Baran Lab C l a s s i c T e r p e n e S y n t h e s e s Tom Maimone I. An Introduction to Terpenes -Terpenes are an enormous class of natural products spanning well over 30,000 members -They have been used throughout history for a broad variety of purposes including perfume, medicine, and flavoring -Recognized early on as being composed of isoprene fragments Isoprene -Isopentyl diphosphate (IPP) and dimethyl allyl diphosphate (DMAPP) later found to be the actual building blocks -There are 2 biosynthetic pathways for the production of IPP and DMAPP, the mevalonate pathway and the more recently discovered deoxyxylulose pathway The Chemistry of the Mevalonate Pathway: O O O O OH Aldol and OH OH OH Claisen HO C NADPH HO C SCoA SCoA Hydrolysis 2 2 HO2C SCoA SCoA O SCoA acetoacetyl-CoA H HMG-CoA mevaldic acid SEnz mevaldic acid hemithioacetal O acetyl-CoA O NADPH O HO P O ADP -CO OH OH 2 O OH 2xATP HO C - Equilibrium OPP 2 OPP Isomerase OH favors DMAPP O OPP DMAPP IPP mevalonic acid (MVA) NH2 The Chemistry of the Deoxyxylulose Pathway: O OH P N OH O OH OH OH O O Pinacol-type NADPH 1. CTP OP O P O P O N O rearrangement OP OP 2. ATP O O OH OH OH OH OH O OH OH OH H+ 2-C-methyl-D-erythritol 4-P HO OH O OH 1-deoxy-D-xylulose 5-P O O (from pyruvic acid) P O P OPP O OPP Isomerase steps not OH DMAPP IPP fully determined OH OH * For an excellent review on natural products and biosynthesis see: Dewick, P.M. Medicinal Natural Products: A Biosynthetic Approach. Wiley, 2002. 1 Baran Lab C l a s s i c T e r p e n e S y n t h e s e s Tom Maimone - All terpenes are formed through the reactions of IPP and DMAPP: stereospecific proton loss Monoterpenes OPP OPP OPP OPP DMAPP IPP H H geranyl PP (GPP) - repeat several times: Sesquiterpenes Hemiterpenes (C5) OPP Monoterpenes (C10) farnesyl PP Sesquiterpenes (C15) Diterpenes (C20) Diterpenes Sesterterpenes (C25) OPP Triterpenes (C30) geranylgeranyl PP Tetraterpenes (C40) Triterpenes (Steroids) squalene - The interesting Chemistry involves the fate of the open-chain terpenes. A seemingly endless number of (enzyme-mediated) carbocation cyclizations leads to many different carbocyclic skeletons, which are often further oxidized OPP and rearranged. OPP OPP with only 2 prenyl units: • 7 unique skeletons • several sites of hydration or elimination to terminate carbocation Pinane Bornane Menthane Fenchane Isocamphane Carane Thujane Take Home Message: Complexity increases Type Type Type Type type type type extremely rapidly with each addition prenyl unit 2 Baran Lab C l a s s i c T e r p e n e S y n t h e s e s Tom Maimone II. Commercially available Terpene Building Blocks* OH OH O OH O O OH HO Cl (-) carveol (isom. mix) Carvacrol Carvone Dihydrocarveol Isopulegol (-) Menthone (-) Menthyl chloride $1.326/g (+) Dihydrocarvone (+)-Isomenthol $2.37/g (+) $1.76/g (-) $14/g (+) $95/g $ 0.54/g $ 16.4/g (-) acetate $7/g (-) $0.20/g isomer mixture $0.7/g $0.18/g isomer mixture $1.6/g (-) $25/g OH O CO2H OH OH OH O OH OH Neomenthol Limonene oxide trans-p-menth- (+) Menthofuran Menthol (+) 11.5/g Perillic acid Perillyl alcohol !-terpineol Limonene mixture of isomers 6-ene-2,8-diol $3.88/g (+) $2.2/g (+) and (-) acetates $14/g (+) $44/g (+) $38/g (+) $0.09/g (+) $0.72/g $1.82/g (-) $0.19/g available (-) $1.9/g (-) $0.4/g (-) $0.23/g (-) $0.58/g O many o-acetylated derivatives available O OH OH NH2 O OH OH !-Pinene Isoborneol Perillaldehyde -Phellandrene Pinanediol Pinene Oxide 2-Hydroxy-3-pinanone ! (+) $0.28/g "-Pinene $0.09g (-) Isobornylamine (+) $53/g $0.164/g (+) $20/g $0.332/g (+) $22/g, (-) $15/g (-) $0.1/g (-) $0.04/g O-acrylate $0.08/g $1360/g (-) $2.88/g (-) $17/g O OH OH O O CO H NH2 OH 2 (-)-Nopol OH (-)-Myrtenal [(1S)-endo]-(-)-Borneol (+) Ketopinic acid (+) Nopinone $0.13/g (-)-Myrtanol (-)-cis-Myrtanylamine (-)-Myrtenol $2.24/g $0.31/g $60/g $31/g Benzyl ether $22.7/g $12.9/g $2.07/g available *Aldrich Prices (some prices are significantly lower from other suppliers) 3 Baran Lab C l a s s i c T e r p e n e S y n t h e s e s Tom Maimone Br H4NO3S Br OAc O O O OH NH2 O Br SO H 3 Camphene Camphor (-) Bornyl acetate (+)-Bornylamine (-)-3-Bromocamphor (+)-3-Bromocamphor-8- (+) Borneol (+)-3-Bromocamphor- (+) $0.045/g (+) $0.205/g $0.18/g $194/g $4.6/g sulfonic acid ammonium $53/g 10-sulfonic acid hydrate (-) $0.055/g (-) $5.49/g salt $6/g $57/g O O O 2 N O O Br O S HN O S O O2 CO H SO2NH2 O2S 4'-Bromo-cis-2',3'-epoxybutyl (1S)-camphor 2 2,10-Camphorsultam (2-Butenoyl)-2,10-camphorsultam Camphanic acid sulfonate $217/g (+) or (-) $45/g Camphorsulfonamide (+) $59/g, (-) $32/g (+) $150/g , (-) $20/g $24/g either ent. (-) acid chloride $22.6/g O O O HO2C CO2H OMe N O N N NHSO2pTs SO Camphorquinone Camphoric acid 2 (+)-2-Carene Camphorquinone 3-oxime Camphor p-tosylhydrazone - (+) $12.5/g , (-) $5.14/g (+) $126/g , (-) $86/g (+) $23.7/g, (-) $73.7/g 10 camphorsulfonyl oxaziridine $3.3/g (+) $1.4/g, (-) $8.8/g (+) $65/g, (-) $61/g O O OH N O S SO3H 3.7Dimethyl-3-octanol O2 Camphor sulfonic acid !-Ionone "-Ionone Alloocimene $4.13/g $0.24/g (-)-Camphorsulfonylimine (-) $0.82/g, (+) $0.32/g $0.27/g $ $0.13/g $26.80/g (-) Ammonium salt $0.92/g sodium salt $0.25/g (+) sulfonyl chloride $2.34/g (-) sulfonyl chloride $10.0/g H 3-Carene !-Copaene OH (-)- Cedrene $0.056/g Guaiazulene (-)-Guaiol (-)-!-Cubebene -terpinene $270/g $46/g # $3.1/g $700/g $ 1180/g $0.39/g 4 Baran Lab C l a s s i c T e r p e n e S y n t h e s e s Tom Maimone OH H CO2H O Br OH O H H (+)-8(15)-Cedren-9-ol !-Citronellene (-) Carophyllene oxide Citronellyl Bromide !-Citronellol Citronellic acid Citronellal (-) $1.70/g $288/g $2/g (+) $6/g, (-) $30/g (+) $50/g, (-) $19/g (+) $16/g, (-) $78,g (+) $16.5/g, (dl) $0.13/g (+/-) $2/g (-) $13/g OH O (+)-Disparlure O (+)-Nootkatone $812/g (+) Longifolene (+)-"-Longipinene (-) Linalool $18/g $10.3/g $342/g $0.63/g O O OH OH X OH O nerolidol geraniol (X=OH) $0.35/g all trans $70/g (S)-cis-Verbenol (-) Verbenone !-Thujaplicin (-)-"-Thujone acetate $0.53/g cis/trans $0.75/g $8/g $2.8/g $8.6/g $25/g bromide $3.88 ",!#mix $5.5/g chloride $5.85 amine $23/g acid $0.92/g OH H O OH Squalene nerolidol O $0.43/g all trans $70/g O cis/trans $0.75/g Parthenolide $3724/g OH Br Totarol Farnesol trans,trans Prenyl Bromide $156/g $1.1/g $ 10/g (also bromide,chloride, acetate) $2.1/g 5 Baran Lab C l a s s i c T e r p e n e S y n t h e s e s Tom Maimone OH OH CO2H H H OH H H O H H H H H H H HO HO HO Estrone Estriol H $14.2/g $72/g Estradiol HO $24.6/g H OH O HO Glycyrrhetinic acid H $5.4/g CO Na HO H H 2 Ergocalciferol (D2) HO H $15.7/g OAc H H O H H HO OH H O CO2H O 17!"Ethynylestradiol OH $28.6/g HO H 11!-Hydroxyprogesterone H $8.3/g O Fusidic acid H $108/g OH H H HO O H OH HO OH H Prednisone HO H $13.4/g H H Ursodeoxycholic acid H H $12.3/g several related O H H derivates available H H O 19-Hydroxy-4-androstene- 3,17-dione O $916/g Norgestrel Ethisterone $290/g $3.4/g O O OH O O HO OH O H H H H H H H H H H H H H H H H O AcO O SAc HO HO H Hydrocortisone Spironolactone Stigmasterol #-Sitosterol $10/g $12.5/g Hecogenin Acetate $26/g $0.26/g $11.2/g 6 Baran Lab C l a s s i c T e r p e n e S y n t h e s e s Tom Maimone O O O AcO O OH O O OH H OH HO N O HO H H H H OH O OH Sclareol H OH OBz O O $32/g Progesterone O Paclitaxel O $2.24/g OH $9500/g O OH H OH O O O OH O OH H O OH (-)-Oubain Hydrate H $75/g O H O H H MeO O O OMe H H O Cortisone Rotenone H O (-)-!-Santonin $22/g (several derivates $4.16/g $2.64/g 5-!-Cholestan-3-one available) H H $20/g (several unsaturated variants H available) 5-!-Cholestane O $60/g O HO OH H H H H H OH H H H HO O H N HO H 2 HO H H Digoxigenin Dehydroabietylamine Cholesterol Dipterocarpol Cholecalciferol $586/g (+) $0.27/g $0.30/g $138/g $19.5/g (many derivatives available) (several derivatives available) 7 Baran Lab C l a s s i c T e r p e n e S y n t h e s e s Tom Maimone O OH OH O O H O O O O OH H H HO O H H H H H O H HO F H HO OH HO O H H O OH Androsterone Artemisinin Chenodeoxycholic acid Betamethasone $45/g $416/g $7.94/g Andrographolide $ 696/g $175.4/g CO2H O O H OH H H H H H H H H H O O H H HO 1,4-androstadiene-3,17-dione 4-Androstene-3,17-dione HO $70/g $7.44/g H Betulin Lithocholic acid $58.6/g $1.24/g 8 Baran Lab C l a s s i c T e r p e n e S y n t h e s e s Tom Maimone III.