Nucleophile‐Dependent Regio‐ and Stereoselective Ring Opening of 1‐Azoniabicyclo[3.1.0]hexane Tosylate

1‐[(1R)‐(1‐Phenylethyl)]‐1‐azoniabicyclo[3.1.0]hexane tosylate was generated as a stable bicyclic aziridinium salt from the corresponding 2‐(3‐hydroxypropyl)aziridine upon reaction with p‐toluenesulfonyl anhydride. This bicyclic aziridinium ion was then treated with various nucleophiles including halides, azide, acetate, and cyanide in CH₃CN to afford either piperidines or pyrrolidines through regio‐ and stereoselective ring opening, mediated by the characteristics of the applied nucleophile. On the basis of DFT calculations, ring‐opening reactions under thermodynamic control yield piperidines, whereas reactions under kinetic control can yield both piperidines and pyrrolidines depending on the activation energies for both pathways.     

Regioselectivity in the ring opening of non-activated aziridines

In this critical review, the ring opening of non-activated 2-substituted aziridines via intermediate aziridinium salts will be dealt with. Emphasis will be put on the relationship between the observed regioselectivity and inherent structural features such as the nature of the C2 aziridine substituent and the nature of the electrophile and the nucleophile. This overview should allow chemists to gain insight into the factors governing the regioselectivity in aziridinium ring openings (81 references).     

Synthesis of a series of vicinal diamines with potential biological activity

A broad range of vicinal diamines based on styrene oxide are synthesisedvia mixtures of regioisomeric amino alcohols. The ring opening of the intermediate aziridinium ions by primary amines proceeds with high regioselectivity, leading to the target diamines as single regioisomers for all reaction series. The compounds are of potential biological interest as ligands for cisplatin analogues. Anticancer activity tests of both groups of compounds are in progress.     

Deconstructive Oxygenation of Unstrained Cycloalkanamines

A deconstructive oxygenation of unstrained primary cycloalkanamines has been developed for the first time using an auto‐oxidative aromatization promoted C(sp³)?C(sp³) bond cleavage strategy. This metal‐free method involves the substitution reaction of cycloalkanamines with hydrazonyl chlorides and subsequent auto‐oxidative annulation to in situ generate pre‐aromatics, followed by N‐radical‐promoted ring‐opening and further oxygenation by 2,2,6,6‐tetramethylpiperidine‐1‐oxyl (TEMPO) and m‐cholorperoxybenzoic acid (mCPBA). Consequently, a series of 1,2,4‐triazole‐containing acyclic carbonyl compounds were efficiently produced. This protocol features a one‐pot operation, mild reaction conditions, high regioselectivity and ring‐opening efficiency, broad substrate scope, and is compatible with alkaloids, osamines, and peptides, as well as steroids.     

Bromenium‐Catalysed Tandem Ring Opening/Cyclisation of Vinylcyclopropanes and Vinylcyclobutanes: A Metal‐Free [3+2+1]/[4+2+1] Cascade for the Synthesis of Chiral Amidines and Computational Investigation

We present a detailed study of a [3+2+1] cascade cyclisation of vinylcyclopropanes (VCP) catalysed by a bromenium species (Br^δ+? X^δ?) generated in situ, which results in the synthesis of chiral bicyclic amidines in a tandem one‐pot operation. The formation of amidines involves the ring‐opening of VCPs with Br? X, followed by a Ritter‐type reaction with chloramine‐T and a tandem cyclisation. The reaction has been further extended to vinylcyclobutane systems and involves a [4+2+1] cascade cyclisation with the same reagents. The versatility of the methodology has been demonstrated by careful choice of VCPs and VCBs to yield bicyclo[4.3.0]‐, ‐[4.3.1]‐ and ‐[4.4.0]amidines in enantiomerically pure form. On the basis of the experimental observations and DFT calculations, a reasonable mechanism has been put forth to account for the formation of the products and the observed stereoselectivity. We propose the existence of a π‐stabilised homoallylic carbocation at the cyclopropane carbon as the reason for high stereoselectivity. DFT studies at B3LYP/6‐311+G** and M06‐2X/6‐31+G* levels of theory in gas‐phase calculations suggest the ring‐opening of VCP is initiated at the π‐complex stage (between the double bond and Br? X). This can be clearly perceived from the solution‐phase (acetonitrile) calculations using the polarisable continuum model (PCM) solvation model, from which the extent of the ring opening of VCP was found to be noticeably high. Studies also show that the formation of zero‐bridge bicyclic amidines is favoured over other bridged bicyclic amidines. The energetics of competing reaction pathways is compared to explain the product selectivity.     

Asymmetric synthesis via aziridinium ions: exploring the stereospecificity of the ring opening of aziridinium ions and a formal synthesis of (−)-swainsonine

The use of aziridinium ions in two different projects is described. First, the stereospecificity of the ring opening of aziridinium ions with MeNH₂ as a route to chiral diamines has been explored. When the aziridinium ion contained a phenyl or para-methoxyphenyl substituent, stereospecific ring opening occurred. In contrast, switching the para-methoxy group to a para-N,N-dimethylamino group gave a racemic diamine product. Second, starting from N-Boc pyrrolidine, asymmetric lithiation-trapping-ring expansion (via an aziridinium ion) was used to synthesise a piperidine alcohol. In this way, a formal synthesis of (?)-swainsonine was completed.     

Lewis Base‐Promoted Ring‐Opening 1,3‐Dioxygenation of Unactivated Cyclopropanes Using a Hypervalent Iodine Reagent

A facile and effective system has been developed for the regio‐ and chemoselective ring‐opening/electrophilic functionalization of cyclopropanes through C?C bond activation by [bis(trifluoroacetoxy)iodo]benzene with the aid of the Lewis basic promoter p‐toluenesulfonamide. The p‐toluenesulfonamide‐promoted system works well for a wide range of cyclopropanes, resulting in the formation of 1,3‐diol products in good yields and regioselectivity.     

Synthesis and Characterization of Novel Ionic Liquids: N‐Substituted Aziridinium Salts

Ionic liquids based on three‐membered ring aziridinium cations have been synthesized for the first time using a straightforward synthetic route. N‐butyl‐N‐methylaziridinium bis(trifluoromethanesulfonyl)imide, N‐propyl‐N‐ethylaziridinium bis(trifluoromethanesulfonyl)imide, N‐butyl‐N‐[2‐(2‐methoxyethoxy)ethyl]aziridinium bis(trifluoromethanesulfonyl)imide, N‐butyl‐N‐methylaziridinium dicyanamide, and N‐butyl‐N‐ethylaziridinium dicyanamide were thus obtained in good yields and satisfactory purity and fully characterized.     

Synthesis of (±)‐Trinervitadiene‐2,3‐diol

The first synthesis of trinervita‐1(15),8(19)‐dien‐2β,3α‐diol ( 2a ) and its 2α‐isomer 2b , which have been isolated from termite soldiers, where they are used as defense chemicals, is documented starting from geranylgeranioic acid in 33 steps. The route for construction of the key intermediate of the trinervitane skeleton 8 has been developed previously (Scheme 1). Noteworthy features include the efficient construction of the trinervitane framework from the corresponding bicyclic 7(16)‐secotrinervitane skeleton and Me₃SiCl (TMSCl)‐induced ring‐opening of tetrasubstituted epoxide to give the corresponding allyl alcohols (Scheme 7). The synthetic route developed in the present study seems applicable to the syntheses of other trinervitane‐type natural products.     

Selective tandem enyne metathesis for the synthesis of functionalized cycloheptadienes

The regio- and site-selective ring expansion of dienes and the regioselective ring expansion of substituted cyclopentenes provide 1,3-cycloheptadienes by enyne metathesis under methylene-free conditions. Site-selectivity results from differential ring strain among two different cycloalkenes in diene reactants. The high regioselectivity found in the ring expansion of tetrahydroindene (THI) is explained on the basis of a selective ring opening by the second generation Grubbs' ruthenium carbene complex. The ring opening of substituted cyclopentenes and cyclopentene contained in a bicyclic ring system was also achieved. The ring expansion of bicyclic dienes provided seven-membered dienes contained in the bicyclo[5.2.0]nonane ring system. Details of the structural analysis are also discussed. A mechanistic analysis is provided to account for the data presented herein.     

Synthesis and cationic ring‐opening polymerization of oxetane monomer containing five‐membered cyclic carbonate moiety via highly chemoselective addition of CO2

The bicyclic amidinium iodide effectively catalyzed the reaction of carbon dioxide and the epoxy‐containing oxetane under ordinary pressure and mild conditions with high chemoselectivity to give the corresponding oxetane monomer containing five‐membered cyclic carbonate quantitatively. The cationic ring‐opening polymerization of the obtained monomer by boron trifluoride diethyl ether proceeded to give linear polyoxetane bearing five‐membered cyclic carbonate pendant group in high yield. The molecular weight of the polyoxetane was higher than that of polyepoxide obtained by the cationic ring‐opening polymerization of epoxide monomer containing five‐membered cyclic carbonate. The cyclic carbonate functional crosslinked polyoxetanes were also synthesized by the cationic ring‐opening copolymerization of cyclic carbonate having oxetane and commercially available bisoxetane monomers. Analyses of the resulting polyoxetanes were performed by proton nuclear magnetic resonance, size exclusion chromatography, thermogravimetric analysis, and differential scanning calorimetry. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019 , 57, 2606–2615     

(4+3) Cycloaddition Reactions of N‐Alkyl Oxidopyridinium Ions

N ‐Methylation of methyl 5‐hydroxynicotinate followed by reaction with a diene in the presence of triethylamine afforded (4+3) cycloadducts in good to excellent yields. High regioselectivity was observed with 1‐substituted and 1,2‐disubstituted butadienes. Density functional theory calculations indicate that the cycloaddition involves concerted addition of the diene onto the oxidopyridinium ion. The process provides rapid access to bicyclic nitrogenous structures resembling natural alkaloids.     

A Highly Stereoselective Synthesis of Glycidic Amides Based on a New Class of Chiral Sulfonium Salts: Applications in Asymmetric Synthesis

A new type of chiral sulfonium salts that are characterized by a bicyclic system has been designed and synthesized from α‐amino acids. Their corresponding ylides, which were prepared by basic treatment of the sulfonium salts, reacted smoothly with a broad array of simple and chiral aldehydes to provide trans‐epoxy amides in reasonable to very good yields and excellent stereoselectivities (>98 %). The obtained epoxy amides were found to be useful as synthetic building blocks. Thus, they were reduced into their corresponding epoxy alcohols and subjected to oxirane‐ring‐opening reactions with different types of nucleophiles.     

Green Regioselective Azidolysis of Epoxides Catalyzed by Multi‐Site Phase‐Transfer Catalyst

A facile synthesis of 1,2‐azidoalcohols from their epoxides using α,α',α”‐N‐hexakis(triethylammoniummethylene chloride)‐melamine as a multi‐site phase‐transfer catalyst in water was developed. By this eco‐friendly and highly atom‐economic method, a variety of 1,2‐azidoalcohols was obtained in high yields with excellent regioselectivity and in short reaction times. Application of this six‐site PTC in the ring opening of epoxides by cyanide, acetate and chloride anions was also studied. The catalyst can be recovered after completion of the reaction and can be recycled without affecting the catalytic property.     

Total Synthesis of the Polyoxygenated Sesquiterpenes Guignarderemophilanes C and D

The total syntheses of the neural anti‐inflammatory agents guignarderemophilanes C and D have been accomplished for the first time starting from γ‐hydroxy carvone in 15 and 14 steps, respectively. The presented synthetic route proceeds via a known intermediate, whose synthesis has been elaborated in our group in the course of the total synthesis of the sesquiterpenoid periconianone A. Key for the successful conversion of this intermediate into both targets was finding a suitable strategy to install the 1,2,3‐trihydroxylated A‐ring scaffold. For this purpose, we effectively employed a Mitsunobu inversion, epoxidation, and regioselective epoxide opening sequence, before the bicyclic ring system was constructed by an aldol condensation reaction on a sterically demanding substrate. Our reported synthesis set the stage for SAR studies to prepare even more potent compounds by modification and derivatization of the natural product's scaffold.     

Imidazo[2,1‐b]thiazoles,imidazo[2,1‐b]imidazoles and Pyrrolo[1,2‐c]imidazoles. synthesis,structure and evaluation of benzodiazepine receptor binding

As a continuation of our studies on bicyclic heterocycles with benzodiazepine receptor affinity, derivatives with a 5:5 bicyclic skeleton, namely imidazo[2,1‐b]thiazoles, imidazo[2,1‐b]imidazoles and pyrrolo[1,2‐c]imidazoles were prepared. The compounds possessed an aromatic substituent with different spatial arrangement and distance to the bicyclic skeleton. X‐ray structure analysis was performed for Z‐2‐(4‐chlorobenzylidene)‐5,5‐diphenyl‐2,3,5,6‐tetrahydroimidazo[2,1‐b]imidazoline‐3,6‐dione ( 6a ) and 5‐amino‐6‐cyano‐7‐phenyl‐1‐oxo‐3‐thioxo‐2,3‐dihydro‐1H‐pyrrolo[1,2‐c]imidazole ( 20a ). In contrast to the previously described arylideneimidazo[2,1‐b]thiazepinones the smaller heterocyclic ring systems investigated in this study were devoid of meaningful benzodiazepine receptor affinity as well as anti‐convulsant activity.     

Enantioselective Synthesis of a Polyfunctionalized Tetracycle Related to Pentacyclic Triterpenes by Using an Anionic Cycloaddition Reaction

Herein we report a convergent enantioselective synthesis of a polyfunctionalized ABCD tetracycle by using an anionic cycloaddition reaction between a chiral bicyclic CD Nazarov intermediate (see 6 ), derived from the (?)‐Weiland–Mischer ketone, and an achiral cyclohexenone (see 5 ) adequately functionalized to furnish the ring A of pentacyclic triterpenes (Scheme 5). The chiral bicyclic CD Nazarov intermediate forms ring B upon cycloaddition with the achiral cyclohexenone to yield an ABCD tetracycle with a cis‐anti‐trans‐anti‐trans configuration (see 4 ). Further transformations on this adduct allowed reduction of the angular aldehyde function at C(10) to a Me group (→ 17 ) and introduction of an unsaturation at C(5)? C(6) by using the ketone function at C(7) (→ 3 ; Scheme 6).     

Synthesis and Reactions of New Dithiolopyrroles

The title compounds were prepared starting from pyrrolinone 4 . Nucleophilic‐displacement and ring‐closure reactions yielded the dithiolopyrrole 5a , which formed salts with electrophiles ( 7, 8 ) as well as with bases. The crystal structure of 5a was determined. Oxidation of the dithioles 5a and 6a led to S(2)‐oxides ( 10a, 11a ) and the corresponding S(2)‐dioxides ( 10b, 11b ) depending on reaction conditions. The thiosulfinate 10a was converted by a ring‐opening/ring‐closure reaction sequence to the bicyclic sulfinamide 12 . The oxidative addition reactions of [Pt(η²‐C₂H₄) (PPh₃)₂] ( 14 ) with the disulfides 5a and 13 led to the dithiolatoplatinum(II) complexes 15 and 16 , respectively. Complex 16 was characterized structurally. The sulfenato‐thiolato complex 17 was synthesized via reaction of 14 with the thiosulfinate 10a . The thiosulfonato Pt^II complex 18 was prepared by an oxidative insertion of Pt⁰ into the C? S bond of the corresponding thiosulfonate 10b . Furthermore, complex 18 was characterized by single‐crystal X‐ray‐diffraction studies.     

Structurally Divergent Lithium Catalyzed Friedel–Crafts Reactions on Oxetan‐3‐ols: Synthesis of 3,3‐Diaryloxetanes and 2,3‐Dihydrobenzofurans

The first examples of 3,3‐diaryloxetanes are prepared in a lithium‐catalyzed and substrate dependent divergent Friedel–Crafts reaction. para‐Selective Friedel–Crafts reactions of phenols using oxetan‐3‐ols afford 3,3‐diaryloxetanes by displacement of the hydroxy group. These constitute new isosteres for benzophenones and diarylmethanes. Conversely, ortho‐selective Friedel–Crafts reactions of phenols afford 3‐aryl‐3‐hydroxymethyl‐dihydrobenzofurans by tandem alkylation–ring‐opening reactions; the outcome of the reaction diverging to structurally distinct products dependent on the substrate regioselectivity. Further reactivity of the oxetane products is demonstrated, suitable for incorporation into drug discovery efforts.     

Access to Optically Active 3‐Substituted Piperidines by Ring Expansion of Prolinols and Derivatives

The ring expansion of prolinols via an aziridinium intermediate gives C3‐substituted piperidines in good yields and enantiomeric excess, the substituent at the C3 position being derived from the most reactive nucleophile in the reaction mixture. Depending on the nucleophile, the reaction proceeds under thermodynamic or kinetic control. The regioselectivity of attack of nucleophiles on the aziridinium intermediate depends on the nature of the substituents on the nitrogen atom and the C4 position of the starting prolinols.