Chiral Lewis Base Catalysts Research Articles

Silyl Ethers as Latent Pronucleophiles in Enantioselective Lewis Base Catalyzed Synthesis of Allylic Ethers from Allylic Fluorides

Allylic ethers are a common occurrence in natural products and are often used as intermediates in target-oriented synthesis. Their synthesis often relies on the use of transition metal catalysts. Here we report an organocatalytic method for allylation of O-centered nucleophiles: Lewis base catalyzed allylation of silyl ethers with allylic fluorides. The method relies on the concept of latent pronucleophiles in Lewis base catalysis to overcome common limitations in substrate scope even allowing for allylation of sterically congested O-pronucleophiles. When chiral Lewis base catalysts are used, the allyl ethers are produced in enantioenriched form via a kinetic resolution of fluorides where streoselectivity is determined by the chiral catalyst.

Enantioselective Lewis base catalysed allylation of picoline- and quinaldine-based latent pronucleophiles.

Picolines and quinaldines are valuable building blocks and intermediates in the synthesis of natural products and pharmaceuticals. Functionalization of the methyl group in picolines and quinaldines under mild conditions is challenging. We report that the concept of latent pronucleophiles enables Lewis base catalysed allylation of picolines and quinaldines with allylic fluorides starting from silylated picolines and quinaldines. Reactions afford enantioenriched allylation products when chiral Lewis base catalysts are used. The allylation products can be rapidly transformed to quinolizine-4-ones.

Lewis-Base-Catalyzed N-Allylation of Silyl Carbamate Latent Pronucleophiles with Allylic Fluorides.

Silyl carbamates, latent pronucleophile surrogates of carbamates, undergo allylation using allylic fluorides in the presence of common Lewis base catalysts. The reactions are rendered enantioselective in the presence of chiral Lewis base catalysts and produce suitably protected derivatives of enantioenriched chiral β-amino acids. The design of the latent pronucleophile featuring both a silyl group and an electron-deficient carbamate is instrumental in lowering the nucleophilicity of nitrogen and enabling enantioselective allylation in the presence of chiral cinchona alkaloid-based catalysts.

Chiral Lewis Base-Catalysed Asymmetric Syntheses of Benzo-fused ϵ-Lactones.

We herein report a two-step protocol for the asymmetric synthesis of novel chiral benzofused ϵ-lactones starting from O-protected hydroxymethyl-para-quinone methides and activated aryl esters. By using chiral isothiourea Lewis base catalysts a broad variety of differently substituted products could be obtained in yields of around 50 % over both steps with high levels of enantioselectivities, albeit low diastereoselectivities only.

Photochemical Wolff Rearrangement Initiated Generation and Subsequent α-Chlorination of C1 Ammonium Enolates.

The enantioselective synthesis of α-chlorinated carboxylic acid esters with er up to 99:1 and yields up to 82% was achieved via a one-pot multistep protocol starting from α-diazoketones. This process proceeds via a photochemical Wolff rearrangement, trapping of the generated ketene with a chiral Lewis base catalyst, subsequent enantioselective α-chlorination, and a final nucleophilic displacement of the bound catalyst. The obtained products were successfully utilized for stereospecific nucleophilic displacement reactions with N- and S-nucleophiles.

Bifunctional Lewis Base Catalyzed Asymmetric N-Allylic Alkylation of 2-Hydroxypyridines.

A chiral Lewis base catalyzed enantioselective N-allylic alkylation of 2-hydroxypyridines and MBH carbonates is documented, affording a convenient access to N-alkylated 2-pyridones with up to 99% ee and 99% yield. Experimental and computational studies have revealed that the strong hydrogen bond interaction between the chiral Lewis base catalyst and 2-hydroxypyridines plays a crucial role in this reaction for the reactivity, chemoselectivity, and enantioselectivity.

Lewis Base Catalyzed, Sulfenium Ion Initiated Enantioselective, Spiroketalization Cascade.

A Lewis base catalyzed, enantioselective sulfenocyclization of alkenes to afford [6,6]spiroketals has been developed. The method uses a chiral Lewis base catalyst with an electrophilic sulfur source to generate enantioenriched thiiranium ion with alkenes. Upon formation, the thiiranium ion is subsequently captured in a cascade-type reaction, wherein a ketone oxygen serves as the nucleophile to open the thiiranium ion and an alcohol provides the secondary cyclization to form biorelevant spiroketals. A variety of electron-rich and electron-neutral E-substituted styrenes form the desired spiroketals in good yields with excellent enantio- and diastereoselectivities. Alkyl-substituted and terminal alkenes participate in the cascade reaction, but with a limited scope compared to the styrenyl substrates. This method allows for rapid formation of highly substituted spiroketals in good yield and excellent enantioselectivity.

Metal-free oxidative cross-coupling enabled practical synthesis of atropisomeric QUINOL and its derivatives

As an important platform molecule, atropisomeric QUINOL plays a crucial role in the development of chiral ligands and catalysts in asymmetric catalysis. However, efficient approaches towards QUINOL remain scarce, and the resulting high production costs greatly impede the related academic research as well as downstream industrial applications. Here we report a direct oxidative cross-coupling reaction between isoquinolines and 2-naphthols, providing a straightforward and scalable route to acquire the privileged QUINOL scaffolds in a metal-free manner. Moreover, a NHC-catalyzed kinetic resolution of QUINOL N-oxides with high selectivity factor is established to access two types of promising axially chiral Lewis base catalysts in optically pure forms. The utility of this methodology is further illustrated by facile transformations of the products into QUINAP, an iconic ligand in asymmetric catalysis.

Developing a Methodology for Catalytic Asymmetric Crotylation of Aldehydes

AbstractAsymmetric crotylation has firmly earned a place among the set of valuable synthetic tools for stereoselective construction of carbon skeletons. For a long time the field was heavily dominated by reagents bearing stoichiometric chiral auxiliaries, but now catalytic methods are gradually taking center stage, and the area continues to develop rapidly. This account focuses primarily on preformed organometallic reagents based on silicon and, to some extent, boron. It narrates our endeavors to design new and efficient chiral Lewis base catalysts for the asymmetric addition of crotyl(trichloro)silanes to aldehydes. It also covers the development of a novel protocol for kinetic resolution of racemic secondary allylboronates to give enantio- and diastereomerically enriched linear homoallylic alcohols. As a separate topic, cross-crotylation of aldehydes by using enantiopure branched homoallylic alcohols as a source of crotyl groups is discussed. Finally, the synthetic credentials of the developed methodology are illustrated by total syntheses of marine natural products, in which crotylation plays a key role in setting up stereogenic centers.1 Introduction2 Pyridine N-Oxides as Lewis Base Catalysts3 Bipyridine N,N′-Dioxides as Lewis Base Catalysts4 Chiral Allylating Reagents5 Synthetic Applications6 Concluding Remarks

Enantioselective Construction of Chiral Cyclopropa[c]coumarins via Lewis Base-Catalyzed Cyclopropanation.

The first highly enantioselective construction of chiral cyclopropa[c]coumarins was described. Using commercially available (bis)cinchona alkaloid (DHQ)2PYR as the chiral Lewis base catalyst, together with Cs2CO3 as the achiral base, the reaction of a series of coumarin-3-carboxylate and 3-benzoyl coumarins with tert-butyl 2-bromoacetate could give rise to the corresponding cyclopropa[c]coumarins bearing three continuous chiral stereocenters in 83-93% ee and 90-97% ee, respectively. The reaction is proposed to proceed via an in situ generated ammonium ylide intermediate.

Latent (Pro)Nucleophiles in Enantioselective Lewis Base Catalyzed Allylic Substitutions

The use of latent nucleophiles, which are molecules that are not nucleophilic but can be activated to act as a nucleophile at an opportune time during the reaction, expands the scope of Lewis base catalyzed reactions. Here, we provide an overview of the concept and show examples of applications to N- and C-centered nucleophiles in allylic substitutions. N- and C-silyl compounds are superior latent (pro)nucleophiles in Lewis base catalyzed reactions with allylic fluorides in which the formation of the strong Si–F bond serves as the driving force for the reactions. The latent (pro)nucleophiles ensure high regio­selectivity in these reactions and enable enantioselective transformations of Morita–Baylis–Hillman adducts by the use of common chiral Lewis base catalysts.1 Introduction2 Substitution of MBH Carbonates3 The Concept of Latent (Pro)Nucleophiles4 Enantioselective Allylation of N-Heterocycles5 Enantioselective Phosphonyldifluoromethylation of Allylic Fluorides6 Conclusion

Studies on Thiourea Catalysed Bromocycloetherification and Bromolactonisations

Lewis base catalysed halofunctionalisation reactions of alkenes are well established and allow access to, among others, various oxygen containing heterocycles. By exploiting the known conversion of N-heterocyclic carbenes into the corresponding thioureas it has been possible to prepare and study a range of chiral and non-chiral Lewis base catalysts for such reactions. Although all thiourea catalysts were found to mediate bromocycloetherification and bromolactonisation reactions, they could not be achieved with enantioselectivity.

Recent Advances in Cooperative Catalysis of Chiral Lewis Base and Transition Metal Catalyst

Recent Advances in Cooperative Catalysis of Chiral Lewis Base and Transition Metal Catalyst

Stereoselective Synthesis of Nitrogen-Containing Compounds from Enamines.

The domino reaction of enamines, electrophiles (N-sulfonylimines, N-tosylisocyanate, or diethyl azodicarboxylate), and trichlorosilane provided trans-amines (trans/cis = > 99:1 to 96:4). Meanwhile, the sequential imino ene-type reaction of enamines and electrophiles/NaBH3CN reduction afforded cis-amines (trans/cis = 1:>99 to 15:85). The reversal of selectivity is discussed on the basis of diastereofacial selection of the plausible iminium ion intermediates. For the domino reaction of cyclic enamines and cyclic imines, high enantioselectivity (er = 95.7:4.3 to 99.9:0.1) was achieved by utilizing chiral Lewis base catalysts.

Construction of polycyclic spirooxindoles through [3+2] annulations of Morita–Baylis–Hillman carbonates and 3-nitro-7-azaindoles

A mild and efficient dearomatic [3+2] annulation reaction of 3-nitro-7-azaindoles and Morita−Baylis−Hillman carbonates from isatins was developed catalyzed by DMAP, affording the corresponding polycyclic spirooxindoles containing fused azaindoline architectures and vicinal quaternary centers in excellent yields (up to 96%) with high regio- and diastereoselectivity (dr>19:1). Moderate enantioselectivity (79% ee) was obtained by employing a chiral DMAP-type Lewis base catalyst.

Asymmetric cyanation of imines via dipeptide-derived organophosphine dual-reagent catalysis.

Over the past few decades, enantioselective phosphine organocatalysis has evolved rapidly into a highly efficient catalytic strategy for a range of useful reactions. However, as restricted by the traditional catalytic modes, some important reactions, such as asymmetric Strecker-type reactions, have thus far been out of reach of this strategy. Reported herein is an application of enantioselective phosphine organocatalysis for asymmetric Strecker-type reactions, enabled by a dual-reagent catalyst system in which the key organophosphorus zwitterion intermediate, generated in situ by mixing a chiral dipeptide-derived multifunctional organophosphine with methyl acrylate, is used as a highly efficient chiral Lewis base catalyst. The high efficiency of this catalytic system is demonstrated in the asymmetric cyanation of isatin-derived ketimines and azomethine aldimines as well as in the kinetic resolution of racemic 3-substituted azomethines. Mechanistic studies provide experimental evidence for the intermediacy of the putative zwitterion and its role as a catalytically active Lewis base.

Enantioselective Aerobic Oxidative C(sp3)–H Olefination of Amines via Cooperative Photoredox and Asymmetric Catalysis

A cooperative photoredox and asymmetric catalysis for the enantioselective aerobic oxidative C(sp3)–H olefination of tetrahydro-β-carbolines (THCs) is reported. This method, which is also effective for tetrahydroisoquinolines (THIQs), features a triple-catalyst strategy, involving a dicyanopyrazine-derived chromophore (DPZ) as the metal-free photoredox catalyst, a chiral Lewis base catalyst, and an inorganic salt cocatalyst. The current protocol provides straightforward access to a series of valuable α-substituted THCs and THIQs in high yields with excellent regio- and enantioselectivities (up to 95% ee).

P-Chiral phosphine oxide catalysed reduction of prochiral ketimines using trichlorosilane

Twelve P-chiral phosphine oxides were screened for their ability to act as a chiral Lewis base catalyst for the asymmetric hydrosilylation of ketimines, providing chiral amines in good conversion and yield, but relatively poor enantioselectivity (ee <30%). Mechanistic studies paralleling work on chiral sulfinamides have shown a non-linear relationship of catalyst enantioselectivity and the chiral amine product.

ChemInform Abstract: Stereoselective Electrophilic Cyclization

AbstractReview: [rational design of monofunctionalized chiral Lewis base catalysts for enantioselective iodo‐ and protocyclizations as well as nucleophilic phosphite‐urea cooperative catalysts for the stereoselective promotion of electrophilic bromocyclizations; 31 refs.

Stereoselective Electrophilic Cyclization.

Electrophilic cyclizations of unactivated alkenes play highly important roles in the synthesis of useful building blocks. This account describes our contributions to the rational design of monofunctionalized chiral Lewis base catalysts for enantioselective iodo- and protocyclizations. For the stereoselective promotion of electrophilic bromocyclizations, nucleophilic phosphite-urea cooperative catalysts have been designed.