Photochemical Reactions as a Key Step in Natural Product Synthesis.

Photochemical Reactions as a Key Step in Natural Product Synthesis.

Presented by: Augusto César Hernandez-Perez

Literature Presentation March 21th 2011

About Me.

Guatemala: Country of Mayan civilisation

San Mateo Ixtatan

2

About Me.

Pointe-Aux-Trembles

UdM

I’m not

Mexican

3

Outline.

• Photocyclizations

•Photochemical Rearrangement

Introduction

4

UV-mediated reactions

• History

• Basics in photochemistry

• Equipment

Introduction.

• Photochemical reactions have been known for almost as long as chemistry

Arnold, D.R.; Baird, N.C.; Bolton, J.R.; Brand, J.C.D.; Jacobs, P.W.M.; de Mayo, P.; Ware, W.R. Photochemistry An Introduction, Academic Press Inc., New York, 1974 5

Brief history

• Most observations remained uninterpreted until the 19th century

•Important work done in Italy by Ciamician, Silber and Paterno

• After World War I, it became the province of the physical chemistry for 35 years

• In the 50’s: general interest in photochemistry by the organic chemist due in part by natural product synthesis

• In the 60’s: emergence of mechanistic organic photochemistry and merging of the organic and physical viewpoints.

Introduction.

Basic laws

• Activation of reaction is provided by the absorption of a photon

E = h

6

E = hc /

E = 1,197×105 kJmol-1/

= c / Energy conversion table

/ nm kJmol-1

200 598

250 479

300 399

350 342

400 299

500 239

600 200

700 171

h: Planck’s constant = 6.627×1034 Js

: frequency (s-1)

c: speed of light = 2,998 ×108 ms-1

N: Avagadro’s number = 6,023 ×1023 mol-1

Arnold, D.R.; Baird, N.C.; Bolton, J.R.; Brand, J.C.D.; Jacobs, P.W.M.; de Mayo, P.; Ware, W.R. Photochemistry An Introduction, Academic Press Inc., New York, 1974

E = Nh = Nhc /

Introduction.

Orbital types

•n orbitals:

7

C O

n

• and * orbitals:

C O

C O

• and * orbitals:

C C

C C


Non-bonding Overlap of p orbitals Not involve in most reaction

Introduction.

Electronic transition

•Photochemical excitation: Involves the transfer of a electron from a lower orbital to a higher one

8Arnold, D.R.; Baird, N.C.; Bolton, J.R.; Brand, J.C.D.; Jacobs, P.W.M.; de Mayo, P.; Ware, W.R. Photochemistry An Introduction, Academic Press Inc., New York, 1974

E

antibonding

bonding

*

*

n

Introduction.

Photochemical reaction

• Photochemically excited molecule:Non-radiative (deactivation) processes between statesRadiative processes between statesIntermolecular energy transferChemical reaction

9

A + h A*

A + h’ (emission)

A + heat (radiationless decay)

C* (change excited state)

B* + A (energy transfer) (i.e.: sensititzer)

chemical reaction

B


10

Introduction.

Jablonski Diagram

E: Energy

A: Photon absorption

F: Fluorescence (R)

P: Phosphorescence (R)

S: Singlet state

T: Triplet state

IC: Internal conversion (N-R)

ISC: Intersystem crossing (N-R)

Electronic ground state

S2

S1

Sn

ICISC

T1

S0

E

PFA

Introduction.

•Multiplicity: Singlet VS Triplet •Sum of the angular quantum number S in (2S+1)•Each electron has a value of 1/2Paired spin: ½ - ½ =0 S = 0, multiplicty is 1 (singlet)Unpaired spin: ½ + ½ =1 S = 1, multiplicity is 3 (triplet)

Antiparrallel SpinPaired Spin

S1

Parrallel SpinUnpaired Spin

T1

HOMO

LUMO


Electronic transition

h ISC

11

Equipment.

Light sources

• Sun:FreeNot practicalExample: 30 days in Cairo sunlight

12

•Mercury lamp:Most popularVersatile

• Laser:Monochromatic, coherentPossibility of extremely high light intensitiesSurface area lowUse to solve special problems

Horspool, W.h Aspect of organic photochemistry, Acedemic Press Inc., New York, 1976

Equipment.

Hg lamps

• Low pressure lamp: 4,010-6 atm 90% at 254nm intensity per area is low

13

• Medium pressure lamp: 4,610-2 atm broader spectral distribution (265nm, 310nm, 635nm) high temperature

• High pressure lamp: 100 atm Emission below 280nm is very weak high temperature

Spectral emission form Hg arc lamps


Equipment.

• For greater degree of selectivity Use of cut-off filters (glass or solution)

14

Filter and glassware

• Choice of lamp: Irradiation between 250 nm – 450 nm

of cut-off / nm Chemical compositionBelow 250 Na2WO4

Below 305 SnCl2 in HCl (0,1M)

Below 330 Na3VO4 (2M)

Below 355 BiCl3 in HCl

Above 450 CoSO4 + CuSO4


Equipment.

• Limited application for large-scale reaction occurs within a short radius of the lamp

Efficiency is scale dependant

15

Setup

Immersion well batch photochemical reactor:

• Others solutions Use various lamps

Concentrated reaction mixture

Hook, B.D.A.; Dohle, W.; Hirst, P.R.; Pickworth, M.; Berry, M.B.; Booker-Milburn, K.I. J. Org. Chem. 2005, 70, 7558-7564

Equipment.

16

Reactor

•Single pass continuous flow reactor: Use of traditional water-cooled immersion well FEP: Fluorinated ethylenepropyleneSolvent resistantPolymeric materialExcellent UV-transmission properties

Hook, B.D.A.; Dohle, W.; Hirst, P.R.; Pickworth, M.; Berry, M.B.; Booker-Milburn, K.I. J. Org. Chem. 2005, 70, 7558-7564

Equipment.

17

Micro-Reactor

• Adopted for photochemical application:

Mikroglas chemtech GmbH, Galileo-Galilei-Str. 28 55129 Mainz, Germany http://www.mikroglas.de

•Serpentine reactor: long path length (1,15m = 20 turns)Heat-exchanging channel on topReagents pre-mixed or not

Introduction.

Natural product synthesis

• UV light: High energy absorption of light facilitates reaction pathways that cannot be accessed by conventional methods

• Access to various natural products

O

O

OMe

O

HOO

HOO

OHN

OH

OH

OHH

H

HHO2C

OHO

OOO

6

18

UV mediated-reactions• Photocyclizations

6 Photocyclization of trienes

19

6 Photocyclization of Stilbenes

6 Photocyclization of enamide

4 Photocyclization of pyridinum salts

• Photochemical Rearrangement

• Photocyclizations: light-induced pericylic ring closing reactions•6 Photocyclizations Photocyclization of TrienesPhotocyclization of Enamides• 4 Photocyclizations

Photocyclization.

A: Carbocycles

B: Heterocyclic productsX

NR

O

A B C

C: X = NR: pyrrolines, dihydroindoles, hexahydrocarbazoles X=O: vinyl aryl ether

Electrons Photochemical Thermic

4n Disrotatory Conrotatory

4n+2 Conrotatory Disrotatory

20Arnold, D.R.; Baird, N.C.; Bolton, J.R.; Brand, J.C.D.; Jacobs, P.W.M.; de Mayo, P.; Ware, W.R. Photochemistry An Introduction, Academic Press Inc., New York, 1974

• Photocyclization of Trienes:

Photocyclization.

Gavagnin, M.; Mollo, E.; Cimino, G.; Ortea, J. Tetrahedron Lett. 1996, 37, 4259-4262 Sharma, P.; Griffiths, N.; Moses, J. E. Org. Lett. 2008, 10, 4025-4027. Sharma, P.; Griffiths, N.; Moses, J. E. Synlett. 2010, 525 – 528 21

O

O

OMe

Tridachiahydropyrone (1), marine-derived natural product isolated in 1996Original structure assigned to 1Unsual fused bicyclic pyrone-contaning ring system

1

O

O

OMe O

O

OMe

Con6h

Dis6

O

O

OMe

Proposed Biosynthetic Origin of 1


Photocyclization.

22

O

O

OMe

h (sunlight)MeOH, 60h, r.t.

29%

O

O

OMe

H O

O

OMe

HH

OOMe

O

150Cxylene

0%

O

O

OMe O

O

OMe

No trans diastereoisomer formed


Photocyclization.

Eade, S. J. ; Walter, M.W.; Byrne, C.; Odell, B.; Rodriguez, R.; Baldwin, J. E.; Adlington, R. M.; Moses, J. E. J. Org. Chem. 2008, 73, 4830-4839.Frstner, A.; Domostoj, M.M.; Scheiper, B. J. Am. Chem. Soc. 2006, 128, 8087 – 8094.Ishikura, M .; Hino, A.; Yaginuma, T.; Agata, I.; Katagiri, N., Tetrahedron 2000, 56, 193 – 207. 23

•Others examples:

Photodeoxytridachione Dictyodendrins B

O

O

OMe

H

N

NHO

HO

OH

OH

SO3Na

HO

HO

N

NH

Ellipticine

•Oxidation of intermediate cyclohexadiene: O2 in air, I2, (PhSe)2

• Photocyclization of Stilbenes:

Photocyclization.

24

• Effective route to phenanthrene.• E/Z isomerisation possible.• Need to shift the equilibrium to the product.

Z

YX

R

Z

YX

R

Z

YX

R

D

G

Z

YX

R

E

F

HH


Photocyclization.

25

Z

YX

R

Z

YX

R

Z

YX

R

VS

D IH

• Problem of regioselectivity if X and Z are different: If Z = H atom or if Z is smaller than X; formation of undesired regioisomers

Solution: Tether the ring if R is in meta or use a vinylbenzene

Z

YX

R

Z

YX

R

X

YZ

R

VS

D IH


Photocyclization.

Valencia, E.; Patra, A.; Freyer, A. J.; Shamma, M.; Fajardo, V. Tetrahedron Lett. 1984, 25, 3163. Markey, M. D. ; Fu, Y.; Kelly, T. R. Org. Lett. 2007, 9, 3255-3257. 26

Santiagonamie (2) extracted from branches of shrub Berberis darwinii 1996Exhibits wound healing properties

2

N

MeO NMe2

O

O

I NCy

MeO

MOMON

IO

PhHN

1. Cu0, Pd(PPh3)4DMF, 100C

39%

1 equiv 1,6 equiv

2. K2CO3, PPh3CH3I18-c-6, DMF, 100C

79% N

MeO

MOMOPhHNOC

N

MeO

MOMOPhHNOC

h, I2, benzene, 0C

O

N

MeO

PhHNOCMOMO


Photocyclization.


2

N

MeO NMe2

O

O

Benzofquinoline instead of Benzohisoquinoline

h, I2, benzene, 0C 83%

O

N

OMe

OMOM

N

MeO

PhHNOCMOMO

N

MeO

MOMOPhHNOC


Photocyclization.


Failure due to repulsive steric interaction between OMOM and PhNHCO

N

MeO

MOMOPhHNOC

N

OMe

OMOM

PhHNOCN

OMe

OMOM

PhHNOCH

I I I2h

h

I

N

OMe

OMOM

PhHNOCN

OMe

OMOM

Backup plan: formation of lactone before photocyclization


Photocyclization.

29Markey, M. D. ; Fu, Y.; Kelly, T. R. Org. Lett. 2007, 9, 3255-3257.

N

O

MeO

MOMOPhHNOC

N

MeO

HOPhHNOC

Br

N

MeO

O

Br

O

TFA, THF, 80C76%

h, I2, DCM, 1h -37C to -18C 89%

O

N

MeO

O

Br

O

N

MeO NMe2

O

O

Medium-pressure Hg lamp

• Photocyclization of Enamides:

Photocyclization.

Ninomiya, I. J. Nat. Prod. 1992, 55, 541-564 Ninomiya, I.; Naito, T. Heterocycles 1981, 15, 1433-1462 30

3 possible reaction products generated from zwitterion G

H: Formed under oxidative conditionsI: Formed by a suprafacial 1,5-H shift (absence of oxidative conditions)

J: Formed under reductive conditions (NaBH4, MeOH)

NR

O

B

NR

O

H

H

G

h NR

O

NR

O

HN

R

O

H

H

H H

H I J


Photocyclization.

Pendrak, I .; Barney, S. Wittrock, R.; Lambert, D.M.; Kingsbury, W.D.; J. Org. Chem. 1994, 59, 2623Kato, I.; Higashimoto, M.; Tamura, O.; Ishibashi, H. J. Org. Chem. 2003, 68, 7983-7989. 31

Mappicine ketone (MPK) (3) : antiviral lead compound against herpes viruses

NN

O

O

3

NN

O

PhS

mCPBA, DCM, 0C98%

NN

CO2Et

O

PhSO

CaCO3, PhMereflux, 13h

63%

CO2Et


Photocyclization.

Kato, I.; Higashimoto, M.; Tamura, O.; Ishibashi, H. J. Org. Chem. 2003, 68, 7983-7989. 32

NN

O

O 10% Pd/C, CH3CO2H, 80C, 3h

28%

1,5-H shiftH

NN

O

O

NN

O

Oh,

MeOH, 1,5h NN

O

O

H

Low-pressure Hg lamp

h (=254 nm)H2O, KOH

NH

Cl

N

N

N

2

34

5 6N

2

34

6N

2

34

6

OHHO

55

65

N

OH3

• 4 Photocyclization:

Photocyclization.

Kaplan, L.; Pavlik, J. W.; Wilzbach, K. E.; J. Am. Chem. Soc., 1972, 94, 3283King, R.A. ; Lüthi, H.P.; Schaefer, F.; Glarner, F.; Burger, U. Chem.-Eur. J. 2001, 7, 1734 33

Based on pyridinium saltsInitial contribution from Kaplan, Pavlik and Wilzbach

Azabenzvalene

Formation of azabenzvalene: * excitation

K: Direct traping of initially formed allylic cationL and M: Trapping of rearragement product

K L M

• 4 Photocyclization:

Photocyclization.

Damiano, T.; Morton, D.; Nelson, A. Org. Biomol. Chem. 2007, 5, 2735-2752Zou, J.; Mariano, P. S. Photochem. Photobiol. Sci. 2008, 7, 393-404Kaplan, L.; Pavlik, J. W.; Wilzbach, K. E.; J. Am. Chem. Soc., 1972, 94, 3283 34

Generates bicyclic aziridine which can undergo nucleophilic ring openingCommon nucleophiles: H2O, MeOH, KOH, etc.Others nucleophiles can be used: Organocuprate reagents

h solvent

N X NH X

Nuc Nuc

NH2R

Nuc

NH

NucNuc

High yields with polar solvent Bicyclic aziridine: neutralisation prior concentrationAminocyclopentene: concentration prior neutralisation

• 4 Photocyclization :

Photocyclization.

Gellert, E. J. Nat. Prod. 1982, 45, 50Pearson, W. H.; Ren, Y.; Powers J. D. Heterocycles 2002, 58, 421Song, L.; Duesler, E. N.; Mariano, P. S. J. Org. Chem. 2004, 69, 7284 – 7293 35

(-)-swainsonine (4), potent glycosidase inhibitor product isolated from different plant species such as Asclepiadaceae, Convulaceae, Moraceae and OrchidaceaePolyhydroxylated Indozilidne alkaloid 4

N

OH

OH

OHH

NH ClO4

1. h (254nm) HClO4, H2O2. Ac2O, DMAP pyr 42%

OAcAcO

HNAc

Acetylcholine esterease

OAcHO

HNAc

OBnTBSO

NAc

EEACE H2O, pH 6.9

68%

• 4 Photocyclization :

Photocyclization.

Ling, R.; Mariano, P.S. J. Org. Chem., 1998, 63, 6072.Li, J.; Lang, F.; Ganem, B. J. Org. Chem., 1998, 63, 3403Zhao, Z.; Song, L.; Mariano, P.S. Tetrahedron Lett., 2005, 61, 8888 36

•Others examples:

(+)-mannostatin A (-)-allosamidine (+)-castanospermine

NH3

HO

HO OH

SMe

Cl

O

N

OH

OH

HO

Me2N

N

OH

OH

OH

H

OH

UV mediated-reactions• Photocyclizations

• Photochemical Rearrangement

37

Oxa-di--Methane Rearrangement (ODPM)

Photo-Fries Rearrangement

Photochemical Rearrangements.

• Oxa-di--Methane Rearrangement (ODPM):

38

2 possibles processes upon irradiation: 1,3-acyl migration or ODPMODPM proceeds via a triplet state to yield the corresponding cyclopropyl ketoneUse of a sensitizer (i.e. acetophenone) to generate the triplet state

Hixson, S.S.; Mariano, P.S.; Zimmerman, H.E. Chem. Rev. 1973, 73, 531-551.Zimmerman, H.E. Armesto, D. Chem. Rev. 1996, 96, 3065-3112.Hoffmann, N. Chem. Rev. 2008, 108, 1052-1103.

,-unsaturated ketones undergo a rearrangement involving a formal 1,2-acyl migration and cyclopropane formation

First example in 1966:

Ph

OPhPh

Ph hPhH, 1h30

7%

Ph

H

H

PhPh

O

Ph


• Oxa-di--Methane Rearrangement (ODPM):

39

Cleavage of bond in position to the photoexcited carbonyl group; acyl group migrates onto the neighbouring C=C bond

Givens, R. S.; Oettle, W. F. J. Chem. Soc., Chem. Commun. 1969, 1164-1165.Zimmerman, H.E. Armesto, D. Chem. Rev. 1996, 96, 3065-3112.

O OO

O

O

O

A

B

High chemical yieldHigh degree of stereoselectivityVery general for many cyclic ,-unsaturated ketones

40

• Oxa-di--Methane Rearrangement :

(-)-phellodonic acid (5) isolated from fermentation of fungus in Tasmania in 1993Exhibits strong inhibitory activities towards various bacteria and cancer cells

M. Stadler, T. Anke, J. Dasenbrock, W. Steglich, Z. Naturforsch. C: J. Biosci. 1993, 48, 545.Reekie, T. A. ; Austin, K. A. B.; Banwell, M. G. ; Willis, A. C. Aust. J. Chem. 2008, 61, 94-106

H

HHO2C

OHO

OOO

6


Obz

O

MeO2C

O

O

6

hAcetophenone

Acetone66% H

HMeO2C

OOO

6BzO

H

HMeO2C

OOO

6BzO

8% 82%

H H

5


41




Obz

O

MeO2C

O

O

6

hAcetophenone

Acetone

H

HMeO2C

OOO

6BzO

Obz

O

MeO2C

O

O

6

*

T1Obz

O

MeO2C

O

O

6

Obz

O

MeO2C

O

O

6

H

HMeO2C

OOO

6BzO

H H

8% 82%

42




hAcetophenone

Acetone96% H

HMeO2C

OOO

6BzO

H

H

HMeO2C

OOO

6BzO

H

•Relief of steric compressions between Me and Bz group by photoenolization or -cleavage process

H

HMeO2C

OOO

6BzO

H

HMeO2C

OOO

6

SmI2, THF-MeOH,

-78C to 18C, 0,25h96%

H H

H

HHO2C O

OOO

6

43


Banwell, M.G.; Edwards, A.J.; Harfoot, G.J.; Jolliffe, K.A. J. Chem. Soc. Perkin Trans. 1 2002, 22, 2439-2441Singh, V.; Prathap, S.; Porinchu, M. J. Org. Chem. 1998, 63, 4011-4017Yen, C.-F.; Liao, C.-C. Angew. Chem. Int. Ed. 2002, 41, 4090-4093


•Others examples:

(-)-hirsutene (-)-complicatic acid

()-capnellene

H

H

H

H

HHO2C O

O

H

H

NH

OHH

H

H

O

()-Magellanine


• Fries Rearrangement:

44

Require strong Lewis acidRecombination can occur in ortho or para position

O

O

RAlCl

ClCl

O

O

R

AlCl

ClCl

OAlCl

ClCl

O

R

r.t.

100COH

OH

OR

R

O



Formation of phenol if aryloxy radical escapes from solvent cageDoes not require strong Lewis acidMild synthetic pathway

45

O

O

RO OH

hO O O

R

OR

• Photo-Fries Rearrangement:


First observed in 1960Does not involve carbonium ionsCleavage of C-O bond proceeds via a triplet state

46

• Photo-Fries Rearrangement :

Kendomycin (6) is a potent endothelin receptor antagonist compound with remarkable antibacterial and cytostatic activity Isolated from different Streptomyces species

Bode, H.B.; Zeeck, A. J. Chem. Soc. Perkin Trans. 1 2000, 3, 323Bode, H.B.; Zeeck, A. J. Chem. Soc. Perkin Trans. 1 2000, 16, 2665Magauer, T.; Martin, H.J.; Mulzer, J. Angew. Chem. Int. Ed. 2009, 48, 6032-6036


O

HOO

HOO

OH

O

OMe

OO

O O

h (=254 nm)cyclohexane

50min75%

HOMe

OO

OO

6


47

• Photo-Fries Rearrangement :

Magauer, T.; Martin, H.J.; Mulzer, J. Angew. Chem. Int. Ed. 2009, 48, 6032-6036


O

OMe

OO

O O

h (=254 nm)cyclohexane

50min75%

HOOMe

OO

OO

O

OMe

OO

O

O

OMe

OO

OO O

O

OMe

OO

O O

O

OMe

OO

O O

OOMe

OO

OO

Conclusion.

• Access to important fragment from simple molecules

•Control in the product generated

Equipment

48

Photochemical reaction

• Use of continuous flow reactor

• Possibilities to scale-up reaction

• Light as the only reactant

N XR

H

HHO2C

OHO

OOO

6

Conclusion.

49

I’m not

Mexican

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Photochemical Reactions as a Key Step in Natural Product Synthesis.

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