Cycloaddition Reactions: Diels-Alder Reaction

D. A. Evans

Chem 206

The Diels-Alder Cycloaddition Reactions

http://www.courses.fas.harvard.edu/colgsas/1063
"Diels-Alder Reactions". Evans, D. A.; Johnson J. S. In
Comprehensive Asymmetric Catalysis, Jacobsen, E. N.; Pfaltz, A.; and
Yamamoto, H. Editors; Springer Verlag: Heidelberg, 1999; Vol III,
1178-1235 (electronic handout)

Chemistry 206
Advanced Organic Chemistry
Lecture Number 16

Cycloaddition Reactions-1
! Cycloadditions: Introduction
! Ketene Cycloadditions
! The Diels-Alder Reaction

The Diels-Alder Reaction in Total Synthesis, K. C. Nicolaou,

Angew Chem. Int. Ed. 2002, 41, 1668-1698 (electronic handout)
Catalytic Enantioselective DielsAlder Reactions: Methods,
Mechanistic Fundamentals, Pathways, and Applications, E. J.
Corey, Angew Chem. Int. Ed. 2002, 41, 1650-1667 (electronic
handout)
Chemistry and Biology of Biosynthetic DielsAlder Reactions
Emily M. Stocking and Robert M. Williams, Angew Chem. Int. Ed.
2003, 42, 3078-3115 (electronic handout)

Reading Assignment for week:

Problem of the Day:

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

Rationalize the sense of asymmetric induction for this Diels-Alder

Reaction reported by MacMillan, JACS, 2000, 122, 4243. (pdf)

Carey & Sundberg: Part B; Chapter 6

Cycloadditions, Unimolecular Rearrangements
Thermal Eliminations

O
PhCH2

CHO

Pavel Nagorny

+
R

5% catalyst
MeOH-H2O

Me

N
H Me

Wednesday,
October 25, 2006

Me
N

catalyst

CHO
R

The Carbonyl Ene Reaction

D.A. Evans

Chem 206

The carbonyl ene reaction is a very powerful transformation that I want to introduce to you. Accordingly, I have prepared a
series of problems taken from the Problems Database to familiarize you with this reaction. Problem 210 is provided as an
introduction to the FMO analysis for the process. Subsequent problems have the ene reaction imbedded in reaction
cascades.
Problem 210. Question and Answer. The carbonyl ene reaction is illustrated below. Using FMO analysis, evaluate the
transition state of this reaction. Your answer should include: a transition state drawing; clear orbital depictions and HOMOLUMO assignments; an indication of the number of electrons from each segment; and indication of whether the reaction is
thermally allowed.
H

O
Ra

CH2

Rb

Ra

Rb

Ra

Rb

Answer
Rb

Rb allyl HOMO

bonding

Ra

bonding
Ra

The ene transition state

O
Ra
H

Rb

bonding

CH2
Rb

Ra
O

H
C

carbonyl LUMO

View the ene TS as a 3-component

cycloaddition
One possible analysis:
allyl anion: 4 eProton
carbonyl: 2 e[2!s + 2!s +2"s]

6!e- "cycloaddition"
suprafacial
thermally allowed

Cycloaddition Reactions-1

D. A. Evans

Why does maleic anhydride react easily with 1,3-butadiene, but not with
ethylene? So what are the "rules"?
O

! Consider [2 + 2] cycloaddition: Photochemical activation

!*

[4+2]

LUMO

new
HOMO

!*

[2+2]

bonding
bonding

C !

light

concerted

C
C

+ energy

[2+2] Cycloaddition - Examples

! Nomenclature
C

suprafacial

!2s

antarafacial

!2a

h!

Using this nomenclature, the Diels-Alder reaction is a !4s

+ !2s cycloaddition
Me

+ !2s]

bonding

C
antibonding

!2s

+ !2s] "forbidden"

Me
Me

h!

Me
Me

Me

["2s + "2s]
Me

Me

Prismane-Der.

[!2s + !2a]

bonding

[ !2s

Schfer, AC 1967, 79, 54.

!2a

C
C

Me

Dewar benzene-Derivative

C
C

bonding

Me

Me

Me

Quadricyclane Dauben, Tet. 1961, 15, 197.

["2s + "2s]

! Consider [2 + 2] cycloaddition: Thermal activation [ !2s

[ !2s

HOMO

C
+

The frontier orbitals of the reacting species must have the proper symmetries

!2s

! We also know that the photochemical variant is concerted

!2s

! The related reaction of 2 ethylenes is nonconcerted: [2 + 2] cycloaddition

heat

+ !2s]

light

[ !2s

Chem 206

+ !2a] "allowed"

must be antarafical for indicated stereochem

TL 1967, 4357, 4723.

Cycloaddition Reactions-2

D. A. Evans

Summary of Ketene Cycloadditions

R

R'

B:

R
R'

ZnCl2

Cl

Electrocyclic
Ring Opening

R'

R'
O

C O
R

Cl

R'

Cl

Zn

Cl

O
O

R'

Chem 30

h!

or "

R
R

R'

H
R

R'

Cycloaddition: FMO Analysis

R
Y

R'

Ketene Preparation

BH

B:
R3N

Antarafacial

R
Cl

E2 Elimination
O

O
OR

Suprafacial

C O

Cl
R

LiNR2

Cl

[!2s!2a]

R = -CH=CH2

C O

or !

N2

R'

h"

Imine

Alkene

Carbonyl

OR
R
E1cb Elimination

bonding
C O

HOMO

bonding

R
LUMO

R
O

Cycloaddition Reactions-3

D. A. Evans

[2+2]: Stepwise Versus Concerted

H

H
C
R'

MeO
R'

Chem 30

O
CMe3

R'

CMe3

2. NBu3, toluene, !

least hindered
bond rotation

Stepwise

1. (COCl)2, PhH, !

CO2H

Very large polar effects

E olefins yield a mixture of cis and trans products

NEt3

Solvent effects observed, but it could merely be a ground state effect

CH2COCl

KIE seen for many reactions support stepwise mechanism

Calculations show a highly asynchronus transition state.

Stereochemical consequence can be rationalized by stepwise mechanism

Concerted

Cl

Ketenes add stereoselectively to Z alkenes.

Cl

Cl

Zn

Cl

Cl

Cl

Cl

Z olefins are much more reactive than E olefins

Cl

Ketene-Alkene [2+2]
O

Me

C
Me

Me

Me

Me
Me

Me

Me

Me

Fast

Me

Me

Me

Me

Me

Ketenes + Aldehydes Afford !-Lactones

ab initio Calulations

Me

Me

O
+

Me
1:2

Me
Me

Me

+
32 kcal/mol

Me
+ Me
Me

Me

H
Me

Me
C O

Me

Me

H
Me

Me
O

Me
H

H
H

38 kcal/mol

path A

path B

O
Pons, J. -M.; et. al.
JACS 1997, 119, 3333.

H
H

favored

Me

Cycloaddition Reactions-4

D. A. Evans

Transformations of !-Lactones
R2

The stepwise mechanism,,,,

R2

" or BF3
-CO2

R1

R1

Most soft Nu
attack Csp3

+S

Me2S

R2N

H H

N
O

conrotatory
closure

R'

R'Li (2eq)

(E) Imine ! Cis Product

CuCN

O
R2N

H H

C
O

Chem 30

R
R

CO2H

Vederas et al JACS 1987, 107, 4649.

(Z) Imine ! Trans Product

The Staudinger Reaction

In this process, the illustrated ketene, generated in situ from an acid
chloride, undergoes reaction with the indicated substrates to form !lactams in a stereoselective process. When the azo-methine (RN=CHR)
geometry in the reactant is (Z) the product stereochemistry is trans (eq 1).
In a complementary fashion, the (E) imine affords the cis-substituted
product (eq 2). While this transformatlion could be viewed as a [2s+2a]
cycloaddition, it is felt that this reaction is stepwise.

H
C

O
conrotatory
closure

S
N

O
S

H H

N
R

R
S

H H
S
N

There are two contortaory modes. If you control the conrotatory mode, you control
the absolute stereochemistry of the reaction:

H
R
Et3N
O

Cl

H H

S
N

(Z)

S
(1)

H
N

Bn

C
O

O
O

Ph

R
R

(E)

H H

(2)
N

Ar

O
Et3N

Cl

Evans, SjogrenTet. Lett. 1985, 26, 3783, 3787.

See also Evans, Williams, Tet. Lett. 1988, 29, 5065.

O
H H

O
Ar

+
Ph

N
O

Bn

Ph

H H
N

diastereoselection > 95:5

80-90% yields

Ar
Bn

Cycloaddition Reactions-5

D. A. Evans

Chem 206
Me

Enantioselective Ketene-Aldehyde Cycloaddiitons

1)

O
+

Me

Br

i-Pr2NEt

R3N

Me3Si

Al
R

SO2CF3

Aldehyde 2 (R)

catalyst
[time (h), temp (C)]

% yield

% ee 3
(configuration)

5b (8, -40)

91

92 (R)

5a (16, -50)

93

92 (S)

PhCH2CH2

5a (72, -78)

89

95 (S)

CH2CH(CH2)8

5b (16, -50)

91

91 (S)

Me2CHCH2

5a (24, -50)

80

93 (S)

BnOCH2CH2

5b (16, -40)

90

91 (S)

TBDPSOCH2

5b (16, -40)

74

89 (R)

BnOCH2

5a (16, -50)

86

93 (R)

Me3C

5a (16, -50)

91

85 (R)

5b (24, -40)

56

54 (R)

C6H11

EtO2C

EtO2C
3: >99% yield, 92% ee

BnOCH2
PhCH2CH2

KF, CH3CN

cat. = 5a: R = Me
5b: R = Cl

2+

Me
entry

EtO2C
77% yield, 93% ee

i-Pr

O
O

-78 C, 24 h

PhMe2Si

Bn

F3CO2S

CH2

R3NHBr

i-Pr

N
OTf
Cu
Me3C H2O OH2 CMe3
OTf
PhMe2Si
OEt
1 mol%, THF, 3 MS

C +

[RCHO cat.]

O
N

catalyst (10 mol%)

Me

H
N
N Cu O R
RO
OR2

Me

Me3Si
observed product

Me3Si

2+

O
N

N
Cu

Me3C

H2O

OH2

R2O

R1
O
H C C

Me Me

R1

CMe3

+ 2 CF3SO3
Nelson, S. G.; Peelen, T. J.; Wan, Z. JACS, 1999, 121, 9742-9743

with J. Janey, Org. Lett. 2001, 3, 2125-2128

D. A. Evans

The Diels-Alder Reaction

Chem 206

Articles and monographs of Significance

HO

"Diels-Alder Reactions". Evans, D. A.; Johnson J. S. In Comprehensive

Asymmetric Catalysis, Jacobsen, E. N.; Pfaltz, A.; and Yamamoto, H. Editors;
Springer Verlag: Heidelberg, 1999; Vol III, 1178-1235 (pdf)

H
NMe2

H
Et

H
H

Lepicidin

Compactin: R = H
Mevinolin: R = Me

Catalytic Enantioselective DielsAlder Reactions: Methods, Mechanistic

Fundamentals, Pathways, and Applications, E. J. Corey, Angew Chem. Int.
Ed. 2002, 41, 1650-1667 (pdf)

Et

Me

The Diels-Alder Reaction in Total Synthesis, K. C. Nicolaou, Angew Chem.

Int. Ed. 2002, 41, 1668-1698 (pdf)

Chemistry and Biology of Biosynthetic DielsAlder Reactions

Emily M. Stocking and Robert M. Williams, Angew Chem. Int. Ed. 2003, 42,
3078-3115 (pdf)

(Synthesis)
JACS, 1993, 115, 4497

H
Me

Me

Me

(Biosynthesis) JACS 1985, 107, 3694

Clive, JACS 1988, 110, 6914
Kozikowski,
JOC 1987, 52, 3541
O
H
Keck, JOC 1986, 51, 2487
H
Me
O
Grieco, JACS 1986, 108, 5908
H
OMe
H
Heathcock,
JACS 1985, 107, 3731
MeO
OMe H
Girotra, Tet. Let. 1983, 24, 3687
Hirama, JACS 1982, 104, 4251

Recent Advances in Natural Product Synthesis by Using Intramolecular

Diels-Alder Reactions, Tadano et al. Chem Rev. 2005, 105, ASAP (pdf)
HN
O

Me

! The Reaction:

Me

These natural products could well have incorporated the DA rxn into the
biosynthesis
Ph

H
H

Endiandric Acid C

Me

Et
Me

ent-FR182877 (WS9885B)
J. Antibiotics 2000, 53, 204
TBSO

TBSO

CO2Et
Me

Me

DA
Het DA

Me

Br
H

OTBS

CO2H

Endiandric Acid B
(Syntheses)
Nicolaou, JACS 1982, 104, 5555-5562

OTBS
CO2Et

H
H

Ph
H

Me

HO

Et

Roush JOC 1984, 49, 3429

Nicolaou JOC 1985, 50, 1440
Ley Chem. Commun. 1983, 630

TBSO
H

OH

X-14547A

! Representative natural products displaying the Diels-Alder retron:

HO2C

O
COOH

Me

TBSO

Br

Me

Me

Sorensen, JACS 2003, 125, 5393

Evans, JACS 2003, 125, 13531

O
Me

Diels-Alder Reaction-Orbital Symmetry Considerations

D. A. Evans
The Alder Endo Rule

The following observation illustrates an example of the

Alder Rule which will be defined below.

H
+
H

disfavored

Orbital Symmetry Considerations for Diels Alder Reaction

If the symmetries of the frontier MO's of reacting partners are "properly matched" the
reaction is referred to as "symmetry-allowed". The Diels-Alder reaction is such a case.
As illustrated, the HOMO and LUMO of both the diene and dienophile, which in this case
are the same, will constructively overlap as indicated in formation of both sigma bonds.

favored

"Exo product"

"Endo product"

Observation: The endo Diels-Alder adduct is formed faster even though the exo
product is more stable. There is thus some special stabilization in the transition state
leading to the endo product which is lacking the exo transition state.
Exo TS

Chem 206

Energy

Endo TS

HOMO-!2

C
C

LUMO-!3

C
C

LUMO-!3

HOMO-!2

Frontier MO Explanation for the Endo Rule

C LUMO-!3

H
H

! Secondary (transient) orbital overlap can also occcur in the

stabilization of certain transition state geometries. Such a
transient stabilizing interaction can occur in the endo, but
not exo, transition state:

C HOMO-!2

The Other Dimerization Possibility for Butadiene

"

Does the possibility for the following

concerted dimerization exist?

! Note that the termini only match at one end for the
HOMO-LUMO pairing. Hence we say that the symmetry
C
requirements for the reaction in question are not met.
This does not mean that the reaction will not occur,
only that the reaction will not be concerted. Such reactions
are called "symmetry-forbidden".

C HOMO-!2
C
C
C

C LUMO-!3
C

Diels-Alder Reaction: The Transition Structure

D. A. Evans

Transition State Modelling is Coming of Age

Chem 206

! Lewis Acid Catalysis of the reaction is possible:

LUMO2

LUMO1

leading references:

Jorgensen, JACS 1993, 115, 2936-2942

Houk, Jorgensen, JACS 1989, 111, 9172

The Critical Energy

Difference:

energy

! The lengths of the forming CC bonds are Ca. 1.5 times the normal bond
distance. This factor comes out of the ab initio work of Jorgensen & Houk

Yates & Eaton,

JACS 1960, 82, 4436

E(LUMO1) - E(HOMO2)
or
E(LUMO2) - E(HOMO1)

HOMO1
HOMO2

Transition Structures of Hydrocarbon Pericyclic Reactions

Houk Angew. chem. Int. Ed. 1992, 31, 682-708

Dienophile

Diene

! The closer the two orbitals are in energy, the better they interact
! As !E decreases for the relevant ground state FMOs, rxn rates increase

Ethylene & Butadiene

Vs Butadiene & Acrolein

O

O
+

LUMO2
LUMO1
LUMO3

E
HOMO1

! Diene Reactivity as measured against Maleic anhydride

HOMO2

Me

HOMO3

Me

!E (LUMO3-HOMO1) < !E (LUMO2-HOMO1)

log k = 4.96

log k = 2.36 log k = 2.19

log k = 2.12

log k = 1.83

Sauer, Angew. Chem. Int. Ed., 1980, 19, 779-807

Rate Acceleration

Lewis acid catalysis not only dramatically increases rates by ca 10+6

it also improves reaction regiochemistry & endo diastereoselectivity

Diels-Alder Reaction: Regiochemistry

D. A. Evans

Chem 206

Here is an interesting problem in reaction design

Orientation of Reacting Partners
CO2H

CO2H
CO2H

CO2H

COX RO

COX

CO2H
RO

RO

favored

CO2H

favored

disfavored

4.5 : 01 @ 100 C

PhS
MgBr2

COX Me

Me

COX

COMe

AcO

disfavored

toluene, 120 C

59 : 41

C6H6, SnCl4, 25 C

96 : 04

Ni(Raney)

PhS

COMe PhS

AcO

AcO

Trost, JACS 1980, 102, 3554

Me

favored

disfavored

However, what if you need the disfavored product?

Lewis acid catalysis improves orientation

COX

COX

disfavored

favored

By employing a removable substituent, it is possible to access the normally

disfavored product diastereomer
O2N

In general, 1-substituted dienes are more regioselective than their

2-substituted counterparts: Sauer, Angew. Chem. Int. Ed., 1967, 6, 16-33

COMe

RO

NO2
CO2Me

RO

CO2Me

Danishefsky, JACS 1978, 100, 2918: The NO2 FG completely dominates directivity

Lewis acid catalysis improves endo diastereoselection

It then can be
removed by elimination

CO2Me

RO

base

CO2Me

NO2

RO

CO2Me

RO

CO2Me

CO2Me
H

CO2Me

favored

NO2

disfavored

CH2Cl2, 0 C

80 : 20

C6H6, SnCl4, 25 C

95 : 05

NO2

or by reduction
Ono, Tet. 1985, 4013
RO

R3SnH

CO2Me
O

83%

R3SnH
86%

DA Reactions Part II: The Reaction Mechanism,

Sauer, Angew. Chem. Int. Ed., 1967, 6, 16-33

NO2

Me

Ono, Chem. Commun. 1982, 33-34

O2N

Me

Me

mixture of ring-fusion
isomers

Chem 206

Diels-Alder Reaction: Regiochemistry

D. A. Evans

Instructive Issues of Regiocontrol with Quinone Dienophiles

O

O
Me

Me

Me
Me

MeOCH2
Cu(BF4)2

CH2OMe

Me

Cl

Cl

0 C

CN

CH2OMe

Cl
CN

CN
MeO

MeO

O
Me

Me

Me

SnCl4 (-20 )

<5 : 95

Me

Diels-Alder Reactions with Chiral Dienes

Comprehensive Organic Synthesis, Vol. 5, Trost, Ed. 1991
4.1 Intermolecular Diels-Alder Reactions, W. Oppolzer, See page 347

80 : 20

O
X

Me
Me

NPh

!+ Me

O
PhN

Me

X=

Me

O
X

Overman, JACS 1988, 110, 4625

selection >95 :5

Sn O
Cl4

PhN

O
MeO

25-50 C

selection 80 : 20
MeO

Ratio: 90 : 10

Corey, JACS 1969, 91, 5675

Ratio
50 : 50

!+

thermal (100 )
BF3OEt2 (-20 )

Me

Conditions

Orientation of Reacting Partners

controlled by Lewis acid structure
Reusch JOC 1980, 45, 5013
F3B

MeO

Me

Me

OR

Similar results provided by Stoodley Chem. Comm. 1982, 929

Me

O
NPh

Ratio

OH

36 : 64

Me

83 : 17

OMe

>97 : 3

Me

OR

OR

O
25-50 C

NPh

NPh

Kelly Tet. Let. 1978, 4311

O

OMe
BF3OEt2

OMe

RO

selection >95 :5

0.4 equiv

OH
Me
O

Franck, Tet. Lett. 1985, 26, 3187

Franck, JACS 1988,110, 3257

Me

selection >95 :5
OH

OMe

Me

Me
H

! Avoid Eclipsing allylic substituents

! better donor (Me) anti to forming bond

0.5 equiv

Me

R = Me: Ratio; 83 : 17
R = Me3Si: Ratio; 88 : 12

Comments on the Transition State

RO

Me

O
O

MgI2

OMe

Me

Me

RO

OH

Me

! avoid gauche OR interaction

Me
PhN
O

RO
H

OR

better than

Me
PhN
O

Diels-Alder Reaction: Selected Problems from the Database

D. A. Evans

Problem 76, Bodwell has disclosed an interesting thermally initiated reaction cascade that
was designed to cuminate in a formal synthesis of strychnine(Angew. Chem. Int. Ed 2002,
41, 3261). One of his reported transformations is illustrated below.
NCO2Me
N

NCO2Me
heat, 48 h

Problem 157. A short reaction sequence that results in the rapid assemblage of the taxane
skeleton has been reported by Winkler (Tetrahedron Lett.1995, 36, 687). This
transformation is illustrated below wherein intermediate A is subsequently induced to react
with divinyl ketone.
Provide a concise mechanism for this reaction. For full credit, the relative stereochemical
relationships at the indicated stereocenters must be provided.

Problem 86. In 1983 Masamune introduced a new family of chiral controllers for the DielsAlder reaction (J. Org. Chem. 1983, 48, 4441).

Me

ZnCl2
45 C

OEt
C7H15

(1)

Please provide a mechanism for the reaction shown in equation 1. Be sure to include
clear transition state drawings in your answer, and predict the stereochemistry of the
major product diastereomer.

C7H15

OH

H
O
OEt

OH

HO

C7H15

Problem 778. Boger and co-workers recently reported the synthesis of the indole alkaloid
minovine (1). This pivotal transformations leads to the construction of the minovine skeleton.
Provide plausible mechanisms for this transformation.

heat

Me
MeAlCl2

Me

Me

CH2Cl2
Me

160 oC

Problem 112. In a recent article, Roush reported the highly endo-selective, Lewis acid
catalyzed Diels-alder reaction illustrated below (Org. Lett 2001, 3, 957). Using your
knowledge of Diels-Alder transition states, draw the transition state of this reaction, and
from this drawing, predict the relative stereochemical relationships that are to be anticipated
in the product.

MgBr2Et3N

CMe3
exo:endo = 94:6
endo diastereoselection >99:1

Me

EtO

OH

+ A

O S

Me

Me
Me

Lewis acid

Problem 739. The rapid assembly of the bicyclo[5.3.1]undecane core of penostatin F was
recently reported by Barriault and coworkers (Org. Lett. 2004, 6, 1317). In this remarkable
transformation dihydropyran 1 is converted to the highly complex tricycle 3 in only two
operations. Please provide a detailed mechanism for this reaction sequence. Be sure to
indicate all pericyclic reactions.

heat

Provide a detailed mechanism for this reaction cascade. Your answer should include threedimensional structures that accurately depict ground and transition state representations.

CMe3

Me

Me

N2

OH

Chem 206

diastereoselection >99:1

Problem 794. Doering and Rosenthal reported the interesting conversion of Nenitzescu's
hydrocarbon (1) to dihydro-naphthalene (2). Provide a mechanistic rationalization for this
transformation. (Reference: Doering, W.v.E.; Rosenthal, J.W., JACS 1966, 88, 2078)

Me
R

300 C