Bifunctional Thiourea Catalyst Research Articles

Stereodivergent Synthesis of Chiral Hydrobenzofuranpyrrolidines by Catalytic Asymmetric Dearomative Cyclization and Controlled Epimerization

A rapid and straightforward way to access stereoisomeric sets of products bearing multiple stereogenic centers is still a significant challenge in asymmetric catalysis. We present herein our experimental studies on the stereodivergent synthesis of chiral hydrobenzofuran‐fused pyrrolidines with three stereogenic centers via organocatalytic asymmetric dearomative cyclization and epimerization process. Chiral bifunctional thiourea catalyst could successfully promote the enantioselective dearomatization cyclization of 2‐nitrobenzofurans with o‐hydroxy aromatic aldimines, which enabled the synthesis of (3S,3aR,8bR)‐hydrobenzofuran[3.2]pyrrolidines in 79‐92% yields with >20:1 stereoselectivities and 93‐99% enantio‐ selectivities. While catalytic amount of DBU could induce the direct intramolecular epimerization of (3S,3aR,8bR)‐hydrobenzofuran[3.2] pyrrolidines to its diastereomers (3R,3aR,8bR)‐hydrobenzofuran[3.2] pyrrolidines in 72‐87% yields without loss of stereoselectivities. The mechanistic pathways of the epimerization process were investigated by a series of control experiments study. This work provides an alternative and forward solution for the stereodivergent preparation of functionalized pyrrolidines with potential bioactivities.

Development of Organocatalytic Reactions for the Synthesis of Natural Products and Pharmaceuticals

This review describes novel organocatalytic methods for the enantioselective construction of spiroindans and spirochromans and the application of the methods to the total synthesis of natural products. We developed an intramolecular Friedel-Craftstype 1,4-addition in which the substrates were a resorcinol derivative and 2-cyclohexenone linked by an alkyl chain. The reaction proceeded smoothly in the presence of a cinchonidine-based primary amine (30 mol%) with water and p-bromophenol as additives. A variety of spiroindanes were obtained with high enantioselectivity under these conditions. The reaction was applied in the first total synthesis of the unusual proaporphine alkaloid (-)-misramine, which included the key steps of enantioselective spirocyclization and double reductive amination of the keto-aldehyde to form a piperidine ring toward the end of the synthesis. The total synthesis of misrametine was achieved by selective demethylation of the methoxy group from the precursor to misramine. Next, a method for highly enantioselective organocatalytic construction of spirochromans containing a tetrasubstituted stereocenter was developed. An intramolecular oxy-Michael addition was catalyzed by a bifunctional cinchona alkaloid thiourea catalyst. A variety of spirochroman compounds containing a tetrasubstituted stereocenter were obtained with excellent enantioselectivity of up to 99% enantiomeric excess. The reaction was applied to the asymmetric formal synthesis of (-)-(R)-cordiachromene.

Controllable 1,3-Bis-Functionalization of 2-Nitroglycals with High Regioselectivity and Stereoselectivity Enabled by a H-Bond Catalyst.

The selective modification of carbohydrates is significant for producing their unnatural analogues for drug discovery. C1-functionalization (glycosylation) and C1,C2-difunctionalization of carbohydrates have been well developed. In contrast, C3-functionalization or C1,C3-difunctionalization of carbohydrates remains rare. Herein, we report such processes that efficiently and stereoselectively modify carbohydrates. Specifically, we found that trifluoroethanol (TFE) could promote 1,3-bis-indolylation/pyrrolylation of 2-nitroglycals generated carbohydrate derivatives in up to 93% yield at room temperature; slightly reducing the temperature could install two different indoles at the C1- and C3-positions. Switching TFE to a bifunctional amino thiourea catalyst leads to the generation of C3 monosubstituted carbohydrates, which could also be used to construct 1,3-di-C-functionalized carbohydrates. This approach produced a range of challenging sugar derivatives (over 80 examples) with controllable and high stereoselectivity (single isomer for over 90% of the examples). The potential applications of the reaction were demonstrated by a set of transformations including the synthesis of bridged large-ring molecules and gram scale reactions. Biological activities evaluation demonstrated that three compounds exhibit a potent inhibitory effect on human cancer cells T24, HCT116, AGS, and MKN-45 with IC50 ranged from 0.695 to 3.548 μM.

Catalyst control over pentavalent stereocentres

A monumental diversity of catalytic methods imparts the ability to select one of two configurations of tetravalent stereocentres. Conversely, catalyst control over pentavalent stereocentres, where a fifth moiety bound to the central atom encodes an expanded stereochemical space, remained a challenge to be accomplished. Herein, we report the feasibility of the catalytic tractability of pentavalent stereocentres. A bifunctional iminophosphorane thiourea catalyst enables enantio- and diastereocontrol over pentavalent phosphoranes to differentiate configurationally stable enantiomers and ensembles of diastereomers which emerge together from a single stereocentre. The desired dioxophosphorane stereoisomers are obtained with excellent yield and selectivity (up to 99% yield, 96:4 e.r. and 99:1 d.r.), while stereodivergent catalysis reroutes the reaction for selective access to each of the viable stereoisomeric states of pentavalent phosphoranes. Considering the diversity of high-valent main group species, it is expected that catalyst control over pentavalent stereocentres significantly increases the synthetically addressable stereochemical space.

Organocatalytic Asymmetric Inverse-Electron-Demand Diels-Alder Reaction between Alkylidene Pyrazolones and Allyl Ketones: Access to Tetrahydropyrano[2,3-c]pyrazoles.

Herein we report a catalytic asymmetric inverse-electron-demand Diels-Alder reaction between alkylidene pyrazolones and allyl ketones. Allyl ketone gets activated by a bifunctional thiourea catalyst and acts as a dienolate in this reaction. The trisubstituted tetrahydropyrano[2,3-c]pyrazoles were obtained in moderate to good yields with high diastereo- and enantioselectivities. Few applications, including a decarbonylation reaction, have been demonstrated.

Enantioselective Synthesis of Fused Butyrolactones via Organocatalytic Formal [2 + 2 + 2] Annulation of γ-Butenolides, Methylene Indolinones, and Nitroolefins.

An organocatalyzed asymmetric synthesis of fused butyrolactones via formal [2 + 2 + 2] annulation between γ-butenolides, methylene indolinones, and nitroolefins in a one-pot process has been established. Products containing six contiguous stereocenters could be obtained in good yields (up to 95%) with excellent enantioselectivities (up to >99% ee) catalyzed by a l-tert-leucine-derived bifunctional thiourea catalyst.

Organocatalytic Aza-Michael/Mannich Cascade Reaction: Synthesis of Enantioenriched 3,3'-Spirooxindole γ-Lactams.

Highly enantioselective synthesis of 3,3'-spirooxindole γ-lactams with three contiguous stereocenters (two quaternary) was achieved. The aza-Michael/Mannich cascade reaction of α-imine-β-oxobutanamides and methyleneindolinones catalyzed by a bifunctional diaminocyclohexane-derived thiourea catalyst gave the desired products in moderate to good yields (up to 78%), moderate to good diastereoselectivities (up to 10:1 dr), and good to excellent enantioselectivities (up to >99% ee). A gram-scale synthesis and some transformations of 3,3'-spirooxindole γ-lactams were also carried out.

Insights into Thiourea-Based Bifunctional Catalysts for Efficient Conversion of CO2 to Cyclic Carbonates.

The bifunctional thiourea catalyst system with both electrophilic and nucleophilic centers has been certified to be effective for fixing CO2 under mild reaction conditions; however, many questions remain, especially concerning the relationship between structure and performance. Herein, we systematically studied a series of such bifunctional catalysts with different chain lengths, nucleophilic anions, and substituents, which impact obvious influence on the catalytic performance. The activation energies of catalysts with different chain lengths are calculated via in situ IR. On this basis, we disclosed for the first time that the spacer length of tetramethylene -(CH2)6- is the optimal spatial effect for the coupling of epoxides and CO2. Particularly, the single crystal X-ray diffraction analysis of the molecular structures of the bifunctional catalyst C8 indicated the discovery of the existence of interaction force between the sulfur atom on the thiourea group and one hydrogen atom on the benzene ring, as well as the intermolecular hydrogen bonding interaction of the bromide (Br-) and two NH groups on the thiourea group. The catalyst structure performance, direct observation of the crystal structure, the thermodynamic study, and a wide range of substrates (12 examples) should be informative on the optimization of the existing catalysts or the design of new catalysts in the future.

Stereoselective glycosylation with conformation-constrained 2-Nitroglycals as donors and bifunctional thiourea as catalyst

Herein, we report a novel method for highly efficient and stereoselective construction 1,2-cis-2-amino-2-deoxy-glycosidic linkages using conformation-constrained 2-nitroglycal donors and bifunctional thiourea catalyst. The method enjoys mild reaction conditions, good to excellent stereoselectivity, broad substrate scope, and good to excellent efficiency.

Catalytic Asymmetric Dearomative 1,3-Dipolar Cycloaddition of 2-Nitrobenzothiophenes and Isatin-Derived Azomethine Ylides.

An enantioselective dearomative 1,3-dipolar cycloaddition of 2-nitrobenzothiophenes and isatin-derived azomethine ylides with a bifunctional hydrogen-bonding thiourea catalyst was established, giving polyheterocyclic compounds in excellent results (up to 99% yield, >20:1 dr for all cases and up to 99% ee). The enantioselectivity could be reversed by the bifunctional hydrogen-bonding squaramide catalyst containing the same chiral source as in the thiourea catalyst. DFT calculations revealed the origin of the observed stereochemistry and the reversal of enantioselectivity.

Organocatalytic Enantioselective Michael‐Aldol[3+2] Annulation for the Synthesis of Nitro‐Methanobenzo[7] annulenes

AbstractWe report an enantioselective Michael‐Aldol[3+2] annulation between 2‐alkyl‐3‐hydroxynaphthalene‐1,4‐diones and nitroalkenes using a bifunctional thiourea catalyst, and a series of nitro‐methanobenzo[7]annulenes with potential biological activities were synthesized in good yields with excellent enantio‐ and diastereoselectivities. A gram‐scale synthesis and further transformation of the product demonstrated the synthetic value of this reaction.

Organocatalytic asymmetric Michael/acyl transfer reaction between α-nitroketones and 4-arylidenepyrrolidine-2,3-diones.

An organocatalytic asymmetric Michael/acyl transfer reaction between α-nitroketones and 4-arylidenepyrrolidine-2,3-diones is reported. A bifunctional thiourea catalyst was found to be effective for this reaction. With 10 mol % of the catalyst, good results were attained for a variety of 1,5-dihydro-2H-pyrrol-2-ones under mild reaction conditions.

Developing a highly potent anthelmintic: study of catalytic application of l-proline derived aminothiourea in rapid synthesis of biscoumarins and their in vitro anthelmintic essay

Due to serious side effects of benzimidazoles such as apoptosis and mitotic arrest, development of alternative anthelmintic drugs with comparable efficacy to target the acetylcholine receptors of parasites is considered very important to control this parasitic disease. Here we have developed an excellent method for synthesis of biscoumarins by employing a mild and efficient proline derived bifunctional thiourea catalyst bearing pyrrolidine and thiourea catalytic sites and tested their anthelmintic activity against helminth parasites Raillietina echinobothrida and Syphacia obvelata. The compounds 2a, 2j, 2k and 2o demonstrated much stronger anthelmintic activity against Raillietina echinobothrida in comparison to the standard drug, Praziquantel. Molecular docking simulations of the optimized compounds with β-tubulin showed excellent binding interactions with several amino acid residues of the active site and the docking scores with β-tubulin were found to be comparable to the in vitro anthelmintic activity. A series of biscoumarins were synthesized and they showed excellent anthelmintic properties in comparison to conventional benzimidazoles.

Enantioselective vinylogous aldol reaction of acylphosphonates with 3-alkylidene oxindoles.

A simple strategy for yielding chiral tertiary α-hydroxy phosphonates that integrates two highly biologically relevant scaffolds namely 3-alkylidene-2-oxindoles and phosphonates has been described. The hydrogen bonding ability of the bifunctional thiourea catalyst allows simultaneous dual activation of a vinylogous oxindole nucleophile and an acylphosphonate electrophile, affording hydroxyphosphonato-3-alkylidene-2-oxindoles as aldol adducts in high yields (up to 92%) with excellent stereocontrol (up to 99% ee).

Remote asymmetric conjugate addition catalyzed by a bifunctional spiro-pyrrolidine-derived thiourea catalyst

A novel spiro-pyrrolidine (SPD)-derived bifunctional thiourea catalyst has been developed and used in a stereoselective conjugate addition of furfurals to β,γ-unsaturated α-ketoesters.

Enantioselective Organocatalytic Construction of Spirochroman Derivatives.

Highly enantioselective organocatalytic construction of spirochromans containing a tetrasubstituted stereocenter was developed. Intramolecular oxy-Michael addition was catalyzed with a bifunctional cinchona alkaloid thiourea catalyst. A variety of spirochroman compounds containing a tetrasubstituted stereocenter were obtained with excellent enantioselectivities of up to 99% enantiomeric excess. The reaction was applied to the asymmetric formal synthesis of (-)-(R)-cordiachromene.

Enantioselective Desymmetrization of Prochiral Cyclopentene-1,3-diones Triggered by Remote C(sp2)-N Bond Formation.

The enantioselective desymmetrization via remote C(sp2)-H amidation of the prochiral 2,2-disubstituted cyclopentene-1,3-dione with N-methoxybenzamide has been developed. The overall process was catalyzed by a chiral bifunctional thiourea catalyst through a sequential conjugate-addition-elimination-tautomerization. This strategy provides rapid access to highly functionalized five-membered carbocycles, bearing an all-carbon quaternary stereogenic center through remote stereocontrol in high yields with moderate to excellent enantioselectivities.

Organocatalytic Asymmetric Mannich Addition of 3-Fluorooxindoles to Dibenzo[b,f][1,4]oxazepines: Highly Enantioselective Construction of Tetrasubstituted C-F Stereocenters.

3-Fluorooxindoles and the dibenzo[b,f][1,4]oxazepane scaffolds are important pharmacophores that have important application in medicinal chemistry. An organocatalyzed asymmetric Mannich reaction of 3-fluorooxindoles with dibenzo[b,f][1,4]oxazepines affording various seven-member cyclic amines containing chiral tetrasubstituted C-F stereocenters was developed. These reactions which were catalyzed by a bifunctional Cinchona alkaloid-derived thiourea catalyst afforded a wide range of substrates in moderate to high yields with excellent diastereo- and enantioselectivities (up to 88% yield, >20:1 dr and >99% ee). A feasible reaction mechanism was also proposed.

Bifunctional Thiourea-Catalyzed Asymmetric Inverse-Electron-Demand Diels-Alder Reaction of Allyl Ketones and Vinyl 1,2-Diketones via Dienolate Intermediate.

Inverse-electron-demand Diels-Alder reactions have attracted intense research focus. However, enolate and enamine are the most employed intermediates to realize such transformation, and the use of dienolate intermediate remains elusive. Reported herein is the asymmetric inverse-electron-demand oxa-Diels-Alder reaction between allyl ketones and alkenyl 1,2-diketones using a bifunctional thiourea catalyst. The reaction afforded various highly functionalized dihydropyrans with good to excellent enantioselectivities under mild conditions, and further novel transformations on the products have also been realized.

Organocatalytic Enantioselective Mannich Reaction: Direct Access to Chiral β-Amino Esters.

An asymmetric Mannich reaction has been developed to generate chiral β-amino esters in good yields with excellent enantiomeric excesses (ee, up to 99%) using a chiral bifunctional thiourea catalyst derived from (R,R)-cyclohexyldiamine. This is the first report on the addition of 3-indolinone-2-carboxylates to N-Boc-benzaldimines generated in situ from α-amidosulfones, which proceeds under mild conditions.