Current Topics in Organic Chemistry

Uwe Rinner uwe.rinner@univie.ac.at

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

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)

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

Vitamine B1 (Thiamine)

Only synthesized by bacteria, fungi and plants; animals must obtain thiamine in their diet Rsponsible for: glucose breakdown and carbohydrate metabolism; production of neurotransmitters

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.

Lentsch, C.; Fürst, R.; Mulzer, J.; Rinner, U. Eur. J. Org. Chem. 2014, 919.

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

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). Elucidation took several years of tedious work.

Biosynthesis of polyketides is carried out by polyketide synthases, which are a family of multi-domain enzymes or enzyme complexes

Biosynthesis of polyketides is closely related to the biosynthesi of fatty acids. Great diversity of polyketides emerges from different starter and extender units. Additionally, the stereochemistry of the methyl substituents and hydroxy moieties is influenced and governed by the enzyme. Functional groups and more complex substituents (sugar moieties) are introduced after the polyketide has been released from the enzyme. Macrolactonization takes also place after the polyketide has been cleaved from the enzyme.

Engineered biosynthesis of a simple polyketide

AT: Acyltransferase ACP: Acyl carrier protein KS: Keto-synthase KR: Ketoreductase DH: Dehydratase ER: Enoylreductase MT: Methyltransferase SH: Sulfhydrolase TE: Thioesterase

Pikromycin On of the first (or the first) isolated macrolide antibiotics. Isolated from Streptomyces venezuelae in 1951 14-Membered macrolactone with desosamine moiety Not used as clinical antibiotic – important scaffold for the preparation of new derivatives of existing antibiotics and biologically relevant compounds (erythromycin, epothilone)

Pikromycin Narbonolide (parent structure)

Introduced after completion of polyketide skeleton

Erythromycin First isolated in 1949 from soil bacteria (Streptomyces erythreus). 14-membered macrolactone with 10 stereocenters (compare to picromycin) The compound was identified as powerful antibiotic active against a variety of Gram-positive bacteria. Good alternative for patients allergic against penicillin. Erythromycin inhibits biosynthesis by binding to 50S ribosoal subunit (prevents formation of peptidyl t-RNA) First total synthesis of erythromycin: Woodward (1981)

Erythromycin is a relatively safe antibiotic with only few side effects; however, the compound is unstable under acidic conditions derivatized or modified to increase metabolic stability

Clarithomycin

First Total Synthesis of Erythromycin – Woodward 1981

Erythromycin Since Woodward‘s pioneering work, several syntheses of srythromycin have been reported. For a short overview see: http://www.scripps.edu/baran/images/grpmtgpdf/Ishihara_Aug_09.pdf For a copy of Woodward‘s presentation of the synthesis of erythromycin (and also vitamine B12 see: http://www.chem.umn.edu/groups/hoye/links/erythromycin.php

Epothilone Highly promising class of macrolide anticancer drugs

Epothilone A: R = H Epothilone B: R = CH3

• Isolated in 1987 from Sorangium cellulosum • NCI confirmed remarkable in vivo activity of

epothilones against several human cancer cell lines

• Epothilones displace paclitaxel (taxol) from binding site

• Similar mode of action as other important anticancer drugs such as colchicine, paclitaxel, combretastatin as epothilones modify stability of microtubuli

• Epothilone s and paclitaxel stabilize microtubuli; colchicine and combretastatin destabilize microtubuli

Colchicin Vinblastin

Paclitaxel (Taxol) Combretastatin

Anticancer drugs which also bind to microtubuli

a-Tubule

Tubule

aHeterodimer

Protofilaments Microtubules,essential for maintaining the cytoskeleton and for cell division

Dimerization

polymerization aggregation

Formation of Microtubules in the Cell

Biosynthesis of epothilones

Total Synthesis of epothilone More than 30 total and formal syntheses of the epothilones have been published. For a review article see (only selected syntheses are discussed in detail): Mulzer, J.; Altmann, K. H.; Höfle, G.; Müller, R.; Prantz, K. C. R. Chim. 2008, 11, 1336 First total syntheses of epothilone by Danishefsky, Nicolaou and Schinzer: Danishefsky: 1.) Bertinato, P.; Sorensen, E. J.; Meng, D.; Danishefsky, S. J. J. Org. Chem. 1996, 61, 7998. 2.) Meng, D.; Sorensen, E. J.; Bertinato, P.; Danishefsky, S. J. J. Org. Chem. 1996, 61, 8000. 3.) Balog, A.; Meng, D.; Kamenecka, T.; Bertinato, P.; Su, D. S.; Sorensen, E. J.; Danishefsky, S. J. Angew. Chem. 1997, 35, 2801. Nicolaou: 1.) Nicolaou, K. C.; He, Y.; Vourloumis, D.; Vallberg, H.; Yang, Z.; Angew. Chem. 1996, 35, 2399. 2.) Nicolaou, K. C.; He, Y.; Vourloumis, D.; Vallberg, H.; Rosenschangar, F.; Sarabia, F.; Ninkovic, S.; Yang, Z.; Trujillo, J. I.; J. Am. Chem. Soc. 1997, 119, 7960. Schinzer: 1.) Schinzer, D.; Limberg, A.; Boehm, O. M. Chem. Eur. J. 1996, 2, 1477. 2.) Schinzer, d.; Bauer, A.; Schieber, J. Chem. Eur. J. 1999, 2492.

Total Synthesis of epothilone

Total Synthesis of epothilone Synthetic challenges: • 16-membered macrolactone • Quarternary center • 7 (or 5) stereocenters • Trisubstituted double bond • Thiazoline ring system

General synthetic solutions: • Late stage epoxidation • Installation of the thiazoline ring by means

of Wittig olefination • Closure of the macrocycle via Yamaguchi

macrolactonization • Alternative ring closure via RCM-reaction • Aldol reactions for the stereoselective

installation of the hydroxyl moieties

Total Synthesis of epothilone – general considerations

Total Synthesis of epothilone – Danishefsky‘s approaches

Total Synthesis of epothilone B – Schinzer‘s synthesis

Metathesis approach Pd-coupling approach

Total Synthesis of epothilone – Schinzer‘s synthesis

Total Synthesis of epothilone – Schinzer‘s synthesis

Total Synthesis of epothilone – Schinzer‘s synthesis

Total Synthesis of epothilone – Schinzer‘s synthesis

Total Synthesis of epothilone – Schinzer‘s synthesis

Total Synthesis of epothilone – Mulzer‘s silicon tether approach

Tetracycline: Class of broad-spectrum polyketide antibiotics; isolated from Streptomyces genus (Streptomyces aureofaciens; Streptomyces rimosus). First isolated in 1948, tetracyclines are active against a variety of Gram-negative and Gram-positve microorganisms.

Tetracycline: Several different derivatives are in medical use – structural variations mainly at the 5, 6, and 7 position. Other derivatives show strongly reduced activity. Tetracyclines are orally administered and the antibiotics are stable under acidic conditions. However, tetracyclines form strong complexes with various metal ions (calcium, aluminum, magnesium). While taking tetracyclines, foods with high calcium and magnisium content should be avoided – especially dairy products. Complexation results in unsatisfactory absorption.

Myer’s synthesis of tetracycline antibiotics

Dihydroxylation of aromatic acids by bacteria

First described by Reiner und Hegeman in 1971,1 the process was not utilized until 2005, when Myers published his pioneering synthesis of tetracycline antibiotics.2

1 Reiner, A. M.; Hegeman, G. D. Biochem. 1971, 10, 2530. 2 Charest, M. G.; Lerner, C. D.; Brubaker, J. D.; Siege, D. R.; Myers, A. G. Science 2005, 308, 395.

Myer’s synthesis of tetracycline antibiotics

Myer’s synthesis of tetracycline antibiotics

Charest, M. G.; Lerner, C. D.; Brubaker, J. D.; Siege, D. R.; Myers, A. G. Science 2005, 308, 395.

Aflatoxin: Exposure to mold and different fungi causes severe health problems. Many fungi produce highly toxic metabolic products, aflatoxins belong to the most serious toxic ingredients in fungi. Aflatoxins are produced by Aspergillus flavus and Aspergillus parasiticus which are associated with corn, rice and peanuts

Acute exposure to aflatoxins: Edema, hemmorrhage, alteration in digestion, mental disorder, coma Chronic exposure to afltoxins: Delayed development in children, liver damage eventually resulting in liver cancer, mutations

Poison Ivy / Poison Oak

Sap sensitizes most humans and results in delayed contact dermatitis watery blisters Poison Ivy / Oak contains different natural products called urushiols (different degree of unsaturation, depending on the starter fatty acid) Diluted solutions of urushiol can be used to stimulate antibody formation.

Statins: Class of drugs which are able to decrease the level of cholesterol in blood. Selective inhibition of HMG-CoA reductase (responsible for the biosnythesis of isoprene units terpenes, steroids…) Isolated from various fungi: Penicillium, Aspergillus, Streptomyces

Statins - Biosynthesis:

Best selling drug in 2004: Atorvastatin (Lipitor®, Pfizer 1997)

HMG-CoA Inhibitor Decreases LDL cholesterol Total sales volume: 120-150 billion $

# 1 Atorvastatin (Lipitor®, Pfizer 1997)

# 1 Atorvastatin (Lipitor®, Pfizer 1997)

# 6 Rosuvastatin (Crestor®, AstraZeneca 2003)

Cholesterol

# 6 Rosuvastatin (Crestor®, AstraZeneca 2003)