Tandem cycloaddition reactions of allenyl diazo compounds forming triquinanes via trimethylenemethane diyls

A tandem reaction strategy for forming triquinanes from linear allenyl diazo compounds through an intramolecular 1,3-dipolar cycloaddition reaction of an allenyl diazo group that generates a trimethylenemethane (TMM) diyl followed by an intramolecular [2 + 3] TMM diyl cycloaddition reaction has been developed. The new tandem cycloaddition reaction is readily applicable to the synthesis of complex molecules with high versatility and efficiency.     

From dimerization, to cycloaddition, to atom transfer cyclization: the further chemistry of TMM diradicals

We describe [a] the first examples of intramolecular cycloaddition of a TMM diyl to a remotely tethered aldehyde, [b] the effect of a Lewis acid upon the course of TMM chemistry, [c] examples of exclusive intramolecular cycloaddition, competitive cycloaddition and ATC, and exclusive ATC, and [d] a set of predictive guidelines with which to assess whether cycloaddition or ATC will be the preferred path, and when the two processes will be competitive. Remarkably, a wide variety of structures can be obtained simply by varying the length of the tether within the diazenes investigated. DFT calculations were used to probe the energy surfaces for both atom transfer and cycloaddition. The transition structure for atom transfer involving the captodative system indicates that it occurs earlier along the reaction coordinate than for a system having only one radical stabilizing group. This is consistent with the existence of an exothermic process leading from the initial diyl to the captodatively stabilized distonic diyl. Gratifyingly, theory agrees with observation and provides substantial insight into the chemistry.     

Total Synthesis of (±)‐Waihoensene

The first total synthesis of waihoensene, a tetracyclic diterpene containing an angular triquinane and a six‐membered ring, with four contiguous quaternary carbon atoms, was achieved through the tandem cycloaddition reaction of an allenyl diazo substrate containing a six‐membered ring via trimethylenemethane (TMM) diyl intermediate.     

Total Synthesis of (±)-Waihoensene

The first total synthesis of waihoensene, a tetracyclic diterpene containing an angular triquinane and a six-membered ring, with four contiguous quaternary carbon atoms, was achieved through the tandem cycloaddition reaction of an allenyl diazo substrate containing a six-membered ring via trimethylenemethane (TMM) diyl intermediate.     

Enantioselective construction of pyrrolidines by palladium-catalyzed asymmetric [3 + 2] cycloaddition of trimethylenemethane with imines

A protocol for the enantioselective [3 + 2] cycloaddition of trimethylenemethane (TMM) with imines has been developed. Central to this effort were the novel phosphoramidite ligands developed in our laboratories. The conditions developed to effect an asymmetric TMM reaction using 2-trimethylsilylmethyl allyl acetate were shown to be tolerant of a wide variety of imine acceptors to provide the corresponding pyrrolidine cycloadducts with excellent yields and selectivities. Use of a bis-2-naphthyl phosphoramidite allowed the successful cycloaddition of the parent TMM with N-Boc imines, and has further permitted the reaction of substituted donors with N-tosyl aldimines and ketimines in high regio-, diastereo-, and enantioselectivity. Use of a diphenylazetidine ligand allows the complementary synthesis of the exocyclic nitrile product shown, and we demonstrate control of the regioselectivity of the product based on manipulation of the reaction parameters.     

Triquinanes from linear alkylidene carbenes via trimethylenemethane diyls

The intramolecular [2+3] cycloaddition reaction of the trimethylenemethane diyl generated from the intramolecular cyclopropanation reaction of alkylidene carbene produced linearly fused triquinanes regio- and stereoselectively. The current tandem cycloaddition reaction was applied to a 14-step total synthesis of hirsutene from methallyl alcohol.     

Palladium-catalyzed asymmetric [3 + 2] trimethylenemethane cycloaddition reactions

Transition-metal-catalyzed trimethylenemethane (TMM) [3 + 2] cycloadditions provide direct routes to functionalized cyclopentanes. This reaction has been shown to be a highly chemo-, regio-, and diastereoselective process. We report a palladium-catalyzed asymmetric [3 + 2] trimethylenemethane (TMM) cycloaddition between 3-acetoxy-2-trimethylsilylmethyl-1-propene and various di- and trisubstituted olefins. Yields of exo-methylenecyclopentane products range from 59 to 99%, and enantiomeric excesses range from 58 to 92% ee.     

Palladium-catalyzed [3 + 3] cycloaddition of trimethylenemethane with azomethine imines

A palladium-catalyzed [3 + 3] cycloaddition of trimethylenemethane (TMM) with azomethine imines has been developed to produce hexahydropyridazine derivatives under simple and mild conditions. The use of substituted TMM precursors highlights the difference of this system from previously reported [3 + 2] cycloaddition of TMMs under palladium catalysis. The present [3 + 3] cycloaddition reactions are also applicable to couplings with nitrones.     

Palladium-catalyzed [3+2] cycloaddition of carbon dioxide and trimethylenemethane under mild conditions

Carbon dioxide undergoes a Pd-catalyzed [3+2] cycloaddition with trimethylenemethane (TMM) under mild conditions (1 atm, 75 degrees C, 30 min) to produce a gamma-butyrolactone product in 63% yield, when the Pd-TMM complex is generated from 2-(acetoxymethyl)-3-(trimethylsilyl)propene. The reaction reported here is more rapid than the all-carbon [3+2] cycloaddition, and only the gamma-butyrolactone is produced in a competition experiment. With substituted substrates, the reaction is completely regioselective, producing the product derived from the kinetic Pd-TMM complex.     

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.     

Intramolecular diyl trapping reactions en route to the bicyclo [3.2.1] framework; an approach to aphidicolin

We describe an application of the intramolecular diyl trapping cycloaddition reaction to the assembly of the bicyclo [3.2.1] framework, and utilize the outcome to complete a formal total synthesis of aphidicolin.     

Development of an asymmetric trimethylenemethane cycloaddition reaction: application in the enantioselective synthesis of highly substituted carbocycles

A protocol for the enantioselective [3+2] cycloaddition of trimethylenemethane (TMM) with electron-deficient olefins has been developed. The synthesis of novel phosphoramidite ligands was critical in this effort, and the preparation and reactivity of these ligands is detailed. The evolution of the ligand design, commencing with acyclic amine-derived phosphoramidites and leading to cyclic pyrrolidine and azetidine structures, is discussed. The conditions developed to effect an asymmetric TMM reaction using 2-trimethylsilylmethyl allyl acetate were shown to be tolerant of a wide variety of alkene acceptors, providing the desired methylenecyclopentanes with high levels of enantioselectivity. The donor scope was also explored, and substituted systems were tolerated, including one bearing a nitrile moiety. These donors were reactive with unsaturated acylpyrroles, giving the product cyclopentane rings bearing three stereocenters in high enantioselectivity and complete diastereoselectivity.     

Development of a flexible approach to Nuphar alkaloids via two enantiospecific piperidine-forming reactions

In this paper we describe the stereoselective synthesis of functionalized lactam 7 via two enantiospecific piperidine-forming techniques and its employment in a general synthetic approach to Nuphar alkaloids. Specifically, the formation of piperidine 18 by formal [3 + 3] cycloaddition and stepwise annelation processes is described; the latter technique was found to be significantly more efficient than the Pd-catalyzed TMM addition process. Finally, exploitation of the exocyclic alkene installed in the piperidine-forming reaction in the transformation of 18 to (-)-deoxynupharidine ((-)-2), (-)-castoramine ((-)-3), and (-)-nupharolutine ((-)-4) via intermediate lactam 7 is delineated.     

Asymmetric synthesis of methylenetetrahydrofurans by palladium-catalyzed [3 + 2] cycloaddition of trimethylenemethane with aldehydes--a novel ligand design

The palladium-catalyzed [3 + 2] cycloaddition of trimethylenemethane (TMM) with aldehydes is a direct and efficient route to methylenetetrahydrofurans. Herein we describe the first asymmetric synthesis of methylenetetrahydrofurans utilizing a palladium-TMM complex in the presence of a novel phosphoramidite ligand possessing a stereogenic phosphorus. The method allows for the formation of chiral disubstituted tetrahydrofurans in good yields and enantioselectivities.     

Development of diamidophosphite ligands and their application to the palladium-catalyzed vinyl-substituted trimethylenemethane asymmetric [3 + 2] cycloaddition

A palladium-catalyzed asymmetric [3 + 2] cycloaddition of a vinyl-substituted trimethylenemethane (TMM) donor with α,β-unsaturated acyl imidazoles is described. A newly designed bisdiamidophosphite ligand derived from (S,S)-trans-1,2-cyclohexanediamine and (2R,4R)-pentanediol has been instrumental for the development of this process. This transformation generates tetrasubstituted cyclopentanes bearing three contiguous stereocenters in high yields, with good diastereo- and enantioselectivity.     

Dinitrogen extrusion from diazene in organic synthesis

Radical-mediated reactions have many advantages in the construction of complex molecular scaffolds by forging chemical bonds of high challenge. Diazenes, including 1,1-diazenes and 1,2-diazenes, can generate biradical species via nitrogen extrusion under thermal or photochemical conditions. The superior reactivity of the generated biradical enables various types of synthetic transformations with excellent chemoselectivity and has been applied to the complex natural products synthesis. In this mini-review, the modes of reaction are summarized and discussed, namely ring contraction via nitrogen deletion, homo or hetero-dimerization, trimethylenemethane (TMM)-diyl cycloaddition. Applications of these classes of reactions in complex natural product synthesis are illustrated. Last but not least, the current state, future directions, and opportunities for dinitrogen extrusion reaction from diazenes are highlighted and discussed.     

Enantio‐ and Diastereoselective Synthesis of Chiral Allenes by Palladium‐Catalyzed Asymmetric [3+2] Cycloaddition Reactions

A protocol for the asymmetric synthesis of highly substituted chiral allenes with control of point and axial chirality has been developed. A palladium‐catalyzed [3+2] cycloaddition using readily available racemic allenes gives access to densely functionalized chiral allenes with excellent yields and functional group tolerance. The catalytic asymmetric protocol utilizes a broad range of allenyl TMM (trimethylenemethane) donors to form cyclopentanes, pyrrolidines, and spirocycles with very good control of regio‐, enantio‐, and diastereoselectivity. The chiral allene moiety is shown to be a valuable functional group for rapid elaboration towards complex targets.     

Detailed Optimization of Polycondensation Reaction via Direct C–H Arylation of Ethylenedioxythiophene

The polycondensation reaction of 3,4‐ethylenedioxythiophene with 2,7‐dibromo‐9,9‐dioctylfluorene via Pd‐catalyzed direct arylation gives poly[(3,4‐ethylenedioxythiophene‐2,5‐diyl)‐(9,9‐dioctylfluorene‐2,7‐diyl)]. The reaction conditions are optimized in terms of the Pd precatalysts, reaction time, and carboxylic acid additives. The combination of 1 mol% Pd(OAc)₂ and 1‐adamantanecarboxylic acid as an additive is the optimized catalytic system, and it yields the corresponding polymer with a molecular weight of 39 400 in 89% yield. The polycondensation reaction, followed by an end‐capping reaction, effectively provides a linear polymer without Br terminals.     

Quinolone Analogs 13: Synthesis of Novel 1,1′‐(2‐Methylenepropane‐1,3‐diyl)di(4‐quinolone‐3‐carboxylate) and Related Compounds

The reaction of the 4‐hydroxyquinoline‐3‐carboxylate 6 with pentaerythritol tribromide gave the 1,1′‐(2‐methylenepropane‐1,3‐diyl)di(4‐quinolone‐3‐carboxylate) 11 , whose reaction with bromine afforded the 1,1′‐(2‐bromo‐2‐bromomethylpropane‐1,3‐diyl)di(4‐quinolone‐3‐carboxylate) 12 . Compound 12 was transformed into the (Z)‐1,1′‐(2‐acetoxymethylpropene‐1,3‐diyl)di(4‐quinolone‐3‐carboxylate) 13 or (E)‐1,1′‐[2‐(imidazol‐1‐ylmethyl)propene‐1,3‐diyl]di(4‐quinolone‐3‐carboxylate) 14 . Hydrolysis of the dimer (Z)‐ 13 or (E)‐ 14 with potassium hydroxide provided the (E)‐1,1′‐(2‐hydroxymethylpropene‐1,3‐diyl)di(4‐quinolone‐3‐carboxylic acid) 15 or (Z)‐1,1′‐[2‐(imidazol‐1‐ylmethyl)propene‐1,3‐diyl]di(4‐quinolone‐3‐carboxylic acid) 16 , respectively. The nuclear Overhauser effect (NOE) spectral data supported that those hydrolysis resulted in the geometrical conversion of (Z)‐ 13 into (E)‐ 15 or (E)‐ 14 into (Z)‐ 16 .     

Planar trimethylenemethane dianion chemistry of lanthanide metallocenes: synthesis, structure, density functional theory analysis, and reactivity of [(C5Me5)2Ln]2[mu-eta3:eta3-C(CH2)(3] Complexes

The unusual formation of planar trimethylenemethane (TMM) dianion complexes of lanthanide metallocenes, [(C5Me5)2Ln]2[mu-eta3:eta3-C(CH2)3] (Ln = Sm, 1; La, 2; Pr, 3; Nd, 4; Y, 5) has been examined by synthesizing examples with metals from La to Y to examine the effects of radial size on structure and to provide closed shell examples for direct comparison with density functional theory (DFT) calculations. Synthetic routes to 1-4 have been expanded from the [(C5Me5)2Ln][(mu-Ph)2BPh2]/neopentyl lithium reaction involving beta-methyl elimination to a [(C5Me5)2Ln][(mu-Ph)2BPh2]/isobutyl lithium route. The synthetic pathways are sensitive to metal radius. To obtain 5, the methylallyl complex, (C5Me5)2Y[CH2C(Me)CH2], 6, was synthesized and treated with [(C5Me5)2YH]x. In the Lu case, the neopentyl complex [(C5Me5)2LuCH2C(CH3)3]x, 7, was isolated instead of the TMM product. X-ray crystallography showed that the metrical parameters of the planar TMM dianions in each complex are similar. The structural data have been compared with DFT calculations on the closed-shell lanthanum and lutetium complexes that suggest only limited covalent interactions with the lanthanide ion. Benzophenone (2 equiv) reacts with 1 to expand the original four-carbon TMM skeleton to a dianionic bis(alkoxide) ligand containing a symmetrically substituted C=CH2 moiety in [(C5Me5)2Sm]2[mu-(OCPh2CH2)2C=CH2], 8. In this reaction, the TMM complex reacts as a bifunctional bisallylic reagent that generates an organic framework containing a central vinyl group.