Current Topics in Organic Chemistry
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Current Topics in Organic Chemistry Uwe Rinner [email protected] Vorlesungsunterlagen: rinner-group.univie.ac.at Vorlesungstermine: Dienstag, 11.03 10:15 – 12:45 MT 127 Mittwoch, 12.03 10:15 – 12:45 T 406 Dienstag, 18.03 10:15 – 12:45 T 406/1 Mittwoch, 19.03 10:15 – 12:45 T 642 Dienstag, 01.04 10:15 – 12:45 Mittwoch, 02.04 10:15 – 12:45 Empfohlene Literatur: Medicinal Natural Products: A Biosynthetic Approach. Paul M. Dewick John Wiley & Sons Ltd. ISBN: 978-0-470-74167-2 Naturstoffe der chemischen Industrie Bernd Schäfer Elsevier, Spektrum Akademischer Verlag ISBN: 978-3-8274-1614-8 Alkaloids: Nature‘s Curse or Blessing? Manfred Hesse Wiley-VCH ISBN: 3-906390-24-1 The Organic Chemistry of Biological Pathways John McMurry, Tadhg Begley Roberts and Company Publishers ISBN: 0-9747077-1-6 The Acetate Pathway Fatty Acids Prostaglandins Polyketides Polyketide Synthase Erythromycin Epothilone Statins Poison Ivy / Poison Oak Aflatoxin Tetracyclines Fatty Acid Biosynthesis Pyruvate is converted to acetyl-CoA and introduced in the Krebs cycle (citric acid cycle). Vitamine B1 (thiamine) plays a crucial role in the pyruvate decarboxylation Only synthesized by bacteria, fungi and plants; animals must obtain thiamine in their diet Rsponsible for: glucose breakdown and carbohydrate Vitamine B1 metabolism; production of neurotransmitters (Thiamine) Lack of thiamine: Korsakoff syndrome (neurological disorder with memory loss and apathy), optic neuropathy, beriberi (occurs only in individuals with serious malnutrition; apathy, memory loss, impairment of sensory, motor and reflex functions) Mechanistic explanation of thiamine-catalyzed decarboxylation of pyruvate – part 1 Mechanistic explanation of thiamine-catalyzed decarboxylation of pyruvate – part 2 Several important reactions employ persistent carbenes and follow similar mechanistic pathways. Ronald Breslow (Columbia University) Benzoin condensation catalyzed by persistent carbenes (Breslow intermediates) Coenzyme A activates acetate and also serves as carrier for acetate moieties Resonance structure is partly responsible for decreased acidity of a-protons in esters Degradation of fatty acids: Fatty acid synthesis: Fatty acid synthesis: Biotin (Vitamine H; Vitamine B7; coenzyme R) plays an important role in the biosynthesis of fatty acids Natural sources: egg, liver, kidney, yeast, milk, cereal; also: made by intestinal microflora ( deficiancies are rare) Deficiancies: hair loss; dermatitis (scaly, red rash in the face); depression, lethargy 1898: first described by German scientist Steinitz: Vitamin H for „Haut and Haar“, skin and hair 1901: Discovery was made, that an aqueous yeast extract was necessary for growth of new yeast cells 1936: Biotin first isolated. 1.1 mg obtained from 250 kg of egg-powder 1942: Structure elucidation 1945: Total synthesis of biotin (Harris) J. Am. Chem. Soc. 1945, 67, 2096-2100 Mechanistic explanation of biotin-mediated carboxylation: Phosphorus-based reagents are also commonly employed in the esterification of carboxylic acids in synthetic organic chemistry Analogy to application of malonic ester in organic synthesis: Knoevenagel condensation: Unsaturated fatty acids are important precursor for different classes of natural products • Oleic acid is a common ingrediant in animal and vegetable oils and fats (main ingredient in olive oil); colorless and odorless oil • Serves as pheromone in some insects (dead bodies excrete oleic acid and are removed from hive • Considered as healthy fatty acid. Oleic acid might decrease cholesterol (LDL) and might play a role in the blood pressure reducing effect of olive oil Animals introduce further unsaturation towards the carboxyl group; fungi and plants introduce unsaturation towards the methyl terminus Essential fatty acids (for humans): linoleic acid and a-linolenic acid Prostaglandins First isolated in 1935 from prostate gland; responsible for several physiological processes: • Contraction and relaxation of smooth muscles (uterus, cardiovascular system, intestinal tract, pronchial tissue) • Inhibiton of gastric acid secretion • Control of blood pressure • Suppress blood platelet aggregation • Act as mediator of inflammation, fever, allergy First total synthesis by Corey in 1969: J. Am. Chem. Soc. 1969, 91, 5675 Biosynthesis of prostaglandins start from unsaturated fatty acids: Most crucial step in the biosynthesis of prostaglandins is the installation of the oxygen functionalities with concomitant closure of the cyclopentane ring Cycloogygenase (COX); prostaglandin-endoperoxide synthase (PTGS) introduces oxygen via a radical reaction mechanism. Enzyme contains two active sites: cyclooxygenase for the formation of cyclic peroxide and a heme with peroxidase activity, to convert PGG2 to PGH2 PGH2 serves as precursor for various various structurally related prostaglanins Prostaglandins derivatives: Prostacyclin: prevents blood platelet aggregation; Also responsible for widening of blood vessels Decreases blood pressure Thromboxane: responsible for blood platelet aggregation; plays important role in clot formation (thrombosis) Because of their pronounced pharmacological properties, prostaglandins are important targets for many important drugs: Acetylsalicyclic acid (aspirin) and ibuprofen selectively inhibit cyclooxygenase and suppress formation of prostaglandins anti-inflammatory, analgesic and antipyretic (fever reducing) properties Acetylation of the OH-group of serine First Total Synthesis of Prostaglandin – Corey 1969 J. Am. Chem. Soc. 1969, 91, 5676. Very important synthetic contribution to total synthesis. Resulted in the development of Corey lactone, which was extensively used in the preparation of various prostaglandin derivatives and other cyclopentane containing natural products. Additionally, an improved version of the synthesis featured the first application of the newly developed CBS-reagent for the stereoselective reduction of ketones. J. Am. Chem. Soc. 1987, 109, 7925. Application of the Corey lactone in the synthesis of jatrophane diterpenes Different strategies for the elaboration of the cyclopentyl moiety have been developed. Preparation of the cyclopentyl fragment of Pl-3 – Advantage of latent symmetry Lentsch, C.; Fürst, R.; Mulzer, J.; Rinner, U. Eur. J. Org. Chem. 2014, 919. Completion of the western fragment of Pl-3 Lentsch, C.; Fürst, R.; Mulzer, J.; Rinner, U. Eur. J. Org. Chem. 2014, 919. Polyketides Polyketides are structurally highly diverse natural products which are derive from the “polyketide pathway“. The polyketide pathway is very active in various moulds, soil bacteria and airborne microorganisms. Many polyketides are biologically potent compounds and of great interest for the production of drugs (antibiotic, anticancer, antifungal, antiparasitic, immunosuppresive properties) Great playground for synthetic chemists and biochemists! Review articles: Polyketide biosynthesis: a millenium review. Staunton, J.; Weissman, K. J. Nat. Prod. Rep. 2001, 18, 380. The Biosynthetic Logic of Polyketide Diversity. Hertweck, C. Angew. Chem. Int. Ed. 2009, 48, 4688. History of polyketide chemistry: In 1893, James Collie attempted to elucidate the structure of dehydroacetic acid. He boiled the compound with Ba(OH)2 and treated the reaction with acid. Collie found that one of the newly formed compounds was orcinol. „lasso mechanism“ was state of the art in the early 1900‘s. Collie was the first chemist to propose that such a mechanism would take place in living cells. Collie‘s ideas were too progressive for the early 1900‘s and soon forgotten… In 1901, Willstätter achieved the first synthesis of tropinone (parent compound of important alkaloids such as atropine and cocaine) via a tedious pathway. In 1917, (ten years after Collie‘s pioneering work on polyketides), Robinson proposed a biochemical pathway for tropinone. Until today, Robinson‘s synthesis of tropinone is considered the ideal synthesis. Robinson also proposed biosynthetic pathways (without the knowledge of biochemistry or biological process!) of terpenes, alkaloids and polyketides – because of his reputation, scientists started to believe in his (and consequently in Collie‘s) ideas. Birch (student of Robinson) proposed a pathway for the biosynthesis of patulain (and 6-methylsalicyclic acid) starting from acetate in the mid 1950‘s. Birch was able to prove his proposed biosynthetic pathway by controled feeding experiments with 14C labeled acetate. Degradation of 6-methylsalicyclic acid yielded in the isolation of three reaction product which contained radioactive 14C. Development of NMR in the 1960‘s was of great importance for the further elucidation of the biosynthetic pathway and the synthesis of polyketides. The biggest progress was made after 13C-labeled material (especially acetic acid) and deuterium labeled compounds became commercially available. Different coupling pattern of adjacent carbon atoms allows the elucidation of the biochemical pathway. NMR studies proofed that acetate serves as starter group for the synthesis of polyketides A combination of synthetic studies, labeling experiments and a genetic approch helped to „fully understand“ the biochemical pathway. In the 1980‘s, Hopwood performed studies on the biosynthesis of actinorhodin (dimeric polyketide; blue pigment Streptomyces coelicolor) Hopwood produced mutant strains of the bacteria and isolated enzmyes responsble for the production of the polyketide. Mutation was compared to structural variation in the polyketide derivatives (color change, reduced antibiotic activity).