Sesquiterpenoids. Biosynthesis and Total Synthesis

Transcription

1 Br Sesquiterpenoids Biosynthesis and Total Synthesis 2 S Justin T. Mohr Stoltz Group Literature Group Meeting 2 April 2007

2 utline 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 General References Sell, A Fragrant Introduction to Terpenoid Chemistry; Royal Society of Chemistry: Cambridge, ewman, Chemistry of Terpenes and Terpenoids, Academic: London, Cordell, "Biosynthesis of Sesquiterpenes" Chem. Rev. 1976, 76, Cane, "Isoprenoid Biosynthesis. Stereochemistry of the Cyclization of Allylic yrophosphates" Acc. Chem. Res. 1985, 18, Roberts, "Sesquiterpene Biogenesis" Q.Rev., Chem. Soc. 1967, 21, Roberts, "Sesquiterpenoids" Terpenoids and Steroids 1982, 11, Roberts, "Sesquiterpenoids" at. rod. Rep. 1984, 1, Roberts, "Sesquiterpenoid Synthesis" at. rod. Rep. 1985, 2, Dewick, "The Biosynthesis of C5-C25 Terpenoid Compounds" at. rod. Rep. 2002, 19, α-cuparenone β-caryophyllene (oyori, 1978) (Corey, 1963) Longifolene Sinularene (ppolzer, 1978) (ppolzer, 1982)? 9(12)-Capnellene α-isocomene Δ irsutene ibiscone C (Wender, 1981) (da, 1986) (Smith, 1982) (Curran, 1985)

3 Terpenoids An Introduction All terpenoids can be formally broken down into isoprene units. 3 6 α-copaene Isoprene entacyclosqualene Isoprene triterpenoid sesquiterpenoid Class names are derived from the number of isoprene units incorporated: # of isoprenes # of carbons class name * hemiterpenoids monoterpenoids sesquiterpenoids diterpenoids sesterterpenoids triterpenoids tetraterpenoids rubber refixes (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 often dimers of lower terpenoids Turpentine terpenoids distilled from sap (largely pinene) are the only compounds correctly called terpenes

4 Terpenoids Methods of Extraction Distillation "Terpeneless" il Expression forcing materials out with physical pressure Dry (Empyrumatic) Distillation high temp direct distillation reserved for high boiling oils "deterpenation" Essential il Steam Distillation oils co-distilled with added water, separated after ydrodiffusion steam introduced to the top of a column of plant, then collected from the bottom lant extraction or distillation Waters of Cohabitation (aqueous layer) "Terpeneless" il Tincture "deterpenation" extraction or distillation distill other solvent Concrete or Resinoid monoterpenoid hydrocarbons + Extraction Et + Essential il + monoterpenoid hydrocarbons Et enfleurage lant plant material pressed into fat omade Et Absolute

5 Terpenoids and You Terpenoid structures are very diverse, incorporating many unique ring systems, funtionalities, and molecular architectures. α-eudesmol sesquiterpenoid Br Elatol sesquiterpenoid Cl Dichroanone norditerpenoid Ineleganolide diterpenoid Ac Ac Ac Cyanthiwigin G diterpenoid Lepistal diterpenoid Guanacastepene diterpenoid Wortmannin diterpenoid C Ac Bielschowskysin diterpenoid Variecolin Sesterterpenoid Garsubellin A triterpenoid

6 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." tail tail head tail head + Geraniol trans,trans-farnesol tail nerolidyl pyrophosate [] Squalene Squalene-2,3-oxide Dammaradienol 256 possible stereoisomers In the lab: 1. TFA, DCE ethylene carbonate 0 C, 3 h 1. 3, Me/C 2 Cl 2 2 min, 70 C 2. Zn, Ac, 1 h 2. 10% aq K 2 C 3 Me (71% yield) 5:1 17α:17β 3. K, Me 20 h (45% yield) (±)-rogesterone Johnson, J. Am. Chem. Soc. 1971, 93, Johnson, J. Am. Chem. Soc. 1978, 100, Johnson, Acc. Chem. Res. 1968, 1, :1 17α:17β

7 Acetyl Coenzyme A A versatile biosynthetic intermediate Terpenoid Biosynthesis An verview 2 S-CoA: S pantothenic acid (vitamin B 5 ) ribose adenine While not directly functional, the sugar and nucleotide fragments are important for selective binding to the enzyme. rigin of Acetyl CoA: Depending on the enzyme, acetyl CoA can be an electrophilic or nucleophilic partner: C photosynthesis Glucose glycolosis S CoA base uc hosphoenol yruvate 3 C2 S CoA Acetyl CoA S CoA uc SCoA * Disclaimer: All intermediates are shown in neutral forms. At physiological p, most acidic FGs are deprotonated.

8 ther Important Coenzymes: Terpenoid Biosynthesis An verview AD (icotinamide Adenine Dinucleotide hosphate) biosynthetic hydride acceptor (oxidizing agent) icotinamide is aromatic, but charged AD biosynthetic hydride donor (reducing agent) icotinamide neutral, but not aromatic * Related coenzymes AD and AD (lacking the 2' phosphate) have similar function in degradation AT (Adenosine Triphosphate) phosphorylating agent Triphosphate is relatively high energy, so phosphate transfer to nucleophiles (e.g., alcohols) is favorable AD (Adenosine Diphosphate)

9 Terpenoid Biosynthesis An verview 2 S CoA Acetyl CoA thiolase SCoA S CoA Acetoacetyl CoA S CoA thiolase CoA MG-CoA S S CoA SCoA synthase S CoA β-hydroxy-β-methylglutaryl-coa (MG-CoA) 2 AD AD + SCoA MG-CoA reductase Mevalonic Acid AT AD mevalonate 5-phosphotransferase 5-hospho-Mevalonic Acid AT AD phosphomevalonate kinase 5-yrophospho-Mevalonic Acid AT AD pyrophosphomevalonate decarboxylase 3-hospho-5-yrophospho- Mevalonate C pyrophosphomevalonate decarboxylase Isopentenyl yrophosphate Mn 2+ Mg 2+ renyl yrophosphate prenyl Geranyl transferase yrophosphate (head to tail) * 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.

10 Terpenoids Linear to Cyclic Terpenoids a b c a c cis-humulane cis,trans-farnesyl germacrane b d e 1,2- shift d f cuparane bisabolane bisabolane e f 1,2-alkyl shift α-santalane campherenane acorane

11 Br Terpenoids Biogenetic Relationship of Various Architectures Cl Ts h (100%) Br Si 2 (100%) Br btusane chamigrane Iso-bromocuparane cuparane Isolaurene rearranged cuparane Cl Br Ac LiCl 4 40 C Cl Br a chamigrane natural product (100%) erforene Br Br 9-ydroxy- Iso-btusene chamigrane Br Cl Ac LiCl 4 (100%) Br Elatol chamigrane Cl m-cba Br Si2 Br Cl Br rhodolaurane González, Tetrahedron Lett. 1980, 21, González, Tetrahedron Lett. 1982, 23,

12 Biosynthesis Synthesis of Sesquiterpenoids α-cuparenone 2 [] cis,trans-farnesyl bisabolane cuparane α-cuparenone Fe 2 (C) 9 (1.4 equiv) Br Br 1 equiv 4 equiv h, 55 C 17 h α-cuparenone (18% yield) (1.2% yield) Fe II Fe II high regioselectivity is attributed to preference for the benzylic carbocation intermediate oyori, Tetrahedron Lett. 1978, 19,

13 Biosynthesis Synthesis of Sesquiterpenoids β-caryophyllene + Clovene cis,trans-farnesyl cis-humulane caryophyllane β-caryophyllene Isoclovene Laboratory Synthesis hν 1. a Me 2 C 3 Li Me Me 40 C (4:1 d.r.) 2. a MeI (3:1 d.r.) C 2 Me C 2 Me 1. 2, d/c 2. Cr 3 K, Me C 2 Me 1. a DMS 2. aq a 3. y, 1. 2, Ra-i (1:1 d.r.) 2. TsCl, y Ts Me Me Corey, J. Am. Chem. Soc. 1963, 85, Corey, J. Am. Chem. Soc. 1964, 86,

14 A stereospecific fragmentation reaction: Synthesis of Sesquiterpenoids β-caryophyllene Ts a DMS; t-bu Ts h 3 C 2 nly Z-olefin Isocaryophyllene Ts a DMS; t-bu Ts nly E-olefin h 3 C 2 β-caryophyllene Stereospecificity can also be viewed by ewman projection: Ts Ts Me Me Me breaking bond nly Z-olefin and leaving group must be anti-periplanar Ts Me Ts Me Me nly E-olefin

15 Biosynthesis Synthesis of Sesquiterpenoids Longifolene cis,trans-farnesyl cis-humulane himchalene longibornane Longifolene Laboratory Synthesis 1. SCl 2 Bn y Cl hν C 2 Bn C 2 Bn 2. (74%) (88%) C 2 Bn (83%) (2:3 d.r.) 2 d/c h 3 C 2 C 2 I 2 Zn-Ag 2 t 2 1. base MeI (83%) (88%) (78%) (96%) 2. MeLi; SCl 2 y (75%) ppolzer, J. Am. Chem. Soc. 1978, 100,

16 Biosynthesis Synthesis of Sesquiterpenoids Sinularene cis,trans-farnesyl cis-germacryl cadinyl Laboratory Synthesis Cl Li 1. LiAl 4 C 2 I Li 2. MsCl, y 3. aq Cl Mg 0 (76%) (37%) (47%) Sinularene C 2 1. LiAl 4 2. a MeI 1. 3 ; DMS 2. K Et Mg Cl MgCl C 2 (88%) Me (90%) Me h 3 C 2 (69%) Me 1. 2, t 2. TMSI (77%) 1. AcCl Et C (77%) ppolzer, Tetrahedron Lett. 1982, 23,

17 Biosynthesis Synthesis of Sesquiterpenoids Isocomene cis,trans-farnesyl cis-humulane caryophyllane presilphiperfolane silphinane α-isocomene Laboratory Synthesis 1. Br Li 0 ; CuI; MVK Li Li 0 hν Cl hme ~240 C 2 d/c (1:1) Wender, Tetrahedron 1981, 37,

18 Biosynthesis initial proposal: Synthesis of Sesquiterpenoids Δ 9(12) -Capnellene trans,trans-farnesyl revised proposal (to account for precapnelladiene): + Δ 9(12) -Capnellene? trans,trans-farnesyl + humulene (a natural product) another proposal ("cyclopropane sliding"): africane recapnelladiene (a natural product) Δ 9(12) -Capnellene + humulene Δ 9(12) -Capnellene

19 Synthesis of Sesquiterpenoids Δ 9(12) -Capnellene Laboratory Synthesis aac MeMgBr CuBr I 2 DBU (56%) orbornenone C 2 I (66%) MgBr 2 C CuBr DMS LiAl 4 1. MsCl 2. ai 1. Cr 3 2 S 4 (10:1 S 2':S 2) (80%) 3. Li 2 2 (43%) 2. C 2 2 (70%) 1. MeMgBr Bu 3 Sn AIB Me 2. TMSBr (90%) Br h, (61%) SnBu 3 Δ 9(12) -Capnellene Curran, Tetrahedron Lett. 1985, 26,

20 Synthesis of Sesquiterpenoids Biosynthesis irsutene trans,trans-farnesyl Laboratory Synthesis humulene (a natural product) + protoilludyl hν TMSI (2.3 equiv) (80%) (95%) irsutene TMS TMS I TMS I TMSI Li, 3 MeI h 3 C 2 Li (47%) (70%) da, J. Chem. Soc., Chem. Commun. 1986,

21 Sesquiterpenoids in ature Blue Mahoe Blue Mahoe is the national tree of Jamaica. The wood has interesting photochemical properties. Blue Mahoe (ibiscus elatus) fresh cut after 1 week enlarged blue-hued woodgrain (after polishing) Some sesquiterpenoid isolates may be responsible hν ca. 20 min in soln, slower in solid state ibiscoquinone A ibiscolactone A ibiscone C purple crystal red in soln λmax = 484 nm colorless λmax = 356 nm major component λmax = 232 and 267 nm Thomson, J. Chem. Soc., erkin Trans ,

22 Synthesis of Sesquiterpenoids Biosynthesis ibiscone C [] cis,trans-farnesyl germacrane cadinane ibiscone C Laboratory Synthesis Et I LDA Et 1. BS, hν; aq workup 2. Cr 3 2y (~40%) or Cr 3 2y (20%) LiAl 4 ; 3 + hν (60%) (60%) (C 2 ) 2 Ts (45%) (1.5:1 d.r.) 1. LMDS MeI 2. aq Cl TF (64%) 1. 3 ; Me 2 S 2. Ts h (50%) Smith, J. Am. Chem. Soc. 1982, 104, aq Cl/TF monoketal isomer doubly ketalized product <7% epimer

23 Conclusion and utlook More naturally occuring terpenoids are constantly isolated. ere is a sample of some on J. at. rod. ASA: Ac Ac a 3 S 2 C C thers remain as standing challenges to synthetic chemistry: 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.

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