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Photoinduced Electron Transfer: Strategies for Organic Synthesis MacMillan Group Meeting Alex Warkentin 2.12.08 D* + Acc = D - + Acc +
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  • Photoinduced Electron Transfer: Strategies for Organic Synthesis

    MacMillan Group Meeting Alex Warkentin 2.12.08

    D* + Acc = D- + Acc+

  • Contents

    •  History of photoinduced electron transfer •  Basics of electron transfer versus energy transfer •  Oxidative PET bond cleavage •  Reductive PET bond cleavage •  Enabling of macrocyclic ring closures •  Intramolecular alpha-amino radical additions •  Intermolecular alpha-amino radical additions and applications •  Catalytic asymmetric? •  Mechanistic verification via spectroscopic analysis

    Griesbeck, A. G.; Mattay, J., Eds. Synthetic Organic Photochemistry Marcel-Dekker, New York, 2005.

    Griesbeck, A. G.; et. al. Acc. Chem. Res. 2007, 40, 128.

    Roth, H. D. Photoinduced Electron Transfer I Springer-Verlag, Heidelberg, 1990. 5.

  • Joseph Priestley, 1733 - 1804 British chemist

    The First Understandings of Photochemistry Priestley was the first to discover photosynthesis, albeit fortuitously

    H2O + CO2 O2 + C6H12O6hν

    Discovered accidentally while Priestly was studying the “influence Of light in the production of ‘dephlogisticated air’ [O2] in water by Means of a ‘green substance’.” Priestley, J. Phil. Trans. Roy. Soc. (London) 1772, 62, 147

    Jan Ingenhousz, 1730 - 1799 Dutch chemist, physicist and physician

    Ingenhousz developed photosynthesis more rigorously

    Ingenhousz, along with Saussure, established the requirement of light in macroscopic photosynthesis.

    But, despite work by Liebig, Baeyer and Willstatter, electron transfer remained unsolved untill the 20th century when J. J. Thompson (1897) and Milikan (1913) convinced the community of the presence

    of the electron.

  • J. W. Dobereiner, 1780 - 1849 German Chemist

    Designed the first actinometer that measures the power of electromagnetic radiation

    Fe2O3 +

    (Fe3+)

    FeO + CO2 + CO2

    (Fe2+)O

    OO

    O

    Electron Transfer and Actinometry Dobereiner foreshadowed photo-redox chemistry with actinometry

    The place and usefulness of actinometry was fiercely debated and no other photo-redox chemistry was studied in-depth in the 19th century

    Furthermore, prior to the advent of NMR, ESR, and CIDNP the presence of ionic radicals remained highly speculative and their identity often erroneously presumed.

    20th Century PET contributions were made by Bauer and Weiss. The latter enunciated the basic form of modern PET theory:

    “Fluorescence quenching in solution can be considered as a simple electron transfer process.”

    D* + Acc = D- + Acc+

    Weiss, J.; Fischgold, H. Z. Physik. Chem. 1936, B32, 135.

  • Photoinduced Electron Transfer: A Representative Mechanism

    Understanding α-amino radical formation is important for utlizing its reactivity

    1 or 3Sens 1 or 3Sens*hν

    RNR

    R

    E

    1 or 3Sens* +R

    NR

    R

    E

    1 or 3Sens +

    PET

    RNR

    R

    E

    Nu + Nu ER

    NR

    R+R

    NR

    R

    RNR

    R Further chemistry

  • Basics of Photoinduced Electron Transfer

    Efficiency dependent on redox potential

    +

    +

    +

    +

    1Sens + D 1Sens + D

    1Sens + A 1Sens + A

    More efficient as distance decreases

    Singlet-excited sensitizer is both a better oxidant AND reductant. Both processes quench fluorescence

    Triplet fluorescence quenching is known

    Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic Chemistry University Science Books, Sausalito, CA. 2005, 955 - 958.

  • Energy Transfer Mechanisms do not Occur Via Polar Intermediates

    Energy Transfer I: Dexter Mechanism

    + +

    3Sens* + A Sens + 3A*

    + +

    1Sens* + A 1Sens + A*

    Energy Transfer II: Forster Mechanism

    Both Energy Transfer Mechanisms Require that E(excited state D) > E(excited state A)

    kee = KJe^(-2rDA/L), so rDA ~ 5 - 10 A

    Primarily triplet sensitization

    Can operate at over 50 A via a dipole- dipole (Coulombic) mechanism (transition dipole coupling) Basis for FRET

    Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic Chemistry University Science Books, Sausalito, CA. 2005. 955 - 958.

  • Kornblum, N; et. al. J. Am. Chem. Soc. 1955, 77, 6269; Angew. Chim. Int. Ed. 1975, 14, 734

    Reductive PET Bond Cleavage

    O2N

    Cl+

    Me NO2

    Me Na PET

    Me

    Me

    NO2

    NO2

    Cl

    O2N

    Me

    Me

    NO2

    O2NMe Me

    NO2

    N

    Cl

    OO

    +

    ambient light

    O2N

    NO2

    Me MeNaN3

    O2N

    N3

    Me MeConditions

    Dark

    ambient

    fluorescentlight (20 W)

    Yield

    0%

    63%

    100%

    Reductive cleavage proceeds by electron transfer to benzyl halide or pseudo-halide

  • Reductive PET Reactions and Non-Halide Examples

    NBoc substituents stabilize benzylic radical formation

    OBocHN

    Ph

    OMeO

    OMe

    OMe

    OO

    OBocHN

    OOMe

    O

    OMe

    OMe

    H

    94%, 10 : 1 dr

    hν, NMQPF6

    O2, Na2S2O3NaOAc, 4 A MS

    DCE, PhMe

    PhOMe

    O OEtO O hν, NMQPF6

    O2, Na2S2O3NaOAc, 4 A MS

    DCE, PhMe

    O OMeOOH

    OEtHH H

    NMQNMe

    OMeOO OEt

    MeOH

    OMe groups stabilize benzylic nucleofuges toward tandem epoxide ring openings

    79%

    Floreancig, P. E. Synlett 2007, 191.

  • Cristol, S. J.; et. al. J. Am. Chem. Soc. 1987, 109, 830 Zimmerman, H.; et. al. J. Am. Chem. Soc. 1963, 85, 913; J. org. Chem. 1986, 51, 4681.

    Wagner-Meerwein rearrangement

    Reductive PET Bond Cleavage

    Homobenzylic chlorides also participate in reductive PET chemistry

    ClCl

    MeO

    MeOPET

    AgOAc, HOAc

    OAcCl

    ClCl

    MeO

    MeO

    MeO

    MeO

    Besides anti/syn considerations, differences occur between homopara vs. homometa C-X bonds

    ClPET

    AgOAc, HOAc

    OAcMeO

    Cl Cl

    ClMeO MeO

    70%

    plus 18% RCl

  • Mariano, P. S.; et. al. J. Am. Chem. Soc. 1982, 104, 617

    Oxidative PET Bond Cleavage

    NMe

    PhClO4SiMe3

    PET

    NMe

    Ph + SiMe3+

    SiMe3 + Nu + NuSiMe3

    NMe

    Ph + NMe

    Ph

    A representative and early example of oxidative PET bond cleavage

  • Oxidative Intramolecular PET Bond Cleavage

    N MeClO4

    Me3Si PET N Me

    ClO4

    Me3Si NuN

    Me

    90% indolizidine

    O

    NBn

    Me3Si

    PET

    CN

    CN

    O

    NBn

    Intramolecular C-C bond formation to form indolizidines

    Intramolecular organocatalytic Hiyama-type coupling

    Difficult to perform this chemistry as efficiently with a non-PET approach (polar reagents)Mariano, P. S.; et. al. J. Am. Chem. Soc. 1984, 106, 6439.

  • Mariano, P. S.; et. al. J. Am. Chem. Soc. 1994, 116, 4211.

    Oxidative PET Bond Cleavage

    Me

    O

    NMe

    Me3SiPET

    MeOH/MeCNDCA

    Me

    O

    NMe

    Me3SiMe

    O

    NMe

    Me

    O

    NMe

    90%

    Me

    O

    NMe3Si

    Less polar and aprotic solvents (MeCN alone) afford product retaining silyl group

    Me

    O

    NMe

    SiOMe

    H

    Me

    O

    NMe

    SiNMe

    vs

  • Hu, S.; Neckers, D. C. Tetrahedron 1997, 53, 2751

    Application to Macrocyclic RIng Closures

    O

    O

    ONR2

    R1

    N

    O

    OHO

    Ph

    R1

    R2

    PET

    O

    O

    OS R1

    R2

    PET

    S

    O

    OHO

    PhR1

    R2

    38 - 76%

    35 - 65%

    N NH

    NH

    SO

    O

    HO

    O 36%

    Hasegawa, T. Tetrahedron, 1998, 54, 12223

    Griesbeck, A. G.; Mattay, J., Eds. Synthetic Organic Photochemistry Marcel-Dekker, New York, 2005. 276.

  • Application to Poison Frog Therapeutics

    NMe

    Me

    HOH

    NN

    OH

    OH

    HO H

    OH

    O

    O

    O

    HOOH

    Carbohydrate-mimetic hydroxylated indolizidines

    (+)-Pumiliotoxin

    Antidiabetics, antiviral, anticancer, immunosuppressant, transplantation medicine

    Pyrrolizidines also offer opportunities for synthetic application

    alexine riddelliine

    Potent glycosidase inhibitor, antiviral, anti HIV, anticancer

    Insect defense agent

    Griesbeck, A. G.; et. al. Acc. Chem. Res. 2007, 40, 128.

    Dendrobates spp.

  • Mariano, P. S.; et. al. J. Am. Chem. Soc. 1991, 113, 8847

    Intermolecular Non-Silylated, Simple Amino-Alkyl Additions

    Triplet sensitizers have very specific transition energies and can markedly improve reaction efficiency

    O OMenthO

    OMenth

    OR

    Me

    Me

    Me

    NMe

    +PET

    O ORO

    O ORO

    H H

    NMe NMeH H

    +

    2 : 1

    60%

    1 : 1.2

    94%

    Ph Ph

    O

    O

    MeO OMe

    N N

    H HOHOH

    (-)-Isoretronecanol (+)-Laburnine

  • Proposed Mechanism for Pyrrolidine Addition

    The catalytic cycle may provide more than one opportunity for a product forming step

    O ORO

    NMe

    O

    MeO OMe

    OH

    MeO OMe

    OOOR

    MeN

    NMe

    O

    O

    ORNMe

    NMe

    productPET

    Mariano, P. S.; et. al. J. Am. Chem. Soc. 1991, 113, 8847

    77 - 94% 5 examples

  • Further Development of Amine Coupling Partners

    Triethyl amine, piperidone and other amines are a viable coupling partner in PET C-C bond construction

    O O+

    PETO O

    NEt2

    TEA350 nm

    sensitizer85%, 1:1 dr

    O ONMe

    +PET O O

    H H

    H H+

    1 : 1

    60%

    1 : ~0

    48%

    MenthORO RO

    EtO

    S

    SMe

    EtO

    S

    SMe

    No

    With

    350 nmsensitizer NMe NMe

    N 2.5 : 1 constitutionalisomeric products

    favoring tertiary radical

    Org. Biomol. Chem. 2006, 4, 1202; Zard Angew. Chim. Int. Ed. 1997, 36, 672.

  • Bertrand, S.; et. al. J. Org. Chem.2000, 65, 8690; Marinkovic, S.; et. al. J. Org. Chem. 2004, 69, 1646.

    Intramolecular Trapping of Presumed Oxy-allyl Radical

    When trapping oxy-allyl radical acetone was necessary to act as benign oxidant

    O O+

    PET O O

    H H+

    38% : 2% : 18%

    74% : 3% : 0%

    MenthORO RO

    With acetone

    Without acetone

    350 nmMichler'sketone

    O

    Me2N NMe2Michler's ketone

    NMeMe

    N NMe Me

    H H + O

    O

    RO

    N

    OO OR

    N

    OO OR

    71%, 1 : 1 dr 74%, 2 : 1 dr

    NO

    O

    OR

    56%, 20 : 1 dr

    Me

  • Demuth, M. J.; et. al. J. Am. Chem. Soc. 1999, 121, 4894; Griesbeck, A. G.; et. al. Angew. Chem. 2001, 113, 586

    Non-Direct Methods for Enantioinduction in PET Reactions

    Cascade cyclization of terpene polyolefins via photoinduced electron transfer

    MeMe

    Me

    O O

    OMe

    Me 1) PET, DCTMB

    BP, MeCN/H2O-25 oC

    2) removal of (-)-menthone HO

    Me

    Me Me

    Me

    MeH

    H H

    OHCO2Me Perfect diastereoinduction

    Only 2 of 256 possible isomers formed and 8

    stereocenters set

    Shortest steroid route

    Remarkably far reachingasymmetric induction

    N

    N

    O

    O

    O

    CO2K

    PET, acetone/H2O

    X N

    N

    O

    O

    OH

    X

    X = H, 45%, 86% eeX = Cl, 50%, 79% ee

    With ethylene di-ortho linker: 0% ee

    Memory of chirality PET study explained by rigidity of amide and aniline bonds toward rotation

    12%

  • NH

    NH

    O

    O

    N N

    N

    O

    N

    OH

    O

    N

    H

    N

    O

    Hhν (λ > 300 nm)

    30% catalystToluene

    64% yield, 70% eesingle diastereomer

    Recent Precedent for Catalytic Asymmetric PET Carbon-Carbon Bond Formation

    The Bach example is the only method thus far for a direct, catalytic, asymmetric reaction with chemical yields above 1%

    Bauer, A.; Westkamper, F.; Grimme, S.; Bach, T. Nature 2005, 436, 1139

  • Evidence Supporting the Occurence of Charge Separation

    NNN

    N

    N

    N O

    RN H

    H

    NMe

    Me

    Rib

    O Rib

    NHH

    hνET

    Rib =O

    ORORHOR

    R = SiMe2tBu

    1 2

    Why should we trust that charge separation is occuring?

    2 Fluoresces upon irradiation and is quenched upon increasing concentration of 1 in solution. This levels off at 1 molar equivalent of 1.

    Quenching of simple anthracene* fluorescence by adition of aniline only occurs at 2%.

    If masked donor (R = COCHMe2) is used, little quenching occurs.

    Thus, diffusion controlled collisional quenching cannot be responsible for electron transfer.

    Ka = 38,000 +/- 1300 M-1 ΔGoCS = -0.41 eV; ΔGoCR = -2.5 eV

    Sessler, J. L.; et. al. J. Am. Chem. Soc. 2001, 123, 3655.

  • PET Projects in Total Synthesis

    Selected natural products formed by PET bond-constructive key steps

    O

    O

    MeMe N

    Bn

    SiMe3

    O

    O

    MeMe N

    Bn

    PET

    NH

    HO

    HO

    OH

    60%

    N

    O

    O

    HOMeO

    MeO

    berberine analog

    NH

    OH

    (+/-)-epilupinine

    (+)-isofagomine

    HN

    O

    O

    OHHO

    HO

    O

    (+)-2.7-dideoxypancratistatin

    O Me

    OOHO

    Me Me

    H

    H

    Me

    Me Me

    (+/-)-stypoldionepolyterpene cyclization

    HOMe

    H

    MeMe

    Me(+/-)-isoafricanol

    O

    HO OH

    HO CO2Me

    C-furanoside

    Griesbeck, A. G.; Mattay, J., Eds. Synthetic Organic Photochemistry Marcel-Dekker, New York, 2005. 292.

  • Conclusions

    •  Photoinduced electron transfer (PET) utilizing alpha-amino radicals was shown to be applicable to problem solving in organic synthesis.

    •  Alpha oxo- and alpha thio-radicals are also useful. •  Advantages - unique and/or expedited carbon-carbon

    bond construction; vastly underexploited asymmetric potential for interesting reactivity.

    •  Disadvantages - Limited substrate scope and/or specific wavelength for some methods.


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