A diastereoselective vinylogous Mannich reaction between the N-tert-butanesulfinyl imines and dioxinone-derived lithium dienolate was developed. A variety of aldimines, ketimines and isatin-derived ketimines are suitable for this process. On the basis of X-ray crystallography of products, a predictive model for this transformation was provided.

Five new neo-clerodane diterpenoids, tiliifolins A–E (1–5), along with ten known ones, were isolated from the aerial part of Salvia tiliifolia. Their structures were proposed based on 1D and 2D NMR spectroscopic data analysis. All new compounds were evaluated for their neurotrophic activity on PC12 cells and cytotoxicity against five human cancer cell lines (HL-60, A-549, SMMC-7721, MCF-7, and SW480), and compound 5 showed statistically significant neuroprotective effect in vitro assay.Download high-res image (215KB)Download full-size image

AbstractOutlined herein is a novel and scalable synthesis of (−)-vindorosine based on two key transformations. A highly diastereoselective vinylogous Mannich addition of dioxinone-derived lithium dienolates with indolyl N-tert-butanesulfinyl imines has been developed. In addition, an intramolecular Heathcock/aza-Prins cyclization was introduced to construct both the C, and the highly substituted E rings for the synthesis of (−)-vindorosine and related alkaloids.

AbstractOutlined herein is a novel and scalable synthesis of (−)-vindorosine based on two key transformations. A highly diastereoselective vinylogous Mannich addition of dioxinone-derived lithium dienolates with indolyl N-tert-butanesulfinyl imines has been developed. In addition, an intramolecular Heathcock/aza-Prins cyclization was introduced to construct both the C, and the highly substituted E rings for the synthesis of (−)-vindorosine and related alkaloids.

Structure units containing all-carbon quaternary stereogenic center are found in many bioactive natural products. However, enantioselective construction of this type of structure units has been a formidable challenge for synthetic community due to the steric hindrance enforced by all-carbon quaternary stereocenters. In this review, we present the achievements made by Chinese scientists in the area of asymmetric synthesis of all-carbon quaternary stereocenters in natural products during the past two years.

GA-13315 is a gibberellin derivative that reveals antitumor and antineoplastic effects both in vitro and in vivo. In the present study, the chemosensitizing effects of GA-13315 in multidrug-resistant cell lines were examined and the underlying mechanisms were investigated.Cytotoxicity and chemosensitizing effects of GA-13315 were determined by MTT assay. Function of ABC transporter was analyzed by measuring intracellular drug accumulation of doxorubicin and rhodamine 123 and by determining the ATPase activity of ABC transporter. Expression levels of apoptosis regulators were analyzed using real-time quantitative PCR and Western blot.GA-13315 selectively killed MCF-7/adr cells that overexpress P-glycoprotein (ABCB1) over the parent MCF-7 cells. In combination with conventional chemotherapeutic agents, GA-13315 at sub-toxic concentrations reversed the multidrug resistance mediated by ABCB1 but exacerbated the resistance conferred by multidrug resistance-associated protein 1 (ABCC1). GA-13315 increased intracellular accumulation of doxorubicin and rhodamine 123 in MCF-7/adr cells and in ABCB1-transfected HEK293 cells but facilitated drug flush-out from cells that overexpress ABCC1. GA-13315 inhibited the ATPase activity of ABCB1 while stimulated that of ABCC1. Moreover, the downregulated expression of Bax in MCF-7/adr cells was restored by GA-13315 markedly.These data suggest that GA-13315 sensitizes multidrug-resistant cells at least partially by impeding the efflux function of ABCB1. The upregulation of Bax by GA-13315 may also contribute to the sensitizing action. The opposite effects of GA-13315 on different ATP-binding cassette transporters and their implications in overcoming drug resistance require further investigation.

In this paper, we report a full account of the synthesis of dimeric hexahydropyrroloindole alkaloids and its analogues. The key feature of our new strategy is the novel catalytic copper (10 %) mediated intramolecular arylations of o-haloanilides followed by intermolecular oxidative dimerization of the resulting oxindoles in one pot. This sequential reaction leads to the key intermediates for the synthesis of (+)-chimonanthine, (+)-folicanthine, (−)-calycanthine and (−)-ditryptophenaline.

In this communication, we report a copper catalyzed sequential arylation−oxidative dimerization reaction as the key step for the synthesis of hexahydropyrroloindole alkaloids (+)-chimonanthine, (+)-folicanthine and (−)-calycanthine.

Facile, straightforward, and asymmetric total syntheses of (+)-chimonanthine (1), (+)-folicanthine (2), and (−)-calycanthine (3) were accomplished in four to five steps from commercially available tryptamine. The synthesis features copper-mediated asymmetric cyclodimerization of chiral tryptamine derivative, which established a new entry into constructing the sterically hindered vicinal quaternary stereogenic carbon centers of dimeric hexahydropyrroloindole alkaloids in one procedure. An unprecedented base-induced isomerization from the chimonanthine skeleton to the calycanthine skeleton was observed and facilitated the synthesis of (−)-calycanthine (3).

An efficient total synthesis of (−)-stenine in 14 steps with an overall yield of 5.9% is described. The key feature is the construction of the densely substituted cyclohexane core of stenine with two consecutive asymmetric Michael additions.

In the presence of iodine, a functional group compatible method for the deprotection of tert-butanesulfinyl and p-toluenesulfinyl units was developed.

•GA-13316/β-CD had determined by apparatuses and experimental approaches.•The water solubility and stability of GA-13316 were significantly enhanced by wrapped.•The stronger binding ability was obtained by phase solubility and molecular modeling.•The antitumor activity against HCT116 and H460 cells was retained.•The GA-13316/β-CD complex should be regarded as a promising anticancer therapy.The inclusion complex of GA-13316 with β-cyclodextrin (β-CD) is one of a unique series of gibberellin derivatives possessed of potential anticancer activities. The complex with β-CD was characterized by means of UV, XRD, DSC, TG, 1H, and 2D NMR spectroscopy. In addition, we investigated the main aspects of the interaction between GA-13316 and β-CD using both experimental and molecular modeling approaches. The complex still maintained its anticancer activity, as shown by in vitro cell survival assay on the human colon carcinoma cell line (HCT116) and the human lung cancer cell line (H460). The results showed that the use of β-CD could be obviously improved the water solubility and stability of GA-13316, implying that the inclusion complex could be a promising future therapeutic agent.

An enantioselective strategy for the synthesis of (+)-brazilin, (−)-brazilein and (+)-brazilide A has been developed. A Lewis acid mediated lactonization established the novel fused bis-lactone core of brazilide A and finalized the first total synthesis of (+)-brazilide A.

An efficient and stereocontrolled synthetic strategy towards the synthesis of montanine-like alkaloids was developed. Our results suggest that the structure elucidation for natural montabuphine needs further elaboration.

This study showed that 13-chlorine-3,15-dioxy-gibberellic acid methyl ester (GA-13315), a gibberellin derivative, possessed high antitumor and antiangiogenic activity in vitro and in vivo. Cytotoxicity assays showed that GA-13315 was a potential and efficient antitumor compound, with inhibitory concentration 50 (IC50) values ranging from 0.13 to 30.28 μg/ml in 12 human tumor cell lines, and it showed moderate toxicity to peripheral blood mononuclear cells with an IC50 value of 14.2 μg/ml. Administration of 0.5 or 2.5 mg/kg GA-13315 for 23 days significantly inhibited tumor growth of human non-small cell lung tumor (A549) xenografts, with relative growth rates ranging from 29.91% to 35.05%. Acute toxicity was determined in ICR mice, and the lethal dose 50 (LD50) was 4.19 g/kg after intragastric administration. The high antitumor potency of GA-13315 occurred in parallel with its antiangiogenic activity. In vitro, GA-13315 inhibited recombinant human epithelial growth factor-induced chemotactic motility and capillary-like tube formation of primary cultured human endothelial cells. Furthermore, GA-13315 decreased the factor VIII+ microvessel density and vascular endothelial growth factor expression in A549 tumors, indicating its antiangiogenic efficacy in vivo. These results indicate that the antiangiogenic activity of GA-13315 contributes to its anticancer properties. Further studies are needed to investigate the use of GA-13315 as an anticancer drug.

In the presence of catalytic amount of copper salt, an efficient and flexible synthetic method towards the synthesis of a structurally new type of spirocyclic lactams was developed.

New synthetic strategies leading to highly functional erythrina, oxindole and pyrrolidinoindoline skeletons have been developed and an efficient formal syntheses of (±)-demethoxyerythratidinone reported.

An imidazolium salt, 1-mesityl-3-(2-naphthoylmethano)-1H-imidazolium bromide (MNIB), has been investigated for its antitumor properties. In vitro studies demonstrate that MNIB is active against K562, SMMC-7721, EJ, AGZY, HEP-2, A549, HepG2, and Raji tumor cells, and can induce the G1 phase cell cycle arrest and apoptosis in K562 cells. Moreover, administration of MNIB significantly inhibited tumor growth in human non-small lung tumor (A549) xenografts.An imidazolium salt, 1-mesityl-3-(2-naphthoylmethano)-1H-imidazolium bromide (MNIB), has been investigated for its antitumor properties. In vitro studies demonstrate that MNIB is active against K562, SMMC-7721, EJ, AGZY, HEP-2, A549, HepG2, and Raji tumor cells, and can induce the G1 phase cell cycle arrest and apoptosis in K562 cells. Moreover, administration of MNIB significantly inhibited tumor growth in human non-small lung tumor (A549) xenografts.

In this work, 23 new amides (14–36) bearing a representative diterpenoid structure unit, the functionalized bicyclo[3.2.1]octane ring, have been synthesized and its antitumor potential is studied. In vitro studies demonstrate that a number of amides with the bicyclo[3.2.1]oct-3-en-2-one subunit are active against HL-60, SMMC-7721, A-549, SK-BR-3, and PANC-1 tumor cell lines. The hybrid derivative, compound 20, was found to be the most potent compound (IC50 = 1.05 μM against HL-60) and more active than cisplatin (DDP), the positive control. Additionally, compound 20 exhibited broad spectrum in vitro anticancer activity with IC50 values of 1.1–4.3 μM against the five tested cancer cell lines.In this work, 23 new amides (14–36) bearing a representative diterpenoid structure unit, the functionalized bicyclo[3.2.1]octane ring, have been synthesized and its antitumor potential is studied. In vitro studies demonstrate that a number of amides with the bicyclo[3.2.1]oct-3-en-2-one subunit are active against HL-60, SMMC-7721, A-549, SK-BR-3, and PANC-1 tumor cell lines. The hybrid derivative, compound 20, was found to be the most potent compound (IC50 = 1.05 μM against HL-60) and more active than cisplatin (DDP), the positive control. Additionally, compound 20 exhibited broad spectrum in vitro anticancer activity with IC50 values of 1.1–4.3 μM against the five tested cancer cell lines.

A flexible and practical strategy toward the synthesis of rare 2H-furo[3,2-b]benzopyran-2-one skeleton has been developed. With a microwave-assisted cyclization–dehydration as the key transformation, the first total synthesis of pulverolide has been completed in 10 steps with 9% overall yield, leading to the revision of its proposed structure.

In recent years, the concept of combining transition metal catalysis and organocatalysis has emerged as a promising strategy for developing new and valuable reactions, and has attracted considerable attention as it could potentially enable unprecedented transformations not currently possible by use of the transition metal complex or the organocatalyst alone. In this critical review, this strategy is illustrated with several recent outstanding examples, with the aim of shedding light on the synthetic utilities and potentials of this concept as a novel tool in organic synthesis (118 references).

New oxidative dearomatization procedures leading to spiro β-lactams and oxindoles were developed. By a variation of the oxidative reaction conditions, the usefulness of phenolic amides, derived from 4-aminophenol, in the synthesis of structurally different types of molecules was demonstrated.

A series of gibberellin based molecules were designed and synthesized. Gibberellin derivatives bearing two α,β-unsaturated ketone units showed strong anticancer activities in MTT assay towards a number of human cancer cell lines including HT29, A549, HepG2 and MKN28. The most potent gibberellin derivative (compound 10, IC50 = 2.9 μM against HT29) inhibited completely the topoisomerase I activity at 8 μg/mL level.A series of gibberellin based molecules were designed and synthesized. Gibberellin derivatives bearing two α,β-unsaturated ketone units showed strong anticancer activities in MTT assay towards a number of human cancer cell lines including HT29, A549, HepG2 and MKN28. The most potent gibberellin derivative (R = Me, IC50 = 2.9 μM against HT29) inhibited completely the topoisomerase I activity at 8 μg/mL level.

A novel synthesis of triarylamines and diaryl ethers is reported; a feature of this process is the ligand-free copper-catalysed C–N and C–O bond formation in tetraethyl orthosilicate.

A versatile and high-yielding procedure for the synthesis of β-enamino esters and β-enaminones is presented: in the presence of tetraethyl orthosilicate, a number of highly functional β-enamino esters were obtained; this method provided an alternative for the formation of β-amino-α,β-unsaturated carbonyl compounds with mild and functional group compatible reaction conditions.

Five 1,3-disubstituted imidazolium salts were synthesized. Their Heck reaction activities were evaluated. A convenient, efficient and high yielding procedure based on these compounds for the arylation of olefins was developed. Heck reactions mediated by these palladium–N-heterocyclic carbene complexes were conducted under air and even in the presence of several common oxidants.

In the presence of catalytic amount of copper iodide, a remote amide-assisted intramolecular arylation followed by alkylation leads to a general and flexible synthetic method toward the synthesis of medicinally interesting hexahydropyrroloindole alkaloids.

New synthetic strategies leading to highly functional erythrina, oxindole and pyrrolidinoindoline skeletons have been developed and an efficient formal syntheses of (±)-demethoxyerythratidinone reported.

In the presence of catalytic amount of copper salt, an efficient and flexible synthetic method towards the synthesis of a structurally new type of spirocyclic lactams was developed.

An enantioselective strategy for the synthesis of (+)-brazilin, (−)-brazilein and (+)-brazilide A has been developed. A Lewis acid mediated lactonization established the novel fused bis-lactone core of brazilide A and finalized the first total synthesis of (+)-brazilide A.

In the presence of iodine, a functional group compatible method for the deprotection of tert-butanesulfinyl and p-toluenesulfinyl units was developed.

A novel synthesis of triarylamines and diaryl ethers is reported; a feature of this process is the ligand-free copper-catalysed C–N and C–O bond formation in tetraethyl orthosilicate.

In recent years, the concept of combining transition metal catalysis and organocatalysis has emerged as a promising strategy for developing new and valuable reactions, and has attracted considerable attention as it could potentially enable unprecedented transformations not currently possible by use of the transition metal complex or the organocatalyst alone. In this critical review, this strategy is illustrated with several recent outstanding examples, with the aim of shedding light on the synthetic utilities and potentials of this concept as a novel tool in organic synthesis (118 references).

An efficient and stereocontrolled synthetic strategy towards the synthesis of montanine-like alkaloids was developed. Our results suggest that the structure elucidation for natural montabuphine needs further elaboration.

In this communication, we report a copper catalyzed sequential arylation−oxidative dimerization reaction as the key step for the synthesis of hexahydropyrroloindole alkaloids (+)-chimonanthine, (+)-folicanthine and (−)-calycanthine.