A new approach to construction of isoindolo[1,2-a]isoquinoline alkaloids Nuevamine, Jamtine, and Hirsutine via IMDAF reaction

The interaction between 1-furyl-1,2,3,4-tetrahydroisoquinolines and unsaturated acids derivatives (acryloyl, methacryloyl, and crotonoyl chloride, maleic and citraconic anhydride) was studied. It was shown that the reaction proceeds via amide formation and subsequent intramolecular Diels-Alder reaction of the furan (IMDAF). The [4+2] cycloaddition proceeded under mild reaction conditions (25-80 °C) and afforded only the exo-adduct in a high yield. With this method, a new approach to the isoindolo[1,2-a]isoquinoline system, the basic structural element of alkaloids Jamtine, Hirsutine, and Nuevamine, is proposed.     

Substituent control in the diastereoselectivity of dipolar cycloadditions of nitrones and their Zn(II) complexes with N-arylmaleimides

The π-π stacking interactions between maleimide's and nitrone's aromatic rings during the 1,3-dipolar cycloaddition were assumed to control the exo-endo selectivity of the reaction. The exo-endo ratios change during the reactions until they reach a constant value, which depends on the substituent. Electron-withdrawing groups favour the exo adduct while electron-donating groups favour the endo adduct. The nitrone ZnBr₂ complexes react much more slowly than the free nitrone and the cycloaddition is exo selective in all cases independent of the substituents on the maleimide's aromatic ring. Thermal retrocycloaddition of the cycloadducts produce the corresponding nitrones. The ring opening in the presence of secondary amines did not induce imine formation. endo Adducts were shown for the first time to be the stable paramagnetic compounds.     

Total syntheses of (±)-frondosin C and (±)-8-epi-frondosin C via a tandem anionic 5-exo dig cyclization-Claisen rearrangement sequence

Microwave-assisted anionic 5-exo dig cyclization-Claisen rearrangement sequence has been investigated as a convenient ‘one-pot’ route to fused cycloheptanoid ring systems. This process was used as the key transformation to construct the tetracyclic framework of frondosin C. Subsequent manipulation of the core allowed the first total syntheses of (±)-frondosin C and (±)-8-epi-frondosin C in a combined overall yield of 20.8% over 14 steps.     

The Beckmann fragmentation of quadricyclanone oxime

The attempted O-tosylation of tetracyclo[3.2.0.0^2,7.0^4,6]heptan-3-one (quadricyclanone) oxime with p-toluenesulfonyl chloride in dichloromethane in the presence of triethylamine/DMAP or pyridine resulted in the Beckmann fragmentation to give a mixture of 4-exo-/4-endo-tosyloxy- and 4-exo-/4-endo-chlorobicyclo[3.1.0]hex-2-ene-6-endo-carbonitriles in 90% overall yield. Solvolysis of all four products in 2,2,2-trifluoroethanol afforded the corresponding 4-exo-trifluoroethoxy derivative as the sole product. Quadricyclanone itself undergoes the fragmentation reaction with hydroxylamine-O-sulfonic acid, selectively affording the 4-exo-hydroxy-6-endo-nitrile in 90% isolated yield.     

Preparation of isoxazol(in)yl substituted selenides and their further deselenenylation reaction to synthesize 3,5-disubstituted isoxazoles

We report a mild 1,3-dipolar cycloaddition protocol for the preparation of 3-aryl-5-phenylselenomethyl isoxazoles and isoxazolines regioselectively. The former was further reacted with LDA and electrophilic substrates followed by selenoxide syn-elimination to afford 3-aryl-5-E-substituted-ethenyl isoxazoles stereoselectively and the latter was subjected to a ‘two-step’ elimination to afford 3-aryl-5-methyl isoxazoles.     

Quantum-chemical study of the Lewis acid influence on the cycloaddition of benzonitrile oxide to acetonitrile, propyne and propene

Quantum chemical methods (MP2 and B3LYP) together with a topological analysis of the charge density have been used to study the BH₃- or BF₃-mediated reaction of benzonitrile oxide with acetonitrile, propyne and propene. In the reaction with propene or propyne, addition of Lewis acids has only little influence on the outcome of the reactions. The cycloaddition of nitrile oxides with nitriles, however, is generally promoted by strong Lewis acids. When the Lewis acid coordination takes place at the nitrile oxide the reactant is activated and the product binds weakly to the Lewis acid so that the reaction is expected to be catalytic. In the case of coordination to the nitrile the reaction is Lewis acid mediated. Here the reactant is not much influenced by addition of Lewis acid, but the transition state and the product are stabilised and consequently such processes require a stoichiometric amount of Lewis acid and form a stable Lewis acid-product complex.It has also been demonstrated that the different activation routes for these reactions involve different reaction mechanisms. Whereas the reaction of a Lewis acid coordinated nitrile oxide is of ‘inverse electron demand’, the Lewis acid coordinated nitrile reacts through a ‘normal electron demand’ cycloaddition.     

Kinetic studies of inverse electron demand Diels–Alder reactions (iEDDA) of norbornenes and 3,6-dipyridin-2-yl-1,2,4,5-tetrazine

Inverse electron demand Diels–Alder additions (iEDDA) between 1,2,4,5-tetrazines and olefins have recently found widespread application as a novel ‘click chemistry’ scheme and as a mild technique for the modification of materials. Norbornenes are, due to their straightforward synthetic availability, especially interesting in the latter context. Therefore, the reactivity of different norbornene-based compounds was compared with unsubstituted norbornene and other alkenes using UV-vis measurements for the determination of reaction rates under pseudo first order conditions. Thereby, exo,exo-5-norbornene-2,3-dimethanol was found to be almost as reactive as unsubstituted norbornene whereas (±)-endo,exo-dimethyl-5-norbornene-2,3-dicarboxylate reacted only insignificanty faster than unstrained alkenes.     

1,3-Dipolar cycloaddition of 2- and 3-nitroindoles with azomethine ylides. A new approach to pyrrolo[3,4-b]indoles

The 1,3-dipolar cycloaddition of unstabilized azomethine ylides with 2- and 3-nitroindoles furnishes the expected hexahydropyrrolo[3,4-b]indole cycloadducts in good to excellent yields. The cycloadducts can be denitrated with Bu₃SnH/AIBN, and cycloadduct 5 was oxidized with MnO₂ to yield the known pyrrolo[3,4-b]indole 13.     

Theoretical study of the walk rearrangement in perfluorotetramethyl (Dewar thiophene) exo-S-oxide

A theoretical study of the ‘walk’ rearrangement in bicyclo[2.1.0]pentene and perfluorotetramethyl (Dewar thiophene) exo-S-oxide has been carried out. Despite the differences between them, the results for both reactions show an enhancement of aromaticity in the transition state, which is consistent with a pericyclic behavior. NBO calculations show that the small activation energy for the second reaction can be interpreted in terms of a strong stabilization of the transition state by the exo-oxide substituent. So, the mechanism proposed in the past should be revised.     

A three-component synthesis of pyrido[2,3-d]pyrimidines

A new, high yield multicomponent reaction providing multifunctionalized pyrido[2,3-d]pyrimidines in a microwave-assisted one-pot cyclocondensation of α,β-unsaturated esters, amidine systems and malononitrile (or ethyl cyanoacetate) is described (the ‘Victory’ reaction).     

Synthesis of seco-psymberin/irciniastatin A: the discovery of a novel PhI(OAc)2 mediated cascade cyclization reaction

The psymberin unsaturated ‘psymberate’ side chain 7 was synthesized in 7 steps (36% yield) with good diastereoselectivity using commercially available starting material to control the stereochemistry at C₄ and C₅. The synthesis of seco-psymberin was completed in an efficient manner based on a CuI mediated coupling reaction between vinyl iodide 8 and ‘psymberamide’ 7. In an attempt to synthesize natural psymberin from the seco-intermediate, a novel PhI(OAc)₂ mediated cascade ring closing reaction was discovered. A possible mechanistic pathway for the formation of the ring closing product was presented.     

Selectivities in the 1,3-dipolar cycloaddition of nitrile oxides to dicyclopentadiene and its derivatives

The 1,3-dipolar cycloaddition of nitrile oxides, generated from aldoximes and nitroalkanes, to dicyclopentadiene proceeds with complete chemo- and stereoselectivity. The approach of the dipole takes place exclusively from the exo-face of the bicycloheptane moiety providing a mixture of regioisomers in approximately 55:45 ratio. On the other hand, nitrile oxide cycloaddition to dimethyldicyclopentadiene dicarboxylate (Thiele's ester), besides exhibiting chemo- and stereoselectivity as in the case of dicyclopentadiene, exhibits complete regioselectivity as well providing a single isomer in good yield. The Influence of remote substituents, including sterically ‘sterile’ ones, on the regioselectivity has also been investigated using 8-hydroxy and 1-keto derivatives of dicyclopentadiene. These experimental observations have been investigated through gas phase and solvent model MO calculations on the transition state geometries at semiempirical (PM3) and hybrid ab initio-DFT levels of theory. The Computational methods employed in this study were rigorously tested by performing model calculations on well-established experimental observations.     

Asymmetric nitrone cycloadditions and their application to the synthesis of enantiopure pyrrolidine and pyrrolizidine derivatives

The cycloaddition reactions of a pair of chiral pyrroline-N-oxides derived from d-ribose with some typical mono and disubstituted alkenes are reported. In all these reactions with monosubstituted alkenes as well as with dimethyl maleate the preferred stereochemical outcome of the cycloaddition step comes from a 5-exo-anti transition state whereas stereoisomers from the 5-exo-syn transition state are also present as minor adducts. In the reaction with dimethyl fumarate the major adduct comes from a 4-exo-5-endo-syn transition state. The further behavior of the obtained isoxazolidines upon reductive ring opening conditions depends on the kind and the geometry of the preexisting substituents and they are transformed to enantiomerically pure pyrrolidine or pyrrolizidinone derivatives.     

Chemical and electrocatalytic cascade cyclization of salicylaldehyde with three molecules of malononitrile: ‘one-pot’ simple and efficient way to the chromeno[2,3-b]pyridine scaffold

А new type of catalytic cascade cyclization was found: the direct ‘one-pot’ simple and efficient transformation of salicylaldehyde and three molecules of malononitrile into the chromeno[2,3-b]pyridine systems. Chemical and electrochemical methods result in direct ‘one-pot’ formation of chromeno[2,3-b]pyridines in 60–90% yields. The implication of electrocatalysis in complex cascade cyclization reaction is an efficient approach to medicinally relevant chromeno[2,3-b]pyridines—the promising small-molecule ligands with pronounced antihistamic, antirheumatic and antiasthmatic activities. The electrocatalytic method is beneficial from the viewpoint of diversity-oriented large-scale processes and represents fast efficient and environmentally benign synthetic concept for cascade reactions strategy.     

H-quadrupolar coupling-based analysis of stereochemical and regiochemical memory in the Pd-catalysed allylic alkylation of iso-cinnamyl type substrates employing the chiral monophosphine ligands ‘MOP’ and ‘MAP’

The reaction of iso-cinnamyl acetate with NaC(Me)(CO₂Me)₂, catalysed by Pd-‘MOP’ (MOP=2-methoxy-2′-diphenylphosphino-1,1′-binaphthalene) is known to proceed with a regiochemical memory effect that results in the predominant generation of the branched alkylation product. The analogous reaction employing ‘MAP’ as ligand (MAP=2-N,N-dimethylamino-2′-diphenylphosphino-1,1′-binaphthalene) proceeds with ‘normal’ regioselectivity to generate predominantly the linear isomer of product. A ²H-NMR based analysis, employing quadrupolar coupling in a chiral liquid crystal matrix, has been developed to facilitate the simultaneous study of the regiochemical and stereochemical outcome of the reaction of both enantiomers of iso-cinnamyl ester substrates in ²H-labelled but racemic samples. The analysis allows the comparison of relative rates of two competing isomerisation processes occurring in the π-allyl intermediates in the Pd-catalysed reaction, one of which facilitates asymmetric induction, the other resulting in loss of regiochemical memory. It is demonstrated that the two processes are partially coupled and that this then limits the attainment of high global enantiomeric excess in the branched product to reactions that proceed with low regiochemical retention. A key factor for the observation of high regiochemical memory is found to be the nucleophilicity of the malonate anion and the electrophilicity of the Pd-π-allyl intermediate with reduction in the reactivity of either partner resulting in the onset of substantial loss of memory.     

Selectivity in cycloadditions—X : Regiochemistry of cycloadditions of nitrile oxides to thiophene and benzothiophene 1,1-dioxides

Thiophene-1,1-dioxide undergoes regioselective cycloaddition to benzonitrile oxide. In the reaction with the less reactive mesitonitrile oxide the sulfur dioxide deriving from the dimerization of the dipolarophile causes a catalytic decomposition of the nitrile oxide, which competes with the cycloaddition. Benzothiophene-1,1-dioxide and the vinyl sulfone system of 2,3-dihydrothiophene-1,1-dioxide and nitrile oxides with lower regioselectivity. The directing effect of the sulfonyl group has been elucidated with the aid of CNDO/2 calculations.     

Chiral bis(2-oxazolinyl)xanthene (xabox)/transition-metal complexes catalyzed 1,3-dipolar cycloaddition reactions and Diels-Alder reactions

A series of chiral 4,5-bis(2-oxazolinyl)-(2,7-di-tert-butyl-9,9-dimethyl)-9H-xanthenes (xabox) and their transition-metal complexes were synthesized. The X-ray analysis of xabox-RhCl₃ complex shows a unique facial type structure. Xabox-Bn-Mn(II) and xabox-Bn-Mg(II) complexes were found to be efficient catalysts in nitrone 1,3-dipolar cycloaddition (1,3-D.C.) reaction resulting in good to excellent enantioselectivities ranging from 96:4 to >99:1of endo/exo ratio and 91-96% ee for the endo adduct. The correlation between enantiomeric excess of the ligand and the product in the nitrone 1,3-D.C. reaction shows a clear linear relationship, which suggests xabox-metal catalyst worked as a single molecular catalyst. In addition, xabox-i-Pr-Mn(II) complex was also found to be an active catalyst for Diels-Alder (D-A) reaction of acryloyloxazolidinone and cyclopentadiene affording the corresponding cycloadduct in quantitative yield along with 82% ee and 98:2 endo/exo ratio.     

Synthesis of cyclic peptides via O-N-acyl migration

We describe here a novel and convenient synthesis of head-to-tail cyclic peptide avoiding racemization. Linear depsipeptides including a serine residue as the key element for ester bond formation and acyl transfer were synthesized on 2-chlorotrityl chloride resin. After cleavage from the resin, intramolecular head-to-tail cyclization was performed in solution by C-terminal activation of urethane protected O-acyl serine residue. After removal of the N^α-serine protecting group, the final step consisted in O-N-acyl migration reaction on the ‘switch’ or ‘click’ element to restore native cyclic peptides.     

An efficient approach to isoindolo[2,1-b][2]benzazepines via intramolecular [4+2] cycloaddition of maleic anhydride to 4-α-furyl-4-N-benzylaminobut-1-enes

Acylation of 4-α-furyl-4-N-benzylaminobut-1-enes with maleic anhydride gave 4-oxo-3-aza-10-oxatricyclo[5.2.1.0^1,5]dec-8-ene-6-carboxylic acid via amide formation followed by intramolecular Diels-Alder reaction of furan (IMDAF). The cycloaddition proceeded under mild reaction conditions (25 °C) and provided only the exo-adduct in quantitative yield. Treatment of this compound with PPA gave isoindolo[2,1-b][2]benzazepine derivatives via ring opening, aromatization and intramolecular electrophilic alkylation. In order to extend the scope of the reaction sequence, 7-oxo-5,11b,12,13-tetrahydro-7H-isoindolo[2,1-b][2]benzazepine-8-carboxylic acids were further transformed into useful synthetic intermediates.     

Synthesis of 5-aminoisoxazolines from N-allyl compounds and nitrile oxides via tandem isomerization-1,3-dipolar cycloaddition

A new strategy for the synthesis of derivatives of 5-aminoisoxazolines via tandem catalytic isomerization (of N-allyl systems to N-(1-propenyl) systems)—1,3-dipolar cycloaddition (of a stable nitrile oxide to N-(1-propenyl) systems) is presented. Rhodium and ruthenium complexes, Verkade’s superbase, and 18-crown-6/KOH system were used for the syntheses of the N-(1-propenyl) systems. 4-P-substituted isoxazoline was also synthesized via cycloaddition of diphenyl(1-propenyl)phosphine (prepared via isomerization of allyldiphenylphosphine) to 2,6-dichlorobenzonitrile oxide. All cycloadditions were regioselective but not stereoselective and not concerted. Cycloaddition to all N-(1-propenyl) systems yielded 5-N-substituted isoxazolines, but cycloaddition to P-(1-propenyl) system lead to the formation of a 4-P-regioisomer. This difference in regioselectivity is predicted by opposite FMO reactivity indices calculated for model compounds: N-(1-propenyl)amine and N-(1-propenyl)phosphine.