Intramolecular formal aza-[3 + 3] cycloaddition approach to indoloquinolizidine alkaloids. A stereoselective total synthesis of (+/-)-tangutorine

[reaction: see text] A 19-step stereoselective total synthesis of (+/-)-tangutorine is described here. The total synthesis features an intramolecular aza-[3 + 3] formal cycloaddition strategy and also a Heck coupling for constructing the C2-C3 bond. This work provides a novel approach toward the indoloquinolizidine family of alkaloids.     

A fast assembly of pentacyclic benz[f]indolo[2,3-a]quinolizidine core by tandem intermolecular formal aza-[3 + 3] cycloaddition/Pictet-Spengler cyclization: a formal synthesis of (+/-)-tangutorine

We have described a concise construction of the pentacyclic benz[f]indolo[2,3-a]quinolizidine intermediate 3 (with an overall yield of 54% for three steps), featuring a tandem intermolecular formal aza-[3 + 3] cycloaddition/Pictet-Spengler cyclization. The present work can be considered as a formal synthesis of beta-carboline alkaloid (+/-)-tangutorine. Our strategy disclosed herein constitutes a new effective general synthetic approach toward the indoloquinolizidine family of alkaloids.     

Indolizines and Their Hetero/Benzo Derivatives in Reactions of [8+2] Cycloaddition

Peculiarities of [8+2] cycloaddition of acetylenes to indolizines are reviewed. Especially mentioned are indolizines with leaving groups at positions 3 and 5. Cycloaddition to aza- and benzo derivatives are reviewed, as well as 1,10-cyclizations and processes leading to cyclazines where indolizines are intermediates. Mechanistic features (adducts and cycloadducts) and theoretical aspects (one- or two-steps mechanism) are reviewed.     

New alkaloid-like heterocycles via formal aza-[3+2] cycloaddition reaction of cyclic enaminones with cyclopropenones

The formal aza-[3+2] cycloaddition reactions of cyclopropenones and cyclic enaminones, including a chiral one, were employed for the first time in the direct formation of new pyrrolidine and indolizidine derivatives. The regiochemistry of cyclization is dependent of both ring size and steric factors of enaminones.     

A formal [3 + 3] cycloaddition reaction. 5. An enantioselective intramolecular formal aza-[3 + 3] cycloaddition reaction promoted by chiral amine salts

A detailed account on chiral secondary amine salt promoted enantioselective intramolecular formal aza-[3 + 3] cycloadditions is described here for the first time. The dependence of enantioselectivity on the structural feature of these chiral amines is thoroughly investigated. This study also reveals a very interesting reversal of the stereochemistry in the respective cycloadducts obtained using C(1)- and C(2)-symmetric amine salts. In addition, the influence of solvents, counteranions, and temperatures on the enantioselectivity is described, and a unified mechanistic model based on experimental results as well as semiempirical calculations is proposed.     

Highly functionalized five-membered carbocycles from (3-dialkylamino-1-ethoxyalkenylidene)pentacarbonylchromium complexes and alkynes: the effects of substituents, solvents, ligand additives, and reagent concentrations on the product distribution

The cocyclization reaction of pentacarbonyl(beta-amino-1-ethoxyalkenylidene)chromium complexes 1 with alkynes has been studied with respect to the effects of substituents, solvents, ligand additives, and reagent concentrations upon the product distribution. This reaction proceeds either as a formal [2 + 2 + 1] cycloaddition to give 5-(1'-dialkylaminoalkylidene)-4-ethoxycyclopent-2-enones 8 or a formal [3 + 2] cycloaddition to give 5-dialkylamino-3-ethoxy-1,3-cyclopentadienes 9. A working hypothesis for the mechanism of this reaction is proposed on the basis of that previously determined for the D?tz reaction. The effects of the aforementioned parameters upon the product distribution of this current reaction are explained in terms of this model. A pronounced ligand-induced allochemical effect has been observed. Conditions for the selective preparation of both classes of cycloadducts 8 and 9 have been determined.     

Formal oxo- and aza-[3 + 2] reactions of α-enaminones and quinones: a double divergent process and the roles of chiral phosphoric acid and molecular sieves

A double divergent process has been developed for the reaction of α-enaminones with quinones through facile manipulation of catalyst and additive, leading to structurally completely different products. The two divergent processes, which involve formal aza- and oxo-[3 + 2] cycloaddition reactions, are mediated by chiral phosphoric acid and molecular sieves, respectively. While inclusion of phosphoric acid in the reaction switched the reaction pathway to favor the efficient formation of a wide range of N-substituted indoles, addition of 4 Å molecular sieves to the reaction switched the reaction pathway again, leading to enantioselective synthesis of 2,3-dihydrobenzofurans in excellent yields and enantioselectivities under mild conditions. Studies in this work suggest that the chiral phosphoric acid acts to lower the transition state energy and promote the formation of amide intermediate for the formal aza-[3 + 2] cycloaddition and the molecular sieves serve to facilitate proton transfer for oxo-[3 + 2] cycloaddition. The reactivity of α-enaminones is also disclosed in this work.

A double divergent process for [3 + 2] cycloadditions of α-enaminones with quinones led to the formation of N-substituted indoles and 2,3-dihydrobenzofurans.     

3 + 2] cycloaddition reactions of 4-alkyl-3-hydroxy-2H-pyrazolo[4,3-c]isoquinolinium inner salts

Heating dipolarophiles with 4-alkyl-3-hydroxy-2H-pyrazolo[4,3-c]isoquinolinium hydroxide inner salts results in [3 + 2] cycloaddition across positions 3a and 5 of the aromatic system to give the [3 + 2] cycloadducts in good yield. When the 4-alkyl substituent is a 2-acetate ester and the methylene group can be deprotonated, a second mode of [3 + 2] cycloaddition becomes available for the resulting anion (across the side chain methine group and position 5 of the aromatic system) and occurs under basic conditions, allowing either of two modes of [3 + 2] cycloaddition to be selected by appropriate choice of reaction conditions.     

Total syntheses of enantiomerically enriched R-(+)- and S-(-)-deplancheine

Total syntheses of indoloquinolizidine alkaloid (+/-)-, R-(+)-, and S-(-)-deplancheine are described here. The synthesis features an enantioselective intramolecular formal aza-[3 + 3] cycloaddition for the construction of the quinolizidine CD-ring. This application serves to introduce a new synthetic strategy for the synthesis of indoloquinolizidine alkaloids.     

Inverse electron-demand aza-[4+2] cycloaddition reactions of allenamides

An inverse electron-demand aza-[4+2] cycloaddition reaction of allenamides with 1-azadiene is described here. Effects of solvents on diastereoselectivity along with synthetic scopes and mechanistic insights are illustrated. Despite some synthetic limitations, this aza-[4+2] cycloaddition does provide a useful template for the synthesis of aza-glycoside related heterocycles.     

Mode selectivity in the intramolecular cyclization of ketenimines bearing N-acylimino units: a computational and experimental study

[reaction: see text] The mode selectivity in the intramolecular cyclization of a particular class of ketenimines bearing N-acylimino units has been studied by ab initio and DFT calculations. In the model compounds the carbonyl carbon atom and the keteniminic nitrogen atom are linked either by a vinylic or an o-phenylene tether. Two cyclization modes have been analyzed: the [2+2] cycloaddition furnishing compounds with an azeto[2,1-b]pyrimidinone moiety and a 6pi-electrocyclic ring closure leading to compounds enclosing a 1,3-oxazine ring. The [2+2] cycloaddition reaction takes place via a two-step process with formation of a zwitterionic intermediate, which has been characterized as a cross-conjugated mesomeric betaine. The 6pi-electrocyclic ring closure occurs via a transition state whose pseudopericyclic character has been established on the basis of its magnetic properties, geometry, and NBO analysis. The 6pi-electrocyclic ring closure is energetically favored over the [2+2] cycloaddition, although the [2+2] cycloadducts are the thermodynamically controlled products. A quantitative kinetic analysis predicts that 1,3-oxazines would be the kinetically controlled products, but they should transform rapidly and totally into the [2+2] cycloadducts at room temperature. In the experimental study, a number of N-acylimino-ketenimines, in which both reactive functions are supported on an o-phenylene scaffold, have been successfully synthesized in three steps starting from 2-azidobenzoyl chloride. These compounds rapidly convert into azeto[2,1-b]quinazolin-8-ones in moderate to good yields as a result of a formal [2+2] cycloaddition.     

Quantum mechanical inspection of the Diels-Alder approach to biaryls mechanism

The Diels-Alder reaction of substituted cyclohexadienes with substituted phenylacetylenes offers an attractive alternative for the synthesis of biaryl compounds via a two-step cycloaddition/cycloelimination pathway. Quantum mechanical calculations using B3LYP and M06-2X density functional methods for the reaction of 2-chloro-6-nitrophenylacetylene with 1-carbomethoxy-cyclohexadiene show the reaction proceeds by a stepwise diradical [4+2] cycloaddition followed by concerted [2+4] cycloelimination of ethylene. [2+2] cycloadducts are also the result of stepwise addition. [2+2] cycloadducts isomerize to [4+2] cycloadducts via diradical pathways, which involve the same diradical intermediate in cycloaddition. There is also a competitive conrotatory ring opening followed by trans-cis double bond isomerization pathway of the [4.2.0] bicycle (the [2+2] cycloadduct) to give the cis,cis,cis-1,3,5-cyclooctatriene.     

Intramolecular [2+2+2] cycloaddition reactions of yne-ene-yne and yne-yne-ene enediynes catalysed by Rh(I): experimental and theoretical mechanistic studies

N-tosyl-linked open-chain yne-ene-yne enediynes 1 and 2 and yne-yne-ene enediynes 3 and 4 have been satisfactorily synthesised. The [2+2+2] cycloaddition process catalysed by the Wilkinson catalyst [RhCl(PPh(3))(3)] was tested with the above-mentioned substrates resulting in the production of high yields of the cycloadducts. Enediynes 1 and 2 gave standard [2+2+2] cycloaddition reactions whereas enediynes 3 and 4 suffered β-hydride elimination followed by reductive elimination of the Wilkinson catalyst to give cycloadducts, which are isomers of those that would be obtained by standard [2+2+2] cycloaddition reactions. The different reactivities of these two types of enediyne have been rationalised by density functional theory calculations.     

Regioselective [3+4] cycloaddition of an azomethine ylide to meso-meso, β-β, β′-β′ triply linked diporphyrins

Thermal reaction of meso-meso, β-β, β′-β′ triply linked diporphyrins with an azomethine ylide produced seven-membered cycloadducts via formal [3+4] cycloaddition at the bay-area. Bischlorin structures of the cycloadducts are characterized on the basis of spectroscopic data and confirmed by single crystal X-ray diffraction analysis. Interestingly, the stability of the cycloadducts depends on the central metal ions in the porphyrin core.     

Enantioselective [4+2] cycloaddition of ketenes and 9,10-phenanthrenequinone catalyzed by N-heterocyclic carbenes

Chiral N-heterocyclic carbenes were found to be efficient catalysts for the formal [4+2] cycloaddition reaction of alkyl(aryl)ketenes and 9,10-phenanthrenequinone to give the corresponding cycloadducts in good yields with high enantioselectivities.     

Solvent and Substituent Effects in the Periselectivity of the Staudinger Reaction between Ketenes and alpha,beta-Unsaturated Imines. A Theoretical and Experimental Study

The outcome of the cycloaddition between activated ketenes and alpha,beta-unsaturated imines has been investigated both experimentally and theoretically. Our results indicate that activated monosubstituted ketenes yield exclusively [2 + 2] cycloadducts. Disubstituted activated ketenes yield [2 + 2] and/or [4 + 2] cycloadducts. In one case, an unexpected piperidin-2-one has been obtained, although its relative abundance with respect to the corresponding [2 + 2] or [4 + 2] cycloadducts can be minimized by the proper choice of experimental conditions. The ability of different ab initio and semiempirical methods to account for these results has been tested. The best agreement between theory and experiment is achieved at the MP2/6-31G level of theory, with solvent effects taken into account. The semiempirical hamiltonian AM1, at the RHF level, tends to overestimate the stability of the transition structures leading to six-membered cycloadducts, whereas 3 x 3CI-HE/AM1 and CASSCF(2,2)/6-31G methods tend to overestimate the stability and the biradical character of the transition structures leading to [2 + 2] cycloadducts.     

A cornucopia of cycloadducts: theoretical predictions of the mechanisms and products of the reactions of cyclopentadiene with cycloheptatriene

The potential cycloaddition reactions between cyclopentadiene and cycloheptatriene have been explored theoretically. B3LYP/6-31G was used to locate the transition states, intermediates, and products for concerted pathways and stepwise pathways passing through diradical intermediates. Interconversions of various cycloadducts through sigmatropic shifts were also explored. CASPT2/6-31G single point calculations were employed to obtain independent activation energy estimates. MM3 was also used to compute reaction energetics. Several bispericyclic cycloadditions in which two cycloadducts are linked by a sigmatropic shift have been identified. B3LYP predicts, in line with frontier molecular orbital predictions, that the [6+4] cycloaddition is the favored concerted pathway, but an alternative [4+2] pathway is very close in energy. By contrast, CASPT2 predicts that a [4+2] cycloaddition is the preferred pathway. B3LYP predicts that the lowest energy path to many of the cycloadducts will involve diradical intermediates, whereas CASPT2 predicts that each of the products of orbital symmetry allowed reactions will be reached most readily by closed shell processes-concerted cycloadditions and sigmatropic shift rearrangements of cycloadducts.     

Catalytic Asymmetric Formal [3+3] Cycloaddition of an Azomethine Ylide with 3‐Indolylmethanol: Enantioselective Construction of a Six‐Membered Piperidine Framework

A catalytic asymmetric formal [3+3] cycloaddition of 3‐indolylmethanol and an in situ‐generated azomethine ylide has been established to construct a chiral six‐membered piperidine framework with two stereogenic centers. This approach not only represents the first enantioselective cycloaddition of isatin‐derived 3‐indolylmethanol, but also has realized an unusual enantioselective formal [3+3] cycloaddition of azomethine ylide rather than its common [3+2] cycloadditions. Besides, this protocol combines the merits of a multicomponent reaction and organocatalysis, which efficiently assembles a variety of isatin‐derived 3‐indolylmethanols, aldehydes, and amino esters into structurally diverse spiro[indoline‐3,4′‐pyridoindoles] with one all‐carbon quaternary stereogenic center in high yields and excellent enantioselectivities (up to 93 % yield, >99 % enantiomeric excess (ee)). Although the diastereoselectivity of the reaction is generally moderate, most of the diastereomers can be separated by using column chromatography followed by preparative TLC.     

Reaction mechanism and chemoselectivity of intermolecular cycloaddition reactions between phenyl-substituted cyclopropenone ketal and methyl vinyl ketone

In this paper, the mechanisms of the intermolecular [3+2] and [1+2] cycloaddition reactions of 1,1/1,3-dipolar π-delocalized singlet vinylcarbenes, which is obtained from cyclopropenone, with an electron-deficient C═O or C═C dipolarophile, to generate five-membered ring products are first disclosed by the density functional theory (DFT). Four reaction pathways, including two concerted [3+2] cycloaddition reaction pathways and two stepwise reaction pathways (an initial [1+2] cycloaddition and then a rearrangement from the [1+2] cycloadducts to the final [3+2] cycloadducts), are investigated at the B3LYP/6-31G(d,p) level of theory. The calculated results reveal that, in contrast to the concerted C═O [3+2] cycloaddition reaction pathway, which is 7.1 kcal/mol more energetically preferred compared with its stepwise reaction pathway, the C═C dipolarophile favors undergoing [1+2] cycloaddition rather than concerted [3+2] cycloaddition (difference of 5.3 kcal/mol). The lowest free energy barrier of the C═O concerted [3+2] cycloaddition reaction pathway shows that it predominates all other reaction pathways. This observation is consistent with the finding that the C═O [3 + 2] cycloadduct is the main product under experimental conditions. In addition, natural bond orbital second-order perturbation charge analyses are carried out to explain the preferred chemoselectivity of C═O to the C═C dipolarophile and the origins of cis-stereoselectivity for C═C [1+2] cycloaddition. Solvent effects are further considered at the B3LYP/6-31G(d,p) level in the solvents CH(3)CN, DMF, THF, CH(2)Cl(2), toluene, and benzene using the PCM model. The results indicate that the relative reaction trends and the main products are insensitive to the polarity of the reaction solvent.     

Organocatalytic asymmetric robinson annulation of alpha,beta-unsaturated aldehydes: applications to the total synthesis of (+)-palitantin

The highly enantioselective organocatalytic Robinson annulation of alpha,beta-unsaturated aldehydes was achieved, catalyzed by l-proline and trialkylamines and providing the formal [4 + 2] cycloaddition adducts. Additionally, in some examples in the catalysis with diarylpyrrolinol silyl ethers, the reactions afforded the [4 + 2] adducts with high enantioselectivity (>99.5% ee). The structure of the adduct, obtained from the reaction of 3-methylbut-2-enal and (E)-3-(2-nitrophenyl)acrylaldehyde, was confirmed by X-ray analysis. The absolute configurations of some [4 + 2] cycloadducts were investigated, and the methodology was applied in the synthesis of (+)-palitantin.