of the 1,5-organodimagnesium reagent to the ester is followed by an immediate 1,4-elimination reaction that leads to the direct [5+1] formation of a new aromatic ring.
Eileen G. Burke and Jennifer M. Schomaker
Regioselectivity in the aziridination of silyl-substituted homoallenic sulfamates is readily diverted to the distal double bond of the allene to yield endocyclic bicyclic methyleneaziridines with excellent stereocontrol. Subsequent reaction with electrophilic oxygen sources initiates facile rearrangement to densely functionalized, fused azetidin-3-ones in excellent d.r., effectively transferring the axial chirality of the allene to central chirality in the products. The steric nature of the silyl group dictates which of the two rings of the fused azetidin-3-one will undergo further functionalization, providing an additional element of diversity for the preparation of enantioenriched azetidine scaffolds with potential biological activity.
Shuhei Sumino, Takahito Ui, Yuki Hamada, Takahide Fukuyama, and Ilhyong Ryu
A carbonylative Mizoroki–Heck reaction using alkyl iodides was achieved with a Pd/photoirradiation system using DBU as a base. In this reaction, alkyl radicals were formed from alkyl iodides via single-electron transfer (SET) and then underwent a sequential addition to CO and alkenes to give β-keto radicals. It is proposed that DBU would abstract a proton α to carbonyl to form radical anions, giving α,β-unsaturated ketones via SET.
Dr. Takuji Kawamoto, Aoi Sato, Prof.Dr. IIhyong Ryu
Transition metal-catalyzed aminocarbonylation of aryl halides with CO and amines, pioneered by Heck and co-workers in the 1970s, is among the most commonly employed reactions to make aromatic amides. A catalyst-free aminocarbonylation of aryl iodides with CO and amines, which simply uses photoirradiation conditions by Xe-lamp, has now been developed. This methodology shows broad functional-group tolerance, including that of heteroaromatic amides. A hybrid radical/ionic chain mechanism, involving electron transfer from zwitterionic radical intermediates generated by nucleophilic attack of amines to aroyl radicals, is proposed.
Melissa Lee and Melanie S. Sanford
This Communication describes the terminal-selective, Pt-catalyzed C(sp3)–H oxidation of aliphatic amines without the requirement for directing groups. CuCl2 is employed as a stoichiometric oxidant, and the reactions proceed in high yield at Pt loadings as low as 1 mol%. These transformations are conducted in the presence of sulfuric acid, which reacts with the amine substrates in situ to form ammonium salts. We propose that protonation of the amine serves at least three important roles: (i) it renders the substrates soluble in the aqueous reaction medium; (ii) it limits binding of the amine nitrogen to Pt or Cu; and (iii) it electronically deactivates the C–H bonds proximal to the nitrogen center. We demonstrate that this strategy is effective for the terminal-selective C(sp3)–H oxidation of a variety of primary, secondary, and tertiary amines.
Aziz Sancar and W. Dean Rupp
The uvrA, uvrB, and uvrC proteins of Escherichia coli were purified from strains that greatly overproduce these proteins. Using the purified proteins, the UVRABC nuclease was reconstituted in vitro. The reconstituted enzyme acted specifically on DNA damaged with UV, cis-platinum, and psoralen plus near UV. When UV-irradiated DNA was used as substrate, the enzyme made two cuts on the damaged DNA strand, one on each side of the damaged region. The enzyme hydrolyzed the eighth phosphodiester bond on the 5’ side of pyrimidine dimers. On the 3’ side of pyrimidine dimers, the UVRABC nuclease cut the fourth or the fifth phosphodiester bond 3’ to pyrimidine dimers. The oligonucleotide with th e damaged ba ses that is generated by these two cuts was released during treatment with the enzyme. We have also obtained evidence suggesting that the enzyme acts by the same mechanism on PydC photoproducts which are thought to be of primary importance in UV-induced mutagenesis.
Yining Ji, R. Erik Plata, Christopher S. Regens, Michael Hay, Michael Schmidt, Thomas Razler, Yuping Qiu, Peng Geng, Yi Hsiao, Thorsten Rosner, Martin D. Eastgate and Donna G. Blackmond
Kinetic, spectroscopic, crystallographic, and computational studies probing a Pd-catalyzed C–H arylation reaction reveal that mono-oxidation of the bis-phosphine ligand is critical for the formation of the active catalyst. The bis-phosphine mono-oxide is shown to be a hemilabile, bidentate ligand for palladium. Isolation of the oxidative addition adduct, with structural elucidation by X-ray analysis, showed that the mono-oxide was catalytically competent, giving the same reaction rate in the productive reaction as the Pd(II)/xantphos precursor. A dual role for the carboxylate base in both catalyst activation and reaction turnover was demonstrated, along with the inhibiting effect of excess phosphine ligand. The generality of the role of phosphine mono-oxide complexes in Pd-catalyzed coupling processes is discussed.
Kazuki Maeda, Takuma Terada, Takahiro Iwamoto, Takuya Kurahashi and Seijiro Matsubara
A new efficient synthetic route to unsymmetrically substituted dihydropyridine scaffolds via dehydrative [4 + 2] cycloaddition of N-tosylated α,β-unsaturated imines with aldehydes has been developed. This transformation is enabled by (i) the remarkable catalytic ability of the cationic Ru(IV) porphyrin complex to activate both the imino and carbonyl groups and (ii) the hydrophobic nature of the porphyrin ligand, which helps realize robust Lewis acidity in the dehydrative cycloaddition.
Alexander Bechtoldt, Carina Tirler, Keshav Raghuvanshi, Svenja Warratz, Christoph Kornhaa and Prof. Dr. Lutz Ackermann
Ruthenium(II) oxidase catalysis by direct dioxygen-coupled turnover enabled step-economical oxidative C-H alkenylation reactions at ambient pressure. Versatile ruthenium(II) biscarboxylate catalysts displayed ample substrate scope and proved applicable to weakly coordinating and removable directing groups. The twofold C-H functionalization strategy was characterized by exceedingly mild reaction conditions as well as excellent positional selectivity.
Anne Mai Wassermann, Eugen Lounkine, Dominic Hoepfner, Gaelle Le Goff, Frederick J King, Christian Studer, John M Peltier, Melissa L Grippo, Vivian Prindle, Jianshi Tao, Ansgar Schuffenhauer, Iain M Wallace, Shanni Chen, Philipp Krastel, Amanda Cobos-Correa, Christian N Parker, John W Davies and Meir Glick
High-throughput screening (HTS) is an integral part of early drug discovery. Herein, we focused on those small molecules in a screening collection that have never shown biological activity despite having been exhaustively tested in HTS assays. These compounds are referred to as 'dark chemical matter' (DCM). We quantified DCM, validated it in quality control experiments, described its physicochemical properties and mapped it into chemical space. Through analysis of prospective reporter-gene assay, gene expression and yeast chemogenomics experiments, we evaluated the potential of DCM to show biological activity in future screens. We demonstrated that, despite the apparent lack of activity, occasionally these compounds can result in potent hits with unique activity and clean safety profiles, which makes them valuable starting points for lead optimization efforts. Among the identified DCM hits was a new antifungal chemotype with strong activity against the pathogen Cryptococcus neoformans but little activity at targets relevant to human safety.
Robert A. CraigII, Steven A. Loskot, Justin T. Mohr, Douglas C. Behenna, Andrew M. Harned, and Brian M. Stoltz
The first general method for the enantioselective construction of all-carbon quaternary centers on cyclopentanones by enantioselective palladium-catalyzed decarboxylative allylic alkylation is described. Employing the electronically modified (S)-(p-CF3)3-t-BuPHOX ligand, α-quaternary cyclopentanones were isolated in yields up to >99% with ee’s up to 94%. Additionally, in order to facilitate large-scale application of this method, a low catalyst loading protocol was employed, using as little as 0.15 mol % Pd, furnishing the product without any loss in ee.
Dr. Lanting Xu,Chao Zhang,Dr. Yupeng He,Dr. Lushi Tan,Prof. Dr. Dawei Ma
An efficient rhodium-catalyzed method for direct C-H functionalization at the C7 position of a wide range of indoles has been developed. Good to excellent yields of alkenylation products were observed with acrylates, styrenes, and vinyl phenyl sulfones, whereas the saturated alkylation products were obtained in good yield with α,β-unsaturated ketones. Both the N-pivaloyl directing group and the rhodium catalyst proved to be crucial for high regioselectivity and conversion.
Dr. Geoffrey M. T. Smith,Dr. Paul M. Burton and Dr. Christopher D. Bray
The development of the homologous Julia–Kocienski reaction has led to the discovery of two new reaction modes of epoxides with sulfones. These pathways allow rapid and direct access to a range of γ-sultones and γ-sultines.
Xuefeng Cong, Huarong Tang, and Xiaoming Zeng
Acting as an environmentally benign synthetic tool, the cross-coupling reactions with aryl ethers via C–O bond activation have attracted broad interest. However, the functionalizations of C–O bonds are mainly limited to nickel catalysis, and selectivity has long been a prominent challenge when several C–O bonds are present in the one molecule. We report here the first chromium-catalyzed selective cross-coupling reactions of aryl ethers with Grignard reagents by the cleavage of C–O(alkyl) bonds. Diverse transformations were achieved using simple, inexpensive chromium(II) precatalyst combining imino auxiliary at room temperature. It offers a new avenue for buildup functionalized aromatic aldehydes with high efficiency and selectivity.
Jennifer M. Howell, Kaibo Feng, Joseph R. Clark, Louis J. Trzepkowski and M. Christina White
Nitrogen heterocycles are ubiquitous in natural products and pharmaceuticals. Herein, we disclose a nitrogen complexation strategy that employs a strong Brønsted acid (HBF4) or an azaphilic Lewis acid (BF3) to enable remote, non-directed C(sp3)—H oxidations of tertiary (3°), secondary (2°), and primary (1°) amine- and pyridine-containing molecules with tunable iron catalysts. Imides resist oxidation and promote remote functionalization.
Rhodium-catalysed asymmetric allylic arylation of racemic halides with arylboronic acids
Mireia Sidera and Stephen P. Fletcher
Csp2–Csp2 cross-coupling reactions between arylboronic acid and aryl halides are widely used in both academia and industry and are strategically important in the development of new agrochemicals and pharmaceuticals. Csp2–Csp3 cross-coupling reactions have been developed, but enantioselective variations are rare and simply retaining the stereochemistry is a problem. Here we report a highly enantioselective Csp2–Csp3 bond-forming method that couples arylboronic acids to racemic allyl chlorides. Both enantiomers of a cyclic chloride are converted into a single enantiomer of product via a dynamic kinetic asymmetric transformation. This Rh-catalysed method uses readily available and inexpensive building blocks and is mild and broadly applicable. For electron-deficient, electron-rich or ortho-substituted boronic acids better results are obtained with racemic allyl bromides. Oxygen substitution in the allyl halide is tolerated and the products can be functionalized to provide diverse building blocks. The approach fills a significant gap in the methods for catalytic asymmetric synthesis.
gem-Difluoroolefination of Diazo Compounds with TMSCF3 or TMSCF2Br: Transition-Metal-Free Cross-Coupling of Two Carbene Precursors
Mingyou Hu, Chuanfa Ni, Lingchun Li, Yongxin Han, and Jinbo Hu*
A new olefination protocol for transition-metal-free cross-coupling of two carbene fragments arising from two different sources, namely, a nonfluorinated carbene fragment resulting from a diazo compound and a difluorocarbene fragment derived from Ruppert–Prakash reagent (TMSCF3) or TMSCF2Br, has been developed. This gem-difluoroolefination proceeds through the direct nucleophilic addition of diazo compounds to difluorocarbene followed by elimination of N2. Compared to previously reported Cu-catalyzed gem-difluoroolefination of diazo compounds with TMSCF3, which possesses a narrow substrate scope due to a demanding requirement on the reactivity of diazo compounds and in-situ-generated CuCF3, this transition-metal-free protocol affords a general and efficient approach to various disubstituted 1,1-difluoroalkenes, including difluoroacrylates, diaryldifluoroolefins, as well as arylalkyldifluoroolefins. In view of the ready availability of diazo compounds and difluorocarbene reagents and versatile transformations of 1,1-difluoroalkenes, this new gem-difluoroolefination method is expected to find wide applications in organic synthesis.
Enantioselective Synthesis of Homoallylic Azides and Nitriles via Palladium-Catalyzed Decarboxylative Allylation
Maria Victoria Vita, Paola Caramenti, and Jerome Waser
Azides and nitriles are important building blocks for the synthesis of nitrogen-containing bioactive compounds. The first example of enantioselective palladium-catalyzed decarboxylative allylation of α-azido and cyano β-ketoesters is reported. Indanone derivatives were obtained in 50–88% yield/77–97% ee and 46–98% yield/78–93% ee for azide and nitrile substituents, respectively. The required starting materials were synthesized in one step from ketoesters via electrophilic azidation and cyanation using benziodoxole hypervalent iodine reagents. The products could be easily converted into useful nitrogen-containing building blocks, such as triazoles, amides, or α- and β- amino ketones.
A Bioorthogonal Reaction of N-Oxide and Boron Reagents
Dr. Justin Kim,Prof. Carolyn R. Bertozzi
The development of bioorthogonal reactions has classically focused on bond-forming ligation reactions. In this report, we seek to expand the functional repertoire of such transformations by introducing a new bond-cleaving reaction between N-oxide and boron reagents. The reaction features a large dynamic range of reactivity, showcasing second-order rate constants as high as 2.3×103 M−1 s−1 using diboron reaction partners. Diboron reagents display minimal cell toxicity at millimolar concentrations, penetrate cell membranes, and effectively reduce N-oxides inside mammalian cells. This new bioorthogonal process based on miniscule components is thus well-suited for activating molecules within cells under chemical control. Furthermore, we demonstrate that the metabolic diversity of nature enables the use of naturally occurring functional groups that display inherent biocompatibility alongside abiotic components for organism-specific applications.
A Novel Internet-Based Reaction Monitoring, Control and Autonomous Self-Optimization Platform for Chemical Synthesis
Daniel E. Fitzpatrick, Claudio Battilocchio, and Steven V. Ley
We have developed a modular software system that enables researchers to monitor and control chemical reactions via the Internet, using any device from any location in the world. It facilitates the automation of synthetic procedures and is able to autonomously self-optimize reaction parameters to find the best conditions meeting customizable, multicomponent optimization functions. In this report, we demonstrate its utility as applied to reaction automation to maximize the output from a fixed volume of catalyst. We also showcase its ability to optimize a three-dimensional heterogeneous catalytic reaction and a five-dimensional Appel reaction against various target functions.
Ligand-Controlled Diastereoselective 1,3-Dipolar Cycloadditions of Azomethine Ylides with Methacrylonitrile
Mary C. Walton, Yun-Fang Yang, Xin Hong, K. N. Houk, and Larry E. Overman
Copper-catalyzed reactions of glycine ester arylimines and methacrylonitrile provide selective access to either the endo or exo pyrrolidine cycloadducts. DFT calculations have elucidated the origins of ligand-controlled diastereoselectivity.
Azide vs Alkyne Functionalization in Pt(II) Complexes for Post-treatment Click Modification: Solid-State Structure, Fluorescent Labeling, and Cellular Fate
Regina Wirth, Jonathan D. White, Alan D. Moghaddam, Aurora L. Ginzburg, Lev N. Zakharov, Michael M. Haley, and Victoria J. DeRose
Tracking of Pt(II) complexes is of crucial importance toward understanding Pt interactions with cellular biomolecules. Post-treatment fluorescent labeling of functionalized Pt(II)-based agents using the bioorthogonal Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) reaction has recently been reported as a promising approach. Here we describe an azide-functionalized Pt(II) complex, cis-[Pt(2-azidobutyl)amido-1,3-propanediamine)Cl2] (1), containing the cisgeometry and difunctional reactivity of cisplatin, and present a comparative study with its previously described alkyne-functionalized congener. Single-crystal X-ray diffraction reveals a dramatic change in the solid-state arrangement with exchange of the alkyne for an azide moiety wherein 1 is dominated by a pseudo-chain of Pt–Pt dimers and antiparallel alignment of the azide substituents, in comparison with a circular arrangement supported by CH/π(C≡C) interactions in the alkyne version. In vitro studies indicate similar DNA binding and click reactivity of both congeners observed by fluorescent labeling. Interestingly, complex 1 showsin vitro enhanced click reactivity in comparison to a previously reported azide-appended Pt(II) complex. Despite their similar behavior in vitro, preliminary in cellulo HeLa studies indicate a superior imaging potential of azide-functionalized 1. Post-treatment fluorescent labeling of 1observed by confocal fluorescence microscopy shows nuclear and intense nucleolar localization. These results demonstrate the potential of 1 in different cell line localization studies and for future isolation and purification of Pt-bound targets.
Imaging Glycosylation In Vivo by Metabolic Labeling and Magnetic Resonance Imaging
Dr. André A. Neves,Dr. Yéléna A. Wainman,Dr. Alan Wright,Dr. Mikko I. Kettunen,Dr. Tiago B. Rodrigues,Sarah McGuire,Dr. De-En Hu,Flaviu Bulat,Dr. Simonetta Geninatti Crich,Dr. Henning Stöckmann,Dr. Finian J. Leeper,Prof. Kevin M. Brindle
Glycosylation is a ubiquitous post-translational modification, present in over 50 % of the proteins in the human genome,1 with important roles in cell–cell communication and migration. Interest in glycome profiling has increased with the realization that glycans can be used as biomarkers of many diseases,2 including cancer.3 We report here the first tomographic imaging of glycosylated tissues in live mice by using metabolic labeling and a gadolinium-based bioorthogonal MRI probe. Significant N-azidoacetylgalactosamine dependent T1 contrast was observed in vivo two hours after probe administration. Tumor, kidney, and liver showed significant contrast, and several other tissues, including the pancreas, spleen, heart, and intestines, showed a very high contrast (>10-fold). This approach has the potential to enable the rapid and non-invasive magnetic resonance imaging of glycosylated tissues in vivo in preclinical models of disease.
Nickel(0)/N-Heterocyclic Carbene-Catalyzed Asymmetric [2 + 2 + 2] Cycloaddition of Two Enones and an Alkyne: Access to Cyclohexenes with Four Contiguous Stereogenic Centers
Ravindra Kumar, Hiromu Tokura, Akira Nishimura, Tadashi Mori, Yoichi Hoshimoto, Masato Ohashi, and Sensuke Ogoshi
A nickel(0)/chiral N-heterocyclic carbene (NHC)-catalyzed fully intermolecular, enantioselective [2 + 2 + 2] cycloaddition of two enones and an alkyne has been developed to access enantioenriched cyclohexenes. A single diastereomer was obtained with a successive generation of four contiguous stereogenic centers. The absolute configuration of cyclohexene derivative 3aa was determined by X-ray diffraction and circular dichroism (CD) spectral studies.
Synthesis of Multiply Substituted Polycyclic Aromatic Hydrocarbons by Iridium-Catalyzed Annulation of Ring-Fused Benzocyclobutenol with Alkyne through C[BOND]C Bond Cleavage
Jiajia Yu,Hong Yan,Prof. Dr. Chen Zhu
The first iridium-catalyzed intermolecular cyclization between alkynes and ring-fused benzocyclobutenols (RBCB) through CC bond cleavage is described. A variety of elusive polycyclic aromatic hydrocarbons (PAHs) with multiple substituents are obtained in good yields under mild conditions. This procedure provides a unique and expeditious tool for the synthesis of PAHs.
Daniel S. Müller and Ilan Marek*
The enantioselective synthesis of cyclopropylzinc reagents has been achieved via a copper-catalyzed carbozincation of 3,3-disubstituted cyclopropenes with diorganozinc reagents. The obtained organozinc compounds can be easily functionalized with a broad range of electrophiles, including palladium-catalyzed cross-couplings, affording highly substituted cyclopropanes. The operationally simple procedure using very low quantities of a commercially available and inexpensive copper catalyst provides a new tool for the synthesis of highly enantioenriched cyclopropanes as single diastereoisomers.
Taku Kitanosono, Lei Zhu, Chang Liu, Pengyu Xu, and Shu̅ Kobayashi*
Acicular purplish crystals were obtained from Cu(acac)2 and a chiral bipyridine ligand. Although the crystals were not soluble, they nevertheless catalyzed asymmetric silyl conjugate addition of lipophilic substrates in water. Indeed, the reactions proceeded efficiently only in water; they did not proceed well either in organic solvents or in mixed water/organic solvents in which the catalyst/substrates were soluble. This is in pronounced contrast to conventional organic reactions wherein the catalyst/substrates tend to be in solution. Several advantages of the chiral Cu(II) catalysis in water over previously reported catalyst systems have been demonstrated. Water is expected to play a prominent role in constructing and stabilizing sterically confined transition states and accelerating subsequent protonation to achieve high yields and enantioselectivities.
Jonas Calleja, Daniel Pla, Timothy W. Gorman, Victoriano Domingo, Benjamin Haffemayer & Matthew J. Gaunt
Aliphatic primary amines are a class of chemical feedstock essential to the synthesis of higher-order nitrogen-containing molecules, commonly found in biologically active compounds and pharmaceutical agents. New methods for the construction of complex amines remain a continuous challenge to synthetic chemists. Here, we outline a general palladium-catalysed strategy for the functionalization of aliphatic C–H bonds within amino alcohols, an important class of small molecule. Central to this strategy is the temporary conversion of catalytically incompatible primary amino alcohols into hindered secondary amines that are capable of undergoing a sterically promoted palladium-catalysed C–H activation. Furthermore, a hydrogen bond between amine and catalyst intensifies interactions around the palladium and orients the aliphatic amine substituents in an ideal geometry for C–H activation. This catalytic method directly transforms simple, easily accessible amines into highly substituted, functionally concentrated and structurally diverse products, and can streamline the synthesis of biologically important amine-containing molecules.
Barry M. Trost* and Chao-I (Joey) Hung
Alkynyl ketones are attractive but challenging nucleophiles in enolate chemistry. Their susceptibility to other reactions such as Michael additions and the difficulty of controlling the enolate geometry make them difficult substrates. Mannich-type reactions, which previously have not been reported using N-carbamoyl-imines with simple ketone enolates, became our objective. In this report, we describe the first direct catalytic Mannich-type reaction between various ynones and N-Boc imines, whose stereocontrol presumably derives from catalyst control of enolate geometry. This method produces α-substituted β-amino ynones with excellent chemo-, diastereo-, and enantioselectivity. The products can be readily transformed into a broad range of molecular scaffolds upon further one-step transformations, demonstrating the utility of ynones as masked synthetic equivalents for a variety of unsymmetrically substituted acyclic ketones. In particular, alkynyl alkyl ketones resolve the long-standing problem of the inability to use the enolates of unsymmetrical dialkyl ketones lacking α-branching for regio- and stereoselective reactions.