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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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Page 1: Photoinduced Electron Transfer: Strategies for …chemlabs.princeton.edu/macmillan/wp-content/uploads/...Photoinduced Electron Transfer: Strategies for Organic Synthesis MacMillan

Photoinduced Electron Transfer: Strategies for Organic Synthesis

MacMillan Group Meeting Alex Warkentin 2.12.08

D* + Acc = D- + Acc+

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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.

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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.

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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.

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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* + RNR

R

E

1 or 3Sens +

PET

RNR

R

E

Nu + Nu ER

NR

R+R

NR

R

RNR

R Further chemistry

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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.

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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.

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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

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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 OMeO OH

OEtHH H

NMQNMe

OMeOO OEt

MeOH

OMe groups stabilize benzylic nucleofuges toward tandem epoxide ring openings

79%

Floreancig, P. E. Synlett 2007, 191.

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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

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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

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Oxidative Intramolecular PET Bond Cleavage

N MeClO4

Me3SiPET N Me

ClO4

Me3SiNu

N

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.

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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

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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.

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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.

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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

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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

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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.

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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

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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%

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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

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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 ΔGo

CS = -0.41 eV; ΔGoCR = -2.5 eV

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

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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.

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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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