Formal synthesis of aspidosperma alkaloids via the intramolecular [3 + 2] cycloaddition of 2-azapentdienyllithiums

[reaction: see text] A formal synthesis of the Aspidosperma alkaloids aspidospermidine, aspidospermine, and quebrachamine is reported through an efficient preparation of Stork's penultimate intermediate. The key step of the sequence involved an intramolecular [3 + 2] cycloaddition of the 2-azapentadienyllithium 21 formed in situ from the corresponding imine 1, which after N-alkylation of the resulting cycloadduct provided 2 in excellent yield. The synthesis represents a new disconnection of the classical tricyclic ketone used for appendage of the requisite indole.     

A new stereocontrolled synthetic route to (-)-echinosporin from D-glucose via Padwa allenylsulfone [3 + 2]-anionic cycloadditive elimination

A new formal total synthesis of (-)-echinosporin has been developed based upon the Padwa [3 + 2]-cycloadditive elimination reaction of allenylsulfone 4 with the D-glucose-derived enone 14 which provides cycloadduct 12.     

Three-component cycloadditions: the first transition metal-catalyzed [5+2+1] cycloaddition reactions

Prompted by our studies of transition metal-catalyzed [4+4], [4+2], [5+2], and [6+2] cycloadditions and by the view that these two-component reactions could be intercepted by a third component of one or more atoms, a new three-component transition metal-catalyzed cycloaddition is described. This new [5+2+1] cycloaddition proceeds in good to excellent yield and with high or complete regioselectivity with a variety of carbonyl-substituted alkynes to give bicyclo[3.3.0]octenone adducts, resulting from transannular closure of the intermediate eight-membered-ring cycloadduct. Effects of concentration, temperature, pressure, and catalyst loading on the efficiency of the reaction are discussed. This process provides access to complex building blocks for synthesis based on simple, readily available components.     

Intramolecular [4+2] cycloaddition reactions of enamines and enamides

An attempt to utilize a new strategy for alkaloid synthesis which features the intramolecular [4+2] cycloaddition of enamines and enamides for the construction of the tetracyclic spiroamine skeleton characteristic of the Erythrina alkaloids was unsuccessful, unexpectedly giving a bridged cycloadduct rather than a fused one.     

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.     

Co-Catalyzed Asymmetric Intramolecular [3+2] Cycloaddition of Yne-Alkylidenecyclopropanes and its Reaction Mechanism

Developing new transition metal-catalyzed asymmetric cycloadditions for the synthesis of five-membered carbocycles (FMCs) is a research frontier in reaction development due to the ubiquitous presence of chiral FMCs in various functional molecules. Reported here is our discovery of a highly enantioselective intramolecular [3+2] cycloaddition of yne-alkylidenecyclopropanes (yne-ACPs) to bicyclo[3.3.0]octadiene and bicyclo[4.3.0]nonadiene molecules using a cheap Co catalyst and commercially available chiral ligand (S)-Xyl-BINAP. This reaction avoids the use of precious Pd and Rh catalysts, which are usually the choices for [3+2] reactions with ACPs. The enantiomeric excess in the present reaction can be up to 92 %. Cationic cobalt(I) species was suggested by experiments as the catalytic species. DFT calculations showed that this [3+2] reaction starts with oxidative cyclometallation of alkyne and ACP, followed by ring opening of the cyclopropyl (CP) group and reductive elimination to form the cycloadduct. This mechanism is different from previous [3+2] reactions of ACPs, which usually start from CP cleavage, not from oxidative cyclization.     

Bay-area selective thermal [4+2] and [4+4] cycloaddition reactions of triply linked ZnII diporphyrin with o-xylylene

A triply linked ZnII diporphyrin underwent site-selective cycloaddition reactions with thermally generated o-xylylene to provide a triply linked porphyrin-chlorin hybrid and a triply linked chlorin dimer in moderate yields. The former product is a symmetry-allowed [4+2] cycloadduct, while the latter is a symmetry-forbidden [4+4] cycloadduct. Oxidation of the latter product with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) provided a triply linked diporphyrin fused with a benzocyclooctatriene segment. This oxidized product and above [4+2] cycloadduct were structurally characterized by single crystal X-ray diffraction analysis. The observed site-selectivity is considered to arise from the large MO coefficients at the bay-area in the LUMO of the triply linked diporphyrin. The anomalous thermal [4+4] cycloaddition may be ascribed to the highly conjugated and quite perturbed electronic properties of triply linked ZnII diporphyrin.     

4 + 2] cycloadditions of N-alkenyl iminium ions: structurally complex heterocycles from a three-component Diels-Alder reaction sequence

N-Alkenyl iminium ions serve as conduits to three-component [4 + 2] cycloaddition reactions accessing structurally and stereochemically diverse piperidine derivatives. These cationic 2-azadienes participate in endo- or exo-selective [4 + 2] cycloadditions with electron-rich and neutral alkene dienophiles to generate a tetrahydropyridinium ion as the initial cycloadduct. In situ nucleophilic addition to the cycloaddition-derived iminium ion completes the three-component coupling sequence and affords a versatile synthesis of structurally complex piperidines.     

4+3] versus [4+2] mechanisms in the dimerization of 2-boryl-1,3-butadienes. A theoretical and experimental study

The thermal dimerization of 2-boryl-1,3-butadienes and the scope of this reaction to prepare six-membered rings difficult to synthesize by other methodologies have been studied. In addition, the nature of this dimerization has been studied theoretically. It has been found that the reaction coordinate associated with the formation of the cycloadduct of lowest energy has significant [4+3] character. This behavior is caused by the favorable carbon-carbon overlap and the large values of the corresponding resonance integrals. However, beyond the transition structure, the [4+2] pathway becomes the preferred one thus leading to the exclusive formation of the [4+2] cycloadduct. Aside from this effect, donating groups at the boryl moiety favor the [4+2] mechanism.     

Synthesis of indolizidines and pyrrolizidines through the [2 + 2]cycloaddition of five-membered endocyclic enecarbamates to alkyl ketenes. Unusual regioselectivity of Baeyer-Villiger ring expansions of alkyl aza-bicyclic cyclobutanones

The total syntheses of two indolizidine skeletons and of the necine base (+/-)-platynecine were accomplished in a concise manner with good overall yields starting from a common five-membered endocyclic enecarbamate. These syntheses feature a [2 + 2]cycloaddition of the five-membered endocyclic enecarbamate 5 to alkylketenes that proceeded in high yields and with high stereoselectivity to provide an endo alkyl cycloadduct as the major or only product. The minor exo alkyl cycloadducts, which can be observed in some [2 + 2]cycloadditions, seem to derive from the endo cycloadduct, the putative kinetic product, by epimerization. An unusual regioselectivity was observed for the Baeyer-Villiger oxidation of 7-alkyl-2-azabicyclic cyclobutanones. Endo-7-alkyl cycloadducts ring-expanded exclusively to a gamma-lactone in which oxygen is inserted into the C6-C7 bond in preference to the bridgehead C5-C6 bond. With the exo-7-alkyl cycloadduct the regioselectivity of the Baeyer-Villiger oxidation is drastically reduced, leading to mixtures of regioisomeric lactones in a ratio of approximately 1.5 to 1. It is hypothesized that the steric strain built into the Criegee cyclobutane intermediate is the regioselective controlling factor in these oxidations, overriding any stereoelectronic bias for ring expansion. A rationale for the mechanism of the [2 + 2]cycloaddition involving enecarbamates and ketenes is presented, which seems to involve the participation of an N-acyliminium-enolate intermediate.     

Total synthesis of (+/-)-hedychenone: trimethyldecalin terpene systems via stepwise allenoate diene cycloaddition

The total synthesis of hedychenone 1 is described. The cycloaddition of the hindered diene 2 and the allenecarboxylate 3 has been shown conclusively to proceed via the [2+2] cycloadduct 5 to give a 2:1 mixture of the desired formal Diels-Alder adducts, the exo and endo isomers 4xn and is thus a stepwise [4+2] cycloaddition. The exo isomer 4x was converted in four steps (reduction, oxidation, olefination, and desilylation) into hedychenone 1. [reaction: see text]     

Enantioselective [2+2+2] cycloaddition of ketenes and carbon disulfide catalyzed by N-heterocyclic carbenes

The chiral N-heterocyclic carbene-catalyzed [2+2+2] cycloaddition of ketenes and carbon disulfide was realized to give the cycloadduct of 1,3-oxathian-6-ones in good yields with excellent enantioselectivities.     

Diels-Alder-Reaktion eines elektronenarmen C-Acylimins mit Tetraethoxyethylen

Summary The synthesis of two C-acylimines and their reactivity towards electron rich dienophiles inDiels-Alder reactions is described. A [4+2] cycloadduct is obtained only in one case: from the reaction of a C-acylimine substituted by two methoxycarbonyl groups with tetraethoxyethylene. No [2+2] cycloadducts are observed.

     

Expedient synthesis of a highly substituted tropolone via a 3-oxidopyrylium [5+2] cycloaddition reaction

An expedient ten-step synthesis of a substituted tropolone is described. The synthesis involves a 3-oxidopyrylium [5+2] cycloaddition reaction with acrylonitrile as the key step, affording a highly functionalized [3.2.1]-bicycle 10 as a single regioisomer. The nitrile substituent of the reduced cycloadduct 12 permits efficient ether-bridge cleavage and tropolone 15 is obtained after a final bis-oxidation procedure. The pyranulose acetate cycloaddition precursor was derived from 3-methyl-2-furoate.     

Understanding the nature of the molecular mechanisms associated with the competitive Lewis acid catalyzed [4+2] and [4+3] cycloadditions between arylidenoxazolone systems and cyclopentadiene: a DFT analysis

The molecular mechanisms of the reactions between aryliden-5(4H)-oxazolone 1, and cyclopentadiene (Cp), in presence of Lewis acid (LA) catalyst to obtain the corresponding [4+2] and [4+3] cycloadducts are examined through density functional theory (DFT) calculations at the B3LYP/6-31G* level. The activation effect of LA catalyst can be reached by two ways, that is, interaction of LA either with carbonyl or carboxyl oxygen atoms of 1 to render [4+2] or [4+3] cycloadducts. The endo and exo [4+2] cycloadducts are formed through a highly asynchronous concerted mechanism associated to a Michael-type addition of Cp to the beta-conjugated position of alpha,beta-unsaturated carbonyl framework of 1. Coordination of LA catalyst to the carboxyl oxygen yields a highly functionalized compound, 3, through a domino reaction. For this process, the first reaction is a stepwise [4+3] cycloaddition which is initiated by a Friedel-Crafts-type addition of the electrophilically activated carbonyl group of 1 to Cp and subsequent cyclization of the corresponding zwitterionic intermediate to yield the corresponding [4+3] cycloadduct. The next rearrangement is the nucleophilic trapping of this cycloadduct by a second molecule of Cp to yield the final adduct 3. A new reaction pathway for the [4+3] cycloadditions emerges from the present study.     

Peri-selective photocycloadditions of methyl 2-pyrone-5-carboxylate with unsaturated cyclic ethers

Photosensitized cycloaddition reaction of methyl 2-pyrone-5-carboxylate ( 1 ) with 2,3-dihydrofuran gave cis- exo- and cis-endo-[2 + 2] cycloadducts across the C₃-C₄ double bond in 1 , and a [4 + 2] cycloadduct which was different in addition-orientation from the Diels-Alder adducts. Each [2 + 2] cycloadduct was obtained by the use of sensitizers having different triplet energies. Photosensitized reactions of 1 with 3,4-dihydro-2H-pyrans afforded cis-endo-[2 + 2] cycloadducts, respectively. The photocycloaddition mechanism was also explained from the excited state of 1 calculated by means of MNDO-Cl method.     

Intramolecular photochemical dioxenone-alkene [2 + 2] cycloadditions as an approach to the bicyclo[2.1.1]hexane moiety of solanoeclepin A.

A synthesis of the bicyclo[2.1.1]hexane substructure of solanoeclepin A (1), the most active natural hatching agent of potato cyst nematodes, was approached via an intramolecular [2 + 2] photocycloaddition. Aldehyde 12 containing the dioxenone chromophore served as a useful starting material, allowing the synthesis of a variety of photocycloaddition substrates via Grignard addition or via a Nozaki-Hiyama-Kishi reaction. Photolysis of the unsubstituted alkene 14 led to the expected crossed cycloadduct bicyclo[2.1.1]hexane 15 according to the so-called rule of five. However, several functionalized alkenes 18, 20, and 31 exhibited a complete reversal of cycloaddition regioselectivity, providing straight cycloadducts bicyclo[2.2.0]hexanes 21-26 and 4, respectively. Their structures were proved by a combination of extensive NMR measurements, X-ray analyses, and subsequent retro-aldol reactions. The latter de Mayo process allowed the formation of spiro-[3.5]nonane 35 and spiro[3.4]octane 36 as well as the cyclobutanes 37 and 38. Finally, the cyclization of the more rigid lactone precursor 28 occurred in high yield in the desired fashion with complete regio- and stereoselectivity to give 3 containing the core bicyclo[2.1.1]hexane skeleton of the natural product.     

Crystal structure of methyl endo-8-cyano-exo-8-methyl-3-oxo-2-oxabicyclo[2.2.2]oct-5-ene-6-carboxylate.

A photochemical cycloaddition reaction of methyl 2-pyrone-5-carboxylate with methacrylonitrile mainly gave a [4 + 2] cycloadduct, assigned as methyl endo-8-cyano-exo-8-methyl-3-oxo-2-oxabicyclo[2.2.2]oct-5-ene-6-carboxylate, whose structure was determined by an X-ray diffraction study. The formation of the cycloadduct was reasonably explained by considering a biradical intermediate having a less steric hindrance between the methoxycarbonyl group and the cyano group.     

Enantioselective Formal [4+2] Cycloadditions to 3‐Nitroindoles by Trienamine Catalysis: Synthesis of Chiral Dihydrocarbazoles

The first enantioselective formal [4+2] cycloadditions of 3‐nitroindoles are presented. By using 3‐nitroindoles in combination with an organocatalyst, chiral dihydrocarbazole scaffolds are formed in moderate to good yields (up to 87 %) and enantioselectivities (up to 97 % ee). The reaction was extended to include enantioselective [4+2] cycloadditions of 3‐nitrobenzothiophene. The reaction proceeds through a [4+2] cycloaddition/elimination cascade under mild reaction conditions. Furthermore, a diastereoselective reduction of an enantioenriched cycloadduct is presented. The mechanism of the reaction is discussed based on experimental and computational studies.     

Total synthesis of (-)-colchicine via a Rh-triggered cycloaddition cascade

[reaction: see text] A synthesis of the antimitotic alkaloids (-)-colchicine and (-)-isocolchicine is reported. Important steps are (a) enantioselective transfer-hydrogenation of an alkynone, (b) iodine/magnesium exchange with subsequent aromatic acylation, (c) Rh-catalyzed transformation of an alpha-diazoketone into an oxatetracyclic key intermediate through intramolecular [3 + 2]-cycloaddition of an in situ generated carbonyl ylide, and (d) regioselective conversion of the cycloadduct into a tropolone derivative. The new synthetic strategy opens an efficient enantioselective access to colchicine and structural analogues.