Tibor Soós

Expanding the scope of metal-free catalytic hydrogenation through frustrated Lewis pair design

The further development of the field of catalysis is based on the discovery, understanding, and implementation of novel activation modes that allow unprecedented transformations and open new perspectives in synthetic chemistry. In this context, the recently introduced concept of frustrated Lewis pair (FLP) from the Stephan research group represents a fundamental and novel strategy to develop catalysts based on main-group elements for small-molecule activation. These sterically encumbered Lewis acid–base systems are not able to form a stable donor–acceptor adduct, nevertheless, an intermolecular association of the Lewis acidic (LA) and basic (LB) components to a unique “frustrated complex” was proposed. Our research group has also shown that this encounter pair cleaves hydrogen in a cooperative manner and the steric congestion implies a strain, which can be directly utilized for bond activation. Using steric hindrance as a critical design element, several combinations of bulky Lewis acid–base pairs were effectively probed for heterolytic cleavage of hydrogen. Moreover, this remarkable capacity of FLPs was exploited in metal-free hydrogenation procedures. Additionally, the bifunctional and unquenched nature of the FLPs makes them capable of reacting with alkenes, dienes, acetylenes, and THF. Although this type of reactivity represents a breakthrough in main-group chemistry, its enhanced and non-orthogonal nature obviously limits the synthetic applicability of FLPs. Herein we report an attempt to develop frustrated Lewis pairs with orthogonal reactivity and improved functional-group tolerance for catalytic metal-free hydrogenation. The previously reported FLP-based hydrogen activation relied mostly on tris(pentafluorophenyl)borane (1) as the LA component. Because of the hard-type Lewis acidity of boron in 1 and its inactivation by common oxygenand/or nitrogen-containing molecules, careful substrate design was needed for successful catalytic hydrogenation reactions. This synthetic limitation triggered us to develop FLP catalysts that have a broader range of applications and possible selectivity in reduction processes. Our design concept for increased functional-group tolerance is based on the simple hypothesis that steric hindrance in FLPs is a relative phenomenon (Figure 1): further increase of

Epi-cinchona based thiourea organocatalyst family as an efficient asymmetric Michael addition promoter: Enantioselective conjugate addition of nitroalkanes to chalcones and α,β-unsaturated N-acylpyrroles

A small set of easily available epi-cinchona based thiourea organocatalysts have been synthesized and tested in enantioselective Michael addition of nitroalkanes to chalcones. These bifunctional catalyst systems promoted the conjugate additions with high enantioselectivities and chemical yields. The extension of this methodology was further explored to encompass alpha,beta-unsaturated N-acylpyrroles, as a chalcone mimic. Functionally, the N-acylpyrrole moiety in the adduct acts as an ester surrogate; therefore, it can easily be transformed to various valuable and biologically relevant compounds. This approach allowed the concise stereoselective synthesis of (R)-rolipram.

Catalytic Hydrogenation with Frustrated Lewis Pairs: Selectivity Achieved by Size‐Exclusion Design of Lewis Acids

Catalytic hydrogenation that utilizes frustrated Lewis pair (FLP) catalysts is a subject of growing interest because such catalysts offer a unique opportunity for the development of transition-metal-free hydrogenations. The aim of our recent efforts is to further increase the functional-group tolerance and chemoselectivity of FLP catalysts by means of size-exclusion catalyst design. Given that hydrogen molecule is the smallest molecule, our modified Lewis acids feature a highly shielded boron center that still allows the cleavage of the hydrogen but avoids undesirable FLP reactivity by simple physical constraint. As a result, greater latitude in substrate scope can be achieved, as exemplified by the chemoselective reduction of α,β-unsaturated imines, ketones, and quinolines. In addition to synthetic aspects, detailed NMR spectroscopic, DFT, and (2)H isotopic labeling studies were performed to gain further mechanistic insight into FLP hydrogenation.

On the Mechanism of Bifunctional Squaramide-Catalyzed Organocatalytic Michael Addition: A Protonated Catalyst as an Oxyanion Hole

A joint experimental-theoretical study of a bifunctional squaramide-amine-catalyzed Michael addition reaction between 1,3-dioxo nucleophiles and nitrostyrene has been undertaken to gain insight into the nature of bifunctional organocatalytic activation. For this highly stereoselective reaction, three previously proposed mechanistic scenarios for the critical CC bond-formation step were examined. Accordingly, the formation of the major stereoisomeric products is most plausible by one of the bifunctional pathways that involve electrophile activation by the protonated amine group of the catalyst. However, some of the minor product isomers are also accessible through alternative reaction routes. Structural analysis of transition states points to the structural invariance of certain fragments of the transition state, such as the protonated catalyst and the anionic fragment of approaching reactants. Our topological analysis provides deeper insight and a more general understanding of bifunctional noncovalent organocatalysis.

Double Diastereocontrol in Bifunctional Thiourea Organocatalysis: Iterative Michael–Michael–Henry Sequence Regulated by the Configuration of Chiral Catalysts

The importance and reactivity consequences of the double diastereocontrol in noncovalent bifunctional organocatalysis were studied. The results suggest that the bifunctional thioureas can have synthetic limitations in multicomponent domino or autotandem catalysis. Nevertheless, we provided a means to exploit this behavior and used the configuration of the chiral catalyst as a control element in organo-sequential reactions.

Synthesis of novel ellipticine analogues and their inhibition of Moloney leukaemia reverse transcriptase

Abstract Two new ellipticine analogues were synthetized as potential non nucleoside inhibitors of reverse transcriptase and were tested on Moloney leukaemia virus reverse transcriptase in vitro. Both derivatives (9a,b) showed considerable inhibitory effect; ID50 was found to be in the range of 2.8 to 4.5 × 10−5 M.

Active conformation in amine-thiourea bifunctional organocatalysis preformed by catalyst aggregation.

Self-activation: Takemotos catalyst gains access to its active conformation by equilibrating between its hydrogen-bonded intra- and intermolecular interactions in apolar aprotic solvents. By destabilization of the inactive monomeric conformations, the extended anti-anti thiourea conformation is preformed in the assembly. On leaving the assembly, this transient conformation has a structural preference to become a catalytically active monomeric species that has the potency for dual activation (see scheme).

A CONCISE SYNTHESIS OF FUROSTIFOLINE

Abstract A five-step total synthesis of the furo[3,2- a ]carbazole alkaloid, furostifoline, was achieved using a Pd(0)-catalyzed cross-coupling reaction.

Expanding the Boundaries of Water-Tolerant Frustrated Lewis Pair Hydrogenation: Enhanced Back Strain in the Lewis Acid Enables the Reductive Amination of Carbonyls

The development of a boron/nitrogen-centered frustrated Lewis pair (FLP) with remarkably high water tolerance is presented. As systematic steric tuning of the boron-based Lewis acid (LA) component revealed, the enhanced back-strain makes water binding increasingly reversible in the presence of relatively strong base. This advance allows the limits of FLPs hydrogenation to be expanded, as demonstrated by the FLP reductive amination of carbonyls. This metal-free catalytic variant displays a notably broad chemoselectivity and generality.

Substituent Effect on the Photoreduction Kinetics of Benzophenone

The kinetics of the photoreduction of four benzophenone derivatives by isopropyl alcohol was examined in acetonitrile, namely, tetra-meta-trifluoromethyl-, di-para-trifluoromethyl-, di-para-methoxy benzophenone, and, for comparison, the unsubstituted molecule itself. The basic spectroscopic (absorption and phosphorescence spectra) and photophysical (quantum yields and excited state energies) properties were established, and the key kinetic parameters were determined by the laser flash photolysis transient absorption technique. The rate coefficients of both the primary and secondary photoreduction reaction show remarkable dependence on ring substitution. This substantial effect is caused by the considerable change in the activation energy of the corresponding process. The experimental results as well as DFT quantum chemical calculations clearly indicate that these benzophenone derivatives all react as n-π* excited ketones, and the rate as well as the activation energy of the reduction steps change parallel with the reaction enthalpies, the determining factor being the stability of the forming aromatic ketyl radicals. The secondary photoreduction of benzophenones by the aliphatic ketyl radical formed in the primary step occurs via a hydrogen bonded complex. The binding energy of the hydrogen bonded complex between the aliphatic ketyl radical reactant and a solvent molecule is a critical parameter influencing the observable rate of the secondary photoreduction.