Novel [2 + 2 + 2 + 1] cycloaddition of enediynes catalyzed by rhodium complexes

[reaction: see text] The first Rh-catalyzed intramolecular [2 + 2 + 2 + 1] cycloaddition reaction of enediynes and CO is reported. This novel higher order cycloaddition process gives the corresponding 5-7-5 ring systems in high yield and selectivity. This process is another significant addition to the arsenal of cycloaddition-based synthetic methods, which provide powerful tools for rapid and efficient construction of complex polycyclic systems.     

Theoretical insights into the metal-free and formal [2 + 2 + 2] cycloaddition strategy via intramolecular cascade propargylic ene/Diels-Alder reactions with tautomerization

A metal-free and formal [2 + 2 + 2] cycloaddition of triynes has emerged recently as a novel methodology for the synthesis of fused tricyclic compounds via an intramolecular cascade propargylic ene reaction, Diels-Alder cycloaddition and tautomerization. DFT calculations on three model systems reveal that the ene reaction with low distortion energy makes the metal-free strategy feasible and, as the rate-determining step, affects the regioselectivity of unsymmetric triynes. Furthermore, the types of final products depend on H-transfer during tautomerization after the Diels-Alder reaction. Generally, the different tethered atoms between the yne moieties are responsible for the different regioselectivities and the final products in the [2 + 2 + 2] cycloadditions. On the basis of a comprehensive theoretical investigation into the mechanism, triynes involving cyclic ynes have been designed and are predicted to react to afford fused tetracyclic products under milder conditions due to dramatically lower energy barriers and by altering the rate-determining step to the Diels-Alder reaction.     

Rhodium N-heterocyclic carbene-catalyzed [4 + 2] and [5 + 2] cycloaddition reactions

[reactions: see text] A rhodium complex of N-heterocyclic carbene (NHC) has been developed for intra- and intermolecular [4 + 2] and intramolecular [5 + 2] cycloaddition reactions. This is the first use of a transition-metal NHC complex in a Diels-Alder-type reaction. For the intramolecular [4 + 2] cycloaddition reactions, all the dienynes studied were converted to their corresponding cycloadducts in 91-99% yields within 10 min. Moreover, up to 1900 turnovers have been obtained for the intramolecular [4 + 2] cycloaddition at 15-20 degrees C. For the intermolecular [4 + 2] cycloadditions, high yields (71-99%) of the corresponding cycloaddition products were obtained. The reaction time and yield were highly dependent upon the diene and the dienophile. For the intramolecular [5 + 2] cycloaddition reactions, all the alkyne vinylcyclopropanes studied were converted to their corresponding cycloadducts in 91-98% yields within 10 min. However, the catalytic system was not effective for an intermolecular [5 + 2] cycloaddition reaction.     

Dicobalt octacarbonyl-catalyzed tandem

Novel 5-5-6 tricyclic compounds containing cyclopentenone have been constructed by the dicobalt octacarbonyl catalyzed tandem [2 + 2 + 1] and [2 + 2 + 2] cycloaddition reaction between a diyne and two phenylacethylene under CO pressure.     

Phosphine‐Catalyzed [3+2] Cycloaddition Reactions of Azomethine Imines with Electron‐Deficient Alkenes: A Facile Access to Dinitrogen‐Fused Heterocycles

An efficient method for the phosphine‐catalyzed [3+2] cycloaddition reaction of azomethine imines with diphenylsulfonyl alkenes to give dinitrogen‐fused bi‐ or tricyclic heterocyclic compounds in high yields has been described. Moreover, two phenylsulfonyl groups installed on the heterocyclic products could be conveniently removed or transformed to other functional groups, making the reaction more useful.     

The Intramolecular Aldol Condensation Route to Fused Bi- and Tricyclic beta-Lactams(1)(,)(2)

Staüdinger cycloaddition of activated acid chlorides to 1,3-ketoaldimines, prepared in quantitative yields from 1,3-ketoaldehydes and amino esters, gave in excellent yields cis-2-azetidinones, 6-8, having the adequate functionality to obtain fused bi- and tricyclic beta-lactams. Reaction of compounds 6 with LHMDS at low temperature gave a single diastereomer of fused bicyclic compounds with a carbapenam or carbacefam skeleton. Treatment of diastereomeric cis-2-azetidinones, 7/8, in analogous conditions resulted either in the exclusive cyclization of one of the two diastereomers to form tricyclic [4.n.m] (n = 5, 6; m = 5, 6) compounds, or in the cyclization of both diastereomers to form tricyclic [4.n.7] (n = 5, 6) 2-azetidinones. In all cases the cyclization step was totally stereoselective. Alternatively, trans-carbapenams and one example of a tricyclic system having a trans-2-azetidinone ring have been obtained by using longer reaction times and higher temperatures. Epimerization at C3 of the 2-azetidinone nucleus occurs in these reaction conditions to obtain a single diastereomer of the final products. This approach to fused policyclic 2-azetidinones is one of the scarce syntheses of this kind of compound making use of the aldol condensation.     

Rhodium(I)‐Catalyzed Bridged [5+2] Cycloaddition of cis‐Allene‐vinylcyclopropanes to Synthesize the Bicyclo[4.3.1]decane Skeleton

Previously reported was that cis‐ene‐vinylcyclopropanes (cis‐ene‐VCPs) underwent Rh‐catalyzed [5+2] reaction to give 5,7‐fused bicyclic products, where vinylcyclopropane (VCP) acts as five‐carbon synthon. Unfortunately, this reaction had very limited scope. Replacing the 2π component of cis‐ene‐VCPs to allene moiety, the corresponding cis‐allene‐VCPs did not undergo the expected normal [5+2] cycloaddition to give 5,7‐fused bicyclic products. Instead, the challenging bicyclo[4.3.1]decane skeleton was obtained via an unprecedented bridged [5+2] cycloaddition. DFT calculations were applied to understand why this bridged [5+2] reaction is favored over the anticipated but not realized normal [5+2] reaction.     

Catalytic Asymmetric [8+2] Annulation Reactions Promoted by a Recyclable Immobilized Isothiourea

Higher‐order cycloaddition reactions constitute an efficient approach towards the construction of medium to large ring systems. However, enantioselective versions of these transformations remain scarce, which hampers their deployment in medicinal chemistry, or any other discipline in which homochirality is deemed crucial. Herein, we report a novel method for the production of enantiomerically enriched cycloheptatrienes fused to a pyrrolidone ring on the basis of an isothiourea‐catalyzed periselective [8+2] cycloaddition reaction between chiral ammonium enolates (generated in situ from carboxylic acids) and azaheptafulvenes. The resulting bicyclic compounds can be hydrogenated, but, most remarkably, they can also undergo completely regioselective [4+2] cycloaddition with active dienophiles to give architecturally complex polycyclic compounds in a straightforward manner.     

Ruthenium(II)-catalyzed selective intramolecular [2 + 2 + 2] alkyne cyclotrimerizations

In the presence of a catalytic amount of Cp*RuCl(cod), 1,6-diynes chemoselectively reacted with monoalkynes at ambient temperature to afford the desired bicyclic benzene derivatives in good yields. A wide variety of diynes and monoynes containing functional groups such as ester, ketone, nitrile, amine, alcohol, sulfide, etc. can be used for the present ruthenium catalysis. The most significant advantage of this protocol is that the cycloaddition of unsymmetrical 1,6-diynes with one internal alkyne moiety regioselectively gave rise to meta-substituted products with excellent regioselectivity. Completely intramolecular alkyne cyclotrimerization was also accomplished using triyne substrates to obtain tricyclic aromatic compounds fused with 5-7-membered rings. A ruthenabicycle complex relevant to these cyclotrimerizations was synthesized from Cp*RuCl(cod) and a 1,6-diyne possessing phenyl terminal groups, and its structure was unambiguously determined by X-ray analysis. The intermediary of such a ruthenacycle intermediate was further confirmed by its reaction with acetylene, giving rise to the expected cycloadduct. The density functional study on the cyclotrimerization mechanism elucidated that the cyclotrimerization proceeds via oxidative cyclization, producing a ruthenacycle intermediate and subsequent alkyne insertion initiated by the formal [2 + 2] cycloaddition of the resultant ruthenacycle with an alkyne.     

Unlocking Access to Enantiopure Fused Uracils by Chemodivergent [4+2] Cross-Cycloadditions: DFT-Supported Homo-Synergistic Organocatalytic Approach

The discovery of chemical methods enabling the construction of carbocycle-fused uracils which embody a three-dimensional and functional-group-rich architecture is a useful tool in medicinal chemistry oriented synthesis. In this work, an unprecedented amine-catalyzed [4+2] cross-cycloaddition is documented; it involves remotely enolizable 6-methyluracil-5-carbaldehydes and β-aryl enals, and chemoselectively produces two novel bicyclic and tricyclic fused uracil chemotypes in good yields with a maximum level of enantiocontrol. In-depth mechanistic investigations and control experiments support an intriguing homo-synergistic organocatalytic approach, where the same amine organocatalyst concomitantly engages both aldehyde partners in a stepwise eliminative [4+2] cycloaddition, whose vinylogous iminium ion intermediate product may diverge—depending upon conditions—to either bicyclic targets by hydrolysis or tricyclic products by a second homo-synergistic trienamine-mediated stepwise [4+2] cycloaddition.     

Rh(I)-catalyzed formal [5 + 1]/[2 + 2 + 1] cycloaddition of 1-yne-vinylcyclopropanes and two CO units: one-step construction of multifunctional angular tricyclic 5/5/6 compounds

A novel Rh(I)-catalyzed formal [5 + 1]/[2 + 2 + 1] cycloaddition of 1-yne-vinylcyclopropanes and two CO units for the construction of multifunctional angular tricyclic 5/5/6 skeletons with one or two adjacent bridgehead quaternary all-carbon stereocenters in one step has been developed. Preliminary density functional theory calculations have been carried out to investigate the reaction mechanism and the substituent effects.     

Stereoselective Rhodium‐Catalysed [2+2+2] Cycloaddition of Linear Allene–Ene/Yne–Allene Substrates: Reactivity and Theoretical Mechanistic Studies

Allene–ene–allene ( 2 and 5 ) and allene–yne–allene ( 3 and 7 ) N‐tosyl and O‐linked substrates were satisfactorily synthesised. The [2+2+2] cycloaddition reaction catalysed by the Wilkinson catalyst [RhCl(PPh₃)₃] was evaluated. Substrates 2 and 5 , which bear a double bond in the central position, gave a tricyclic structure in a reaction in which four contiguous stereogenic centres were formed as a single diastereomer. The reaction of substrates 3 and 7 , which bear a triple bond in the central position, gave a tricyclic structure with a cyclohexenic ring core, again in a diastereoselective manner. All cycloadducts were formed by a regioselective reaction of the inner allene double bond and, therefore, feature an exocyclic diene motif. A Diels–Alder reaction on N‐tosyl linked cycloadducts 8 and 10 allowed pentacyclic scaffolds to be diastereoselectively constructed. The reactivity of the allenes on [2+2+2] cycloaddition reactions was studied for the first time by density functional theory calculations. This mechanistic study rationalizes the order in which the unsaturations take part in the catalytic cycle, the reactivity of the two double bonds of the allene towards the [2+2+2] cycloaddition reaction, and the diastereoselectivity of the reaction.     

Synthesis of Fluorine‐Containing Multisubstituted Phenanthridines by Rhodium‐Catalyzed Alkyne [2+2+2] Cycloaddition and Tandem sp2 C?H Difluoromethylenation

A highly efficient method for the synthesis of fluorine‐containing multisubstituted phenanthridines through Rh‐catalyzed alkyne [2+2+2] cycloaddition reactions has been developed. This method exhibits excellent functional‐group compatibility. When a bromodifluoromethyl group, rather than a trifluoromethyl group, was employed in the cycloaddition reaction, more‐complicated polycyclic compounds were obtained through tandem Rh‐catalyzed cycloaddition/C? H difluoromethylenation. This route provides convenient access to fluorine‐containing polycyclic compounds.     

Dicobaltoctacarbonyl-mediated synthesis of tricyclic 5,6-diydropyran-2-one derivatives via tandem cycloaddition reaction between cis-epoxyalkynes, a tethered olefin, and carbon monoxide

Cobalt carbonyl complex Co2(CO)8 implemented an intramolecular carbonylation of cis-epoxyalkynes to generate Co2(CO)6-stabilized gamma-lactonyl allene species. For 1,1,2-trisubstituted epoxyalkynes, this Co2(CO)6-allene species reacted with a tethered olefin to give [2+2]-cycloadducts, and with CO and a tethered olefin to produce [2+2+1]-cycloadducts. These resulting cycloadducts have a 5,6-diydropyran-2-one core fused with a cyclobutane and a cyclopentanone ring, respectively. For 1,2-disubstituted cis-epoxyalkyne and 1,1,2-trisubstituted cis-epoxyalkynes bearing a heteroatom constituent, cyclization of the corresponding epoxyalkyne with a tethered alkene is invariably accompanied by incorporation of CO to produce a [2+2+1]-cycloadduct, even in the absence of CO. We have prepared various 1,1,2-trisubstituted and 1,2-disubstituted cis-epoxyalkynes to generalize such cycloaddition pathways. Attempt to use an organic promoter to perform these tandem cycloadditions was unsuccessful because of a competing Pauson-Khand reaction. Cyclization of a 1,2-disubstituted epoxyalkyne with a tethered diene was achieved successfully in one case, but the yield was low (25%).     

On the [2+2] cycloaddition of 2-aminothiazoles and dimethyl acetylenedicarboxylate. Experimental and computational evidence of a thermal disrotatory ring opening of fused cyclobutenes

The reaction of 2-(phenylamino)- and 2-(dimethylamino)thiazoles with dimethyl acetylenedicarboxylate led unexpectedly to dimethyl 6-(phenylamino)- and 6-(dimethylamino)-3,4-pyridinedicarboxylates. Those compounds reasonably result from a sequence of reactions initiated by a [2 + 2] cycloaddition of the alkyne to the formal C=C of the thiazole ring. These pyridines were obtained in nearly all the cases assayed as the exclusive reaction products under rather mild conditions and in fair to good yields. In contrast, the regioisomeric 2-amino-3,4-pyridinedicarboxylates, which would result from a [4 + 2] cycloaddition followed by sulfur extrusion, were only obtained in one particular case. The two reaction paths leading alternatively to both regioisomers were investigated computationally. The respective [2 + 2] and [4 + 2] cycloadducts were found to be formed stepwise from a common dipolar intermediate. Notably, the step following the [2 + 2] cycloaddition (i.e., the ring opening of the fused cyclobutene intermediate to give an all-cis 1,3-thiazepine) was found to take place in a disrotatory mode. Although geometric constraints and electronic factors may reduce the energy for the disrotation, the implication of the fused five-membered ring in the electronic reorganization leading to the 1,3-thiazepine is determinant. In this sense, this step could be regarded also as a thermally allowed six-electron five-center disrotatory electrocyclic ring opening. The proposed mechanism was experimentally supported by the isolation of several intermediates and other experimental facts.     

Rhodium‐Catalyzed Intramolecular [3+2+2] Cycloadditions between Alkylidenecyclopropanes,Alkynes, and Alkenes

A Rh‐catalyzed intramolecular [3+2+2] cycloaddition is reported. The cycloaddition affords synthetically relevant 5,7,5‐fused tricyclic systems of type 2 from readily available dienyne precursors. The transformation takes place with moderate or good yields, high diastereoselectivity, and total chemoselectivity.     

Asymmetric Synthesis of a Fused Tricyclic Hydronaphthofuran Scaffold by Desymmetric [2+2+2] Cycloaddition

A rhodium(I)‐BINAP‐catalyzed highly enantioselective [2+2+2] cycloaddition of enynes with alkynes has been developed. Diverse fused tricyclic hydronaphthofuran scaffolds with three consecutive stereogenic centers were constructed in one step from easily available materials with excellent chemo‐, regio‐, diastereo‐, and enantioselectivity. Notable features of these reactions include 100 % atom economy, very broad scope, and mild reaction conditions.     

Studies towards the synthesis of FCRR toxin: an expeditious entry into 7-5-6 ring systems via [5+2] oxidopyrylium-alkene cycloaddition

Synthetic studies towards the diterpene natural product FCRR toxin have been undertaken. An intermolecular [5+2] oxidopyrylium-alkene cycloaddition reaction was employed to construct the 7-5-6 tricyclic framework. The reaction proceeded with very high regio- and stereoselectivity and the bridging ether was reductively cleaved to unmask the carbocycle.     

Rh-catalyzed [7 + 1] cycloaddition of buta-1,3-dienylcyclopropanes and CO for the synthesis of cyclooctadienones

Discovering new carbon building blocks is very significant to advance transition-metal-catalyzed cycloadditions for the synthesis of various-sized ring compounds. A new seven-carbon building block from buta-1,3-dienylcyclopropanes (BDCPs) has been developed, showing that, under the catalysis of [Rh(CO)(2)Cl](2), BDCPs react with CO to give [7 + 1] cycloaddition products, cyclooctadienones. The present [7 + 1] reaction provides an efficient entry to the synthetically challenging eight-membered carbocyclic skeleton, which is present in many natural products of medicinal and biological significance.     

Transition metal-catalyzed intermolecular [5+2] and [5+2+1] cycloadditions of allenes and vinylcyclopropanes

Initial examples of the intermolecular Rh(I)-catalyzed [5+2] cycloaddition reaction of bifunctional allenes and vinylcyclopropanes are described. The reactions proceed with facility and in yields of up to 99% with a variety of alkyne-, ester-, styrene-, or cyano-substituents on the allene to afford the corresponding cycloadducts. In the presence of CO, the reaction proceeds to an eight-membered ring cycloadduct and its transannularly closed product, providing the first example of a three-component [5+2+1] cycloaddition with allenes.