Asymmetric Synthesis of Tertiary α-Hydroxylation-Cyclopentanones via Synergetic Catalysis of Chiral-at-Metal Rhodium(III) Complexes/Pyrrolidine.

Catalytic and asymmetric domino Michael/aldol reaction of 1,2-dicarbonyl compounds with α,ß-unsaturated ketones under the synergetic catalysis of chiral-at-metal rhodium complexes and pyrrolidine to deliver tertiary α-hydroxylation-cyclopentanones (45-89% yields with 81-99% ee and up to >20:1 dr) bearing three contiguous stereogenic centers had been established. Moreover, the scalability and practical utility of this protocol were well demonstrated by employing a gram-scale reaction and some representative transformations.

Organophosphine as an Alkyl Transfer Shuttle for the Direct ß-Alkylation of Chalcones Using Alkyl Halides.

We report an efficient alkyl transfer strategy for the direct ß-alkylation of chalcones using commercially available alkyl bromides as alkyl reagents. In this transformation, the ortho-phosphanyl substituent in the chalcones is crucial for controlling their reactivity and selectivity. It also serves as a reliable alkyl transfer shuttle to transform electrophilic alkyl bromides into nucleophilic alkyl species in the form of quaternary phosphonium salts and transfer the alkyl group effectively to the ß-position of the chalcones. This alkyl transfer strategy can be further extended to the alkenylation of ortho-phosphanyl benzaldehydes to assemble functionalized polyenes.

Asymmetric Formal (3 + 2) Cyclocondensation of Coumarin-3-Formylpyrazoles as 3-Carbon Partners with 3-Hydroxyoxindoles via Esterification/Michael Addition Sequence.

The first enantioselective formal (3 + 2) cyclocondensation involving α,ß-unsaturated pyrazoleamides as 3-carbon partners was accomplished in a stepwise fashion. The stepwise esterification/Michael addition sequence is promoted by Zn(OTf)2 and quinine-squaramide derivative, respectively. The protocol enables access to spiro-fused pentacyclic spirooxindoles from coumarin-3-formylpyrazoles and 3-hydroxyoxindoles in good to satisfactory overall yields (up to 91%) with excellent dr (all cases >20:1 dr) and high ee values (up to 99%). Mechanistic investigations contributed to shedding light on the enantioselective event of the process.

Advances in chromone-based reactants in the ring opening and skeletal reconstruction reaction: access to skeletally diverse salicyloylbenzene/heterocycle derivatives.

Salicyloylbenzene/heterocycles are privileged scaffolds found in many natural products and bioactive molecules. Numerous useful approaches for the preparation of these privileged scaffolds have been developed in recent years. Among these approaches, chromone-based reactants have demonstrated their importance in the synthesis of these salicyloylbenzene/heterocycle scaffolds with structural complexity and potential biological appeal. In this review, the recent advances in the synthesis of salicyloylbenzene/heterocycles are summarized and discussed according to the chromone-based reactants which could be achieved in one step via ring-opening and skeletal reconstruction reactions. Both the mechanisms and the applications of the corresponding products in organic and medicinal chemistry are also described.

Catalytic asymmetric Michael/cyclization reaction of 3-isothiocyanato thiobutyrolactone: an approach to the construction of a library of bispiro[pyrazolone-thiobutyrolactone] skeletons.

Here, we demonstrate the first example of 3-isothiocyanato thiobutyrolactone serving as a useful building block in the Michael/cyclization reaction with alkylidene pyrazolones for the enantioselective construction of optically active structural bispiro[pyrazolone-thiobutyrolactone] skeletons containing three contiguous stereocenters with two spiroquaternary stereocenters. These products were smoothly afforded in up to 90% yield, >20 : 1 dr and >99% ee with chiral squaramide as the catalyst under mild conditions. Notably, this is also the first example of the merger of a spirocyclic pyrazolone scaffold with a spirocyclic thiobutyrolactone scaffold, potentially useful in medicinal chemistry.

Ring opening and skeletal reconstruction of 3-vinyl benzofuranone-chromone synthons: catalyst-free access to skeletally-diverse 2-pyridone and optically active imidazoline derivatives.

Herein is reported the first example of ring opening and skeletal reconstruction of 3-vinyl benzofuranone-chromones 1 as versatile synthons, which can react with ammonia or primary aliphatic amines as binucleophiles, for the eco-friendly and atom-economical synthesis of diverse and functionalized 2-pyridones 3 with potential biological activity in good to excellent yields (77-93%). When using optically active 1,2-diphenylethylenediamine 2 as the binucleophile, the in situ generated 2-pyridone intermediates are successfully transformed to novel optically active functionalized imidazoline derivatives 4 with high efficiency (up to 87% yield). In particular, this is the first report on the catalyst-free intramolecular cyclization occurring between an amide and a primary aliphatic amine for the construction of imidazoline molecules.

Hyperoside suppresses osteoclasts differentiation and function through downregulating TRAF6/p38 MAPK signaling pathway.

Hyperoside (HP), as a natural product, can promote proliferation and differentiation of osteoblasts and presents a protective effect on ovariectomized (OVX) mice. However, the inhibitory effect of HP on osteoclasts (OCs) and the potential mechanism remain to be elucidated. In this study, it was found that HP could effectively inhibit the differentiation and bone resorption of OCs, and its intrinsic molecular mechanism was related to the inhibition of TRAF6/p38 MAPK signaling pathway. Therefore, HP could be a promising natural compound for lytic bone diseases.

Synthesis of methanesulfone-containing tetrasubstituted carbon stereocenters.

A methanesulfonylation reaction for the synthesis of sulfone-containing tetrasubstituted carbon stereocenters is described for the first time by simple treatment of indanedione-chromanone synthons with Et3N and easily accessible MsCl without any use of organometallic chemistry. This technology gave the corresponding valuable chromone-based 2-methanesulfonylated 1,3-indanediones in good yields (up to 89% yield) under mild conditions. The present work provides an attractive strategy for the construction of biologically interesting sulfone-containing tetrasubstituted carbon stereocenters, which might be valuable in medicinal chemistry.

Study on antitumor activities of the chrysin-chromene-spirooxindole on Lewis lung carcinoma C57BL/6 mice in vivo.

The our previous study synthesized the chrysin-chromene-spirooxindole hybrids 3, and further found compound 3e had good antitumor activity against A549 cells in vitro through multi-target co-regulation of the p53 signalling pathway to inhibit the proliferation of A549 cells. This study was designed to evaluate the antitumor effects of compound 3e on Lewis lung carcinoma of C57BL/6 mice in vivo. Compound 3e significantly inhibited the growth of transplanted tumors in C57BL/6 mice and induced the apoptosis of tumor cells. Further studies showed that compound 3e activates and expands the anti-cancer activity of p53 by inhibiting the expression of MDM2, Akt and 5-Lox proteins, accordingly promotes the expressions Bax and inhibit the Bcl-2 protein, the release of Cyt c as well, which resulted in the activation of apoptotic pathway in tumor cells eventually. Moreover, Compound 3e inhibited tumor metastasis by down-regulating VEGF, ICAM-1 and MMP-2 protein expression and angiogenesis. These results suggested that compound 3e exerts an effective antitumor activity in vivo through activating the p53 signaling pathway, which could be exploited as a promising candidate for the development of new anti-tumour drugs.

Regioselective synthesis and evaluation of 2-amino 3-cyano chromene-chrysin hybrids as potential anticancer agents.

The first example of Ca(OH)2-activated p-regioselective synthesis of chrysin-fused chromene was reported through a cascade Michael/cyclization of chrysin and arylidenemalononitrile. The newly synthesized structurally diverse 2-amino 3-cyano chromene-chrysin hybrids 3 were evaluated for their in vitro anticancer activity, and some of the compounds showed stronger anti-proliferative activity against K562, PC-3, A549 and NCI-H1299 than parent compound chrysin, and demonstrated equipotent potency compared with the reference drug of cisplatin. In particular, compound 3h had the highest cytotoxicity towards K562 cells (IC50 = 6.41 µM). Furthermore, compound 3h induced apoptosis of K562 cells in a concentration-dependent manner, as well as induced the apoptosis possibly through promoting the formation of apoptotic DNA of cancer cell via the intrinsic apoptotic pathway. Thus, our results provide in vitro evidence that compound 3h may be a potential candidate for the development of new anti-tumour drugs.

Transition-metal-free cascade benzannulations for synthesizing 2-hydroxybenzophenones.

A set of cascade benzannulations of readily accessible chromone-3-carboxaldehydes and γ-nitroaldehydes for synthesizing biologically relevant 2-hydroxybenzophenones has been developed. The cascade was found to provide a transition-metal-free strategy for synthesizing 2-hydroxybenzophenones in acceptable yields (up to 57%).

Organocatalytic Reaction of Chromone-Oxindole Synthon: Access to Chromanone-Based Spirocyclohexaneoxindoles with Five Adjacent Stereocenters.

An efficient strategy for stereo-controlled synthesis of potential biological and structurally complex chromanone-based spirocyclohexaneoxindoles via an organocatalytic domino formal double Michael cycloaddition of bifunctional chromone-oxindole synthons and nitroolefins is reported. These products possessing five adjacent stereocenters including one spiro quaternary carbon center, were smoothly afforded in up to 85% yield, >99% ee, and >20:1 dr. This strategy benefits from the intramolecular nature of the second Michael reaction step, through counterbalancing the lower electrophilicity of these unactivated chromones to facilitate the reaction.

Thermal-mediated [1,3]-hydrogen transfer as the key step: access to oxindole-chromone hybrid collection with structural diversity.

Inspired by the chemistry and biology of chromone and oxindole derivatives, herein we report the first example of thermal-mediated [1,3]-hydrogen transfer as the key step for the efficient synthesis of oxindole-chromone hybrid collections 2, which avoids additional catalyst and solvent conditions. All the oxindole-chromones 2 are smoothly obtained in >99% yields in all cases, avoiding column chromatography purification. In particular, the products 2 can act as potential synthons for further elaboration in structural diversity, which might be valuable in organic and medicinal chemistry.

An asymmetric iminium ion catalysis-enabled cascade cycloaddition reaction of chromone-oxindole synthons with enals: construction of a spirooxindole-hexahydroxanthone framework.

We report the first asymmetric iminium ion catalysis-enabled cascade cycloaddition reaction of bifunctional chromone-oxindole synthons and α,ß-unsaturated aldehydes. This allowed one quaternary and four tertiary contiguous stereogenic centers to be constructed in a single operation. A range of spirooxindole-hexahydroxanthone molecules are obtained with up to 62% yield, >20 : 1 dr and >99% ee. This reaction has not only provided a new approach for constructing hexahydroxanthone-fused scaffolds by utilizing asymmetric iminium ion catalysis, but also advanced the chemistry of diversity-oriented synthesis based on bifunctional chromone synthons.

Regio- and stereoselective [3 + 2] cycloaddition reaction: access to isoxazole-dispirobisoxindoles featuring three contiguous stereocenters.

A novel methodology toward the diversity-oriented asymmetric construction of densely functionalized isoxazole-dispirobisoxindoles was developed. This approach is distinguished by an organocatalytic stereo- and appealing ß-regioselective [3 + 2] cycloaddition reaction of 3-methyl-4-nitro-5-isatylidenyl-isoxazoles and 3-isothiocyanato oxindoles. Complex polycyclic oxindoles 3 featuring two different oxindole moieties and three contiguous stereocenters were smoothly afforded in up to 96% yield, 96% ee, and >20 : 1 dr. The described method, which is different from our previous work of α-regioselective asymmetric annulation of 3-methyl-4-nitro-5-isatylidenyl-isoxazoles, is the first ß-regioselective asymmetric annulation.

Design, synthesis and evaluation of structurally diverse chrysin-chromene-spirooxindole hybrids as anticancer agents.

A series of structurally diverse chrysin-chromene-spirooxindole hybrids were designed, synthesized via a Knoevenagel/Michael/cyclization of chrysin and isatylidene malononitrile derivatives through utilizing a hybrid pharmacophore approach. The newly synthesized compounds were evaluated for their in vitro anticancer activity, and most of the compounds showed stronger anti-proliferative activity than parent compound chrysin. In particular, compound 3e had the highest cytotoxicity towards A549 cells (IC50 = 3.15 ±â€¯0.51 µM), and had better selectivity in A549 cells and normal MRC-5 cells. Furthermore, compound 3e could significantly inhibit the proliferation and migration of A549 cells in a dose-dependent manner, as well as induce the apoptosis possibly through mitochondria-mediated caspase-3/8/9 activation and multi-target co-regulation of the p53 signaling pathway. Thus, our results provide in vitro evidence that compound 3e may be a potential candidate for the development of new anti-tumour drugs.

Rapid, microwave-accelerated synthesis and anti-osteoporosis activities evaluation of Morusin scaffolds and Morusignin L scaffolds.

Described herein is a facile and efficient methodology toward the synthesis of Morusin scaffolds and Morusignin L scaffolds 4-9 and 12via a novel three-step approach (Michael addition or prenylation, cyclization and cyclization) and use a rapid, microwave-accelerated cyclization as the key step. Furthermore, their biological activities have been preliminarily demonstrated by in vitro evaluation for anti-osteoporosis activity. These Morusin, Morusignin L and newly synthesized compounds 5b, 6a, 8e, 8f greatly exhibited the highest potency, especially at the 10-5mol/L (P<0.01), and had good in vitro anti-osteoporosis activities using the commercially available standard drug Ipriflavone as a positive control. The mechanisms associated with anti-osteoporosis effects of these compounds may be through the inhibition of TRAP enzyme activity and bone resorption in osteoclasts, and promotion effect of osteoblast proliferation in vitro. The results indicated that Morusin scaffolds and Morusignin L scaffolds may be useful leads for further anti-osteoporosis activity screenings.

Alcohols as Substrates and Solvents for the Construction of 3-Alkoxylated-2-Oxindoles by Direct Alkoxylation of 3-Halooxindoles.

Described herein is an environmentally benign method for the synthesis of multisubstituted 3-alkoxylated-2-oxindoles 3 via direct alkoxylation of 3-halooxindoles 1. A wide variety of such multisubstituted 3-alkoxylated-2-oxindole scaffolds were smoothly obtained in good yields (up to 94%) by heating in an oil bath at 35 °C for 24 h. A particularly valuable feature of this method was the development of environment-friendly chemistry using alcohols 2 as both the substrates and solvents in the presence of a catalytic amount of base.

Molecular Hybridization-Guided One-Pot Multicomponent Synthesis of Turmerone Motif-Fused 3,3'-Pyrrolidinyl-dispirooxindoles via a 1,3-Dipolar Cycloaddition Reaction.

Described herein is the development of a facile and efficient methodology for the synthesis of novel turmerone motif-fused 3,3'-pyrrolidinyl-dispirooxindoles 3-5 via a multicomponent 1,3-dipolar cycloaddition of dienones 2 with azomethine ylides (thermally generated in situfrom isatins and proline or thioproline or sarcosine). Products bearing four or three consecutive stereocenters consist of two oxindole moieties and a pyrrolidinyl core, including vicinal spiroquaternary stereocenters fused in one ring structure were smoothly obtained in high yields (up to 93% yield) with good diastereoselectivity (up to >20:1). Another valuable application of this method was for the design of new hybrid architectures for biological screening through the adequate fusion of these sub-units of turmerone and 3,3'-pyrrolidinyl-dispirooxindole, generating drug-like molecules.

A highly efficient and eco-friendly method for the synthesis of 1,3-indandione ring-fused 3-oxindoles bearing two contiguous quaternary stereocenters via an aldol reaction in aqueous media.

A highly efficient and environmentally benign method for the synthesis of oxindoles featuring two contiguous quaternary carbon centers via an aldol reaction starting from various 3-substituted oxindoles has been established. A wide variety of such featured multi-substituted 1,3-indandione ring-fused 3-oxindole scaffolds were obtained smoothly in good yields (up to 98%) employing the most green of solvents, namely water, as reaction medium. Furthermore, their biological activity has been preliminarily demonstrated by in vitro evaluation against human prostate cancer cells PC-3, human lung cancer cells A549 and human leukemia cells K562 by MTT-based assays, using the commercially available standard drug, cisplatin, as a positive control. Gratifyingly, compounds 3s, 3u, 3y and 3c' exhibited the best levels of in vitro inhibitory activity against human leukemia cells K562, which were almost 2.0, 2.8, 2.5 and 2.2 times, respectively, the activity of the positive control, cisplatin. Compound 3y had 2.7 times the activity of the positive control, cisplatin, against PC-3 cancer cells, and 3s, 3u and 3c' showed levels of in vitro inhibitory activity against PC-3 cancer cells that were comparable to that of cisplatin. Compounds 3s, 3u and 3y had good inhibitory ability against human lung cancer cells A549. The results indicated that 1,3-indandione ring-fused 3-oxindole analogs may be useful leads for further biological screenings.