Enantioselective synthesis of spirooxindole-pyran derivatives via a remote inverse-electron-demand Diels-Alder reaction of ß,γ-unsaturated amides.

Novel construction methods for obtaining 3,4'-pyran spirooxindole heterocyclic skeletons have always been the focus of attention. Herein, we report a highly enantioselective inverse-electron-demand oxa-Diels-Alder cycloaddition reaction of a ß,γ-unsaturated pyrazole amide and a N-diphenyl isatin-derived oxodiene using a bifunctional catalyst. In addition, large-scale experiments confirmed the reliability of the reaction. The resultant products of this study can be further transformed.

Enantioselective Palladium(II)-Catalyzed Desymmetrizative Coupling of 7-Azabenzonorbornadienes with Alkynylanilines.

A PdII -catalyzed, domino enantioselective desymmetrizative coupling of 7-azabenzonorbornadienes with alkynylanilines is disclosed herein. This operationally simple transformation generates three covalent bonds and two contiguous stereocenters with excellent enantio- and diastereo-selectivity. The resulting functionalized indole-dihydronaphthalene-amine conjugates served as an appealing platform to streamline the diversity-oriented synthesis (DOS) of other valuable enantioenriched compounds. DFT calculations revealed that the two stabilizing non-covalent interactions contributed to the observed enantioselectivity.

Brusatol has therapeutic efficacy in non-small cell lung cancer by targeting Skp1 to inhibit cancer growth and metastasis.

Skp1-Cul1-F-box protein (SCF) ubiquitin E3 ligases play important roles in cancer development and serve as a promising therapeutic target in cancer therapy. Brusatol (Bru), a known Nrf2 inhibitor, holds promise for treating a wide range of tumors; however, the direct targets of Bru and its anticancer mode of action remain unclear. In our study, 793 Bru-binding candidate proteins were identified by using a biotin-brusatol conjugate (Bio-Bru) followed by streptavidin-affinity pull down-based mass spectrometry. We found that Bru can directly bind to Skp1 and disrupt the interactions of Skp1 with the F-box protein Skp2, leading to the inhibition of the Skp2-SCF E3 ligase. Bru inhibited both proliferation and migration via promoting the accumulation of the substrates p27 and E-cadherin; Skp1 overexpression attenuated while Skp1 knockdown enhanced these effects of Bru in non-small cell lung cancer (NSCLC) cells. Moreover, Bru binding to Skp1 also inhibited the ß-TRCP-SCF E3 ligase. In both subcutaneous and orthotopic NSCLC xenografts, Bru significantly inhibited the growth and metastasis of NSCLC through targeting SCF complex and upregulating p27 and E-cadherin protein levels. These data demonstrate that Bru is a Skp1-targeting agent that may have therapeutic potentials in lung cancer.

Organocatalytic ß,γ-Selective Activation of Deconjugated Butenolides Access to Chiral Tricyclic Chroman-butyrolactones.

A highly efficient method for the ß,γ-selective activation of deconjugated butenolides has been developed through an organocatalytic asymmetric vinylogous cascade reaction. This protocol enables the construction of a broad range of substituted tricyclic chroman-butyrolactones by vinylogous Michael/oxa-Michael pathways in good yield (up to 89%) with good to high enantioselectivity (up to 97:3 er) and excellent diastereoselectivity. The ring-opening esterification of butyrolactones was also demonstrated.

Asymmetric Michael reaction of 3-homoacyl coumarins with chromone-fused dienes toward enantioenriched coumarin chromone skeletons.

Asymmetric Michael reaction of 3-homoacyl coumarins and chromone-fused dienes was developed by employing a chiral squaramide, and a series of coumarin chromone skeletons were furnished in moderate to high yields (up to 99%) and stereoselectivities (up to 98 : 2 dr, 99% ee).

Organocatalytic 1,4-Addition of Azadienes with 3-Homoacyl Coumarins toward Highly Enantioenriched Benzofuran Coumarin Skeletons.

A highly enantioselective 1,4-addition reaction of azadiene with 3-homoacyl coumarin has been accomplished by low amounts of bifunctional cinchona alkaloid catalysis under mild conditions. Varieties of benzofuran coumarin skeletons were obtained in moderate to high yields (up to 99%) with excellent enantioselectivities (up to 99% ee) and complete diastereoselectivity.

Enantioselective Synthesis of Benzofuran-Fused N-Heterocycles via Chiral Squaramide Catalyzed [4 + 2] Cyclization of Azadienes with Azlactones.

An asymmetric cyclization reaction of azadienes and azlactones was investigated by employing a Cinchona squaramide catalyst, which could afford a series of benzofuran-fused six-membered heterocycles containing a α,α-disubstituted amino acid unit in a highly diastereoselective (>20:1 dr) and enantioselective (up to 99% ee) manner with good to excellent yields (up to 92%). A plausible pathway was proposed to explain the reaction process.

Enantioselective synthesis of pyrano[2,3-c]pyrrole via an organocatalytic [4 + 2] cyclization reaction of dioxopyrrolidines and azlactones.

An enantioselective [4 + 2] cyclization reaction of dioxopyrrolidines and azlactones has been successfully developed through a squaramide catalysis strategy. This protocol provides an efficient and mild access to obtain pyrano[2,3-c]pyrrole scaffolds containing contiguous quaternary and tertiary stereogenic centers in excellent yields (up to 99%) with high levels of diastereo- and enantioselectivities (up to 99% ee). Two possible pathways were proposed to explain the observed stereoselectivity.

Synthesis, Biological Evaluation and Low-Toxic Formulation Development of Glycosylated Paclitaxel Prodrugs.

Paclitaxel (PTX) is a famous anti-cancer drug with poor aqueous solubility. In clinical practices, Cremophor EL (polyethoxylated castor oil), a toxic surfactant, is used for dissolution of PTX, which accounts for serious side effects. In the present study, a single glucose-conjugated PTX prodrug (SG-PTX) and a double glucose-conjugated PTX prodrug (DG-PTX) were synthesized with a glycosylated strategy via succinate linkers. Both of the two prodrugs presented significant solubility improvement and drug-like lipophilicities. Compared to DG-PTX, SG-PTX manifested more promising release of the parent drug in serum. A high percentage of PTX released from SG-PTX could be detected after enzymatic hydrolysis of ß-glucuronidase. Besides, both of the two prodrugs exhibited effective cytotoxicity against breast cancer cells and ovarian cancer cells, but presented reduced cytotoxicity against normal breast cells. Moreover, SG-PTX manifested impressive solubility in a low toxic formulation (without ethanol) with a different percentage of Cremophor EL. These results indicated that glycosylation is a promising strategy for PTX modification and SG-PTX may be a feasible and potential type of PTX prodrug. In addition, ethanol-free formulation with a low percentage of Cremophor EL might have the potential to develop a safer formulation for further studies of glycosylated PTX prodrugs.

Stereoselective synthesis of spirooxindole derivatives using an organocatalyzed tandem Michael-Michael reaction.

A highly efficient stereoselective method for the synthesis of functionalized spirooxindole derivatives with three stereogenic centers was realized through an organocatalytic tandem Michael-Michael reaction. By employing (S)-α,α-diphenylprolinol trimethylsilyl ether as the catalyst and N,N'-bis[3,5-bis(trifluoromethyl)phenyl]thiourea as the cocatalyst, the reaction between N-tritylisatylidenemalononitriles and (E)-7-alkyl-7-oxohept-5-enals yields the desired spirooxindole products in good yields (76-95%) and with excellent diastereoselectivities (up to 97 : 3 dr) and enantioselectivities (up to 98% ee), which can be stereoselectively converted into the spiro[indoline-3,8'-isoquinoline] derivative through an intramolecular reductive amination reaction.

Diastereodivergent Catalysis Using Modularly Designed Organocatalysts: Synthesis of both cis- and trans-Fused Pyrano[2,3-b]pyrans.

Both enantiomers of cis- and trans-fused 3,4,4a,8a-tetrahydro-2H,5H-pyrano[2,3-b]pyran-7-carboxylates have been obtained in high diastereoselectivities and enantioselectivities from the same starting materials using a tandem inverse-electron-demand hetero-Diels-Alder/oxa-Michael reaction catalyzed by modularly designed organocatalysts (MDOs). Diastereodivergence was achieved in these reactions through the direct control of the stereochemistry of the bridgehead atoms of the fused ring using new MDOs self-assembled from both enantiomers of proline and cinchona alkaloid thiourea derivatives.

Organocatalyzed asymmetric aldol reactions of ketones and ß,γ-unsaturated α-ketoesters and phenylglyoxal hydrates.

Enantioselective aldol reactions of acetophenone with ß,γ-unsaturated α-ketoesters and cyclic ketones with phenylglyoxal hydrates were realized with cinchona alkaloid-derived thiourea catalysts. The corresponding aldol products were obtained in high yields and good to excellent diastereoselectivities and enantioselectivities (up to 95% ee).

Highly diastereodivergent synthesis of tetrasubstituted cyclohexanes catalyzed by modularly designed organocatalysts.

A highly diastereodivergent synthesis of tetrasubstituted cyclohexanes has been achieved using modularly designed organocatalysts (MDOs) which are self-assembled in situ from amino acids and cinchona alkaloid derivatives. Diastereodivergence is realized through controlling the stereoselectivity of the individual steps of a tandem Michael/Michael reaction. Up to 8 of the 16 possible stereoisomers have been successfully obtained in high stereoselectivities using MDOs for the tandem reaction and an ensuing epimerization. The method was used in the enantioselective synthesis of the natural products (-)-α- and ß-lycoranes.

Palladium/Amine Dual-Catalyzed Tsuji-Trost Fluoroallylation of Aldehydes with gem-Difluorinated Cyclopropanes.

We herein disclose the Pd/amine dual-catalyzed ring-opening cross-coupling reaction between gem-difluorinated cyclopropanes (gem-F2CPs) with aldehydes, which enables the diversity-oriented synthesis (DOS) of 2-fluoroallylic aldehydes bearing all-carbon quaternary centers with features of broad scope and excellent functional group tolerance. The synthetic value of this Tsuji-Trost system was further demonstrated by late-stage functionalization of natural product-derived gem-F2CPs and the diverse synthesis of various fluoroallylic aldehyde derivatives, including alcohol, alkyne, alkene, and amine.

Visible-Light-Promoted [4π + 2σ] Annulation of Dienes and Alkylamines via Dual Inert C(sp3)-H Bond Activation.

Herein, visible-light-promoted [4π + 2σ] annulation of dienes and alkylamines was achieved via dual C(sp3)-H bond functionalization of alkylamines. The elusive enamine precursors are generated under mild conditions by photoredox catalysis, efficiently annulated by the diene, and simultaneously functionalized with two aliphatic C(sp3)-H bonds, resulting in the productive synthesis of new aromatic rings. The aromatic ring construction provides direct access to 2-hydroxybenzophenone derivatives in high yields (up to 90%). This [4π + 2σ] annulation reaction demonstrates mild reaction conditions, high reaction efficiency, and broad functional group tolerance, and this synthetic protocol has been made available for the late-stage transformation of natural products and commercial drugs.

Highly diastereo- and enantioselective cross-cascade reactions of different enones.

Cascading ketones! The first highly efficient asymmetric cross-cascade reaction of different α,ß-unsaturated ketones catalyzed by an easily prepared bulky primary amine salt has been developed. It affords the corresponding diverse products containing three to four contiguous stereocenters with excellent enantio- and diastereoselectivities (see scheme).

Highly stereoselective synthesis of trisubstituted cyclohexanols using a guanidine-catalyzed tandem Henry-Michael reaction.

A highly diastereoselective (dr >99:1) and enantioselective (ee value up to 98%) synthesis of trisubstituted cyclohexanols was achieved by using a tandem Henry--Michael reaction between nitromethane and 7-oxo-hept-5-enals catalyzed by the Misaki-Sugimura guanidine.

Skeletal Editing of Chromone-Fused Dienes to Cyclopropane by Photochemical Carbon Deletion.

A visible-light-driven, photocatalyst-free, air-assisted carbon cleavage of dienes was achieved. Photochemical editing of dienes via an electron donor-acceptor (EDA) complex facilitates direct access to cyclopropane derivatives. This innovative methodology creates an opportunity for the efficient access to valuable cyclopropane derivatives under mild and ambient conditions.

Nickel-Catalyzed, Enantioselective Hydrofluoromethylation of Olefins: Access to Chiral α-Fluoromethylated Amides and Esters.

We herein report the nickel-catalyzed enantioselective hydrofluoromethylation of enamides and enol esters with CH2FI as the fluoromethyl source to enable the diversity-oriented synthesis (DOS) of chiral α-fluoromethylated amides as well as esters with features of wide functional group compatibility as well as excellent enantioselectivity. The synthetic value of this protocol was demonstrated by transformations of the resulted α-fluoromethylated amides to different scaffolds including amine, oxazoline, thiazoline, and α-fluoromethylated tetrahydroquinoline.

Catalytic asymmetric Michael addition with curcumin derivative.

Catalytic asymmetric Michael additions with curcumin derivatives were achieved by a new series of tertiary amine-thiourea organocatalysts to afford the Michael adducts in high yields and excellent enantioselectivities.