Aziridinium Ion Research Articles

On the Selectivity in the Synthesis of 3-Fluoropiperidines Using BF3-Activated Hypervalent Iodine Reagents.

Fluorinated piperidines find wide applications, most notably in the development of novel therapies and agrochemicals. Cyclization of alkenyl N-tosylamides promoted by BF3-activated aryliodine(III) carboxylates is an attractive strategy to construct 3-fluoropiperidines, but it suffers from selectivity issues arising from competitive oxoaminations and the inability to easily modulate the reactions diastereoselectivity. Herein, we report an itemized optimization of the reaction conditions carried out on both cyclic and acyclic substrates and outline the origins of substrate- and reagent-based stereo-, regio-, and chemoselectivity. Extensive mechanistic studies encompassing multinuclear NMR spectroscopy, deuterium labeling, rearrangements on stereodefined substrates, and careful structural analyses (NMR and X-ray) of the reaction products are performed. This revealed the processes and interactions crucial for achieving controlled preparation of 3-fluoropiperidines using I(III) chemistry and has provided an advanced understanding of the reaction mechanism. In brief, we propose that BF3-coordinated I(III) reagents attack C═C to produce the corresponding iodiranium(III) ion, which then undergoes diastereodetermining 5-exo-cyclization. Transiently formed pyrrolidines with an exocyclic σ-alkyl-I(III) moiety can further undergo aziridinium ion formation or reductive ligand coupling processes, which dictate not only the final product's ring size but also the chemoselectivity. Importantly, the selectivity of the reaction depends on the nature of the ligand bound to I(III) and the presence of electrolytes such as TBABF4. Reported findings will facilitate the usage of ArI(III)-dicarboxylates in the reliable construction of fluorinated azaheterocycles.

Synthesis of 3‐Aminopiperidines via I(III)‐Mediated Olefin Diamination with (Hetero)aryl Nucleophiles

Abstract3‐Aminopiperidines are a valuable motif present in small molecule pharmaceuticals and bioactive natural products. Synthesis of these moieties via olefin diamination would be an attractive approach, however significant challenges remain with regards to both regioselectivity and exogenous nucleophile scope. Herein, we report a metal‐free olefin diamination via a “heterocyclic group transfer“ (HGT) reaction of I(III) N‐HVI reagents, giving rise to 3‐aminopiperidines with high selectivity. The HGT strategy leverages heteroarenes as oxidatively masked amine nucleophiles, giving rise to (hetero)arylonium salt products which are isolated via simple trituration and provide a versatile handle for downstream diversification. This represents only the second 6‐endo selective I(III)‐mediated diamination reaction and mechanistic studies indicate ring opening of an intermediate aziridinium ion is responsible for the 6‐endo selectivity.

General Approach to Enantiopure 1-Aminopyrrolizidines: Application to the Asymmetric Synthesis of the Loline Alkaloids.

The synthesis of a range of loline alkaloids is reported. The C(7) and C(7a) stereogenic centers for the targets were formed by the established conjugate addition of lithium (S)-N-benzyl-N-(α-methylbenzyl)amide to tert-butyl 5-benzyloxypent-2-enoate, ensuing enolate oxidation to give an α-hydroxy-β-amino ester, and then formal exchange of the resultant amino and hydroxyl functionalities (via the intermediacy of the corresponding aziridinium ion) to give an α-amino-β-hydroxy ester. Subsequent transformation gave a 3-hydroxyprolinal derivative which was converted to the corresponding N-tert-butylsulfinylimine. Mannich-type reaction with the enolate derived from O-Boc protected methyl glycolate then formed the remaining C(1) and C(2) stereogenic centers for the targets. The 2,7-ether bridge was formed by a displacement reaction, completing construction of the loline alkaloid core. Facile manipulations then gave a range of loline alkaloids, including loline itself.

Acute Effect of Selective Chemical Inactivation of Sympathetic or Parasympathetic Atrial Ganglionated Plexus Structures on Atrial Fibrillation Inducibility in Pigs.

We studied the role of both parts of the autonomic intracardiac nervous system in the pathogenesis of atrial fibrillation (AF). In 12 pigs weighing 39±3 kg, AF was induced by burst stimulation. Chemical inactivation of intrinsic cardiac neurons within the right atria was performed by transendocardial injections of liposomal neuromodulators into the dorsal part of the right atrial wall. Sympathetic and parasympathetic terminals were inactivated with 6-hydroxydopamine (6-OHDA, n=6) and ethylcholine aziridinium ion (AF64A, n=6), respectively. Neuromodulators were encapsulated in liposomes (LS) with diameters of 310±50 nm for OHDA and 290±50 nm for AF64A. LS-6-OHDA and LS-AF64A were injected into the ganglionated plexuses after measuring the baseline effective refractory period and assessing myocardial resistance to AF. These measurements were repeated 90 min after the injections. The optimal doses were 0.2 mg/kg for LS-6-OHDA and 0.4 mg/kg for LS-AF64A (in 4 ml of suspension). Immediately after injections of liposomal neuromodulators, almost all pigs showed an increase in HR, and a short-term BP elevation was observed in the LS-AF64A group. At the end of the experiment, similar decrease in the effective refractory period and similar increase in the resistance to AF were observed in all animals. Thus, selective chemical inactivation of cholinergic and adrenergic terminals of the intracardiac nervous system with liposomal neuromodulators increased the resistance to AF in an acute experiment. However, the short observation period does not allow making a definite conclusion about the role of the autonomic nervous system in the pathogenesis of AF, which requires verification of the obtained data in a chronic experiment.

Environmental degradation of human metabolites of cyclophosphamide leads to toxic and non-biodegradable transformation products

The present study assessed the ready biodegradability of the prodrug cyclophosphamide (CPA) and its stable human metabolites in the closed bottle test (CBT). The results of the CBT showed that only the main human metabolite, carboxyphosphamide (CXP), was biodegradable to a certain extent (23 ± 2.4 % ThODNH3). All other metabolites showed neither biodegradation under these conditions nor were any toxic effects on the inoculum observed. Yet, HRMSn results revealed partial primary elimination of all human metabolites and formation of 25 new transformation products. Abiotic degradation via SNi and SN2 reactions was proposed as the main degradation pathway during the CBT. The main degradation products were assigned as 3-(2-chloroethyl)oxazolidin-2-one (COAZ), cytotoxic N-2-chloroethylaziridine (CEZ) and nor‑nitrogen mustard (NNM), an analogue of the chemical warfare agent HN2. While the acute ecotoxicity of the detected products is widely unknown, many have already been reported in medical literature to be either mutagenic, genotoxic, cytotoxic or carcinogenic and may therefore cause a greater risk than their precursors. QSAR models predicted that 16 of them are mutagenic and genotoxic, thus classifying the majority of the chemicals as potential environmental hazards. The central intermediates during the degradation process were proposed as CEZ and its corresponding aziridinium ion. However, other degradation products may occur depending on the type and strength of nucleophiles present in the matrices. Overall, the results demonstrated the importance to include human metabolites in the evaluation of the environmental fate of pharmaceuticals and their risk assessment especially when investigating prodrugs. The results underline the importance of identifying possible degradation products of metabolites, as they can be more toxic than related parent compounds and metabolites and can cause a greater risk to the environment and humans.

Separation of the Thorpe−Ingold and Reactive Rotamer Effect by Using the Formation of Bicyclic Aziridinium Ions

AbstractThe geminal dialkyl effect is widely used in organic synthesis to promote cyclization reactions, although the exact origin of its rate enhancement remains unclear. In the present study, we demonstrate the applicability of this effect for the intramolecular formation of bicyclic aziridinium ions and assign it to angle contractions provided by introduction of sterically demanding substituents. Due to the cyclic structure of the examined 3‐chloropiperidines the acceleration of this ring closure cannot be explained by an increased population of reactive gauche rotamers and therefore agrees with the original Thorpe‐Ingold theory. Furthermore, introduction of strained aliphatic rings resulted in internal angle expansions and were accompanied by a preliminary decrease of rate constants for the investigated aziridinium ion formation. These results lead to a linear correlation between internal angle and relative reaction rate, supported by computational and X‐ray crystallographic structural data.

Alkylating Agents, the Road Less Traversed, Changing Anticancer Therapy.

Cancer is considered one of the gruelling challenges and poses a grave health hazard across the globe. According to the International Agency for Research on Cancer (IARC), new cancer cases increased to 18.1 million in 2018, with 9.6 million deaths, bringing the global cancer rate to 23.6 million by 2030. In 1942, the discovery of nitrogen mustard as an alkylating agent was a tremendous breakthrough in cancer chemotherapy. It acts by binding to the DNA, and creating cross linkages between the two strands, leading to halt of DNA replication and eventual cell death. Nitrogen lone pairs of 'nitrogen mustard' produce an intermediate 'aziridinium ion' at the molecular level, which is very reactive towards DNA of tumour cells, resulting in multiple side effects with therapeutic consequences. Owing to its high reactivity and peripheral cytotoxicity, several improvements have been made with structural modifications for the past 75 years to enhance its efficacy and improve the direct transport of drugs to the tumour cells. Alkylating agents were among the first non-hormonal substances proven to be active against malignant cells and also the most valuable cytotoxic therapies available for the treatment of leukaemia and lymphoma patients. This review focus on the versatile use of alkylating agents and the Structure Activity Relationship (SAR) of each class of these compounds. This could provide an understanding for design and synthesis of new alkylating agents having enhanced target specificity and adequate bioavailability.

Cover Feature: Understanding the Alkylation Mechanism of 3‐Chloropiperidines – NMR Kinetic Studies and Isolation of Bicyclic Aziridinium Ions (Eur. J. Org. Chem. 44/2021)

The Cover Feature shows the NMR kinetic analysis of the DNA alkylation mechanism of 3-chloropiperidines. The structure of the bicyclic aziridinium ion proposed as the reaction intermediate was confirmed by single crystal XRD and is shown in the center. These highly electrophilic intermediates are readily attacked by nucleophiles such as DNA bases, resulting in an alkylation product shown in the bottom right corner. An alkylated DNA double strand, containing a single strand break, as well as the corresponding depurination products are depicted on the top. In the background multiple stacked NMR spectra of a kinetic analysis in aqueous solution are shown. More information can be found in the Full Paper by R. Göttlich et al.

Understanding the Alkylation Mechanism of 3‐Chloropiperidines – NMR Kinetic Studies and Isolation of Bicyclic Aziridinium Ions

AbstractThe present study describes the kinetic analysis of the 3‐chloropiperidine alkylation mechanism. These nitrogen mustard‐based compounds are expected to react via a highly electrophilic bicyclic aziridinium ion, which is readily attacked by nucleophiles. Halide abstraction using silver salts with weakly coordinating anions lead to the isolation of these proposed intermediates, whereas their structure was confirmed by single crystal XRD. Kinetic studies of the aziridinium ions also revealed notable reactivity differences of the C5 gem‐methylated compounds and their unmethylated counterparts. The observed reactivity trends were also reflected by NMR studies in aqueous solution and DNA alkylation experiments of the related 3‐chloropiperidines. Therefore, the underlying Thorpe‐Ingold effect might be considered as another option to adjust the alkylation activity of these compounds.

Chiral Vicinal Diamines Derived from Mefloquine.

Novel 1,2-diamines based on the mefloquine scaffold prepared in enantiomerically pure forms resemble 9-amino-Cinchona alkaloids. Most effectively, 11-aminomefloquine with an erythro configuration was obtained by conversion of 11-alcohol into azide and hydrogenation. Alkylation of a secondary amine unit was needed to arrive at diastereomeric threo-11-aminomefloquine and to introduce diversity. Most of the substitution reactions of the hydroxyl group to azido group proceeded with net retention of the configuration and involved actual aziridine or plausible aziridinium ion intermediates. Enantiomerically pure products were obtained by the resolution of either the initial mefloquine or one of the final products. The evaluation of the efficacy of the obtained vicinal diamines in enantioselective transformations proved that erythro-11-aminomefloquine is an effective catalyst in the asymmetric Michael addition of nitromethane to cyclohexanone (up to 96.5:3.5 er) surpassing epi-aminoquinine in terms of selectivity.

Synthetic Applications of Aziridinium Ions.

Nonactivated aziridine with an electron-donating group at the ring nitrogen should be activated to an aziridinium ion prior to being converted to cyclic and acyclic nitrogen-containing molecules. This review describes ways to generate aziridinium ions and their utilization for synthetic purposes. Specifically, the intra- and intermolecular formation of aziridinium ions with proper electrophiles are classified, and their regio- and stereoselective transformations with nucleophiles are described on the basis of recent developments.

Alkylative Aziridine Ring-Opening Reactions.

In this study, the highly strained three-membered aziridine ring was successfully activated as the aziridinium ion by alkylation of the ring nitrogen with a methyl, ethyl or allyl group, which was followed by ring opening with external nucleophiles such as acetate and azide. Such alkylative aziridine ring opening provides an easy route for the synthesis of various N-alkylated amine-containing molecules with concomitant introduction of an external nucleophile at either its α- or β-position.

Tuning the activity of nitrogen mustards with heterocyclic substituents at nitrogen: A DFT study

The thermodynamic and kinetic effects of substituting nitrogen mustards with heterocyclic ring systems on the formation of aziridinium ion have been studied using DFT calculations. We have described the observed lowering in activities of heterocyclic substituted nitrogen mustards with the help of NBO and pKa calculations. Aziridinium ion formation reaction steps are endothermic and activation energy barriers are increased in all the cases. The increased activation energy barrier is attributed to delocalization of the positive charge on the aziridinium into the heterocyclic aromatic ring.

Application of α-Amino-β-fluorophosphonates in Construction of their Dipeptide Analogues

Herein, we present application of α-amino-β-fluorophosphonates for the construction of their dipeptide analogues. α-Amino-β-fluorophosphonates were prepared in a XtalFluor-E mediated deoxyfluorination of α-hydroxy-β-aminophosphonates. The reaction proceeds through an aziridinium ion formation, which was confirmed by the formation­ of a hexacoordinate phosphorus compound. Moreover, the absolute configuration of the obtained compounds was determined by X-ray analysis, which proved the stereochemistry.

Alkylative Ring-Opening of Bicyclic Aziridinium Ion and Its Application for Alkaloid Synthesis.

Alkylative ring-opening of bicyclic aziridinium ion generated from 4-hydroxybutylaziridine with organocopper reagent was achieved successfully to afford 2-alkylsubstituted piperidine in high or moderate yield. This method allowed carbon-carbon bond formation of “non-activated” aziridine via aziridinium ion ring-opening in regio- and stereo-selective manner for the first time. This newly developed reaction was applied for an efficient synthesis of alkaloid with the representative example of conine and epiquinamide.

Front Cover: Preparation of a Stable Bicyclic Aziridinium Ion and Its Ring Expansion toward Piperidines and Azepanes (Asian J. Org. Chem. 9/2017)

Front Cover: Preparation of a Stable Bicyclic Aziridinium Ion and Its Ring Expansion toward Piperidines and Azepanes (Asian J. Org. Chem. 9/2017)

An efficient synthesis of the opioid analgesic (R)-phenampromide via an aziridinium ion

A simple and efficient synthesis of the opioid analgesic agent (R)-phenampromide with high enantiopurity (>99% ee) via the formation of an aziridinium ion as a key step using commercially available starting material is described.

Preparation of a Stable Bicyclic Aziridinium Ion and Its Ring Expansion toward Piperidines and Azepanes

AbstractThe formation of the stable form of 1‐azabicyclo[4.1.0]heptane tosylate was successfully achieved from 2‐[4‐tolenesulfonyloxybutyl]aziridine, by stirring in MeCN at room temperature. The ring strain in the three‐membered ring could be released through the cleavage of either C−N bond, but ring opening with various nucleophiles proceeded in a highly regio‐ and stereoselective manner. Two possible pathways, in which the aziridine ring was opened by nucleophilic attack at the bridge and the bridgehead, yielded piperidine and azepane rings, respectively. This selective transformation starting from chiral aziridines constitutes an efficient route for the asymmetric synthesis of biologically important natural products, such as fagomines, febrifugine, sedamine, hydroxypipecolic acid, and balanol.

Intramolecular Aminoalkoxylation of Unfunctionalized Olefins via Intramolecular Iodoamination and Aziridinium Ion Ring-Opening Sequence.

The preparation of prolinol ether type compounds was realized via MnI2-catalyzed intramolecular iodoamination of unfunctionalized olefins and subsequent ring opening of an aziridinium ion intermediate with alcohols/phenols. In the presence of a catalytic amount of MnI2 and 2 equiv of NaI, intramolecular aminoalkoxylation of different N-benzyl-5-methylhex-4-en-1-amine substrates proceeded readily in alcoholic solvents, leading to 2-(alkoxyalkyl)pyrrolidine products in up to 90% isolated yields.

Anticancer activity of a chelating nitrogen mustard bearing tetrachloridoplatinum(iv) complex: better stability yet equipotent to the Pt(ii) analogue.

Two Pt(iv) complexes cis,cis,trans-[Pt(IV)(L1)Cl4] (1a) & cis,cis,trans-[Pt(IV)(L2)Cl4] (2a) containing the nitrogen mustard moieties -N(CH2CH2Cl)2 & -NHCH2CH2Cl, were prepared in a single step from the Pt(ii) complexes containing -N(CH2CH2OH)2 (1) & -NHCH2CH2OH (2) moieties respectively using only thionyl chloride. The characterization of both the Pt(iv) complexes was performed by NMR, IR, UV and elemental analysis. Complex 1a was also characterized by single crystal X-ray diffraction. 1a crystallized in the I2/a space group. 1a exhibited much higher solution stability than 2a in kinetic studies by (1)H NMR. 1a shows a prodrug like activity as it converts to its Pt(ii) congener, [Pt(II)(L1)Cl2] (3) after 2 days in buffered solution. The binding experiment of 1a with model nucleobase 9-ethylguanine (9-EtG), showed that 1a converts to 3 and forms mono-adducts with 9-EtG. In the presence of reduced glutathione (GSH), the formation of 3 from 1a is quicker and upon the formation of 3 it binds almost instantaneously to GSH to form cis-[PtCl(L1)SG] (3c). Complex 3c transformed within a day to give a free aziridinium ion of L1 (3b) by dissociation. The in vitro cytotoxicity of the complexes and the clinical anticancer drug cisplatin show that 1a is potent against MCF-7, A549, HepG2 and MIA PaCa-2. The potency is highest against MIA PaCa-2 exhibiting an IC50 value of 4.4 ± 0.5 μM. The in vitro cytotoxicity data also showed that between the two complexes only 1a is active against MCF-7, A549 and MIA PaCa-2 in normoxia and hypoxia, both in the presence and absence of added GSH. Even in the presence of excess GSH in hypoxia, 1a exhibits significant cytotoxicity against MIA PaCa-2 and MCF-7 with IC50 values of 4.5 ± 0.3 and 11.2 ± 1.8 μM respectively. Platinum accumulation studies by ICP-MS display greater internalization of 1a, than 2a, 3 and cisplatin inside MCF-7 cells. 1a arrests cell cycle at the G2/M phase in MCF-7, exhibits capability to inhibit metastasis, induces apoptotic cell death and displays blood compatibility with human blood.