Chem 206D. A. Evans Pericyclic Reactions: Part–4

D. A. EvansFriday,October 20, 2006

! Reading Assignment for week:

Carey & Sundberg: Part A; Chapter 11Concerted Pericyclic Reactions

Chemistry 206

Advanced Organic Chemistry

Lecture Number 14

Pericyclic Reactions–4

! [3,3] Sigmatropic Rearrangements: Introduction

! Cope Rearrangements & Variants

! Claisen Rearrangements & Variants

K. Houk, Transition Structures of Hydrocarbon Pericyclic RxnsAngew Chem. Int. Ed. Engl. 1992, 31, 682-708

K. Houk, Pericyclic Reaction Transition States: Passions & Punctilios, Accts. Chem. Res. 1995, 28, 81-90

Angew Chem. Int. Ed. Engl. 1992, 31, 682-708

http://www.courses.fas.harvard.edu/colgsas/1063! Other Reading Material:

! Problems of the Day:

[3,3] Sigmatropic Rearrangements

Trost, Ed., Comprehensive Organic Synthesis 1992, Vol 5, Chapter 7.1: (Cope, oxy-Cope, Anionic oxy-Cope) Chapter 7.2, Claisen

S. J. Rhoades, Organic Reactions 1974, 22, 1 (Cope, Claisen)

S. R. Wilson, Organic Reactions 1993, 43, 93 (oxy-Cope)

T. S. Ho, Tandem Organic Reactions 1992, Chapter 12 (Cope, Claisen)

Paquette, L. A. (1990). “Stereocontrolled construction of complex cyclic ketones by oxy-Cope rearrangement.” Angew. Chem., Int. Ed. Engl. 29: 609.

Predict the stereochemical outcome of this Claisen rearrangement

diastereoselection>87:13

144 °C, 6h

CMe3

O

Et

CMe3

O

Et

H3O+ quench

Schreiber, JACS 1984, 106, 4038

Me

Me

OH

HMe

O

HMe

KH, ! THF

Provide a mechanism for the indicated fransformation

Ireland, JOC 1983, 48, 1829

Database Problem numberDatabase Problem number 117: Key words: Rearrangement + 117: Key words: Rearrangement + ClaisenClaisen

In a recent article, MacMillan and Yoon (JACS 2001, 123, 2448) reported the complex rearrangement illustrated below.

Part A. Provide a mechanism for this overall transformation. In answering this question, you should illustrate those transition states where stereocenters are generated and where stereochemcal information is relayed.

Part B. From your answer in Part A, illustrate the stereochemical relationships in the diamide product A.

Me

R2N

R2N

ClMe

OYb(OTf)3

CH2Cl2, R3N R2N NR2

O

Me

Me

Me

O

diastereoselection >95:5

several equivA

S

O

Ar

O

O

SAr

H Cl Cl

Provide a mechanism for the indicated transformation that accounts for the observed stereochemical outcome (JACS, 1984, 7643).

OC

Cl

Cl

Database Problem numberDatabase Problem number 195: Key words: Rearrangement + 195: Key words: Rearrangement + ClaisenClaisen

Introduction to [3, 3]-Sigmatropic RearrangementsD. A. Evans Chem 206

General Reviews:

S. J. Rhoades, Organic Reactions 1974, 22, 1 (Cope, Claisen)

T. S. Ho, Tandem Organic Reactions 1992, Chapter 12 (Cope, Claisen)

Trost, Ed., Comprehensive Organic Synthesis 1992, Vol 5, Chapter 7.1: (Cope, oxy-Cope, Anionic oxy-Cope) Chapter 7.2, Claisen

S. R. Wilson, Organic Reactions 1993, 43, 93 (oxy-Cope)

•

•

‡

?

X & Z = C, O, N etc

Cope Rearrangement, Ea = 33.5 kcal/mol Claisen Rearrangement Ea = 30.6 kcal/mol

X

Z Z

X

X

Z

X

Z

X XOO

The Reaction Energetics Goldstein, JACS 1972, 94, 7147

!G523‡ = 46.3

‡

‡

!G523‡ = 40.5

E

X XX

X

X

The Boat and Chair geometries for these transition structures are well defined.

Relative Energy !G°: 0 + 5.3 kcal/mol

+ 5.8 kcal/mol0Relative Energy !!G‡:

The CopeTransition States

‡X

CHAIR BOAT

BOATCHAIR

The FMO Analysis (Fleming page 101)

Bring two allyl radicals together to access for a possible bonding interaction between termini.

•

•

‡

bonding

bonding

It is evident that synchronous bonding is possible in this rearrangement

The nonbonding allyl MO

!2

Chem 206D. A. Evans The Doering–Roth Experiments

Meso isomer

The Geometry of the transltion state (boat vs chair) can be analyzed via the rearrangement of substituted 1,5-dienes:

Threo isomer

Doering/Roth Experiments: Tetrahedron 18, 67, (1962):

Me

Me

Me

Me Me

Me

MeMe

Me

Me

Predictions:

Threo isomer

! Measure product composition from rearrangement of each diene isomer

less favored

trans-trans

cis-cis

favored Me

Me

H

HH

H

Me

Me

Me

Me

H

HH

H

Me

Me

trans-cisdisfavored

Me

H

MeHMe

HMe

Predictions:

Meso isomer

disfavoredtrans-trans

trans-cis

Me

H

Me

HH

Me

H

Me

Me

Me

HHH

H

MeMe

favored

favored

Results:

Threo isomer

The Resultstrans-trans:

90%Me

Me

H

H HMe

Me

H

less favored cis-cis:

10%

Me

Me

H

H H

H

Me

Me

disfavoredtrans-cis:

< 1%Me H

MeH H Me

H

Me

disfavored

trans-cis: 99.7%

trans-trans: 0.3%

favored

Results:

Meso isomer

Me Me

HH H H

Me

Me

Me

H

Me

H H

Me

H

Me

!!G‡

~ 5.7 kcal/mol

The Boat and Chair geometries for these transition structures are well defined.

Relative Energy !G°: 0 + 5.3 kcal/mol

+ 5.8 kcal/mol0Relative Energy !!G‡:

The CopeTransition States

‡X

CHAIR BOAT

BOATCHAIR

Strain–Accelerated Cope RearrangementsD. A. Evans Chem 206

equilibrium stongly favors this isomer

Reese Chem. Commun. 1970, 151960 °C

120 °C Vogel Annalen 1958, 615, 1

Brown Chem. Commun. 1973, 3195-20 °C

Ring Strain can be employed to drive the Cope process:

H

H

H

H

H

H

‡20 °C

! !!

Bullvalene: Ea = 13.9 kcal/mol

At 100 °C one carbon is observed in nmr spectrum

Carey, Vol 1, page 630–631

Ring Strain can be employed to drive the Cope process:

W. von E. Doering's Bullvalene

EtNH2/THF LDA

LDA

"quantitative"

1.5 equiv

! Ring extension via divinylcyclopropane rearrangement

–

heatxylene

90%

!-himachalenePiers, Can J. Chem. 1983, 61, 1226, 1239

Me

Me

Me

Me

MeP

O(EtO)2

O

P

O

(EtO)2 Cl

Me

Me

MeO

MeMeMe

O

I

O

Me

Me

Me

Me

(PhS)Cu

O Me

Me

Me

Me

Me

Me

Li (Ph3)3RhCl

H2

MeI

Li+

Wharton J. Org. Chem. 1973, 38, 4117

Vogel Angew. Chem. Int. Ed. 1963, 2, 739

favored

! Position of Equilibrium dictated by ring strain issues:

H

H

H

H

Energetically, how much does tautomerization give you?

Marvell, Tet. Lett. 1970, 509

90%

3h

220 °C

! However, tautomerism can shift the equilibrium:

OH

H

OH O

keq ~ 10+5

The Anionic Oxy-Cope RearrangementD. A. Evans Chem 206

!G‡O – = !G‡

OH + 2.3RT [ pka TS – pka SM]

+ 2.3RT [18 – 29] (in DMSO)= !G‡OH!G‡

O –

!G‡O – = !G‡

OH + 1.4 [– 11]

= !G‡OH – 15 kcal/mol at 298 K (in DMSO)!G‡

O –

No Rxn66 °C

10 +12 rate acceleration

!!G‡estimate = 15 kca mol -1

!!G‡experiment = 13 kca mol -1

(HMPT)10 °C

4.4 min–O- +K

11 hrs

66 °C

1.4 min

1.2 hrs

no rxn

(66 yrs)

Half-life

66 °C

Documentation of Alkoxy Substituent Effect

OX

MeO

XO

MeO

OMe

OX

H

H

THF

–OK

–OK

–ONa

–OLi

–OH

–OX

THF

Maximal rates are observed under conditions where reactant is maximally destabilized

Origin of the Rate Effect ‡

‡

Effect probably comes from bothreactant destabilization

& transition state stabilization

~ 15 kcal/mol–

HO

– O

HO

– O

!

"!"

‡

!GOH!G‡

OH

!G‡O – !GO –

‡

pka (SM) pka (TS)

??

HO HOHO

– O – O– O

Evans, Golob, JACS 1975, 97, 4765.

‡

Accelerated Cope Rearrangements

k1

k2k2

k1= 10 + 10 10 + 17

Trost, Ed., Comprehensive Organic Synthesis 1992, Vol 5,

Chapter 7.1: (Cope, oxy-Cope, Anionic oxy-Cope)

"Recent applications of anionic oxy-Cope rearrangements."

Paquette, L. A. Tetrahedron 1997, 53, 13971-14020

HO HOHO

– O – O

O

A priori Estimate of the Acceleration (DAE)

Chem 206D. A. Evans Anionic Substituent Effects: Bond Homolysis

ketyl

+ •CR3

DI!I

+ •CR3

Substituent Effects in Bond Homolysis

HO C CR3

–O C•

C•HO

C CR3–O

B •A

DI

DI – DII = 2.3 RT [pka (A) – pka (B)]

pKa = 9.2pKa = 10.7

Acidities of these radicals are known in H2O, Hayon, Accts.

Chem. Res. 1974, 7, 114

HO C•C•

H

H

HO HO C•

Ph

Ph(H2O)

In DMSO, ΔD = 2.3 RT [ 29 – 18] ~15 kcal/mol

(Evans, Goddard, JACS 1979, 101, 1994)

!D+16.5 kcal/mol

(BDE = 91.8 expt)

BDE = 74.2BDE = 79.0BDE = 80.6BDE = 90.7

! Substituent Effect based on ab initio calculations

C H

H

H

HO NaO C

H

H

H C H

H

H

KO –O C

H

H

H

– –

[3,3]

[1,3]

––

– –

[1,2]

–

[2,3]

–

–

ene

–

Substituent Effects in Molecular Rearrangements

Y

R

X X

Y X

R

X X

R

X

R

R

YX YX

R

H

X

H

X

– –

– –

–

–

Y X Y X

C

C

Y X

C

CC

Y X

C

X

CC

CC

X

– •

•–

–

R •

– •X C H

X CCX

CX

R–H

Anionic Oxy-Cope Rearrangement: Applications Chem 206D. A. Evans

75%

Jung, JACS 1980, 102, 2463

Jung, JACS 1978, 100, 4309

KH, THFLevine, JOC 1981, 46, 2199

KH, THF

Gadwood, JOC, 1982, 47, 2268

MeO OMe

O OH

OMeMeO

MgX

HO

OMeOMe

H

H

H

OH

O

Me

Me

OH

Me

Me

O

NaH

50 °C

50 % yield

poitediol

Gadwood, JACS, 1986, 108, 6343dactylol

Me

O

HH

OH

MeHMe

OH

OMe H

HC CLi

HMeMe

OH

Me

MeMe

OH

MeMe H

OH

200 µg from 75,000 virgin female cockroaches

Periplanone-B Synthesis

MeH

OO

Me

H2C

Me

Me

OO

O

H

O

Still, JACS 1979, 101, 2493

OH

MeH

ROH2C

Me

ROH2C

Me

Me

OR

! THF

KH

2 stepsSchreiber, JACS 1984, 106, 4038

Me

Me

OH

H

OR

Me

Me

Me

O

HMe

KH

! THF

Synthesis of (+)-CP-263,114: Shair, JACS 2000, 122, 7424-7425.

O

OO

O

O

O

CO2H

Me

O

Me

H

XMgO

MeO2C

R

R

H

CH2OR

H

H

XMgO

C

R

R

H

CH2OR

HOOMe

O R

R

H

CH2OR

H

O[3,3]

–78!23 °C

Dieckmann 53%

Chem 206D. A. Evans The Claisen Rearrangement

There is good thermodynamic driving force for this reaction.

Bonds Broken: C-C! (65 kcal mol-1) & C-O" (85 kcal mol-1)

Bonds Made: C-O! (85 kcal mol-1) and C-C" (85 kcal mol-1)

#H ~ –20 kcal mol-1

! The Reaction:

! General Reviews:

S. J. Rhoades, Organic Reactions 1974, 22, 1 (Cope, Claisen)Trost, Ed., Comprehensive Organic Synthesis 1992, Vol 5, Ch 7.2Ziegler, Accts. Chem. Res. 1977, 10, 227 (Claisen)Bennett, Synthesis 1977, 589 (Claisen)Blechert, Synthesis 1989, 71 (HeteroCope)R. K. Hill, Asymmetric Synthesis vol 3, Ch 8, p503 (chirality transfer)Ziegler, Chem Rev. 1989, 89, 1423 (Claisen)

R

O O

R

#

(Benson estimates)

~ 20

! Themodynamics of Claisen Variants:Substituent !H (kcal mol-1)

X = H

X = OH

X = NH2 –30

–31

–16

~ 20 kcal/mol

~ 30

~ 30 kcal/mol

Heteroatom substitution at the indicated position increases exothermicity as well as reaction rate

H

OO

X X

H

O

O

OR

OR

O

O

Recognition Pattern for Organic Synthesis: An Enforced SN2'

Claisen –SN2'

R

R

X

O

R

R

O

R

O

R

Stereochemical outcome is syn and controlled by hydroxyl stereocenter

2

2

1

1

Control of stereocenter 2 evolves into a decision how toestablish the hydroxyl-bearing stereocenter

O

R

X

O

X

R

X

O

R

XO

R

R

O

180-200 oC

Rearrangements of Aryl Allyl Ethers: Traditional Applications

77%

65%

E:Z = 6.7:1

91%

180-200 oC Cope

O OH

OH

O MeMe

MeMe

N

O Me

Me

O

H

Me Me

Me Me

MeMe

OH

MeO OH

Me

N

Chem 206D. A. Evans The Claisen Rearrangement-2

! Endocyclic Olefins: Ireland, JOC 1983, 48, 1829

diastereoselection>87:13

144 °C, 6h

CMe3

O

Et

Me3C

H CH2

H

Et

O

For endocyclic olefins, overlap between developing sigma and pi bonds required. Best overlap for forming chair geometry. As shown below, bring a radical up to either face of the allylic radical. As the bond is formed, overlap must be maintained. Path A evolves into a chair conformation while Path B evolved into a boat conformation.

C CH2C H

R

H2CH

H

Me3C

H

Me3C

R

H

Me3C H

H2C

AB

•

R•

R•

ratio 75:25

heat

ratio 52:48

heat

! Exocyclic Olefins: House, JOC 1975, 40, 86

for exoocyclic olefins, overlap between developing sigma and pi bonds is equally good from either olefin diastereoface. In this instance, steric effects dominate & this systemshows a modest preference for "equatorial attack." A related case is provided below.

O

OEt

H

Me3C

O

CMe3

Me3C

H

OEt

O

OEt

H

Me3C

CMe3

O

Me3C

H

O

O

H

H

(review) S. H. Pines, Organic Reactions 1993, 43, 1

Synthesis of Allyl Vinyl Ethers

-EtOH

75%

Watanabe, Conlon, JACS 1957, 79, 2828

Bronsted acids can also serve as catalysts

96%

Use of Tebbe's Reagent: Evans, Grubbs, J. Am. Chem. Soc. 1980, 102, 3272.

(solvent)

AcOHgOH O

OEt

O

OPh

O CH2

Ph OCH2

Cp2Ti

Cl

AlMe2

OEt

Hg(OAc)2

X = H

Claisen

The Ireland approach to the bicyclic acid A: JOC 1962, 27, 1118

Me

HO

Me Me

O

X

O

MeMe

HO

H

MeMe

HO

Me Me

OH

A

!

The new stereocenter (!) introduced via the rearrangement had the wrong configuration!

53% overall

OH

MeMeHO

Me Me

H

HOMe Me

O

H

H

MeMe

Me

H

O

OH

H

Hg(OAc)2

EtOCH=CH2

Chem 206D. A. Evans The Claisen Rearrangement: Stereoselective Olefin Synthesis

!G‡a - !G‡

e = 1.5 kcal/mol

Consider the following rearrangement:

a‡

e‡

ka

ke

Claisen Rearrangement as vehicle for stereoselective olefin synthesis

O

Me

O

H

Me

H

Me

O

Me

CHO

MeCHO

!!G‡ = +1.5 kcal/mol

Faulkner & Perrin (Tet. Lett. 2783 (1969) have made the correlation between

!!G‡ for rearrangement & !G° for the corrresponding cyclohexane# equilibria:

O

Me

HMe

H

O

!G° = +1.75 kcal/mol

H

Me H

Me

#Note: The A-value of 2-methyl-tetrahydropyran is +2.86 kcal/mol (Lecture No. 6)

Faulkner, JACS 1973, 95, 553

91:990:10Et–Et–

Me– iPr– 93:07 94:6

91:990:10Et–Me–

(E):(Z) predicted(E):(Z) found

110 °C

(Z)(E)

They then suggest that there is a good correlation between cyclohexane "A-values" &

!!G‡ for the rearrangement process. Their case is fortified by the following expamples:

R2

O CHO

R2

CHOR2

R1 R1 R1

R2R1

Faulkner, Tet Let 1969, 3243

Johnson, JACS 1970, 92, 741

Faulkner, JACS 1973, 95, 553

>98:2

110 °C

110 °C

(E):(Z) found

90:10

>99:1Me–

>99:1

(E)

(Z)

The R2!X interaction should destabilize a‡ as X gets progressively larger.

ke

ka

e‡

a‡

Faulkner suggests that the installation of other substituents on Claisen transition states will lead to enhanced reaction diastereoselection:

R2

R2

O

R2

H

R2

H

O

R2

O

X

X

X

O

O

Me

Me

MeMe

Me

X

X

Me2N–

X

H–

MeO–

For R2 = Et

‡

! Another comparison: (DAE) M. DiMare, Ph. D. Harvard University, 1988

97:3

94:6

97.5:2.580

130

-78!+55

T, °C

LDA, TMSCl

HC(OMe)3, H+

Y = H, Eschenmoser

Y = H, Johnson

Y = Ac, Ireland

(E):(Z) ratioconditionsprocedure

OPMB

Me

Et

OY

Me

O

Et

OPMBX

Me

O

Et

X

R

MeO–

TMSO–

Me2N–

X

MeC(OMe)2NMe2