Synthesis of chiral sulfinate esters by asymmetric condensation.

Achiral sulfur functional groups, such as sulfonamide, sulfone, thiol and thioether, are common in drugs and natural products. By contrast, chiral sulfur functional groups are often neglected as pharmacophores1-3, although sulfoximine, with its unique physicochemical and pharmacokinetic properties4,5, has been recently incorporated into several clinical candidates. Thus, other sulfur stereogenic centres, such as sulfinate ester, sulfinamide, sulfonimidate ester and sulfonimidamide, have started to attract attention. The diversity and complexity of these sulfur stereogenic centres have the potential to expand the chemical space for drug discovery6-10. However, the installation of these structures enantioselectively into drug molecules is highly challenging. Here we report straightforward access to enantioenriched sulfinate esters via asymmetric condensation of prochiral sulfinates and alcohols using pentanidium as an organocatalyst. We successfully coupled a wide range of sulfinates and bioactive alcohols stereoselectively. The initial sulfinates can be prepared from existing sulfone and sulfonamide drugs, and the resulting sulfinate esters are versatile for transformations to diverse chiral sulfur pharmacophores. Through late-stage diversification11,12 of celecoxib and other drug derivatives, we demonstrate the viability of this unified approach towards sulfur stereogenic centres.

Ion Pair Catalyst - Pentanidinium.

In this account, we further describe our already developed N-sp2 hybrid guanidinium as an efficient phase-transfer catalyst and ion pair catalysis based on N-sp2 hybrid pentanidinium and its application in some new reactions. The sp3 hybrid quaternary ammonium salt has a tetrahedral structure, which means that three sides of it can be effectively steric, allowing the remaining side to be close to the substrate. However, the sp2 hybrid ammonium salt allows the substrate to form ion pairs from both directions respectively, so it is a greater challenge to control the stereoselectivity of the reaction. Van der Waals forces, such as hydrogen bonds and π - π ${\pi -\pi }$ interactions, have been used to make electrophiles approach from a certain direction, leading to a higher enantioselectivity. Based on the above idea, we designed an N-sp2 hybrid phase-transfer catalyst, pentanidinium. Pentanidinium has five conjugated nitrogen atoms, one of which has a formal positive charge, which is necessary for it to become an ion pair catalyst. We have confirmed that pentanidinium can catalyze α-hydroxylation of 3-substituted-2-oxindoles, Michael addition of 3-alkyloxindoles with vinyl sulfone, and alkylation reactions of sulfenate anions and dihydrocoumarins, desymmetrization of pro-chiral sulfinate to afford enantioenriched sulfinate esters. Pentanidinium with side chain structure changes can also be catalyzed efficiently with enantioconvergent halogenophilic nucleophilic substitution, including azidation and thioesterification. In the reaction catalyzed by pentanidinium, it always attracts us with the advantages of low catalytic load and good enantioselectivity.

Guanidinium Hypoiodite-Catalyzed Intramolecular Oxidative Coupling Reaction of Oxindoles with ß-Dicarbonyls.

Spiro[indoline-3,4'-piperidine] is a fundamental motif present in various biologically active compounds. Here, we report an intramolecular oxidative coupling reaction of oxindoles with ß-dicarbonyls in the presence of a guanidinium hypoiodite catalyst, providing spiro-coupling products in moderate to excellent yields. Furthermore, a chiral hypoiodite catalyst derived from the chiral guanidinium organocatalyst is effective for the challenging asymmetric carbon-carbon bond-forming reaction, affording optically active spiro[indoline-3,4'-piperidines].

Organobase-Catalyzed Umpolung of Amides: The Generation and Transfer of Carbamoyl Anion.

A novel organobase-catalyzed umpolung reaction of amides was disclosed. This method provides an efficient method to generate and transfer carbamoyl anions. In this transformation, some of the inherent disadvantages of carbamoyl metal were avoided. The mechanistic analysis revealed that the reaction proceeds through polarity inversion of amide, and various carbamoyl anions were applied in the reaction. Moreover, a wide range of substrates was achieved with moderate to excellent yield.

Ground-state intramolecular proton transfer inhibits the selective methylation on quinoline and pyridine derivatives.

Methylation is one of the crucial steps for drug discovery, organic synthesis, and catalysis. Despite being a versatile and well-known chemical reaction, its chemoselectivity has not been well addressed. In this paper, we reported a thorough experimental and computational investigation of the selective N-methylation of N-heterocyclic compounds, mainly quinolines and pyridines. These reactions were conducted in a base-free manner under ambient conditions using iodomethane as the methylating reagent, exhibited good chemoselectivity, and were tolerant of other amine, carboxyl, or hydroxyl functional groups without needing protection. To this end, 13 compounds were synthesized as a proof-of-concept and 7 crystal structures were obtained. However, the chemoselectivity failed in the presence of a thiol group. Detailed quantum chemical calculations provided insights into the N-methylation mechanism and its selectivity and demonstrated that the isomerization induced by ground-state intramolecular proton transfer (GSIPT) in the presence of a thiol group inhibits the N-methylation.

Direct SN2 or SN2X Manifold─Mechanistic Study of Ion-Pair-Catalyzed Carbon(sp3)-Carbon(sp3) Bond Formation.

Density functional theory (DFT) is used in this work to predict the mechanism for constructing congested quaternary-quaternary carbon(sp3)-carbon(sp3) bonds in a pentanidium-catalyzed substitution reaction. Computational mechanistic studies were carried out to investigate the proposed SN2X manifold, which consists of two primary elementary steps: halogen atom transfer (XAT) and subsequent SN2. For the first calculated model on original experimental substrates, XAT reaction barriers were more kinetically competitive than an SN2 pathway and connect to thermodynamically stable intermediates. Extensive computational screening modeling was then done on various substrate combinations designed to study the steric influence and to understand the mechanistic rationale, and calculations reveal that sterically congested substrates prefer the SN2X manifold over SN2. Different halides as leaving groups were also screened, and it was found that the reactivity increases in the order of I > Br > Cl > F, in agreement with the strength of C-X bonds. However, DFT modeling suggests that chlorides can be a viable substrate for the SN2X process, which should be further explored experimentally. ONIOM calculations on the full catalyst model predicted the correct stereochemical outcome, and further catalyst screening with cationic Me4N+ and K+ predicted that pentanidium is still the choice for SN2X C-C bond formation.

A Descriptor for Accurate Predictions of Host Molecules Enabling Ultralong Room-Temperature Phosphorescence in Guest Emitters.

Although doping can induce room-temperature phosphorescence (RTP) in heavy-atom free organic systems, it is often challenging to match the host and guest components to achieve efficient intersystem crossing for activating RTP. In this work, we developed a simple descriptor ΔE to predict host molecules for matching the guest RTP emitters, based on the intersystem crossing via higher excited states (ISCHES) mechanism. This descriptor successfully predicted five commercially available host components to pair with naphthalimide (NA) and naphtho[2,3-c]furan-1,3-dione (2,3-NA) emitters with a high accuracy of 83 %. The yielded pairs exhibited bright yellow and green RTP with the quantum efficiency up to 0.4 and lifetime up to 1.67 s, respectively. Using these RTP pairs, we successfully achieved multi-layer message encryption. The ΔE descriptor could provide an efficient way for developing doping-induced RTP materials.

Catalytic Reductive Cross Coupling and Enantioselective Protonation of Olefins to Construct Remote Stereocenters for Azaarenes.

A novel enantioselective protonation protocol that is triggered by reductive cross coupling of olefins is reported. When under cooperative photoredox and chiral hydrogen-bonding catalytic conditions and using a terminal reductant, various α-branched vinylketones with diverse vinylazaarenes could provide important enantioenriched azaarene derivatives containing tertiary stereocenters at their remote δ-position with high yields and enantioselectivities. This reaction system is also suitable for α-branched vinylazaarenes, thus successfully assembling elusive 1,4-stereocenters. The convenient late-stage modifications of products, especially the formation of remote ε-tertiary and ε-heteroquaternary carbon stereocenters, further highlight the important synthetic value of this method. Control experiments and density functional theory (DFT) calculations were conducted to elucidate the plausible reaction mechanism and origins of regioselectivity and stereoselectivity.

In silico characterization and prediction of thiourea-like neutral bidentate halogen bond catalysts.

Preorganization is a common strategy to align halogen bond (XB) donors to form two or more halogen bonds simultaneously. Previous approaches have utilized various non-covalent interactions such as steric interactions, ππ stacking, and hydrogen bond interactions. However, some of the introduced aligning interactions may compete with halogen bond interactions if the donors are employed in catalysis. To achieve thiourea-like properties, we have designed in silico several neutral bidentate halogen bond donors in whose structures the donor moieties are connected via covalent bonds. Compared to previous XB catalyst designs, the new design does not involve other potentially competitive non-covalent interactions such as hydrogen bonds. One of the designed XB donors can deliver strong halogen bonds, with a O-I distance as short as 2.64 Å. Density functional theory (DFT) calculations predicted that our designed catalysts may catalyze important organic reactions on their own, particularly for those reactions that involve (developing) soft anions such as thiolates.

Restriction of Twisted Intramolecular Charge Transfer Enables the Aggregation-Induced Emission of 1-(N,N-Dialkylamino)-naphthalene Derivatives.

Understanding the mechanisms of aggregation-induced emission (AIE) is essential for the rational design and deployment of AIEgens toward various applications. Such a deep mechanistic understanding demands a thorough investigation of the excited-state behaviors of AIEgens. However, because of considerable complexity and rapid decay, these behaviors are often not experimentally accessible and the mechanistic comprehension of many AIEgens is lacking. Herein, utilizing detailed quantum chemical calculations, we provide insights toward the AIE mechanism of 1-(N,N-dialkylamino)-naphthalene (DAN) derivatives. Our theoretical analysis, corroborated by experimental observations, leads to the discovery that modulating the formation of the twisted intramolecular charge transfer (TICT) state (caused by the rotation of the amino groups) and managing the steric hindrance to minimize solid-state intermolecular interactions provides a plausible explanation for the AIE characteristics of DAN derivatives. These results will inspire the deployment of the TICT mechanism as a useful design strategy toward AIEgen development.

Enantioselective Addition-Alkylation of α,ß-Unsaturated Carbonyls via Bisguanidinium Silicate Ion Pair Catalysis.

Silicon hydrides, alkynylsilanes, and alkoxylsilanes were activated by fluoride in the presence of bisguanidinium catalyst to form hypervalent silicate ion pairs. These activated silicates undergo 1,4-additions with chromones, coumarins, and α-cyanocinnamic esters generating enolsilicate intermediates, for a consequent stereoselective alkylation reaction. The reduction-alkylation reaction proceeded under mild conditions using polymethylhydrosiloxane, a cheap and environmentally friendly hydride source. The addition-alkylation reactions with alkynylsilanes and alkoxylsilanes resulted in the construction of two vicinal chiral carbon centers with excellent enantioselectivities and diastereoselectivities (up to 99% ee, >99:1 dr). Density functional theory calculations and experimental NMR studies revealed that penta-coordinated silicates are crucial intermediates.

Golden Jubilee of Singapore National Institute of Chemistry (1970-2020): Celebrating its Partnership with Wiley-VCH.

This year Singapore National Institute of Chemistry (SNIC) is celebrating its golden jubilee (1970-2020). Wiley-VCH has been a steadfast partner accompanying the rapid rise of chemistry research in Singapore. In celebration of this golden jubilee, we highlight 50 significant papers published in Angewandte Chemie by scholars currently based in Singapore, covering the widest possible spectrum of chemistry research.

Kinetic and Dynamic Kinetic Resolution of Racemic Tertiary Bromides by Pentanidium-Catalyzed Phase-Transfer Azidation.

We have developed a method to afford enantiomerically enriched tertiary azides and bromides through pentanidium-catalyzed kinetic resolution (KR) of racemic tertiary bromides under base-free conditions. We found that the absence of water is crucial to attain a high selectivity factor (s). On the other hand, new experimental observations and DFT modeling led us to propose that enantioconvergent azidation of tertiary bromides proceeded through dynamic kinetic resolution (DKR). The investigations particularly identified the crucial roles of base and water in the enantioconvergent process, thus supporting the proposal that the tertiary bromide isomerizes in the presence of base and water through a SN 2X pathway.

Hyperfast Water Transport through Biomimetic Nanochannels from Peptide-Attached (pR)-pillar[5]arene.

Synthetic water channels offer great promise to replace natural aquaporins (AQPs) for making new-generation biomimetic membranes for water treatment. However, the water permeability of the current synthetic water channels is still far below that of AQPs. Here, peptide-attached (pR)-pillar[5]arene (pR-PH) channels are reported to mimic the high permeability of AQPs. It is demonstrated that the pR-PH channels with an open pore can transport water smoothly and efficiently. The pR-PH channels are competitive with AQPs in terms of water permeability and are much superior to diastereomer peptide-attached (pS)-pillar[5]arene (pS-PH) and other reported synthetic water channels. The exceptional water-transport properties of the pR-PH channels are further demonstrated in a composite polymeric membrane that incorporates the nanochannels into the top selective layer. This membrane gives a significantly improved water flux while retaining high salt rejection. The results establish a tangible foundation for developing highly efficient artificial water channel-based biomimetic membrane for water purification applications.

Metal-catalysed reactions enabled by guanidine-type ligands.

Guanidines, which exist widely in nature, have been frequently utilised as strong Brønsted bases in organic chemistry. As ligands, guanidines can have different coordination modes with the metal center. However, the exploitation of these guanidine complexes as catalysts has been much less successful. The anionic counterpart of guanidine, which is known as guanidinate, is also able to function as a ligand. The catalytic activities of metal-guanidinate complexes are of great interest to chemists. The potential of catalytic guanidine or guanidinate metal complexes to catalyse unique chemical transformations is immensely promising. This field is currently being pursued with great interest by synthetic organic chemists. In this review, the representative reactions enabled by guanidine and guanidinate metal complexes are highlighted.

Guanidine-Copper Complex Catalyzed Allylic Borylation for the Enantioconvergent Synthesis of Tertiary Cyclic Allylboronates.

An enantioconvergent synthesis of chiral cyclic allylboronates from racemic allylic bromides was achieved by using a guanidine-copper catalyst. The allylboronates were obtained with high γ/α regioselectivities (up to 99:1) and enantioselectivities (up to 99 % ee), and could be further transformed into diverse functionalized allylic compounds without erosion of optical purity. Experimental and DFT mechanistic studies support an SN 2' borylation process catalyzed by a monodentate guanidine-copper(I) complex that proceeds through a special direct enantioconvergent transformation mechanism.

Enantioselective 1,2-Anionotropic Rearrangement of Acylsilane through a Bisguanidinium Silicate Ion Pair.

Highly enantioselective bisguanidinium-catalyzed tandem rearrangements of acylsilanes are reported. The acylsilanes were activated via an addition of fluoride on the silicon to form a penta-coordinate anionic silicate intermediate. The silicate then underwent alkyl or aryl group migration from the silicon atom to the neighboring carbonyl carbon atom (1,2-anionotropic rearrangement), followed by [1,2]-Brook rearrangement to provide the secondary alcohols in high yields with excellent enantioselectivities (up to 95% ee). The isolation of an α-silylcarbinol intermediate as well as DFT calculations revealed that the 1,2-anionotropic rearrangement occurred via a bisguanidinium silicate ion pair, which is the stereodetermining step. The chiral center formed is then retained without inversion through the subsequent [1,2]-Brook rearrangement. Crotyl acylsilanes were smoothly transformed into homoallylic linear crotyl alcohols with retention of E/Z geometry, and no branched alcohols were detected. This clearly suggested that the 1,2-anionotropic rearrangement occurred through a three-membered instead of a five-membered transition state.

(Guanidine)copper Complex-Catalyzed Enantioselective Dynamic Kinetic Allylic Alkynylation under Biphasic Condition.

Highly enantioselective allylic alkynylation of racemic bromides under biphasic condition is furnished in this report. This approach employs functionalized terminal alkynes as pro-nucleophiles and provides 6- and 7-membered cyclic 1,4-enynes with high yields and excellent enantioselectivities (up to 96% ee) under mild conditions. Enantioretentive derivatizations highlight the synthetic utility of this transformation. Cold-spray ionization mass spectrometry (CSI-MS) and X-ray crystallography were used to identify some catalytic intermediates, which include guanidinium cuprate ion pairs and a copper-alkynide complex. A linear correlation between the enantiopurity of the catalyst and reaction product indicates the presence of a copper complex bearing a single guanidine ligand at the enantio-determining step. Further experimental and computational studies supported that the alkynylation of allylic bromide underwent an anti-SN2' pathway catalyzed by nucleophilic cuprate species. Moreover, metal-assisted racemization of allylic bromide allowed the reaction to proceed in a dynamic kinetic fashion to afford the major enantiomer in high yield.

Phase-Transfer and Ion-Pairing Catalysis of Pentanidiums and Bisguanidiniums.

Catalysts accelerate biological processes and organic reactions in a controlled and selective fashion. There are continuing efforts in asymmetric catalysis to develop efficient catalysts with broad reaction scope and industrial practicability. Among the various modes of asymmetric catalysis, phase-transfer catalysis has attracted intense interest due to its facile scale up and low catalyst loading. Chiral quaternary ammonium and phosphonium salts are well-studied classes of chiral phase-transfer catalysts, and they are typically composed of sp3-hybridized quaternary onium salts. In this Account, we describe our recent attempts to develop N-sp2-hybridized guanidinium-type salts as efficient phase-transfer catalysts as well as ion-pair catalysis based on N-sp2 hybridized bisguanidinium-type salts. The sp2-quaternized ammonium salts, pentanidiums, which contain five nitrogen atoms in conjugation, displayed remarkable phase-transfer catalytic efficiency. We have shown that pentanidium can catalyze Michael additions of tert-butyl glycinate-benzophenone Schiff bases with various α,ß-unsaturated acceptors, such as vinyl ketones, acrylates, and chalcones, in high enantioselectivities. The structurally amendable pentanidium phase-transfer catalysts supply diverse reactivity and selectivity to various other organic transformations, such as α-hydroxylation of 3-substituted-2-oxindoles, Michael addition of 3-alkyloxindoles with vinyl sulfone, and alkylation reactions of sulfenate anions and dihydrocoumarins. Pentanidium salts are applicable to enantioselective transformations on a preparative scale at low catalyst loading, allowing for the synthesis of a broad range of enantiopure compounds. From computational and experimental results, we also proposed that the halogenated pentanidium catalysts participated in halogen bonding and that this contributed to the excellent stereocontrol in alkylation reactions. Subsequently, we determined that chiral cations can direct functional anions besides basic anions in traditional Brønsted basic phase-transfer reactions, including metal-centered anions. We identified dicationic bisguanidinium as an excellent ion-pairing catalyst, first demonstrating that bisguanidinium formed an ion pair with permanganate and directed the anion in enantioselective dihydroxylation and oxohydroxylation of a,ß-unsaturated esters. This initial success led us to explore chiral cationic ion-pairing catalysis as a general mode of catalysis. This mode of catalysis is at the interphase between organocatalysis, phase-transfer catalysis and organometallic catalysis. We then identified bisguanidinium diphosphatobisperoxotungstate and bisguanidinium dinuclear oxodiperoxomolybdosulfate ion pairs as the active catalysts in enantioselective sulfoxidations using aqueous H2O2 as the oxidant. The structure of the bisguanidinium dinuclear oxodiperoxomolybdosulfate ion pair was elucidated using single-crystal X-ray analysis. Bisguanidinium-catalyzed sulfoxidations emerged as a practical methodology for the synthesis of enantioenriched sulfoxides including armodafinil and lansoprazole, which are commercial drugs. Finally, we are also able to show that pentanidium and bisguanidinium hypervalent silicates are intermediates in enantioselective alkylations using silylamide as a Brønsted probase.

Repurposing the anticancer drug cisplatin with the aim of developing novel Pseudomonas aeruginosa infection control agents.

Antibiotic resistance threatens effective treatment of microbial infections globally. This situation has spurred the hunt for new antimicrobial compounds in both academia and the pharmaceutical industry. Here, we report how the widely used antitumor drug cisplatin may be repurposed as an effective antimicrobial against the nosocomial pathogen Pseudomonas aeruginosa. Cisplatin was found to effectively kill strains of P. aeruginosa. In such experiments, transcriptomic profiling showed upregulation of the recA gene, which is known to be important for DNA repair, implicating that cisplatin could interfere with DNA replication in P. aeruginosa. Cisplatin treatment significantly repressed the type III secretion system (T3SS), which is important for the secretion of exotoxins. Furthermore, cisplatin was also demonstrated to eradicate in vitro biofilms and in vivo biofilms in a murine keratitis model. This showed that cisplatin could be effectively used to eradicate biofilm infections which were otherwise difficult to be treated by conventional antibiotics. Although cisplatin is highly toxic for humans upon systemic exposure, a low toxicity was demonstrated with topical treatment. This indicated that higher-than-minimal inhibitory concentration (MIC) doses of cisplatin could be topically applied to treat persistent and recalcitrant P. aeruginosa infections.