Bicyclic Guanidine Research Articles

Aminolysis of five-membered cyclic carbonate catalyzed by guanidines: Solvent effects on the formation of guanidine dimers

This paper presents an experimental and computational investigation on the aminolysis reactions of five-membered cyclic carbonate (5CC) catalyzed by mono- or bi-cyclic guanidines in various solvents. For both liquid and solid 5CC substrate employed, higher polar solvent favors the monomeric active guanidine responsible for the catalytic aminolysis reactions. The formation of the dimeric state of the guanidine catalyst, which is seemingly inert to catalytic activity, is prevented by the bulkier substituents connecting to the guanidine moiety. Extensive DFT calculations further confirm that the relative stabilities of dimeric guanidine is depended on both the polarities of the solvents and the bulkiness of the substituents connected to the guanidine moiety, which is consistent with the experimental kinetic results.

Small Cationic Boron and Boron‐Nitrogen Rings, Synthesized from Diboranes with Charge‐Delocalizing Guanidinate Substituents

AbstractWe report the straightforward synthesis and characterization of small polycationic boron and boron‐nitrogen rings, stabilized by charge‐delocalizing guanidinate substituents. Reaction between a ditriflato‐diborane with two electron‐donating bridging bicyclic guanidinate substituents and the corresponding dihydrido‐diborane leads to a dicationic B4 ring with a 4c,4e‐bond in the planar rhomboid B4 skeleton. Reaction of the same ditriflato‐diborane with the corresponding diazido‐diborane gives a dicationic compound with a B4N2 core. On the basis of experimental data in combination with quantum‐chemical calculations, pathways leading to these dicationic boron and boron‐nitrogen rings are suggested, and further preliminary studies demonstrate the scope of this strategy for the synthesis of polycationic boron‐nitrogen rings.

Crystal structures of sulfonamide protected bicyclic guanidines: (S)-8-{[(tert-butyl-dimethyl-sil-yl)-oxy]meth-yl}-1-[(2,2,4,6,7-penta-methyl-2,3-di-hydro-benzo-furan-5-yl)sulfon-yl]-1,3,4,6,7,8-hexa-hydro-2H-pyrimido[1,2-a]pyrimidin-1-ium tri-fluoro-methane-sulfonate and (S)-8-(iodo-meth-yl)-1-tosyl-1,3,4,6,7,8-hexa-hydro-2H-pyrimido[1,2-a]pyrimidin-1-ium iodide.

Two compounds, (S)-8-{[(tert-butyl-dimethyl-sil-yl)-oxy]meth-yl}-1-[(2,2,4,6,7-penta-methyl-2,3-di-hydro-benzo-furan-5-yl)sulfon-yl]-1,3,4,6,7,8-hexa-hydro-2H-pyrimido[1,2-a]pyrimidin-1-ium tri-fluoro-methane-sulfonate, C27H46N3O4SSi+·CF3O3S-, (1) and (S)-8-(iodo-meth-yl)-1-tosyl-1,3,4,6,7,8-hexa-hydro-2H-pyrimido[1,2-a]pyrimidin-1-ium iodide, C15H21IN3O2S+·I-, (2), have been synthesized and characterized. They are bicyclic guanidinium salts and were synthesized from N-(tert-but-oxy-carbon-yl)-l-me-thio-nine (Boc-l-Met-OH). The guanidine is protected by a 2,2,4,6,7-penta-methyl-dihydro-benzo-furan-5-sulfonyl (Pbf, 1) or a tosyl (2) group. In the crystals of both compounds, the guanidinium group is almost planar and the N-H forms an intra-molecular hydrogen bond in a six-membered ring to the oxygen atom of the sulfonamide protecting group.

Bicyclic guanidine superbase carboxylate salts for cellulose dissolution.

Bicyclic guanidines are utilized in organic synthesis as base catalysts or reagents. They also offer a platform for coordination chemistry, for example in CO2 activation, and their carboxylate salts offer an efficient media for cellulose dissolution. We have studied a series of bicyclic guanidines with varying ring sizes and with varying methyl substituents with a specific aim to find hydrolytically stable acetate salts for dissolution and processing of cellulose. Different superbase synthesis pathways were tested, followed by hydrolytic stability and cellulose dissolution capacity tests. The synthesis pathways were designed to enable the scale up of the production of the superbases considering the availability of the starting molecules and the feasibility of the synthesis. As a result, we found several hydrolytically stable bicyclic guanidine structures, which can overcome many of the reoccurring problems as carboxylate salts or free bases.

Bicyclic Guanidine Promoted Mechanistically Divergent Depolymerization and Recycling of a Biobased Polycarbonate.

We here report the organocatalytic and temperature-controlled depolymerization of biobased poly(limonene carbonate) providing access to its trans-configured cyclic carbonate as the major product. The base TBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene) offers a unique opportunity to break down polycarbonates via end-group activation or main chain scission pathways as supported by various controls and computational analysis. These energetically competitive processes represent an unprecedented divergent approach to polycarbonate recycling. The trans limonene carbonate can be converted back to its polycarbonate via ring-opening polymerization using the same organocatalyst in the presence of an alcohol initiator, offering thus a potential circular and practical route for polycarbonate recycling.

Bicyclic Guanidine Promoted Mechanistically Divergent Depolymerization and Recycling of a Biobased Polycarbonate

AbstractWe here report the organocatalytic and temperature‐controlled depolymerization of biobased poly(limonene carbonate) providing access to its trans‐configured cyclic carbonate as the major product. The base TBD (1,5,7‐triazabicyclo[4.4.0]dec‐5‐ene) offers a unique opportunity to break down polycarbonates via end‐group activation or main chain scission pathways as supported by various controls and computational analysis. These energetically competitive processes represent an unprecedented divergent approach to polycarbonate recycling. The trans limonene carbonate can be converted back to its polycarbonate via ring‐opening polymerization using the same organocatalyst in the presence of an alcohol initiator, offering thus a potential circular and practical route for polycarbonate recycling.

1,3-Diaza-Claisen Rearrangements of Vinyl Pyrrolidines Tethered to In Situ Generated Carbodiimides Afford Ring-Expanded [9,5]- and [9,6]-Bicyclic Guanidines

Vinyl pyrrolidines tethered to isothioureas are activated to the corresponding carbodiimides with AgOTf and Et3N. Intramolecular addition of the vinyl pyrrolidine amine to the carbodiimide followed by a 1,3-diaza-Claisen rearrangement affords [9,5]- and [9,6]-bicyclic guanidines depending on the tether length in good to excellent yields. Density functional theory calculations reveal that the pathway involving intramolecular addition of the amine to carbodiimide to afford a zwitterionic intermediate followed by the zwitterionic 1,3-diaza-Claisen rearrangement was consistently a higher energy pathway than the path involving protonation of the zwitterionic intermediate followed by the cationic 1,3-diaza-Claisen rearrangement.

Cationic Symmetrically and Unsymmetrically Substituted Diboranes and Bis(diboranes) with Direct Boron‐Boron Bond: Synthesis by Substitution, Stability and Properties

AbstractStarting with diboranes with two electron‐rich bridging bicyclic guanidinate substituents, we report in this work the rational synthesis of new dicationic symmetrically‐ and unsymmetrically‐substituted diboranes in SN1‐type substitution reactions in which triflato or bromo substituents are replaced by neutral Lewis bases. The scope of such substitution reactions and their rate are analyzed with different pyridine derivatives of variable Lewis basicity. The first substitution step, leading to a monocationic diborane with one anionic substituent (triflate or bromide) and one neutral Lewis base, proceeds much faster than the second substitution step leading to a dicationic diborane with two neutral Lewis bases. The different time scales for the substitution steps could be used to conveniently synthesize in one‐pot reactions several dicationic, unsymmetrically‐substituted diboranes with two different neutral Lewis bases.

Achmatowicz approach to the asymmetric synthesis of (+)- and (−)-monanchorin

The full account of our development of a de novo asymmetric total synthesis of (+)-monanchorin has been reported. The optimized synthesis provided access to either enantiomer of the guanidine alkaloid natural product in nine steps from the commodity chemicals furan and caproic acid. The route relied upon the asymmetric Noyori hydrogen transfer reduction of an achiral acylfuran to introduce the absolute stereochemistry. In addition, an Achmatowicz rearrangement, a diastereoselective palladium-catalyzed glycosylation, a reductive amination and an acid-catalyzed bicyclic guanidine mixed acetal formation were used to complete the synthesis.

Synthesis of multifunctional 4-hydroxymethyl 2-oxazolidinones from glycidyl carbamate derivatives catalyzed by bicyclic guanidine

4-Hydroxymethyl 2-oxazolidinones have been successfully synthesized under mild conditions by the intramolecular cyclization of glycidyl carbamate derivatives with a bicyclic guanidine as the efficient catalyst. This reaction system, which is also applicable to the multifunctional compounds, can provide bi- and tri-functional alcohols having oxazolidinone moieties.

Synthesis of poly(hydroxyurethane) from 5‐membered cyclic carbonate under mild conditions in the presence of bicyclic guanidine and their reaction process

AbstractA series of amines are applied as catalysts in the aminolysis reactions of five‐membered cyclic carbonate (5CC). Kinetic results display that TBD, which has a guanidine structure, exhibits the best catalytic efficacy and the reaction rate constant is about 100 times higher than the blank system without catalyst. The reaction medium, NMP is found to be as both solvent and promoter in the aminolysis of 5CC. Finally, with TBD and NMP as catalyst and solvent, respectively, the polymerization of bis‐functional 5CC (B5CC) and 1, 6‐diaminohexane can proceed almost 100% at room temperature in less than 4 h to obtain poly(hydroxyurethane)s (PHUs) with moderate molecular weight.

Synthesis of Saxitoxin and Its Derivatives.

The chiral synthesis of (+)-saxitoxin and its derivatives is described. Two consecutive carbon-nitrogen bonds at C-5 and C-6 in saxitoxin were effectively installed by the sequential Overman rearrangement of an allylic vicinal diol derived from d-malic acid. The bicyclic guanidine unit was constructed by the intramolecular aminal formation of an acyclic bis-guanidine derivative possessing a ketone carbonyl at C-4. From the bicyclic aminal intermediate, (+)-saxitoxin, (+)-decarbamoyl-β-saxitoxinol [(+)-dc-β-saxitoxinol], and the unnatural skeletal isomer, (-)-iso-dc-saxitoxinol, were synthesized.

New insights into the Lewis acidity of guanidinium species: Lewis acid interaction provides reactivity

A unique reactivity pattern in which the catalyst and the reactant motifs are joined together in a substrate is investigated using density functional theory calculations. The versatile triaza CN3 functionality in bicyclic guanidines is combined with a diversity of functional groups about the molecular scaffold which, upon addition of N-nucleophiles, transfers the substrate to its hitherto unreported tricyclic analogues. Unprecedentedly, the guanidine/guanidinium dyad advances the reaction by displaying all possible chemical functionalities, including Brønsted acid–base and Lewis acid–base activation modes. This study presents the first example of a guanidine-catalyzed thioamidation reaction. Furthermore, it evidences the first participation of guanidinium’s Lewis acid activation in a cyclization reaction. In addition to the several mono- and bifunctional activation modes, two rare examples of Lewis acid interaction were observed, which provides important mechanistic points. The first one in the thioamidation step suggests the preference for stepwise elimination of MeSH over the alternative concerted mechanisms. However, the second one in the N-Michael addition step provides a new insight into the Lewis acidity activation mode of guanidinium species. The interaction first traps the side branch of the substrate containing the nucleophilic motif and then, by positioning the anionic nucleophile and the Michael acceptor site in close proximity, navigates the regioselective N-Michael addition.

Urupocidin C: a new marine guanidine alkaloid which selectively kills prostate cancer cells via mitochondria targeting

New bicyclic guanidine alkaloid, urupocidin C (Ur-C) along with the previously known urupocidin A (Ur-A) were isolated from the rare deep-sea marine sponge Monanchora pulchra, harvested in Northwestern Pacific waters. The unique structure of Ur-C was elucidated using 1D and 2D NMR spectroscopy as well as mass spectra. We discovered a promising selectivity of both alkaloids for human prostate cancer (PCa) cells, including highly drug-resistant lines, compared to non-malignant cells. In cancer cells, marine derived compounds were able to induce G1- and S-cell cycle arrest as well as caspase-mediated cell death. For the first time we have identified mitochondrial targeting as a central mechanism of anticancer action for these and similar molecules. Thus, treatment with the isolated alkaloids resulted in mitochondrial membrane permeabilization consequently leading to the release of cytotoxic mitochondrial proteins to cellular cytoplasm, ROS upregulation, consequent activation of caspase-9 and -3, followed by PARP cleavage, DNA fragmentation, and apoptosis. Moreover, synergistic effects were observed when Ur-A and Ur-C were combined with clinically approved PARP inhibitor olaparib. Finally, these alkaloids exhibited additive effects in combination with docetaxel and androgen receptor inhibitor enzalutamide, both applied in PCa therapy. In conclusion, urupocidin-like compounds are promising lead molecules for the development of new drugs for the treatment of advanced PCa.

"Intrinsic" Anion Exchange Polymers through the Dissociation of Strong Basic Groups: PPO with Grafted Bicyclic Guanidines.

We synthesized anion exchange polymers by a reaction of chloromethylated poly(2,6-dimethyl-1,4-phenylene)oxide (PPO) with strongly basic 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD). TBD contains secondary and tertiary amine groups in the guanidine portion. To favor the functionalization with the secondary amine, TBD was activated with butyl lithium. The yield of amine formation via the reaction of the benzyl chloride moiety with TBD was 85%. Furthermore, we prepared polymers with quaternary ammonium groups by the reaction of PPO-TBD with CH3I. The synthesis pathways and ionomer structure were investigated by NMR spectroscopy. The thermal decomposition of both ionomers, studied by thermogravimetry, started above 200 °C, corresponding to the loss of the basic group. The ion exchange capacities, water uptake and volumetric swelling are also reported. The “intrinsic” anion conductivity of PPO-TBD due to the dissociation of grafted TBD was in the order of 1 mS/cm (Cl form). The quaternized ionomer (PPO-TBD-Me) showed an even larger ionic conductivity, above 10 mS/cm at 80 °C in fully humidified conditions.

Marine Bacterium Vibrio sp. CB1-14 Produces Guanidine Alkaloid 6-epi-Monanchorin, Previously Isolated from Marine Polychaete and Sponges.

Twenty-three bacterial strains were isolated from the secreted mucus trapping net of the marine polychaete Chaetopterus variopedatus (phylum Annelida) and twenty strains were identified using 16S rRNA gene analysis. Strain CB1-14 was recognized as a new species of the genus Vibrio using the eight-gene multilocus sequence analysis (MLSA) and genome sequences of nineteen type Vibrio strains. This Vibrio sp. was cultured, and 6-epi-monanchorin (2), previously isolated from the polychaete and two sponge species, was found in the cells and culture broth. The presence of the 6-epi-monanchorin was confirmed by its isolation followed by 1H NMR and HRESIMS analysis. These results showed the microbial origin of the bicyclic guanidine alkaloid 2 in C. variopedatus.

Weak acids with super-electron-donor dimetal complexes: Synergy in bifunctional activity

Dimetal paddlewheel complexes with bicyclic guanidine ligands are extremely strong thermodynamic electron donors. As a probe of the chemical potential and sites for chemical reactivity of these complexes, the interaction of Mo2(TEhpp)4 with weak acids was investigated (TEhpp is the anion of the bicyclic guanidine 3,3,9,9-tetraethyl-1,5,7-triazabicyclo[4.4.0.]dec-4-ene). Mo2(TEhpp)4 is readily protonated by acetic acid and trifluoroacetic acid as expected, but surprisingly by a mechanism that is more complicated than a simple acid-base proton exchange. Electrochemistry measurements of the shifts in potentials with successive additions of acid reveals that the conjugate base of the acid plays a critical role throughout the reaction. Computations indicate that initially the acid hydrogen bonds to a TEhpp nitrogen atom bound to the metal, and then a facile rearrangement of the conjugate base toward the axial site of the Mo–Mo bond concomitantly results in protonation of the nitrogen atom. Interestingly, the dimetal complex is bifunctional in this process, acting as a nucleophile at the nitrogen atoms of the TEhpp ligands, and as an electrophile at the Mo–Mo axial bond sites. The protonation requires a novel synergism of these disparate bonding interactions, in which protonation is not favored without enhancement by the coordinated base, and coordination of the base is enhanced by the protonation.

Optimizing Amine‐Mediated Alkyne–Allene Isomerization to Improve Benzannulation Cascades: Synergy between Theory and Experiments

A synergy between theory and experiments leads to a milder protocol for base‐mediated high‐temperature benzannulation of alkynylpyridine substrates. Computational analysis identifies mechanistic and energetic nuances in the previously postulated 1,3‐proton transfer isomerization which results in replacement of DBU with a bicyclic guanidine, 1,5,7‐triazabicyclo[4.4.0]dec‐5‐ene (TBD). We have also outlined the general stereoelectronic and geometric hurdles for the design of 1,3‐proton transfer catalysts. Considerable reductions in time, temperature, and equivalents of base underscore the potential of computational analysis to impact experimental design in the laboratory.

Diphenyl Carbonate: A Highly Reactive and Green Carbonyl Source for the Synthesis of Cyclic Carbonates

A practical, safe, and highly efficient carbonylation system involving a diphenyl carbonate, an organocatalyst, and various diols is presented herein and produces highly valuable cyclic carbonates. In reactions with a wide range of diols, diphenyl carbonate was activated by bicyclic guanidine 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) as a catalyst, which successfully replaced highly toxic and unstable phosgene or its derivatives while maintaining the desired high reactivity. Moreover, this new system can be used to synthesize sterically demanding cyclic carbonates such as tetrasubstituted pinacol carbonates, which are not accessible via other conventional methods.

Enantioselective Biginelli Reaction of Aliphatic Aldehydes Catalyzed by a Chiral Phosphoric Acid: A Key Step in the Synthesis of the Bicyclic Guanidine Core of Crambescin A and Batzelladine A

An efficient chiral phosphoric acid catalyzed Biginelli reaction for the synthesis of optically pure 4-alkyl-3,4-dihydropyrimidin-2-(1H)-ones has been developed, with a wide range of the desired products being obtained in moderate to high yields with good to excellent enantioselectivities (up to >99% ee after one recrystallization). The synthetic utility of this reaction is illustrated in various aliphatic bicyclic guanidine compounds, which is applied in the formal synthesis of the bicyclic guanidine core of crambescin A and batzelladine A.