The Phosphinamide-Based Catalysts: Discovery, Methodology Development, and Applications in Natural Product Synthesis.

In the total synthesis of natural products, synthetic efficiency has been an important driver for designing and developing new synthetic strategies and methodologies. To this end, the step, atom, and time economy and the overall yield are major factors to be considered. On the other hand, developing unified routes that can be used for synthesizing multiple molecules, specifically skeletally different classes of molecules, are also important aspects with which to be concerned. In the efforts toward efficient and flexible synthesis of structurally unique terpenoid and indole alkaloid natural products, we have designed and developed several phosphinamide-based new catalysts and reaction methodologies that have been compellingly demonstrated to be widely useful as strategic protocols for the diverse synthesis of various complex terpenoids and indole alkaloids. The important progress of these results will be summarized in this Account.In the first part, we present the stories of successful design and establishment of a novel method for the synthesis of P-stereogenic phosphinamides (P-SPhos) via a Pd-catalyzed C-H desymmetric enantioselective arylation, as well as the flexible derivatization of the P-stereogenic phosphinamides into various types of skeletally unique tricyclic and N,P-bidentate P-stereogenic compounds. Subsequently, the discovery of P-stereogenic phosphinamides as chiral organocatalysts for the desymmetric enantioselective reduction of cyclic 1,3-diketones and of phosphinamide-based cyclopalladium complex (C-Pd) as precatalysts for highly efficient Suzuki-Miyaura cross-coupling reaction of sterically congested nonactivated enolates is introduced. The notable features of the P-stereogenic phosphinamide-catalyzed desymmetric enantioselective reduction are highlighted by the broad substrate compatibility and excellent stereoselectivity, as well as most significantly, the good recoverability and reusability of catalysts. With regard to the sterically congested nonactivated enolates, such substrates are challenging for Suzuki cross-coupling reactions. We demonstrate that the phosphinamide-based cyclopalladium is a type of highly active precatalyst that allows the reaction to proceed under mild conditions and to be easily scaled up. Following the methodology development, the practical applications of these methods serving as strategic transformations are highlighted by the unified synthesis of four cyathane-type and two hamigeran-type terpenoids.In the second part, we describe the development of a robust method for oxidative Heck cross-coupling of indolyl amides by using the phosphinamide-based cyclopalladium as catalyst or phosphinamide as coligand. The method provides a general and straightforward method for diverse synthesis of indolyl δ-lactam derivatives, which present as a common core in a variety of Aspidosperma-derived indole alkaloids. The successful demonstration of this protocol for a concise and divergent synthesis of leuconodine-type indole alkaloids is also presented. We believe the results presented in this Account would have significant implications beyond our results and would find further applications in the field of synthetic methodology and natural product synthesis.

Synthetic Studies on the Synthesis of Toxicodenane A and 8,11-epi-Toxicodenane A.

The diverse synthesis of oxatricyclotridecanes and oxatricyclododecanes, which are the core structures of toxicodenane A and its skeletal analogues, via a unified manner is presented. The stereochemistry at the bridgehead position of the oxa-bridged bicycle could be efficiently controlled through a diastereoselective anti- and syn-Grignard allylation reaction by appropriately tuning the reaction conditions such as the solvent, the counterion of the Grignard reagent, the substrate, or a combination of these. The ring size could be precisely elaborated via a Lewis acid-mediated intramolecular transacetalation and Prins cyclization cascade reaction by varying the steric hindrance of olefin moiety. Namely, substrates bearing a terminally unsubstituted olefinic functionality afforded oxatricyclotridecanes with an overwhelming preference, while those bearing a dimethyl-substituted olefinic group produced exclusively oxatricyclododecanes. The wide utility and generality of the above key transformations are highlighted by the applications in the unified synthesis of (±)-toxicodenance A, (+)-toxicodenane A, (+)-8,11-epi-toxicodenane A, and other oxatricyclic cores with different stereochemistries and ring sizes.

Synthesis and Biological Evaluation of Diversified Hamigeran B Analogs as Neuroinflammatory Inhibitors and Neurite Outgrowth Stimulators.

We describe the efficient synthesis of a series of new simplified hamigeran B and 1-hydroxy-9-epi-hamigeran B norditerpenoid analogs (23 new members in all), structurally related to cyathane diterpenoid scaffold, and their anti-neuroinflammatory and neurite outgrowth-stimulating (neurotrophic) activity. Compounds 9a, 9h, 9o, and 9q exhibited moderate nerve growth factor (NGF)-mediated neurite-outgrowth promoting effects in PC-12 cells at the concentration of 20 µm. Compounds 9b, 9c, 9o, 9q, and 9t showed significant nitric oxide (NO) production inhibition in lipopolysaccharide (LPS)-activated BV-2 microglial cells, of which 9c and 9q were the most potent inhibitors, with IC50 values of 5.85 and 6.31 µm, respectively. Two derivatives 9q and 9o as bifunctional agents displayed good activities as NO production inhibitors and neurite outgrowth-inducers. Cytotoxicity experiments, H2O2-induced oxidative injury assay, and ELISA reaction speculated that compounds may inhibit the TNF-α pathway to achieve anti-inflammatory effects on nerve cells. Moreover, molecular docking studies provided a better understanding of the key structural features affecting the anti-neuroinflammatory activity and displayed significant binding interactions of some derivatives (like 9c, 9q) with the active site of iNOS protein. The structure-activity relationships (SARs) were also discussed. These results demonstrated that this structural class compounds offered an opportunity for the development of a new class of NO inhibitors and NGF-like promotors.

Synthetic Studies on Enantioselective Total Synthesis of Cyathane Diterpenoids: Cyrneines A and B, Glaucopine C, and (+)-Allocyathin B2.

The details for the synthetic studies on enantioselective total synthesis of cyathane diterpenoids cyrneine A (1) and B (2), glaucopine C (3), and (+)-allocyathin B2 are presented. We established a mild Suzuki coupling for heavily substituted nonactivated cyclopentenyl triflates using a phosphinamide-derived palladacycle as precatalyst and a chelation-controlled highly regioselective Friedel-Crafts cyclization. The utilization of these two key reactions enabled a rapid construction of the 5-6-6 tricyclic skeleton. In the middle stage of the synthesis, a Birch reductive methylation, a modified Wolff-Kishner-Huang reduction, and a carbenoid-mediated ring expansion were employed as the key reactions to furnish the 5-6-7 tricyclic core bearing two antiorientated all-carbon quaternary stereocenters at the C6 and C9 ring junctions. By applying these key transformations, a more efficient total synthesis of cyrneine A and allocyathin B2, and the first total synthesis of cyrneine B and glaucopine C, were accomplished through a collective manner. The late-stage conversions involving a base-mediated double bond migration and a double bond migration/aerobic γ-CH oxidation cascade for the stereoselective synthesis of cyrneine B and glaucopine C were interesting.

Pd(II)-catalyzed enantioselective synthesis of P-stereogenic phosphinamides via desymmetric C-H arylation.

We present the enantioselective synthesis of P-stereogenic phosphinamides through Pd-catalyzed desymmetric ortho C-H arylation of diarylphosphinamides with boronic esters. The method represents the first example of the synthesis of P-stereogenic phosphorus compounds via the desymmetric C-H functionalization strategy. The reaction proceeded efficiently with a wide array of reaction partners to afford the P-stereogenic phosphinamides in up to 74% yield and 98% ee. The efficiency was further demonstrated by gram scale syntheses. Moreover, the flexible conversion of the P-stereogenic phosphinamides into various types of P-stereogenic phosphorus derivatives was also elaborated. Thus, the protocol provides a novel tool for the efficient and versatile synthesis of P-stereogenic compounds.

Alcohol consumption and liver cancer risk: a meta-analysis.

PURPOSE: Alcohol is a confirmed risk factor of liver cancer. Yet, its dose-response function and synergistic effects with other risk factors remain unclear. METHODS: We performed a meta-analysis on publications up to May 2014. A total of 112 publications were identified. The meta-relative risk (mRR) and the dose-response trend were calculated. Tests for heterogeneity, publication bias, and sensitivity analyses were performed. The synergy index (SI) was recorded or calculated, whenever possible. RESULTS: Compared to individuals who never drank or drank at very low frequencies, the mRR for ever drinkers was 1.29 (95% confidence interval, CI 1.16-1.42) and 1.46 (95% CI 1.27-1.65) for case-control studies, and 1.07 (95% CI 0.87-1.27) for cohort studies. Being a current drinker was associated with an increased liver cancer risk in case-control studies (mRR = 1.55, 95% CI 0.38-2.73), but not in cohort studies (mRR = 0.86, 95% CI 0.74-0.97). The dose-response relation between alcohol and liver cancer was apparent with RR = 1.08 (95% CI 1.04-1.11) for 12 g/day (~1 drink), 1.54 (95% CI 1.36-1.74) for 50 g/day, 2.14 (95% CI 1.74-2.62) for 75 g/day, 3.21 (95% CI 2.34-4.40) for 100 g/day, and 5.20 (95% CI 3.25-8.29) for 125 g/day of alcohol consumption. There were synergistic effects of alcohol consumption with hepatitis (S = 2.14, 95% CI 1.31-2.98) and with diabetes (S = 3.57, 95% CI 2.29-4.84) on the risk of liver cancer, although this may be subject to publication bias. CONCLUSION: Overall, one alcoholic drink per day (~12 g/day) may be associated with a 1.1 times higher liver cancer risk. Further studies on the synergistic effects of alcohol consumption and other major risk factors are warranted.

Pd(II)-catalyzed mild C-H ortho arylation and intramolecular amination oriented by a phosphinamide group.

A novel protocol for the Pd-catalyzed ortho-arylation of aryl phosphinamide with boronic acid is reported. By using phosphinamide as a new directing group, the reaction proceeds efficiently under mild conditions at 408C. Mechanistic studies reveal that the reaction proceeds via a PdII to Pd0 cycle. The phosphinamide group is also shown to be an effective orienting group for direct C-H amination.

[NiCl2(dppp)]-catalyzed cross-coupling of aryl halides with dialkyl phosphite, diphenylphosphine oxide, and diphenylphosphine.

We present a general approach to C-P bond formation through the cross-coupling of aryl halides with a dialkyl phosphite, diphenylphosphine oxide, and diphenylphosphane by using [NiCl(2) (dppp)] as catalyst (dppp=1,3-bis(diphenylphosphino)propane). This catalyst system displays a broad applicability that is capable of catalyzing the cross-coupling of aryl bromides, particularly a range of unreactive aryl chlorides, with various types of phosphorus substrates, such as a dialkyl phosphite, diphenylphosphine oxide, and diphenylphosphane. Consequently, the synthesis of valuable phosphonates, phosphine oxides, and phosphanes can be achieved with one catalyst system. Moreover, the reaction proceeds not only at a much lower temperature (100-120 °C) relative to the classic Arbuzov reaction (ca. 160-220 °C), but also without the need of external reductants and supporting ligands. In addition, owing to the relatively mild reaction conditions, a range of labile groups, such as ether, ester, ketone, and cyano groups, are tolerated. Finally, a brief mechanistic study revealed that by using [NiCl(2) (dppp)] as a catalyst, the Ni(II) center could be readily reduced in situ to Ni(0) by the phosphorus substrates due to the influence of the dppp ligand, thereby facilitating the oxidative addition of aryl halides to a Ni(0) center. This step is the key to bringing the reaction into the catalytic cycle.

Enantioselective Total Synthesis and Absolute Configuration Assignment of (+)-Toxicodenane A.

We present the first enantioselective total synthesis and absolute configuration assignment of (+)-toxicodenane A via a nine-step sequence from the readily available material. The synthesis features a desymmetric enantioselective reduction of 2,2-disubstituted 1,3-cyclohexanedione for the synthesis of a chiral 2,2-disubstituted 3-hydroxy cyclohexanone building block, a highly diastereoselective Grignard reaction for the incorporation of an allyl group, and a Lewis acid-mediated intramolecular transacetalation and Prins cascade reaction for the construction of oxa-bridged bicyclic rings.

Natural Products with Analgesic Effect from Herbs and Nutraceuticals Used in Traditional Chinese Medicines.

BACKGROUND: Pain is one of the most common clinical symptoms . This review aims to describe research on herbs and their active ingredients in treating pain and provide a valuable reference for the development and utilization of analgesic traditional Chinese medicine (TCM). MATERIAL AND METHODS: The literature search was performed from 1995 to October 2016, covering the relevant studies that concern the treatment of pain with TCM. Active ingredients extracted from TCM with analgesic activity are summarized and classified into six categories, including polysaccharides, saponins, alkaloids, flavonoids, terpenoids, and other constituents. RESULTS: There are two pathways constituting the analgesic mechanisms of TCM: through the central nervous system and the peripheral nervous system. The former pathway includes increasing the content of endogenous analgesic substances like opiate peptide, cutting down the second messenger of neurotransmitter like nitric oxide (NO), reducing the content of prostaglandin E2 (PGE2) in brain tissues, blocking the central calcium channel, reducing excitatory amino acids in brain tissues, inhibiting their receptors and raising the content of the central 5-hydroxytryptamine (5-HT). The latter one usually involves the decrease in the secretion of peripheral algogenic substances, the induction of pain-sensitive substances, the accumulation of a local algogenic substance, the increase in the release of peripheral endogenous analgesia materials and the regulation of c-Fos gene (immediate early gene).

Total synthesis of cyrneines A-B and glaucopine C.

The cyrneine diterpenoids represent a structurally intriguing subfamily of cyathane diterpenoids and could significantly induce neurite outgrowth. Therefore, the efficient synthesis of these natural products is of great importance. Herein, we present a route for the collective synthesis of cyrneines A, B, and glaucopine C. As the key precursor, the 5-6-6-tricyclic scaffold is efficiently constructed by employing a mild Suzuki coupling of heavily substituted nonactivated cyclopentenyl triflate and a chelation-controlled regiospecific Friedel-Crafts cyclization as key transformations. The stereoselective installation of the all-carbon quaternary center at C6 ring junction of the tricycle is achieved via Birch reductive methylation. Subsequently, a carbenoid-mediated ring expansion furnishes the essential 5-6-7-tricyclic core. Finally, manipulation of this core by several appropriately orchestrated conversions accomplishes a more step-economic synthesis of cyrneine A (20 steps), and the first synthesis of cyrneine B (24 steps) and glaucopine C (23 steps).

A Total Synthesis of (-)-Hamigeran B and (-)-4-Bromohamigeran B.

A concise synthesis of (-)-hamigeran B and (-)-4-bromohamigeran B is presented. The key reactions include a Suzuki coupling of enol triflate 15 with arylboronic ester for efficient synthesis of the densely 1,2,3-trisubstituted cyclopentene 23, a coordination-controlled intramolecular Friedel-Crafts cyclization of free phenol 13 for highly regioselective construction of tricyclic core 12, and a LiOH/O2-promoted hydrolysis and concomitant aerobic oxidation of 31 for atom- and step-economic accessing of diketone 32. The application of these key transformations allowed for a rapid and efficient synthesis of (-)-hamigeran B and (-)-4-bromohamigeran B in 13 steps from the readily available chiral material 18.

Associations between Medical Conditions and Breast Cancer Risk in Asians: A Nationwide Population-Based Study in Taiwan.

BACKGROUND: The breast cancer incidence in Asia is rising. To explore whether the etiology of breast cancer is different from the known risk factors from studies in Western countries, we conducted a nested case-control study using data from the Taiwan National Health Insurance Research Database (NHIRD). METHODS: All medical conditions based on the first three digits of the ICD-9 and a list of medical conditions based on literature review were retrieved for each case and control. The odds ratios (OR) and 95% confidence intervals (CI) of the associations between medical conditions and breast cancer risks were estimated using conditional logistic regression and adjusted for occupation, number of breast cancer screening, and the average number of outpatient visits prior the diagnosis. The associations were also estimated for younger (<50 years old) and older subjects separately. RESULTS: The analyses included 4,884 breast cancer cases and 19,536 age-matched controls. Prior breast diseases (OR, 95% CI: 2.47, 2.26-2.71), obesity (1.43, 1.04-1.96), endometriosis (1.44, 1.15-1.80), uterine leiomyoma (1.20, 1.03-1.40), hypertensive diseases (1.14, 1.05-1.25), and disorders in lipid metabolism (1.13, 1.04-1.24) were associated with increased breast cancer risk. No heterogeneity was observed between age groups (<50 and ≥50 years old). CONCLUSIONS: In addition to benign breast diseases, obesity, endometriosis, uterine leiomyoma, hypertensive diseases, and disorders of lipid metabolism were associated with a subsequent breast cancer risk. IMPACTS: Our results suggest that estrogen related factors may play an important role in breast cancer risks in the Taiwanese female population.

Ni-catalyzed construction of C-P bonds from electron-deficient phenols via the in situ aryl C-O activation by PyBroP.

The C-P bond forming reaction using electron-deficient phenol substrates was considerably challenging. Herein, we present a new protocol that allows for one-pot construction of C-P bonds via the cross-coupling of phenols and phosphine oxide or phosphite in the presence of a nickel catalyst.