Enantioselective Cascade Reactions of Aminocatalytic Dienamines and Trienamines Initiated by a Cycloaddition Reaction.

Cycloadditions are widely accepted as a group of reactions that rapidly generate molecular complexity. Being highly atom economic and often predictable, these reactions can generate up to four stereogenic centers and two C-C (or C-X) bonds in one reaction step. During the last two decades, asymmetric aminocatalysis has shown to be a successful strategy for controlling stereoselectivity and enabling reactivity of cycloaddition reactions. By increasing the conjugation of the carbonyl species employed, dienamines and trienamines can be catalytically formed. Not only can these facilitate the cycloaddition, often accompanied by high levels of stereocontrol, but they also leave a residual enamine or carbonyl (by hydrolysis) in the cycloadduct. This residual functionality can engage in further intramolecular reactions generating complex cyclic systems in a one-pot cascade manner. In this regard, asymmetric aminocatalysis can add another layer of complexity to the already complex nature of cycloadditions. In this review, we will present the general concept of such reactivity patterns of dienamines and trienamines, and hereafter showcase examples in the literature. We aspire that the chemical community can use these concepts to design new enantioselective aminocatalytic cascade reactions to access enantioenriched, complex compounds, and perhaps use these in complex molecule synthesis.

Synthesis, Molecular Docking, and Anticancer Screening of Ester-based Thiazole Derivatives.

This study investigates the potential of five compounds as novel anticancer agents. We examined their efficacy, mechanisms of action, and impact on various cancer cell lines, through a comprehensive set of experiments. Notably, compound 3e demonstrated superior activity compared to the positive control cisplatin, with a GI50 value of 6.3±0.7 µM against the breast cancer cell line (MCF-7). Compound 3b also displayed remarkable growth inhibition, yielding GI50 values of 8.7±0.2 µM (MCF-7) and 8.9±0.5 µM against the colon cancer cell line (HCT-116). Cell count experiments further confirmed the potent inhibitory effects of compounds 3e, 3b, and 3c on MCF-7 and HCT-116 cell growth. Compound 3e demonstrated a reduction of 55-60 % at GI50 and complete inhibition (100 %) at 2x GI50. Compound 3b exhibited 50-55 % reduction (GI50) and 90-95 % inhibition (2x GI50) in HCT-116 cells. Compound 3c displayed 75-80 % inhibition (2x GI50) and 35-40 % inhibition (GI50) in HCT-116 cells. In-depth mechanistic investigations unveiled valuable insights into the mode of action of compound 3e. The cell-cycle assay demonstrated G2/M phase arrest, DNA damage, and caspase-mediated apoptosis in both MCF-7 and HCT-116 cells. Caspase activation indicated a significant increase in apoptosis following exposure to compound 3e. Furthermore, compound 3e induced reactive oxygen species (ROS) production, influencing HCT-116 and MCF-7 cells differently. Elevated ROS production in HCT-116 cells and distinct effects in MCF-7 cells contribute to a deeper understanding of the cytotoxic mechanisms of compound 3e. Overall, these findings highlight the potential of the investigated compounds, particularly compound 3e, as effective inducers of apoptosis in cancer cells. Mechanistic insights into cell cycle arrest, caspase-mediated apoptosis, and ROS modulation provide a comprehensive understanding of their cytotoxic effects. This study offers significant contribution to the development of promising anticancer agents and their therapeutic applications.

Alcohols as Efficient Intermolecular Initiators for a Highly Stereoselective Polyene Cyclisation Cascade.

The use of benzylic and allylic alcohols in HFIP solvent together with Ti(Oi Pr)4 has been shown to trigger a highly stereoselective polyene cyclisation cascade. Three new carbon-carbon bonds are made during the process and complete stereocontrol of up to five new stereogenic centers is observed. The reaction is efficient, has high functional group tolerance and is atom-economic generating water as a stoichiometric by-product. A new polyene substrate-class is employed, and subsequent mechanistic studies indicate a stereoconvergent mechanism. The products of this reaction can be used to synthesize steroid-analogues in a single step.

N-Fluoroalkylated Morpholinos - a New Class of Nucleoside Analogues.

The first concise and efficient synthesis of some fluorine-containing morpholino nucleosides has been developed. One synthetic strategy was based on the oxidative ring cleavage of the vicinal diol unit of uridine, cytidine adenosine and guanosine derivatives, followed by cyclisation of the dialdehyde intermediates by double reductive amination with fluorinated primary amines to obtain various N-fluoroalkylated morpholinos. Another approach involved cyclisation of the diformyl intermediates with ammonia source, followed by dithiocarbamate formation and desulfurization-fluorination with diethylaminosulfur trifluoride yielding the corresponding morpholine-based nucleoside analogues with a N-CF3 element in their structure.

Synthesis of a Cyclooctapeptide, Cyclopurpuracin, and Evaluation of Its Antimicrobial Activity.

Cyclopurpuracin is a cyclooctapeptide isolated from the methanol extract of Annona purpurea seeds with a sequence of cyclo-Gly-Phe-Ile-Gly-Ser-Pro-Val-Pro. In our previous study, the cyclisation of linear cyclopurpuracin was problematic; however, the reversed version was successfully cyclised even though the NMR spectra revealed the presence of a mixture of conformers. Herein, we report the successful synthesis of cyclopurpuracin using a combination of solid- and solution-phase synthetic methods. Initially, two precursors of cyclopurpuracin were prepared, precursor linear A (NH2-Gly-Phe-Ile-Gly-Ser(t-Bu)-Pro-Val-Pro-OH) and precursor linear B (NH-Pro-Gly-Phe-Ile-Gly-Ser(t-Bu)-Pro-Val-OH, and various coupling reagents and solvents were trialled to achieve successful synthesis. The final product was obtained when precursors A and B were cyclised using the PyBOP/NaCl method, resulting in a cyclic product with overall yields of 3.2% and 3.6%, respectively. The synthetic products were characterised by HR-ToF-MS, 1H-NMR, and 13C-NMR, showing similar NMR profiles to the isolated product from nature and no conformer mixture. The antimicrobial activity of cyclopurpuracin was also evaluated for the first time against S. aureus, E. coli, and C. albicans, showing weak activity with MIC values of 1000 µg/mL for both synthetic products, whereas the reversed cyclopurpuracin was more effective with an MIC of 500 µg/mL.

Epimerisation in Peptide Synthesis.

Epimerisation is basically a chemical conversion that includes the transformation of an epimer into another epimer or its chiral partner. Epimerisation of amino acid is a side reaction that sometimes happens during peptide synthesis. It became the most avoided reaction because the process affects the overall conformation of the molecule, eventually even altering the bioactivity of the peptide. Epimerised products have a high similarity of physical characteristics, thus making it difficult for them to be purified. In regards to amino acids, epimerisation is very important in keeping the chirality of the assembled amino acids unchanged during the peptide synthesis and obtaining the desirable product without any problematic purification. In this review, we report several factors that induce epimerisation during peptide synthesis, including how to characterise and affect the bioactivities. To avoid undesirable epimerisation, we also describe several methods of suppressing the process.

Dual Activation of Unsaturated Amides with Schwartz's Reagent: A Diastereoselective Access to Cyclopentanols and N,O-Dimethylcyclopentylhydroxylamines.

The diastereoselective access to cyclopentanols and N,O-dimethylcyclopentylhydroxylamines from 4-pentenoic acid-derived Weinreb amides is described. Based on the concomitant generation of both the nucleophilic and the electrophilic poles by hydrozirconation of the amide and the C=C double bond, the cyclisation may be tuned towards cyclopentanols or N,O-dimethylcyclopentylhydroxylamines depending on the ring-closure promotor. An extension to cis 3-substituted N,O-dimethylcyclohexylhydroxylamines is also presented.

Elucidating the structure and cytochrome P450-mediated mechanism for novel metabolites of GDC-0575 in rats.

1. GDC-0575 is an ATP-competitive small-molecule inhibitor of ChK1 that is being developed by Genentech for the treatment of various human malignancies.2. In a radiolabeled mass balance study of GDC-0575 in rats, two novel metabolites, named M12 (-71 Da,) and M17 (+288 Da), were detected as abundant circulating metabolites.3. Subsequent mass spectrometry and nuclear magnetic resonance analysis showed that M12 was a cyclized metabolite of GDC-0575, whereas M17 was its heterodimer to the parent. We further determined that M12 was mainly generated by cytochrome P450 (Cyp) 2d2.4. We proposed the potential mechanism was initiated by the oxidation on the pyrrole ring and subsequent cyclisation of the free primary amine onto C-3 of the pyrrole ring. This was followed by expulsion of cyclopropylcarboxamide and a loss of water to form intermediate I, which can be further oxidised to form M12, or dimerise with another molecule of GDC-0575 as nucleophile to form M17.5. To verify this hypothesis, we attempted to trap the intermediate I with glutathione (GSH) trapping assay and the GSH conjugate on the pyrrole ring was identified. This suggests the oxidation on the pyrrole led to reactive metabolite formation and supported this proposed mechanism.

Convenient Synthesis of N-Heterocycle-Fused Tetrahydro-1,4-diazepinones.

A general approach towards the synthesis of tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one, tetrahydro[1,4]diazepino[1,2-a]indol-1-one and tetrahydro-1H-benzo[4,5]imidazo[1,2-a][1,4]diazepin-1-one derivatives was introduced. A regioselective strategy was developed for synthesizing ethyl 1-(oxiran-2-ylmethyl)-1H-pyrazole-5-carboxylates from easily accessible 3(5)-aryl- or methyl-1H-pyrazole-5(3)-carboxylates. Obtained intermediates were further treated with amines resulting in oxirane ring-opening and direct cyclisation-yielding target pyrazolo[1,5-a][1,4]diazepin-4-ones. A straightforward two-step synthetic approach was applied to expand the current study and successfully functionalize ethyl 1H-indole- and ethyl 1H-benzo[d]imidazole-2-carboxylates. The structures of fused heterocyclic compounds were confirmed by 1H, 13C, and 15N-NMR spectroscopy and HRMS investigation.

Design, synthesis and evaluation of amino-3,5-dicyanopyridines and thieno[2,3-b]pyridines as ligands of adenosine A1 receptors for the potential treatment of epilepsy.

Due to the implication of adenosine in seizure suppression, adenosine-based therapies such as adenosine receptor (AR) agonists have been investigated. This study aimed at investigating thieno[2,3-b]pyridine derivatives as non-nucleoside A1 agonists that could be used in pharmaco-resistant epilepsy (PRE). Compound 7c (thieno[2,3-b]pyridine derivative), displayed good binding affinity to the rA1 AR (K i = 61.9 nM). This could be a breakthrough for further investigation of this heterocyclic scaffold as potential ligand. In silico evaluation of this compound raised bioavailability concerns but performed well on drug-likeness tests. The effect of intramolecular cyclisation that occurs during synthesis of thieno[2,3-b]pyridines from the lead compounds, amino-3,5-dicyanopyridine derivatives (6a-s) in relation to AR binding was also evaluated. A significant loss of activity against rA1/rA2A ARs with cyclisation was revealed. Amino-3,5-dicyanopyridines exhibited greater affinity towards rA1 ARs (K i < 10 nM) than rA2A. Compound 6c had the best rA1 affinity (K i = 0.076 nM). Novel compounds (6d, 6k, 6l, 6m, 6n, 6o, 6p) were highly selective towards rA1 AR (K i between 0.179 and 21.0 nM). Based on their high selectivity for A1 ARs, amino-3,5-dicyanopyridines may be investigated further as AR ligands in PRE with the right structural optimisations and formulations. A decrease in rA1 AR affinity is observed with intramolecular cyclisation that occurs during synthesis of thieno[2,3-b]pyridines (7a, 7d, 7c) from amino-3,5-dicyanopyridine derivatives (6a, 6f, 6g).

Cytochrome P450Blt Enables Versatile Peptide Cyclisation to Generate Histidine- and Tyrosine-Containing Crosslinked Tripeptide Building Blocks.

We report our investigation of the utility of peptide crosslinking cytochrome P450 enzymes from biarylitide biosynthesis to generate a range of cyclic tripeptides from simple synthons. The crosslinked tripeptides produced by this P450 include both tyrosine-histidine (A-N-B) and tyrosine-tryptophan (A-O-B) crosslinked tripeptides, the latter a rare example of a phenolic crosslink to an indole moiety. Tripeptides are easily isolated following proteolytic removal of the leader peptide and can incorporate a wide range of amino acids in the residue inside the crosslinked tripeptide. Given the utility of peptide crosslinks in important natural products and the synthetic challenge that these can represent, P450 enzymes have the potential to play roles as important tools in the generation of high-value cyclic tripeptides for incorporation in synthesis, which can be yet further diversified using selective chemical techniques through specific handles contained within these tripeptides.

Rerouting and Improving Dauc-8-en-11-ol Synthase from Streptomyces venezuelae to a High Yielding Biocatalyst.

The dauc-8-en-11-ol synthase from Streptomyces venezuelae was investigated for its catalytic activity towards alternative terpene precursors, specifically designed to enable new cyclisation pathways. Exchange of aromatic amino acid residues at the enzyme surface by site-directed mutagenesis led to a 4-fold increase of the yield in preparative scale incubations, which likely results from an increased enzyme stability instead of improved enzyme kinetics.

Transition Metal/Lewis Acid Catalyzed Reactions of Zerumbone for Diverse Molecular Motifs.

Zerumbone is a naturally occurring humulene type sesquiterpene, isolated from the rhizomes of Zingiber zerumbet (L.) Smith with excellent therapeutic potential and is recognized as a valuable synthon for the construction of diverse array of natural product motifs. In this review, we intended to highlight our achievements in utilizing abundant natural product zerumbone and its derivatives for the development of pharmacologically relevant molecular scaffolds. We provided an account of the transition-metal catalyzed 1,4-conjugate addition reactions of zerumbone and its derivatives along with palladium-catalyzed cross-couplings, transition metal-based Lewis acid promoted interrupted Nazarov cyclisation reaction with substituted indoles and transannular cyclizations, photo-induced transformations of zerumbone and its epoxide.

Cyclisations and Strategies for Stereoselective Synthesis of Piperidine Iminosugars.

This personal account focuses on synthesis of polyhydroxylated piperidines, a subset of compounds within the iminosugar family. Cyclisations to form the piperidine ring include reductive amination, substitution via amines, iminium ions and cyclic nitrones, transamidification (N-acyl transfer), addition to alkenes, ring contraction and expansion, photoinduced electron transfer, multicomponent Ugi reaction and ring closing metathesis. Enantiomerically pure piperidines are obtained from chiral pool precursors (e. g. sugars, amino acids, Garner's aldehyde) or asymmetric reactions (e. g. epoxidation, dihydroxylation, aminohydroxylation, aldol, biotransformation). Our laboratory have contributed cascades based on reductive amination from glycosyl azide precursors as well as Huisgen azide-alkene cycloaddition. The latter's combination with allylic azide rearrangement has given substituted piperidines, including those with quaternary centres adjacent to nitrogen.

New Methods for the Synthesis of Spirocyclic Cephalosporin Analogues.

Spiro compounds provide attractive targets in drug discovery due to their inherent three-dimensional structures, which enhance protein interactions, aid solubility and facilitate molecular modelling. However, synthetic methodology for the spiro-functionalisation of important classes of penicillin and cephalosporin ß-lactam antibiotics is comparatively limited. We report a novel method for the generation of spiro-cephalosporin compounds through a Michael-type addition to the dihydrothiazine ring. Coupling of a range of catechols is achieved under mildly basic conditions (K2CO3, DMF), giving the stereoselective formation of spiro-cephalosporins (d.r. 14:1 to 8:1) in moderate to good yields (28-65%).

Indium-Catalysed Transfer Hydrogenation for the Reductive Cyclisation of 2-Alkynyl Enones towards Trisubstituted Furans.

Indium tribromide catalysed the transfer hydrogenation from dihydroaromatic compounds, such as the commercially available γ-terpinene, to enones, which resulted in the cyclisation to trisubstituted furan derivatives. The reaction was initiated by a Michael addition of a hydride nucleophile to the enone subunit followed by a Lewis-acid-assisted cyclisation and the formation of a furan-indium intermediate and a Wheland intermediate derived from the dihydroaromatic starting material. The product was formed by protonation from the Wheland complex and replaced the indium tribromide substituent. In addition, a site-specific deuterium labelling of the dihydroaromatic HD surrogates resulted in site specific labelling of the products and gave useful insights into the reaction mechanism by H-D scrambling.

Me3Al-mediated domino nucleophilic addition/intramolecular cyclisation of 2-(2-oxo-2-phenylethyl)benzonitriles with amines; a convenient approach for the synthesis of substituted 1-aminoisoquinolines.

A simple and efficient protocol for the construction of 1-aminoisoquinolines was achieved by treating 2-(2-oxo-2-phenylethyl)benzonitriles with amines in the presence of Me3Al. The reaction proceeds via a domino nucleophilic addition with subsequent intramolecular cyclisation. This method provides a wide variety of substituted 1-aminoisoquinolines with good functional group tolerance. Furthermore, the synthetic utility of this protocol was demonstrated in the successful synthesis of the antitumor agent CWJ-a-5 in gram scale.

Hydrogen Atom Transfer-Mediated Domino Cyclisation Reaction to Access (Spiro)Quinazolinones.

A radical domino cyclisation reaction of N-cyanamide alkenes, mediated by hydrogen atom transfer (HAT) has been developed. This method, using PhSiH3 and catalytic Fe(acac)3 , allows for the synthesis of challenging (spiro)quinazolinone scaffolds from simple, tractable (hetero)aryl carboxylic acid and cyanamide building blocks.

Bioinspired Divergent Oxidative Cyclization from Strictosidine and Vincoside Derivatives: Second-Generation Total Synthesis of (-)-Cymoside and Access to an Original Hexacyclic-Fused Furo[3,2-b]indoline.

The second-generation synthesis of (-)-cymoside as well as the formation of a new hexacyclic-fused furo[3,2-b]indoline framework is reported. After a Pictet-Spengler condensation between secologanin tetraacetate and tryptamine, the course of the cyclization of the 7-hydroxyindolenine intermediate, generated by oxidation with an oxaziridine, depended on the stereochemistry of the 3-position. The 3-(S)-strictosidine stereochemistry delivered efficiently the scaffold of cymoside via intramolecular coupling with the C16-C17 enol ether, while the 3-(R)-vincoside stereochemistry directed towards the reaction with the C18-C19 terminal alkene and the formation of the unexpected caged compound.

Facile Synthesis of a Stable Side-on Phosphinyne Complex by Redox Driven Intramolecular Cyclisation.

Alkyne complexes with vicinal substitution by a Lewis acid and a Lewis base at the coordinated alkyne are prospective frustrated Lewis pairs exhibiting a particular mutual distance and, hence, a specific activation potential. In this contribution, investigations on the generation of a WII alkyne complex bearing a phosphine as Lewis base and a carbenium group as Lewis acid are presented. Independently on potential substrates added, an intramolecular cyclisation product was always isolated. A subsequent deprotonation step led to an unprecedented side-on λ5 -phosphinyne complex, which is interpreted as highly zwitterionic according to visible absorption spectroscopy supported by TD-DFT. Low-temperature 31 P NMR and EPR spectroscopic measurements combined with time-dependent IR-spectroscopic monitoring provided insights in the mechanism of the cyclisation reaction. Decomposition of the multicomponent IR spectra by multivariate curve resolution and a kinetic hard-modelling approach allowed the derivation of kinetic parameters. Assignment of the individual IR spectra to potential intermediates was provided by DFT calculations.