Electrocyclic Reactions - University of...

Electrocyclic Reactions

OO

OMeMe

OPMB

XX

OTBSLecture Notes

Key Reviews:

Electrocyclic Reactions:Comprehensive Organic Synthesis, Vol. 5, p. 699

Nazarov Cyclization (4π-electrocyclization):S. E. Denmark, Org. React. 1994, 45, 1-158.

A Series of Observations:The Birth of the Woodward-Hoffmann Rules and Electrocyclizations

OO

OMeMe

OPMB

XX

OTBS

E. Havinga and co-workers, Tetrahedron 1960, 11, 276.E. Havinga and co-workers, Tetrahedron 1961, 12, 146.

HO

Me

MeMe Me

Me

precalciferol(previtamin D)

HO

MeMe Me

Me

ergosterol

HO

MeMe Me

Me

lumisterol

Me

H

Me

H

hν


OO

OMeMe

OPMB

XX

OTBS


HO

Me

MeMe Me

Me


HO

MeMe Me

Me

ergosterol

HO

MeMe Me

Me

lumisterol

Me

H

Me

H

HO

MeMe Me

MeMe

H

HO

MeMe Me

MeMe

H

pyrocalciferol

isopyrocalciferol

100-200 °Chν


OO

OMeMe

OPMB

XX

OTBS


HO

Me

MeMe Me

Me


HO

MeMe Me

Me

ergosterol

HO

MeMe Me

Me

lumisterol

Me

H

Me

H

HO

MeMe Me

MeMe

H

HO

MeMe Me

MeMe

H

pyrocalciferol

isopyrocalciferol

100-200 °Chν6π-conrotatory

electrocyclization 6π-disrotatoryelectrocyclization

Electrocyclic Reactions:Background and Basic Principles

OO

OMeMe

OPMB

XX

OTBSA

BB

AA

AB

B

A

BB

AA

BA

B

Conrotatory versus disrotatory cyclization: how can I differentiate them?

or

B

AB

A

disrotatoryring opening

conrotatoryring opening

conrotatoryring closing

disrotatoryring closing


OO

OMeMe

OPMB

XX

OTBSA

BB

AA

AB

B

A

BB

AA

BA

B


A

B

A

BAB

AB A

BB

A

or

B

AB

A










OO

OMeMe

OPMB

XX

OTBS


HO

Me

MeMe Me

Me


HO

MeMe Me

Me

ergosterol

HO

MeMe Me

Me

lumisterol

Me

H

Me

H

HO

MeMe Me

MeMe

H

HO

MeMe Me

MeMe

H

pyrocalciferol

isopyrocalciferol

100-200 °Chν6π-conrotatory

electrocyclization 6π-disrotatoryelectrocyclization


OO

OMeMe

OPMB

XX

OTBS

The Woodward-Hoffmann rules predict that photochemical reactionswill be precisely complementary to thermal reactions. Thus, what is allowed

photochemically is forbidden thermally, and vice versa. This prediction is true.

butadiene HOMO (Ψ2)(4π-electron system)

Thermal reactionbutadiene HOMO (Ψ3)(4π-electron system)

disallowedallowed

e thermal photochemical

2 4 6 8

disrotatoryconrotatorydisrotatoryconrotatory

conrotatorydisrotatoryconrotatorydisrotatory

Photochemical reaction

disallowed allowed


OO

OMeMe

OPMB

XX

OTBSA

BB

AA

AB

B

A

BB

AA

BA

B


A

B

A

BAB

AB A

BB

A

or

B

AB

A










OO

OMeMe

OPMB

XX

OTBS

Guiding Principle:Electron donors go outward;

electron withdrawers go inward.4π-conrotatoryelectrocyclicring opening

F

F

CF3

FCF3

FΔ

F

F

F

CF3F

CF3

F

F

CF3

FCF3

FF

F

CF3

CF3F

Fhν

4π-disrotatoryelectrocyclicring opening

What happens when the rotating groups are different? Will one product predominate?

Here, the products aredegenerate; i.e., the same


OO

OMeMe

OPMB

XX

OTBS


2 4 6 8



O

O

OH

H

O

O

O

HH

HH

H

H

hν4π-disrotatory

electrocyclization


OO

OMeMe

OPMB

XX

OTBS


2 4 6 8



O

O

OH

H

O

O

O

HH

HH

H

H

hν4π-disrotatory

electrocyclization

O

O

OH

H

H

H

H

O

O

O

HH

Himpossiblestructure!4π-conrotatory

electrocyclizationtrans-fused

4-membered ring

Δ

X


OO

OMeMe

OPMB

XX

OTBS


2 4 6 8



HH hν

4π-disrotatoryelectrocyclization


OO

OMeMe

OPMB

XX

OTBS


2 4 6 8



HH

HH

H

HH

H

hν4π-disrotatory

electrocyclization

4π-conrotatoryelectrocyclization

Δ

X impossiblestructure!


OO

OMeMe

OPMB

XX

OTBS


2 4 6 8



impossiblestructure!

cb

a

d

bd

a

c

H

H

a

c

bd

cb

a

d

bc

a

d

H

H

a

d

bc

hν



Δ

Xhν



Δ


OO

OMeMe

OPMB

XX

OTBS


2 4 6 8



O OH

OH

Δ4π-conrotatory

electrocyclizationO

Note: Electrocyclic reactions can involve both cationic and anionic intermediates

H3PO4


OO

OMeMe

OPMB

XX

OTBS


2 4 6 8



O OH

OH

Δ4π-conrotatory

electrocyclizationO

Note: Electrocyclic reactions can involve both cationic and anionic intermediates

H3PO4

This reactionis known as the

Nazarovcyclization and

was firstdiscovered

in 1948


OO

OMeMe

OPMB

XX

OTBS


2 4 6 8



O OHH3PO4

OH O

The Nazarov reaction is highly regioselective based on carbocation stability

S. E. Denmark and co-workers, J. Am. Chem. Soc. 1982, 104, 2642.


OO

OMeMe

OPMB

XX

OTBS


2 4 6 8



O OHH3PO4

OH O

The Nazarov reaction is highly regioselective based on carbocation stability

O OHFeCl3

OH O

TMS TMS TMS

Cl

S. E. Denmark and co-workers, J. Am. Chem. Soc. 1982, 104, 2642.

Electrocyclic Reactions:First Discovery of an Electrocyclic Reaction

For discussion, see: E. J. Corey, F. N. M. Kuhnle, Tetrahedron Lett. 1997, 38, 8631.

Alexander Borodin (1833-1887)

Piece you heard was from the Prince Igor opera:Polovetsian Dances

ONH3

Ph

N N

Ph

Ph

Ph

N N

Ph

Ph

NHN

Ph

Ph Ph


NH2H2N

Ph Ph

NH2H2N

Ph Ph

Process is still used today . . .

120 °C

amarine


OO

OMeMe

OPMB

XX

OTBS


2 4 6 8



OTs


OO

OMeMe

OPMB

XX

OTBS


2 4 6 8



MeMeMe

Me OTs

krel1

MeMe

OTs Me

Me

40,000

OTs

4


OO

OMeMe

OPMB

XX

OTBS


2 4 6 8



MeMeMe

Me OTsMe

Me

krel1

MeMe

OTs

MeMe

Me

Me

40,000

OTs

4

lobe system requiredafter opening for cation

Rule: groups oppositeleaving group migrate

outwards


OO

OMeMe

OPMB

XX

OTBS


2 4 6 8



krel1

1,000,000


outwards

H OTs Essentially animpossible structure!

TsO H


OO

OMeMe

OPMB

XX

OTBS


2 4 6 8



krel1

1,000,000


outwards

H OTs Essentially animpossible structure!

TsO H

LVG1

LVG2 LVG2Can predict easilywhich of the two

groups will depart

OO

OMeMe

OPMB

XX

OTBS

W. Oppolzer, C. Robbiani, Helv. Chim. Acta 1983, 66, 1119.

O

O

N OOBnO

O

O

O

N

O

BnOO

O

O

O

N

O

BnOO

O

O

O

NMeO

O

H

H

OH

o-quinodimethane

chelidonine

o-xylene, Δ

IntramolecularDiels-Alder (73%)

4π-conrotatoryelectrocyclicring opening

Electrocyclic Reactions:Examples You Have Already Seen

Remember: Electron donatingsubstituents turn outward

Electrocyclic Reactions:Examples You Have Already Seen

P. Garner, W.B. Ho, H. Shin, J. Am. Chem. Soc. 1993, 115, 10742.

N

N

HCO2H

Me

OH

quinocarcin

N

O

O

HOMeO

Me

MeN3toluene,

25 °C

(99%)

N

O

O

HOMeO

MeNN

N

Me

N

O

O

HOMeO

Me

N Mehν,

Pyrexdioxane(90%)

hν,quartz

MeON

HOMeO

Me

NO

O

Me

NO2S

OMe Me

Me

N

N

CONX

Me

MeO

O

O

HO

4π-disrotatoryelectrocyclicring opening

A

A[3+2]

addition

[3+2] addition

exo product

H

H

4π-Electrocyclic Reactions:Part of a Total Synthesis of Periplanone B

OO

OMeMe

OPMB

XX

OTBS

S. L. Schreiber, C. Santini, J. Am. Chem. Soc. 1984, 106, 4038.For a review, see: Classics in Total Synthesis I, Chapter 21

OH

Me

Me

OH

Me

Me

O

Me

Me

H

Me

Me

175 °C, toluene

O

Me

Me

hν

O

Me

Me

O

O

O

periplanone B

Oxy-Coperearrangement


KH,18-Crown-6

OO

OO

O

O

18-crown-6

(75%)

(82%)

Olefin isomerization

+

4π-Electrocyclic Reactions:Part of a Cascade Sequence to Coriolin

OO

OMeMe

OPMB

XX

OTBS

L. A. Paquette and co-workers, J. Am. Chem. Soc. 2002, 124, 9199.For a review, see: L. A. Paquette, Eur. J. Org. Chem. 1998, 1709.

O

O

i-PrO

i-PrO

O OMeMe

Li

O

i-PrO

i-PrO

O

O

O

MeMe i-PrO Oi-Pr

OO

O

Oring

openingtrans AdditionLi

4π-Electronconrotatory

i-PrO

i-PrO

OO

MeMe

HO

O

Ringopening

i-PrO

i-PrO

OO

O

O

MeMe

H

Dianionicoxy-Cope

i-PrO

i-PrO

OO

MeMe

HO

O

H

i-PrOHO

H

MeMe

i-PrO

H

O

O

aq. NH4Cl(24%)

Aldol

Note: The electrocyclizationpoints the carbon substituents inward

6π-Electrocyclic Reactions:Erasure of the Ring-Opened Product

OO

OMeMe

OPMB

XX

OTBS

E. J. Corey, A. G. Hortmann, J. Am. Chem. Soc. 1965, 87, 5736.

OO

MeMe

Me

dihydrocostunolide

H

OO

MeMe

H

Me

HO

Br

OO

MeMe

H

Me

HOO

O

MeMe

H

Me

HHO

OO

MeMe

H

Me

HOO

MeMe

Me Hhν, MeOH,

-18 °C

Al(Oi-Pr)3,i-PrOH, Δ

Al2O3,pyridine,

220 °C

LiBr,DMF,

120 °C

What is the name reaction in the second step?

H2,Raney NiMeOH,-18 °C


25 °C

OO

MeMe

H

Me

H


6π-Electrocyclic Reactions:Total Synthesis of Torreyanic Acid

OO

OMeMe

OPMB

XX

OTBS

J. A. Porco and co-workers, J. Am. Chem. Soc. 2000, 122, 10484.

HO

O

O

O

Me

CO2t-BuMe

O

O

O

O

Me

CO2t-BuMe

Dess-Martinperiodinane,CH2Cl2, SiO2,

25 °C, 1 h

Tandem oxidation/6π-conrotatory

electrocyclization

O

O

O

O

Me

CO2t-Bu

O

O

O

OCO2t-Bu

Me

MeMe

Dimerization

Diels-Alderreaction

(39%)OOO

OMe

CO2RH

O

OMe

CO2R

O O

H

H

H

Me

Me

TFA R = t-BuR = H, (+)-torreyanic acid

6π-Electrocyclic Reactions:One of Three Pericyclic Reactions in a Colchicine Total Synthesis

OO

OMeMe

OPMB

XX

OTBS

A. Eschenmoser and co-workers, Helv. Chim. Acta 1961, 44, 540.

O

O

MeO

MeOMeO

O

O

O

Cl

Diels-Alderreaction

MeO

MeOMeO

OH

O

O

Cl

O O

MeO

MeOMeO

OH

O

O

Cl

MeO

MeOMeO

CO2Me

CO2Me

H

ClMeO

MeOMeO

CO2Me

CO2Me

norcaradiene derivative

MeO

MeOMeO

CO2Me

CO2Me

colchicine

RetroDiels-Alder

reaction

-[CO2]

t-BuOK

1. MeOH, H2SO42. CH2N2

6π-disrotatory electrocyclic ring openings are often referred to as norcaradiene rearrangements

6π-dis-

rotatoryopening

25 °C

Hetero Diels-Alder Reactions:Oxime Ethers as Diene Components

D. L. Boger, S. Ichikawa, H. Jiang, J. Am. Chem. Soc. 2000, 122, 12169.

N

O

MeN

O

MenPrOR

N

O

MeOR

R = Me or Bn

TIB,175 °C,

36 hHeteroDiels-Alder

nPr

-[ROH](70%)

nPr

N MenPr

MeOMeO

O

O

O

O

MeMe A, 25 °C,45 min

NMe

nPr

OO

O

O

MeMe

MeOMeO

exo transition state

(97%)(100% exo)

N MenPr

MeOMeO

O

OO

O

MeMe H

HH

H

N

O

O

MeMe

OHHO

rubrolone aglycon

Rare dienes unless usedin an intramolecular sense

A

6π-Electrocyclic Reactions:A Pericyclic Reaction in a Rubrolone Total Synthesis

D. L. Boger, S. Ichikawa, H. Jiang, J. Am. Chem. Soc. 2000, 122, 12169.

N MenPr

MeOMeO

O

OO

O

MeMe H

HH

H

N

O

O

MeMe

OHHO

rubrolone aglycon

N MenPr

O

OO

O

MeMe H

HH

H

BrOMe

O

N MenPr

O

OO

O

MeMe H

H

OOMe

N MenPr

OO

O

MeMe H

H

O

N

O

O

MenPr

OOOHHO

OH

OH

6π-dis-

rotatoryopening

1. NBS, MeOH

(80%)2. TFA

DBU

aq. TFA

(72% overall)

6π-Electrocyclic Reactions:A Pericyclic Reaction in the Synthesis of Tropoisoquinolines

D. L. Boger, K. Takahashi, J. Am. Chem. Soc. 1995, 117, 12452.

O

O

MeMeH

H

6π-disrotatoryring opening

(40-60%)

N

MeOMeO

MeO

O O

O

O

MeMeN

MeOMeO

MeO

O

ODiels-Alder

reaction

CH3Cl, pyridine,25 °C, 2.5 h

HCl, EtOAc25 °C,6 days

O

O

MeMeH

H

N

MeOMeO

MeO

N

MeOMeO

MeO

Ogranditropone

N

MeOMeO

MeO

O

grandirubrine

KOH,MeOH

OH

N

MeOMeO

MeO

O

imerubrineOMe

N

MeOMeO

MeO

OMe

isoimerubrineO

(76%)

RetroDiels-Alder

reaction

(1:1)

CH2N2+

8π-Electrocyclic Reactions:Possible Role in the Biosynthesis of Trichodimerol

OO

OMeMe

OPMB

XX

OTBS

K. C. Nicolaou and co-workers, Chem. Eur. J. 1999, 5, 3651.

Me

O O

OHHOO

O

MeHO

Me OHMe

trichodimerol

MeMe

Aldolreaction

Me

O O

ORRO

MeHO

Me OHMe

8π-electronelectrocyclization

[4+4] Me

O O

ORRO

MeHO

Me OHMe

Electrocyclization Cascades:Black's Hypothesis for the Biosynthesis of the Endiandric Acids

OO

OMeMe

OPMB

XX

OTBS

D. St. C. Black and co-workers, Aust. J. Chem. 1982, 35, 2247.

CO2H

HO2C

Ph

CO2H

PhCO2H

Ph

Ph

HO2CPh

HH

H

CO2H

HH

HPh

endiandric acid D

endiandric acid E

Diels-Alderreaction

A = conrotatory 8πelectrocyclization

B = disrotatory 6πelectrocyclization

A

A

B

B

HH

PhH

HH

endiandric acid A

CO2H

Electrocyclization Cascades:Black's Hypothesis for the Biosynthesis of the Endiandric Acids

OO

OMeMe

OPMB

XX

OTBS

D. St. C. Black and co-workers, Aust. J. Chem. 1982, 35, 2247.

Diels-Alderreaction

A = conrotatory 8πelectrocyclization

B = disrotatory 6πelectrocyclization

A

A

B

B

HH

HPh CO2H

endiandric acid F

Ph

HH

HHO2C

endiandric acid G

HO2CH

H

H HH

Ph

endiandric acid C

H

H

H H

PhH

HH CO2H

Diels-Alderreaction

endiandric acid B

Ph

Ph

Ph

Ph

CO2H

CO2H

HO2C

CO2H

Electrocyclization Cascades:Total Synthesis of the Endiandric Acids

OO

OMeMe

OPMB

XX

OTBS

K. C. Nicolaou and co-workers, J. Am. Chem. Soc. 1982, 104, 5555.For a review, see Classics in Total Synthesis I.

CO2Me

Ph Ph CO2Me

CO2Me

Ph PhCO2Me1. H2, Pd/BaSO4,

quinoline2. toluene, 100 °C

same conditions

Electrocyclization Cascades:Total Synthesis of the Endiandric Acids

OO

OMeMe

OPMB

XX

OTBS

K. C. Nicolaou and co-workers, J. Am. Chem. Soc. 1982, 104, 5555.For a review, see Classics in Total Synthesis I.

CO2Me

Ph Ph CO2Me

CO2Me

Ph PhCO2Me1. H2, Pd/BaSO4,

quinoline2. toluene, 100 °C

H H

PhH

HHendiandric acid A

CO2Me

MeO2CH

H

H HH

Ph

endiandric acid CHH

H H

PhH

HH CO2Meendiandric acid B

same conditions

Current Frontiers in Electrocyclic Reactions:Access to Benzodiazepine Derivatives

H. Nemoto and co-workers, J. Am. Chem. Soc. 2006, 128, 13072.

OR

LiN N O

R

N N

OR

NN

NN

O R

NHN

O R

diazepam (valium)



Cl N

NOMe

(67-82%)

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