倍半萜的生物合成途径及其全合成2007_Mohr

Sesquiterpenoids Biosynthesis and Total Synthesis Justin T. Mohr Stoltz Group Literature Group Meeting 2 April 2007 HO H OH O Br H O H O H OH OH H H O OH O O H O OH H OHH O O H N NN N NH2 O OHO O P OH O O P O OH O OH H N O H N O S P OH HO O O O Title Outline H H H Hirsutene (Oda, 1986) H H H Δ9(12)-Capnellene (Curran, 1985) Longifolene (Oppolzer, 1978) α-Isocomene (Wender, 1981) Sinularene (Oppolzer, 1982) H H β-Caryophyllene (Corey, 1963) O α-Cuparenone (Noyori, 1978) O O O H Hibiscone C (Smith, 1982) ? • Introduction to terpenes and terpenoids • Traditional isolation of terpenoids • The Isoprene Rule • Terpenoid biosynthesis • Coenzymes • The mevalonate pathway • Cyclization examples • Case studies in biosyntheses and laboratory total syntheses Outline • Sell, A Fragrant Introduction to Terpenoid Chemistry; Royal Society of Chemistry: Cambridge, 2003. • Newman, Chemistry of Terpenes and Terpenoids, Academic: London, 1972. • Cordell, "Biosynthesis of Sesquiterpenes" Chem. Rev. 1976, 76, 425-460 • Cane, "Isoprenoid Biosynthesis. Stereochemistry of the Cyclization of Allylic Pyrophosphates" Acc. Chem. Res. 1985, 18, 220-226. • Roberts, "Sesquiterpene Biogenesis" Q.Rev., Chem. Soc. 1967, 21, 331-363. • Roberts, "Sesquiterpenoids" Terpenoids and Steroids 1982, 11, 3-90. • Roberts, "Sesquiterpenoids" Nat. Prod. Rep. 1984, 1, 105-169. • Roberts, "Sesquiterpenoid Synthesis" Nat. Prod. Rep. 1985, 2, 97-145. • Dewick, "The Biosynthesis of C5-C25 Terpenoid Compounds" Nat. Prod. Rep. 2002, 19, 181-222. General References Terpenoids An Introduction All terpenoids can be formally broken down into isoprene units. α-Copaene sesquiterpenoid Isoprene 3 H H H Pentacyclosqualene triterpenoid Isoprene 6 Class names are derived from the number of isoprene units incorporated: # of isoprenes # of carbons class name 1 5 hemiterpenoids 2 10 monoterpenoids 3 15 sesquiterpenoids 4 20 diterpenoids 6 30 triterpenoids 5 25 sesterterpenoids 8 40 tetraterpenoids ∞ 5*∞ rubber Prefixes (many of these are now antiquated): • α, β, γ – usually olefin isomers, occassionally stereochemistry • seco – designates cleavage of one bond • cyclo – with one additional bond forming a ring • abeo – designates a rearranged bond • nor – lacking one carbon • homo – with one additional carbon Turpentine terpenoids distilled from sap (largely pinene) are the only compounds correctly called terpenes often dimers of lower terpenoids Terpenoids Methods of ExtractionDistillation Plant • Expression – forcing materials out with physical pressure • Dry (Empyrumatic) Distillation – high temp direct distillation reserved for high boiling oils • Steam Distillation – oils co-distilled with added water, separated after • Hydrodiffusion – steam introduced to the top of a column of plant, then collected from the bottom Essential Oil + Waters of Cohabitation (aqueous layer) "Terpeneless" Oil + monoterpenoid hydrocarbons "deterpenation" extraction or distillation Plant Extraction EtOH other solvent Tincture Concrete or Resinoid Pomade enfleurage plant material pressed into fat "Terpeneless" Oil + monoterpenoid hydrocarbons "deterpenation" extraction or distillation Essential Oil distill EtOH EtOH Absolute Group terpenoids Cl Br HO Elatol sesquiterpenoid O H Cyanthiwigin G diterpenoid O O O H HO H O OH OH H OAc Bielschowskysin diterpenoid AcO O H O OH Guanacastepene diterpenoid OO OH O H Ineleganolide diterpenoid AcO O Lepistal diterpenoid O O H OHC HH H HO Variecolin Sesterterpenoid O O O O O AcO H O Wortmannin diterpenoid H OH α-Eudesmol sesquiterpenoid O O OH Dichroanone norditerpenoid Terpenoids and You O Terpenoid structures are very diverse, incorporating many unique ring systems, funtionalities, and molecular architectures. H O O O O H OH Garsubellin A triterpenoid Johnson progesterone Isoprene to Terpenoids Isoprene units can (formally) combine in two ways to make higher terpenoids. The skeletons derived directly from isoprene subunits are said to obey the "Isoprene Rule." OH H+ tail head OH Geraniol OH tail head HO trans,trans-Farnesol nerolidyl pyrophosate tail tail Squalene [O] O H HO Squalene-2,3-oxide Dammaradienol 256 possible stereoisomers Johnson, J. Am. Chem. Soc. 1971, 93, 4332-4334. Johnson, J. Am. Chem. Soc. 1978, 100, 4274-4282. HO 1. TFA, DCE ethylene carbonate 0 °C, 3 h 2. 10% aq K2CO3 MeOH H H H O (71% yield) O O H H H (±)-Progesterone 1. O3, MeOH/CH2Cl2 2 min, –70 °C 2. Zn, HOAc, 1 h 3. KOH, MeOH 20 h (45% yield)5:1 17α:17β 5.7:1 17α:17β In the lab: Johnson, Acc. Chem. Res. 1968, 1, 1-8. OPP Terpenoid Biosynthesis An Overview Acetyl Coenzyme A – A versatile biosynthetic intermediate N NN N NH2 O OHO OP OH O O PO OH O OHH N O H N O HS P OH HO O ribose adenine HS-CoA: • While not directly functional, the sugar and nucleotide fragments are important for selective binding to the enzyme. Origin of Acetyl CoA: CO2 + H2O photosynthesis OHO HO OH OHHO Glucose glycolosis O OH O P OH OH O Phosphoenol Pyruvate –HPO3 O OH O –CO2 O S CoA Acetyl CoA Depending on the enzyme, acetyl CoA can be an electrophilic or nucleophilic partner: O S CoA O S CoA O Nuc SCoA base Nuc– pantothenic acid (vitamin B5) * Disclaimer: All intermediates are shown in neutral forms. At physiological pH, most acidic FGs are deprotonated. Terpenoid Biosynthesis An Overview N NN N NH2 O OOH P OH OH O O P O OH O P OH O N O OH OH O H H NH2 O N NN N NH2 O OOH P OH OH O O P O OH O P OH O N O OH OH O NH2 O NADP (Nicotinamide Adenine Dinucleotide Phosphate) biosynthetic hydride acceptor (oxidizing agent) • Nicotinamide is aromatic, but charged NADPH biosynthetic hydride donor (reducing agent) • Nicotinamide neutral, but not aromatic +H– –H– Other Important Coenzymes: N NN N NH2 O OHOH O P O OH O P OH O HO N NN N NH2 O OHOH O P O OH O P OH O O ATP (Adenosine Triphosphate) phosphorylating agent • Triphosphate is relatively high energy, so phosphate transfer to nucleophiles (e.g., alcohols) is favorable –HPO3 +HPO3 P HO OH O ADP (Adenosine Diphosphate) * Related coenzymes NAD and NADH (lacking the 2' phosphate) have similar function in degradation. Terpenoid Biosynthesis An Overview O S CoA2 O S CoA thiolase –HSCoA O Acetyl CoA Acetoacetyl CoA HMG-CoA synthase O S CoA O S CoA thiolase –HSCoA OHO S CoA O S CoA OHO HO β-hydroxy-β-methylglutaryl-CoA (HMG-CoA) OH OHO HO Mevalonic Acid 2 NADPH 2 H+ –2 NADP+ –HSCoA HMG-CoA reductase O OHO HO 5-Phospho-Mevalonic Acid P OH OH OATP –ADP O OO O 3-Phospho-5-Pyrophospho- Mevalonate P OH HO O P OH O P OH OH OO mevalonate 5-phospho- transferase O OHO HO 5-Pyrophospho-Mevalonic Acid P OH O P OH OH OO ATP –ADP pyrophospho- mevalonate decarboxylase ATP –ADP phospho- mevalonate kinase pyrophospho- mevalonate decarboxylase –CO2 –H2PO4– O Isopentenyl Pyrophosphate P OH O P OH OH OO O Prenyl Pyrophosphate P OH O P OH OH OO Mn2+ Mg2+ * The mevalonate pathway is shown. This occurse in plant cytoplasm and all animals. A mevalonate independent pathway is known to occur in plant chloroplasts and in many bacteria. OPP prenyl transferase (head to tail) –H4P2O7 O P O OH O P OH OH O Geranyl Pyrophosphate Terpenoids Linear to Cyclic Terpenoids cis,trans-farnesyl H cis-humulane a a b germacrane c c b bisabolane d d cuparane e e campherenane 1,2-H shift bisabolane f acorane f 1,2-alkyl shift α-santalane Natural rearrangements Terpenoids Biogenetic Relationship of Various Architectures González, Tetrahedron Lett. 1980, 21, 1151-1154. González, Tetrahedron Lett. 1982, 23, 2395-2398. Cl Br Obtusane chamigrane Br TsOH PhH (100%) Iso-bromocuparane cuparane Br SiO2 (100%) Isolaurene rearranged cuparane Br Br a chamigrane natural product Cl HO AcOH LiClO4 40 °C (100%) Perforene Cl Br Cl Br Br HO AcOH LiClO4 (100%) Cl Br Elatol chamigrane HO 9-Hydroxy- Iso-Obtusene chamigrane m-CPBA Cl Br HO O SiO2 O HO Br O HO Br rhodolaurane Synthesis of Sesquiterpenoids α-Cuparenone Biosynthesis cis,trans-farnesyl bisabolane cuparane H2O HO [O] O α-Cuparenone Noyori, Tetrahedron Lett. 1978, 19, 993-994. O Br Br 1 equiv 4 equiv Fe2(CO)9 (1.4 equiv) PhH, 55 °C 17 h O α-Cuparenone (18% yield) O (1.2% yield) • high regioselectivity is attributed to preference for the benzylic carbocation intermediate OFeII FeIIO Synthesis of Sesquiterpenoids β-Caryophyllene Biosynthesis Laboratory Synthesis Corey, J. Am. Chem. Soc. 1963, 85, 362-363. Corey, J. Am. Chem. Soc. 1964, 86, 485-492. H H β-Caryophyllenecis,trans-farnesyl H H HH O hν –40 °C O H H O H H (4:1 d.r.) KOH, MeOH 1. NaH Me2CO3 2. NaH MeI O H H CO2Me (3:1 d.r.) Li OMe OMe H H CO2Me OH MeO OMe 1. H2, Pd/C 2. CrO3 H H CO2Me O O 1. NaH DMSO 2. aq NaOH 3. Py, ∆ H H O HO 1. H2, Ra-Ni (1:1 d.r.) 2. TsCl, Py H H OTs HO cis-humulane caryophyllane H+ H Clovene Isoclovene Synthesis of Sesquiterpenoids β-Caryophyllene H H Isocaryophyllene H H OTs HO OH OTs H NaH DMSO; t-BuOH A stereospecific fragmentation reaction: H H Ph3PCH2 Only Z-olefin H H β-Caryophyllene H H OTs HO NaH DMSO; t-BuOH H H O Ph3PCH2 Only E-olefin OTs H H H OH Stereospecificity can also be viewed by Newman projection: OTs H MeHO breaking bond and leaving group must be anti-periplanar OTs H MeHO H Me Only Z-olefin H OTs MeHO H OTs MeHO H Me Only E-olefin Synthesis of Sesquiterpenoids Longifolene Biosynthesis Laboratory Synthesis Oppolzer, J. Am. Chem. Soc. 1978, 100, 2583-2584. Longifolenecis,trans-farnesyl cis-humulane H himchalene longibornane O OH 1. SOCl2 2. NO O O Py O OCO2Bn (74%) (88%) BnO O Cl hν O OCO2Bn O OCO2Bn (83%) (2:3 d.r.) (83%) H2 Pd/C O O O O O (88%) Ph3PCH2 (78%) CH2I2 Zn-Ag (96%) H2 PtO2 (75%) 1. base MeI 2. MeLi; SOCl2 Py Synthesis of Sesquiterpenoids SinulareneBiosynthesis Laboratory Synthesis Oppolzer, Tetrahedron Lett. 1982, 23, 4673-4676. Sinularene cis,trans-farnesyl cis-germacryl H H H H cadinyl I CO2H Cl Mg Cl H MgCl H CO2H H OMe H OMe OLi OLi 1. LiAlH4 2. MsCl, Py 3. aq HCl Mg0 (76%) (37%) (47%) 1. LiAlH4 2. NaH MeI (88%) 1. O3; DMS 2. KOH EtOH (90%) Ph3PCH2 (69%) O H OMe 1. H2, Pt 2. TMSI (77%) H OH 1. AcCl Et3N 2. 500 °C (77%) CO2 Synthesis of Sesquiterpenoids IsocomeneBiosynthesis Laboratory Synthesis Wender, Tetrahedron 1981, 37, 4445-4450. cis,trans-farnesyl α-Isocomene H H H cis-humulane H H H caryophyllane H silphinane H Br Li 0; CuI; MVK O 1. Li0 2. NH3 3. NH4Cl Li hν (1:1) H H H2 Pd/C H H PhMe ~240 °C H presilphiperfolane H H H Δ9(12)-Capnellene Synthesis of Sesquiterpenoids Δ9(12)-CapnelleneBiosynthesis H Precapnelladiene (a natural product) H+ H HHH africanetrans,trans-farnesyl humulene (a natural product) H+ H H H ? humulene H H H+ H H H H another proposal ("cyclopropane sliding"): HH H H HH H H H H H H H H H Δ9(12)-Capnellene trans,trans-farnesyl H revised proposal (to account for precapnelladiene): H H H Δ9(12)-Capnellene initial proposal: Capnellene synthesis Curran, Tetrahedron Lett. 1985, 26, 4991-4994. Synthesis of Sesquiterpenoids Δ9(12)-Capnellene Laboratory Synthesis O Norbornenone O O OH NaOAc (56%) OO H H MeMgBr CuBr CO2H OO H H I I2 DBU (66%) CuBr•DMS MgBrO O LiAlH4 (80%) (10:1 SN2':SN2) O O HO2C O O 1. MsCl 2. NaI 3. Li N H2 H2 N (43%) 1. CrO3 H2SO4 2. CH2N2 (70%) OMeO 1. MeMgBr 2. TMSBr (90%) Br O O Bu3SnH AIBN PhH, ∆ (61%) OO H H H SnBu3 H H H Δ9(12)-Capnellene OH Synthesis of Sesquiterpenoids HirsuteneBiosynthesis Laboratory Synthesis Oda, J. Chem. Soc., Chem. Commun. 1986, 1049-1050. H H H Hirsutene trans,trans-farnesyl humulene (a natural product) H H+ protoilludyl H H H H H H HH H O O O O H H H H hν (80%) TMSI (2.3 equiv) (95%) Li, NH3 O H H H Ph3PCH2 (70%) H H H O O H H H H TMS O H HH TMSO I O H HH TMSO I TMSI O H HH OLi H H H MeI (47%) O H H fresh cut after 1 week Sesquiterpenoids in Nature Blue Mahoe • Blue Mahoe is the national tree of Jamaica. The wood has interesting photochemical properties. enlarged blue-hued woodgrain (after polishing) Blue Mahoe (Hibiscus elatus) • Some sesquiterpenoid isolates may be responsible HO OH O O Hibiscoquinone A purple crystal red in soln λmax = 484 nm hν ca. 20 min in soln, slower in solid state HO O O OH Hibiscolactone A colorless λmax = 356 nm O O O Hibiscone C major component λmax = 232 and 267 nm H Thomson, J. Chem. Soc., Perkin Trans. 1 1980, 249-256. Hibiscone C synthesis Synthesis of Sesquiterpenoids Hibiscone CBiosynthesis Laboratory Synthesis Smith, J. Am. Chem. Soc. 1982, 104, 5568-5570. Hibiscone Ccis,trans-farnesyl EtO O LDA I EtO O LiAlH4; H3O+ O hν O H H H (1.5:1 d.r.) 1. O3; Me2S 2. TsOH PhH ∆ (60%) (60%) (50%) O O H 1. NBS, hν; aq workup 2. CrO3•2Py (~40%) O O H (CH2OH)2 TsOH (45%) O or CrO3•2Py (20%) O H O O O monoketal isomer doubly ketalized product aq HCl/THF 1. LHMDS MeI 2. aq HCl THF O H O (64%) O <7% epimer O O O cadinane [O] germacrane H Conclusions Conclusion and Outlook OH O OH H OH OH OH O H OC13H27 O H H OH OH NaO3SO O HO OH H H O HHO2C OH OH N N O OAc H H H More naturally occuring terpenoids are constantly isolated. Here is a sample of some on J. Nat. Prod. ASAP: The important bioactivity of these molecules ensures continued interest in synthesis. Understanding the biosynthesis of these molecules may aid in the development of new approaches and a better understanding of the relationship to function. Others remain as standing challenges to synthetic chemistry: O O O HO AcO O H O OH OH OH H O O H H HO HO HO HO O O OHHO HO HO O OHHO HO OH OH OO NH