Intermolecular rhodium-catalyzed [3+2+2] carbocyclization of alkenylidenecyclopropanes with activated alkynes: regio- and diastereoselective construction of cis-fused bicycloheptadienes

Polycyclic structures that contain seven-membered carbocycles constitute important structural motifs that are ubiquitous in several classes of bioactive natural products. We have developed the first regio- and diastereoselective intermolecular rhodium-catalyzed [3+2+2] carbocyclization of carbon- and heteroatom-tethered alkenylidenecyclopropanes with mono- and disubstituted alkynes for the construction of cis-fused bicycloheptadienes. This study delineates some of the critical features for controlling regioselectivity in this process and demonstrates that E-alkenes can be incorporated in a stereospecific manner to afford products with up to three new stereogenic centers. The latter feature is particularly significant given that related carbocyclization reactions are often limited in this respect.     

Diastereoselective synthesis of five- and seven-membered rings by [2+2+1], [3+2], [3+2+2], and [4+3] carbocyclization reactions of beta-substituted (alkenyl)(methoxy)carbene complexes with methyl ketone lithium enolates

beta-Substituted alkenylcarbene complexes react with methyl ketone lithium enolates to give different carbocyclization products depending on the structure of the lithium enolate, on the metal of the carbene complex, and on the reaction media. Thus, the reactions of aryl and alkyl methyl ketone lithium enolates with beta-substituted alkenyl chromium and tungsten carbene complexes in diethyl ether afford 1,3-cyclopentanediol derivatives derived from a formal [2+2+1] carbocyclization reaction. However, the lithium enolates of acetone and tungsten complexes furnish formal [3+2+2] carbocyclization products. In the case of alkynyl methyl ketone lithium enolates, competitive formal [2+2+1] and [3+2] carbocyclization reactions occur and 1,3-cyclopentanediol and 3-cyclopentenol derivatives are formed. Conversely, alkenyl methyl ketone lithium enolates react with alkenylcarbene complexes under the same reaction conditions to form 2-cycloheptenone derivatives by a formal [4+3] carbocyclization reaction. Finally, when the reaction was performed in the presence of a coordinating medium, the [3+2] carbocyclization pattern was observed independently of the nature of the methyl ketone lithium enolate used.     

Diastereoselective intramolecular temporary silicon-tethered rhodium-catalyzed [4+2+2] cycloisomerization reactions: regiospecific incorporation of substituted 1,3-butadienes

Transition metal-catalyzed carbocyclization reactions represent powerful methods for the construction of complex polycyclic systems. We have developed a regiospecific and diastereoselective intramolecular temporary silicon-tethered rhodium-catalyzed [4+2+2] cycloisomerization reaction of a tethered enyne for the construction of tricyclic eight-membered heterocycles and carbocycles. This methodology also allows (E)- and (Z)-olefins to be utilized in a stereospecific manner. The incorporation of either alkene geometry is particularly significant, since related carbocyclization reactions are often limited in this respect. Finally, the ability to utilize carbon-tethered 1,6-enynes and to regiospecifically incorporate substituted 1,3-butadiene derivatives provides exciting opportunities for future applications toward the total synthesis of cyclooctanoid containing diterpenes.     

Ruthenium‐Catalyzed [2+2+2] Cycloaddition of 1,6‐Enynes and Unactivated Alkynes: Access to Ring‐Fused Cyclohexadienes

The [2+2+2] intermolecular carbocyclization reactions between 1,6‐enynes and alkynes catalyzed by [RuCl(cod)(Cp*)] (cod=1,5‐cyclooctadiene, Cp*=pentamethylcyclopentadienyl) are reported to provide bicyclohexa‐1,3‐dienes. The presented reaction conditions are compatible with internal and terminal alkynes and the chemo‐ and regioselectivity issues are controlled by the presence of substituents at the propargyl carbon center of the alkyne(s) partner(s).     

Rhodium-catalyzed chemo-, regio-, and enantioselective [2 + 2 + 2] cycloaddition of alkynes with isocyanates

[reaction: see text] We have developed a cationic rhodium(I)/modified-BINAP complex-catalyzed chemoselective [2 + 2 + 2] cycloaddition of alkynes with isocyanates leading to a wide range of 2-pyridones. This method was successfully applied to the chemo-, regio-, and enantioselective synthesis of axially chiral 2-pyridones from unsymmetrical alpha,omega-diynes, bearing an ortho-substituted phenyl at one terminal position, and alkyl isocyanates.     

Intermolecular rhodium-catalyzed [2+2+2] carbocyclization reactions of 1,6-enynes with symmetrical and unsymmetrical alkynes

The crossed intermolecular rhodium-catalyzed [2+2+2] carbocyclization of carbon and heteroatom tethered 1,6-enynes can be accomplished with symmetrical and unsymmetrical alkynes, to afford the corresponding bicyclohexadienes in an efficient and highly selective manner.     

Stereoselective route to oxetanocin carbocyclic analogues based on a [2 + 2] photocycloaddition to a chiral 2(5H)-furanone

The synthesis of the trisubstituted cyclobutane 7, which is a suitable precursor for the preparation of oxetanocin carbocyclic analogues, is described. The key step involves a regio- and diastereoselective [2 + 2] photochemical reaction of ketene diethyl acetal with (S)-5-pivaloyloxymethyl-2(5H)-furanone, 3. As an application of this methodology, (-)-cyclobut-A has been prepared from the intermediate 7.     

Rhodium-catalysed chemo- and regio-selective [3 + 2+2] cycloadditions of bis(methylenecyclopropanes) and alkynes: Synthesis of spirocyclic 5–7 condensed cycloheptenes

Abstract

Rhodium-catalyzed intermolecular [3?+?2+2] cycloaddition reactions of bis(methylenecyclopropanes) with different alkynes are described. The rhodium-catalyzed [3?+?2+2] cycloadditions resulted in the formation of functionalized 5–7–3 spirocyclic carbocycles in moderate yields with excellent regio- and chemo-selectivity.     

4 + 2]-Cycloaddition Reactions between beta-Acceptor-Substituted Enamines and 2-Vinylindole Radical Cations Acting as Hetero-Dienes

[4 + 2]-Cycloaddition reactions between 2-vinylindoles acting as hetero-dienes and beta-acceptor substituted cyclic and acyclic enamines can be induced by formation of 2-vinylindole radical cations either via anodic oxidation or photoelectron transfer (PET) using catalytic amounts of triarylpyrylium tetrafluoroborates as sensitizers. In this way, pyrido[1,2-a]indoles or indolo[1,2-a]hexahydro-1,8-naphthyridines are formed in one step with complete regio- and stereochemical control.     

Recent advances in [2+2+2] cycloaddition reactions

The [2+2+2] cycloaddition is an elegant, atom-efficient and group tolerant process for the synthesis of carbo- and heterocycles, mostly aromatic, involving the formation of several C-C bonds in a single step. Cyclotrimerisation is catalyzed by a variety of organometallic complexes, including more than 15 different metals. The aim of this tutorial review is to point out the most recent advances in this field and to encourage the use of this reaction enroute to complex molecules. After summarizing the most common catalysts and reaction conditions generally used, we survey the mechanistic features currently accepted for this reaction. Section 4 covers the scope of the different [2+2+2] cycloaddition versions starting with the cyclotrimerisation of three triple bonds, including nitriles, with especial emphasis on asymmetric reactions that create central, axial or planar chirality. Then, reactions that use double bonds are addressed. Finally, the most outstanding examples of natural products synthesis using [2+2+2] cycloadditions as a key step reported recently are shown.     

DABCO and Bu(3)P catalyzed [4 + 2] and [3 + 2] cycloadditions of 3-acyl-2H-chromen-ones and ethyl 2,3-butadienoate

DABCO-catalyzed [4 + 2] and Bu(3)P-catalyzed [3 + 2] cycloadditions between 3-acyl-2H-chromen-ones and ethyl 2,3-butadienoate were developed for the synthesis of dihydropyran-fused and cyclopenten-fused chromen-2-ones with high regio- and stereo-selectivities, respectively. The synthetic procedures have the advantages of mild reaction conditions, convenient handling and good atom economy as well as a wide substrate scope, which make this method useful for the synthesis of potentially biologically active dihydropyran-fused and cyclopenten-fused chromen-2-ones derivatives. Possible reaction mechanisms have also been proposed on the basis of previous literature and our investigation.     

Diastereoselective metal-catalyzed [4 + 2 + 2] carbocyclization reactions utilizing a rhodium N-heterocyclic carbene (NHC) complex: the first example of a rhodium NHC-catalyzed [m + n + o] carbocyclization

The air and moisture stable rhodium N-heterocyclic carbene (NHC) complex, RhCl(IMes)(COD)(IMes =N,N[prime or minute]-bis(2,4,6-trimethylphenyl)imidazole-2-ylidine; COD = 1,5-cyclooctadiene), facilitates a diastereoselective metal-catalyzed [4 + 2 + 2] carbocyclization of 1,6-enynes in the presence of silver triflate and 1,3-butadiene.     

Palladium-catalyzed bisdiene carbocyclizations: a facile [3 + 2] cycloaddition reaction mode

[reaction: see text] In contrast to alkyl-substituted bisdienes, aryl-substituted substrates undergo surprisingly facile palladium-catalyzed carbocyclization via a novel [3 + 2] cycloaddition mode.     

Ruthenium-catalyzed [2 + 2] cycloadditions of 2-substituted norbornenes

The studies of remote substituent effects in controlling regio- and stereoselectivities in chemical reactions provide important information in understanding long-range stereoelectronic effects. The effect of remote substituents on ruthenium-catalyzed [2 + 2] cycloadditions of 2-substituted norbornenes has been investigated. The cycloadditions occurred at room temperature in excellent yields, and regioselectivities of 1.2:1 to 7.5:1 were observed with various 2-substituted norbornenes.     

Solid-supported [2+2+2] cyclotrimerizations

The transition-metal-catalyzed [2+2+2] cyclotrimerization of a diyne and an alkyne provides a convergent route to highly-substituted aromatic rings. This reaction possesses distinct drawbacks, especially low chemo- and regioselectivities, which hamper its application in combinatorial synthesis. These problems have been solved by the development of solid-supported [2+2+2]-cycloaddition reactions. If conducted on a solid-support, this reaction enables rapid combinatorial access to diverse sets of carbo- and heterocyclic small-molecule arrays. The scope of this methodology has been investigated by examining different immobilization strategies, different diyne precursors, and a variety of functionalized alkyne reaction partners. Overall, isoindoline, phthalan, and indan libraries were assembled in good to excellent yields and with high purities.     

Silver-catalyzed [2 + 2] cycloadditions of siloxy alkynes

We have described the first [2 + 2] cycloadditions of siloxy alkynes with a range of unsaturated carbonyl compounds. The reactions are efficiently promoted by substoichiometric amount of silver trifluoromethanesulfonimide and display excellent regio- and diastereoselectivity combined with a broad substrate scope. Our studies have established unambiguously the stepwise mechanism of this process and provided evidence for a novel role of silver in the catalytic cycle of the reaction, which involves silver-based complexation and activation of siloxy alkyne toward the subsequent 1,4-addition.     

Diastereoselective synthesis of three-, five-, six-, and seven-membered rings from Fischer carbene complexes and 4-unsubstituted 1-amino-1,3-dienes

Fischer carbene complexes react with 4-unsubstituted 1-amino-1,3-dienes to give different carbocyclization products depending on the nature of the carbene complex and on the substitution pattern of the aminodiene. Thus, the reaction of arylcarbene chromium complexes and 1-aminodienes diastereoselectively affords cyclopropane derivatives by means of a formal [2+1] carbocyclization reaction. In particular, pentacarbonyl[(2-furyl)(methoxy)methylene]chromium complex furnishes formal [4+1] carbocyclization products. Starting from beta-substituted alkenylcarbene complexes, formal [4+1] reactions occur and cyclopentenamine derivatives are diastereoselectively formed. However, when the alpha,beta-disubstituted alkenylcarbene complex pentacarbonyl[(5,6-dihydro-2H-pyran-2-yl)(methoxy)methylene]tungsten is used, the outcome of the reaction depends on the substitution on the carbon atom at the 3-position of the aminodiene, generating the [3+2] or [4+3]-cyclization products if the substituent is or is not a hydrogen atom, respectively. Finally, when the reaction is performed with alkynylcarbene complexes, benzaldehyde derivatives are obtained if the triple-bond substituent is a phenyl group or indene derivatives if the group is an alkenyl moiety.     

Tandem double intramolecular [4 + 2]/[3 + 2] cycloadditions of nitroalkenes

[reaction: see text]. A new class of tandem [4 + 2]/[3 + 2] cycloadditions of nitroalkenes is described in which both pericyclic processes are intramolecular. Two subclasses of intra [4 + 2]/intra [3 + 2] cycloadditions have been explored in which the dipolarophile is tethered at either C(5) or C(6) of the nitronate. For both families of precursors, the cycloadditions occur in good yield and are found to be highly regio- and stereoselective. This method converts linear polyenes to functionalized polycyclic systems bearing up to six stereogenic centers.     

A highly regio- and stereo-selective [3+2] annulation of allylic compounds and 2-substituted 1,1-dicyanoalkenes through a catalytic carbon-phosphorus ylide reaction

A highly regio- and stereo-selective phosphine-catalyzed [3+2] annulation reaction between allylic compounds and 2-substituted 1,1-dicyanoalkenes through a catalytic phosphorus ylide reaction was developed. This reaction has the total reversed regioselectivity compared to that of the reactions of activated alkenes without the 2-substituents or reactions using the allenoates as the C3 component.     

Rhodium‐Catalyzed [(3+2)+2] Carbocyclization of Alkynylidenecyclopropanes with Substituted Allenes: Stereoselective Construction of Tri‐ and Tetrasubstituted Exocyclic Olefins

The development of the stereoselective rhodium‐catalyzed [(3+2)+2] carbocyclization of alkynylidenecyclopropanes (ACPs) with substituted allenes is described. This work demonstrates that activated and unactivated allenes preferentially undergo carbometalation at the distal terminus to generate tri‐ and tetrasubstituted exocyclic olefins with a neutral rhodium catalyst. In addition, this method provides a strategy for the total synthesis of the guaiane family of sesquiterpenes, which are not directly accessible using alkynes as exogenous π‐components. Finally, the preparation of the bicyclo[5.4.0]undecane ring system using a homologated ACP tether serves to further illustrate the versatility of this approach.