Donor-Acceptor Cyclopropanes: Activation Enabled by a Single,Vinylogous Acceptor

A novel class of highly activated donor-acceptor cyclopropanes bearing only a single, vinylogous acceptor is presented. These strained moieties readily undergo cycloadditions with aldehydes, ketones, thioketones, nitriles, naphth-2-ols and various other substrates to yield the corresponding carbo- and heterocycles. Diastereocontrol can be achieved through the choice of catalyst (Brønsted or Lewis acid). The formation of tetrahydrofurans was shown to be highly enantiospecific when chiral cyclopropanes are employed. A series of mechanistic and kinetic experiments was conducted to elucidate a plausible catalytic cycle and to rationalize the stereochemical outcome.     

Cyclopropane-aldehyde annulations at quaternary donor sites: stereoselective access to highly substituted tetrahydrofurans

A diastereoselective synthesis of pentasubstituted tetrahydrofurans via a Lewis acid catalyzed (3 + 2)-annulation of quaternary donor site cyclopropanes and aldehydes is described. The reaction is catalyzed by Sn(OTf)(2), SnCl(4), or Hf(OTf)(4) in yields up to 95% and diastereomeric ratios as high as 99:1.     

Donor-Acceptor Cyclopropanes: Activation Enabled by a Single,Vinylogous Acceptor

A novel class of highly activated donor-acceptor cyclopropanes bearing only a single, vinylogous acceptor is presented. These strained moieties readily undergo cycloadditions with aldehydes, ketones, thioketones, nitriles, naphth-2-ols and various other substrates to yield the corresponding carbo- and heterocycles. Diastereocontrol can be achieved through the choice of catalyst (Brønsted or Lewis acid). The formation of tetrahydrofurans was shown to be highly enantiospecific when chiral cyclopropanes are employed. A series of mechanistic and kinetic experiments was conducted to elucidate a plausible catalytic cycle and to rationalize the stereochemical outcome.     

Scope and mechanism for lewis acid-catalyzed cycloadditions of aldehydes and donor-acceptor cyclopropanes: evidence for a stereospecific intimate ion pair pathway

In this work, the one-step diastereoselective synthesis of cis-2,5-disubstituted tetrahydrofurans via Lewis acid catalyzed [3 + 2] cycloadditions of donor-acceptor (D-A) cyclopropanes and aldehydes is described. The scope and limitations with respect to both reaction partners are provided. A detailed examination of the mechanism has been performed, including stereochemical analysis and electronic profiling of both reactants. Experimental evidence supports an unusual stereospecific intimate ion pair mechanism wherein the aldehyde functions as a nucleophile and malonate acts as the nucleofuge. The reaction proceeds with inversion at the cyclopropane donor site and allows absolute stereochemical information to be transferred to the products with high fidelity. The mechanism facilitates the stereospecific synthesis of a range of optically active tetrahydrofuran derivatives from enantioenriched D-A cyclopropanes.     

New reactions of gamma-halocarbanions: simple synthesis of substituted tetrahydrofurans

The treatment of 4-chlorobutyronitrile, 3-chloropropyl phenyl sulfone, and other related compounds with a base afforded gamma-halocarbanions that undergo fast intramolecular substitution of the halogen to produce substituted cyclopropanes. We found that these short-lived carbanionic intermediates can be trapped with active external electrophilic partners, such as aldehydes, to give the aldol anions. These anions then undergo rapid intramolecular substitution of chloride to produce 2,3-disubstituted tetrahydrofurans. Under the right conditions, yields of tetrahydrofurans are excellent. Similar reactions with ketones gives 2,2,3-trisubstituted furans, but this process is usually less efficient. Ratios between the rates of intramolecular and intermolecular processes were qualitatively estimated by competitive experiments. It was shown that gamma-halo and gamma-trimethylammonium substituents substantially increase the kinetic CH acidity of alkane nitriles and sulfones.     

Intermolecular Reactions of γ‐Halocarbanions – Stepwise Analogs of 1,3‐Dipolar Cycloaddition

γ‐Halocarbanions, short‐lived intermediates, add to electron‐deficient double bonds of aldehydes, Michael acceptors, and imines to form anionic adducts that enter intramolecular 1,5‐substitution to form five‐membered rings of tetrahydrofurans, cyclopentanes, and pyrrolidines, respectively. Although the γ‐halocarbanions can be generated by simple deprotonation of appropriate precursors, a wealth of other methods based on Lewis acid‐catalyzed opening of cyclopropanes with formation of dipolar species utilizes a similar mechanistic scheme. In our review, we analyze kinetic relations of elementary processes in the multistep transformations, and demonstrate how structural factors influence the mechanisms and selectivity of the reaction.     

Cycloadditions of diazoesters to α,β-unsaturated aldehydes

The reaction of α,β-unsturated aldehydes with diazoesters primarily gives unstable 1,3-dipolar adducts (1-pyrazolines) which evolve according to their substitution pattern: whenever there is a proton geminal to the formyl group, conjugation with the latter is highly favoured, yielding 3-formyl-2-pyrazolines which subsequently polymerize. On the other hand, if no proton is available for conjugation with the formyl group, two competitive reactions take place: tautomerisation into an ester conjugated pyrazoline and loss of nitrogen with formation of cyclopropanes, the latter reactionnal pathway being favoured with electronwithdrawing substituents.     

A three-step route to a tricyclic steroid precursor

2-Alkyl cyclohexenones are useful intermediates for organic synthesis. The Wittig reaction of a series of aldehydes with (cyclopropylmethyl)triphenylphosphonium bromide delivered the corresponding alkenyl cyclopropanes. UV irradiation in the presence of Fe(CO)5 converted the alkenyl cyclopropanes to the 2-substituted cyclohexenones. This approach enabled a three-step synthesis of the tricyclic core of estrone methyl ether.     

A highly diastereoselective approach to tetrahydrofurans via [3+2] cycloadditions of silylmethyl-substituted cyclopropanes with aldehydes and ketones

An efficient and highly diastereoselective synthesis of highly substituted tetrahydrofurans from the reaction of a vicinal t-butyldiphenylsilylmethyl-substituted cyclopropyl diester with aldehydes and ketones has been developed. The 2,5-cis-disubstitution predominates over the 2,5-trans-disubstitution by as much as 12:1. The reaction with cyclic ketones generates spiro-fused tetrahydrofurans in good yields.     

Polarity inversion of donor-acceptor cyclopropanes: disubstituted δ-lactones via enantioselective iridium catalysis

The coupling of carbonyl electrophiles at the donor position of donor-acceptor cyclopropanes is described, representing an inversion of polarity with respect to conventional reactivity modes displayed by these reagents. Specifically, upon exposure of donor-acceptor cyclopropanes to alcohols in the presence of a cyclometalated iridium catalyst modified by (S)-BINAP, catalytic C-C coupling occurs, providing enantiomerically enriched products of carbonyl allylation. Identical products are obtained upon isopropanol-mediated transfer hydrogenation of donor-acceptor cyclopropanes in the presence of aldehydes. The reaction products are directly transformed to cis-4,5-disubstituted δ-lactones.     

Organocatalytic enantioselective cascade Michael-alkylation reactions: synthesis of chiral cyclopropanes and investigation of unexpected organocatalyzed stereoselective ring opening of cyclopropanes

The development of efficient methods for the facile construction of important molecular architectures is a central goal in organic synthesis. An unprecedented organocatalytic asymmetric cascade Michael-alkylation reaction of alpha,beta-unsaturated aldehydes with bromomalonates has been developed. The process, efficiently catalyzed by chiral diphenylprolinol TMS ether in the presence of base 2,6-lutidine, serves as a powerful approach to the preparation of synthetically and biologically important cyclopropanes in high levels of enantio- and diastereoselectivities. Remarkably, the power of the cascade process is fueled by its high efficiency of the production of two new C-C bonds, two new stereogenic centers, and one quaternary carbon center in one single operation, which otherwise is difficult to achieve by traditional strategies. Moreover, the beauty of the cascade process is further underscored by the nature of the product formation depending on the reaction conditions. With the alternation of base from 2,6-lutidine (1.1 equiv), which is effective for the cyclopropanations, to NaOAc (4.0 equiv), the spontaneous ring-opening of cyclopropanes takes place to lead to stereoselective (E) alpha-substituted malonate alpha,beta-unsaturated aldehydes. A possible reaction mechanism, which involves a Michael-alkylation-retro-Michael pathway, is proposed and verified by experimental studies. This investigation represents the first example of an organocatalyst-promoted ring opening of the cyclopropanes, whereas such reactions have been intensively explored by Lewis acid-based catalysis.     

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.     

Transition‐Metal‐Free Coupling Reaction of Vinylcyclopropanes with Aldehydes Catalyzed by Tin Hydride

Donor–acceptor cyclopropanes are useful building blocks for catalytic cycloaddition reactions with a range of electrophiles to give various cyclic products. In contrast, relatively few methods are available for the synthesis of homoallylic alcohols through coupling of vinylcyclopropanes (VCPs) with aldehydes, even with transition‐metal catalysts. Here, we report that the hydrostannation of vinylcyclopropanes (VCPs) was effectively promoted by dibutyliodotin hydride (Bu₂SnIH). The resultant allylic tin compounds reacted easily with aldehydes. Furthermore, the use of Bu₂SnIH was effectively catalytic in the presence of hydrosilane as a hydride source, which established a coupling reaction of VCPs with aldehydes for the synthesis of homoallylic alcohols without the use of transition‐metal catalysts. In contrast to conventional catalytic reactions of VCPs, the presented method allowed the use of several VCPs in addition to conventional donor–acceptor cyclopropanes.     

Stereocontrolled assembly of tetrasubstituted tetrahydrofurans: a concise synthesis of virgatusin

The condensation of substituted allylsiloxanes with aldehydes leads to the highly stereoselective construction of 2,3,4,5-tetrasubstituted tetrahydrofurans. With electron-rich aryl and alpha,beta-unsaturated aldehydes as substrates, the stereochemical outcome at C5 can be dictated by appropriate choice of Lewis acid. The reaction has been applied to a concise (nine step) synthesis of (+)-virgatusin (ent-1). [reaction: see text]     

Donor cyclopropanes in synthesis: utilising silylmethylcyclopropanes to prepare 2,5-disubstituted tetrahydrofurans

The use of donor-only silylmethylcyclopropanes in the Lewis acid promoted reaction with aldehydes to generate 2,5-disubstituted tetrahydrofurans is described. The diastereoselectivity obtained in the product is very much dependent upon the temperature of the reaction.     

A Facile Three-Component One-Pot Synthesis of Structurally Constrained Tetrahydrofurans, Which Are t-RNA Synthetase Inhibitor Analogues

A one-pot procedure for the efficient synthesis of a small library of t-RNA inhibitor analogues was developed. Thus,Rh2(OAc)4 catalyzed three-component 1,3-dipolar cycloaddition reactions of carbonyl ylides derived from diazoindan-1,3-dione and aldehydes with other dipolarophiles in 1,1,2,2-tetrachloroethane at 80 ℃ gave ring fused tetrahydrofurans having three stereocenters in good yield.     

Examination of homo-[3 + 2]-dipolar cycloaddition: mechanistic insight into regio- and diastereoselectivity

The reaction of 2,3-disubstituted-1,1-cyclopropanediesters with nitrones under Lewis acid conditions produces tetrahydro-1,2-oxazines in which the cis/trans relationship of the cyclopropanes is not conserved. Reacting nitrones with 2,3-cis-disubstituted cyclopropanes lead to 5,6-trans-oxazines, and 2,3-trans-disubstituted cyclopropanes lead to 5,6-cis-oxazines. This observed stereochemical inversion provides evidence for a stepwise annulation mechanism in the preparation of tetrahydro-1,2-oxazines.     

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.     

Asymmetric oxidative Lewis base catalysis-unifying iminium and enamine organocatalysis with oxidations

Enantioselective oxidative domino reactions of allylic alcohols to functionalized aldehydes have been developed. The one pot domino oxidation-iminium activation represents a convenient strategy for the enantioselective addition of malonates to allylic alcohols and the asymmetric formation of formyl cyclopropanes.     

A facile three-component one-pot synthesis of structurally constrained tetrahydrofurans that are t-RNA synthetase inhibitor analogues

A one-pot procedure for the efficient synthesis of tRNA inhibitor analogues was developed. Thus, three-component 1,3-dipolar cycloaddition reactions of carbonyl ylides derived from diazoindan-1,3-dione and aldehydes with other dipolarophiles in 1,1,2,2-tetrachloroethane in 80 degrees C gave ring-fused tetrahydrofurans having three stereocenters in good yield.