Chem 206D. A. Evans 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 a73 Stabilized Carbocations: Oxo–Carbenium Ions (C=OR(+)) a73 Introduction to Terpene Biosynthesis a73 Squalene, Lanosterol, & Cholesterol Biosynthesis a73 Polyene Cyclizations a73 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 Me2. HOAc, NH4OAc 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 Carbon- Carbon 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: Chem 206D. A. Evans Terpene Biosynthesis "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-epi- Aristolochene", 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 Chem 206 (error in R/S nomenclature in paper) R LiBr, BF 3 Et 2 O, -78 o C CuBr, PBu 3 P. Mangeney & Co-workers,Tetrahedron Lett. , 1987 , 28 , 2363. HBr Br 2 CCl 4 94 % yield de = 86 % G. Castaldi & Co-workers,Angew. Chem. I. E. , 1986 , 25, 259. Ratio = 72 : 28 de = 84% SnCl 4 C 6 H 6 , R.T. LiAlD 4 AlCl 3 Chiral Acetal Auxiliaries-1 W. J. Richter, J. Org. Chem., 1981 , 46 , 5119. W. J. Richter, J. Org. Chem. , 1981 , 46 , 5119. AlCl 3 LiAlH 4 J. M. McNamara, Y. Kishi, J. Am. Chem. Soc. , 1982 , 104 , 7371. SnCl 4 CH 3 CN, -20 o C P. A. Bartlett & Co-workers, J. Am. Chem. Soc. , 1983 , 105 , 2088 R = C 8 H 17 Ratio = 88 : 12 TiCl 4 CH 2 Cl 2 , -78 o C 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, CH 2 I 2 Et 2 O, ? 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 O HO R D Me Me O O O OH R R D Me Me Me Me Me O HO R Me Me Me OO H R Me O Me Me OO O O R CH 2 C OTMSEt O Et O O H Me Me O Et R O Me Me OH O RMe Me O R TMS O O H Me Me O R O Me Me O Me OH RMe Me Me Me OO Me Me Me Me RO H Me RO H MeO 2 C CO 2 Me Ph CH 3 OO MeO 2 C CO 2 Me Ph CH 3 Br OO H MeO 2 C CO 2 Me Ph CH 3 O OMOM MOMO OMOM MOMO ( CH 2 ) 6 O O O ( CH 2 ) 6 R Cu Me Me OH Me Me H R ratio Ett-BuPh 01:9922:7814:86 R ratio Ett-BuPh 73:2485:1551:46 R ratio Phn-C 9 H 19 16:103:1 32A-10-chiral acetals-1 12/17/99 8:57 AM Chiral Acetal Auxiliaries-2 Chem 206 D. A. Evans S. L. Schreiber & J. Reagan Tetrahedron Lett., 1986 , 27, 2945. diastereoselection >99% CH 2 Cl 2 , 0 o C 90 % yield DIBAL H. Yamamoto & Co-workers,Tetrahedron Lett. , 1986 , 27 , 983. + diastereomer Ratio = 97 : 3 TiCl 4 CH 2 Cl 2 , -78 o C 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 CH 2 Cl 2 , -78 o C 96% yield TiCl 4 + diastereomer + diastereomer TiCl 4 CH 2 Cl 2 , -20 o C 97% yield Ratio = 96.5 : 3.5 W. S. Johnson & Co-workers, J. Org. Chem. , 1983 , 48 , 2294. Ratio = 23 : 1 + diastereomer Br 2 AlH Et 2 O, -20 o 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 CH 2 Cl 2 , 0 o C 92% yield TiCl 4 RLi, CuBr Me 2 S Et 2 O R Temp.( o C) % Yield % de Me 0 58 94 Ph -30 90 97 J. D. Elliott & Co-workers,Tetrahedron Lett. , 1985 , 26 , 2535. Ratio = 98 : 2 1) TiCl 4 , CH 2 Cl 2 , -78 0 C 2) CF 3 COOH, 22 o C 98 % yield H. Yamamoto & Co-workers,Tetrahedron Lett. , 1984 , 25 , 5911. 1) Me 3 Al 2) Ac 2 0 - Py 97% yield de = 77% OO C 8 H 17 H OO H OO C 8 H 17 Me Me C 8 H 17 H OO H Me Me C 8 H 17 Me TMS Me OO Me Me C 6 H 5 H OO H Me Me C 8 H 17 TMS CN O TMS C N O Me Me c-C 6 H 11 CH 3 OO H Me Me c-C 6 H 11 CH 3 OO 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 Me 2 NCO CONMe 2 H 3 C OX c O OH HO O Me Ar CN C 8 H 17 OO C 6 H 13O H Me O COOH Me C 6 H 13 R H Me C 8 H 17 C 8 H 17 COOH O OTBSOtBu HO Me Me OO Me Me 32A-11-chiral acetals-2 12/17/99 8:59 AM nepetalactone oil of catnip active at nanomolar-femptomolar concentrations is this related to a feline pheromone? steroid hormones cholesterol a73 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 a73 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 a73 Role in plants: hormones, defense etc. a73 Occurance: Plants, insects, higher organisms (R)-carvone spearmint (S)-carvone caraway menthol Natural products whose carbon skeletons are built uplargely from isoprene subunits: Chem 206 Terpenes: Occurance in Nature isoprene periplanone sex attractant pheromone of the American cockroach a73 Definition: D. A. Evans Me O Me OMe Me Me Me O O OH Me Me Me Me O Me HH Me HH Me Me Me Me Me Me Me Me HO H Me O HH O Me Me MeMe H H O O Me O MeMe Me H Me O Me Me CHO CHO OH OH H H Me Me Me H 2 C 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 ≡ ≡ n Chem 206 geraniol H 2 O/OH - geranyl pyrophosphate -HB -OX - B - 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 cinnamolideantifungicide ?-carotene natural rubber monoterpenes : 10 C-atoms (2 isoprene units)sesquiterpenes : 15 C-atoms (3 isoprene units) Classification of terpenes h t h t a73 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 RO P O O P O O OH RO SO O CH 3 O OX Me Me Me Me CH 2 OX Me Me Me Me OX H H Me Me OX Me Me Me Me OH H 2 C Me Me O O O H 32A-03-terpenes-2 12/17/99 8:00 AM - H + H + bornene -H + ≡ 1,2 shift α? pinene ≡ -H + limonene -H + -OX - isomerization geranyl pyrophosphate DMAP From isoprene to αααα ???? 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 Chem 206 Isoprene : Building Block of Nature (3) D. A. Evans -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 R 3 C R 1 R 4 CH 3 R 2 C R 2 CH 3 C R 4 R 1 R 3 CH 3 CH 3 Me OH OH HO CH 3 C 5 H 11 HO OH Me Me O Me OH Me C 5 H 11 C 5 H 11 Me OH Me OH Me 32A-04-terpenes-3 12/17/99 8:03 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 HH H Me Me Me OH H Me Me Me Me Me Me Me Me Me Me Me OH Me Me Me Me HO 2 C OH Me HO CO 2 H CO 2 H Me HO Me Me O Chem 206 N. Finney, D. A. Evans Cyclic and "Irregular" Monoterpenes Cyclic Monoterpenes + + + α -terpineol O Me OR HO + α -pinene borneol carene CO 2 CH 3 terpinolene O OR terpinenol Irregular Monoterpenoids CO 2 CH 3 PP CH 2 α -thujene OHC Biosynthetic Study of Monoterpenes Me Me CO 2 H Me Me (±) MVA lactone (±) MVA GPP O Me Me Iridoids and Secoiridoids loganin secologanin chrysanthemic acid Me nezukone R = β - D -glucose H 14 C 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 Me Me Me Me Me Me Me Me O O Me Me Me Me CH 3 Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me CH 3 Me Me Me CH 3 Me Me Me Me OH 2 CM e O O Me OH O O Me Me Me Me Me OH Me Me Me Me Me Me Me Chem 206 N. Finney Sesquiterpenes–C 15 Terpenoids PP PP + Me Me Me Me Me CH 2 H 3 C Me picrotoxinin humulene caryophyllene cuparene widdrol thujopsene (Z) -FPP (E) -FPP [Ox] 32A-06-Sesquiterpenes 12/8/00 8:54 AM Me Me Me Me Me Me Me Me Me Me O Me Me Me Me O Me Me Me Me O Me Me Enz-X Me Me Me Me H b H a Me Me O Me Me Me Me Me Me H a Me Me Me Me Me Me Me Me H Me Me Me Me Chem 206 N. Finney Me Me Me Me Squalene Biosynthesis; Squalene Oxide Cyclization H P NAD H squalene oxide P PP Enz-X – PP 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 (C 30 ) 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 Me Me HO Me Me Me Me H Me H Me H Me Me HO Me H Me H Me H H Me Me HO Me H Me Me Me Me Me Chem 206 N. Finney, D. A. Evans The Corey Addendum to the Cyclization Process H squalene oxide Squalene Oxide Cyclase - Cornforth Proposal: ACIEE , 1968 , 903. Me Me HO Me H Me H Me H H Me Me Me X-Enz Me Me HO Me H Me H Me H H Me Me Me X-Enz Me Me Me O Me Me Me Me Me H Me Me Me H Me Me HO Me H H Me O Me Me O OM e Me Me Me Me H Me Me Me H Me Me Me MeMe Me HO Me Me Me Me HO Me H Me H Me H Me X H Me Me Corey–Virgil Revision: JACS 1991 , 113 , 4025-4026; 8171-8172 + lanosterol + lanosterol in vivo Me H H O Me NOT anti-migration anti-migration stereocenter in question 64 kcal/mol 81 kcal/mol (MM2) –17 kcal/mol "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: in vivo 32A-08-Revised SqOC 12/8/00 8:57 AM OO Me SiEt 3 Me Me CH 2 Me O H Me Me HO CH 2 Me O H Me Me HO Me Me R Me O OH H 2 C Me Me R Me OO Me R' Me Me HO CO 2 i Pr PrO 2 i C CH 2 Me RO AcO Me Me R' Me Me Me Me Me MeMe Me HO Cyclization to Form Simpler Bicyclics Chem 206 N. Finney Cationic Cyclizations in the Laboratory Johnson, et al. JACS 1984 , 106 , 1138. TiCl 4 Me Me Me Me Me MeMe Me R = OH, R' = H 20%, 24 hr.R = OAc, R' = CH=CH 2 80%, 1 min. TiCl 4 –78 °C + –78 °C Johnson, et al. JACS 1987 , 109 , 2517. Biomimetic Polyene Cyclizations R = H ca. 30%R = CH=CH 2 77% 96 : 4 O S iPhMe 2 Johnson, et al. JACS 1987 , 109 , 5852. MeAlCl 2 –78 °C, 57% E. J. Corey, et al. Tetrahedron Lett. 1994 , 35 , 9149. SiEt 3 Introduction of chiral auxiliaries for C=O groups Me Me Post cyclization transformation: Johnson O Me O Me O 3 Base Me O Me Me Me O 3 Base Me O A B B B C C DD 32A-09-Synth Appl 12/8/00 8:48 AM