Asymmetric cascade reaction sequences via chiral lithiated intermediates

The (-)-sparteine-mediated enantioselective intermolecular carbolithiation of (E)-2-propenylarylamines allows for the generation of chiral lithiated intermediates which have broad synthetic potential. These intermediates have been exploited in a series of further in situ reactions with electrophiles to generate a collection of products each containing a common stereogenic center. The stereogenic center, formed in high enantiomeric ratio in the first carbolithiation step, is carried through the cascade reaction sequence to the final products and is independent of electrophile used. The methodology is demonstrated by the synthesis of structurally diverse chiral anilines, indoles, and indolones all with an er of 92:8 (+/-1). The heterocyclic syntheses involve an enantioselective alkene carbolithiation and subsequent trapping of the intermediate organolithium with a suitable electrophile, followed by an in situ ring closure and dehydration to generate the indole or indolone rings.     

Asymmetric carbolithiation of conjugated enynes: a flow microreactor enables the use of configurationally unstable intermediates before they epimerize

We found that a flow microreactor system enables the generation of a configurationally unstable chiral organolithium intermediate and allows for its use in a reaction with an electrophile before it epimerizes. Based on this method, the enantioselective carbolithiation of conjugated enynes followed by the reaction with electrophiles was accomplished to obtain enantioenriched chiral allenes.     

Carbolithiation of vinyl pyridines as a route to 7-azaindoles

An effective synthesis of the 7-azaindole ring system has been developed from substituted 2-amino-3-vinyl pyridines. The methodology involves a novel cascade reaction sequence of controlled carbolithiation of the vinyl double bond, subsequent trapping of the intermediate organolithium with a suitable electrophile, followed by ring closure and dehydration.     

Carbolithiation of o-Amino-(E)-stilbenes: diastereoselective electrophile substitution with applications to quinoline synthesis

A regioselective carbolithiation of o-amino-(E)-stilbenes has been achieved with a series of alkyllithiums when THF is employed as the reaction solvent. The use of other solvents, such as diethyl ether or hydrocarbons, leads to a pronounced loss in regioselectivity. Moreover, high levels of diastereoselectivity have been obtained following reaction of the lithiated intermediate in THF with different electrophiles such as MeOD, CO2, and Bu3SnCl. It was shown that diastereoselectivity was influenced by the ortho-amino substituent and the alkyllithium utilized for carbolithiation with N-Boc substituent and t-BuLi proving optimal. In the case of carbolithiated intermediate 3a, obtained from the reaction of N-Boc substituted stilbene with t-BuLi, 1H and 13C NMR analysis revealed predominantly one diastereoisomer which was stable at room temperature. Application of the carbolithiation/electrophile reaction methodology to the synthesis of six-membered quinoline ring systems is demonstrated with substituted 3,4-dihydroquinolin-2-ones, 1,2,3,4-tetrahydroquinolines, 1,4-dihydroquinolines, and quinolines all prepared by a common cascade route.     

7-Azaindoles via carbolithiation of vinyl pyridines

The sequential reactions of a pyridine vinylation and alkene carbolithiation constitutes a new route to substituted 7-azaindoles. The methodology involves a reaction sequence of controlled carbolithiation of the vinyl double bond, subsequent trapping of the formal di-anion intermediate with a suitable electrophile, followed by an in situ ring closure and dehydration. The reaction sequence allows for aryl, heteroaryl, alkyl and keto substituents to be included at different positions around the heterocycle.     

Electrophile-Dependent Reactivity of Lithiated N-Benzylpyrene-1-Carboxamide

In this paper, we describe the lithiation of N-benzylpyrene-1-carboxamide with RLi-TMEDA. We found that the reaction outcome strongly depends on the electrophile used in the quenching step. The electrophile can be introduced at either the benzylic position or at the C-2 position in the pyrene nucleus. Furthermore, when H⁺ was used as the quencher, the product of the intramolecular carbolithiation of the pyrene K-region was formed. Dehydrogenation of the obtained compound with DDQ allowed the synthesis of a novel nitrogen polycyclic compound with an aza-benzo[c,d]pyrene (azaolympicene) skeleton. Attempts to extend the reaction scope to the amides substituted in the phenyl ring 8a and 8b gave an unexpected result. The reaction of both compounds with BuLi gave 1-valerylpyrene (9) in good yield. Photophysical properties, including absorption spectra, emission spectra and quantum yields of the emission of selected products, were studied and discussed.     

Chiral Brønsted Acid Catalyzed Enantioconvergent Propargylic Substitution Reaction of Racemic Secondary Propargylic Alcohols with Thiols

Despite the significant progress of the enantioselective reaction using chiral catalysts, the enantioselective nucleophilic substitution reaction at the chiral sp³-hybridized carbon atom of a racemic electrophile has not been largely explored. Herein, we report the enantioconvergent propargylic substitution reaction of racemic propargylic alcohols with thiols using chiral bis-phosphoric acid as the chiral Brønsted acid catalyst. The substitution products were formed in high yields with high enantioselectivities in most cases. The cation-stabilizing effect of the sulfur functional group introduced at the alkynyl terminus is the key to achieving the efficient enantioconvergent process, in which chiral information originating from not only the racemic stereogenic center but also the formed contact ion pair is completely eliminated from the present system.     

Regioselective carbolithiation of o-amino-(E)-stilbenes: cascade route to the quinoline scaffold

[reaction: see text] The regioselective carbolithiation of substituted ortho-amino-(E)-stilbenes can be exploited to initiate cascade reaction sequences that can be utilized as new routes to substituted 3,4-dihydro-1H-quinolin-2-ones, 1,2,3,4-tetrahydroquinolines, 1,4-dihydroquinolines, and quinolines.     

Organocatalytic kinetic resolution cascade reactions: new mechanistic and stereochemical manifold in diphenyl prolinol silyl ether catalysis

A new cascade reaction involving an iminium-catalyzed intramolecular oxa-Michael addition followed by an enamine-catalyzed intermolecular Michael addition is reported herein. This cascade reaction generates enantiopure, highly functionalized tetrahydropyrans and tetrahydrofurans in a one-pot reaction and in up to 89?% combined yield and up to 99?% ee. This cascade reaction is catalyzed by diaryl prolinol silyl ethers, which are a privileged class of catalysts. The stereochemical outcome of these cascade reactions is unprecedented. Computational studies indicate that this stereochemical outcome arises from nonclassical hydrogen-bonding interactions between the electrophile and the substrate, and from entropic considerations of preorganization. The unprecedented configurations of the cascade products, combined with the computational models, reveal for the first time that asymmetric induction by diaryl prolinol silyl ether catalysts is not always exclusively reagent controlled. The stereochemical outcome also arises from a kinetic resolution or dynamic kinetic resolution of the β-stereocenter through an enamine-catalyzed intermolecular reaction. This unprecedented organocascade reaction mechanism may be adaptable to diaryl prolinol silyl ether-catalyzed cascade reactions, in which both the iminium- and enamine-catalyzed steps are intermolecular, an underdeveloped type of cascade reaction.     

Diastereoselective tandem 6-exo carbolithiation intramolecular ring opening in (-)-8-aminomenthol-derived perhydrobenzoxazines. A new synthesis of enantiopure 4-substituted tetrahydro isoquinolines and 2-azabenzonorbornanes.

Aryllithiums prepared by bromine-lithium interchange in chiral 2-(o-bromophenyl)-substituted perhydro-1,3-benzoxazines participate in the intramolecular 6-exo carbolithiation reaction with unactivated double bonds attached to the nitrogen substituent of the heterocycle. When the reaction time is extended or no TMEDA is used, the cyclized lithium intermediates react intramolecularly with the N,O-acetal system leading to 2-azabenzonorbornane derivatives. The reactions are highly stereoselective and constitute a high-yielding synthesis of enantiopure 4-substituted tetrahydroisoquinolines or 7-substituted 2-azabenzonorbornanes.     

Intramolecular carbolithiation of allyl o-lithioaryl ethers: a new enantioselective synthesis of functionalized 2,3-dihydrobenzofurans

A new and easy method for the diastereoselective synthesis of 3-functionalized 2,3-dihydrobenzofuran derivatives from allyl 2-bromoaryl ethers is described. The key step of this transformation involves an intramolecular carbolithiation reaction of allyl 2-lithioaryl ethers. The substituents in both the allyl and the aryl moieties play an important and decisive role in stopping the reaction at the benzofuran thus avoiding a gamma-elimination reaction. Finally, this process is amenable to the synthesis of enantiomerically enriched compounds by using (-)-sparteine as a chiral inductor.     

Diastereo- and enantioselective carbolithiation of allyl o-lithioaryl ethers. New chiral cyclopropane derivatives

[reaction: see text] Different allyl 2-lithioaryl ethers undergo a tandem carbolithiation/gamma-elimination in Et(2)O/TMEDA affording o-cyclopropyl phenol or naphthol derivatives in a diastereoselective manner. The use of (-)-sparteine as a chiral ligand instead of TMEDA allows the synthesis of cyclopropane derivatives with up 81% ee.     

Mechanistic insight into stereoselective carbolithiation

This article addresses the mechanistic features of asymmetric carbolithiation of β‐methylstyrenes. While often the presence of functional groups is required to obtain high enantioselectivities in carbolithiation reactions, simple β‐methylstyrene also gives high selectivities in (?)‐sparteine‐mediated addition of alkyl lithium compounds. Computational studies on the carbolithiation of β‐methylstyrene with (?)‐sparteine show that the observed selectivities are the result of repulsion effects in the diastereomeric transition states between the (?)‐sparteine ? alkyl lithium adduct and the β‐methylstyrene, upon approximation of the two reactants. In contrast, for the ortho‐amino β‐methylstyrene (E)‐benzyl(2‐propenylphenyl)amine ( 4 ) X‐ray structure analyses of intermediate lithium amides indicate a carbolithiation mechanism in which one side of the double bond is shielded by the amide moiety, leaving only one side free for approach of the chiral alkyl lithium adduct.     

Applications of enantioselective carbolithiation of ortho-substituted beta-methylstyrenes

The enantioselective carbolithiation of ortho-substituted (E)-beta-methylstyrenes provides access to chiral lithiated intermediates with broad synthetic potential. Specifically, beta-methylstyrenes with o-aminomethyl, ether, and oxazoline groups have been employed in the synthesis of chiral aromatics and heteroaromatics such as isoquinolines, isoquinolinones, benzofurans, and isobenzofuranones.     

Asymmetric synthesis of 3-hydroxy-pyrrolidines via tin-lithium exchange and cyclization

We report a method for the synthesis of chiral pyrrolidines using tin-lithium exchange and cyclization reactions. The precursors are formed readily from simple starting materials and undergo tin-lithium exchange by treatment with n-butyllithium. Subsequent intramolecular carbolithiation is stereoselective to give highly enantiomerically enriched pyrrolidines in excellent yields.     

Highly enantioselective Friedel-Crafts alkylation of indole and pyrrole with β,γ-unsaturated α-ketoester catalyzed by chiral dicationic palladium complex

The chiral dicationic Pd complexes, bearing sterically demanding diphosphine ligands as Lewis acid catalysts, are shown to catalyze the asymmetric Friedel-Crafts (F-C) alkylations of indoles and pyrroles with β,γ-unsaturated α-ketoesters, to provide the F-C alkylation products with benzylic stereocenters in high yields and enantioselectivities. The reactive chelated structure, formed by the chiral dicationic Pd complex and the electrophile, would be important to gain a high level of asymmetric induction in the F-C alkylation. The F-C products can be readily functionalized to give α-hydroxy esters via catalytic asymmetric ene sequences.     

The palladium catalyzed asymmetric addition of oxindoles and allenes: an atom-economical versatile method for the construction of chiral indole alkaloids

The Pd-catalyzed asymmetric allylic alkylation (AAA) is one of the most useful and versatile methods for asymmetric synthesis known in organometallic chemistry. Development of this reaction over the past 30 years has typically relied on the use of an allylic electrophile bearing an appropriate leaving group to access the reactive Pd(π-allyl) intermediate that goes on to the desired coupling product after attack by the nucleophile present in the reaction. Our group has been interested in developing alternative approaches to access the reactive Pd(π-allyl) intermediate that does not require the use of an activated electrophile, which ultimately generates a stoichiometric byproduct in the reaction that is derived from the leftover leaving group. Along these lines, we have demonstrated that allenes can be used to generate the reactive Pd(π-allyl) intermediate in the presence of an acid cocatalyst, and this system is compatible with nucleophiles to allow for formation of formal AAA products by Pd-catalyzed additions to allenes. This article describes our work regarding the use of oxindoles as carbon-based nucleophiles in a Pd-catalyzed asymmetric addition of oxindoles to allenes (Pd-catalyzed hydrocarbonation of allenes). By using the chiral standard Trost ligand (L1) and 3-aryloxindoles as nucleophiles, this hydrocarbonation reaction provides products with two vicinal stereocenters, with one being quaternary, in excellent chemo-, regio-, diastereo-, and enantioselectivities in high chemical yields.     

Gold-catalyzed ketene dual functionalization and mechanistic insights: divergent synthesis of indenes and benzo[d]oxepines

An unprecedented gold-catalyzed ketene C=O/C=C bifunctionalization method has been developed. Mechanistic studies and density function theory(DFT) calculations indicate that the reaction is initiated by gold-catalyzed Wolff rearrangement of diazoketone to form the ketene intermediate, followed by intermolecular nucleophilic addition and terminated with two divergent cyclization processes via enol intermediates. In the case with alcohols as the nucleophiles, the reaction goes through a C-5-endodig carbocyclization to give the indene products; whereas, O-7-endo-dig cyclization occurs dominantly when indoles/pyrroles are used as the nucleophiles, delivering the 7-membered benzo[d]oxepines. In comparison with the well-documented cycloaddition and nucleophilic addition reactions, this cascade reaction features a novel reaction pattern for the ketene dual functionalization through addition with nucleophile and electrophile in sequence.     

Dynamic thermodynamic and dynamic kinetic resolution of 2-lithiopyrrolidines

Dynamic resolution has been studied as a method for the asymmetric synthesis of 2-substituted pyrrolidines. Highly enantioselective electrophilic substitutions of racemic 2-lithiopyrrolidines in the presence of a chiral ligand have been achieved. The organolithium compounds were prepared by tin-lithium exchange from the corresponding tributylstannanes and n-butyllithium or by deprotonation of N-(tert-butyloxycarbonyl)pyrrolidine with sec-butyllithium. A range of N-substituents and chiral ligands were investigated for the dynamic resolution. Electrophilic quench of the resolved diastereomeric 2-lithiopyrrolidine-chiral ligand complexes provided the enantiomerically enriched 2-substituted pyrrolidines. With N-alkyl derivatives, the resolution occurs conveniently at (or just below) room temperature and either enantiomer of the product can be formed by appropriate choice of the chiral ligand. The asymmetric induction occurs as a result of a thermodynamic preference for one of the diastereomeric complexes. The minor complex was found to have a faster rate of reaction with the electrophile. The use of N-allylic derivatives provides a means to prepare the N-unsubstituted pyrrolidine products. Best results were obtained with the N-2,3-dimethylbut-2-enyl derivative, and this N-substituent could be cleaved using 1-chloroethyl chloroformate. With N-Boc-2-lithiopyrrolidine, the enantioselectivity arises by a kinetic resolution and high levels of asymmetric induction in the presence of excess n-butyllithium can be obtained. Dynamic kinetic resolution of the N-Boc derivative is limited in the scope of electrophile that can be used.     

Tandem Intermolecular - Intramolecular Carbolithiation: A Versatile Method for Synthesis of Cyclopentanes

Polysubstituted cyclopentanes from readily available starting materials? A versatile anionic [3+2] approach is offered by the reaction of difunctional organolithium reagents 1 with alkenes 2 in a tandem intermolecular - intramolecular carbolithiation (see scheme). This convergent sequence is especially attractive as, not only are the precursors readily available, but the products provide valuable synthetic building blocks.