Development of a [3+3] cycloaddition strategy toward functionalized piperidines

This paper describes a novel route to functionalized piperidines via a formal [3+3] cycloaddition reaction of activated aziridines and palladium-trimethylenemethane (Pd-TMM) complexes. The cycloaddition reaction generally proceeds enantiospecifically with ring opening at the least hindered site of the aziridine. Therefore, readily available enantiomerically pure 2-substituted aziridines can be utilized to prepare enantiomerically pure 2-substituted piperidines in good to excellent yield. The N-substituent on the aziridine proved to be crucial to the success of this reaction with only 4-toluenesulfonyl (Ts) and 4-methoxybenzenesulfonyl (PMBS) aziridines permitting smooth cycloaddition to take place. Additionally, spirocyclic aziridines have been found to participate in the [3+3] cycloaddition reaction, whereas 2,3-disubstituted aziridines can be applied to provide fused bicyclic piperidines, albeit in low yield.     

Accessing substituted pyrrolidines via formal [3+2] cycloaddition of 1,3,5-triazinanes and donor-acceptor cyclopropanes

The formal [3+2] cycloaddition of 1,3,5-triaryl-1,3,5-triazinanes with donor-acceptor cyclopropanes has been found to provide pyrrolidines in good to excellent yields under mild reaction conditions. Preliminary mechanistic investigation indicates that this formal [3+2] cycloaddition reaction proceeds through competing S_N1 and S_N2 pathways.     

Formal [3 + 2] cycloadditions of donor-acceptor cyclopropanes and nitriles

Donor-acceptor cyclopropanes activated with Me3SiOTf cleave to reactive intermediates that can be efficiently intercepted by nitriles in a formal [3 + 2] dipolar cycloaddition reaction. Aliphatic, aromatic, and alpha,beta-unsaturated nitriles are excellent reaction partners, giving synthetically useful 2H-3,4-dihydropyrrole cycloaddition products in high yield.     

A formal [3+2] cycloaddition process with nonactivated aziridines to polysubstituted indolizidines

[chemical reaction: see text]. Heating a mixture of ethyl 7-iodo-2-heptynoate (or its analogues), 2-aryl aziridines, and K2CO3 in dry CH(3)CN delivers polysubstituted indolizidines. This reaction goes through an S(N)2/formal [3+2] cycloaddition process and represents the first synthetically useful example of the formal [3+2] cycloaddition process through a C-N bond cleavage of nonactivated aziridines.     

Formal Asymmetric Organocatalytic [3+2] Cyclization between Enecarbamates and 3‐Indolylmethanols: Rapid Access to 3‐Aminocyclopenta[b]indoles

A highly enantio‐ and diastereoselective synthesis of 3‐aminocyclopenta[b]indoles has been developed through formal [3+2] cycloaddition reaction of enecarbamates and 3‐indolylmethanols. This transformation is catalyzed by a chiral phosphoric acid that achieves simultaneous activation of both partners of the cycloaddition. Mechanistic data are also presented that suggest that the reaction occurs through a stepwise pathway.     

Regioselective and stereoselective synthesis of tetrahydrofurans from a functionalized allylic silane and an aldehyde via formal [3+2]-cycloaddition reaction

Allylsilanes are known as useful reagents for the stereoselective formation of ring systems. Previous studies have shown that tetrahydrofurans can be constructed via formal [3+2]-cycloadditions of aldehydes and allylsilanes. A new challenge is to understand the intermediate, after a nucleophile attacks a carbonyl activated by the Lewis acid, in which two silyl-protected alkoxy groups with chemical equivalency could undergo formal cycloaddition reaction to afford a disubstituted and/or a trisubstituted tetrahydrofuran. Preparation of the protected α-hydroxy aldehyde and a functionalized allylic silane is discussed, as well as their formal cycloaddition reaction to form tetrahydrofurans.     

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.     

Scope of the formal [3+2] cycloaddition for the synthesis of substituted 3-arylindanes and related compounds

We report the single step synthesis of several 3-arylindanes and related compounds via a formal [3+2] cycloaddition. A study of the influence of the aromatic ring substitution pattern on the reaction was carried out.     

Development of a stepwise [3 + 3] annelation to functionalized piperidines

[reaction: see text] A stepwise formal [3 + 3] cycloaddition sequence via a Grignard addition-cyclization reaction leads to a much improved piperidine synthesis. This methodology provides improved flexibility in both the aziridine substrate and TMM equivalent.     

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.     

Asymmetric synthesis of 1,3-dioxolanes by organocatalytic formal [3 + 2] cycloaddition via hemiacetal intermediates

A novel asymmetric formal [3 + 2] cycloaddition reaction for the synthesis of 1,3-dioxolanes using cinchona-alkaloid-thiourea-based bifunctional organocatalysts is reported. The reaction proceeds via the formation of hemiacetal intermediates between γ-hydroxy-α,β-unsaturated ketones and aldehydes.     

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.     

Enantioselective Formal [3+2] Cycloaddition of Epoxides with Imines under Brønsted Base Catalysis: Synthesis of 1,3‐Oxazolidines with Quaternary Stereogenic Center

The formal [3+2] cycloaddition of epoxides and unsaturated compounds is a powerful methodology for the synthesis of densely functionalized five‐membered heterocyclic compounds containing oxygen. Described is a novel enantioselective formal [3+2] cycloaddition of epoxides under Brønsted base catalysis. The bis(guanidino)iminophosphorane as a chiral organosuperbase catalyst enabled the enantioselective reaction of β,γ‐epoxysulfones with imines, owing to its strong basicity and high stereocontrolling ability, to provide enantioenriched 1,3‐oxazolidines having two stereogenic centers, including a quaternary one, in a highly diastereo‐ and enantioselective manner.     

The formal [4+3] cycloaddition between donor-acceptor cyclobutanes and nitrones

The formal [4+3] cycloaddition of 2-alkoxy-1,1-dicarboxylate activated donor-acceptor cyclobutanes with nitrones is disclosed. The reaction forms structurally unique oxazepines in moderate to high yield with a wide scope of nitrones. In most cases either a diastereomeric mixture or a single diastereomer may be formed, depending on the reaction conditions.     

PyBidine/Copper Catalyst: Asymmetric exo′‐Selective [3+2] Cycloaddition using Imino Ester and Electrophilic Indole

Electrophilic indoles having two electron‐withdrawing groups undergo nucleophilic attack at C2 and electrophilic functionalization at C3. This is the first enantioselective formal [3+2] cycloaddition using electrophilic indoles. The PyBidine/Cu catalyst smoothly promoted highly enantio‐ and exo′‐selective [3+2] cycloaddition using imino esters and 3‐nitroindoles. This reaction provides a method for the preparation of diverse and complex chiral pyrroloindoline compounds.     

Enantioselective N-heterocyclic carbene catalyzed formal [3+2] cycloaddition using α-aroyloxyaldehydes and oxaziridines

An enantioselective N-heterocyclic carbene catalysed formal [3+2] cycloaddition has been developed for the synthesis of oxazolindin-4-one products. The reaction of oxaziridines and α-aroyloxyaldehydes under N-heterocyclic carbene catalysis provides the formal cycloaddition products with excellent control of the diastereo- and enantioselectivity (12 examples, up to >95:5 dr, >99:1 er). A matched-mismatched effect between the enantiomer of the catalyst and oxaziridine was identified, and preliminary mechanistic studies have allowed the proposal of a model to explain these observations.     

An organocatalytic direct Mannich-cyclization cascade as [3+2] annulation: asymmetric synthesis of 2,3-substituted pyrrolidines

A new method for asymmetric synthesis of 2,3-substituted pyrrolidines from N-PMP aldimines and succinaldehyde via formal [3+2] cycloaddition is reported. This reaction involves proline catalyzed direct Mannich reaction and acid catalyzed reductive cyclization with high yields (up to 78%) and excellent enantioselectivities (up to >99%).     

A 4 + 3 cycloaddition approach to the synthesis of spatol. A formal total synthesis of racemic spatol

[reaction: see text] A formal total synthesis of racemic spatol is presented. The key steps involved a 4 + 3 cycloaddition of a halogenated cyclopentenyl cation to cyclopentadiene and a quasi-Favorskii rearrangement.     

Ring Expansion of Epoxides under Brønsted Base Catalysis: Formal [3+2] Cycloaddition of β,γ‐Epoxy Esters with Imines Providing 2,4,5‐Trisubstituted 1,3‐Oxazolidines

A novel ring‐expansion reaction of epoxides under Brønsted base catalysis was developed. The formal [3+2] cycloaddition reaction of β,γ‐epoxy esters with imines proceeds in the presence of triazabicyclodecene (TBD) as a superior Brønsted base catalyst to afford 2,4,5‐trisubstituted 1,3‐oxazolidines in a highly diastereoselective manner. This reaction involves the ring opening of the epoxides with the aid of the Brønsted base catalyst to generate α,β‐unsaturated esters having an alkoxide at the allylic position, which would formally serve as a synthetic equivalent of the 1,3‐dipole, followed by a cycloaddition reaction with imines in a stepwise fashion. This methodology enables the facile synthesis of enantioenriched 1,3‐oxazolidines from easily accessible enantioenriched epoxides.     

Lewis acid induced tandem Diels-Alder reaction/ring expansion as an equivalent of a [4 + 3] cycloaddition

Aluminum chloride induced reaction between cyclopentadiene and alpha,beta-unsaturated aldehydes results in the stereoselective formation of the products of a formal [4 + 3] cycloaddition. The reaction proceeds by a tandem Diels-Alder reaction/ring expansion.