A Regio- and Diastereoselective Stille Coupling/Intramolecular Diels-Alder Cascade for the Generation of Fused Pyridines and Application in the Synthesis of (+)-Lycopladine A and (-)-Lycoposerramine R.

2-Pyrones with a chiral branched allylic silyl ether substituent underwent intramolecular Diels-Alder reactions with remarkably high π-facial- and endo-selectivities. The resulting diastereomerically and enantiomerically pure cycloadducts were transformed into the natural products (+)-lycopladine A and (-)-lycoposerramine R.

A Stereodivergent Strategy for Total Syntheses of Antirhine Alkaloids.

Total syntheses of the antirhine alkaloids are described. The cyanide-catalyzed imino-Stetter reaction of the aldimine derived from ethyl 2-aminocinnamate and 4-bromopyridine-2-carboxaldehyde provided a 2-pyridinyl substituted indole-3-acetate, which was further converted into the corresponding indoloquinolizidinium intermediate through C-ring formation. Subsequent trans-selective installation of the homoallylic alcohol side-chain at C-15 in the resulting indoloquinolizidinium allowed the total syntheses of antirhine and its known epimer.

Transition-metal-catalyzed ortho-selective C-H functionalization reactions of free phenols.

Phenols are important readily available chemical feedstocks and versatile synthetic building blocks for diverse synthetic transformations. Their motifs are prevalent in a diverse array of natural products, pharmaceuticals, functional materials, and privileged chiral ligands. Consequently, the development of facile and direct site-selective C-H bond functionalization of free phenols is of great importance and considerable interest to both industry and academic research. Over the past decades, transition-metal-catalyzed C-H bond functionalization has become as a powerful synthetic tool in organic synthesis. In this review, we provide a brief overview of recent progress in the transition-metal-catalyzed direct ortho-selective C-H functionalization of free phenols.

Aminooxygenation of Ynamides with N-Hydroxybenzotriazoles: Synthesis of α-Benzotriazolyl Carbonyl Compounds.

Addition of N-hydroxybenzotriazoles to ynamides causes spontaneous rearrangement, resulting in α-benzotriazolyl imides. The transformation proceeded at rt in the absence of any catalyst but could be efficiently catalyzed by Zn(OTf)2. Crossover experiments confirmed that the rearrangement is an intramolecular process, most likely via a concerted mechanism. However, heating the mixture above 110 °C resulted in isomerization of N2 into N1 product, via heterolytic C-N bond dissociation. This tandem addition-rearrangement sequence provides an efficient and atom-economical synthetic route for the synthesis of α-benzotriazolyl carbonyl compounds.

Total Synthesis of (±)-Clivonine via Diels-Alder Reactions of 3,5-Dibromo-2-pyrone.

New synthetic routes to (±)-clivonine were devised starting with the Diels-Alder cycloadditions of 3,5-dibromo-2-pyrone with styrene pinacol boronate dienophiles. In the first-generation synthesis, the pivotal perhydroindoline system including the C5-hydroxyl group was constructed via a reaction sequence involving the Eschenmoser-Claisen rearrangement and regio/stereoselective epoxide opening reaction. In the second-generation synthesis, a radical-mediated cyclization approach was employed for the rapid assembly of the pyrrolidine ring. In this route, the C5-hydroxyl group provided by the dienophile in a stereochemically defined form was preserved throughout the synthesis.

Total Syntheses of Lobaric Acid and Its Derivatives from the Antarctic Lichen Stereocaulon alpinum.

The first total syntheses of the natural products lobaric acid (1) and its derivatives isolated from the Antarctic lichen Stereocaulon alpinum are reported in this study. Lobarin (3), with a pseudodepsidone structure, was synthesized first in 11 steps by utilizing an Ullmann aryl ether coupling reaction, and lobaric acid was synthesized in an additional three steps by a seven-membered lactonization reaction. Various derivatives were also obtained from the prepared lobaric acid, and the synthetic compounds exhibited significant PTP1B inhibitory activities.

Divergent Asymmetric Total Syntheses of (-)-Alloaristoteline and (+)-Aristoteline via Directed Indolization Strategies.

A divergent asymmetric synthetic route to (-)-alloaristoteline and (+)-aristoteline is described. The key doubly bridged tricyclic enol triflate common intermediate prepared via enantioselective deprotonation and stepwise annulation was successfully bifurcated to complete the first completely synthetic construction of the titled natural alkaloids upon strategic implementation of the late-state directed indolization methods.

A new 2-pyrone derivative, 5-bromo-3-(3-hydroxyprop-1-ynyl)-2H-pyran-2-one, suppresses stemness in glioma stem-like cells.

Glioma cells with stem cell properties, termed glioma stem-like cells (GSCs), have been linked to tumor formation, maintenance, and progression and are responsible for the failure of chemotherapy and radiotherapy. Because conventional glioma treatments often fail to eliminate GSCs completely, residual surviving GSCs are able to repopulate the tumor. Compounds that target GSCs might be helpful in overcoming resistance to anticancer treatments in human brain tumors. In this study, we showed that 5-bromo-3-(3-hydroxyprop-1-ynyl)-2H-pyran-2-one (BHP), a new 2-pyrone derivative, suppressed the maintenance of the GSC population in both a glioma cell line and patient-derived glioma cells. Treatment of GSCs with BHP effectively inhibited sphere formation and suppressed the CD133(+) cell population. Treatment with BHP also suppressed expression of the stemness-regulating transcription factors Sox2, Notch2, and ß-catenin in sphere-cultured glioma cells. Treatment of GSCs with BHP significantly suppressed two fundamental characteristics of cancer stem cells: self-renewal and tumorigenicity. BHP treatment dramatically inhibited clone-forming ability at the single-cell level and suppressed in vivo tumor formation. BHP markedly inhibited both phosphoinositide 3-kinase/Akt and Ras/Raf-1/extracellular signal-regulated kinase signaling, which suggests that one or both of these pathways are involved in BHP-induced suppression of GSCs. In addition, treatment with BHP effectively sensitized GSCs to chemotherapy and radiotherapy. Taken together, these results indicate that BHP targets GSCs and enhances their sensitivity to anticancer treatments and suggest that BHP treatment may be useful for treating brain tumors by eliminating GSCs.

Anti-leukemic effect of 2-pyrone derivatives via MAPK and PI3 kinase pathways.

Substituted 2-pyrones are important structural sub-units present in a number of natural products having broad range of biological activity. However, little is known about the anti-cancer effect of 2-pyrone derivatives including leukemia. Therefore, this present study was undertaken to investigate the effect of 2-pyrone derivatives in human acute myeloid leukemia (AML). Among 23 synthesized derivatives, 5-bromo-3-(3-hydroxyprop-1-ynyl)-2H-pyran-2-one (code name; pyrone 9) showed the most potent antileukemic activity with 5 × 10(-6) M to 5 × 10(-5) M of IC(50) in various AML cell lines as well as primary leukemic blasts from AML patients, while normal peripheral blood mononuclear cells was not affected by pyrone 9. Flow cytometric analysis indicated that pyrone 9 induced the G1 and G2 phase dual arrest of the cell cycle in HL-60 cells. To address the mechanism of the antileukemic effect of pyrone 9, we examined the effect of pyrone 9 on cell cycle-related proteins in HL-60 cell. The levels of CDK2, CDK4, CDK6, CDK1, cyclin B1 and cyclin E were decreased; in contrast, cyclin A was not altered. In addition, pyrone 9 not only increased the p27 level but also enhanced its binding to with CDK2, CDK4 and CDK6 which resulted in the reduction of CDK2-, CDK4- and CDK6-associated kinase activities. Pyrone 9 also induced the apoptosis in HL-60 cells. The apoptotic process of HL-60 cells was associated with increased Bax, decreased Bcl-2 and activation of caspase-8, -9, -3 and PARP. Antileukemic effect of pyrone 9 was associated with activation of mitogen-activated protein kinase (MAPK) pathway, as evidenced by activation of p-ERK and p38 MAPK. In addition, pyrone 9 was influenced PI3 kinase pathway. Expressions of p-Akt (ser473), p-Raf, and p-PDK were down-regulated; in contrast, those of PTEN and p-PTEN were up-regulated. Furthermore, pyrone 9 suppressed NF-κB pathway signaling. To gain insights into the antileukemic activity of pyrone 9 in vivo, BALB/c mouse leukemic model was established using intraperitoneal inoculation of syngeneic WEHI-3BD(+) mouse leukemic cells. Pyrone 9 inhibited in vitro and in vivo the growth of WEHI-3BD(+) cells, and ultimately, prolonged the survival of pyrone 9-treated mice. These findings suggest that the pyrone 9 inhibits the cell proliferation of human AML cell line, HL-60, through MAPK and PI3 kinase pathway as well as induction of cell cycle arrest. In particular, pyrone 9 prolonged the survival of pyrone 9-treated leukemic mice.

A new 2-pyrone derivative, 5-bromo-3-(3-hydroxyprop-1-ynyl)-2H-pyran-2-one, synergistically enhances radiation sensitivity in human cervical cancer cells.

Radiation resistance can be overcome by a combination treatment with chemical modifiers. Here, we showed that treatment with 5-bromo-3-(3-hydroxyprop-1-ynyl)-2H-pyran-2-one (BHP), a new 2-pyrone derivative, in combination with ionizing radiation enhances the sensitivity of human cervical cancer cells to ionizing radiation through overproduction of reactive oxygen species (ROS). The combined treatment with BHP and ionizing radiation caused a decrease in clonogenic survival and an increase in apoptotic cell death in cervical cancer cells. The combined treatment promoted conformational activation of Bax and led to mitochondrial apoptotic cell death. The combination treatment also induced a marked increase in intracellular ROS level. Inhibition of ROS attenuated the radiosensitizing effect of BHP, concurrent with a decrease in Bax activation, a decrease in mitochondrial cell death, and an increase in clonogenic survival. These results indicate that BHP synergistically enhances sensitivity of human cervical cancer cells to ionizing radiation through elevation of intracellular ROS and that ROS-dependent Bax activation is critically involved in the increase in apoptotic cell death induced by the combined treatment with BHP and ionizing radiation.

Asymmetric Divergent Total Syntheses of (+)-Decursivine and (+)- Serotobenine via Intramolecular Fischer Indole Synthesis.

A new asymmetric synthetic route to (+)-decursivine and (+)-serotobenine is formulated. The key developments are the de novo construction of the crucial eight-membered 3,4-fused tricyclic indole ring engaged by the intramolecular Fischer indole synthesis and the stereocontrolled assembly of the dihydrobenzofuran subunit mediated by the asymmetric intramolecular Rh-carbenoid C-H insertion. BF3-mediated selective C15 epimerization followed by removal of the amine masking groups completed the target natural compounds' asymmetric and divergent total syntheses.

General Strategy for the Synthesis of Antirhine Alkaloids: Divergent Total Syntheses of (±)-Antirhine, (±)-18,19-Dihydroantirhine, and Their 20-Epimers.

A general synthetic strategy for antirhine alkaloids was developed in this study. The cyanide-catalyzed imino-Stetter reaction of ethyl 2-aminocinnamate and 4-bromopyridine-2-carboxaldehyde afforded the corresponding indole-3-acetic acid derivative. Subsequent formation of the six-membered C ring followed by trans-selective installation of the two-carbon unit at C-15 provided rapid access to the key intermediate. Stereoselective installation of substituents at C-20 allowed the total syntheses of (±)-antirhine, (±)-18,19-dihydroantirhine, and their 20-epimers, all of the known natural products in the antirhine family.

Imidazole-Selective Alkyne Hydroamination under Physiological Conditions.

Imidazole-selective intermolecular hydroamination reaction has been discovered. This unprecedented additive-free addition reaction proceeds in an exclusively regioselective and stereoselective manner with high atom economy under extremely mild reaction conditions.

New Synthetic Routes to (+)-Uleine and (-)-Tubifolidine: General Approach to 2-Azabicyclo[3.3.1]nonane Indole Alkaloids.

Novel asymmetric synthetic routes to (+)-uleine and (-)-tubifolidine are reported herein. The regioselective formation of enol triflates from 2-azabicyclo[3.3.1]nonane ketones followed by indolizations of the resultant ene-hydrazides allowed the efficient construction of key indole intermediates, facilitating the total synthesis of the target natural alkaloids.

Transforming Oxadiazolines through Nitrene Intermediates by Energy Transfer Catalysis: Access to Sulfoximines and Benzimidazoles.

Subtle differences in reaction conditions facilitated unprecedented photocatalytic reactions of oxadiazolines by energy transfer catalysis. A set of compounds, sulfoximines and benzimidazoles, were ingeniously prepared from oxadiazolines via nitrene intermediates by photocatalytic N-O/C-N bond cleavages. The synthesis of sulfoximines was realized through intermolecular N-S bond formation between nitrene intermediates and sulfoxides, whereas benzimidazoles were obtained via intramolecular aromatic substitution of the nitrene to the tethered aryl substituent.

Antileukemic effect of a synthetic vitamin D3 analog, HY-11, with low potential to cause hypercalcemia.

1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3] is capable of inhibiting the proliferation of acute myelogenous leukemia (AML). However, toxicity of hypercalcemia has limited the use of 1,25(OH)2D3 in clinical trials. We have evaluated 11 synthesized vitamin D3 analogs for their ability to inhibit clonal growth of HL-60 myeloid leukemic cells. Among the 11 vitamin D3 analogs, HY-11 (code name) showed the most potent antileukemic activity with 2.5x10(-6) M of IC50, however, it did not affect the cellular growth of normal peripheral blood mononuclear cells until 10(-6) M. Flow cytometric analysis indicated that HY-11 induced the G1 arrest in a dose-dependent manner, which was mediated via inactivation of CDK4 and CDK6 in association with up-regulation of CDKI (cyclin-dependent kinase inhibitor), p27 and Rb protein. Induction of apoptosis was mediated via caspase-3 pathway in HY-11-treated HL-60. In addition, HY-11 enhanced the expression of TGF-beta1, TGF-beta receptor type I and II and vitamin D3 receptor (VDR). VDR expression was increased by TGF-beta1, suggesting that TGF-beta1 might be involved in the antiproliferative effect of HY-11 on HL-60 cells by autocrine and paracrine regulation. Serum calcium levels were within normal limit when HY-11 was given intraperitoneally (i.p.) every other day for 5 weeks to BALB/c mice at the doses of 10(-7), 10(-6)and 10(-5) M. HY-11 inhibited the growth of WEHI-3BD+ mouse leukemic cells in vitro, and syngeneic BALB/c mice that received WEHI-3BD+ mouse leukemic cells and HY-11 had a significantly longer survival without producing hypercalcemia compared to control group. In summary, HY-11 is a vitamin D3 analog that inhibited the proliferation of human AML cell line, HL-60, through induction of cell cycle arrest, triggering apoptosis as well as modulation of TGF-beta1 and its receptors. In particular, HY-11 significantly increased the survival of mice that had myeloid leukemia without producing hypercalcemia.

Total synthesis of (+/-)-crinine via the regioselective Stille coupling and Diels-Alder reaction of 3,5-dibromo-2-pyrone.

The regioselective synthesis and Diels-Alder cycloaddition of 3-(3,4-methylenedioxyphenyl)-5-bromo-2-pyrone provided a new synthetic route to crinine. The vinyl bromide group can be used as a handle for further derivatization.

Total syntheses of (+/-)-crinine, (+/-)-crinamine, and (+/-)-6a-epi-crinamine via the regioselective synthesis and Diels-Alder reaction of 3-aryl-5-bromo-2-pyrone.

We have devised a new unified synthetic protocol to (+/-)-crinine, (+/-)-crinamine, and (+/-)-6a- epi-crinamine from the Diels-Alder cycloadduct of 3-(3,4-methylenedioxyphenyl)-5-bromo-2-pyrone with TBS vinyl ether. The requisite 3-(3,4-methylenedioxyphenyl)-5-bromo-2-pyrone was prepared from the C3-selective Stille coupling reaction of 3,5-dibromo-2-pyrone. Also noted is that the vinyl bromide can be used as a handle for further derivatization.

H-Bonding Mediated Asymmetric Intramolecular Diels-Alder Reaction in the Formal Synthesis of (+)-Aplykurodinone-1.

An asymmetric formal total synthesis of (+)-aplykurodinone-1 was achieved using a route, in which hydrogen bonding serves as a stereochemical control element governing the π-facial selectivity of intramolecular Diels-Alder (IMDA) reaction of an enone tethered 2-pyrone. In the IMDA process, the configuration at a stereogenic, hydroxyl bearing an α-carbon in the enone dienophile is conveyed in a highly effective manner through intramolecular hydrogen bonding with the enone carbonyl oxygen. The tricyclic lactone, generated in this process, was successfully converted to a late stage intermediate in Danishefsky's synthesis of aplykurodinone-1.

Total synthesis of (+/-)-joubertinamine from 3-(3,4-dimethoxyphenyl)-5-bromo-2-pyrone.

The regioselective synthesis and Diels-Alder cycloaddition of 3-(3,4-dimethoxyphenyl)-5-bromo-2-pyrone provided a new efficient synthetic route to joubertinamine (9.6% total yield over 10 steps).