Chemistry 206 Advanced Organic Chemistry Handout-36A Intramolecular Enone-Olefin Photocycloadditions Directed Toward Natural Product Synthesis Travis dunn Evans group seminar, March 31, 2000 DAE Group Friday Afternoon Seminar arch31.2000 Friday Matthew d. shair December 20. 2002
Chemistry 206 Advanced Organic Chemistry Handout–36A Intramolecular Enone-Olefin Photocycloadditions Directed Toward Natural Product Synthesis Matthew D. Shair Friday December 20, 2002 Travis Dunn Evans Group Seminar, March 31, 2000 DAE Group Friday Afternoon Seminar March 31, 2000
ntramolecular Enone-Olefin Photocycloadditions Directed Toward Natural Product Synthesis Travis dunn DAE Group Friday Afternoon Seminar March 31. 2000 Lead References. a Intramolecular Enone-Olefin Photocycloaddition Crimmins. M.T. Chem. Rev. 1988. 88. 1453-1473 a Cycloaddition/Fragmentation Strategies in Synthesis Winkler, J D. et al. Chem. Rev. 1995. 95. 2003-2020 Mechanism of Enone-Olefin Photocycloadditic Introduction and scope D)Mechanistic considerations of the enone-olefin photocycloaddition II) Selected synthetic examples A) The Oppolzer syntheses B)The Pattenden syntheses C)The Pirrung syntheses D)One hit wonders E)The Crimmins syntheses F)The Winkler syntheses The following will not be covered in this seminar Non-target motivated studies of the intramolecular photocycloaddition II)Intramolecular Paterno-Buchi reactions Ill)Intramolecular ketene cycloadditions IV)Other intramolecular photocycloadditions(e.g. arene-olefin meta cycloadditions) 36A-01 handout3/31/001:29PM
Intramolecular Enone-Olefin Photocycloadditions Directed Toward Natural Product Synthesis Travis Dunn DAE Group Friday Afternoon Seminar March 31, 2000 O O hν Lead References: ■ Intramolecular Enone-Olefin Photocycloaddition Crimmins, M.T. Chem. Rev. 1988, 88, 1453-1473. ■ Cycloaddition/Fragmentation Strategies in Synthesis Winkler, J.D., et al. Chem. Rev. 1995, 95, 2003-2020. ■ Mechanism of Enone-Olefin Photocycloaddition Schuster, D.I., et al. Chem. Rev. 1993, 93, 3-22. Introduction and Scope I) Mechanistic considerations of the enone-olefin photocycloaddition II) Selected synthetic examples: A) The Oppolzer syntheses B) The Pattenden syntheses C) The Pirrung syntheses D) One hit wonders E) The Crimmins syntheses F) The Winkler syntheses The following will not be covered in this seminar: I) Non-target motivated studies of the intramolecular photocycloaddition II) Intramolecular Paterno-Büchi reactions III) Intramolecular ketene cycloadditions IV) Other intramolecular photocycloadditions (e.g. arene-olefin meta cycloadditions) 36A-01-Handout 3/31/00 1:29 PM
Mechanistic Considerations of the Enone-Olefin Photocycloaddition 1,4 Adducts Exciplex Adducts Possibility of alkene Product Alken Enone A note on light sources The source of light is usually a met used to remove light below a certain wavelength. The two most ommon are Pyrex glass, which allows light with2>29 can als wavelength to num"glass, which allows light with i>350 nm vIa s Schuster, D L, et a. Chem. Rev. 1993, 93. 3. (±)β- BulInesene and Epi-B- bulnesene Unknown I 1)MeMgl, Et. rt. 3 h OAC OAC c:B33:1 and 23% 67% :1-Epi阝- bulnesene Stereochemical rationale (TBD) B: B-Bulnesene Oppolzer, W, et al. He/v Chim Acta, 1980, 63, 1198 36A-02 handout3/31/001:30PM
Mechanistic Considerations of the Enone-Olefin Photocycloaddition Schuster, D.I., et al. Chem. Rev. 1993, 93, 3. Enone Enone1 Enone3 Alkene 1,4 Biradical3 Adducts 1,4 Biradical1 Adducts Product O hν InterSystem Crossing Exciplex InterSystem Crossing Product formation Reversion to starting materials O 1 O 3 O X X O X O X 3 3 O X O X 1 1 + + O X Enone O Alkene X + 3 Decay ? ? Possibility of alkene isomerization The source of light is usually a mercury lamp. A filter is usually used to remove light below a certain wavelength. The two most common are Pyrex glass, which allows light with λ > 290 nm to pass, and "uranium" glass, which allows light with λ > 350 nm wavelength to pass. A note on light sources: O X This product can also arise via similar intermediates (±) β-Bulnesene and Epi-β-bulnesene O OAc Me H O Me hν, Pyrex, c-Hex, rt, 3 h α:β 3.3: 1 Oppolzer, W., et al. Helv. Chim. Acta., 1980, 63, 1198. OAc H Me H O OAc H Me H O H Me OAc Me MsO OH 1) MeMgI, Et2O Me O H Me H Me Me HO OH Me H Me Me Me 2) KOH, dioxane 67% MsCl, NEt3 Ph3P=CMe2 72% α: 1-Epi-β-bulnesene β: β-Bulnesene Major Product Stereochemical rationale (TBD) Grob 76% Unknown mixture 67% Prepared in 5 steps and 23% yield from 3-methyl-5-bromo-1-pentene 36A-02-Handout 3/31/00 1:30 PM
(+)-Longifolene and (+)-Sativene COOH 77% rt2 h 95%ee Ten steps 18% xture 85% at starred carbon 7% This intermediate could be crystallized to optical unity in 56% yield (+)-Longifolene Oppolzer, W, et al. J. Am. Chem. Soc. 1978, 100, 2583 Oppolzer, w, et al. Hel. Chim Acta. 1984, 67, 1154 (+)-Epiprecapnelladiene hv, Pyrex Three st hexane rt, 6 h 56% 98% OMe One diastereomer 1)LiHMDS, Mel 2)KOH, DMSO Stereochemical rationale(Pattenden) 36% Csi Epiprecapnelladiene the smal Pattenden, G, et al. J. Chem. Soc., Chem. Comm. 1980. 1195. Pattenden, G, et al J. Chem. Soc., Perkin Trans. 11983, 1913 36A-03 Handout3/31/001:32PM
(+)-Longifolene and (+)-Sativene Oppolzer, W., et al. J. Am. Chem. Soc. 1978, 100, 2583. Oppolzer, W., et al. Helv. Chim. Acta. 1984, 67, 1154. Three steps 77% O O OBn O COOH H H hν, Pyrex, cyclohexane, rt, 2 h 3:2 epimeric mixture at starred carbon 95% ee H2, Pd/C AcOH 96% O OCO2Bn O OCO2Bn H H O H O H H Me Me Me Me Me Me (+)-Longifolene (+)-Sativene Six steps 47% Ten steps 18% 85% ee This intermediate could be recrystallized to optical purity in 56% yield. H * H (±)-Epiprecapnelladiene Pattenden, G., et al. J. Chem. Soc., Perkin Trans. I 1983, 1913. Pattenden, G., et al. J. Chem. Soc., Chem. Comm. 1980, 1195. OMe OMe O OBz Me Three steps 56% O Me OBz H hν, Pyrex hexane, rt, 6 h 98% 1) LiHMDS, MeI 2) KOH, DMSO Me H H Me Me O O 36% Me H Me Me Me Six steps 28% Stereochemical rationale (Pattenden) O OBz H Me H O OBz H Me Irradiation of the enol acetate resulted in a 92:8 mixture, presumably due to the smaller size of the acetate versus benzoate. One diastereomer Epiprecapnelladiene 36A-03-Handout 3/31/00 1:32 PM
entalenene H hexane rt, Th 81% ep are 2. 2-die ty- per 1)Ph3 P=CH2 . nH 42% (±) Pentalenene Pattenden, G, et al. Tetrahedron Lett. 1984. 25, 30 Pattenden, G, et al. Tetrahedron 1987, 43, 5637 (±)- Isocomene hv(350 nm), hexane rt. 24h Me One isomer 7% 73 Ph3 P=CH2 98% Pirrung, M.C. J. Am. Chem. Soc. 1979, 101, 7130. Pirrung, M.C. J. Am. Chem. Soc. 1981, 103, 82. 36A-04 handout3/31/001:33PM
(±)-Isocomene Pirrung, M.C. J. Am. Chem. Soc. 1979, 101, 7130. Me Me O Me Me O Me hν (350 nm), hexane, rt, 24h 77% Me Me Ph3P=CH2 77% Me Me Me Me TsOH, C6H6 98% One isomer Isocomene Me Me Pirrung, M.C. J. Am. Chem. Soc. 1981, 103, 82. O Me OEt Three steps 73% (±)-Pentalenene O OTBS Me Me O H OTBS Me Me hν, Pyrex, hexane, rt, 7h 81% H OTBS Me Me Me3CuLi2 Me Me H Me O HF, H2O THF 82% 73% Me Me H Me Me Me Me H Me Me BF3•OEt2 CH2Cl2 42% 38% "only product" Me Me H Me Me 30% (±) Pentalenene Pattenden, G., et al.Tetrahedron 1987, 43, 5637. Me OH 1) Ph3P=CH2 2) RhCl3•3H2O Pattenden, G., et al. Tetrahedron Lett. 1984, 25, 3021. Prepared in eleven steps and 28% yield from 2,2-dimethyl-4-pentenal 36A-04-Handout 3/31/00 1:33 PM
(+)-Pentalenolactone G Methyl Ester Two steps Mixture of anomers Four steps LiBr. HMPA COOMe Nine steps Pirrung, M.C., et al.Tetrahedron Lett 1986, 27, 2703. Pirrung, M.C., et al. J. Org. Chem. 1988, 53, 227. Ten steps hv(350 nm), hexane 47% COOMe 10% Hatakeyama, S, Takano, s, et al. J Am. Chem. Soc. 1994, 116, 408 36A-05 Handout3/31/001:34PM
Me (-)-Paeoniflorin Hatakeyama, S., Takano, S., et al. J. Am. Chem. Soc. 1994, 116, 4081. Me H O O O O O COOMe Me Ten steps 47% O O Me MeOOC Me O O Me MeOOC Me hν (350 nm), hexane, 64% O Me MeOOC Me H O R* O O O O OH BzO O OH HOHO OH H 1) NaBH4 2)Acylation 3)Resolution (-)-Paeoniflorin Twelve steps 10% 47% (±)-Pentalenolactone G Methyl Ester Pirrung, M.C., et al. J. Org. Chem. 1988, 53, 227. O O COOMe Me Me O H O O O Me Me O O Me Me O O Me Me Two steps 46% H O O Me Me H MeO O hν, Pyrex, CH2Cl2, rt 70% Four steps 62% O O Me Me MeO O H O LiBr, HMPA C6H6 95% Nine steps 2% Pentalenolactone G Methyl Ester Pirrung, M.C., et al.Tetrahedron Lett. 1986, 27, 2703. Me Mixture of anomers. One anomer. Stereochemistry unknown. 36A-05-Handout 3/31/00 1:34 PM
(±)- Valeranone 0-15°c,10 1: 1 mixture of diastereomers Separated after photolysis DIBAL-H TsOH 4: 1 mixture Seperable mixture Epi-valeranone Takeshita, H. et al. Bull. Chem. Soc. Jpn. 1993, 66, 2699 Studies toward Cytochalasin C le Base Oxidation state crucia Me hv(254 nm), MeCN rt. 40 min 3.7:1.0 Fuchs, P- L, et al J. Org Chem. 1982, 47, 3121. 36A-06 handout3/31/001:35PM
H (±)-Valeranone Takeshita, H. et al. Bull. Chem. Soc. Jpn. 1993, 66, 2699. Me Me O Me Me O O O Me H Me O O Me Me O Me Me O O TsOH 61% hν, Pyrex, MeCN/acetone (9:1), 0-15 o C, 10h H O O Me Me OH Me Me Me Me O O 1) DIBAL-H 2) TsOH 98% 50% Seperable mixture α:β 3:2 Me Me O Four steps 74% 1:1 mixture of diastereomers. Separated after photolysis. 4:1 mixture Valeranone:7-Epi-valeranone 7 Studies toward Cytochalasin C Fuchs, P.L., et al. J. Org Chem. 1982, 47, 3121. O EtO Me O O Br Seventeen steps 17% O O Me S O Me Me Me O O O Me Me Me Me O SO2 H H O O O Me Me Me Me O SO2 H H O hν (254 nm), MeCN, rt, 40 min 94% Oxidation state crucial O O Me Me Me Me O SO2 H H O Base O O 3.7 : 1.0 Me Me OH H NH H Bn Me OH O Me O OAc Cytochalasin C 36A-06-Handout 3/31/00 1:35 PM
(±)- Hibiscone c hv, uranium glas hexane. rt 24h 60% 15:1.0 Four steps TSOH, C6H6 Hibiscone c Smith, A.B., Ill, et al J. Am. Chem. Soc. 1982. 104, 5568 Smith, A.B., Ill, et al J. Am. Chem 1984.106.2115 Studies toward Perhydrohistrionicotoxin n-CaHg Perhydrohistrionicotoxin hv, uranium glass, CAHg n-C4Hg Three steps CAHg Meoh NaOAc rt2 d Photoadduct not 3)AC2O, DMAP Smith, A.B., Ill, et al. J. Org. Chem. 1984, 49, 832. 36A-07 handout3/31/001:36PM
(±)-Hibiscone C Smith, A.B., III, et al. J. Am. Chem. Soc. 1984, 106, 2115. EtO O i-Pr O i-Pr H Six steps 60% O i-Pr O i-Pr H H hν, uranium glass, hexane, rt, 24h 60% O O i-Pr H O3; Ph3P TsOH, C6H6 50% Four steps 7% O O i-Pr H O Me O i-Pr H CHO O 1.5 : 1.0 Not isolated Smith, A.B., III, et al. J. Am. Chem. Soc. 1982, 104, 5568. Hibiscone C Studies toward Perhydrohistrionicotoxin Smith, A.B., III, et al. J. Org. Chem. 1984, 49, 832. O n-C4H9 OEt O Three steps n-C4H9 42% O n-C4H9 1) NaBH4 2) O3; Ph3P 3) Ac2O, DMAP OAc O n-C4H9 CHO OAc O n-C4H9 CHO hν, uranium glass, MeOH,NaOAc rt, 2 d Photoadduct not isolable 9% 17% OAc O n-C4H9 H Wilkinson's catalyst OH n-C4H9 H H N n-C5H11 Perhydrohistrionicotoxin 36A-07-Handout 3/31/00 1:36 PM
(±) Hirsuteine Vacuum Seven steps Me H Hirsute Formal syntheses of capnellene and corioli were reported sing a similar photoaddition/fragmentation reaction (±)- Pentalenene,(±)- Pentalenic Acid and (+)-Deoxypentalenic Acid from a Common Precursor CODE CooT hexane rt. 36 h Three steps The stereochemistry at the starred carbon determined, but the products were isolated as a mixture COoMe Stereochemical rationale(Crimmins R C-9 dr COOT CooT FPr>20:1 Consistent with predominant stereochemistry at C-9 nfluenced th stereoselectivity et al J. Am. Chem. Soc. 1986. 108. 800 36A-08 handout3/31/001:37PM
Me (±)-Hirsutene O O O O C6H6 90% O O H H Me H O O hν, Pyrex, EtOAc, rt, 30 min 85% Flash Vacuum Pyrolysis 500 oC "Quantitative" Seven steps 8% Formal syntheses of capnellene and coriolin were reported using a similar photoaddition/fragmentation reaction. Me Me Hirsutene Mehta, G., et al. J. Am. Chem. Soc. 1986, 108, 3443. Me Me Me Me O O Me Me H H Me H Me Me Mehta, G., et al. J. Chem. Soc., Chem. Comm. 1981, 756. H (±)-Pentalenene, (±)-Pentalenic Acid and Crimmins, M.T., et al. J. Am. Chem. Soc. 1986, 108, 800. (±)-Deoxypentalenic Acid from a Common Precursor. COOEt O Me Me COOMe Me O Me Me Me COOMe COOEt H hν, uranium glass hexane, rt, 36 h 73% 9 Me O COOR Me Me COOEt H Me O C O O R Me Me COOEt H H Consistent with predominant stereochemistry at C-9 Stereochemical rationale (Crimmins) Crimmins, M.T., et al. J. Org. Chem. 1984, 49, 2076. R C-9 dr Me Et i-Pr 13:1 17:1 >20:1 O Me Me Me COOMe COOEt H 9 1 : 13 + COOMe COOMe Me Me Three steps 44% Varying the size of the indicated alkyl group influenced the stereoselectivity The stereochemistry at the starred carbon was not determined, but the products were isolated as a mixture. 36A-08-Handout 3/31/00 1:37 PM
(±)- Pentalenene,(±)- Pentalenic Acid and (+)-Deoxypentalenic Acid from a Common Precursor COME Li. NH?. THF Reduction performed on mixture of photoadducts Diastereomers separated after reduction. R=H. R'=Me. Pentalenene nine steps, 27% R=OH. R=COOH Pentalenic acid Steps eight steps, 42% R=H, R=COOH, Deoxypentalenic acid Crimmins, M.T, et al. J. Org. Chem. 1984, 49, 2076 Crimmins. M.T. et aL J Am. Chem. Soc. 1986. 108. 800. (±)- Silphinene hv, uranium glass Seven steps hexane. rt 4 h 46% TMSI reflux uMe 1)LDA, THF (Eto)2POC Me Bu3 SnH, CBH6 Plus a 14% yield of Crimmins. M.T. et al. J. Am. Chem. Soc. 8.3435. Crimmins. M.T. et al Tetrahedron Lett. 36A-09 handout3/31/001:38PM
R=H, R'=Me, Pentalenene, nine steps, 27% R=OH, R'=COOH, Pentalenic acid, eight steps, 42% R=H, R'=COOH, Deoxypentalenic acid, eleven steps, 22% R Me Me Me H R' H O Me Me Me O H Three steps 89% Me Me OH COOMe COOEt Me Li, NH3, THF 90% Reduction performed on mixture of photoadducts. Diastereomers separated after reduction. O Me Me Me COOMe COOEt H 9 O Me Me Me COOMe COOEt H 9 1 : 13 + (±)-Pentalenene, (±)-Pentalenic Acid and (±)-Deoxypentalenic Acid from a Common Precursor. Steps Crimmins, M.T., et al. J. Am. Chem. Soc. 1986, 108, 800. Crimmins, M.T., et al. J. Org. Chem. 1984, 49, 2076. (±)-Silphinene Crimmins, M.T., et al. J. Am. Chem. Soc. 1986, 108, 3435. Me Me H Me Me Me Me Me O Me Me Me O H Me Me H Me CH2I O Me Me O Crimmins, M.T., et al. Tetrahedron Lett. 1985, 26, 997. Seven steps 46% hν, uranium glass hexane, rt, 4 h 94% Me Me H Me Me O TMSI MeCN reflux 89% Bu3SnH, C6H6 98% 63% Silphinene 2) Li, MeNH2 1) LDA, THF (EtO)2POCl Plus a 14% yield of isosilphinene 36A-09-Handout 3/31/00 1:38 PM