Employing Pressurized Hot Water Extraction (PHWE) to Explore Natural Products Chemistry in the Undergraduate Laboratory

A recently developed pressurized hot water extraction (PHWE) method which utilizes an unmodified household espresso machine to facilitate natural products ...

University of Tasmania

A new, practical, rapid, and high-yielding process for the pressurized hot water extraction (PHWE) of multigram quantities of shikimic acid from star anise (Illicium verum) using an unmodified household espresso machine has been developed. This operationally simple and inexpensive method enables the efficient and straightforward isolation of shikimic acid and the facile preparation of a range of its synthetic derivatives. 

New method for the rapid extraction of natural products: efficient isolation of shikimic acid from star anise.

The dearomatization of heterocycles has been a powerful means for producing functional molecules in synthesis. In the case of pyrroles, reductive methods (such as the Birch reduction) have been most widely exploited, while oxidative methods are generally dismissed as too difficult or unpredictable to be useful. However, since the early twentieth century considerable research has been carried out on the controlled oxidation of pyrroles to give highly functionalized products, using a variety of oxidants. This review presents a summary of all work up until the present day in the area of pyrrole oxidation, looking at the use of peroxide, singlet oxygen, hypervalent iodine reagents, a range or organic and inorganic oxidants, and electrochemical approaches. It also offers some perspective on the potential future role of pyrrole oxidation in synthesis. 

The Oxidation of Pyrrole.

Polygodial, a valuable sesquiterpene dialdehyde featuring an epimerizable stereocenter was efficiently extracted and isolated in gram-scale quantities (3.3% w/w) from Tasmannia lanceolata (Tasmanian native pepper) via a recently developed rapid pressurised hot water extraction (PHWE) technique that utilises an unmodified household espresso machine. This method was compared to the maceration of T. lanceolata under a range of conditions. Polygodial was used to achieve semi-syntheses of closely related sesquiterpene natural products drimendiol, (-)-drimenol, (+)-euryfuran, and some non-natural derivatives. 

Practical isolation of polygodial from Tasmannia lanceolata: a viable scaffold for synthesis.

Covering: 2008 to 2016The total synthesis of natural products and their derivatives continues to inspire organic chemists to identify and test new synthetic strategies and develop and explore novel methodology. In recent years, visible light photoredox catalysis has risen to prominence as a powerful technology that enables the selective formation of chemical bonds under mild reaction conditions. Herein we review applications of photoredox catalysis to the synthesis of natural products and related complex molecules, showcasing a range of powerful transformations that include: reductive couplings, photocycloadditions, intermolecular C-H functionalisation processes, fragmentations, and cyclisations.

Applications of visible light photoredox catalysis to the synthesis of natural products and related compounds.

The photooxidation of pyrrole is typically low yielding due to the absorbance of ultraviolet light, which leads to uncontrolled polymerisation and decomposition. Presented herein is the development of a simple and cost-effective photoreactor utilising Light Emitting Diodes (LEDs) as the light source, and its application to the dye-sensitised oxidation of a range of pyrroles to give corresponding 3-pyrrolin-2-ones. The broader applicability of this approach to the generation of O is also explored.

Visible light dye-photosensitised oxidation of pyrroles using a simple LED photoreactor.

Seven new and two known ent-labdane diterpenoids have been isolated from a single plant specimen of Dodonaea viscosa ssp. spatulata, found in Tasmania, Australia. Prior to this study, only seven different labdane diterpenoids had been isolated from D. viscosa. The structures of the natural products were assigned via 1D and 2D NMR spectroscopy and other standard spectroscopic methods. The absolute configuration of three ent-labdane diterpenoids was determined by single-crystal X-ray crystallography of synthetic derivatives. Significantly, the results of this study suggest that the absolute configuration of some known labdane diterpenoids may have been misassigned.

ent-Labdane Diterpenoids from Dodonaea viscosa.

Pressurised hot water extraction (PHWE) was employed to effect the extraction of two carboxylic acid-containing ent-labdane diterpenoids from Dodonaea viscosa. The different extraction profile provided by PHWE in this case suggests that this recently developed method also has applications as a complementary tool for natural products extraction.

Extraction of carboxylic acid-containing diterpenoids from Dodonaea viscosa via pressurised hot water extraction.

Pyrrole, pyrrolidine, and indolizidine alkaloids represent important classes of natural products. Historically, these heterocycles and their derivatives have been the focus of significant interest in organic synthesis. In this report, we review the methods that have been employed to synthesise annulated pyrroles via transformations that include: Friedel-Crafts acylations and alkylations, Michael additions, Heck couplings, hydroarylations, carbenoid insertions, and radical cyclisations.

Methods for the synthesis of annulated pyrroles via cyclisation strategies.

Counterion-induced stereocontrol is a powerful tool in organic synthesis. However, such enantiocontrol on tetrahedral ammonium cations remains challenging. Described here is the first example of using chiral anion phase-transfer catalysis to achieve intermolecular ring-opening of azetidiniums with excellent enantioselectivity (up to 97 % ee). Precise control over the formation and reaction of the chiral ion pair as well as inhibition of the background reaction by the biphasic system is key to the success of the reaction.

Counterion-Induced Asymmetric Control in Ring-Opening of Azetidiniums: Facile Access to Chiral Amines.

It has been reported that pulsed irradiation can improve photosynthetic activity and phytochemical production in plants. Intrigued and inspired by these observations, we postulated that pulsed irradiation strategies may have broader implications in organic synthesis. We report here the results of a proof-of-concept study demonstrating that pulsed LED irradiation enhances the efficiency of a visible light-mediated photoredox-catalysed reaction. The design and construction of an inexpensive multiphase circuit (∼US$5) enabling power and pulse frequency modulation, which is connected to light-emitting diodes (LEDs), provides a source of pulsed visible light. This technology was then utilised to establish a novel copper-photocatalysed dual α-amino C-H/C-F functionalisation reaction. Pulsed blue LED irradiation was shown to be crucial for facilitating a much more efficient process and increasing the rate of product formation. Our results suggest that pulsed irradiation strategies have the potential to contribute to enhancing the synthetic utility and extending the scope of first row transition metal-based photoredox catalysts. We also anticipate that this approach will find wider applications in synthesis.

Identifying the potential of pulsed LED irradiation in synthesis: copper-photocatalysed C-F functionalisation.

Extensive phytochemical studies of the paleoendemic Tasmanian Proteaceae species Bellendena montana, Cenarrhenes nitida, and Persoonia gunnii were conducted employing pressurized hot water extraction. As part of these studies, six novel glycosides were isolated, including rare examples of glycoside-containing natural products featuring tiglic acid esters. These polar molecules may represent potential phytochemical markers in ancient Proteaceae.

Arbutin Derivatives Isolated from Ancient Proteaceae: Potential Phytochemical Markers Present in Bellendena, Cenarrhenes, and Persoonia Genera.

An investigation of the previously unexamined ancient Tasmanian clone Lomatia tasmanica W. M. Curtis (Proteaceae) and two other endemic species Lomatia tinctoria R. Br. and Lomatia polymorpha (Labill.) R. Br. was undertaken. This represents the first extensive natural products study in which individual phytochemical components have been isolated and identified from these three Lomatia species. Extraction of L. tasmanica leaves provided the naphthoquinone juglone (0.34% w/w), and n-alkanes nonacosane and heptacosane (0.30% w/w combined). L. polymorpha afforded the flavonoid glycosides dihydroquercetin 3-O-β-D-xyloside (0.22% w/w) and quercetin 3-O-β-d-glucose (0.14% w/w), as well as the naphthalene glucoside 1,4,8-trihydroxynaphthalene-1-O-β-d-glucose (0.04% w/w) and 4-O-p-coumaroyl-d-glucose (0.03% w/w). In addition, both L. polymorpha and L. tinctoria contained juglone (0.32% w/w and 0.58% w/w, respectively). L. polymorpha provided tetracosan-1-ol, hexacosan-1-ol and octacosan-1-ol (0.07% w/w combined), while L. tinctoria gave nonacosane (0.13% w/w). Analysis of three individual specimens from each of the three species demonstrated consistency in the respective phytochemical profiles of these populations and tentatively suggests limited intraspecific variation.

Phytochemical profile of the rare, ancient clone Lomatia tasmanica and comparison to other endemic Tasmanian species L. tinctoria and L. polymorpha.

Platelet-activating factor (PAF) and its receptor (PAFr) have been implicated in a wide range of diseases and disorders that originate from the activation of inflammatory pathways. Although the exact structure of the binding site on the PAFr remains unknown, the PAFr is a well-established therapeutic target, and an array of structurally diverse PAFr antagonists have been identified. These include compounds that are structurally similar to the natural PAF ligand, synthetic heterocycles, complex polycyclic natural products, and various metal complexes. This review provides an update on more than 20 years of progress in this area. The development and synthesis of new PAFr antagonists, structure-activity relationship studies, the biological activity of these molecules, and their therapeutic potential are discussed.

Progress in the Development of Platelet-Activating Factor Receptor (PAFr) Antagonists and Applications in the Treatment of Inflammatory Diseases.

Polygodial, a drimane sesquiterpenoid dialdehyde isolated as a pungent component of the water pepper Persicaria hydropiper, exhibits antifeedant, antimicrobial, anti-inflammatory and anticancer effects. Polygodial also activates transient receptor potential vanilloid subtype 1 (TRPV1) channels. Previously, we described the synthesis of a C12-Wittig derivative of polygodial, termed P3, with significant antiproliferative effects against multiple cancer types including oral squamous cell carcinoma (OSCC). In the present study, a more potent derivative, P27, with superior anti-proliferative effects in vitro and antitumor effects in Cal-27 derived xenografts is described. Polygodial, P3, and P27 all significantly decreased OSCC tumor growth, with P27 being equipotent with polygodial and P3 being the least efficacious. However, neither analog elicited the adverse effect observed with polygodial: Profound transient inflammation. Although P3 and P27 pharmacophores are based on polygodial, novel effects on OSCC cell cycle distribution were identified and shared anticancer effects that are independent of TRPV1 activity were observed. Polygodial elicits an S-phase block, whereas P3 and P27 lead to G2/M phase arrest. Pretreatment of OSCC cells with the TRPV1 antagonist capsazepine does not affect the antiproliferative activity of P3 or P27, indicating that TRPV1 interactions do not regulate OSCC cell proliferation. Indeed, calcium imaging studies identified that the analogs neither activate nor antagonize TRPV1. Behavioral studies using a rat model for orofacial pain confirmed that these analogs fail to induce nocifensive responses, indicating that they are non-noxious in vivo. All compounds induced a significant concentration-dependent decrease in the mitochondrial transmembrane potential and corresponding apoptosis. Considering that P27 is equipotent to polygodial with no TRPV1-associated adverse effects, P27 may serve as an efficacious novel therapy for OSCC.

Alex C. Bissember

School of Natural Sciences - Chemistry

University of Tasmania

Employing Pressurized Hot Water Extraction (PHWE) to Explore Natural Products Chemistry in the Undergraduate Laboratory

Alex C. Bissember

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}School of Natural Sciences - Chemistry

University of Tasmania

Employing Pressurized Hot Water Extraction (PHWE) to Explore Natural Products Chemistry in the Undergraduate Laboratory

School of Natural Sciences - Chemistry