Chemistry 206 Advanced Organic Chemistry Handout–36A Intramolecular Enone-Olefin Photocycloadditions Directed Toward Natural Product Synthesis Matthew D. Shair FridayDecember 20, 2002 Travis Dunn Evans Group Seminar, March 31, 2000 DAE Group Friday Afternoon Seminar March 31, 2000 Intramolecular Enone-Olefin Photocycloadditions Directed Toward Natural Product Synthesis Travis Dunn DAE Group Friday Afternoon Seminar March 31, 2000 O O hν Lead References: a73 Intramolecular Enone-Olefin Photocycloaddition Crimmins, M.T. Chem. Rev. 1988, 88, 1453-1473. a73 Cycloaddition/Fragmentation Strategies in Synthesis Winkler, J.D., et al. Chem. Rev. 1995, 95, 2003-2020. a73 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 Schuster, D.I., et al. Chem. Rev. 1993, 93, 3. Enone Enone 1 Enone 3 Alkene 1,4 Biradical 3 Adducts 1,4 Biradical 1 Adducts Product O hν Inter- System Crossing Exciplex Inter- System 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 OMe 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, Et 2 O Me O H Me H MeMe HO OH Me H Me Me Me 2) KOH, dioxane 67% MsCl, NEt 3 Ph 3 P=CMe 2 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 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 H 2 , Pd/C AcOH 96% O OCO 2 Bn O OCO 2 Bn 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 (±)-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 Ph 3 P=CH 2 77% Me Me Me Me TsOH, C 6 H 6 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 Me 3 CuLi 2 MeMe H Me O HF, H 2 O THF 82% 73% MeMe H Me Me MeMe H Me Me BF 3 ?OEt 2 CH 2 Cl 2 42% 38% "only product" MeMe H Me Me 30% (±) Pentalenene Pattenden, G., et al.Tetrahedron 1987, 43, 5637. Me OH 1) Ph 3 P=CH 2 2) RhCl 3 ?3H 2 O 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 Me (-)-Paeoniflorin Hatakeyama, S., Takano, S., et al. J. Am. Chem. Soc. 1994, 116, 4081. Me H OO 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 HO HO OH H 1) NaBH 4 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, CH 2 Cl 2 , rt 70% Four steps 62% O O Me Me MeO O H O LiBr, HMPA C 6 H 6 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 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 OO 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 SO 2 O HH O O O Me Me Me Me SO 2 O HH O hν (254 nm), MeCN, rt, 40 min 94% Oxidation state crucial O O Me Me Me Me SO 2 O HH O Base OO 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 Smith, A.B., III, et al. J. Am. Chem. Soc. 1984, 106, 2115. OEtO i-Pr O i-Pr H Six steps 60% O i-Pr O i-Pr HH hν, uranium glass, hexane, rt, 24h 60% O O i-Pr H O 3 ; Ph 3 P TsOH, C 6 H 6 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-C 4 H 9 OEt O n-C 4 H 9 Three steps 42% O n-C 4 H 9 1) NaBH 4 2) O 3 ; Ph 3 P 3) Ac 2 O, DMAP OAc O n-C 4 H 9 CHO OAc O n-C 4 H 9 CHO hν, uranium glass, MeOH,NaOAc rt, 2 d Photoadduct not isolable 17%9% OAc O n-C 4 H 9 H Wilkinson's catalyst OH n-C 4 H 9 H H N n-C 5 H 11 Perhydrohistrionicotoxin 36A-07-Handout 3/31/00 1:36 PM Me (±)-Hirsutene O O O O C 6 H 6 90% O O HH Me H OO hν, Pyrex, EtOAc, rt, 30 min 85% Flash Vacuum Pyrolysis 500 o C "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 HH 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 HH 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 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, NH 3 , 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 CH 2 I 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% Bu 3 SnH, C 6 H 6 98% 63% Silphinene 2) Li, MeNH 2 1) LDA, THF (EtO) 2 POCl Plus a 14% yield of isosilphinene 36A-09-Handout 3/31/00 1:38 PM (±)-Laurenene Crimmins, M.T., et al. J. Am. Chem. Soc. 1987, 109, 6199. Me Me Me O Me COOMe Me Me Me H Me Me Me Me Me H Me COOEt O Me Me Me H Me O COOEt Me Me Me H Me O COOMe H H Me Me Me H O COOMe H Me H hν, uranium glass 100 o C, PhCl 87% 1.5:1 α:β at starred carbon * Crimmins, M.T., et al. Tetrahedron Lett. 1985, 26, 997. * Three steps 89% 1) Na, NH 3 , Et 2 O 2) H 2 , Pd/C 80% Eight steps 7% Prepared in twelve steps and 27% yield from 4,4-Dimethyl-cyclopenteneone Laurene O O O COOMe Me MeMe Me O O Me Me Me H Me H O E O O Me Me Me H Me H O E For E=Me, MM2 calculations suggest that 1 should be more stable than 2 by 1.1 kcal/mol. 1 2 O O E O MeMe Me Me O O E O MeMe Me Me H 3 4 hν 97% H H (±)-Lubiminol O O O Me MeMe Me H H O O O Me MeMe Me H H H COOMe 3 COOMe 483:17 Crimmins, M.T., et al. J. Am. Chem. Soc. 1998, 120, 1747. Crimmins, M.T., et al. Tetrahedron Lett. 1996, 37, 8703. 36A-10-Handout 3/31/00 1:39 PM Me O O O COOMe Me MeMe Me (±)-Lubiminol O O H H O O E H O MeMe Me Me O O E H O MeMe Me Me H 7 8 Me Me Me E O Me O O H HMe Me Me O E 5 6 H H O O O Me MeMe Me H H For E=Me, MM2 calculations suggest that 5 should be more stable than 6 by 1.5 kcal/mol. COOMe 7 Only isolated product hν 98% Crimmins, M.T., et al. J. Am. Chem. Soc. 1998, 120, 1747. Crimmins, M.T., et al. Tetrahedron Lett. 1996, 37, 8703. (±)-Lubiminol Crimmins, M.T., et al. J. Am. Chem. Soc. 1998, 120, 1747. EtO OOH Five steps 48% O O O COOMe Me MeMe Me H H O O H COOMe H O Me Me Me Me hν, uranium glass hexane/CH 2 Cl 2 rt, 15 h 98% OH O H COOMe H O Me Me 77% imid S 2) (imid) 2 C=S, O COOMe OH OH H COOMe O Me Me H H Bu 3 SnH AIBN 92% OH CH 2 OHMe α:β 2:3 Dowd- Beckwith Eleven steps 12% Lubiminol 1) TsOH, H 2 O DMAP Crimmins, M.T., et al. Tetrahedron Lett. 1996, 37, 8703. 36A-11-Handout 3/31/00 1:39 PM (±)-Bilobalide O O X TMSO t-BuY O O TMSO t-Bu Y X O O COOEt TMSO O O TMSO COOEt O O COOEt O O COOEt hν, uranium glass hexane/CH 2 Cl 2 rt, 6 h 78% one diastereomer hν, uranium glass hexane/CH 2 Cl 2 rt, 5 h 100% O O COOEt 1.5 1.0 t-Bu t-Bu t-Bu Crimmins, M.T., et al. J. Am. Chem. Soc. 1993, 115, 3146. Crimmins, M.T., et al. J. Am. Chem. Soc. 1992, 114, 5445. t-Bu OH O O O O O O OH Bilobalide (±)-Bilobalide O COOEt OTMSO O TMSO O EtOOC O COOEt O O O EtOOC t-Bu t-Bu O COOEt OTMSO O TMSO O COOEt O TMSO O EtOOC O TMSO O COOEt O COOEt O O O EtOOC t-Bu t-Bu O O COOEt O O COOEt t-Bu t-Bu 1 2 3 4 Desired Undesired Desired Undesired MM2 calculations suggested that 1 was more favored than 2 by approximately 1.6 kcal/mol, while there was almost no difference in energy between 3 and 4 (0.2 kcal/mol). Crimmins, M.T., et al. J. Am. Chem. Soc. 1993, 115, 3146. Crimmins, M.T., et al. J. Am. Chem. Soc. 1992, 114, 5445. 36A-12-Handout 3/31/00 1:41 PM OH (±)-Bilobalide O OHC Seven steps 20% O O OPiv TMSO t-BuHO O O TMSO t-Bu OH OPiv O O TMSO t-Bu OH OPiv O O TMSO t-Bu OH OPiv hν, uranium glass hexane, rt, 18 h 80% 5% 25% 50% MeOOC O t-Bu OH OPiv O MeO O OPiv OTMSO t-Bu OH O OPiv OTMSO t-Bu LDA, MoOPH 76% 2) MeOH, TsOH 92% O O TMSO t-Bu OH OPiv HO 1) Pb(OAc) 4 , MeOH Crimmins, M.T., et al. J. Am. Chem. Soc. 1993, 115, 3146. Crimmins, M.T., et al. J. Am. Chem. Soc. 1992, 114, 5445. (±)-Bilobalide MeOOC O t-Bu OH OPiv O MeO O t-Bu OH O MeO O 1) LiAlH 4 2) Pb(OAc) 4 80% t-Bu OH O MeO O O O m-CPBA 94% t-Bu OH O O O O O t-Bu OH O O O O O O OH Jones reagent 99% 1) dimethyldioxirane 2) Jones reagent 81% Bilobalide Crimmins, M.T., et al. J. Am. Chem. Soc. 1993, 115, 3146. Crimmins, M.T., et al. J. Am. Chem. Soc. 1992, 114, 5445. 36A-13-Handout 3/31/00 1:42 PM Crimmins, M.T. et al. J. Am. Chem. Soc. 1999, 121, 10249. (±)-Ginkgolide B Eight steps 71% O O COOEt TESO O O TESO COOEt hν, uranium glass hexane, rt, 18 h 100% t-Bu O EtOOC t-Bu Crimmins, M.T. et al. Tetrahedron Lett. 1989, 30, 5997. O O t-Bu O O Four steps 49% O O t-Bu O O OH OMe OMe O O O O O O O t-Bu H OH HO H Me HO dimethyldioxirane 2) MeOH, TsOH, 89% 1) H 2 O, TsOH CH(OMe) 3 Twelve steps 11% Ginkgolide B One isomer Synthesis of the Core of the Ingenane Diterpenes Winkler, J.D., et al. J. Am. Chem. Soc. 1987, 109, 2850. O O O O Me Me H Three steps 40% O O O Me Me H H H O COOH hν, Pyrex MeCN, Acetone (9:1) 0 o C, 90 min 83% KOH MeOH 83% O O O Me Me H H One isomer H HO O CH 2 OH Me Me H H Me HO HO Ingenol Stereochemical rationale (Winkler) Ingenane Core 36A-14-Handout 3/31/00 1:44 PM Synthetic Studies Toward the Taxane Core Winkler, J.D., et al.Tetrahedron Lett. 1986, 27, 5959. OO Me H O Me Me OMe H OH O Me H OMe H O O Me Me HO OH H Me OMe EHO H hν, Pyrex MeCN/Acetone (9:1) rt, 30 min 75% 1) KOH, MeOH 2) CH 2 N 2 82% Winkler, J.D., et al. J. Org. Chem. 1989, 54, 4491. Winkler, J.D., et al.Tetrahedron 1992, 48, 7049. E=COOMe O HO Me O H Me Me O AcO OH AcO Me Ph NHBz OH O Taxol O O Me HH O Me Me hν, Pyrex MeCN/Acetone (9:1) rt Me HH O O O Me Me None of the desired photoadduct could be isolated. One isomer (-)-Perhydrohistrionicotoxin Winkler, J.D., et al. J. Am .Chem. Soc. 1989, 111, 4852. HN O Br O H N n-C 5 H 11 OO O Me Me Six steps 34% O HN O O O Me Me n-C 5 H 11 HH N OO O H C 5 H 11 H O Me Me N H C 5 H 11 H O O O O Me Me H H HN O O n-C 5 H 11 O 1) NaBH 4 2) NaH, THF 63% hν, Pyrex, MeCN, 0 o C, 30 min 95% Derived from glutamic acid HN n-C 4 H 9 n-C 5 H 11 15:1 ratio of epimers at starred carbon. Major isomer shown. Minor isomer epimerizes to major upon chromatography. Seven steps 43% OH Stereochemical rationale (Winkler) * Perhydrohistrionicotoxin Winkler, J.D., et al. Tetrahedron Lett. 1986, 27, 5177. 36A-15-Handout 3/31/00 1:45 PM Formal Synthesis of Vindorosine Winkler, J. D., et al. J. Am. Chem. Soc. 1990 112, 8971. N Me N Et OAc COOMe OHH N H COOH NHCbz N Cbz HN O O O Me Me O Five steps 48% N Cbz NH (RO) 3 C H Me O H N Cbz N (RO) 3 C H Me O N Me NAc H O hν, Pyrex, MeCN, 0 o C, 65 min 91% One diastereomer Eight steps 20% NC(OR) 3 H N O Me H Cbz H Stereochemical rationale (Winkler) Intermediate in Büchi's racemic synthesis Büchi, G., et al. J. Am. Chem. Soc. 1971, 93, 3299. Büchi L-Tryptophan >97%ee C(OR) 3 = O O O Me Vindorosine Eight steps 3% (±)-Manzamine A Winkler, J.D., et al. Tetrahedron Lett. 1993, 34, 6509. N N N H N H H OH H PN N O H H H PN N O H H YY PN N H H Y H O N H Y Manzamine A O PN Winkler, J.D., et al. Isr. J. Chem. 1997, 37, 47. Winkler, J.D., et al.Tetrahedron 1998, 54, 7045. Winkler, J.D., et al. J. Am. Chem. Soc. 1998, 120, 6425. PN O N H H H Y RR RR R For an analysis of the total synthesis of Manzamine A, see the Evans Group Seminar "Approaches the the Total Synthesis of the Manzamine Alkaloids," Hemaka Rajapakse, Jan. 21, 2000. 36A-16-Handout 3/31/00 1:46 PM (±)-Manzamine A MeN N H H H Me O N H Me O MeN MeN O N H H H Me Model system: Saturated ring Wrong relative stereochemistry at three new centers. hν, Pyrex benzene, rt, 90 min 100% Possible solution: Epimerize after cyclization N H Me O MeOOCN O hν, Pyrex MeCN, rt, 1h 25% N Me MeOOCN O N Me O MeOOCN O Only isolable product is from photochemical cleavage, rearrangement. PN N O H H H Manzamine Core Winkler, J.D., et al. Tetrahedron Lett. 1993, 34, 6509. Winkler, J.D., et al. Isr. J. Chem. 1997, 37, 47. Winkler, J.D., et al.Tetrahedron 1998, 54, 7045. Winkler, J.D., et al. J. Am. Chem. Soc. 1998, 120, 6425. (±)-Manzamine A N H Me O MeOOCN HO MeOOCN N O H H H HO 1) hν, Pyrex MeCN, 0 o C, 2) NEt 3 ?HCl 3) DMAP 12 h 41% Solution to the solution: Mask the ketone as an easily accessible alcohol MeOOCN N O H H H O PN N O H H H Manzamine Core dr 2.3:1.0 Major Swern Readily available by L-Selectride reduction of the ketone MeOOCN N O H H H HO MeOOCN N O H H H O Minor Swern Again, the predominant product has the wrong stereochemistry and cannot be isomerized to the correct stereochemistry. 1 2 1 NaOMe MeOH Ent-2 Winkler, J.D., et al. Tetrahedron Lett. 1993, 34, 6509. Winkler, J.D., et al. Isr. J. Chem. 1997, 37, 47. Winkler, J.D., et al.Tetrahedron 1998, 54, 7045. Winkler, J.D., et al. J. Am. Chem. Soc. 1998, 120, 6425. 36A-17-Handout 3/31/00 1:47 PM (±)-Manzamine A N H Me O MeOOCN HO MeOOCN N O H H H HO 1) hν, Pyrex MeCN, 0 o C, 2) NEt 3 ?HCl 3) DMAP 3 h 50% PN N O H H H Manzamine Core dr 2.5:1.0 Minor Minor diastereomer of ketone reduction with NaBH 4 . MeOOCN N O H H H HO Major The correct stereochemistry is obtained as the major product, but this substrate is synthetically inaccessible in high yield. Partial solution: The opposite diastereomer provides the desired stereochemistry Winkler, J.D., et al. Tetrahedron Lett. 1993, 34, 6509. Winkler, J.D., et al. Isr. J. Chem. 1997, 37, 47. Winkler, J.D., et al.Tetrahedron 1998, 54, 7045. Winkler, J.D., et al. J. Am. Chem. Soc. 1998, 120, 6425. (±)-Manzamine A N H O BocN 1) hν, Pyrex MeCN, rt, 2) Pyr?AcOH 6 h 20% BocN O N H H HR BocN N O H H H R R R= OH Ultimate solution: The olefinic linkage in the natural product provides for the correct stereoinduction N N N H N H H OH H Manzamine A Steps One diastereomer Stereochemistry not determined See Rajapakse seminar Winkler, J.D., et al. Tetrahedron Lett. 1993, 34, 6509. Winkler, J.D., et al. Isr. J. Chem. 1997, 37, 47. Winkler, J.D., et al.Tetrahedron 1998, 54, 7045. Winkler, J.D., et al. J. Am. Chem. Soc. 1998, 120, 6425. 36A-18-Handout 3/31/00 1:47 PM Me Me (±)-Saudin Winkler, J.D., et al. J. Am. Chem. Soc. 1999, 121, 7425. O O O O Me Me O Me O O H Winkler, J.D., et al. Tetrahedron Lett. 1998, 39, 2253. O O O Me O X Me Me O Me Me Y O O O Me Me O O Y Me Me X Me Me OO O O O Me Me Me H Me O Me O O O Me H O Me Me Me O O H O O O Me Me H Me Me OO O O O Me Me H 1 3 2 4 MM2 calculations suggest that 1 should be approximately 1.6 kcal/mol more stable than 3. Irradiation of the substrate (Pyrex, MeCN/Acetone (9:1), 0 o C, 2 h) led to the formation of a 2.5:1 epimeric mixture of 2 in 97% yield. Saudin Me Me * O Me (±)-Saudin O O O O Me Me O Me O O H O O O O O Me OMe H Me Me OO O O O Me Me O O Me Me Me OO O O O Me Me O O Me H Me Me OO O O O Me Me O Me H O Me COOH O O O O Me Me H O Saudin hν, Pyrex MeCN/acetone (9:1) 0 o C, 30 min 80% One diastereomer 1) n-BuLi, THF, TMEDA, 2) (3-furyl)SnBu 3 , LiCl, -95 o C; Tf 2 O Pd(AsPh 3 ) 4 , THF, reflux 77% LiOH MeOH PPTS, C 6 H 6 52% 16% Eleven steps O O Me OH Winkler, J.D., et al. J. Am. Chem. Soc. 1999, 121, 7425. Winkler, J.D., et al. Tetrahedron Lett. 1998, 39, 2253. 36A-19-Handout 3/31/00 1:48 PM Conclusions a73 Intramolecular enone-olefin photocycloaddition is useful for the stereoselective contruction of carbocycles, especially five membered rings. a73 Multiple quaternary and congested centers can be constructed in a single operation. a73 Stereoinduction from existing stereocenters is usually explicable in a rational and satisfying manner. a73 Molecular modeling simulations have proven useful in predicting the stereoselectivity of several photocycloadditions. a73 Great creativity is possible in the fragmentation of the derived cyclobutane to access useful synthetic intermediates. a73 A lack of complete mechanistic understanding has not prevented the successful application of the enone-olefin photocycloaddition to a great many synthetic challenges. 36A-20-Handout 3/31/00 1:49 PM