Aziridine Ring Research Articles

Efficient and Easy Access to Optically Pure Tetrasubstituted Tetra­hydrofurans via Stereoselective Opening of C2‐Symmetric Epoxide and Aziridine Rings

AbstractAn efficient and facile protocol to functionalize position C‐3 of 2,5‐anhydro‐D‐mannitol via diastereoselective ring opening of a C2‐symmetric epoxide 2,5:3,4‐dianhydro‐D‐allitol 3 has been developed. This method is protecting‐group‐free, high‐yielding, and provides access to C‐3‐modified 2,5‐anhydro‐D‐mannitols 5a, 11a–15a and 16–17. This method was then extrapolated to the synthesis of a C2‐symmetric aziridine, which underwent ring opening with various nucleophiles to provide access to C‐3‐ and C‐4‐modified 2,5‐anhydro‐D‐mannitols 19–27 in excellent global yields and moderate to good diastereoselectivities. These structures and their derivatives are potentially useful in a variety of applications, including organocatalysis of asymmetric Michael additions as demonstrated with diamine monosulfonamides 28a and 28b, which provide adducts with complementary enantioselectivity.

ChemInform Abstract: Modular, One‐Pot, Sequential Aziridine Ring Opening—SNAr Strategy to 7‐, 10‐, and 11‐Membered Benzo‐Fused Sultams.

ChemInformVolume 47, Issue 9 Heterocyclic Compounds ChemInform Abstract: Modular, One-Pot, Sequential Aziridine Ring Opening—SNAr Strategy to 7-, 10-, and 11-Membered Benzo-Fused Sultams. Joanna K. Loh, Joanna K. Loh Dep. Chem., Univ. Kans., Lawrence, KS 66045, USASearch for more papers by this authorNaeem Asad, Naeem Asad Dep. Chem., Univ. Kans., Lawrence, KS 66045, USASearch for more papers by this authorThiwanka B. Samarakoon, Thiwanka B. Samarakoon Dep. Chem., Univ. Kans., Lawrence, KS 66045, USASearch for more papers by this authorPaul R. Hanson, Paul R. Hanson Dep. Chem., Univ. Kans., Lawrence, KS 66045, USASearch for more papers by this author Joanna K. Loh, Joanna K. Loh Dep. Chem., Univ. Kans., Lawrence, KS 66045, USASearch for more papers by this authorNaeem Asad, Naeem Asad Dep. Chem., Univ. Kans., Lawrence, KS 66045, USASearch for more papers by this authorThiwanka B. Samarakoon, Thiwanka B. Samarakoon Dep. Chem., Univ. Kans., Lawrence, KS 66045, USASearch for more papers by this authorPaul R. Hanson, Paul R. Hanson Dep. Chem., Univ. Kans., Lawrence, KS 66045, USASearch for more papers by this author First published: 11 February 2016 https://doi.org/10.1002/chin.201609195Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume47, Issue9February, 2016 RelatedInformation

Synthesis of Canthardin Sulfanilamides and Their Acid Anhydride Analogues via a Ring-Opening Reaction of Activated Aziridines and Their Associated Pharmacological Effects.

The cantharidinimide derivatives, 5a–h, including sulfanilamides containing pyrimidyl, pyrazinyl, hydrogen, thiazolyl, and oxazolyl groups were synthesized. Modification of cantharidinimide by means of the reaction of activated aziridine ring opening led to the discovery of a novel class of antitumor compounds. The analogues 10i–k, 11l–n, 12o–p, and 16q–s were obtained from treating cantharidinimide 6 and analogues (7, 8, and 13) with activated aziridines, which produced a series of ring-opened products including normal and abnormal types. Some of these compounds showed cytotoxic effects in vitro against HL-60, Hep3B, MCF7, and MDA-MB-231 cancer cells. The most potent cytostatic compound, N-cantharidinimido-sulfamethazine (5a), exhibited anti-HL-60 and anti-Hep3B cell activities. Two compounds 5g and 5h displayed slight effects on the Hep3B cell line, while the other compounds produced no response in these four cell lines.

ChemInform Abstract: Design, Synthesis and Diversification of Natural Product‐Inspired Hydantoin‐Fused Tetrahydroazepino Indoles.

A facile and efficient synthesis of novel oxo, thio and seleno hydantoin fused tetrahydroazepino [4,5-b]indoles was reported. A naturally occurring iboga class alkaloid inspired seven-membered azepino[4,5-b]indole ring was synthesized as a new scaffold through Pictet–Spengler reaction followed by skeletal rearrangement of the aziridine ring. To improve the efficiency of the synthetic route, the double bond of the rearranged olefinic product 5 was reduced and a privileged hydantoin moiety was constructed on the core system through urea formation using a variety of isocyanates, isothiocyanates and isoselenocyanates followed by intramolecular cyclization to incorporate elements of diversity. The regeneration of the double bond of intermediate 9 afforded hydantoin-fused tetrahydroazepino [4,5-b]indoles.

ChemInform Abstract: Tandem Aziridine Ring Opening‐Disulfide Formation‐Reduction‐Michael Addition in One‐Pot Mediated by Tetrathiomolybdate.

AbstractAn efficient procedure is elaborated for the synthesis of β‐sulfonamidosulfides from aziridines, alkenes, and tetrathiomolybdate.

Palladium-catalyzed regioselective and stereo-invertive ring-opening borylation of 2-arylaziridines with bis(pinacolato)diboron: experimental and computational studies.

A palladium catalyzed regioselective borylative ring opening reaction of 2-arylaziridines to give β-amino-β-arylethylborates was developed. The reaction reported herein represents the first example of ring-opening borylation of non-vinylic aziridines and direct borylative C(sp3)-N bond cleavage of neutral organic substrates. NMR studies and density functional theory (DFT) calculations suggested that the active intermediate for the reaction is a PdL2 complex [L = P(t-Bu)2Me]. The multi-component artificial force-induced reaction method (MC-AFIR) located the transition states for the regioselectivity-determining aziridine ring opening that proceeds in an SN2 fashion, and explained the selectivity of the reaction. The full catalytic cycle consists of a selectivity-determining aziridine ring opening (oxidative addition), a proton transfer, phosphine ligand dissociation from the catalyst, boron-boron bond cleavage, and reductive elimination. Water is important to the drive the transmetalation step. The calculated overall mechanism and selectivity are consistent with the experimental results.

Infrared spectra and UV-induced photochemistry of methyl aziridine-2-carboxylate isolated in argon and xenon matrices

Methyl aziridine-2-carboxylate (MA2C) has been isolated in low temperature argon and xenon matrices and its structure and photochemistry were studied by FTIR spectroscopy. The reactant as well as the main photoproducts were characterized by comparison of their experimental IR spectra with spectra calculated at the DFT(B3LYP)/6-311++G(d,p) level. The theoretical calculations predicted the existence of two low energy MA2C conformers, differing by the orientation of the OCCN dihedral angle. Both conformers were identified in the studied matrices. Both narrowband tunable and broadband UV irradiations of matrix-isolated MA2C yielded isomerization photoproducts resulting from cleavage of the CC and weakest CN bonds of the aziridine ring. Irradiation with UV laser-light at λ=235nm resulted in the formation of the E isomer of methyl 2-(methylimino)-acetate (MMIA) and the Z isomer of methyl 3-iminopropanoate (M3IP). Subsequent irradiation at 290nm led to observation of new bands resulting from E→Z isomerization of MMIA, while bands due to M3IP remained unchanged. The photoproduced Z isomer of MMIA could be subsequently consumed upon higher-wavelength irradiation (λ=330nm). The initially produced MMIA conformer was found to obey the nonequilibrium of excited rotamers (NEER) principle. No photoproducts resulting from the cleavage of the strongest CN bond of the MA2C aziridine ring were observed, nor that of methyl 3-aminoacrylate (M3AA), which could in principle be obtained also by cleavage of the weakest CN bond of the MA2C aziridine ring, but would imply a different H-atom migration simultaneous with the ring opening process. These results indicate that both the differential electronic characteristics of the CN bonds of substituted aziridine rings and the type of required H-atom migration are major factors in determining the specific photochemistries of substituted aziridines. Photofragmentation reactions of MA2C were also observed, through identification of various related products, e.g., acetonitrile, methanol, methane, CO and CO2.

ChemInform Abstract: Reactivity of Aziridinium Salts in Different Solvents Unraveled by a Combined Theoretical and Experimental Approach

This chapter focuses on the importance of aziridinium ions as intermediates in organic chemistry. The principal aim is to gain insight into the factors to take into account for the selective synthesis of a variety of functionalized amines via aziridinium salts, such as the nature of the aziridinium ion (ring strain and N- and C-substituents of the aziridine ring), the nucleophile, and the solvent environment. Molecular modeling is used to investigate kinetics, electrostatics, and frontier molecular orbitals of reactions involving intermediate aziridinium ions, such as the nucleophilic ring opening of aziridines, the ring expansion of nitrogen heterocycles, and the ene reactions with triazolinedione. Open image in new window

Ring Expansion of N-H Ketoaziridines to Five and Six-Membered NHeterocycles

This review reports the chemistry of 2,3-disubstituted N-H aziridines to Five and sixmemberd N-heterocycles. Emphasis will be put on the aspects of stereo- and regioselectivity of appropriate reactions such as 1,3-dipolar, ring expansion reactions as well as C-C or C-N bond cleavage of aziridine ring. Keywords: Ketoaziridine, rearrangement, ring expansion, stereo- and regioselectivity.

Modular, One-Pot, Sequential Aziridine Ring Opening-S(N)Ar Strategy to 7-, 10-, and 11-Membered Benzo-Fused Sultams.

The generation of common and stereochemically rich medium-sized benzo-fused sultams via complementary pairing of heretofore-unknown (o-fluoroaryl)sulfonyl aziridine building blocks with an array of amino alcohols/amines in a modular one-pot, sequential protocol using an aziridine ring opening and intramolecular nucleophilic aromatic substitution is reported. The strategy employs a variety of amino alcohols/amines and proceeds with 6 + 4/6 + 5 and 6 + 1 cycloetherification pathways in a highly chemo- and regioselective fashion to obtain skeletally and structurally diverse, polycyclic, 10- to 11- and 7-membered benzo-fused sultams for broad-scale screening.

Improving the tensile strength of carbon nanotube yarn via one-step double [2+1] cycloadditions

The tensile strength of a CNT yarn was improved through simple one-step double [2+1] cycloaddition reactions that crosslinked the constituent CNTs using a polyethylene glycol (PEG)-diazide crosslinker. The FT-IR spectrum confirmed that the azide groups in the PEG-diazide were converted into aziridine rings, indicating that the cycloaddition reaction was successful. The generation of crosslinked CNTs was also supported by the observation of N1s peak in the XPS spectrum and the increased thermal stability of the material, as observed by TGA. The tensile strength of the CNT yarn was increased from 0.2GPa to 1.4GPa after the crosslinking reaction when twisted at 4000 twists/ meter. The appropriate selection of the crosslinker may further optimize the CNT yarn crosslinking reaction. The simplicity of this one-step crosslinking reaction provides an economical approach to the mass production of high-strength CNT yarns.

Regiochemistry‐Directed Syntheses of Polyhydroxylated Alkaloids from Chiral Aziridines

AbstractIn this study, two possible regiochemical pathways of aziridine ring opening, termed “regiochemistry‐directed branches for 2‐substituted aziridines” are described, providing easy access to two classes of compound from a common synthetic intermediate. Application of this synthetic strategy, with stereoselective dihydroxylation and reductive amination as the key steps, allowed the asymmetric synthesis of natural and unnatural polyhydroxylated alkaloids including the calyculin fragment C33–C37, 1,4‐dideoxy‐1,4‐imino‐l‐ribitol and analogues of hyacinthacine, swainsonine, castanospermine, and deoxynojirimycin. The initial domino reactions consisted of aziridine ring opening and debenzylation, and reductive double annulations were established for the preparation of bicyclic pyrrolizidine and indolizidine—represented by 8‐deoxyhyacinthacine and (3R)‐methyl‐8‐deoxyswainsonine—with remarkable stereoselectivity and in high yield.

Generation and Ring Opening of Aziridines in Telescoped Continuous Flow Processes

A simple method for the preparation of a variety of N-sulfonyl aziridines (10 examples) from 1,2-amino alcohols under continuous flow conditions is described. Using flow based methods, the aziridines can be further ring opened with oxygen, carbon, and halide nucleophiles or ring expanded to imidazolines by Lewis acid promoted reaction with nitriles. Telescoping the aziridine generation and ring opening steps together in a microfluidic reactor allows the chemistry to be undertaken with limited exposure to the potentially hazardous aziridine intermediates.

K5[PW11ZnO39].23H2O-catalyzed acylation/ring expansion of ketoaziridines in a single pot: a new regio- and stereo-selective route for the synthesis of oxazolines

A new and one-pot synthesis of oxazolines has been accomplished by K5[PW11ZnO39].23H2O—catalyst acylation followed by C–N ring opening/C–O bond formation in NH ketoaziridines. This regio- and stereo-selective reaction presumably proceeds via a domino sequence resulting in the in situ generation of acyl aziridine which undergoes a ring expansion reaction via an initial C–N rupture of aziridine ring followed by ring closure to the oxazolines. The methodology provided novel one-pot procedure for the synthesis of trans-2,5-diaryl-4-aroyloxazolines.

The First Synthesis of 3-epi-Xestoaminol C

A new 1-deoxysphingoid, 3-epi-xestoaminol C (1), isolated from the New Zealand brown alga Xiphophora chondrophylla was firstly synthesized for the identification of its absolute stereochemistry via stereoselective reduction of 2-acylaziridine followed by hydrogenolysis. Sphingosine as a class of lipid described almost two centuries ago 1 was characterized structurally as 2-amino-1,3diol in long alkyl chain most of which participate in cell structure and its regulation. 2 Up to now hundreds of sphingosines were isolated and their structures were identified and some of them showed important biological activities to lead for a new drug development program. 2,3 Most of them have different number of carbon backbones, position of double bonds and the stereochemistry of olefin and other functionalities in alcohol and amine. Due to the same biosynthetic origin of sphingosine from serine and fatty acids most of them have 2-amino-1,3-diols as the common functionalities even though their carbon backbones are different. However, few isolated natural products including spisulosine, 4 clavaminol, 5 xestoaminol 5a,6 and obscuraminol 7 have only 2-amino-3-ol functionalities without one alcohol at the end of the backbone as 1-deoxysphingoid. The absolute stereochemistries of two functional groups are important for their biological actives. The epimer of the previously isolated xestoaminol C (2), 5a,6 3-epi-xestoaminol C (1), was isolated for the first time from a brown alga Xiphophora chondrophylla by bioassay-guided isolation method last year. 8 Its structure was identified by extensive 1 H NMR analysis including NOE correlations of its oxazolidinone derivative. To confirm its chemical structure and absolute stereochemistry we decided to synthesize both isomers, xestoaminol C and 3-epi-xestoaminol C, starting from chiral aziridine. At first we prepared 2-acylaziridine (3) from (2S)-aziridine-2-carboxylate 9 by the known method whose 2S configuration should be ended at the C2 of the final product bearing amine functional group. The hydroxy groups at C3 of the target molecules are 2R in xestoaminol C and 2S in 3-epi-xestoaminol C. Thereby we decided to reduce the ketone in 2-acylaziridine (3) in stereoselective manner which we already established well. Reduction with L-Selectride yielded the threo product (4) while NaBH4 with ZnCl2 gave erythro product (5) by different transition states. 4a Hydrogenolysis with H2 in the presence of catalyst Pd(OH)2 yielded the product 3-epi-xestoaminol C and xestoaminol C with concomitant aziridine ring opening in regioselective manner and the removal of the α-methylbenzyl group at the amine. However, we were not able to get the final products in analytically pure forms by single operation. We decided to get the products as their Boc-protected forms by performing hydrogenolysis in the presence of 1.1 equiv. of (Boc)2O to afford analytically pure products 6 and 7 from 4 and 5, respectively. Once we had Boc-protected forms of the 3

Solid-Phase Parallel Synthesis of Functionalised Medium-to-Large Cyclic Peptidomimetics through Three-Component Coupling Driven by Aziridine Aldehyde Dimers.

The first solid-phase parallel synthesis of macrocyclic peptides using three-component coupling driven by aziridine aldehyde dimers is described. The method supports the synthesis of 9- to 18-membered aziridine-containing macrocycles, which are then functionalized by nucleophilic opening of the aziridine ring. This constitutes a robust approach for the rapid parallel synthesis of macrocyclic peptides.

Electrocatalytic Aziridination of Alkenes in an Undivided Cell Mediated By Iodide

Efficient synthesis of aziridines is of significant importance due to their various biological activities and potential application in organic synthesis. The most popular approach to construct aziridine ring is the reaction of alkene with nitrene or its precursors. To this end, a variety of chemical protocols have been developed using chloramine-T or N-aminoheterocycles as nitrogen source in the presence of chemical oxidant. On the other hand, an electrochemical process for aziridination of alkenes with PhthNH2 was also reported in a divided cell at a controlled potential using Pt as a working electrode. Based on our previous work, we hypothesized that the electrochemically generated oxidative state of halide species may also apply to the catalytic aziridination reaction of alkene and PhthNH2. Herein, we reported an electrochemical approach for the efficient catalytic aziridination of alkenes using iodine ion as a redox catalyst. The process is conveniently carried out at constant current in an undivided cell.

Tandem aziridine ring opening-disulfide formation-reduction-Michael addition in one-pot mediated by tetrathiomolybdate

A detailed study of tetrathiomolybdate mediated tandem regio- and stereoselective ring opening of aziridine, disulfide formation, reduction of disulfide bond and Michael reaction in a one-pot operation is reported. This constitutes four reactions that take place in one-pot operation. In the reaction of [BnEt3N]4MoS4 with an aziridine derived from cyclohexene and in the absence of Michael acceptor intermediates sulfonamidodisulfide and sulfonamidothiol were isolated and fully characterized. It has also been shown that it is possible to carry out selective opening of the aziridine ring in the presence of an epoxide. By incorporating a suitable Michael acceptor as part of the substrate, intramolecular 1,4-addition could be performed, to achieve the synthesis of sulfur containing acyclic, cyclic amino acid ester derivatives and thia-bicyclo[3.3.1]nonane derivatives in good yields.

Azirinium ylides from α-diazoketones and 2H-azirines on the route to 2H-1,4-oxazines: three-membered ring opening vs 1,5-cyclization.

Strained azirinium ylides derived from 2H-azirines and α-diazoketones under Rh(II)-catalysis can undergo either irreversible ring opening across the N–C2 bond to 2-azabuta-1,3-dienes that further cyclize to 2H-1,4-oxazines or reversibly undergo a 1,5-cyclization to dihydroazireno[2,1-b]oxazoles. Dihydroazireno[2,1-b]oxazoles derived from 3-aryl-2H-azirines and 3-diazoacetylacetone or ethyl diazoacetoacetate are able to cycloadd to acetyl(methyl)ketene generated from 3-diazoacetylacetone under Rh(II) catalysis to give 4,6-dioxa-1-azabicyclo[3.2.1]oct-2-ene and/or 5,7-dioxa-1-azabicyclo[4.3.1]deca-3,8-diene-2-one derivatives. According to DFT calculations (B3LYP/6-31+G(d,p)), the cycloaddition can involve two modes of nucleophilic attack of the dihydroazireno[2,1-b]oxazole intermediate on acetyl(methyl)ketene followed by aziridine ring opening into atropoisomeric oxazolium betaines and cyclization. Azirinium ylides generated from 2,3-di- and 2,2,3-triaryl-substituted azirines give rise to only 2-azabuta-1,3-dienes and/or 2H-1,4-oxazines.

A novel and selective fluoride opening of aziridines by XtalFluor-E. synthesis of fluorinated diamino acid derivatives.

The selective introduction of fluorine onto the skeleton of an aminocyclopentane or cyclohexane carboxylate has been developed through a novel and efficient fluoride opening of an activated aziridine ring with XtalFluor-E. The reaction proceeded through a stereoselective aziridination of the olefinic bond of a bicyclic lactam and regioselective aziridine ring opening with difluorosulfiliminium tetrafluoroborate with the neighboring group assistance of the sulfonamide moiety to yield fluorinated diamino acid derivatives. The method based on the selective aziridine opening by fluoride has been generalized to afford access to mono- or bicyclic fluorinated substances.