Photochemistry and Applications in Synthesis

Photochemistry and 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 E = hν = hc/ λ

short λ light corresponds to high energy

-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 S1 have a shorter lifetime T1 have a longer lifetime and higher E (10-9 to 10-5) b/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 hν R

R R

-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 : 8/92 w sensitizer photostationary state: E / Z :50/50 Geometrical Isomerism

hν

2-C10H7COMe 5% 95%

Ph hν Ph

toluene

hν Ar Ar Ar

Ar

O hν, quartz ∆

EtOH 6π-elec. O O λ>180nm -pyran β-ionone α

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

O hν O hν

O O

O O O H H hν, uranium DCM, -75°C 77% H H H H H H λ>340nm 10:1

O O O H H hν, pyrex O O O cyclohexane 70% H 5:1 H λ>285nm H H

H. Dorr, V. Rawal J. Am. Chem. Soc. 1999, 121, 10229 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 Photochemical Reactions -occur via HOMO -occur via LUMO 4n - conrotatory 4n - disrotatory 4n + 2 - disrotatory 4n + 2 - conrotatory 4π-Electrocyclizations

hν H H

hν 4π-electrocyclizations occur with disrotatory 254nm ring closure under 95% photochemical hν conditions O O 59% H O hν H hν Fe O O Fe(CO)5 OC CO O CO 8and6π-Electrocyclizations

8π-electrocyclizations occur with disrotatory hν ring closure under photochemical conditions and 6π-systems undergo hν conrotatory ring closure C9H17

C9H17 C9H17 hν H >20°C

6π 1,7 H-shift H HO HO Ergosterol Precalciferol (provitamin D) (previtamin D) HO Vitamin D2 (calciferol) 6π-Electrocyclization in Synthesis

H O N H H H O N H

H H H OH O Ikarugamycin

Wittig Reaction

H 1. hν, -78°C, hex. H H 2. HCl O OH OH 50% H H O H H OH OH H H 4:1 H

J. Whitesell and M. Minton J. Am. Chem. Soc. 1987, 109,6403 retro-6π-Electrocyclization

H2 hν Raney Ni

MeOH H MeOH O O O -18°C -15°C O 1:1 O O dihydrocostunolide

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

hν

hν 61%

barrelene semibullvalene

O O hν 66% Oxa-di-π-methane rearrangement

R R R 2 R R2 R3 2 3 R3 2 O O R3 R1 hν O R O R 5 R1 R1 R 1 R 5 R4 R5 R4 5 R4 R4

hν

O pyrex t-BuOH O 50%

O hν acetone 70% O Di-π-methane rearrangement in Natural Products

OAc OAc

O H H OH hν OH O Cl Cl AcO quartz AcO O AcO O PhH AcO 87% conv O in 3 hr O

erythrolide B or erythrolide A 5% methanolic seawater (glass) with sunlight 37% conv in 8 days

S. Look, W. Fenical, D. Van Engen, J. Clardy J. Am. Chem. Soc. 1984, 106, 5026. Oxa-di-π-methane vs. 1,3-Acyl Migration

O O O hν hν

254nm 300nm acetone O hexane 62% 50%

O X steps OMe hν

pyrex O THF MeO 59% O X = O pinguisone X = H2 deoxypinguisone

T. Uyehara, Y. Kabasawa, T. Kato Bull.Chem.Soc.Jpn. 1986, 59, 2521 1,3-Acyl Migration in Natural Products

O O

O

hν calyculone D back 8.8% calyculone F up 10.6% calyculone E 6.2% calyculone G 15.9% quartz PhH 3h O O

cembratriene 10.6% cembratriene 11.5%

J. Shin, W. Fenical J. Org. Chem. 1991, 56, 1227 [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 hν O

carvone carvone camphor

-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 O -this [2 + 2] follows the "rule of 5" and none of the other regioisomer is observed not observed "Rule of 5"

O O O H hν not observed 70% O O O O

O

hν

O O O [2 + 2] Cycloaddition in Synthesis

O O O H hν • H H H H H Et2O 72% H 2:1 H

O O

O O O O O O O O H H hν steps O periplanone B 0°C O O O O O CH3CN/ O acetone O O O O O (9:1) O O 80% saudin

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

O O O CO2Me CO2Me hν retro-aldol

[2 + 2] CO2Me OH OH O

-[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

O* O hν O O

T1

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

OH hν HI

acetone O AcOH AcO 42% 82% O AcO AcO

vitamin D3 analogs: M. Mihailovic, L. Lorenc, V. Pauolvic, J. Kalvoda Tetrahedron 1977, 33, 441 Paterno-Büchi Reaction in Synthesis

1. i-Pr2NMgI, ∆ hν 2. PDC, DMF corex 65% λ>250nm PhH O O O 90% obtained via Diels-Alder LDBB THF -78°C 66%

H H H H NaBH4 O TFA

DCM, CH3CN H 69% H endo-hirsutene

V. Rawal, A. Fabré, S. Iwasa Tetrahedron Letters 1995, 36,6851 Furan-Carbonyl Variant of the Paterno-Büchi Reaction

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

OH H H Ph 2 H Ph 0.01N HCl 5% Rh/ Al2O3 Ph O O O THF O O O

wet celite S. Toki, K. Shima, H. Sakurai Bull. Chem. Soc. Jpn. 1965, 38, 760 OH K. Shima, H. Sakurai Bull. Chem. Soc. Jpn. 1966, 39, 1806 S. Schreiber, A. Hoyveda, H. Wu J. Am. Chem. Soc. 1983, 105, 660 Ph OH O Furan-Carbonyl Variant of the Paterno-Büchi Reaction

OBn H OBn hν

O PhH, Et2O O O O 63% H

establishes 2 sterocenters present in OH OH asteltoxin (architecture used to install remaining stereocenters in next few steps)

O O O H O

asteltoxin

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

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

ORTHO CYCLOADDITIONS

R1 R1 R2 R = OMe R = CN R2 hν 1 2 R1 = CN R2 = OAc R1 = H R2 = CN

O

O O O hν ∆ O O O O

O O O

O Para Cycloadditions

hν •

CN CN hν Meta Cycloadditions

Bryce-Smith and Blair dispelled hν the long standing myth that arenes are photochemically inert

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

H H H R hν R R H R

R R Meta Cycloadditions in Synthesis

MeO

hν vycor pentane H OMe H OMe 65% Wender pioneered 1. Br the use of [3 + 2] 2 arene/olefin 2. R3SnH cyc loadditions in 59% synthesis

H2NNH2 KOH O 200°C H H cedrene

P. Wender, J. Howbert J. Am. Chem. Soc. 1981, 103,688 Meta Cycloadditions in Synthesis

∆

hν vycor cyclohexane 85-90% ∆ toluene 230-244°C 90%

H2 Pd/C

hexane 98% isocomene

P. Wender, G. Dreyer Tetrahedron 1981, 37,4445 Photoinduced Electron Transfer

hν Acceptor Donor A•- D•+ chemistry

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

Witkop Cyclization

O H O H N CO2H HO H N CO2H N CO2H Cl hν Cl -HCl

H2O 40% N N H after N H esterification H

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

H H N N TeocHN TeocHN O O N N O N O N hν (300nm)

O O CH3CN/ NH aq. LiOH O N NH O N Br 72% H H OAc OH steps N H N H O N HO O (32-40% in initial N O O N Li+ NH synthesis of the Cl nominal O diazonamides) Cl O O N NH Br H NH diazonamide A

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

N 2 O Br OTIPS hν vycor HO OTIPS ClCH2CH2Cl Br rt then O 80°C N2 Br 60-71%

reaction sequence used in Danheiser's synthesis of salvilenone either substrate can be used to generate the product and both give essentially the same yield of tricycle

R. Danheiser, A. Helgason J. Am. Chem. Soc. 1994, 116,9471 Problem 1 Solution

O N2 N2 O Br Br OTIPS hν vycor HO OTIPS ClCH2CH2Cl -N2 -N Br 2 rt then O 80°C O 60-71% Br Br

6π electro. (tautomer.)

Wolff rearr. O OTIPS • 4π • [2 + 2] O OTIPS electro. O Br Br Br

R. Danheiser, A. Helgason J. Am. Chem. Soc. 1994, 116,9471 Problem 2

1. hν, 87% 2. EtOH, reflux 3. cat. PPTS O EtOH 87% 2 steps NBoc N Boc O

Y. Kwak, J. Winkler J. Am. Chem. Soc. 2001, 123, 7429 Problem 2 Solution

1. hν, 87% 2. EtOH, reflux 3. cat. PPTS O EtOH 87% 2 steps NBoc N Boc O

cat. PPTS hν EtOH Mannich

O EtOH, reflux O NBoc retro-Mannich BocN

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