Photochemistryand

Applications in Synthesis

Jason M. Rohde

September 1, 2004

Photochemistry

-chemical reactions initiated by light-energy is absorbed or emitted by matter in discrete quanta called photons -absorption of light leads to an electronic excitation (ground state→excited state)-promote an e- like n→π∗ or π→π∗

-most chemistry takes place from S1 and T1 excited states

E = hν = hc/ λshort λ light corresponds to high energy

S1 have a shorter lifetimeand higher E (10-9 to 10-5)

T1 have a longer lifetimeb/c spin flip req. (10-5 to 10-3)

Photochemistry-If a molecule absorbs energy, it can undergo a reaction or undergo loss of energy by two methods: •radiative processes-involve emission of a photon -phosphorescence-relaxation to a lower state with different multiplicity, such as T1→S0 (spin forbidden) -fluorescence-relaxation to lower state of same multiplicity, such as S1→S0 (spin allowed) •non-radiative processes-no emission -internal conversion-involves no spin change, such as S1→S0 -intersystem crossing-involves change in spin multiplicity •one way competes with phophorescent decay of the lowest triplet state to the ground state •another way converts the lowest excited singlet state to the lowest triplet state (competes with fluorescence and IC)[gives access to triplet state]-Excitation by E transfer is Sensitization (deactivation is Quenching)

Geometrical Isomerism

R

R R

Rhν

-cis/trans (E / Z) isomerism under photochemical conditions commonly leads to thermodynamically less stablecis-isomer -cis-isomer typically absorbs at a lower λ due to decreased conjugation b/c of non-bonded interactions-reactions come to photostationary state unless optical pumping is performed (irradiation of just 1 isomer to drive the equilibrium)

hν

w/o sensitizer photostationary state: E / Z : 8/92w sensitizer photostationary state: E / Z :50/50

Geometrical Isomerism

α-pyran: G. Büchi and N.C. Yang J. Am. Chem. Soc. 1957, 79, 2318.

OO

O

β-ionone

hν, quartz

EtOH

α-pyran

5% 95%

hν

2-C10H7COMe

Ph Phhν

toluene

Ar ArAr

Ar

hν

λ>180nm6π-elec.

∆

Geometrical Isomerism

O O

OO

hν hν

O

H

H

HH

O

H

H

HH

O

O

O

H

HH

O

O

H

HH

O

O

hν, pyrex

cyclohexane70%

hν, uranium

DCM, -75°C77%

10:1

5:1

H. Dorr, V. Rawal J. Am. Chem. Soc. 1999, 121, 10229

λ>285nm

λ>340nm

Electrocyclizations

-reactions generate a new σ-bond between the termini of the conjugated π-system-concerted process-bond breaking occurs at the same time as bond formation-reactions also come to photostationary state based on absorption coefficient at the λ of irradiation

Thermal Reactions -occur via HOMO4n - conrotatory4n + 2 - disrotatory

Photochemical Reactions -occur via LUMO4n - disrotatory4n + 2 - conrotatory

4π-Electrocyclizations

H

H

hν

hν

OO

O

O

OO

HH

hν

hν

4π-electrocyclizationsoccur with disrotatoryring closure under photochemical conditions

95%

59%

254nm

hνFe

OCCO

COFe(CO)5

8 and 6π-Electrocyclizations

hν

hν

8π-electrocyclizationsoccur with disrotatoryring closure under photochemical conditions and 6π-systems undergo conrotatory ringclosure

C9H17

HOH

Ergosterol(provitamin D)

C9H17

HO

H

Precalciferol(previtamin D)

C9H17

HOVitamin D2(calciferol)

hν

6π

>20°C

1,7 H-shift

6π-Electrocyclization in Synthesis

H H

H H HO

HNO

HNO

OH

H

Ikarugamycin

H HH H OH

OH

OH

OH

H

H

H

HO

O

H

H

Wittig Reaction

1. hν, -78°C, hex.2. HCl

50%

4:1

J. Whitesell and M. Minton J. Am. Chem. Soc. 1987, 109, 6403

retro-6π-Electrocyclization

OO

dihydrocostunolide

E. Corey and A. Hortmann J. Am. Chem. Soc. 1963, 85, 4033

OO

OO

H

hν

1:1

MeOH-18°C

H2Raney Ni

MeOH-15°C

Di-π-methane rearrangement

-Howard E. Zimmerman has studied this reaction extensively-Reaction takes 1,4-dienes or 3-phenylalkenes to vinyl or phenyl cyclopropanes

barrelene semibullvalene

61%

hν

hν

O O

66%

hν

Oxa-di-π-methane rearrangement

O

pyrext-BuOH

50%

hν

hν

acetone70%

hν

R1

R5R4

R3R2

OR1 R4

R5

R3R2O

R1

R3R2

R4R5

O

R1

R3R2

R4R5

OO

O

O

Di-π-methane rearrangement in Natural Products

S. Look, W. Fenical, D. Van Engen, J. Clardy J. Am. Chem. Soc. 1984, 106, 5026.

O

O

AcO

H

AcO O

OH

O

Cl

OAc

AcO

H

AcOO

OHCl

OAc

O

erythrolide Aerythrolide B

hν

quartz PhH

87% convin 3 hr

or5% methanolic

seawater(glass)

with sunlight

37% convin 8 days

Oxa-di-π-methane vs. 1,3-Acyl Migration

T. Uyehara, Y. Kabasawa, T. Kato Bull. Chem. Soc. Jpn. 1986, 59, 2521

O

OO

hν

300nmhexane

254nmacetone

hν

50%

O

62%

OOMe

MeOO

O

X

hν

pyrexTHF59%

steps

X = O pinguisone X = H2 deoxypinguisone

1,3-Acyl Migration in Natural Products

J. Shin, W. Fenical J. Org. Chem. 1991, 56, 1227

O

O O

O O

hν

quartzPhH3h

cembratriene 10.6% cembratriene 11.5%

calyculone D back 8.8%calyculone E 6.2%

calyculone F up 10.6%calyculone G 15.9%

[2 + 2] Cycloaddition-[2+ 2] photocycloadditon is the cyclization of two olefinic units to provide a cyclobutane (generate 2 new C-C bonds and up to four new stereocenters)-1908 Ciamician observed the first [2 + 2] reaction when exposure to Italian sunlight for 1 year generated carvone camphor from carvone

O

O

carvone carvone camphor

hν

-photochemical conditions create charge like umpolung of enone (β-carbon is electron rich)-intermolecular variants also well known, but regioselec. can be highly dependent on both olefinic partners-this [2 + 2] follows the "rule of 5" and none of the other regioisomer is observed

O

not observed

"Rule of 5"

O

O

H

O

O

O O

hν

70%

O

O

notobserved

O

O

hν

O

O

[2 + 2] Cycloaddition in Synthesis

O

H•

HH

HH

H

O

H

H

Ohν

Et2O72% 2:1

O

OO

periplanone B

periplanone: S. Schreiber, C. Santini Tetrahedron Lett. 1981, 22, 4651saudin: J. Winkler, E. Doherty J. Am Chem. Soc. 1999, 121, 7425

O

O

OO

H

O

O

saudin

O

O

O

OO

O

O

H

O

OO

O

O

O

O

hν

0°CCH3CN/acetone

(9:1)80%

steps

de Mayo Reaction

O

OH

CO2Me

O

O

CO2MeOH

CO2MeO

hν

[2 + 2]

retro-aldol

-[2 + 2] cycloaddition involving double bond of an enol and another olefin and the retro-aldol reaction

Paterno-Büchi Reaction

-Paterno and Chieffi observed the first example of a [2 + 2] cycloaddition between a carbonyl and an olefin to make an oxetane

OO*

T1

O Ohν

-many examples of intermolecular reaction, but regioselectivity and product distributions are highly case dependent-many synthetic examples of intramolecular variant

OH

AcOAcOO AcO

O

hν

acetone42%

HI

AcOH82%

vitamin D3 analogs: M. Mihailovic, L. Lorenc, V. Pauolvic, J. Kalvoda Tetrahedron 1977, 33, 441

Paterno-Büchi Reaction in Synthesis

Oobtained viaDiels-Alder

O

hν

corexλ>250nm

PhH90%

O

1. i-Pr2NMgI, ∆2. PDC, DMF

65%

O H H

H

LDBBTHF

-78°C66%

H

H

H

endo-hirsutene

NaBH4TFA

DCM, CH3CN69%

V. Rawal, A. Fabré, S. Iwasa Tetrahedron Letters 1995, 36, 6851

Furan-Carbonyl Variant of the Paterno-Büchi Reaction

OPhCHO

hν

O O

PhH

OH

OH

Ph

O

O O

PhH

wet celite

O

OH

Ph

O

0.01N HCl

THF

H25% Rh/ Al2O3

S. Toki, K. Shima, H. Sakurai Bull. Chem. Soc. Jpn. 1965, 38, 760K. Shima, H. Sakurai Bull. Chem. Soc. Jpn. 1966, 39, 1806S. Schreiber, A. Hoyveda, H. Wu J. Am. Chem. Soc. 1983, 105, 660

-this variant of the [2 + 2] offers a photochemical variant of the aldol reaction through transformations of the photoadduct

Furan-Carbonyl Variant of the Paterno-Büchi Reaction

O

hν

S. Schreiber, K. Satake J. Am. Chem. Soc. 1983, 105, 6723S. Schreiber, K. Satake J. Am. Chem. Soc. 1984, 106, 4186

O OO

OH

H

OH

O

asteltoxin

H

O

OBn

O OH

OBn

PhH, Et2O63%

establishes 2 sterocenters present inasteltoxin (architecture used to install

remaining stereocenters in next few steps)

Arene-Olefin Cycloadditions

-cycloadditions between arenes and an olefin •ortho cycloadditions-[2 + 2] •para cycloadditions-[4 + 2] •meta cycloadditions-[3 + 2]

R1 R2R1 R2hν R1 = OMe R2 = CN

R1 = CN R2 = OAcR1 = H R2 = CN

O

O

O

O

O

O

O

O

O

O

O

O

hν ∆

ORTHO CYCLOADDITIONS

Para Cycloadditions

hν•

CNCN

hν

R

Meta Cycloadditions

hν

H H H

H R

RR

R

hνBryce-Smith and Blair dispelledthe long standing myth that arenesare photochemically inert

In 1966, Wilzbach and Kaplan and Bryce-Smith, Gilber and Orger codiscovered the meta arene olefin cycloaddition

R

Meta Cycloadditions in Synthesis

MeO

H OMe H OMe

hν

1. Br22. R3SnH 59%

H

cedreneH

O

H2NNH2KOH

Wender pioneered the use of [3 + 2]

arene/olefin cyc loadditions in

synthesis

P. Wender, J. Howbert J. Am. Chem. Soc. 1981, 103, 688

vycorpentane

65%

200°C

Meta Cycloadditions in Synthesis

hν

H2Pd/C

P. Wender, G. Dreyer Tetrahedron 1981, 37, 4445

isocomene

∆

vycorcyclohexane

85-90%∆

toluene230-244°C

90%

hexane98%

Photoinduced Electron Transfer

Acceptor Donor A•- D•+hν

chemistry

polar solvents facilitate the generation of radical ions and subsequent chemical reactions

Witkop Cyclization

NH

HN

OCO2H

NH

HN

OCO2H

Cl

NH

HN

HOCO2H

Clhν -HCl

H2O40%after

esterification

O. Yonemitsu, P. Cerutti, B. Witkop J. Am. Chem. Soc. 1966, 88, 3941

Witkop Cyclization in Synthesis

A. Burgett, Q. Li, Q. Wei, P. Harran Angew. Chem. Int. Ed. 2003, 42, 4961

O NH

NH

N

O

NO

HN

O

HN

O

HO

Cl

Cl

diazonamide A

O NH

NH

N

O

NO

HN

OTeocHN

OAcBr

O NH

NH

N

O

NO

HN

OTeocHN

OH

hν (300nm)

CH3CN/aq. LiOH

72%

NHBr

NH

N

O

O

Li+

steps

(32-40% in initialsynthesis of the

nominal diazonamides)

Additional Photochemical Reactions

-Norrish Type I and II (α-cleavage of carbonyl and H-abstraction and fragmentation)-nitrogen extrusion (generate carbenes such as the Wolff rearrangment or to give diradical)-sigmatropic rearrangements such as (1,3), (1,5), and (1,7)-1O reactions-deprotections (such as cleavage of nitroarenes)-many other PET reactions •isomerizations •rearrangements •fragmentations •arene substitutions and reductions •photooxygenations •and many more reactions

Problem 1 (Were you paying attention to the last slide?)

R. Danheiser, A. Helgason J. Am. Chem. Soc. 1994, 116, 9471

Br

N2 O

Br

ON2

OTIPShν

vycorClCH2CH2Cl

rt then80°C

60-71%

OTIPSHO

Br

either substrate can be usedto generate the product and

both give essentially the sameyield of tricycle

reaction sequence usedin Danheiser's synthesis

of salvilenone

Problem 1 Solution

R. Danheiser, A. Helgason J. Am. Chem. Soc. 1994, 116, 9471

Br

N2 OBr

ON2

OTIPShν

vycorClCH2CH2Cl

rt then80°C

60-71%

OTIPSHO

Br

BrO

Br

O

O

•Br Br

O OTIPS

OTIPS

BrO •

-N2 -N2

Wolff rearr.

[2 + 2]4π

electro.

6π electro.(tautomer.)

Problem 2

Y. Kwak, J. Winkler J. Am. Chem. Soc. 2001, 123, 7429

O

NBoc

NBoc

O

1. hν, 87%2. EtOH, reflux3. cat. PPTS EtOH 87% 2 steps

Problem 2 Solution

Y. Kwak, J. Winkler J. Am. Chem. Soc. 2001, 123, 7429

O

NBoc

NBoc

O

1. hν, 87%2. EtOH, reflux3. cat. PPTS EtOH 87% 2 steps

hν

NBocO

BocN

OEtOH, reflux

cat. PPTS EtOH

retro-Mannich

Mannich