Cycloaddition reactions of 1,2-diazepines with nitrile oxides. synthesis of 1,2,9-triaza-8-oxabicyclo-[5.3.0]-3,5,9-decatriene derivatives

A new heterocyclic system, 1,2,9-triaza-8-oxabicyclo-[5.3.0]-3,5,9-decatriene 4, has been synthesized by regiospecific 1,3-dipolar cycloaddition of nitrile oxides to the imine double bond of 1,2-diazepines. Bis-adduct 5a is obtained in only trace amounts showing that the imine double bond is more reactive than the Δ⁴-olefinic bond.     

Approaches to the regiospecific synthesis of Anthracycline antibiotics

Synthetic approaches to anthracycline antibiotics were studied through the use of Claisen rearrangements on 1-methallyloxy-5-methoxyantraquinone (9) which required reducing conditions to proceed through a hydroquinone intermediate in situ. 1-(2′-Methylene-4′-pentenoxy)-5-methoxyanthraquinone (13) underwent a similar reductive rearrangement but also produced a spiro compound 16 as a result of an ene reaction between the phenol and side chain double bond. 1-Hydroxy-2-methally-5-methoxyanthraquinone (11) could not be oxidized to quinizarin 17. 1-Hydroxy-2-methally-5,9,10-trimethoxyanthracene (21) was oxidatively coupled to the dimer at C-2. Dimer 23 reacted with diazomethane to form a 1,3-dipolar adduct 24.     

The first regio- and diastereoselective synthesis of homochiral perhydroimidazoisoxazoles via the 1,3-dipolar cycloaddition of imidazoline 3-oxides with (1S)-(−)-β-pinene

The 1,3-dipolar cycloaddition of imidazoline 3-oxides 1 with (1S)-(−)-β-pinene proceeds regio- and diastereoselectively to give homochiral perhydroimidazoisoxazole derivatives 3 in high yields in the cases of imidazoline 3-oxides 1a–e but in low yields in the reactions of 1f–g. The preferred attack of (1S)-(−)-β-pinene to the cyclic nitrone was shown to be anti–endo. The reaction of racemic nitrones (±)-1f–g with the homochiral β-pinene gave the adduct from the (S)-nitrone and the corresponding imidazole. The adducts 3 undergo retro-1,3-dipolar cycloaddition when heated in the condensed phase or in diphenyl ether to give the corresponding imidazole and β-pinene.     

Regioselectivity in the 1,3-dipolar cycloaddition of nitrile oxides to alkylidenecyclopropanes.

The 1,3-dipolar cycloaddition of nitrile oxides to methylenecyclopropanes substituted on the exocyclic double bond gives prevalently or exclusively 4-spirocyclopropane isoxazolines when the substituent is arylic or alkylic group, 5-spirocyclopropane isoxazolines when the substituent is an electron-withdrawing group. Adducts 16 and 17 selectively rearrange photochemically to the enaminoenone 19.     

Novel 1,3-dipolar cycloadditions of fulvenes and hydrazonyl chlorides: a facile synthesis of the cyclopenta[d]pyridazines

A simple and convenient route for one-pot synthesis of cyclopenta[d]pyridazine through 1,3-dipolar cycloaddition of fulvenes and hydrazonyl chlorides is described. The reaction of fulvenes with hydrazonyl chlorides in the presence of silver carbonate smoothly afforded a series of cyclopenta[d]pyridazines.     

Stereoselective intramolecular cycloadditions of homochiral nitrilimines as a source of enantiopure 2,3,3a,4,5,6-hexahydro-pyrrolo[3,4-c]pyrazoles

Starting from the methyl esters of glycine, l-alanine, l-phenylalanine and (S)-2-phenylglycine, we developed a synthetic route to the title compounds in the enantiopure form by means of a stereoselective intramolecular 1,3-dipolar cycloaddition of homochiral nitrilimines 5a–d. Fair to good overall product yields and high cycloaddition diastereoselectivity were obtained.     

Synthesis of the tricyclic core structure of vindoline

An efficient synthesis of the core tricyclic structure (18) of vindoline has been achieved using the strategy, which features an intramolecular 1,3-dipolar cycloaddition of the azido dienone (12) to give aziridine (13) with complete region- and stereocontrol.     

Acid-catalyzed aza-Diels-Alder versus 1,3-dipolar cycloadditions of methyl glyoxylate oxime with cyclopentadiene

The acid-catalyzed 1,4- and 1,3-cycloadditions between methyl glyoxylate oxime (1) and cyclopentadiene were investigated using various Lewis and/or Bronsted acids at different temperatures in dichloromethane as solvent. Besides the expected new adducts, (±)-methyl [(3-exo)-2-hydroxy-2-azabicyclo[2.2.1]hept-5-ene]-3-carboxylate (2) and (±)-methyl [(3-endo)-2-hydroxy-2-azabicyclo[2.2.1]hept-5-ene]-3-carboxylate (3), a third adduct, (±)-methyl (1R,4R,5R)-(2-oxa-3-azabicyclo[3.3.0]oct-7-ene)-4-carboxylate (4), whose formation can be explained by a 1,3-dipolar cycloaddition, was obtained. Yields and product ratios were found to be more dependent on the catalyst than on the temperature; these results and the stereochemistry of the adducts, confirmed by spectroscopic data (¹H and ¹³C NMR) and by X-ray crystallography, were used to analyze and propose a mechanistic explanation for both cycloadditions.     

Preparation of 2-alkenylperhydro-1,3-benzoxazines and application for 2-isoxazolines synthesis

Various 2-substituted-N-benzyl-4,4,7-trimethyl-trans-octahydro-1,3-benzoxazines 2 were prepared from the condensation of (?)-8-benzylaminomenthol 1 derived from (+)-pulegone, with acrolein, crotonaldehyde, cinnamaldehyde, 2(E)-N,N-diisopropyl-4-oxobut-2-enamide, ethyl (2E)-4-oxobut-2-enoate, and 2-furaldehyde in 71–96% yield. The 1,3-dipolar cycloaddition with aceto- and benzonitrile oxide gave the corresponding 2-isoxazoline cycloadducts. The origin of the stereoselectivity (4′S, 5′S-cycloadducts up to 64% de) arises from the cycloaddition of the dipole to the top of the Re,Re-alkene face of dipolarophile 2.     

Semi-synthesis of bioactive fluorescent analogues of the cytotoxic marine alkaloid discorhabdin C

Semi-synthetic N-13 alkylated analogues of the cytotoxic marine alkaloid discorhabdin C have been found to exhibit cytotoxicity towards tumour cell lines at comparable levels to that of the natural product. Incorporation of an ethylenediamine linker facilitated the synthesis of a variety of fluorophore-labelled probes, of which dansyl analogue 20 exhibited biological activity, providing a tool for mechanism of action and cellular localization studies. An alternative probe design was also exemplified, whereby a bioactive alkyne-terminated analogue (24) was found to undergo Huisgen 1,3-dipolar cycloaddition ‘click’ reactions with fluorescent azides, enabling studies directed towards activity-based protein profiling.     

Cycloaddition reactions of carbohydrate derivatives. Part 7: [3+2] cycloadditions of chiral nitrilimines

The diastereoselective 1,3-dipolar cycloaddition reactions of chiral alkenes with a nitrilimine derived from d-galactose phenylhydrazone were studied. The best stereoselectivity was observed with N-acryloyl-(−)-camphor sultam 9, as the chiral inductor, to produce compound 8.     

An improved synthesis of enantiomerically pure CIP-AS,a potent and selective AMPA-kainate receptor agonist

CIP-AS (−)-2, a chiral amino acid structurally related to glutamic acid, behaves as a potent agonist at the ionotropic AMPA-kainate receptors and was previously prepared in low overall yield through the 1,3-dipolar cycloaddition of ethoxycarbonylformonitrile oxide to N-BOC-3,4-didehydro-(S)-proline methyl ester (−)-6. Herein, we report an alternative strategy based on the cycloaddition of the same dipolarophile to N-(4-methoxybenzyl)-α-ethoxycarbonylnitrone 12. The mixture of stereoisomeric 3-ethoxycarbonyl-N-(4-methoxybenzyl)isoxazolidinyl prolines 13 was then converted into the corresponding 3-ethoxycarbonyl-Δ²-isoxazolinyl prolines by DDQ mediated oxidation. The new strategy yielded the precursor of CIP-AS in satisfactory overall yield and represents an improvement upon the existing procedure in terms of yield and efficiency.     

Electrostatic origin towards the reversal of π-facial selectivity of 5,6-cis,exo-disubstituted bicyclic[2.2.2]oct-2-enes with m-chloroperbenzoic acid and diazomethane: a computational study

A computational (B3LYP/6-31G∗ and MP2/6-31G∗) study shows that electrostatic interaction is controlling the π-facial selectivity for the addition of peracid and diazomethane to 5,6-cis,exo-disubstituted bicyclic[2.2.2]oct-2-enes (1). The nitrogen centre of diazomethane which does not participate in bond formation governs the π-face selectivity in 1,3-dipolar cycloaddition reactions with 1. The calculated results show that Cieplak model is less important in controlling the face selectivity in these cases.     

Diastereoselective and enantioselective synthesis of 4′-aza analogues of 2′,3′-dideoxynucleosides

A diastereo- and enantioselective synthesis of 4′-aza analogues of 2′,3′-dideoxynucleosides has been designed by the strategy of the 1,3-dipolar cycloaddition reaction of a Vasella-type nitrone. The reaction leads to (1′R)- and (1′S)-4′-aza analogues of 2′,3′-dideoxythimidine and fluorouridine, in enantiomerically pure forms.     

Stereoselective total synthesis of 1α,25S,26-trihydroxycholecalciferol

A total synthesis of 1α,25S,26-trihydroxycholecalciferol (2) has been accomplished via an efficient convergent approach. The remote chiral center at C-25 was introduced by a regiospecific and diastereoselective 1,3-dipolar cycloaddition of the C-23 nitrone 27 with methyl methacrylate. Subsequent transformation of the resulting isoxazolidine led to the key synthon 3, which on coupling to the anion 4 and deprotection produced the metabolite 2.     

1,3-Dipolar cycloaddition reaction of a d-galactose derived nitrone with allyl alcohol: synthesis of polyhydroxylated perhydroazaazulene alkaloids

Diastereofacial intermolecular 1,3-dipolar cycloaddition of d-galactose derived nitrone with allyl alcohol followed by tosylation afforded, in a 1:1 ratio endo- and exo-isooxazolidines 4a and 4b with complete diastereoselectivity at the nitrone carbon. The N–O bond reductive cleavage and S_N2 displacement afforded the pyrrolidine ring with a galactose appendage that on acetonide cleavage and reductive amino-cyclization afforded pentahydroxylated perhydroazaazulenes 1a and 1b.     

Regioselective synthesis of 5-trifluoromethyl-1,2,3-triazole nucleoside analogues via TBS-directed 1,3-dipolar cycloaddition reaction

Herein described was a straightforward method for the highly regioselective synthesis of 5-trifluoromethyl-1,2,3-triazole nucleoside analogues, which featured the utilization of tert-butyldimethylsilyl (TBDMS) group as the directing group in the 1,3-dipolar cycloaddition reactions. 4-tert-Butyldimethylsilyl-5-trifluoromethyl-1,2,3-triazole nucleoside analogues were generated as the only cycloaddition products in moderate yields (15-79%) via the treatment of glycosyl azides with 3,3,3-trifluoro-1-tert-butyldimethylsilylpropyne 1 in toluene at 85 °C. Removal of TBS groups in these triazole cycloadducts with tetrabutylammonium fluoride (TBAF) smoothly afforded the various 5-trifluoromethyl-1,5-disubstituted 1,2,3-triazole nucleoside analogues in good yields (40-88%).     

Synthesis of ethyl 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylate via regioselective dipolar cycloaddition

Efforts to prepare ethyl 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylate (1) by developing a regioselective 1,3-dipolar cycloaddition between phenyl nitrile oxide and various 4,4,4-trifluoromethyl crotonates are described. The substitution at the C2-position of crotonate dipolarophile 4 significantly influenced the regiochemistry and yield of the cycloaddition. Enol and enol ether-based crotonates underwent regioselective cycloadditions with phenyl nitrile oxide to provide 4-trifluoromethyl isoxazoles in good yields.     

1, 3-dipolar cycloaddition of C-phenyl carbamoyl-N-phenyl nitrone with some dialkyl-substituted 2-benzylidenecyclopropane-1,1-dicarboxylates: theoretical analysis of mechanism and regioselectivity

The regiochemistry of 1,3-dipolar cycloaddition reactions of C-phenyl carbamoyl-N-phenyl nitrone with some dialkyl-substituted 2-benzylidenecyclopropane-1,1-dicarboxylates as dipolarophile was investigated using density functional theory-based reactivity indexes and activation energy calculations at B3LYP/6-31G(d) level of theory. Analysis of the geometries and bond orders at the TS structures associated with the different reaction pathways shows that these 1,3-dipolar cycloaddition reactions occur via an asynchronous concerted mechanism. Analysis of the local electrophilicity and nucleophilicity indexes based on Parr functions only for reaction between 1 + 2a and based on Fukui functions only for 1 + 2b gives correct regioselectivity. The theoretical results obtained in the work clearly predict the regiochemistry of the isolated cycloadducts and agree to experimental results.     

Diels-Alder reaction with phosphaalkenes. Synthesis of functionalized λ3 phosphabenzenes.

The reaction of phosphaalkenes (1 and2) with 1,3 dienes such as methyl sorbate and 1-methoxy 3-trimethylsilyloxy-1,3 butadiene leads to functionalized λ³ phosphabenzenes6,9,12,13 and16 after aromatization of the primary adducts. The aromatization may occur either spontaneously or after chemical transformations. The reversible cycloaddition has allowed the synthesis of isomeric phosphabenzenes6 and9. Diels-Alder reaction with phosphaalkenes appears to be a general method for the obtention of functionalized λ³ phosphabenzenes.