Synthesis, anti-leukemia activity, and molecular docking of novel 3,16-androstenedione derivatives.

In this study, we synthesized androsta-4,14-diene-3,16-dione, 12ß-hydroxyandrosta-4,14-diene-3,16-dione, and other 3,16-androstenedione derivatives from commercially available dehydroepiandrosterone as a starting material in 9-13 steps with high yields. The bioactivity of the obtained compounds was evaluated. Compounds 14a and 23a were shown to have high antitumor activity against acute lymphoblastic leukemia cell lines Nalm-6 and BALL-1, respectively. Network pharmacology analysis showed that the anti-leukemia activity of compounds 14a and 23a might be related to the JAK2, ABL1 protein, and PI3K/Akt signaling pathways. The molecular docking of compounds 14a and 23a identified possible active sites, with the lowest docking scores for PTGS2 and MAPK14, respectively. In addition, the absorption, distribution, metabolism, and excretion prediction results revealed the drug-likeness of the two compounds. Therefore, compounds 14a and 23a should be considered anti-leukemia candidates in future studies.

Synthesis of Chiral 1,1,1-Trifluoro-α,α-disubstituted 2,4-Diketones via Palladium-Catalyzed Asymmetric Allylation.

Trifluoromethyl ketones are important enzyme inhibitors and versatile synthons for the preparation of trifluoromethylated heterocycles and complex molecules. An efficient methodology for the synthesis of chiral 1,1,1-trifluoro-α,α-disubstituted 2,4-diketones via palladium-catalyzed allylation with allyl methyl carbonates under mild conditions has been developed. This method surmounts the major obstacle of detrifluoroacetylation, and a chiral trifluoromethyl ketone library could be rapidly built up from simple substrates in good yields and enantioselectivities, thereby offering a new choice for scientists in pharmaceutical and material industries.

Highly Enantioselective Synthesis of [1,2,4]Triazino[5,4-a]isoquinoline Derivatives via (3 + 3) Cycloaddition Reactions of Diazo Compounds and Isoquinolinium Methylides.

An array of chiral [1,2,4]triazino[5,4-a]isoquinoline derivatives were obtained in excellent yields (up to 98%) and with excellent enantioselectivities (up to 99% ee) via a new highly asymmetric (3 + 3) cycloaddition reaction of diazo compounds and isoquinolinium methylides, with a bifunctional chiral phase-transfer catalyst (PTC). Density functional theory calculations show that PTC has a bridge role in the deprotonation/protonation process. The obtained products were transformed into densely functionalized polycyclic heterocompounds with multiple stereocenters.

Asymmetric Addition of α-Diazomethylphosphonate to Alkylideneindolenine Catalyzed by a Trifunctional BINAP-Based Monophosphonium Salt.

A series of trifunctional BINAP-based monophosphonium phase-transfer catalysts were developed and used in the asymmetric addition of α-diazomethylphosphonates to vinylogous imines formed in situ from sulfonylindoles. This methodology tolerates a broad scope of 2-unsubstituted sulfonyl indoles, which have seldom achieved high enantioselectivities in similar asymmetric reactions with other nucleophiles. Chiral 3-sec-alkyl-substituted indoles containing α-diazophosphonate were afforded in up to 99% yield and 95% ee.

Catalytic Asymmetric (3 + 3) Cycloaddition of Oxyallyl Zwitterions with α-Diazomethylphosphonates.

The unique structure of oxyallyls represents a significant challenge for their catalytic asymmetric applications. Herein, an unprecedented chiral imidodiphosphoric acid-catalytic enantioselective (3 + 3) cycloaddition between oxyallyl zwitterions generated in situ from α-haloketones and α-diazomethylphosphonates was developed. Pharmaceutically interesting chiral pyridazine-4(1H)-ones were obtained in up to 98% yields with excellent stereoselectivities (up to 99% ee, > 99:1 dr).

Catalytic Asymmetric Tandem Reaction of o-Alkynylbenzaldehydes, Amines, and Diazo Compounds.

An efficient asymmetric tandem reaction of o-alkynylbenzaldehydes, amines, and diazo compounds catalyzed by chiral silver imidodiphosphate has been established. Chiral 1,2-dihydroisoquinoline analogues have a tertiary stereocenter at the C1 position, and substituents at the C3 position are available with up to 97% yields and 98% ee. These products can be elaborated into the corresponding ß-aminophosphonates or PARP1-inhibitor analogues.

Asymmetric acyl-Mannich reaction of isoquinolines with α-(diazomethyl)phosphonate and diazoacetate catalyzed by chiral Brønsted acids.

An efficient asymmetric acyl-Mannich reaction of isoquinolines with α-(diazomethyl)phosphonate and diazoacetate has been developed using chiral spiro phosphoric acids as catalysts. This reaction allowed the construction of a series of chiral 1,2-dihydroisoquinolines bearing a tertiary stereocenter at the C1 position with up to 98% yield and 99% ee.

Catalytic Asymmetric Three-Component Reaction of 2-Alkynylbenzaldehydes, Amines, and Dimethylphosphonate.

An efficient enantioselective synthesis of cyclic α-aminophosphonates via multicomponent reactions of 2-alkynylbenzaldehydes, amines, and dimethylphosphonate has been developed with the use of a chiral silver spirocyclic phosphate as the catalyst. This protocol provides straightforward access to a series of chiral C1-phosphonylated 1,2-dihydroisoquinoline derivatives with high yields (up to 99%) and high enantioselectivities (up to 94% ee) for a broad substrate scope. The products could be further transformed into densely functionalized compounds and corresponding α-aminophosphonic acids.

Cyano-borrowing: titanium-catalyzed direct amination of cyanohydrins with amines and enantioselective examples.

The direct amination of cyanohydrins with amines via a catalytic cyano-borrowing reaction was developed. The transformation features broad substrate scope, excellent functional group compatibility, and very mild and simple operations. Moreover, a titanium catalyst supported by quinine and (S)-BINOL ligands enabled an asymmetric cyano-borrowing reaction with moderate to high enantioselectivity.

Titanium-Catalyzed Cyano-Borrowing Reaction for the Direct Amination of Cyanohydrins with Ammonia.

α-Aminonitrile was an important building block in natural products and key intermedia in organic chemistry. Herein, the direct amination of cyanohydrins with the partner of ammonia to synthesis N-unprotected α-aminonitriles is developed. The reaction proceeds via titanium-catalyzed cyano-borrowing reaction, which features high atom economy and simple operation. A broad range of ketone or aldehyde cyanohydrins was tolerated with ammonia, and the N-unprotected α-aminonitriles were synthesis with moderate to high yields under mild reaction conditions.

Asymmetric Cyclization/Nucleophilic Tandem Reaction of o-Alkynylacetophenone with (Diazomethyl)phosphonate for the Synthesis of Functional Isochromenes.

An efficient asymmetric reaction between (diazomethyl)phosphonate with o-alkynylacetophenone has been established by employing different stereocontrol strategy. A variety of isochromenes bearing tetrasubstituted stereocenters and (diazomethyl)phosphonate at the 1-position were prepared in yield up to 99% with enantioselectivity up to 94% enantiomeric excess (ee) for the first time. These functional isochromenes could be transformed to important structural motifs in biologically active compounds. Moreover, density functional theory calculations were conducted to gain insight into the process and the stereoselectivity.

Cyano-borrowing reaction: nickel-catalyzed direct conversion of cyanohydrins and aldehydes/ketones to ß-cyano ketone.

A direct nickel-catalyzed, high atom- and step-economical reaction of cyanohydrins with aldehydes or ketones via an unprecedented "cyano-borrowing reaction" has been developed. Cleavage of the C-CN bond of cyanohydrins followed by aldol condensation and conjugate addition of cyanide to α,ß-unsaturated ketones proceeded to deliver a range of racemic ß-cyano ketones with good to high yields. The practical procedure with the use of a commercial and less-toxic CN source bodes well for wide application of this protocol.

Formal Asymmetric Cycloaddition of Activated α,ß-Unsaturated Ketones with α-Diazomethylphosphonate Mediated by a Chiral Silver SPINOL Phosphate Catalyst.

An efficient method for preparing highly functionalized chiral nonspiro-phosphonylpyrazolines via an asymmetric formal 1,3-dipolar cycloaddition reaction of α-diazomethylphosphonate with activated, acyclic α,ß-unsaturated ketones, bearing an additional nitrile electron-withdrawing group, has been developed, utilizing an in situ generated chiral silver phosphate catalyst, affording excellent stereoselectivities (up to 98% ee, 99:1 dr) and yields (up to 95%). A stepwise mechanism is proposed based upon density functional M11 calculations.

Switchable Synthesis of 3-Substituted 1H-Indazoles and 3,3-Disubstituted 3H-Indazole-3-phosphonates Tuned by Phosphoryl Groups.

3-Alkyl/aryl-1H-indazoles and 3-alkyl/aryl-3H-indazole-3-phosphonates were synthesized efficiently through a 1,3-dipolar cycloaddition reaction between α-substituted α-diazomethylphosphonates and arynes under simple reaction conditions. The product distribution was controlled by the phosphoryl group, which acted both as a tuning group and a traceless group in the reaction.

Enantioselective 1,3-Dipolar Cycloaddition of Methyleneindolinones with α-Diazomethylphosphonate to Access Chiral Spiro-phosphonylpyrazoline-oxindoles Catalyzed by Tertiary Amine Thiourea and 1,5-Diazabicyclo[4.3.0]non-5-ene.

A methodology to access chiral 3,3'-spiro-phosphonylpyrazoline oxindoles via an asymmetric 1,3-dipolar cycloaddition reaction of substituted methyleneindolinones with α-diazomethylphosphonate in the catalysis of tertiary amine thiourea and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) has been established. This method exhibits high functional group compatibility, where a wide range of methyleneindolinones with various substituents and heterocyclic rings are accommodated by this reaction. The resulting chiral 3,3'-spiro-phosphonylpyrazoline oxindoles can be further transformed into spiro-phosphonylcyclopropane oxindoles by ring contraction.

Silver-Catalyzed Oxidative C(sp3 )-P Bond Formation through C-C and P-H Bond Cleavage.

The silver-catalyzed oxidative C(sp3 )-H/P-H cross-coupling of 1,3-dicarbonyl compounds with H-phosphonates, followed by a chemo- and regioselective C(sp3 )-C(CO) bond-cleavage step, provided heavily functionalized ß-ketophosphonates. This novel method based on a readily available reaction system exhibits wide scope, high functional-group tolerance, and exclusive selectivity.

Asymmetric Reaction of α-Diazomethylphosphonates with α-Ketoesters To Access Optically Active α-Diazo-ß-hydroxyphosphonate Derivatives.

The first example for asymmetric reaction of diazomethylphosphonates with α-ketoesters was realized in the catalysis of hydroquinidine-derived bifunctional thiourea. A methodology was established to access a series of chiral α-diazo-ß-hydroxyphosphonate derivatives containing various functional groups with high enantioselectivities and yields. The resulting products could be further transformed into chiral tertiary ß-hydroxyphosphonate and α-halogenated fosfomycin derivatives, especially α-fluoride analogues.

Asymmetric Mannich Reaction of Isatin-Based Ketimines with α-Diazomethylphosphonates Catalyzed by Chiral Silver Phosphate.

An efficient asymmetric Mannich reaction of isatin-based ketimines with α-diazomethylphosphonates has been developed using a chiral binaphthanol-derived silver phosphate as the catalyst. This reaction allowed the construction of a series of chiral oxindoles bearing a quaternary stereocenter and amino group at the C3 position with up to 95% yields and 99% ee. Those products could be further transformed into promising densely functionalized compounds by merging of the oxindole and ß-aminophosphonate.

Asymmetric Multicomponent Sulfa-Michael/Mannich Cascade Reaction: Synthetic Access to 1,2-Diamino-3-Organosulfur Compounds and 2-Nitro Allylic Amines.

A novel catalytic asymmetric three-component intermolecular sulfa-Michael/Mannich cascade reaction has been developed using a chiral multifunctional catalyst. This reaction provides facile access to 1-amino-2-nitro-3-organosulfur compounds bearing three consecutive stereocenters in high yields (up to 96%) with good diastereo- (up to 91:4:4:1 dr) and excellent enantioselectivities (93-99% ee). Furthermore, the products of this reaction could be facilely transformed into potentially bioactive 1, 2-diamino-3-organosulfur compounds and 2-nitro allylic amines.

A Cation-Directed Enantioselective Sulfur-Mediated Michael/Mannich Three-Component Domino Reaction involving Chalcones as Michael Acceptors.

A new approach has been developed for an asymmetric sulfur-mediated three-component intermolecular Michael/Mannich domino reaction using chalcones as Michael acceptors. This reaction is catalyzed by chiral quaternary ammonium salts derived from modified quinine and provides facile access to complex sulfur-containing compounds with three contiguous stereogenic centers in yields of up to 93%, with 95:5 dr and 95% ee. These compounds were further elaborated to give the equivalent of a chiral aza-Morita-Baylis-Hillman reaction involving chalcones and azetidines bearing four chiral centers.