Electrocyclizations and Torquoselectivity · PDF fileThe Nazarov reaction follows typical 4e ... Torquoselectivity in Electrocyclic Reactions! What is a "torquoselective" reaction?!

Electrocyclizations and Torquoselectivity

MacMillan Group MeetingAndrew Capacci

4/24/13

Pericyclic Reactions

! Classes of pericyclic reactions

SigmatropicRearrangements

ElectrocyclicRearrangements

CycloadditionReactions

!" = ± 2!# = ± 2

!" = ± 1!# = ± 1

!" = 0!# = 0






!" = ± 2!# = ± 2

!" = ± 1!# = ± 1

!" = 0!# = 0

What is a pericyclic reaction?






!" = ± 2!# = ± 2

!" = ± 1!# = ± 1

!" = 0!# = 0

! A concerted reaction wherein the transition state ischaracterized as having a cyclic array of interacting orbitals.







!" = ± 2!# = ± 2

!" = ± 1!# = ± 1

!" = 0!# = 0

! A concerted reaction wherein the transition state ischaracterized as having a cyclic array of interacting orbitals.







!" = ± 2!# = ± 2

!" = ± 1!# = ± 1

!" = 0!# = 0

disrotatoryring-closure

! Basic look at orbital motion:

Electrocyclic Reactions

! What other systems participate in electrocyclic reactions?







HH







R

R R

R

R RR R

R R

RR





R

R R

R

R RR R

R R

R R

RR

R R



R

R R

R

R RR R

R R

RR



conrotatoryring-closure


R

RR

R

RRR R

R R

RR

R

R

R

R





! Higher order systems also undergo electrocyclic rearrangement in the same manner

R

RR

R

RRR R

R R

RR

R

R

R

R

Frontier Molecular Orbital Analysis

! Taking a closer look at the electrocyclization



LUMO

HOMO



LUMO

HOMO




LUMO

HOMO





LUMO

HOMO


!




HOMO

SHOMO


hv




HOMO

SHOMO


hv



LUMO

HOMO



LUMO

HOMO



LUMO

HOMO





LUMO

HOMO



!



LUMO

HOMO



!



LUMO

HOMO



!


! FMO analysis derived rules for electrocyclization

thermalreaction disrotatory conrotatory

photochemicalreaction disrotatoryconrotatory

R

R R

R

RR RR

Hückel / Möbius Analysis

! Alternative method for analysis of pericyclic reactions

! Model reaction:



! Model reaction:



! Model reaction:



! Model reaction:

"con"



! Model reaction:

"con"



! Model reaction:

1 phase inversion

"con"



! Model reaction:

1 phase inversion

Phase inversions:

odd = Möbius

even = Hückel

"con"



! Model reaction:

1 phase inversion

Phase inversions:

odd = Möbius

even = Hückel

Hückel

Möbius

Aromatic Anti-aromatic

4q+2

4q

4q

4q+2

"con"



! Model reaction:

1 phase inversion

Phase inversions:

odd = Möbius

even = Hückel

Hückel

Möbius


4q+2

4q

4q

4q+2

! Aromatic allowed thermally, Anti-aromatic allowed photochemically

"con"



! Model reaction:

1 phase inversion

Phase inversions:

odd = Möbius

even = Hückel

Hückel

Möbius


4q+2

4q

4q

4q+2


"con"

allowed



! Model reaction:


"con"

Phase inversions:

odd = Möbius

even = Hückel

Hückel

Möbius


4q+2

4q

4q

4q+2

flipped orbital



! Model reaction:


2 phase inversions

"con"

Phase inversions:

odd = Möbius

even = Hückel

Hückel

Möbius


4q+2

4q

4q

4q+2



! Model reaction:

3 phase inversions


2 phase inversions

"con"

Phase inversions:

odd = Möbius

even = Hückel

Hückel

Möbius


4q+2

4q

4q

4q+2



! Model reaction:

3 phase inversions


2 phase inversions

"con"

Phase inversions:

odd = Möbius

even = Hückel

Hückel

Möbius


4q+2

4q

4q

4q+2

allowed



! Model reaction:


"dis"

Phase inversions:

odd = Möbius

even = Hückel

Hückel

Möbius


4q+2

4q

4q

4q+2



! Model reaction:


"dis"

Phase inversions:

odd = Möbius

even = Hückel

Hückel

Möbius


4q+2

4q

4q

4q+2



! Model reaction:

0 phase inversions


"dis"

Phase inversions:

odd = Möbius

even = Hückel

Hückel

Möbius


4q+2

4q

4q

4q+2



! Model reaction:

0 phase inversions


"dis"

Phase inversions:

odd = Möbius

even = Hückel

Hückel

Möbius


4q+2

4q

4q

4q+2

forbiddenthermally



! Model reaction:


"dis""con"

Phase inversions:

odd = Möbius

even = Hückel

Hückel

Möbius


4q+2

4q

4q

4q+2



! Model reaction:


"dis""con"

Phase inversions:

odd = Möbius

even = Hückel

Hückel

Möbius


4q+2

4q

4q

4q+2



! Model reaction:

0 phase inversions,allowed thermally


"dis""con"

Phase inversions:

odd = Möbius

even = Hückel

Hückel

Möbius


4q+2

4q

4q

4q+2



! Model reaction:



"dis""con"

Phase inversions:

odd = Möbius

even = Hückel

Hückel

Möbius


4q+2

4q

4q

4q+2



! Model reaction:



"dis""con"

1 phase inversion,allowed photochemically

Phase inversions:

odd = Möbius

even = Hückel

Hückel

Möbius


4q+2

4q

4q

4q+2

Nazarov Cyclization through Electrocyclization

! The Nazarov reaction follows typical 4e– electrocyclic behavior

O



OHOH+

5 carbons, 4 e–



OH OHOH+

O

5 carbons, 4 e–



OH OHOH+

OH OH

R R'

R

R'

O

! Conrotatory reactivity for thermal electrocyclic reactions with 4 e–

5 carbons, 4 e–



OH OHOH+

OH OH

R R'

R

R'

O

! Conrotatory reactivity for thermal electrocyclic reactions with 4 e–

H HH H5 carbons, 4 e–

Dewar Benzene

! Why does dewar benzene show remarkable stability?

electrocyclicopening (?)

Dewar Benzene



R R

RR

Dewar Benzene



R R RR

RR!

4 e– = conrotatory

Dewar Benzene



R R RR

RR!

4 e– = conrotatory too unstable!

Dewar Benzene



R R RR

RR!

4 e– = conrotatory too unstable!

! The alternative, disrotatory opening does occur but is only allowed photochemically

Torquoselectivity in Electrocyclic Reactions

! What is a "torquoselective" reaction?



! Using substituted cyclobutenes as an example, both clockwise and counterclockwiserotation is possible and produces products of different olefin geometry / stereochemistry




R

!

"conrotatory"R

R R' R R'

!

"conrotatory"RR'

HR

HH




R

!

"conrotatory"

"con" "con"

R

R R' R R'

!

"conrotatory"RR'

HR

HH




R

!

"conrotatory"

"con" "con"

R

R R' R R'

!

"conrotatory"

"con" "con"

RR'

HR

HH




R

!

"conrotatory"

"con" "con"

R

R R' R R'

!

"conrotatory"

"con" "con"

RR'

How does differential substitution effect the direction of opening?

HR

HH


! Unusual examples of torquoselectivity could not be explained using FMO analysis

Me Me

!

"conrotatory"

<0.2%

only ~1 kcal/mol energy difference

>99.8%

Me

Frey, H. M. Trans. Faraday. Soc., 1964, 60, 83.Curry, M. J., Stevens, I. D. R. J. Chem. Soc., Perkin Trans. 2, 1980, 1391.



Me Me

!

"conrotatory"

R

!

"conrotatory"R

<0.2%

only ~1 kcal/mol energy difference

>99.8%

Me

MeR

MeMe

65 : 35

Frey, H. M. Trans. Faraday. Soc., 1964, 60, 83.Curry, M. J., Stevens, I. D. R. J. Chem. Soc., Perkin Trans. 2, 1980, 1391.

Et:

i-Pr:

68 : 32

t-Bu: 32 : 68

Ph: 30 : 70

R =



CF3

F3C

Dolbier, W. R., Koroniak, H., Burton, D., Bailey, A. R., Shaw, G. S., Hansen, S. W. J. Am. Chem. Soc., 1984, 106, 1871.

FF3C CF3

F

F F F F

CF3

FFF

CF3F

FF!

"conrotatory"

(Z,Z) (E,E)

! Thermodynamic analysis of perfluorinated system yields remarkable results:



CF3

F3C


FF3C CF3

F

F F F F

CF3

FFF

CF3F

FF!

"conrotatory"

Ea = 30.5 kcal/mol Ea = 49.7 kcal/mol

(Z,Z) (E,E)

kZZ/kEE (at 112 °C): 1.9 x 109




CF3

F3C


FF3C CF3

F

F F F F

CF3

FFF

CF3F

FF!

"conrotatory"

Ea = 30.5 kcal/mol Ea = 49.7 kcal/mol

(Z,Z) (E,E)

kZZ/kEE (at 112 °C): 1.9 x 109


! Sterics are clearly not the dominant factor in determining direction of rotation


! Further thermodymanic analysis towards a rational for torquoselectivity

Kirmse, W., Rondan, N. G., Houk, K. N. J. Am. Chem. Soc., 1984, 106, 1989.Rondan, N. G., Houk, K. N. J. Am. Chem. Soc., 1985, 107, 2099.

R

!

"inward" "outward"

R R

! Substituent preference for outward rotation determined




R

!

"inward" "outward"

R R


Ea (kcal/mol)Substituent Erel (R–H, kcal/mol)

H 32.5 0




R

!

"inward" "outward"

R R



H

Me

32.5

31.6

0

–0.9




R

!

"inward" "outward"

R R



H

Me

Cl

OAc

32.5

31.6

29.4

27.8

0

–0.9

–3.1

–4.7




R

!

"inward" "outward"

R R



H

Me

Cl

OAc

OEt

32.5

31.6

29.4

27.8

23.5

0

–0.9

–3.1

–4.7

–9.0




Cl

!

"inward" "outward"

Cl Cl

! Substituent preference for inward rotation determined

XX

X




Cl

!

"inward" "outward"

Cl Cl


Ea (kcal/mol)Substituent Erel (X–H, kcal/mol)

H 29.4 0

XX

X




Cl

!

"inward" "outward"

Cl Cl


Ea (kcal/mol)Substituent Erel (X–H, kcal/mol)

H

Me

Cl

29.4

31.6

35.6

0

+2.2

+6.2

XX

X




R

!

"inward" "outward"

R R

! Overall substituent preferences can be determined




R

!

"inward" "outward"

R R


inward (kcal/mol)Substituent outward (kcal/mol)

Me

OAc

OR

+3

+6

+5

–1

–3

–5

–9

Cl

Substituent effect on Ea:




R

!

"inward" "outward"

R R


inward (kcal/mol)Substituent outward (kcal/mol)

Me

OAc

OR

+3

+6

+5

–1

–3

–5

–9

Cl

Substituent effect on Ea:

Eout – Ein (kcal/mol)

–4

–9

-14




F

!

"inward" "outward"

F F





F

!

"inward" "outward"

F F


~13 kcal/mol preferencefor outward TS (calculated)




F

!

"inward" "outward"

F F


F

!

"inward" "outward"

F FF

FF





F

!

"inward" "outward"

F F


F

!

"inward" "outward"

F FF

FF




! Transition state analysis of torquoselective electrocyclic opening


OR

!

OR RO




OR

!

OR RO

inward TS

HH

H

HH

H

HOMO

LUMO




OR

!

OR RO

inward TS outward TS

HH

H

H

H

H

HH

H

H

H

H

HOMO

LUMO




OR

!

OR RO


HH

H

H

H

H

HH

H

H

H

H

HOMO

LUMO

Unfavorable 4e– interactionof p-orbital with "




OR

!

OR RO


HH

H

H

H

H

HH

H

H

H

H

HOMO

LUMOStabilization of TS

through "* / p-orbitaloverlap

Unfavorable 4e– interactionof p-orbital with "


! Unique control arises from torquoselective reactivity

Dolbier, W. R., Koroniak, H., Houk, K. N., Sheu, C. Acc. Chem. Res., 1996, 29, 471.Houk, K. N., Spellmeyer, D. C., Jefford, C. W., Rimbault, C. G., Wang, Y., Miller, R. D. J. Org. Chem., 1988, 53, 2125.

t-Bu!

t-BuMet-Bu Me

Me

30 : 70




t-Bu!

t-BuMet-Bu Me

Me

30 : 70

t-Bu!

t-BuOMet-Bu OMe

MeO

> 99 : 1




OR

!

OR RO




OR

!

OR RO




OR

!

OR RO




OR

!

OR RO

1 phaseinversion

6 e–, Möbius array




OR

!

OR RO

1 phaseinversion


Anti-aromatic, forbidden



Rudolf, K., Spellmeyer, D. C., Houk, K. N. J. Org. Chem., 1987, 52, 3708.

CHO

!

CHO OHC




CHO

!

CHO OHC< 2% observed




CHO

!

CHO OHC


HH

H

H

H

H

HH

H

H

H

H

HOMO

LUMO

< 2% observed




CHO

!

CHO OHC


HH

H

H

H

H

HH

H

H

H

H

HOMO

LUMO

Favorable 2e– interactionof p-orbital with "

< 2% observed




CHO

!





CHO

!





CHO

!





CHO

!


1 phaseinversion





CHO

!


1 phaseinversion


Aromatic, allowed




H!

HRR

R

! Linear relationship between in-outpreference and Taft substituent parameter for "-donating or accepting ability



Niwayama, S., Houk, K. N. Tetrahedron Lett., 1993, 34, 8, 1251.

!

COCH3

COCH3H3COC

Benzene, !: 66 : 34



Niwayama, S., Houk, K. N. Tetrahedron Lett., 1993, 34, 8, 1251.

!

COCH3

COCH3H3COC

Benzene, !:

ZnI2/Na2CO3, Benzene, !:

66 : 34

17 : 83

! Increasing acceptor strength increases inward torquoselectivity


! Additional examples of torquoselective effects

Thomas, B. E., Evenseck, J. D., Houk, K. N. J. Am. Chem. Soc., 1993, 115, 4165.

!

R

R R




!

! Octatetraenes adopt a helicalelectrocyclic transition state

R

R R

! Electronic effects in elecrocyclizationare minimal; steric effects dominate




!

! Octatetraenes adopt a helicalelectrocyclic transition state

R

R R

! Electronic effects in elecrocyclizationare minimal; steric effects dominate



Thomas, B. E., Evenseck, J. D., Spellmeyer, D. C., Houk, K. N. J. Org. Chem., 1995, 60, 7134.

!R

RR




!

! Hexatrienes undergo disrotatorythermal electrocyclization

! Pseudoaxial hydrogens are calculatedto be within van der Waals radii (1.2 Å, H)

R

RR




!

! Hexatrienes undergo disrotatorythermal electrocyclization

! Pseudoaxial hydrogens are calculatedto be within van der Waals radii (1.2 Å, H)

R

RR




!R

RR


HOMO

LUMO ! Additional steric repulsion in inward transition state vs cyclobutene

! Reduced overlap with " bonddecreases electronic contribution



DePuy, C. H. Acc. Chem. Res., 1968, 1, 33.Faza, O. N., López, C. S., Álvarez, R., de Lera, A. R. Org. Lett., 2004, 6, 905.

OTs




OTs




OTs




OTs

OTs

MeMeMeMe




OTs

OTs

MeMeMeMe

MeMe




OTs

OTs

MeMeMeMe

MeMe




OTs

OTs

OTs

MeMeMeMe

MeMe

MeMe

MeMe




OTs

OTs

OTs

MeMeMeMe

MeMe

MeMe

MeMe

Me

Me




OTs

OTs

OTs

MeMeMeMe

MeMe

MeMe

MeMe

Me

Me




OTs

OTs

OTs

MeMeMeMe

MeMe

MeMe

MeMe

Me

Me

Rel. Rate

1




OTs

OTs

OTs

MeMeMeMe

MeMe

MeMe

MeMe

Me

Me

Rel. Rate

1

4




OTs

OTs

OTs

MeMeMeMe

MeMe

MeMe

MeMe

Me

Me

Rel. Rate

1

4

18,000


! Additional examples of torquoselective reactivity

Denmark, S. E., Wallace, M. A., Walker, C. B. J. Org. Chem., 1990, 55, 5543.

OTMS OH

HH

88% ee 88% ee58% yield

FeCl3

CH2Cl2, -50 °C




OTMS OH

HH


FeCl3

CH2Cl2, -50 °C

O[Fe]TMS




OTMS OH

HH


FeCl3

CH2Cl2, -50 °C

O[Fe]TMS

axial TMS




OTMS OH

HH


FeCl3

CH2Cl2, -50 °C

O[Fe]TMS

equatorial TMS axial TMS



Hutson, G. E., Türkmen, Y. E., Rawal, V. H. J. Am. Chem. Soc., 2013, 135, 4988.

O

R

Me

55-78% yield80-90% ee

R = Alkyl, Aryl

Cr-Salen (A)

CH2Cl2, rt,

O

Me

R4Å MS

O

N N

O

t-Bu

MesMes

t-Bu

H H

Cr

SbF6

Cr-Salen (A):



Hutson, G. E., Türkmen, Y. E., Rawal, V. H. J. Am. Chem. Soc., 2013, 135, 4988.

O

R

Me

55-78% yield80-90% ee

R = Alkyl, Aryl

Cr-Salen (A)

CH2Cl2, rt,

O

Me

R4Å MS



Barcan, G. A., Patel, A., Houk, K. N., Kwon, O. Org. Lett., 2012, 14, 5388.Ashay, P., Barcan, G. A., Kwon, O., Houk, K. N. J. Am. Chem. Soc., 2013, 135, 4878.

Pd(PPh3)4 (10 mol%)

THF, reflux

NBoc

NMeO

H

BrMeO2C

NBoc

NMeO

H

MeO2CO

O

MeMe

55% (20:1 dr)

OO

MeMe

ClZn

Remote 1,6-stereoinductionin 6!-electrocyclization




Pd(PPh3)4 (10 mol%)

THF, reflux

NBoc

NMeO

H

BrMeO2C

NBoc

NMeO

H

MeO2CO

O

MeMe

55% (20:1 dr)

OO

MeMe

ClZn

Remote 1,6-stereoinductionin 6!-electrocyclization

OO

MeMe

MeO2C

Via:


! Studies on differentially 3-substituted electrocyclization substrates


xylenes, reflux

NBoc

NH

R

NBoc

NH

RMe Me




xylenes, reflux

NBoc

NH

R

NBoc

NH

RMe Me

R

H

A-value

0

Product dr

3.5 : 1




xylenes, reflux

NBoc

NH

R

NBoc

NH

RMe Me

R

H

SPh

CO2Me

Me

A-value

0

0.8

1.3

1.7

Product dr

3.5 : 1

6.7 : 1

15.7 : 1

13.3 : 1




xylenes, reflux

NBoc

NH

R

NBoc

NH

RMe Me

R

H

SPh

CO2Me

Me

TMS

A-value

0

0.8

1.3

1.7

2.4

Product dr

3.5 : 1

6.7 : 1

15.7 : 1

13.3 : 1

4.3 : 1




xylenes, reflux

NBoc

NH

R

NBoc

NH

RMe Me

major product




xylenes, reflux

NBoc

NH

R

NBoc

NH

RMe Me

Additional eclipsing and allylic strain

minor product

Electrocyclic Reactions in Synthesis

! Nicolaou's key cascade towards endiandric acids B, C, F and G

CO2Me

Ph

Nicolaou, K. C., Zipkin, R. E., Petasis, N. A. J. Am. Chem. Soc., 1982, 104, 5558.Nicolaou, K. C., Petasis, N. A., Zipkin, R. E. J. Am. Chem. Soc., 1982, 104, 5560.

Nicolaou, K. C., Petasis, N. A., Zipkin, R. E., Uenishi, J. J. Am. Chem. Soc., 1982, 104, 5555.Nicolaou, K. C., Petasis, N. A., Uenishi, J., Zipkin, R. E. J. Am. Chem. Soc., 1982, 104, 5557.



CO2Me

Ph CO2MePh

1. H2, Pd/BaSO4,quinoline

2. toluene, !





CO2Me

Ph CO2MePh

CO2MePh


2. toluene, !

8"





CO2Me

Ph CO2MePh

CO2MePh

CO2MePh

HH


2. toluene, !

8"

6"





CO2Me

Ph CO2MePh

CO2MePh

CO2MePh

HH


2. toluene, !

endiandric acids F and Gmethyl ester

8"

6"






CO2MePh

HH

endiandric acid Gmethyl ester

CO2MePh

HH

endiandric acid Fmethyl ester





CO2MePh

HH


CO2MePh

HH


CO2Me

Ph

H

H

H

HH

H

endiandric acid Bmethyl ester

[4+2]





CO2MePh

HH


[4+2]

CO2MePh

HH


MeO2C

Ph

CO2Me

Ph

H

H

H

HH

H

endiandric acid Bmethyl ester

endiandric acid Cmethyl ester

[4+2]


Documents

Electrocyclizations and Torquoselectivity · PDF fileThe Nazarov reaction follows typical 4e ... Torquoselectivity in Electrocyclic Reactions! What is a "torquoselective" reaction?!