A Second Generation Total Synthesis of (±)-Cycloclavine and Progress Toward an Asymmetric Total Synthesis of (+)-Cycloclavine N H NH Steph McCabe Research Topic Seminar 30th January 2016 1 Steph McCabe @ Wipf Group Page 1 of 25 3/27/2016 Overview PART 1: 1.1 Ergot alkaloids § Classification § Natural sources/ history § Biological activity and use as pharmaceuticals 1.2 Clavine Alkaloids § Classification/ examples § Biosynthesis of clavine alkaloids § Summary of recent syntheses of clavine alkaloids based on strategic disconnections • Clavicipitic acid • Aurantioclavine • Rugulovasine A & B • Cycloclavine § Recent syntheses of cycloclavine PART 2: Experimental Data § Retrosynthetic analysis § Second generation total synthesis of cycloclavine § Efforts toward an asymmetric synthesis of cycloclavine § Future directions § Conclusions 2 Steph McCabe @ Wipf Group Page 2 of 25 3/27/2016 Classification of Ergot Alkaloids ERGOT ALKALOIDS Clavines Lysergic Acid 8 NH D R = H or OH R H HO C 8 8 C 2 NH NH D H D H A B 2 C H C N H H 1 A B 2 A B 2 Ergoline Core N 1 N 1 H H lysergic acid tetracyclic clavines R O (ergolines) O N R = H, CH2OH, CHO R NRR' R N O NH HN N OH H H O N H O N H H H NH NH NH NH tricyclic clavines Rearranged clavines Lysergic acid amides ergopeptines (secoergolines) 3 Steph McCabe @ Wipf Group Page 3 of 25 3/27/2016 Ergot Alkaloids Occurrence of Ergot Alkaloids in Nature § Ergot alkaloids are produced by the Clavicipitaceae and Trichocomaceae families of filamentous fungi § These fungi infect cereal grains causing ‘ergot’ § The fungi have a symbiotic relationship with the plant causing no symptoms of infection • Ergot alkaloids produced by the fungi help protect the plant from predation and improve growth, while the fungi gain nutrition and shelter from the plant Ergot on wheat stalks fruiting C. purpurea sclerotia Nat. Prod. Rep., 2011, 28, 496 Nat. Prod. Rep., 2014, 31, 1328 4 Steph McCabe @ Wipf Group Page 4 of 25 3/27/2016 History Ergot & Ergotism § Consumption of ergot contaminated grains leads to ergotism (St. Anthony’s fire), a disease common in central Europe in the middle ages § Two types of ergotism are recognized: • ergotismus convulsivus: characterized by hallucinations, convulsions, confusion and irrational behaviour • ergotismus gangrenous: characterized by gangrene of the feet, legs, hands and arms § Ergotism in humans is now rare due to strict guidelines governing the acceptable concentration of ergot bodies in grain, however ergotism still produces serious epidemics in livestock fed contaminated grain. § Modern control of ergot is focused on limiting the presence of sclerotia in cereal grains largely through preventative measures or in particularly bad seasons crops can be saved by separating the ergot kernels from cereal grains based on density or colour 5 Steph McCabe @ Wipf Group Page 5 of 25 3/27/2016 828 A. M. Beekman and R. A. Barrow Biological Activity of Ergot Alkaloids Owing to the concurrent development of many of the drugs the pharmaceutical classes. Within each class, the name of discussed, and the spectrum of activity some pharmaceuticals the fungal metabolite is presented as well as the pharmaceutical Bu iPr HO OH H O O iPr N N O HO display, this review is presented in fungal metabolite classes companies thatN supply it and brand names that it is sold under. N HO O R2N H 6 O NH OH NH O O NH H H OMe O OMe N N O O H R N H H COOH O O rather than chronologicallyHO or by pharmacology.S To provideR N S ForH thoseiBu classes that haveO HN OH several members, a time-line O HO O O O N O O OH O O N O N HO NH 7 MeO O MeO O O O R OH COOH O 1 iPr O H N Cl O HO NH H O NH O iBu N context, Fig. 1 displays a timeline of the original discoveryO ofOH displayingO approval dates is presented forNH clarity. Table 1 HO N N OH 2 H N O OH O iBu O HO * MycophenolicErgot acid alkaloidsPenicillins Griseofulvin Coumarins CephalosporinsFusidic acidCyclosporin EchinocandinsStatins Fingolimod 1896 1918 1928 1939 1941 1948 1962 1971 1974 1976 1995 Figure 1. Timeline of the initial discovery of pharmaceutical classes of fungal metabolites Fig. 1. Timeline of the original discovery of the pharmaceutical classes of fungal metabolites. § These classes of fungal metabolites have produced some of the best known/ profitable pharmaceuticals in human Table 1. Pharmaceuticals currentlymedicine available in Australia and New Zealand, displaying drug name, structure, pharmaceutical class (underlined), original fungus (italicised),• Anti-cholesterol nature statins of discovery, e.g. rosuvastatin and earliest (crestor), year atorvastatin of approval (lipitor), inantibiotic Australia penicillin[11] and New Zealand[12] and immunosuppressant cyclosporin A § Ergot alkaloids possess the widest spectrum of biological activity Cephalothin • Ranging from anti-migraineCephalexin to anti-Parkinson agents Cephazolin Cefuroxime axetil N N N O Aus. J. Chem., 2014, 67, 827 N N NH2 O H H O N H H O HN6 H S N S S S HN H O Steph McCabe @ Wipf Group O Page 6 of 25 S N 3/27/2016 N O N O O O N O O O OOH O O O OOH S S NH O OH O 2 N N O Cephalosporins Cephalosporins Cephalosporins Cephalosporins Cephalosporium acremonium Cephalosporium acremonium Cephalosporium acremonium Cephalosporium acremonium Semi-synthetic Semi-synthetic Semi-synthetic Semi-synthetic 1988 1969 1974 1989 Cefaclor Cefotaxime Ceftriaxone Ceftazidime H2N S H2N H2N N S NH2 S N H N N H O N S O H H HN S N O O N N H N S O H O N HN S O Cl O N O O O ϩ O S N OH N N OOH NH O O OH O O OH N Ϫ O O O O Cephalosporins Cephalosporins Cephalosporins Cephalosporins Cephalosporium acremonium Cephalosporium acremonium Cephalosporium acremonium Cephalosporium acremonium Semi-synthetic Semi-synthetic Semi-synthetic Semi-synthetic 1980 1981 1983 1984 Cefepime Warfarin Cyclosporin Caspofungin OH H2N OH OH S H N N HN HO O HO NH2 O O O O O N H OH O NH N O HO N H N N N O O N S N O HN O O HN OH O NH NH N N ϩ N O H N O OH O O N N O O O N OH NH2 H HN Ϫ O O O O O Cephalosporins Coumarins Cyclosporin Echinocandins Cephalosporium acremonium Penicillium sp. Tolypocladium inflatum Zalerion arboricola Semi-synthetic Designed Natural Semi-synthetic 1997 1954 1983 2002 (Continued) Biological Activity of Ergot Alkaloids § The broad spectrum of bioactivity exhibited by ergot alkaloids is due to their structural similarity to natural neurotransmitters 7 8 6 NH H 9 10 5 4 H11 16 3 12 2 13 1 15 NH 14 Ergoline NH2 NH2 NHMe NH2 HO HO HO N HO HO HO H OH OH OH serotonin (5-HT) dopamine (DA) norepinephrine (noradrenalin) epinephrine (adrenalin) § Ergot alkaloid drugs generally act by mimicking (agonist) or blocking (antagonist) the binding of natural neurotransmitters to their receptors 7 Steph McCabe @ Wipf Group Page 7 of 25 3/27/2016 Ergot Alkaloid Pharmaceuticals § The majority of ergot alkaloid pharmaceuticals are semi-synthetically prepared from lysergic acid derivatives OH Et2N O NH NH H O N H NH Lysergic acid diethylamide (LSD) NH Ergometrine prevents post partum haemorrhage MOA: a-1A adrenergic agonist O Ph 5-HT2 agonist N N N H O O HO O NH O N HN O N N O NH OH O N O N H O N H H H H Br N NH NH H Ergotamine Cabergoline Bromocriptine migraine treatment Parkinson's disease Parkinson's disease MOA: 5-HT1B agonist MOA: D2 agonist Type 2 diabetes MOA: D2 agonist 8 Steph McCabe @ Wipf Group Page 8 of 25 3/27/2016 Clavine Alkaloids 1.2 Clavine Alkaloids § Classification/ examples § Biosynthesis of clavine alkaloids § Summary of recent syntheses of clavine alkaloids based on strategic disconnections • Clavicipitic acid • Aurantioclavine • Rugulovasine A & B • Cycloclavine § Recent syntheses of cycloclavine 9 Steph McCabe @ Wipf Group Page 9 of 25 3/27/2016 Clavine Alkaloids OH OH OH N 8 N N HO N N N N N H H H H H H H H H HO AcO AcO H H H H H N N N N N NH N H H H N H H H H agroclavine setoclavine penniclavine festuclavine elymoclavine fumigaclavine B fumigaclavine A fumigaclavine C tetracyclic clavines tricyclic clavines Clavine Alkaloids Rearranged clavines OH OH O O 7 HN HN N NHMe 6 NHMe O O H H H H H N N NH NH NH H H isochanoclavine-I chanoclavine-I rugulovasine A rugulovasine B Cycloclavine OH CHO O N NHMe NHMe NMe2 H H H COOH N H HN HN O H H H H H H NH NH NH N N H N N H H chanoclavine-I chanoclavine-II 6,7-seco-agroclavine H aldehyde paspaclavine clavicipitic acid aurantioclavine epoxyagroclavine 10 Steph McCabe @ Wipf Group Page 10 of 25 3/27/2016 Biosynthesis of Clavine Alkaloids § The first 5 steps in the biosynthetic pathway are common to all ergot alkaloids and are responsible for the formation of the core ergoline scaffold • Most diversification occurs late stage via functionalization of ergoline core however, in some fungi diversification can occur early on via short diverted pathways COOH HN HN decarboxylation N N H H clavicipitic acid aurantioclavine benzylic oxidation /aminocyclisation CO2H CO2H CO2H DmaW EasF NH2 NH2 N prenyltransferase N-methyltransferase H SAM N OPP N N H H H L-tryptophan DMAPP DMAT N-Me-DMAT ACIE, 2015, 54, 3004-3007 (aurantioclavine) J.