Natural Product Chemistry - Chapter 2 (a) PDF

BWK20803 NATURAL PRODUCT CHEMISTRY Chapter 2: Phytochemicals – Terpenes & Terpenoids Phenolics - Flavonoids ChM. Dr. Saliza Asman Semester 2 2032/2024 Introduction of phytochemistry Classification of phytochemicals Terpenes, terpenoids, flavo...

BWK20803 NATURAL PRODUCT CHEMISTRY Chapter 2: Phytochemicals – Terpenes & Terpenoids Phenolics - Flavonoids ChM. Dr. Saliza Asman Semester 2 2032/2024 Introduction of phytochemistry Classification of phytochemicals Terpenes, terpenoids, flavonoids, phenolics, alkaloids, sulphur containing compounds and steroids. Major classes of organic natural products ◦ Peptides and proteins (basically consist of amino acids) ◦ Fats and oils ◦ Nucleotides (purines) ◦ Vitamins ◦ Steroids ◦ Terpenes (terpenoids) ◦ Carteins (carotenoids) ◦ Anthocyanines ◦ Alkaloids  TERPENES & TERPENOIDS  Introduction oTerpenes – class of >20,000 compounds containing carbon atoms in multiples of five. oTerpenoids – oxygen-containing terpenes (alcohols, ketones, aldehydes) http://www.chm.bris.ac.uk/motm/isoprene/isopreneh.htm  Introduction o The name “terpene” is derived from the word “turpentine” o They originate from Turpentine, which flows on cutting or curving the bark and new wood of several pine tree species. o Terpenes are strong-smelling natural compounds which are produced by a variety of plants, especially conifers. o Terpenes and terpenoids are the primary constituents of the essential oils of many types of plants and flowers. Many terpenes are derived commercially from conifer resins, such as those made by this pine. https://www.youngliving.com/en_MY/ Introduction oExamples of terpenes and terpenoids. oTerpenoids are substituted terpenes. Terpenes oTerpenes are natural products that are structurally related to isoprene (C5) CH3 or H2C C CH CH2 Isoprene (2-methyl-1,3-butadiene) Terpenes oMyrcene (isolated from the oil of bayberry) is a typical terpene. bayberry CH3 CH2 CH3C CHCH2CH2CCH CH2 or Isoprene rule and special isoprene rule oThese rules state that: oThe molecules of all terpenes are constituted of two or more isoprene units. oIn natural terpenoids isoprene units were linked head to tail arrangement, the head being the branched end.  The Isoprene Unit (𝑪𝟓 ) o An isoprene unit is the carbon skeleton of isoprene (ignoring the double bond) Myrcene contains two isoprene units. The Isoprene Unit (𝑪𝟓 ) o The isoprene units of myrcene are joined “head-to-tail”. tail head tail head  Classification of Terpenes oMost natural terpenoid Class No. of carbon atoms hydrocarbon have the general Hemiterpene 5 formula (𝑪𝟓 𝑯𝟖 )n. They can be Monoterpene 10 classified on the basis of value of ‘n’ or ‘number of carbon atoms Sesquiterpene 15 present in the structure. Diterpene 20 Sesterterpene 25 Triterpene 30 Tetraterpene 40 Polyterpene >40  Classification of Terpenes According to the Number of Rings oEach class can be further subdivided into subclasses according to the number of rings present in the structure. Classification of Terpenes oThe simpler mono and sesqui terpenes are the chief constituent of the essential oils obtained from sap and tissues of certain plants and trees. oThe di and triterpenoids are not steam volatile. They are obtained from plant and tree gums and resins. oTetraterpenoids form a separate group of compounds called “Carotenoids’. Representative Monoterpenes Identify the building block/ isoprene unit OH O H a-Phellandrene Menthol Citral (eucalyptus) (peppermint) (lemon grass) Representative Monoterpenes OH O H a-Phellandrene Menthol Citral (eucalyptus) (peppermint) (lemon grass) Representative Monoterpenes a-Phellandrene Menthol Citral (eucalyptus) (peppermint) (lemon grass) Representative Sesquiterpenes Identify the building block/ isoprene unit a-Selinene (celery) Representative Sesquiterpenes a-Selinene (celery) Representative Sesquiterpenes The isoprene units; a-Selinene (celery) Representative Diterpenes OH Vitamin A Identify the building block/ isoprene unit Representative Diterpenes OH Vitamin A Representative Diterpenes Vitamin A Representative Triterpenes tail-to-tail linkage of isoprene units Squalene (shark liver oil) Finding the isoprene building block - cyclic compounds Finding the isoprene building block - sesquiterpenes (C15) Representative Triterpenes Finding the isoprene building block - triterpenes (C30) - Squalene has a natural and vital part in the synthesis of all plant and animal sterols, including cholesterol, steroid hormones, and vitamin D in the human body  Representative Tetraterpenes Finding the isoprene building block - tetraterpenes (C40) Lycopene is responsible for the red color in tomatoes and watermelon Representative Tetraterpenes  -carotene is the compound that causes carrots and apricots to be orange Biosynthesis ◦ The precursor to C10 terpenoids (monoterpenes) is Geranyl pyrophosphate (GPP), also known as geranyl diphosphate (GDP), which consists of two C5 “isoprene units” that are joined “head-to-tail” PP Geranyl pyrophosphate head - tail head - tail Biosynthesis C15 sesquiterpenoids o are derived from Farnesyl diphosphate, o which consists of three C5 “isoprene units” that are joined o “head-to-tail” Biosynthesis C20 diterpenoids o are derived from Geranylgeranyl diphosphate (GPP), o which consists of four C5 “isoprene units” that are joined o “head-to-tail” OPP Terpenoid nomenclature 1. Groups and subgroups 2. Based on pathways 3. Classification 4. IUPAC 5. CAS (Chemical Abstracts Service)- registry number 6. Trivial name (derived from the structural family or relate to natural source) Examples of the co-existence of systematics Semi-systematic and trivial names  Menthol – a cyclic terpenoid H3C CH3 CH This terpene has been oxidised to a terpenoid CH OH H2C CH H2C CH2 CH CH3 Menthol (peppermint) Absinthe – a cyclic terpenoid a potent green aniseed-flavored liqueur, originally made with the shrub wormwood. (the seed of the anise, used in cooking and herbal medicine) H3C CH3 CH C H2C CH2 HC C CH O This terpene has been oxidised to a terpenoid CH3 Thujone (Absinthe) Camphor – a cyclic terpenoid CH3 H3C C CH CH2 CH2 C H2C C H3C O Camphor (Camphor tree)  a-Selinene – a cyclic terpene CH3 CH2 CH2 3 isoprene units H2C C CH2 H2C CH C 15 carbon atoms CH2 C CH2 C H CH3 CH2 a-Selinene  β-carotene – a linear terpene H3C CH2 C CH2 CH3 CH3 H3C CH3 CH C CH2 CH CH CH C CH C CH C CH CH C C CH C H2C C CH CH CH CH CH H3C CH3 CH3 CH3 H2C C CH2 CH3 -carotene 8 isoprene units 40 carbon atoms THE ROLE OF TERPENOIDS IN NATURE oTerpenoids are produced by a wide variety of plants, animals, and microorganisms. oAs for all metabolites, the synthesis of terpenoids places a metabolic load on the organism which produces them and so, almost invariably, there is a role that the material plays and for which it is synthesized. oThe roles which the terpenoids play in living organisms: o Defense (producing resins and gums, e.g. Acacia gummiferae) o Functional o Communication  FUNCTIONAL o Vitamin A, or retinol, is the precursor for the pigment in the eyes which detects light and is therefore responsible for the sense of sight. o Vitamin E, or tocopherol, is an important antioxidant that prevents oxidative damage to cells. Tocopherol  FUNCTIONAL o Vitamin D2, also known as calciferol, regulates calcium metabolism in the body and is therefore vital for the building and maintenance of bone. Calciferol o Chlorophyll-A is a green pigment found, for example, in plant leaves and is a key factor of photosynthesis through which atmospheric carbon dioxide is converted to glucose. Chlorophyll-A  COMMUNICATION o Terpenoids are also used as chemical messengers. o If the communication is between different parts of the same organism, the messenger is referred to as a hormone. o Giberellic acid is a hormone used by plants to control their rate of growth. COMMUNICATION Semiochemicals o Chemicals that carry signals from one organism to another are known as semiochemicals. oThese can be grouped into two main classes: i. Pheromones ii. Allelochemicals COMMUNICATION Semiochemicals: Pheromones o If the signal is between two members of the same species, the messenger is called a pheromone. o Pheromones carry different types of information. o Not all species use pheromones. o One example of a hormone as a pheromone in plants is ethylene, which is produced by an individual plant to stimulate the ripening of fruit, loss of leaves, and other physiological changes. Ethylene COMMUNICATION Semiochemicals: Pheromones o Wild potato plants produce the alarm pheromone of the aphid Myzus persicae, (E)-β –farnesene, and prevent the aphids from feeding by releasing their alarm response. (E)-β -Farnesene COMMUNICATION Semiochemicals : Allelochemicals o Chemicals that carry messages between members of different species are known as allelochemicals. a) Allomones benefit the sender of the signal, b) Kairomones benefit its receiver c) Synomones both the sender and receiver benefit.  COMMUNICATION Semiochemicals: Allelochemicals Examples Allomones ◦ Camphor and d-limonene are Allomones in that the trees which produce them are protected from insect attack by their presence. ◦ These trees are protected from termite attack because the d-limonene, they produce is an alarm pheromone for termites that live in the same area. Camphor d-limonene https://mast-producing-trees.org/do-termites-eat-camphor-laurel/  COMMUNICATION Semiochemicals: Allelochemicals ◦ Similarly, antifeedants (a naturally occurring substance in certain plants that adversely affects insects or other animals that eat them) could be considered to be Allomones since the signal generator, the plant, receives. ◦ The benefit of not being eaten. A neem tree (Azadirachta indica) showing developing fruits, the source of the outstanding antifeedant azadirachtin. https://www.researchgate.net/publication/248843209_Insect_antifeedants COMMUNICATION Semiochemicals: Allelochemicals Kairomones Myrcene is a Kairomone, in that it is produced by the ponderosa pine and its presence attracts the females of the bark beetle, Dendroctonous brevicomis COMMUNICATION Semiochemicals: Allelochemicals Synomones o Geraniol is found in the scent of many flowers such as the rose. o Its presence attracts insects to the flower and it can be classified as a Synomone since the attracted insect finds nectar and the plant obtains a pollinator. Task 4 Terpenes are class of compounds containing carbon atoms in multiples of five, while terpenoids are oxygen-containing terpenes. Search from related journal article/s regarding terpene and terpenoid compounds; i. Name ONE(1) compound of terpene & terpenoid each, ii. Draw each structure, iii. Classify into their subclass, iv. Point out and state the number of isoprene units in each compound, v. State the function of each compound in plant. *Note: 1. The compound should be different from the example given in the slide 2. Please write the citation of the journal article in full  Summary 01 02 03 Classification Biosynthesis The roles which of terpenes Terpenoid the terpenoids Isoprene rule nomenclature play in living and special organisms isoprene rule PHENOLICS - FLAVONOIDS PHENOL ◦ an attached hydroxyl (OH) group to a carbon atom of an aromatic ring. ◦ The term “phenol” refers to organic substances that have at least one –OH group directly linked to the benzene ring. ◦ Also known as benzenol or carbolic acid. ◦ Phenol is a weak acid. PHENOL ◦ Three categories of phenol depending on how many hydroxyl groups are linked to the benzene ring. 1. Monohydric phenols – hydroxybenzene (phenol), is the most basic compound in this group. While the others are referred to as substituted phenols. The term “cresols” refers to the three isomeric hydroxyl toluenes. 2. Dihydric phenols – catechol, resorcinol, and quinol are the three isomeric dihydroxyl benzenes. 3. Trihydric phenols – also referred to as trihydroxy phenols, also known as pyrogallol, hydroxyquinol and phloroglucinol. NATURAL OCCURRENCE OF PHENOLS ◦ In excess of 8000 phenolic structures have been reported and they are widely dispersed throughout the plant kingdom. ◦ Tyrosine is one of the standard amino acids found in most proteins. ◦ Epihephrine (adrenaline), is a stimulant hormone produced by the adrenal medulla. ◦ The essential oils of plants are utilized as flavors and fragrances. For instance, the flavor vanillin is extracted from vanilla beans. ◦ From the distillation of coal tar or crude petroleum, phenol, cresols (methyl phenols), and other simple alkylated phenols can be produced.  PHENOLIC COMPOUNDS o Phenolics range from simple, low molecular- weight, single aromatic- ringed compounds to large and complex tannins and derived polyphenols. o Revolution of vascular plants: in cell wall structures, plant defense, features of woods and barks, flower color, flavors.  PHENOLIC COMPOUNDS o They can be classified based on the number and arrangement of their carbon atoms and are commonly found conjugated to sugars and organic acids. o Phenolics can be classified into two groups: 1. Flavonoids 2. Non-flavonoids o Various phenolic compounds are lignin and suberin  FLAVONOIDS Flavonoids are products from a cinnamoyl-CoA starter unit, with chain extension using 3 molecules of malonyl-CoA.  FLAVONOIDS o Chalcones act as precursors for a vast range of flavonoid derivatives found throughout the plant kingdom. o Most contain a six-membered heterocyclic ring, formed by nucleophilic attack of a phenol group on to the unsaturated ketone. Chalcone FLAVONOIDS  FLAVONOIDS o The flavonoids are polyphenolic compounds possessing 15 carbon atoms with two benzene rings joined by a linear three-carbon chain. o The skeleton can be represented as the C6-C3-C6 system  FLAVONOIDS 1. Based on the biosynthesis pathway, oxygen (hydroxyl group) usually exist at C5 and C7 in ring A. 2. While in ring B, the hydroxyl group may exist at C4’ or C3’, C4’ or C3’, C4’, C5’. Activity 1 From Irchhaiya et al (2015) article, determine at least ONE example of flavonoid which has characteristic as in (1) &/ (2)  FLAVONOIDS o In general, there are 12 classes of flavonoids: 1. Antocyanin 2. Chalcone 3. Aurones 4. Flavones 5. Flavonols 6. Flavonones 7. Dihydroxychalcones 8. Catechins/flavanonols/dihydroflavonols 9. Flavone 3,4-diols 10. Biflavones 11. Isoflavones 12. Proantocyanidines FLAVONOIDS FLAVONOIDS oFlavonoid type anthocyanin, flavone, flavonol, and flavon 3,4-diol, are well distributed, however flavonone, chalcone, aurone, and isoflavone are not well distributed. oHeteroside compound is found well distributed in flowers, fruits, and leaves, while aglycones compound is found in wooden tissue. oSugar moieties mostly involve in glycoside bonding are D-glucose, L-rhamnose, L-arabinose, etc. oDue to the presence of different sugar moieties, there were more than 2000 types of flavonoid compounds have been isolated and characterized. FLAVONOIDS o The three carbon (-C3-) is included through an oxygen bond between the two phenyl rings into: 1. A five-membered heterocyclic ring (furan) as in aurones (heterocyclic chemical compound). 2. A six-membered heterocyclic ring (pyran) to give flavonoids which constitute the largest group. FLAVONOIDS o Flavonoids occur as aglycones, glycosides and methylated derivatives. o The flavonoid aglycone consists of a benzene ring (A) condensed with a six- membered pyran ring (C), which in the 2- position carries a phenyl ring (B) as a substituent. Activity 2 From Irchhaiya et al (2015), Ahmed et al (2017) & Hounsome et al (2008) articles, determine, draw & name at least ONE type of flavonoid which occurred as aglycones. FLAVONOIDS The flavonoid glycosides GLYCOSIDES → AGLYCONE (non-sugar part) + GLYCONE (sugar part) ◦ When glycosides are formed, the glycosidic linkage can be located in position 3 or 7 and maybe L-rhamnose, D-glucose, galactose, or arabinose.  FLAVONOIDS o Most flavonoids exist in the form of O-glycosides with one or more hydroxyl groups attached with sugar moiety through hemiacetal linkage; E.g: apigenin 7-O--D-glucopyranoside o Usually hydroxyl group (OH) in sugar moiety attaches at: Activity 3 From Irchhaiya et al (2015), ✓ C-7 in flavone, isoflavone, and dihydroxychalcone Ahmed et al (2017) & Hounsome et al (2008) articles, determine, ✓ C-3 & C-7 in flavonol draw & name at least ONE type of flavonoid which sugar moiety ✓ C-3 & C-5 in antocyanidin attach at C7, C3&C7, C3&C5.  FLAVONOIDS o C-glycoside type of flavonoids also exist but are not well distributed. o These types of flavonoids sustain acid hydrolysis. o Usually attach at C-6 or C-8. o Type of sugar moieties mostly attached are glucose, rhamnose, arabinose and xylose; E.g: Apigenin 6-C--D-glucopyranoside Apigenin 8-C--D-glucopyranoside  FLAVONOIDS - FLAVONES Flavones and flavonols (flavus—Latin for yellow) are present in plants and fungi as secondary metabolites and are naturally yellow in color. The chemical structure has a 15-carbon skeleton, with two phenyl rings (A and B) and one heterocyclic ring (C); abbreviated as C6–C3–C6. FLAVONOIDS - FLAVONES o Apigenin, a flavone with –OH groups added to positions 5, 7, and 4’. o Another flavone is luteolin, found in sweet red peppers. o Both act as signaling molecules that induce NOD factors (nodulation factors or NF) incompatible interaction with Rhizobium bacteria (nitrogen-fixing root nodules) in legumes (e.g. alfalfa)  FLAVONOIDS – ISOFLAVONES (ISOFLAVONOIDS) Isoflavones are characterized by a 3-phenyl-chromen-4-one skeletal structure with diverse substituents, such as glycoside, hydroxyl, or methoxyl groups  FLAVONOIDS – ISOFLAVONES (ISOFLAVONOIDS) o Found almost exclusively in leguminous plants with the highest concentration in soybean. Genistein, daidzein – phytoestrogens (can affect reproduction of grazing animals) FLAVONOIDS - FLAVONOL Flavonols, which are primary flavonoids in nature, are found in various fruits and vegetables, such as apples, berries, grapes, tomatoes, and onions, and play a key role in attracting pollinators and seed disseminators  FLAVONOIDS - FLAVONOL o Quercetin o The most abundant flavonol in the diet and is found in hundreds of herbs and foods. o Onions are especially rich in Quercetin o It has proven antioxidant effects. FLAVONOIDS - FLAVANONE Flavanone is the simplest member of the class of flavanones that consists of flavan bearing an oxo substituent at position 4. It derives from a hydride of a flavan.  FLAVONOIDS - FLAVANONE o Naringenin o An antioxidant flavanone from citrus species. o Has –OH groups attached at positions 5, 7, and 4’ o Studies have indicated that it has anti-inflammatory, anti-cancer, and liver protective effects.  FLAVONOIDS - FLAVAN The flavans are benzopyran derivatives that use the 2-phenyl-3,4-dihydro-2H-chromene skeleton. They may be found in plants. These compounds include the flavan-3-ols, flavan-4- ols and flavan-3,4-diols (leucoanthocyanidin).  FLAVONOIDS - FLAVANOL Flav-3-ols (sub-class of flavanol), such as epicatechin, catechin and epigallocatechin (and procyanidins their polymers) are: o Powerful antioxidants o Have beneficial effects on cardiac health, immunity and longevity. o Levels of flav-3-ols decline in roasting – (Roasting at 150 °C or greater significantly reduced the levels of these compounds compared to those in unroasted control beans, and roasting at 170°C for 40 min resulted in the greatest losses of 4 – 6 (85 – 92%) (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868974/#:~:text=Roasting%20at%201 50%C2%B0C%20or%20greater%20significantly%20reduced%20the,6%20(85%20%E2% 80%93%2092%25).  FLAVONOIDS - NEOFLAVONOIDES The isoflavonoids and neoflavonoids can be regarded as abnormal flavonoids. The basic structure of flavonoid compounds consist of a pyran ring (C) and a flavan nucleus that is connecting to two aromatic rings (A and B). The flavonoids, isoflavonoids, and neoflavonoids are differentiated by the difference in the position of linkage between B-ring and C-ring.  FLAVONOIDS - ANTOCYANIDINS Anthocyanins belong to a parent class of molecules called flavonoids synthesized via the phenylpropanoid pathway. They occur in all tissues of higher plants, including leaves, stems, roots, flowers, and fruits. Anthocyanins are derived from anthocyanidins by adding sugars. The anthocyanins are subdivided into the sugar-free anthocyanidin aglycones and the anthocyanin glycosides. ACTION OF FLAVONOIDS 1. As antioxidants ◦ The flavones and catechins seem to be the most powerful flavonoids for protecting the body against reactive oxygen species (ROS). Flavonoids are oxidized by radicals, resulting in a more stable, less-reactive radical. Because of the high reactivity of the hydroxyl group of the flavonoids, radicals are made inactive. Epicatechin and rutin are also powerful radical scavengers. 2. Anti-ulcer effect ◦ Majority of peptic ulcers are associated with helicobacter pylori, a spiral-shaped bacterium that lives in the acidic environment of the stomach. Quercetin seems to play a very important role in the prevention and treatment of peptic ulcers. It acts by promoting mucus secretion, thereby serving as gastroprotective agent, also quercetin has been shown to inhibit the growth of helicobacter pylori bacterium in-vitro studies. ACTION OF FLAVONOIDS 3. Anti-atherosclerotic effects ◦ Atherosclerosis is a condition that results from the gradual build-up of fatty substances, including cholesterol, on the walls of the arteries. This build-up called plaque, reduces the blood flow to the heart, brain, and other tissues and can progress to cause a heart attack or stroke. This process is commonly referred to as hardening of the arteries. ◦ An elevated plasma low-density lipoprotein (LDL) concentration is a primary risk factor for the development of atherosclerosis and coronary artery disease. Flavonoids seem to suppress LDL oxidation and inflammatory progression in the artery wall. ◦ A Japanese study reported an inverse correlation between flavonoid intake and total plasma cholesterol concentrations, other clinical studies, as mentioned earlier, stated that flavonoid intakes protect against coronary heart disease.  ACTION OF FLAVONOIDS 4. Anti-inflammatory effect ◦ Cyclooxygenase (COX) is an enzyme that plays an important role as an inflammatory mediator and is involved in the release of arachidonic acid, which is a precursor for biosynthesis of eicosanoids like prostaglandins and prostacyclin. ◦ The release of arachidonic acid can be considered starting point for a general inflammatory response. Select flavonoids like quercetin are shown to inhibit the cyclooxygenase pathway. This inhibition reduces the release of arachidonic acid. 5. Hepatoprotective activity ◦ Many flavonoids have also been found to possess hepato-protective activity e.g. silymarin, apigenin, quercetin, and naringenin. ◦ The results of several clinical investigations showed the efficacy and safety of flavonoids in the treatment of hepato-biliary dysfunction and digestive complaints, such as sensation of fullness, loss of appetite, nausea and abdominal pain.  FLAVONOIDS Task 4: Identify at least TWO (2) compounds of flavonoids. The compounds chosen should be from different class/type, a. Write the name – IUPAC/common b. Draw the structure c. State the class of flavonoids d. Identify the species of plant/s that contain the compounds in (a) e. Determine the use/s  TERPENES/TERPENOIDS/FLAVONOIDS Task 5: Identify at least TWO (2) compounds of flavonoid and terpenes respectively. The compounds chosen should be from different class/type, a. Write the name – IUPAC/common b. Draw the structure c. State the class of flavonoids/terpenes d. Identify the species of plant/s that contain the compounds in (a) e. Determine the use/s  Summary 01 02 03 Classification Flavonoid and The roles/uses of flavonoid its structure of flavonoids with each example.  THANK YOU & MAY ALLAH GUIDE YOU!