Publications 2013 → 2012 2011 2010 2009 2008 2007 2006 2005 2004 2003 2002 2001 2000 1999 1998 1997 1996 1995 1994 1993 1992 1991 1990 1989 1988 1987 1986 1985 1984 1983 1982 1981 1980 1979 1978 1977 1976 1975 1974 1973 1972 1971 1970 of the Department of Organic Chemistry

The photoreduction of azide-based immolative linker by Ru(II) conjugates to uncage rhodamine was achieved using different oligomeric protein templates. The generality of the approach was validated with three sets of ligand having varying affinity to their target (biotin, desthiobiotin and raloxifene). The reaction rates of the templated reaction was found to be at least 30-fold faster than the untemplated reaction providing a clear fluorescent signal in response to the protein oligomer within 30 min. The templated reaction was found to also proceed in cellulo and could be used to identify acetyl coenzyme A carboxylase (ACC) in Pseudomonas aeruginosa and human cell lines as well the and estrogen receptor (ER).

Nine new N-heterocyclic carbene gold chloride complexes (10–18) were synthesized starting from bulky chiral imidazolium salts (1–9) developed in this laboratory. Full characterization of all complexes, including the X-ray structures of gold(I)(1,3-bis((S)-1-(2-methoxyphenyl)-2,2-dimethylpropyl)-1H-imidazol-2(3H)-ylidene) chloride (13) and gold(I)(1,3-bis((S)-2,2-dimethyl-1-(naphthalen-1-yl)propyl)-1H-imidazol-2(3H)-ylidene) chloride (16), is reported. The complexes 10–18 were applied in the methoxycyclization of 1,6-enynes using AgNTf₂ as an additive. Synthesis of the N-heterocyclic carbene gold triflimidate (19) was achieved by treating complex 12 with AgNTf₂. The complex gold(I)(1,3-bis((R)-1-(2-methoxyphenyl)-2,2-dimethylpropyl)imidazolidin-2-ylidene)(1,1,1-trifluoro-N-(trifluoromethylsulfonyl)methylsulfonamido) (19) was isolated and spectroscopically and structurally (X-ray) characterized.

Lessons from lobster coloration and the chemistry of vision suggested an approach to responsive fluorescent probes that can sense membrane potential, fluidity, and tension. Fluorophore deplanarization by lateral crowding along the scaffold (red circles) and fluorophore polarization by terminal donors (D), acceptors (A), and charges (+) are coupled to provide such membrane probes, as studies with unilamellar vesicles of phospholipids (DOPC, DPPC) show.

A valuable Cu-free protocol is reported where NHC ligand has been employed to form quaternary centers bearing fluoroalkyl unities. Importantly the results obtained, from this allylic substitution, are better in terms of enantioselectivity and regioselectivity compared to the copper catalyzed system. Moreover the catalysis is performed directly on the substrate containing the fluoroalkyl moiety. The use of FSBM as fluoromethide equivalent is not anymore required. The reaction has been extended to CF2H group (isosteric to carbinol function) and to CF3 group.

Since the initial reports in the mid 90s, metal catalyzed asymmetric conjugate addition (ACA) reactions evolved as an important tool for the synthetic chemist. Most of the research efforts have been done in the field of rhodium and copper catalyzed ACA reactions employing aryl and alkyl nucleophiles. Despite the great synthetic value of the double bond, the addition of alkenyl nucleophiles remains insufficiently explored. In this account, an overview of the developments in the field of rhodium and copper catalyzed ACA reactions with organometallic alkenyl reagents (B,Mg, Al, Si, Zr, Sn) will be provided. The account is intended to give a comprehensive overview of all the existing methods. However, in many cases only selected examples are displayed in order to facilitate comparison of different ligands and methodologies.

The first total synthesis of (+)-5-epi-eudesma-4(15)-ene-1β,6β-diol has been achieved in 12 steps by starting from the known (-)-cis-piperitol and using an Ireland-Claisen rearrangement of a glycolate ester and an intramolecular nitrile oxide dipolar cycloaddition as key steps.

Directional growth of π-basic oligothiophene stacks on solid substrates is achieved by self-organizing, surface-initiated disulfide exchange polymerization. Successful addition of co-axial π-acidic stacks by templated hydrazone exchange provides general access to multicomponent architectures of unique complexity.

Complementary to enzymatic methods, catalytic enantioselective desymmetrisation of meso-diols (EDMD) by small molecule catalysts has emerged as a powerful tool that provides highly enantioenriched materials of considerable value in organic synthesis. This review traces the evolution of easily accessible catalysts used in the EDMD and compares their performance with the existing enzymatic methods.

The fungus Coniothyrium cereale was isolated from the Baltic Sea alga Enteromorpha sp. Upon cultivation in saline medium, C. cereale produced the structurally unprecedented isoindole pseudoalkaloid conioimide (1) and the polyketide cereoanhydride (2). Because of the very limited amount of compounds isolated, the structures of 1 and 2 were established from extensive NMR spectroscopic and mass spectrometric analyses, and in the case of 1, the structural analysis was completed by NMR shielding calculations. Conioimide and cereoanhydride represent new structural types of polyketides. Experiments with ¹³C-labeled acetate proved the polyketide nature of the major and known C. cereale metabolite (–)-trypethelone (3), which is proposed to be the precursor of cereoanhydride. Conioimide has prominent and selective inhibitory activity towards the protease human leukocyte elastase (HLE), an enzyme involved in many inflammatory diseases, with an IC₅₀ (half maximal inhibitory concentration) value of 0.2 μg mL^–1.

A novel efficient NaOtBu-mediated protocol for the synthesis of 3,3-disubstituted aza-oxindoles proceeds via a Truce–Smiles rearrangement–cyclisation pathway.

In this paper, the first stereoselective annulation reaction between α-cyano-1,4-diketones and ynals, mediated by catalytic amounts of a triazolium salt precatalyst and cocatalytic amounts of a weak carboxylate base, is disclosed. The title transformation proceeds smoothly under mild reaction conditions and generates three contiguous stereogenic centers, one of which is a quaternary acetal carbon. This reaction tolerates a wide variety of electronically distinct substituents on both reaction partners and affords privileged bicyclic scaffolds in 61–90% isolated yields and with up to 20:1 diastereomeric preference.

Self-sorting on surfaces is one of the big challenges that must be addressed in preparing the organic materials of the future. Here, we introduce a theoretical framework for templated self-sorting on surfaces, and validate it experimentally. In our approach, the transcription of two-dimensional information encoded in a monolayer on the surface into three-dimensional supramolecular architectures is quantified by the intrinsic templation efficiency, a thickness-independent value describing the fidelity of transcription per layer. The theoretical prediction that exceedingly high intrinsic efficiencies will be needed to experimentally observe templated self-sorting is then confirmed experimentally. Intrinsic templation efficiencies of up to 97%, achieved with a newly introduced templated synthesis strategy, result in maximal 47% effective templation efficiency at a thickness of 70 layers. The functional relevance of surface-templated self-sorting and meaningful dependences of templation efficiencies on structural modifications are demonstrated.

In this paper, we disclose our recent advances in the copper-catalyzed enantioselective conjugate addition of Grignard reagents to 3-substituted cyclic enones. Several new N-heterocyclic carbene (NHC) ligands have been synthesized in high yields by starting from inexpensive materials. These new NHCs were evaluated as ligands for copper, for the Michaeladdition of ethylmagnesium bromide leading to chiral 3,3-disubstituted cyclohexanones (up to 93 % ee). The best ligand was then engaged in conjugate additions of various Grignard reagents, allowing the formation of quaternary centers with high levels of regio- and enantioselectivity with only 0.75 mol-% catalyst loading. The reaction is also robust to scale-up. The addition of ethylmagnesium bromide for the construction of a 3,3-disubstituted cyclopentanone (up to 86 % ee), a synthetically useful chiral synthon, is noteworthy. A tentative mechanism for the catalytic cycle is also discussed.

A new room-temperature chromium tricarbonyl-mediated cycloaromatization of enediynes is reported. The reaction occurs with both cyclic and acyclic enediynes in the presence of [Cr(CO)₃(η⁶-naphthalene)] and both a coordinating solvent and a hydrogen atom source, providing chromium–arene complexes in reasonable yield and good diastereocontrol. The mechanism of the reaction has been probed through DFT computational and spectroscopic methods. These studies suggest that direct C1–C6 bond formation from an η⁶-enediyne complex is the lowest-energy path, forming a metal-bound p-benzyne biradical. NMR spectroscopy suggests that enediyne alkene coordination occurs in preference to alkyne coordination, forming a THF-stabilized olefin intermediate; subsequent alkyne coordination leads to cyclization. While biradical quenching occurs rapidly and primarily via the singlet biradical, the triplet state biradical is detectable by EPR spectroscopy, suggesting intersystem crossing to a triplet ground state.

An unprecedented and strong positive nonlinear effect (NLE) was observed in Cu/DiPPAM-catalyzed asymmetric 1,6-conjugate addition of Et₂Zn on (E)-3-(prop-1-en-1-yl)cyclohex-2-enone (71% ee reached with a 40% ee ligand). Moreover, similar behaviors were observed in Cu/DiPPAM-catalyzed 1,4-asymmetric conjugate additions of Et₂Zn on both cyclohexenone and (E)-3-non-3-en-2-one (83% and 70% ee, respectively, reached with a 40% ee ligand).

The total syntheses of the Lythracea alkaloids (+)-vertine and (+)-lythrine are described. Enantioenriched pelletierine is used as a chiral building block and engaged into a two step pelletierine condensation leading to two quinolizidin-2-one diastereomers in a 8:1 ratio. The major product is used in the synthesis of (+)-vertine via aryl–aryl coupling and ring closing metathesis to provide a Z-alkene α to the lactone carbonyl function. The same procedure was used for (+)-lythrine after base induced epimerization of the main quinolizidin-2-one diastereomer. Alternative classical ring closure strategies like macrolactonisation or aryl–aryl coupling failed.

In biology and chemistry, the transport of anions across lipid bilayer membranes is usually achieved by sophisticated supramolecular architectures.  Significant size reduction of transporters is hampered by the intrinsically hydrophilic nature of typical anion binding functionalities, hydrogen-bond donors or cations.  To maximize the atom efficiency of anion transport to the extreme, the hydrophobic nature, directionality, and strength of halogen bonds appeared most promising.  Unlike the ubiquitous, structurally similar hydrogen bonds, halogen bonds have never really been explored for anion transport.  Here, we report that transport across lipid bilayers can be achieved with small perfluorinated molecules that are equipped with strong halogen-bond donors.  At extreme reductionism down to the “single-carbon” transporter, activity is observed with trifluoroiodomethane (boiling point = -22 ºC).  Contrary to the destructive action of small-molecule detergents, transport with halogen bonds is leakage-free, cooperative, non-ohmic and highly selective (anion/cation permeability ratios as high as 37).

Introduction of a pseudoaxial substituent at a stereogenic centre adjacent to the nitrogen atom in binaphthyl- and biphenyl- derived azepinium salt organocatalysts affords improved enantioselectivities and yields in the epoxidation of unfunctionalized alkenes. In the biphenyl-derived catalysts, the atropoisomerism at the biphenyl axis is controlled by the interaction of this substituent with the chiral substituent at nitrogen.

The copper-catalyzed conjugate addition of various Grignard reagents to polyconjugated enones (dienone and enynone derivatives) is reported. The catalyst system, composed of copper triflate and an NHC ligand, led to the unusual selective formation of the 1,4-addition products. This reaction allows for the creation of all-carbon chiral quaternary centers with enantiomeric excesses up to 99 %. The remaining unsaturation on the 1,4 adducts give access to valuable synthetic transformations.

Novel endo,endo-2,5-diaminonorbonanederived tertiary C2-symmetrical diamines were synthesized via the one-pot reductive amination of enantiomerically pure norbornane-2,5-dione. These ligands were applied to various catalytic reactions such as asymmetric deprotonation, asymmetric bromine-lithium exchange, and enantioselective addition of aryl- and allkylithium reagents to aromatic aldimines.

Atherosclerosis results in the narrowing of arterial blood vessels and this causes significant changes in the endogenous shear stress between healthy and constricted arteries. Nanocontainers that can release drugs locally with such rheological changes can be very useful. Here, we show that vesicles made from an artificial 1,3-diaminophospholipid are stable under static conditions but release their contents at elevated shear stress. These vesicles have a lenticular morphology, which potentially leads to instabilities along their equator. Using a model cardiovascular system based on polymer tubes and an external pump to represent shear stress in healthy and constricted vessels of the heart, we show that drugs preferentially release from the vesicles in constricted vessels that have high shear stress.

Dynamic amphiphiles have a “bridge” between their charged head and their hydrophobic tails. The presence of dynamic covalent bonds is of interest for differential and biosensing applications as well as for rapid access to the libraries needed to screen for gene delivery or cellular uptake of siRNA. However, efforts to develop libraries have so far concentrated on hydrazone bridges to monocationic heads. Here, we report synthesis efforts to enlarge this focused library with oxime and disulfide bridges and dynamic amphiphiles with more than one positive charge. Evaluation in fluorogenic vesicles reveals best activation of DNA as ion transporters by dynamic amphiphiles with dendritic scaffolds, doubly charged heads and four tails. Moreover, oximes, contrary to hydrazones, remain active under acidic conditions. Linear elongation of dendritic head-groups seems to cause increasing detergent effects and should therefore be avoided.

[CpRu(CH₃CN)₃][PF₆] and diimine ligands catalyze the decomposition of α-diazo-β-ketoesters in THF leading to original products of 1,4-C−H insertion. In contrast with previous results, only novel enol-acetal motifs are obtained through intermolecular C-O instead of C-C bond forming reactions.

A new tripodal ligand has been designed by coupling pyridyldicarbonyl binding strands with a triazatriangulenium platform (TATA). The complexation reaction with europium provides a C₃-symmetrical mononuclear compound that is characterized with NMR, ESMS and qualitatively with single-crystal X-ray crystallography. In addition, photophysical studies of this dual emissive system have been performed, since the combination of the TATA fluorophore with trivalent lanthanides is of potential interest for the further development of imaging applications.

Dynamic amphiphiles provide access to transmembrane ion transport, differential sensing and cellular uptake. In this report, we introduce dynamic amphiphiles with fluorescent tails. Core-substituted naphthalenediimides (cNDIs) and perylenediimides (cPDIs) are tested. Whereas the latter suffer from poor partitioning, dynamic cNDI amphiphiles are found to be purifiable by RP-HPLC, to partition selectively into liquid-disordered (Ld) microdomains of mixed lipid bilayers and to activate DNA as transporters. Importantly, fluorescence properties, partitioning and activity can be modulated by changes in the structure of mixed amphiphiles. These results confirm the potential of dynamic fluorescent amphiphiles to selectively label extra- and intracellular membrane domains and visualize biological function.

α-Diazo β-ketoesters and diketones react with cyclic acetals under Rh(II)-catalysis to yield in one-pot unprecedented polyoxygenated 8- and 9-membered rings. The reactions occur under mild conditions with yields up to 90%. The medium-sized ring formation and perfect regioselectivity are direct consequences of Baldwin’s rules.

Readily available vinyl alanes are used in the Cu-catalyzed asymmetric conjugate addition reaction to N-substituted-2-3-dehydro-4-piperidones. The enhanced reactivity of recently developed and easily prepared phosphine amine ligands in combination with inexpensive Cu(II)naphtenate (CuNp) allows the introduction of a great variety of alkenyl, alkyl, and aryl aluminums in high enantioselectivity.

A series of substrates containing a vinylic bromide were employed in a copper-free methodology using bidendate NHC ligands. The desired compounds are generally obtained with good enantioselectivity and good regioselectivity. Importantly the copper-catalyzed system afforded a lower enantioselectivity value. The catalytic products could be transformed into a broad scope of new 1,1-disubstituted olefins in a single step transformation without erosion of the enantioselectivity.

A short synthetic route readily gives access to a new class of chiral (P,N) ligands characterized by three distinct elements of chirality. These ligands are highly enantioselective in the challenging Pd-catalyzed intramolecular asymmetric α-arylation of α-branched aldehydes.

In this study, we demonstrate, for the first time, that SOSIP, self-organizing surface-initiated polymerization, a method introduced for facile access to complex surface architectures, is compatible with perylenediimides (PDIs), i.e., established chromophores with very important properties. Highly ordered face-to-face π-stacks are shown to coincide with a more than 100-fold increase of the activity of PDI photosystems, and with significant fill factors. This breakthrough with electron-transporting PDI stacks promises access to powerful combinations with hole-transporting channels.

Don't forget poly(disulfide)s. There is a rich literature pointing out the advantages of the dynamic nature of single disulfide bridges to explore self-sorting, biomolecular engineering, biomembrane analysis, and so on. Disulfide bonds between polymer chains are essential for protein folding, materials properties and the stabilization of various supramolecular architectures. However, poly(disulfide)s with disulfide bonds in the main chain are rarely used today to create interesting structures or functions. To attract attention and outline scope and limitations of poly(disulfide)s to build modern supramolecular systems, the rather eclectic recent literature on the topic is summarized. The review is moving from fascinating basic studies including photoinduced metathesis, polycatenanes and polyrotaxanes to applications in biosupramolecular systems such as micelles, membranes, tubes, gels, carriers, pores, sensors, catalysts and photosystems.

N-Aryl, N-branched alkyl carbamates react with an in situ generated chiral Pd-NHC catalyst by coupling a Pd-Ar moiety with an aliphatic C-H bond at high temperature to give enantioenriched 2-substituted and 2,3-disubstituted indolines. Prochiral precursors give single products with very high asymmetric induction. Chiral racemic precursors react in a regiodivergent reaction of a racemic mixture to yield enantioenriched indolines resulting from either methyl C-H activation or asymmetric methylene C-H activation. In favorable cases this can result in a complete separation of an enatiomeric mixture into two different highly enantioenriched indolines.

A CuCl₂ mediated oxidative Csp²-H and Csp³-H coupling protocol gives access to aza-oxindoles in good to excellent yield in the presence of NaOtBu as base and toluene as solvent.

Self-sorting at interfaces is one of the big challenges we face to prepare the functional organic materials of the future. As a first and decisive step to self-sorting into π-stacks or bundles, we here elaborate self-sorting of π-dimers in solution. Design, synthesis and study of planar naphthalenediimides (NDIs) with one shielded and one free chiral π-surface to direct self-assembly into dimers are described. Stereoisomers are isolated by chiral, preparative HPLC and characterized by X-ray crystallography. NMR studies show that racemates with almost planar, nearly identical π-surfaces prefer uniform self-sorting into homodimers at large differences in π-acidity and alternate self-sorting into heterodimers at small differences in π-acidity. In contrast, enantiomers self-sort "narcissistically" into heterodimers and diastereomers show moderate preference for homodimers. Whereas the lessons learned from dimerization are directly applicable to self-sorting of π-stacks on surfaces, anion transport in lipid bilayers is shown to require a more subtle, somewhat inverse interpretation, with diastereomeric transporters differing dramatically in activity but the least visible supramolecule being confirmed as the best performer.

A new family of chiral N-heterocyclic carbene borane complexes was synthesized starting from their corresponding imidazolium salts. The complexes were fully characterized. X-ray crystal structures of the complexes were obtained.

Recently, our group reported on the development of an unprecedented process in copper-catalyzed Asymmetric Allylic Alkylation. This method allowed for the quantitative transformation of a racemic substrate into an enantioenriched product. While a high level of asymmetric induction (up to 99% ee) was observed, the mechanistic understanding of the reaction remained fuzzy. In the present article, a thorough mechanistic analysis, based on computational investigations, led to the identification of the reaction pathway. Notably, it uncovered that both enantiomers of the starting material converged independently to the same product via two different mechanistic routes. This specific feature established this process as a rare example of Direct Enantioconvergent Transformation. Finally, the modelling results prompted a valuable improvement of the reaction, relying on the use of a more accessible range of substrates.

A select few: Several prochiral enyne chlorides were employed as substrates in the title reaction using Grignard reagents as the alkylation reagents (see scheme; CuTC=copper(I) thiophenecarboxylate). Excellent 1,3 substitution regioselectivities and good to excellent enantioselectivities were obtained. The substrate scope is additionally extended to diene chlorides.

Not a cop out: The copper-catalyzed asymmetric conjugate addition of organometallic reagents to Michael acceptors is an important methodology for forming a C—C bond in an enantioselective manner. Such an addition of Me₃Al to β,γ-unsaturated α-ketoesters is described to proceed in high yield and selectivity. CuTC=copper(I) thiophene-2-carboxylate.

Nonracemic ethano-bridged Tröger bases are prepared using CuTC-catalyzed decomposition of diazo compounds. Excellent levels of diastereo- and enantio-control (dr and ee up to 12:1 and 95% respectively) are now obtained with aryl diazoketone precursors.

Two complementary artificial diether phospholipids were synthesized that can undergo a Cu(I)-catalyzed Huisgen-Sharpless click reaction. The resulting lipid can bridge the membranes of large unilamellar vesicles and cause their aggregation and ultimately their fusion.

A dinuclear Ir(I) complex with a bis-NHC ligand was formed in situ from 1,1’-((4,6-dimethyl-1,3-phenylene)bis(methylene))bis(3-methyl-1H-imidazol-3-ium) in the presence of Cs₂CO₃ and [Ir(μ-Cl)(cod)]₂. Its solid-state structure, determined by X-ray diffraction, shows a figure-of-eight loop with both the P and M enantiomers being present. Solution NMR studies were performed to examine the enantiodiscrimination between them by applying the enantiopure anions tris(tetrachlorobenzenediolato)phosphate(V) (Δ-TRISPHAT) and bis(tetrachlorobenzenediolato)mono([1,10]binaphthalenyl-2,20-diolato)phosphate(V) (Λ-BINPHAT).

1,3-Dipolar cycloadditions afforded fast access to isoxazolidines bearing N-alkyl or N-benzyl substituents. The electronic properties of the substituents in the nitrones define the activity of the dipoles and modulate diastereoselectivity in the non-catalyzed reactions. Using a chiral one-point binding ruthenium Lewis acid catalyst, products were obtained in good yields and with excellent regio-, diastereo-, and enantioselectivity.

This contribution describes recent progress made with the design, synthesis and evaluation of supramolecular architectures for artificial photosynthesis. Emphasis is on the possible introduction of antiparallel redox gradients into the co-axial hole- and electron-transporting channels of supramolecular n/p-heterojunctions, and on directional, uniform axial and alternate lateral self-sorting to get there. Recent results suggest that two-component gradients in both channels are sufficient for photoinduced charge separation over very long distances. Removal of one gradient leads to charge recombination at the usual critical distances, inversion of both gradients causes photocurrent inhibition. These promising results call for user friendly, cheap and fast approaches to oriented multicomponent architectures on solid surfaces. However, the reduction of efforts devoted to covalent organic synthesis will have to be compensated by the development of strategic concepts on the supramolecular level to tackle basic questions such as self-sorting on surfaces.

The efficiency of organocopper reagents in the displacement of allylic leaving groups has been well established during the past five decades. In sharp contrast, catalytic asymmetric version of this reaction using a chiral catalyst is a more recent field of research. This chapter presents an overview of tremendous studies towards the development of an “ideally” active catalyst achieving high regio- and enantioselectivities. The comparative reactivity and generality of peptides, phosphorus, as well as N-heterocyclic carbenes based catalysts are discussed in the first part. Then, relevant scope and synthetic applications are reviewed. Noteworthily, this chapter is restricted to C–C bond formation processes, excluding C–B and C–Si bond formations.