The Current State of Synthetic Organic Photochemistry

Frontiers in Chemistry Series

Stephen Lynch

1/24/04

Steve Lynch @ Wipf Group 1 1/25/2004 The Current State of Synthetic Organic Photochemistry

► Introduction to Photochemistry

► Some Historical Aspects

► Recent Applications of Photochemistry in Organic Synthesis - Isomerizations - Cycloadditions - Rearrangements - Cyclizations

► New Directions in Organic Photochemistry - Photoactivated Scavengers - Photolabile Protecting Groups - Photochirogenesis

► Summary

Steve Lynch @ Wipf Group 2 1/25/2004 Overview of Photochemistry

• Molecules absorb radiation which results in excited electronic states. → usually C=C and C=O • Chemically useful light is generally in the range of 200-400 nm. • Often employ filters to regulate the wavelength of the radiation.

π∗ π∗ π∗ π∗ π∗

n n n n n π π π π π ground n→π* n→π* π→π* π→π* state singlet triplet singlet triplet

• Triplet state lower in energy than singlet state (due to Hund’s rule) Steve Lynch @ Wipf Group 3 1/25/2004 What is the Fate of an Excited Molecule?

vc IC S 2 vc IC ISC 80-75 S vc hν 1 ISC 75-80 ν T1 h f hν hν vc p ν

Energy h = light excitation

(kcal/mol) ν h f = fluorescence ν h p = phosphorescence vc = vibrational quenching IC = internal conversion ISC = intersystem crossing

S0 0 Jablonski Diagram Steve Lynch @ Wipf Group 4 1/25/2004 Physical Processes Undergone by Excited Molecules

ν v S0 + h → S1 Excitation v S1 → S1 + heat Vibrational Relaxation ν S1 → S0 + h Fluorescence

S1 → S0 + heat Internal Conversion v S1 → T1 Intersystem Crossing v T1 → T1 + heat Vibrational Relaxation ν T1 → S0 + h Phosphorescence

T1 → S0 + heat Intersystem Crossing

S1 + A(S0) → S0 + A(S1) Singlet-Singlet Transfer

T1 + A(S0) → S0 + A(T1) Triplet-Triplet Transfer

photosensitization

Steve Lynch @ Wipf Group 5 1/25/2004 Chemical Processes Undergone by Excited Molecules

1. (A-B-C) → A-B• + C• Simple Cleavage into Radicals 2. (A-B-C) → E + F Decomposition into Molecules 3. (A-B-C) → A-C-B Intramolecular Rearrangement 4. (A-B-C) → A-B-C’ Photoisomerization 5. (A-B-C) RH→ A-B-C-H + R• Hydrogen-atom Abstraction

6. (A-B-C) → (ABC)2 Photodimerization 7. (A-B-C) →A ABC + A* Photosensitization

O hν O Norrish Type I R' RR' R

HR' HR' OH O O R' R' Norrish Type II hν OH Yang R R R R cyclization

fragmentation

OH R'

Steve Lynch @ Wipf Group 6 R 1/25/2004 Some Common Photosensitizers

Me O O O

acetone p-xylene acetophenone acetonaphthone

O O

xanthone benzophenone triphenylene

A good sensitizer must: - absorb light entirely in order to avoid concurrent reactions - not undergo chemical alteration until reaction is complete - be easily eliminated from the reaction mixture upon completion

Steve Lynch @ Wipf Group Review: Albini, A. Synthesis7 1981 249. 1/25/2004 Woodward-Hoffman Rules and Orbital Symmetry

Number of π electrons Thermal Photochemical

2 disrotatory conrotatory 4 conrotatory disrotatory 6 disrotatory conrotatory 8 conrotatory disrotatory

∆ hν conrotatory disrotatory

ψ 2 is HOMO ψ3 is HOMO

Stereochemical outcome will be impacted!

Steve Lynch @ Wipf Group 8 1/25/2004 Why Use Photochemistry?

√ Overcome large kinetic barriers in a short amount of time √ Produce immense molecular complexity in a single step √ Form thermodynamically disfavored products √ Allows reactivity that would otherwise be inaccessible by almost any other synthetic method √ The reagent (light) is cheap, easily accessible, and renewable

Drawbacks?

X Reactivity is often unpredictable X Many substrates are not compatible X Selectivity and conversion are sometimes low

Steve Lynch @ Wipf Group 9 1/25/2004 Emergence of Photochemistry in Natural Product Synthesis

MeR R H Me H Me X Me H H H H HO HO H H

Provitamin D Lumisterol hν hν R Me H HOH

X H X

R Previtamin D Me H R ∆ Me H hν

H H

Me CH2 OH X H HO H

Tachysterol Vitamin D

Quinkert, G.; Eis, K. In Essays in Contemporary Chemistry; Quinkert, G.; Kisakurek, M. V., Eds.; Steve Lynch @ Wipf Group 10 1/25/2004 Wiley-VCH: Weinheim, 2001, pp 189-282. Recent Applications of Traditional Photochemical Methodology

■ [2+2] Cycloadditions ■ [4+2] Cycloadditions ■ Photoisomerizations ■ Photoenolizations ■ Photorearrangements ■ Electrocyclizations

Steve Lynch @ Wipf Group 11 1/25/2004 Highly Facial Selective Intramolecular [2+2] Photocyclization

O OMe 1. O O Cl hν

N 2. i-PrMgCl N acetone N + 3. H3O O O 75% 90% single diastereomer

O 1. PhSeCl O OH 2. H2O2 SmI2

3. H2, Pd/C N THF/DMPU N N O O

(±)-Plumerinine

Comins, D. L.; Zheng, X.; Goehring, R. R. Org. Lett. 2002, 4, 1611. Steve Lynch @ Wipf Group 12 1/25/2004 Highly Diastereoselective Intramolecular Photocycloaddition

CO2Me O OEt CO2Me OOH 4 steps OTMS EtO O ZnCl2, Et2O O CuBr•SMe2 O O 83%

O O CO2Me CO2Me H O hν R R O H H O O vs. O 95% O O H O H O O

single diastereomer ∆∆G = 1.5 kcal/mol

O O CO Me O CO2Me 2 CO2Me hν H H 97% O O O

O O O 83 : 17

Steve Lynch @Crimmins, Wipf Group M. T.; Wang, Z.; McKerlie, L. A.13 J. Am. Chem. Soc. 1998, 120, 1747. 1/25/2004 Elaboration of the Photocycloadduct

O CO2Me O O CO2Me CO2Me p-TsOH (imid) C=S 2 Bu SnH, AIBN H S 3 THF H H DMAP C H , 80°C O OH O N N 6 6

O OH 87% OH 92%

O O CO Me O CO Me 2 2 O CO2Me H CO2Me

OH OH OH HO 3:2 (β:α) Dowd-Beckwith Rearrangement

(±)-Lubiminol

Steve Lynch @Crimmins, Wipf Group M. T.; Wang, Z.; McKerlie, L. A.14 J. Am. Chem. Soc. 1998, 120, 1747. 1/25/2004 Photocycloaddition/Fragmentation Sequence

Cl O O 1. SeO , TBHP O 1. LDA, MeO2CCN O 2 O hν 2. PMB-OH 2. triphosgene CH3CN, 0°C H 3. TFAA/TFA/Ac2O PPh H 3 H Me2CO 60% 80% (3 steps) 66% (2 steps)

Cl Cl Cl H H H O K2CO3 retro- O O O OMe OMe MeOH aldol H O H O H O 5:2 (β:α) De Mayo Reaction H

O Cl 30 steps O H H H

H HOHO OH CO2Me HO (±)-Ingenol

SteveWinkler, Lynch J. D.;@ WipfRouse, Group M. B.; Greaney, M. F.; Harrison,15 S. J.; Jeon, Y. T. J. Am. Chem. Soc. 2002, 1241/25/2004, 9726. Paterno-Büchi Type Photocycloaddition/Fragmentation

Me Me 1. O Me Me 3 Me Me 2. base Me 10% Eu(FOD)3 Me 77% O toluene, 80°C OMe 84%

Me Me Me hν LiDBB Me Me Me

Corex filter -78°C to 10°C 19h O Me OH OH 57% Me Me 79% radical fragmentation

HO Me O Me PDC Me Me H 84% H Me Me Me Me (±)-5-Oxosilphiperfol-6-ene

Steve Lynch @ Wipf Group Reddy, T. J.; Rawal, V. H.16 Org. Lett. 2000, 2, 2711. 1/25/2004 Photoisomerization Diels-Alder Reactions

O O H 140°C

xylenes, 24 h H 45%

O O O O H H H hν uranium filter H H H 25°C, 30 min H H H H H H 88% 3 : 2 : 1 O O O O H H H hν uranium filter H H H -75°C, 3 h H H H H H H 77% 10 : -- : 1

O O

Additional Substrates: O

Steve Lynch @ Wipf GroupDorr, H.; Rawal, V. H. J. Am. Chem.17 Soc. 1999, 121, 10229. 1/25/2004 Application of Photoenolization Diels-Alder Reaction

OH O hν

Me OH OH O R [4+2] hν R Ox R fast R' R' R' orthoquinodimethane tetralones R = electron withdrawing group

O OH OH OH O OH H R hν [4+2] R Br R CO2Me fast Me Me H

(±)-Hamigeran A

Nicolaou, K. C.; Gray, D. L. F.; Tae, J. J. Am. Chem. Soc. 2004, 126, 613. Steve Lynch @ Wipf Group 18 1/25/2004 Application of Photoenolization Diels-Alder Reaction

OMe O OMe OOMeOTBS NHtBu t-BuLi O 1. LAH Me O 2. TBSCl Me Me 89% then p-TsOH, C6H6 HO 91%

OMe OTBS OMe OTBS Pd(OAc)2 MOMCl O Cu(OAc)2 (MeO)2P CH2CO2Me DMA/H O, O O Me 2 2 Me NaH 83% MOMO 81% MOMO 94%

OMe OTBS OMe O CO2Me 1. HF•py CO2Me Me 2. SO •py 3 Me MOMO MOMO 84% (2 steps) E/Z = 3.5:1

Nicolaou, K. C.; Gray, D. L. F.; Tae, J. J. Am. Chem. Soc. 2004, 126, 613. Steve Lynch @ Wipf Group 19 1/25/2004 Application of Photoenolization Diels-Alder Reaction

OMe O OMe OH OMe CO Me CO2Me 2 hν, Pyrex 1% HCl/MeOH CO2Me Me Me Me 25 min Me Me H H MOMO 85% (2 steps) MOMO HO

OMe OH CO2Me H

Me upon irradiation the Me OH O olefin readily undergoes OH MOMO E/Z isomerization Br CO2Me Me observed product arises Me bulky MOM ether also from endo cycloaddition H contributes to good selectivity of the E olefin

avoids unfavorable interaction with methyl group (±)-Hamigeran A

Nicolaou, K. C.; Gray, D. L. F.; Tae, J. J. Am. Chem. Soc. 2004, 126, 613. Steve Lynch @ Wipf Group 20 1/25/2004 Photochemical Isomerization/Diels-Alder Cycloaddition Applied to Biomimetic Synthesis

CHO CO Et CO Et 2 toluene 2 1. DIBAL-H CHO O N PPh3 reflux 2 O N 2. Swern Ox. 2 O2N 95% 94%

CHO CO Et repeat sequence PPh3CHCO2Et 2

2 times toluene, reflux O2N O2N 25% (6 steps) 98% very strained due to steric interactions between the methyl substituents

Moses, J. E.; Baldwin, J. E.; Marquez, R.; Adlington, R. M.; Claridge, T. D. W.; Odell, B. Org. Lett. 2003, 5, 661. Steve Lynch @ Wipf Group 21 1/25/2004 Photochemical Isomerization/Diels-Alder Cycloaddition Applied to Biomimetic Synthesis

Me Me CO2Et 600W CO2Et Me Me Me tungsten bulb Me O2N H H OMe E, E, E, E 60% O2N Me MeO O Me hν O H H Me Me Me Me Me

Crispatene

NO 2 Me Me Me hν

CO2Et CO2Et

Me Me Me NO2

Z, E, E, E Z, Z, E, E

Moses, J. E.; Baldwin, J. E.; Marquez, R.; Adlington, R. M.; Claridge, T. D. W.; Odell, B. Org. Lett. 2003, 5, 661. Steve Lynch @ Wipf Group 22 1/25/2004 Photochemistry Completes First Asymmetric Total Synthesis of (+)-Sparteine

O OH O HO LDA O 1. MsCl O O TsOH O HO O 2. DBU O O enantiomerically H pure OBn 64% (4 steps) OBn

O O O O 1. H2, Pd/C, Pd(OH)2 N3 H O TiCl4 N OBn O 2. Zn(N ) •2pyr, DEAD, PPh 3 2 3 O H O 78% 62%

Smith, B. T.; Wendt, J. A.; Aubé, J. Org. Lett. 2002, 4, 2577. Steve Lynch @ Wipf Group 23 1/25/2004 Photochemistry as a Key Step in (+)-Sparteine Total Synthesis

O 1. Lawesson's N reagent 1. LDA, I(CH2)4Cl N N Schmidt does H O 2. Raney Ni H O 2. NaI, acetone H O not work! N3 3. NaN3 76% (5 steps)

OBoc N HN Boc N TFA, 4Å MS N H O K CO H 2 3 O then NaHCO3 H N I N OBoc 95% O Boc 74%

hν N LAH N N H N benzene O N H N O H 76% 95% (+)-Sparteine photo-Beckmann rearrangement

Steve Lynch @ Wipf GroupSmith, B. T.; Wendt, J. A.; Aubé,24 J. Org. Lett. 2002, 4, 2577. 1/25/2004 Photochemically Induced Ring Expansion

O O OLi H O Nt-Bu t-BuLi Nt-Bu -78°C NH4Cl Nt-Bu HMPA, -78°C Nt-Bu Ph Li Ph 16 h H Ph H 80% Ph

hν

72% O

NHt-Bu

CONHt-Bu CONHt-Bu Ph R R Ph or O Ph 1. t-BuLi H Nt-Bu HMPA, -78°C R 2. hν Ph 3. NH4Cl CONHt-Bu CONHt-Bu or HCl R R H or product isolated depends on H Ph substrate and reaction conditions Ph 24 - 80 % yield

Steve Lynch Clayden,@ Wipf Group J.; Knowles, F. E.; Menet, C. J. J.25 Am. Chem. Soc. 2003, 125, 9278. 1/25/2004 Photochemically Induced Ring Expansion

suprafacial & retentive

O OLi hν CONHt-Bu CONHt-Bu Nt-Bu [1,3] 6e- R R R Nt-Bu R Ph Ph Ph H Ph H

h hν ν invertive suprafacial migration [1,7] X [1,5]

CONHt-Bu - CONHt-Bu R 6e R H H Ph Ph disrotatory opening

O O 1. t-BuLi N HMPA, -78°C N Stereospecificity persists H 99% ee through deprotonation, cyclization, Ph 2. hν and rearrangement! 3. NH4Cl Ph

80%

Steve Lynch @Clayden, Wipf Group J.; Knowles, F. E.; Menet, C. J.26 J. Am. Chem. Soc. 2003, 125, 9278. 1/25/2004 New Directions in Organic Photochemical Methodology

■ Photoactivated Reagent Scavengers ■ Photolabile Protecting Groups ■ Photoreleasable “Caged” Molecules ■ Photochirogenesis (Asymmetric Photochemistry)

Steve Lynch @ Wipf Group 27 1/25/2004 Photoactivated Reagent Scavangers (Precipitons)

O C O N NH2 THF/Et2O N N NH H H 2

1.1 - 1.2 equiv 1.0 equiv excess

O C N insoluble: precipitates from solution! hν

350 nm, 15 min

NH NH NH O O NH O O N N N N H H H H 95% yield >95% pure Steve Lynch @ Wipf Group 28 1/25/2004 Bosanac, T.; Wilcox, C. S. J. Am. Chem. Soc. 2002, 124, 4194. Photolabile Protecting Groups

NO2 NO hν HO X OX CHO O O

X = NR1R2, R, OR NO2 O OH N OH O N OX O 350nm O O O MeO NO2 X Norrish Type II OH MeO 320nm O OH N N OH O OX OX

O O

Steve Lynch @ WipfReview: Group Bochet, C. G. J. Chem. Soc.,29 Perkin Trans. 1, 2002, 125. 1/25/2004 Photochemical Release of “Caged” Molecules

Inositol Triphosphate (InsP3)

plasma membrane OMe OMe O O O O O (PMO)2 P O - O (PMO) P O O P (OPM) ( O)2 P O 2 2 (-O) P O O P (O-) O O O 2 2 diffusion esterases O O O NO2 NO2 MeO cmIP3/PM MeO cmIP3 OMe OMe

PM = O hν O 350 nm

OMe

O O 2+ - O regulation of Ca levels ( O)2 P O - - and gene expression ( O)2 P O O P (O )2 O HO O

mIP3 Steve Lynch @ Wipf Group 30 1/25/2004 Li, W.-H.; Liopis, J.; Whitney, M.; Zlokarnik, G.; Tsien, R. Y. Nature, 1998, 392, 936. Photochemical Release of “Caged” Molecules

R' OH R O OH HO O O HO hν Br RR' Br 365 nm Br O HO OO PPTS, MgSO4 HO OO pH 7.2 KMOPS HO OO RR' toluene buffer Bhc-diol

Lu, M.; Fedoryak, O. D.; Moister, B. R.; Dore, T. M. Org. Lett. 2003, 5, 2119.

hν 370 nm O O OH HO N pH 7.2 KMOPS HO N HO Br O buffer Br

BHQ-OAc

Fedoryak, O. D.; Dore, T. M. Org. Lett. 2002, 4, 3419.

Steve Lynch @ Wipf Group 31 1/25/2004 Attempts at Asymmetric Photochemistry

• Stoichiometric chirality transfer from pre-existing stereocenters present in the substrate

• Use of chiral auxiliaries

• Solid state photochemical transformations in clays and chirally modified zeolites

• Chiral solvents, liquid crystalline phases and polymer matrices

• Chiral molecular receptors

• Circularly polarized light

• Chiral photosensitizers

Review: Inoue, Y.; Wada, T.; Asaoka, S.; Sato, H.; Pete, J.-P. J. Chem. Soc., Chem. Commun. 2000, 251. Steve Lynch @ Wipf Group 32 1/25/2004 Chiral Auxiliary

H O NH HO2CCO2H CO2H CO2H SOCl 2 O O NH O OHC Kemp's triacid

O O O H O N O N hν H H

N O O toluene, -10°C H O NH O O O O NH O O 56% NH O

95 : 5

Steve Lynch @ WipfBach, Group T.; Bergmann, H.; Harms, K. J.33 Am. Chem. Soc. 1999, 121, 10650. 1/25/2004 Chiral Molecular Receptors (Host-Guest Systems)

O O B (2.6 eq) H hν O N H 93% ee NH N O -60°C, toluene H N O O H 77%

H O B (2.6 eq) hν O H >90% ee -60°C, toluene N O N O H H 87%

Bach, T.; Bergmann, H.; Grosch, B.; Harms, K. J. Am. Chem. Soc. 2002, 124, 7982. Steve Lynch @ Wipf Group 34 1/25/2004 Chiral Molecular Receptors (Host-Guest Systems)

OMe HO H A (2.6 eq) MeO OH hν H 81% ee N O toluene, -60°C H N O 80% H H O O N N

OMe AcO H A (2.6 eq) MeO OAc hν A H 92% ee N O toluene, -60°C H N O 80% H

Bach, T.; Bergmann, H.; Grosch, B.; Harms, K. J. Am. Chem. Soc. 2002, 124, 7982.

OH B (1.2 eq) CO Me O 2 CO Me 2 hν O NH N toluene, -60°C 94% ee HN HN O 73% O O B

Grosch, B.; Orlebar, C. N.; Herdtweck, E.; Masa, W.; Bach, T. Angew. Chem. Int. Ed. 2003, 42, 3693. Steve Lynch @ Wipf Group 35 1/25/2004 Solid State or Crystalline Reactions Can Induce Asymmetry

100% transfer of ee

Ellison, M. E.; Ng, D.; Dang, H.; Garcia-Garibay, M. A. Org. Lett. 2003, 5, 2531.

O OMe

'In' O OMe hν 50% ee (-)-norephedrine NaY, -20°C 'Out' O OMe

Steve Lynch @ Wipf Group 36 1/25/2004 Joy, A.; Scheffer, J. R.; Corbin, D. R.; Ramamurthy, V. J. Chem. Soc. Chem. Commun. 1998, 1379. Sensitization by Chiral Aromatic Esters

Ph Ph O (S,S) O hν / Sens* Ph Ph 77% ee -80°C, hexane -70°C Ph 1Z (R)-1E (S)-1E O (R,R)

*RO2C CO2R*

*RO2C CO2R* Ph Sensitizer* (-)-bornyl (-)-menthyl (-)-8-phenylmenthyl

Steve Lynch @ Wipf GroupHoffmann, R.; Inoue, Y. J. Am. Chem.37 Soc. 1999, 121, 10702. 1/25/2004 Designing a Catalytic Asymmetric Sensitizing Receptor

Requirements for such an endeavor:

1. The substrate must be placed in a well-defined chiral micro- environment upon binding to a template

- Host-guest system where hydrogen bonding dictates orientation in predictable fashion

2. Substrate-template binding confers a kinetic advantage to the transformation of interest

- Sensitizer which contains a highly localized sphere of energy transfer (exciplex)

If the lifetime of the exciplex is comparable to the rate of desired reaction, the exciplex formation can be enantiodiscriminating!

Steve Lynch @ WipfCauble, Group D. F.; Lynch, V.; Krische, M. 38J. J. Org. Chem. 2003, 68, 15. 1/25/2004 Designing a Catalytic Asymmetric Sensitizing Receptor

O O O HN hν, Sens* HN NH 100 mol%; 22% ee O -70°C, 70 h 25 mol%; 19% ee O O

100%

Steve Lynch @ WipfCauble, Group D. F.; Lynch, V.; Krische, M.39 J. J. Org. Chem. 2003, 68, 15. 1/25/2004 Summary

► Traditional photochemistry will continue to occupy a unique niche in the realm of organic synthesis.

- New and creative applications of established reactions will continue to solve important synthetic problems

- Photochemistry allows access to reactive intermediates that would prove difficult to achieve by almost any other synthetic method.

► The field of photochirogenesis will continue to be developed with hopes of unlocking its full potential, especially in applications toward total synthesis.

► New directions in organic photochemistry will likely focus on more contemporary biological and analytical applications.

Steve Lynch @ Wipf Group 40 1/25/2004