Chemistry 206 Advanced rganic Chemistry andout 36A Intramolecular Enone-lefin Photocycloadditions Directed Toward atural Product Synthesis Travis Dunn Evans Group Seminar, March 31, 2000 DAE Group Friday Afternoon Seminar March 31, 2000 D. A. Evans Monday September 27, 1999 36A-00-Cover page 2/26/02 6:42 PM
Intramolecular Enone-lefin Photocycloadditions Directed Toward atural Product Synthesis Travis Dunn DAE Group Friday Afternoon Seminar March 31, 2000 hν Lead References: Intramolecular Enone-lefin 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. chanism of Enone-lefin Photocycloaddition Schuster, D.I., et al. Chem. Rev. 1993, 93, 3-22. Introduction and Scope I) chanistic considerations of the enone-olefin photocycloaddition II) Selected synthetic examples: A) The ppolzer syntheses B) The Pattenden syntheses C) The Pirrung syntheses D) ne hit wonders E) The Crimmins syntheses F) The Winkler syntheses The following will not be covered in this seminar: I) on-target motivated studies of the intramolecular photocycloaddition II) Intramolecular Paterno-Büchi reactions III) Intramolecular ketene cycloadditions IV) ther intramolecular photocycloadditions (e.g. arene-olefin meta cycloadditions) 36A-01-andout 3/31/00 1:29 PM
chanistic Considerations of the Enone-lefin Photocycloaddition 1 3 Inter- System Crossing Enone 1 Enone 3 Alkene 3 + 3 1,4 Biradical 3 Adducts hν Decay? 3? Inter- System Crossing 1 1 Enone Exciplex + 1,4 Biradical 1 Adducts Possibility of alkene isomerization + Reversion to starting materials Product formation Alkene Enone A note on light sources: 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. Product Schuster, D.I., et al. Chem. Rev. 1993, 93, 3. This product can also arise via similar intermediates (±) β-bulnesene and Epi-β-bulnesene Ac Prepared in 5 steps and 23% yield from 3-methyl-5-bromo-1-pentene hν, Pyrex, c-ex, rt, 3 h 76% Ac α:β 3.3: 1 1) MgI, Et 2 2) K, dioxane 67% Unknown mixture MsCl, Et 3 Ph 3 P=C 2 72% Grob 67% Ms α: 1-Epi-β-bulnesene β: β-bulnesene Stereochemical rationale (TBD) Ac Ac Major Product 36A-02-andout 3/31/00 1:30 PM ppolzer, W., et al. elv. Chim. Acta., 1980, 63, 1198.
(+)-Longifolene and (+)-Sativene C Three steps Bn hν, Pyrex, cyclohexane, C 2 Bn 95% ee 77% rt, 2 h (+)-Sativene Ten steps 18% Six steps 47% 2, Pd/C Ac 96% 85% ee This intermediate could be recrystallized to optical purity in 56% yield. * C 2 Bn 3:2 epimeric mixture at starred carbon (+)-Longifolene ppolzer, W., et al. J. Am. Chem. Soc. 1978, 100, 2583. ppolzer, W., et al. elv. Chim. Acta. 1984, 67, 1154. (±)-Epiprecapnelladiene Three steps 56% Bz hν, Pyrex hexane, rt, 6 h 98% Bz ne diastereomer Stereochemical rationale (Pattenden) 1) LiMDS, I 2) K, DMS 36% Bz Bz Six steps 28% Irradiation of the enol acetate resulted in a 92:8 mixture, presumably due to the smaller size of the acetate versus benzoate. Epiprecapnelladiene Pattenden, G., et al. J. Chem. Soc., Chem. Comm. 1980, 1195. Pattenden, G., et al. J. Chem. Soc., Perkin Trans. I 1983, 1913. 36A-03-andout 3/31/00 1:32 PM
(±)-Pentalenene TBS Prepared in eleven steps and 28% yield from 2,2-dimethyl-4-pentenal hν, Pyrex, hexane, rt, 7h 81% TBS "only product" 3 CuLi 2 82% TBS F, 2 TF 73% BF 3 Et 2 C 2 Cl 2 1) Ph 3 P=C 2 2) RhCl 3 3 2 42% 30% 38% (±) Pentalenene Pattenden, G., et al. Tetrahedron Lett. 1984, 25, 3021. Pattenden, G., et al.tetrahedron 1987, 43, 5637. (±)-Isocomene hν (350 nm), hexane, rt, 24h 77% ne isomer Three steps 73% Ph 3 P=C 2 77% Et Ts, C 6 6 98% Isocomene 36A-04-andout 3/31/00 1:33 PM Pirrung, M.C. J. Am. Chem. Soc. 1979, 101, 7130. Pirrung, M.C. J. Am. Chem. Soc. 1981, 103, 82.
(±)-Pentalenolactone G thyl Ester Two steps 46% hν, Pyrex, C 2 Cl 2, rt 70% Mixture of anomers. Four steps 62% Pentalenolactone G thyl Ester C ine steps 2% LiBr, MPA C 6 6 95% ne anomer. Stereochemistry unknown. Pirrung, M.C., et al.tetrahedron Lett. 1986, 27, 2703. Pirrung, M.C., et al. J. rg. Chem. 1988, 53, 227. (-)-Paeoniflorin Ten steps 47% C hν (350 nm), hexane, 64% C Bz Twelve steps 10% C R * 1) ab 4 2)Acylation 3)Resolution 47% C (-)-Paeoniflorin atakeyama, S., Takano, S., et al. J. Am. Chem. Soc. 1994, 116, 4081. 36A-05-andout 3/31/00 1:34 PM
(±)-Valeranone Ts 61% 1:1 mixture of diastereomers. Separated after photolysis. hν, Pyrex, C/acetone (9:1), 0-15 o C, 10h 98% 1) DIBAL- 2) Ts 50% 7 4:1 mixture Valeranone:7-Epi-valeranone Four steps 74% Seperable mixture α:β 3:2 Takeshita,. et al. Bull. Chem. Soc. Jpn. 1993, 66, 2699. Studies toward Cytochalasin C Br Et S 2 Ac Bn Cytochalasin C Seventeen steps 17% xidation state crucial Base S hν (254 nm), C, rt, 40 min 94% S 2 S 2 3.7 : 1.0 36A-06-andout 3/31/00 1:35 PM Fuchs, P.L., et al. J. rg Chem. 1982, 47, 3121.
(±)-ibiscone C Et Six steps hν, uranium glass, i-pr 60% i-pr hexane, rt, 24h 60% i-pr 1.5 : 1.0 i-pr 3 ; Ph 3 P C i-pr Four steps 7% i-pr Ts, C 6 6 50% i-pr ibiscone C ot isolated Smith, A.B., III, et al. J. Am. Chem. Soc. 1982, 104, 5568. Smith, A.B., III, et al. J. Am. Chem. Soc. 1984, 106, 2115. Studies toward Perhydrohistrionicotoxin n-c 4 9 n-c 5 11 Perhydrohistrionicotoxin n-c 4 9 Three steps n-c 4 9 hν, uranium glass,,aac n-c4 9 Et 42% rt, 2 d Photoadduct not isolable 1) ab 4 Ac n-c 4 9 Wilkinson's catalyst Ac C n-c 4 9 Ac C n-c 4 9 2) 3 ; Ph 3 P 3) Ac 2, DMAP 9% 17% Smith, A.B., III, et al. J. rg. Chem. 1984, 49, 832. 36A-07-andout 3/31/00 1:36 PM
(±)-irsutene C 6 6 hν, Pyrex, EtAc, 90% rt, 30 min 85% Flash Vacuum Pyrolysis 500 o C "Quantitative" irsutene Seven steps 8% Formal syntheses of capnellene and coriolin were reported using a similar photoaddition/fragmentation reaction. hta, G., et al. J. Am. Chem. Soc. 1986, 108, 3443. hta, G., et al. J. Chem. Soc., Chem. Comm. 1981, 756. (±)-Pentalenene, (±)-Pentalenic Acid and (±)-Deoxypentalenic Acid from a Common Precursor. C CEt hν, uranium glass hexane, rt, 36 h 73% 9 C CEt + 1 : 13 C CEt 9 Three steps 44% The stereochemistry at the starred carbon was not determined, but the products were isolated as a mixture. C Stereochemical rationale (Crimmins) C R C-9 dr Et i-pr 13:1 17:1 >20:1 Varying the size of the indicated alkyl group influenced the stereoselectivity CEt CEt CR C Consistent with predominant stereochemistry R at C-9 36A-08-andout 3/31/00 1:37 PM Crimmins, M.T., et al. J. rg. Chem. 1984, 49, 2076. Crimmins, M.T., et al. J. Am. Chem. Soc. 1986, 108, 800.
(±)-Pentalenene, (±)-Pentalenic Acid and (±)-Deoxypentalenic Acid from a Common Precursor. C CEt + 9 C CEt 9 Li, 3, TF 90% C CEt 1 : 13 Reduction performed on mixture of photoadducts. Diastereomers separated after reduction. Three steps 89% R=, R'=, Pentalenene, nine steps, 27% R=, R'=C, Pentalenic acid, eight steps, 42% R=, R'=C, Deoxypentalenic acid, eleven steps, 22% R R' Steps Crimmins, M.T., et al. J. rg. Chem. 1984, 49, 2076. Crimmins, M.T., et al. J. Am. Chem. Soc. 1986, 108, 800. (±)-Silphinene Seven steps 46% hν, uranium glass hexane, rt, 4 h 94% TMSI C reflux 89% Silphinene 1) LDA, TF (Et) 2 PCl 2) Li, 2 63% Bu 3 Sn, C 6 6 98% C 2 I Plus a 14% yield of isosilphinene Crimmins, M.T., et al. J. Am. Chem. Soc. 1986, 108, 3435. Crimmins, M.T., et al. Tetrahedron Lett. 1985, 26, 997. 36A-09-andout 3/31/00 1:38 PM
(±)-Laurenene C hν, uranium glass 100 o C, PhCl 87% C * C Prepared in twelve steps and 27% yield from 4,4-Dimethyl-cyclopenteneone 1.5:1 α:β at starred carbon Three steps 89% Eight steps 7% CEt 1) a, 3, Et 2 2) 2, Pd/C 80% * CEt Laurene Crimmins, M.T., et al. J. Am. Chem. Soc. 1987, 109, 6199. Crimmins, M.T., et al. Tetrahedron Lett. 1985, 26, 997. (±)-Lubiminol E 1 E For E=, MM2 calculations suggest that 1 should be more stable than 2 by 1.1 kcal/mol. E E 3 2 4 C 36A-10-andout 3/31/00 1:39 PM hν 97% C 3 83:17 C 4 Crimmins, M.T., et al. Tetrahedron Lett. 1996, 37, 8703. Crimmins, M.T., et al. J. Am. Chem. Soc. 1998, 120, 1747.
(±)-Lubiminol E 5 6 E For E=, MM2 calculations suggest that 5 should be more stable than 6 by 1.5 kcal/mol. E E 7 8 C C hν 98% 7 nly isolated product Crimmins, M.T., et al. Tetrahedron Lett. 1996, 37, 8703. Crimmins, M.T., et al. J. Am. Chem. Soc. 1998, 120, 1747. (±)-Lubiminol Et Five steps 48% C hν, uranium glass hexane/c 2 Cl 2 rt, 15 h 98% C 1) Ts, 2 2) (imid) 2 C=S, DMAP 77% Eleven steps Dowd- C Bu 3 Sn AIB C S Lubiminol C 2 12% C Beckwith α:β 2:3 92% imid 36A-11-andout 3/31/00 1:39 PM Crimmins, M.T., et al. Tetrahedron Lett. 1996, 37, 8703. Crimmins, M.T., et al. J. Am. Chem. Soc. 1998, 120, 1747.
(±)-Bilobalide TMS Y TMS Y Bilobalide CEt hν, uranium glass hexane/c 2 Cl 2 CEt TMS rt, 6 h 78% TMS one diastereomer CEt hν, uranium glass hexane/c 2 Cl 2 CEt CEt rt, 5 h 100% 1.5 1.0 Crimmins, M.T., et al. J. Am. Chem. Soc. 1992, 114, 5445. Crimmins, M.T., et al. J. Am. Chem. Soc. 1993, 115, 3146. (±)-Bilobalide TMS TMS CEt Desired 1 EtC CEt EtC CEt TMS CEt TMS TMS Undesired 2 TMS CEt Desired 3 CEt CEt EtC EtC CEt Undesired 4 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. 1992, 114, 5445. Crimmins, M.T., et al. J. Am. Chem. Soc. 1993, 115, 3146. 36A-12-andout 3/31/00 1:41 PM
(±)-Bilobalide Seven steps Piv hν, uranium glass hexane, rt, 18 h 5% Piv C 20% TMS 80% TMS TMS Piv TMS Piv 25% TMS Piv C Piv 1) Pb(Ac) 4, 2), Ts Piv 50% Piv 92% TMS TMS LDA, MoP 76% Crimmins, M.T., et al. J. Am. Chem. Soc. 1992, 114, 5445. Crimmins, M.T., et al. J. Am. Chem. Soc. 1993, 115, 3146. (±)-Bilobalide C Piv 1) LiAl 4 2) Pb(Ac) 4 80% m-cpba 94% Jones reagent 1) dimethyldioxirane 2) Jones reagent 81% 99% Bilobalide Crimmins, M.T., et al. J. Am. Chem. Soc. 1992, 114, 5445. Crimmins, M.T., et al. J. Am. Chem. Soc. 1993, 115, 3146. 36A-13-andout 3/31/00 1:42 PM
(±)-Ginkgolide B Eight steps CEt hν, uranium glass hexane, rt, 18 h CEt EtC 71% TES 100% TES ne isomer Four steps 49% Twelve steps 11% 1) 2, Ts dimethyldioxirane 2), Ts, C() 3 Ginkgolide B 89% Crimmins, M.T. et al. J. Am. Chem. Soc. 1999, 121, 10249. Crimmins, M.T. et al. Tetrahedron Lett. 1989, 30, 5997. Synthesis of the Core of the Ingenane Diterpenes Three steps 40% C 2 hν, Pyrex Ingenol C, Acetone (9:1) 0 o C, 90 min 83% Stereochemical rationale (Winkler) C K 83% Ingenane Core ne isomer 36A-14-andout 3/31/00 1:44 PM Winkler, J.D., et al. J. Am. Chem. Soc. 1987, 109, 2850.
Synthetic Studies Toward the Taxane Core hν, Pyrex C/Acetone (9:1) rt one of the desired photoadduct could be isolated. Ph Bz Taxol Ac Ac hν, Pyrex C/Acetone (9:1) rt, 30 min 75% 1) K, 2) C 2 2 82% E ne isomer E=C Winkler, J.D., et al.tetrahedron Lett. 1986, 27, 5959. Winkler, J.D., et al. J. rg. Chem. 1989, 54, 4491. Winkler, J.D., et al.tetrahedron 1992, 48, 7049. (-)-Perhydrohistrionicotoxin n-c 5 11 Br Derived from glutamic acid Six steps 34% n-c 5 11 hν, Pyrex, C, 0 o C, 30 min 95% 15:1 ratio of epimers at starred carbon. Major isomer shown. Minor isomer epimerizes to major upon chromatography. * 1) ab 4 2) a, TF Stereochemical rationale (Winkler) 63% C 5 11 C 5 11 n-c 5 11 Seven steps 43% n-c 4 9 Perhydrohistrionicotoxin n-c 5 11 36A-15-andout 3/31/00 1:45 PM Winkler, J.D., et al. Tetrahedron Lett. 1986, 27, 5177. Winkler, J.D., et al. J. Am.Chem. Soc. 1989, 111, 4852.
Formal Synthesis of Vindorosine L-Tryptophan C Cbz Five steps 48% Cbz hν, Pyrex, C, 0 o C, 65 min 91% (R) 3 C Cbz Stereochemical rationale (Winkler) Cbz C(R) 3 Intermediate in Büchi's racemic synthesis >97%ee Ac Büchi Eight steps 3% Et Ac C Vindorosine Eight steps 20% C(R) 3 = (R) 3 C Cbz Winkler, J. D., et al. J. Am. Chem. Soc. 1990 112, 8971. Büchi, G., et al. J. Am. Chem. Soc. 1971, 93, 3299. ne diastereomer (±)-Manzamine A P R P R Y Y Manzamine A P Y R P Y R P Y 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," emaka Rajapakse, Jan. 21, 2000. 36A-16-andout 3/31/00 1:46 PM 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 Model system: Saturated ring hν, Pyrex benzene, rt, 90 min 100% Possible solution: Epimerize after cyclization Wrong relative stereochemistry at three new centers. C hν, Pyrex C, rt, 1h C C 25% P Manzamine Core nly isolable product is from photochemical cleavage, rearrangement. 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 Solution to the solution: Mask the ketone as an easily accessible alcohol C Swern C C Readily available by L-Selectride reduction of the ketone 1) hν, Pyrex C, 0 o C, 12 h 2) Et 3 Cl 3) DMAP 41% C Minor dr 2.3:1.0 1 C a 1 Ent-2 Swern P Manzamine Core 36A-17-andout 3/31/00 1:47 PM Major Again, the predominant product has the wrong stereochemistry and Winkler, J.D., et al. Tetrahedron Lett. 1993, 34, 6509. cannot be isomerized to the correct stereochemistry. 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. 2
(±)-Manzamine A Partial solution: The opposite diastereomer provides the desired stereochemistry C C Minor diastereomer of ketone reduction with ab 4. 1) hν, Pyrex C, 0 o C, 3 h 2) Et 3 Cl 3) DMAP 50% C Major dr 2.5:1.0 P Manzamine Core The correct stereochemistry is obtained as the major product, but Minor this substrate is synthetically inaccessible in high yield. 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 Ultimate solution: The olefinic linkage in the natural product provides for the correct stereoinduction Boc R 1) hν, Pyrex C, rt, 6 h Boc R 2) Pyr Ac 20% Steps See Rajapakse seminar Boc R Stereochemistry not determined Manzamine A R= 36A-18-andout 3/31/00 1:47 PM ne diastereomer 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.
(±)-Saudin Y Y Saudin MM2 calculations suggest that 1 should be approximately 1.6 kcal/mol more stable than 3. 1 3 Irradiation of the substrate (Pyrex, C/Acetone (9:1), 0 o C, 2 h) led to the formation of a 2.5:1 epimeric mixture of 2 in 97% yield. 2 * 4 Winkler, J.D., et al. J. Am. Chem. Soc. 1999, 121, 7425. Winkler, J.D., et al. Tetrahedron Lett. 1998, 39, 2253. (±)-Saudin Eleven steps 16% Saudin hν, Pyrex C/acetone (9:1) 0 o C, 30 min 80% ne diastereomer 1) n-buli, TF, TMEDA, -95 o C; Tf 2 2) (3-furyl)SnBu 3, LiCl, Pd(AsPh 3 ) 4, TF, reflux 77% PPTS, C 6 6 52% Li C 36A-19-andout 3/31/00 1:48 PM Winkler, J.D., et al. J. Am. Chem. Soc. 1999, 121, 7425. Winkler, J.D., et al. Tetrahedron Lett. 1998, 39, 2253.
Conclusions A lack of complete mechanistic understanding has not prevented the successful application of the enone-olefin photocycloaddition to a great many synthetic challenges. Intramolecular enone-olefin photocycloaddition is useful for the stereoselective contruction of carbocycles, especially five membered rings. Multiple quaternary and congested centers can be constructed in a single operation. Great creativity is possible in the fragmentation of the derived cyclobutane to access useful synthetic intermediates. Stereoinduction from existing stereocenters is usually explicable in a rational and satisfying manner. Molecular modeling simulations have proven useful in predicting the stereoselectivity of several photocycloadditions. 36A-20-andout 3/31/00 1:49 PM