D A. Evans Polyene Cyclizations http://www.courses.fasharvardedu/-chem206/ Several Complex Mechanisms 206 Advanced Organic Chemistry OHC Handout 32 A 2. HOAC, NHO Introduction to Carbonium Ions-4 Angew. Chem. Int. Ed. Engl. 1978, 17, 476 J. Org. Chem.1990,57,2544 Stabilized Carbocations: Oxo-Carbenium lons(C=OR(+) Introduction to Terpene Biosynthesis Squalene, Lanosterol, Cholesterol Biosynthesis TFA, reflux Polyene Cyclization Chiral Acetals as C=O auxiliaries TIPS Bu3SnH Reading Assignment for this Lecture: Carey& Sundberg, Advanced Organic Chemistry, 4th Ed A. P. Johnson et al. Jcs Chem. Commun. 1994. 6. 765 Part A Chapter 5, Nucleophilic Substitution, 263-350 That outpost of empire Australia Heathcock, C H (1992). The enchanting alkaloids of Yuzuriha. " Angew.i produces some curious mammalia, the kangaroo rat, Other Excellent References the blood-sucking bat and Aurthur Birch, inter alia et, P. A (1984). "Olefin Cyclisation Processes That Form Carbon- etric Synthesis. Stereodifferentiating Reactions Part. J.D. Morrison New york. AP. vol 3: 341 If you are anxious for over-exposure, to prepublication disclosure, Thebtaranonth, C and Y. Thebtaranonth(1994). "Cyclization Reactions Boca Raton. FL. CRC Press Sir John Cornforth to good food and good drink, without leisure to think Corey Liu, enzyme"Mechanism for Polycyclic Triterpene Formation, Angew. Chem. Int Ed 2000, 39, 2812-2833 IUPAC symposia Matthew D Shair Monday December 9. 2002
D. A. Evans Chem 206 Matthew D. Shair Monday, December 9 , 2002 http://www.courses.fas.harvard.edu/~chem206/ Reading Assignment for this Lecture: Polyene Cyclizations Carey & Sundberg, Advanced Organic Chemistry, 4th Ed. Part A Chapter 5, "Nucleophilic Substitution", 263-350 . Chemistry 206 Advanced Organic Chemistry Handout 32A Introduction to Carbonium Ions–4 ■ Stabilized Carbocations: Oxo–Carbenium Ions (C=OR(+)) ■ Introduction to Terpene Biosynthesis ■ Squalene, Lanosterol, & Cholesterol Biosynthesis ■ Polyene Cyclizations ■ Chiral Acetals as C=O Auxiliaries NMe O Br OMe O TIPSO N O O Me O TFA, reflux Bu3SnH A. P. Johnson et al., JCS Chem. Commun. 1994, 6, 765 OHC Me Me Me OBn OHC HN Me OBn Me 2. HOAc, NH Me 4OAc 75% Heathcock, C. H. (1992). “The enchanting alkaloids of Yuzuriha.” Angew. Chem., Int. Ed. Engl. 31: 665. (handout) Other Excellent References Thebtaranonth, C. and Y. Thebtaranonth (1994). "Cyclization Reactions". Boca Raton, FL, CRC Press. Bartlett, P. A. (1984). "Olefin Cyclisation Processes That Form CarbonCarbon Bonds". Asymmetric Synthesis. Stereodifferentiating Reactions, Part B. J. D. Morrison. New York, AP. vol 3: 341. Several Complex Mechanisms Angew. Chem. Int. Ed. Engl. 1978, 17, 476. J. Org. Chem. 1990, 57, 2544. 1. MeNH2 Corey & Liu, enzyme "Mechanism for Polycyclic Triterpene Formation," Angew. Chem. Int Ed. 2000, 39, 2812-2833 "That outpost of empire Australia, produces some curious mammalia, the kangaroo rat, the blood-sucking bat, and Aurthur J. Birch, inter alia." If you are anxious for over-exposure, to prepublication disclosure, to good food and good drink, without leisure to think, try IUPAC symposia." Sir John Cornforth:
D A. Evans Terpene Biosynthesis Chem 206 Suggested Reading Representative Terpenes An Experimental Demonstration of the Stereochemistry of Enzymic Cyclization of 2, 3-Oxidosqualene E.J. Corey, S. C. Virgil JACS, 1991, 113, 4025 New Mechanistic and Stereochemical Insights on the Biosynthesis H of Sterols from 2, 3-Oxidosqualene Cyclase E.J. Corey, et al. JACS 1991, 113, 8171 Enzymatic Cyclization of Squalene and Oxidosqualene to Sterols and Terpenoids"Abe, et al. Chem. Rev. 1993, 93, 2189 lanosterol cholesterol Algic pyrophosphates D. Stereochemistry of the Cyclization of E Cane Acc. Chem. Res. 1985. 18. 220 Biomimetic Polyene Cyclizations W.S. Johnson Angew. Chem. Int. Ed Engl, 1976, 15, 9 OH taxol RO Interesting Reading nce,1997,V277 Icture and Function of the Squalene Cyclase, G. Shultz, p 1811 "Structural Basis for Cyclic Terpene Biosynthesis by Tobacco 5-epi- Aristolochene", J. P. Noel, p. 1815 Terpenoid Cyclization Reactions in Biology, D W Christianson,p./ ME Crystal Structure of Pentalene Synthase: Mechanistic Insights on caryophyllene 1821 The Stereochemistry of Allylic pyrophosphate Metabolism D.E. Cane Chem. Rev. 1980.36 1109 Biosynthesis of Natural Products"P. Manitto: Wiley&Sons, NY: 1981 gibberellic acid
D. A. Evans Terpene Biosynthesis Chem 206 "An Experimental Demonstration of the Stereochemistry of Enzymic Cyclization of 2,3-Oxidosqualene...." E. J. Corey, S. C. Virgil JACS, 1991, 113, 4025. "New Mechanistic and Stereochemical Insights on the Biosynthesis of Sterols from 2,3-Oxidosqualene Cyclase" E. J. Corey, et al. JACS 1991, 113, 8171. "Enzymatic Cyclization of Squalene and Oxidosqualene to Sterols and Terpenoids" Abe, et al. Chem. Rev. 1993, 93, 2189. "Isoprenoid Biosynthesis. Stereochemistry of the Cyclization of Allylic Pyrophosphates." D. E. Cane Acc. Chem. Res. 1985, 18, 220. "Biomimetic Polyene Cyclizations" W. S. Johnson Angew. Chem. Int. Ed. Engl, 1976, 15, 9. Suggested Reading Science, 1997, v277: "Structure and Function of the Squalene Cyclase", G. Shultz, p. 1811. "Structural Basis for Cyclic Terpene Biosynthesis by Tobacco 5-epiAristolochene", J. P. Noel, p. 1815. "Crystal Structure of Pentalene Synthase: Mechanistic Insights on Terpenoid Cyclization Reactions in Biology", D. W. Christianson, p. 1821. "The Stereochemistry of Allylic Pyrophosphate Metabolism." D. E. Cane Chem. Rev. 1980, 36, 1109. "Biosynthesis of Natural Products" P. Manitto; Wiley&Sons, NY: 1981. Interesting Reading Me Me HO Me Me Me Me Me Me O HO RO BzO AcO O Me OH OAc taxol cholesterol H H Me Me Me Me Me Me Me Me HO H lanosterol Me CH2 Me Me caryophyllene O H2C Me O O Me OH O O picrotoxinin CO2H OH Me HO O OC gibberellic acid Representative Terpenes H H H
D. A. Evans Chiral Acetal auxiliaries-1 Chem 206 H6, R T 91% yield P.A. Bartlett& Co-workers Rato=72:28de=84% JAm.Chem.Soc,1983,105,2088 JAm.chem.Soc,1976.98,6188 LiVIDA D MeO2C CO2 Me CO M MeO2C CO2Me 94 yield de=86% W.J. Richter, J.Org. Chem., 1981, 46, 5110 gu14:86 Zn-Cu, CH2l2 Et20 LiAIHa MOMO OMOM MOMO OMOM K. A Nelson &E.A. Mash R J. Org. Chem,1986,51,2721 de=>95% J. Richter, J. Org. Chem. 1981, 46, 5119 Et 732 PhEu -Et Et CuBr. PB CHa=c- SnCl4 J M. McNamara. Y Kishi J.Am.chem.Soc,1982.104,7371 签/ (error in R/S nomenclature in paper) 2 2A-10-chiral acetals- 1 12/17/99 8: 57 AM
D. A. Evans Chem 206 (error in R/S nomenclature in paper) R LiBr, BF3 Et2O, -78oC CuBr, PBu3 P. Mangeney & Co-workers, Tetrahedron Lett., 1987, 28, 2363. HBr Br2 CCl4 94 % yield de = 86 % G. Castaldi & Co-workers, Angew. Chem. I. E., 1986, 25, 259. Ratio = 72 : 28 de = 84% SnCl4 C6H6, R.T. LiAlD4 AlCl3 Chiral Acetal Auxiliaries-1 W. J. Richter, J. Org. Chem., 1981, 46, 5119. W. J. Richter, J. Org. Chem. ,1981, 46, 5119. AlCl3 LiAlH4 J. M. McNamara, Y. Kishi, J. Am. Chem. Soc., 1982, 104, 7371. SnCl4 CH3CN, -20oC P. A. Bartlett & Co-workers, J. Am. Chem. Soc., 1983, 105, 2088 R = C8H17 Ratio = 88 : 12 TiCl4 CH2Cl2, -78oC 91% yield W. S. Johnson & Co-workers, J. Am. Chem. Soc., 1976, 98, 6188. K. A. Nelson & E. A. Mash, J. Org. Chem., 1986, 51, 2721. Zn-Cu, CH2I2 Et2O, ∆ de = >95 % Isomer Agent (R) E/Z % Yield % de E (1) 100/0 75 95 (R) E (2) 95/5 70 85 (R) Z (1) 100/0 75 69 (S) Acetal Alkylating Product PhCu (2) (1) O O R H Me Me HO O R D Me Me O O O OH R R D Me Me Me Me Me HO O R Me Me Me O OH R Me O Me Me O O O O R CH2 C OTMS Et O Et O O H Me Me O Et R O Me Me OH O R Me Me O R TMS O O H Me Me O R O Me Me O Me OH R Me Me Me Me O O Me Me Me Me RO H Me RO H MeO2C CO2Me Ph CH3 O O MeO2C CO2Me Ph CH3 Br O OH MeO2C CO2Me Ph CH3 O MOMO OMOM MOMO OMOM ( CH2)6 O O O ( CH2)6 R Cu Me Me OH Me Me H R ratio Et t-Bu Ph 01:99 22:78 14:86 R ratio Et t-Bu Ph 73:24 85:15 51:46 R ratio Ph n-C9H19 16:1 03:1 32A-10-chiral acetals-1 12/17/99 8:57 AM
D A. Evans Chiral Acetal auxiliaries-2 Chem 206 TMs→CEN H2Ch, C 92% yield P A Bartlett Coworkers J Am Chem. Soc.,1983,105,2088 Rato=87:13 Co-workers Rato=97:3,88%de -MS + diastereomer RLi, CuBr Me 96% yie COOH WASm. chem. .C. 1983. 585 Ratio 93 R Temp. C)%Yield %de Tetrahedron e :. 1986. 2a 2945 CH2Cl2, -20 972 vield OTBS 1)TiCl, CH2, -78%c CgHi7 Rato=965:3.5 2)CF3COOH, 22"C c-CgH11, CH3 J. D. Ellott& Co-workers E2O,20° Tetrahedron Left. 1985. 25. 2535 Ratio 98.2 t diastereomer 99% yield Ratio 23 diastereomer 97% yield de=77% dias ertioselecion 2A-11-chiral acetals-2 12/17/99 8: 59 AM
D. A. Evans Chiral Acetal Auxiliaries-2 Chem 206 S. L. Schreiber & J. Reagan Tetrahedron Lett., 1986, 27, 2945. diastereoselection >99% CH2Cl2, 0oC 90 % yield DIBAL H. Yamamoto & Co-workers, Tetrahedron Lett., 1986, 27, 983. + diastereomer Ratio = 97 : 3 TiCl4 CH2Cl2, -78oC 98% yield Ratio = 87 : 13 P. A. Bartlett & Co-workers, J. Am. Chem. Soc., 1983, 105, 2088. W. S. Johnson & Co-workers, J. Am. Chem. Soc., 1983, 105, 2904. Ratio = 93 : 7 CH2Cl2, -78oC 96% yield TiCl4 + diastereomer + diastereomer TiCl4 CH2Cl2, -20oC 97% yield Ratio = 96.5 : 3.5 W. S. Johnson & Co-workers, J. Org. Chem., 1983, 48, 2294. Ratio = 23 : 1 + diastereomer Br2AlH Et2O, -20o C 99% yield H. Yamamoto & Co-workers, Tetrahedron Lett., 1983, 24, 4581. W. S. Johnson & Co-workers, Tetrahedron Lett., 1984, 25, 591. Ratio = 97 : 3, 88% de CH2Cl2, 0oC 92% yield TiCl4 RLi, CuBr Me2S Et2O R Temp.(oC) % Yield % de Me 0 58 94 Ph -30 90 97 J. D. Elliott & Co-workers, Tetrahedron Lett., 1985, 26, 2535. Ratio = 98 : 2 1) TiCl4, CH2Cl2, -780C 2) CF3COOH, 22oC 98 % yield H. Yamamoto & Co-workers, Tetrahedron Lett., 1984, 25, 5911. 1) Me3Al 2) Ac20 - Py 97% yield de = 77% O O C8H17 H O OH O O C8H17 Me Me C8H17 H O OH Me Me C8H17 Me Me TMS O O Me Me C6H5 H O OH Me Me C8H17 TMS C N O TMS C N O Me Me c-C6H11 CH3 O OH Me Me c-C6H11 CH3 O O Me H HO O Me Ar CN O TMS C N PhO O Me Me Et OH O Me Me O Bu Et Bu O Me2NCO CONMe2 H3C OXc OH O O HO Me Ar CN C8H17 O O C6H13 O H Me O COOH Me C6H13 R H Me C8H17 C8H17 COOH O OTBS OtBu HO Me Me O O Me Me 32A-11-chiral acetals-2 12/17/99 8:59 AM
D. A. Evans Terpenes: Occurance in Nature Chem 206 I Definition: Natural products whose carbon skeletons are built a Role in insects: hormones, pheromones(communication chemicals) largely from isoprene subunits sex attractant pheromone of the American cockroach menthol (R)-carvone spearmint Cecropia juenile hormone blocks development at larval growth stage a Occurance: Plants, insects, higher organisms ote that the stared methyls a Role in plants: hormones, defense etc example: pyrethrin insecticides Me alarm pheromone for aphids a Role in mammals: hormones, pheromones ?? 一 cholester steroid example:antifeedants such as warburganal example: flavor constituents nootkatone grapefruit flavor active at nanomolar- femi is this related to 32A02 - terpene-11/2500249PM
nepetalactone oil of catnip active at nanomolar-femptomolar concentrations is this related to a feline pheromone? steroid hormones cholesterol ■ Role in mammals: hormones, pheromones ?? alarm pheromone for aphids note that the starred methyls are not derived from isoprene ✻ ✻ Cecropia junenile hormone blocks development at larval growth stage ■ Role in insects: hormones, pheromones (communication chemicals) citronellal lemon oil nootkatone grapefruit flavor example: flavor constituents chrysanthemic acid example: antifeedants such as warburganal example: pyrethrin insecticides ■ Role in plants: hormones, defense etc. ■ Occurance: Plants, insects, higher organisms (R)-carvone spearmint (S)-carvone caraway menthol Natural products whose carbon skeletons are built up largely from isoprene subunits: Terpenes: Occurance in Nature Chem 206 isoprene periplanone sex attractant pheromone of the American cockroach ■ Definition: D. A. Evans Me O Me OMe Me Me Me O O OH Me Me Me Me Me O H H Me H H Me Me Me Me Me Me Me Me HO H Me O H H O Me Me Me Me H H O O Me O Me Me Me H Me O Me Me CHO CHO OH OH H H Me Me Me H2C Me Me O O O H Me Me O Me H Me O Me Me 32A-02-terpene-1 1/25/00 2:49 PM
D. A. Evans Isoprene: Building Block of Nature(2) Chem 206 Classification of terpenes a Terpene Biosynthesis tail monoterpenes: 10 C-atoms(2 isoprene units sesquiterpenes: 15 C-atoms(3 isoprene units)i There are two isoprene units which are used to build up terpenes 2-methyl-1, 3-butadiene 20 C-atoms(4 iso 30 C-atoms(6 is 人~ 1 yme Yr-dimethylallyl pyrophosphate 00 R0--0-1-0H≡ROXR+o H3≡RoTs menthol camphor nature's leaving group chemist's leaving group 9 The basic process: alkene addition to electrophiles -0X sex attractant pheromone of the cinnamide DMAP HB otene natural rubber geraniol Practice: Recognize the isoprene units in the above structures 32A-03 terpenes212/17998:00AM
≡ ≡ n Chem 206 geraniol H2O/OHgeranyl pyrophosphate -HB -OXB- DMAP The basic process: alkene addition to electrophiles: tosylate: chemist's leaving group ROX ROTs pyrophosphate: nature's leaving group γ,γ-dimethylallyl pyrophosphate (DMAP) isopentenyl pyrophosphate (IPP) enzyme There are two isoprene units which are used to build up terpenes: Isoprene : Building Block of Nature (2) 2-methyl-1,3-butadiene isoprene head tail geraniol citronellol two components in rose oil menthol camphor sex attractant pheromone of the American cockroach cinnamolide antifungicide ß-carotene natural rubber monoterpenes : 10 C-atoms (2 isoprene units) sesquiterpenes : 15 C-atoms (3 isoprene units) Classification of terpenes h t h t ■ Terpene Biosynthesis Practice: Recognize the isoprene units in the above structures. D. A. Evans diterpenes : 20 C-atoms (4 isoprene units) triterpenes : 30 C-atoms (6 isoprene units) Me OH OH OH O O O O O Me OX OX Me Me ROP O O P O O OH ROS O O CH3 O OX Me Me Me Me CH2 OX Me Me Me Me OX H H Me Me OX Me Me Me Me OH H2C Me Me O O O H 32A-03-terpenes-2 12/17/99 8:00 AM
D. A. Evans Isoprene Building Block of Nature(3) Chem 206 From isoprene to a-pinene and bornene The Basic Process: 1-2 rearrangement DMAP geranyl pyrophosphate o Me The precursor of bornene could also lead to camphene Show the mechanism CH3 Tetrahydrocannabinol (THC) CH3 H1 chrysanthenol oliveto bornene 32A04 -terpenes312/17/99803AM
- H + H + bornene -H+ ≡ 1,2 shift α−pinene ≡ -H+ limonene -H+ -OXisomerization geranyl pyrophosphate DMAP From isoprene to α−pinene and bornene + The Basic Process: 1-2 rearrangement + The precursor of bornene could also lead to camphene. Show the mechanism! camphene Tetrahydrocannabinol (THC) chrysanthenol olivetol aromatic substitution D. A. Evans Isoprene : Building Block of Nature (3) Chem 206 -OX OX - Me Me Me Me OX Me Me Me Me Me Me Me OX Me Me OX Me Me Me Me Me Me Me Me Me Me Me Me Me C R3 C R1 R4 CH3 R2 C R2 CH3 R C 4R1 R3 CH3 CH3 Me OH OH HO CH3 HO C5H11 OH Me Me O Me OH Me C5H11 Me C5H11 OH Me O H Me 32A-04-terpenes-3 12/17/99 8:03 AM
N. Finney, D. A. Evans Cyclic and"lrregular"Monoterpenes Chem 206 Cyclic Monoterpenes Biosynthetic Study of Monoterpenes HO2C a-terpineol Me CO2H (±) MVA lactone drugs operate here ⊙ H carene Thujone Iridoids and secoiridoids 比H OHC CO2CH3 R=β D-glucose 32A-05-Monoterpenes 12/8/00 8: 52 AM
Me Me Me Me Me Me OH Me Me Me Me Me Me H Me Me Me Me Me Me Me Me H Me Me Me H H H Me Me Me OH H Me Me Me Me Me Me Me Me Me Me Me OH Me Me Me Me HO2C OH HO Me CO2H CO2H Me HO Me Me O N. Finney, D. A. Evans Cyclic and "Irregular" Monoterpenes Chem 206 Cyclic Monoterpenes + + + α-terpineol O Me OR HO + α-pinene borneol carene CO2CH3 terpinolene O OR terpinenol Irregular Monoterpenoids CO2CH3 P P CH2 α-thujene OHC Biosynthetic Study of Monoterpenes Me Me CO2H Me Me (±) MVA lactone (±) MVA GPP O Me Me Iridoids and Secoiridoids loganin secologanin chrysanthemic acid Me nezukone R = β-D-glucose H 14C label O O Me HO hydroxy-methyl glutarate OH Me OH Me O Me Me O camphor α-thujone cholesterol-lowering drugs operate here 32A-05-Monoterpenes 12/8/00 8:52 AM
N Finney Sesquiterpenes-C15 Terpenoid Chem 206 El-FPP CH cuprene widdrol thujopsene caryophyllene humulene 32A-06-Sesquiterpenes 12/8/00 8: 54 AM
Me Me Me Me Me Me Me Me O O Me Me Me CH3 Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me CH3 Me Me Me CH3 Me Me Me Me O H2C Me O O Me OH O O Me Me Me Me Me OH Me Me Me Me Me Me Me N. Finney Sesquiterpenes–C15 Terpenoids Chem 206 P P P P + Me Me Me Me Me CH2 H3C Me picrotoxinin caryophyllene humulene cuparene widdrol thujopsene (Z)-FPP (E)-FPP [Ox] 32A-06-Sesquiterpenes 12/8/00 8:54 AM
N Finney Squalene Biosynthesis; Squalene Oxide Cyclization Chem 206 ne Biosynthesis Me(oDe Squalene Oxide Cycl famesyl pyrophosphate Prestwich, et al. Chem. Rev. 1993. 93. 2189-2206 Cornforth Proposal: ACIEE, 1968, 903 人 squalene oxide Enz-X presqualene pyrophosphate o(O lanosterol squalene(C30) 32A-07- Squalene, Lanosterol 12/8/00 8: 55 AM
Me Me Me Me Me Me Me Me Me Me Me O Me Me Me O Me Me Me Me O Me Me Enz-X Me Me Me Me Hb Ha Me Me O Me Me Me Me Me Me Ha Me Me Me Me Me Me Me Me H Me Me Me Me N. Finney Chem 206 Me Me Me Me Squalene Biosynthesis; Squalene Oxide Cyclization H P NAD H squalene oxide P P P Enz-X– P P Squalene Biosynthesis Me Me Me Me Me Me Me Me Squalene Oxide Cyclase O Me Me O Me H Me Me Me Me Me Me HO Me Me Me Me H Me H Me H Me Me HO Me H Me H Me H Me H Me Me Me Me Me HO Me H Me Me Me Me Me P + P H lanosterol presqualene pyrophosphate squalene (C30) farnesyl pyrophosphate (C15) Prestwilch, et. al. Chem. Rev. 1993, 93, 2189-2206 Cornforth Proposal: ACIEE, 1968, 903. 32A-07- Squalene, Lanosterol 12/8/00 8:55 AM
