Complex Molecule Synthesis Enabled by Photochemistry O Me Me hv Me O Me Joseph Badillo MacMillan Group Meeting March 23, 2016 Complex Molecule Synthesis Enabled by Photochemistry Outline General outline 1) Why are photochemical reactions interesting? 2) 2+2 cycloaddtions and cyclobutane ring-opening reactions 3) Norrish type I and II applications to complex architectures 4) Oxa-di-!-methane rearrangement 5) Paternò−Büchi reaction 6) meta-photocycloaddition reaction in total synthesis 7) Photoredox applications to complex molecule synthesis 8) Summary Complex Molecule Synthesis Enabled by Photochemistry why photochemistry? Why are photochemical reactions interesting? 1) Since excited states are rich in energy, highly endothermic reactions are possible. Such as highly strained (up-hill) targets! 2) In the excited state antibonding orbitals are occupied, which allow for reactions to occur that are not possible in the ground state 3) Photochemical reactions have the potentail to be Green as they only consume photons Complex Molecule Synthesis Enabled by Photochemistry Thermal vs photochemical topography Reactant (R) goes through intermediate (I) to form product (P) Karkas, M. D.; Porco, J. A.; Stephenson, C. R. J. Chem. Rev. 2016, 116, 9683. Complex Molecule Synthesis Enabled by Photochemistry typical absorption range of organic compounds Most organic molecules absorb light in the UV-region Simple alkenes 190 - 200 nm Acyclic diene 220 - 250 nm Cyclic diene 250- 270 nm Ultra Violet Styrene 270 - 300 nm (UV) Saturated ketones 270 - 280 nm α,β-Unsaturated ketones 280 - 300 nm Aromatic compounds 250 - 280 nm Common photocatalysts 350 - 440 nm Visible Complex Molecule Synthesis Enabled by Photochemistry Energy absorbed from light Energy as a function of wavelength is hyperbolic A molecule absorbing blue light, with a wavelength of 400 nm, absorbs about 71 kcal of energy Purves, W. K., G. H. Orians, H. C. Heller, and D. Sadava. 1998. Life: The Science of Biology (Fifth Edition). Sinauer Associates, Sunderland, MA. Complex Molecule Synthesis Enabled by Photochemistry 2 basic laws governing photochemical reactions Grotthus-Draper law (Principle of Photochemical Activation): Only the light which is absorbed by a system can bring about chemical change Stark-Einstein law (Law of Photochemical Equivalence): Each reactant molecule absorbs a single photon to provide an activated species to form products one photon (hv) A A B reactant excited product molecule molecule molecule Complex Molecule Synthesis Enabled by Photochemistry reactivity of excited state intermediates physical quenching ionization luminescence AB AB + hv AB + e + M intramolecular AB† A + B dissociation energy transfer AB✻ + CD + E AE + B or ABE direct reaction AB + CD‡ BA charge transfer intermolecular AB + E or AB + E energy transfer isomerization For more physics details see: Physical Organic Photochemistry - Scott Simonovich Group Meeting (2011) Complex Molecule Synthesis Enabled by Photochemistry Outline General outline 1) Why are photochemical reactions interesting? 2) 2+2 cycloaddtions and cyclobutane ring-opening reactions 3) Norrish type I and II applications to complex architectures 4) Oxa-di-!-methane rearrangement 5) Paternò−Büchi reaction 6) meta-photocycloaddition reaction in total synthesis 7) Photoredox applications to complex molecule synthesis 8) Summary Complex Molecule Synthesis Enabled by Photochemistry first report on the [2 + 2] photocycloaddition In 1908 Ciamician and Silber observed carvone camphor formation from carvone when exposed to sunlight for one year O Me Me hv Me Me Me O O Me carvone carvone camphor not observed Ciamician, G.; Silber, P. Chemische Lichwirkungen. Ber. Dtsch. Chem. Ges. 1908, 41, 1928. Complex Molecule Synthesis Enabled by Photochemistry photoexcitation of enones α,β-unsaturated carbonyl compounds are often employed due to ease of excitability ✻ ✻ ✻ O O O O R R hv • ISC • • • • • singlet triplet triplet exciplex O O O spin R R R • • inversion • • triplet 1,4-biradical singlet 1,4-biradical Crimmins, M. T.; Reinhold, T. L. Org. React. 1993, 44, 297. Complex Molecule Synthesis Enabled by Photochemistry photoexcitation of enones Regioselectivity in [2 + 2] photocycloadditions O O O R R + hv + R head-to-head head-to-tail O O O R R HN + hv HN + HN Me Me Me Me Me Me R head-to-head head-to-tail R rr (A: B) A B OEt 5:95 CN 82:18 Crimmins, M. T.; Reinhold, T. L. Org. React. 1993, 44, 297. Complex Molecule Synthesis Enabled by Photochemistry Total synthesis of (−)-littoralisone [2 + 2] photocycloaddition enables the the total sysnthesis of (−)-littoralisone OBn OH O O hv (!"= 350 nm) O O Me H H H 12 steps rt, 2h, C6H6 Me O O O OH O O then H2, Pd/C O H Me H Me Me O OBn 84% yield O OH O O (−)-citronellol OBn OH OBn OH (−)-littoralisone 13 steps 13% yield overall Mangion, I. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 3696. Complex Molecule Synthesis Enabled by Photochemistry [2 + 2] cycloadditions using allenes Optically active allenes can be employed with retention of steroechemisitry t-Bu O hv (!"≧ 300 nm) H O t-Bu • rt, 4h, cyclohexane H H O O 88% yield O O 92% ee 92% ee Carreira, E. M.; Hastings, C. A.; Shepard, M. S.; Yerkey, L. A.; Millward, D. B. J. Am. Chem. Soc. 1994, 116, 6622. Complex Molecule Synthesis Enabled by Photochemistry [2 + 2] photocycloaddition, followed by ring-opening Exploiting the inherent ring strain found in cyclobutanes to access medium-sized rings a ✻ d b n c n m n m m photoexcited olefin cyclobutane ring-opening at positions a-d give rise to different size rings Karkas, M. D.; Porco, J. A.; Stephenson, C. R. J. Chem. Rev. 2016, 116, 9683. Complex Molecule Synthesis Enabled by Photochemistry [2 + 2] photocycloaddition, followed by ring-opening Three common stratagies for cyclobutane ring opening X R O R O R O O R O R O O O Grob fragmentation radical fragmentation De Mayo reaction Karkas, M. D.; Porco, J. A.; Stephenson, C. R. J. Chem. Rev. 2016, 116, 9683. Complex Molecule Synthesis Enabled by Photochemistry Synthesis of (±)-epikessane A [2 + 2] cycloaddition followed by Grob fragmentaion enables the synthesis of (±)-epikessane O O 1) hv (! > 300 nm) H CO2Me MeO2C C H + 6 6 steps AcO AcO 2) p-TsOH, C6H6 H OAc 60% (2-steps) OH Me H H H p-TsCl steps O Me rt, 18 h Me H OH Me H H Me pyridine O Me 83% (±)-epikessane Grob fragmentation Liu, H.-J.; Lee, S. P. Tetrahedron Lett. 1977, 3699. Complex Molecule Synthesis Enabled by Photochemistry [2 + 2] photocycloaddition, followed by ring-opening Three common stratagies for cyclobutane ring opening X R O R O R O O R O R O O O Grob fragmentation radical fragmentation De Mayo reaction Karkas, M. D.; Porco, J. A.; Stephenson, C. R. J. Chem. Rev. 2016, 116, 9683. Complex Molecule Synthesis Enabled by Photochemistry radical fragmentation 1) Li CO2Et OCH OMe 2 EtO2C ZnI OHC Me Me 2) MeOCH Cl 2 CuCN, LiCl, Me3SiCl 65% EtO2C 60% O O CO2Et 1) 10% HCl, EtOH CO2Et ! = 365 nm hexanes Me 2) (imid)2C=S, NEt3 Me 80% 81% MeOCH O OCH2OMe 2 O CO2Et Bu SnH, AIBN EtO2C 3 Me Me O C6H6, 80 °C O 76% N S N radical fragmentation Crimmins, M. T.; Huang, S.; Guise-Zawacki, L. E. Tetrahedron Lett. 1996, 37, 6519. Complex Molecule Synthesis Enabled by Photochemistry radical fragmentation 1) Li CO2Et OCH OMe 2 EtO2C ZnI OHC Me Me 2) MeOCH Cl 2 CuCN, LiCl, Me3SiCl 65% EtO2C 60% O O CO2Et 1) 10% HCl, EtOH CO2Et ! = 365 nm hexanes Me 2) (imid)2C=S, NEt3 Me 80% 81% MeOCH O OCH2OMe 2 O CO2Et Bu SnH, AIBN EtO2C 3 Me Me O C6H6, 80 °C 76% radical fragmentation Crimmins, M. T.; Huang, S.; Guise-Zawacki, L. E. Tetrahedron Lett. 1996, 37, 6519. Complex Molecule Synthesis Enabled by Photochemistry radical fragmentation O O O R Me H Bu3SnH, C6H6 Me Bu3SnH, C6H6 Me Me Me AIBN, 80 °C AIBN, 80 °C CO Me Me 2 R = H I R = CO2Me 80% yield 75% yield • + H O O R H Me Me Me Me • • Crimmins, M. T.; Huang, S.; Guise-Zawacki, L. E. Tetrahedron Lett. 1996, 37, 6519. Complex Molecule Synthesis Enabled by Photochemistry radical fragmentation O O O R Me H Bu3SnH, C6H6 Me Bu3SnH, C6H6 Me Me Me AIBN, 80 °C AIBN, 80 °C CO Me Me 2 R = H I R = CO2Me 80% yield 75% yield • • + H + H • O O R R O O H Me Me • Me R Me Me Me Me Me • • Crimmins, M. T.; Huang, S.; Guise-Zawacki, L. E. Tetrahedron Lett. 1996, 37, 6519. Complex Molecule Synthesis Enabled by Photochemistry [2 + 2] photocycloaddition, followed by ring-opening Three common stratagies for cyclobutane ring opening X R O R O R O O R O R O O O Grob fragmentation radical fragmentation De Mayo reaction Karkas, M. D.; Porco, J. A.; Stephenson, C. R. J. Chem. Rev. 2016, 116, 9683. Complex Molecule Synthesis Enabled by Photochemistry Synthesis of (−)-perhydrohistrionicotoxin De Mayo fragmentaion enables the synthesis of (−)-perhydrohistrionicotoxin n-C5H11 n-C5H11 O O HN steps hv (! > 300 nm) HN Me O OH OH O Me Me 0 °C, 30 min NH O 2 Me O O CH3CN H H L-glutamic acid O OH O then NaBH4 61% (2-steps) n-C5H11 n-C5H11 H HN Me NaH HN O N n-C5H11 steps Me O O rt, 30 min O H H THF HO n-C4H9 OH O O 95 % (−)-perhydrohistrionicotoxin De Mayo reaction Winkler, J. D.; Hershberger, P. M. J. Am. Chem. Soc. 1989, 111, 4852. Complex Molecule Synthesis Enabled by Photochemistry Synthesis of (−)-perhydrohistrionicotoxin De Mayo fragmentaion enables the synthesis of (−)-perhydrohistrionicotoxin n-C5H11 n-C5H11 O O HN steps hv (! > 300 nm) HN Me O OH OH O Me Me 0 °C, 30 min NH O 2 Me O O CH3CN H H L-glutamic acid O OH O then NaBH4 61% (2-steps) n-C5H11 n-C5H11 H HN Me HN O N n-C5H11 steps Me H O O − acetone O HO n-C4H9 O O O (−)-perhydrohistrionicotoxin De Mayo reaction Winkler, J.