Chem 206D. A. Evans Cycloaddition Reactions: Diels-Alder Reaction

Problem of the Day:

The Diels-Alder Cycloaddition Reactions

"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)

X

CHO

R

XCHO

R

+5% catalyst

MeOH-H2O

NH

N

O Me

PhCH2Me

Mecatalyst

Rationalize the sense of asymmetric induction for this Diels-Alder Reaction reported by MacMillan, JACS, 2000, 122, 4243. (pdf)

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

Angew Chem. Int. Ed. 2002, 41, 1668-1698 (electronic handout)

Catalytic Enantioselective Diels–Alder 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 Diels–Alder Reactions

Emily M. Stocking and Robert M. Williams, Angew Chem. Int. Ed.

2003, 42, 3078-3115 (electronic handout)

Pavel Nagorny

Wednesday, October 25, 2006

Reading Assignment for week:

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

Chemistry 206

Advanced Organic Chemistry

Lecture Number 16

Cycloaddition Reactions-1

! Cycloadditions: Introduction

! Ketene Cycloadditions

! The Diels-Alder Reaction

Carey & Sundberg: Part B; Chapter 6Cycloadditions, Unimolecular Rearrangements

Thermal Eliminations

http://www.courses.fas.harvard.edu/colgsas/1063

Problem 210. Question and Answer. The carbonyl ene reaction is illustrated below. Using FMO analysis, evaluate thetransition state of this reaction. Your answer should include: a transition state drawing; clear orbital depictions and HOMO-LUMO assignments; an indication of the number of electrons from each segment; and indication of whether the reaction isthermally allowed.

OH

Ra

O CH2

Ra RbH

Rb

+

The Carbonyl Ene Reaction

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.

Chem 206D.A. Evans

HO

Ra

HRb

H

H

Rb

Ra

H

The ene transition state

H

Rb

Ra

H

View the ene TS as a 3-component cycloaddition

allyl HOMO

carbonyl LUMO

Rb

HRa

H

bondingbonding

bonding

[2!s + 2!s +2"s]

One possible analysis:

allyl anion: 4 e-

Proton

carbonyl: 2 e-

6!e- "cycloaddition"

suprafacial

thermally allowed

Answer

O

C

O

C

O

C

O

Ra

H

CH2

Rb

H

Cycloaddition Reactions-1 Chem 206D. A. Evans

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

O

O

O

O

O

O

O

O

O

X[4+2] [2+2]

heat

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

X

Y

X

Y Y

X

••

! We also know that the photochemical variant is concerted

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

! Nomenclature

C

C

!2sC

C

!2a

Using this nomenclature, the Diels-Alder reaction is a !4s + !2s cycloaddition

antarafacialsuprafacial

bonding

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

C

C!2s

C

C!2s

antibonding

[ !2s + !2s] "forbidden"

C

C

!2aC

C

!2s

[ !2s + !2a] "allowed"

bonding

bonding

!

!*

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

CC

!*

!

light !

newHOMO

light

CCconcerted + energy

!

+

CC

CC

C C

C

C

C

C

!

bonding

bonding

HOMO

LUMO

C

C

C

C

[2+2] Cycloaddition - Examples

Me

h!

["2s + "2

s]

Me

MeMe

Me

Me

Me h!

["2s + "2

s]

MeMe

Me

Me

Me

Quadricyclane

Prismane-Der.

Dauben, Tet. 1961, 15, 197.

Schäfer, AC 1967, 79, 54.

Dewar benzene-Derivative

[!2s + !2

a]

H

TL 1967, 4357, 4723.must be antarafical for indicated stereochem

Cycloaddition Reactions-2 Chem 30D. A. Evans

C

O

R R'

OR

R'

OR

R'

R'

RO

O

OR

R'

R'

R

Alkene

Summary of Ketene Cycloadditions

N

OR

R'

O

OR

R'

Imine

Carbonyl

X

Y

Y

X O

R'

R

O

R'

R = -CH=CH2

Ketene Preparation

HCl

OR3N

R

C O

H

R

H

Cl

O

R

B:B–H

Cl

E2 Elimination

HOR

O

R

H

OR

O

R

LiNR2

C O

H

R

E1cb Elimination

–ZnCl2ClCl

O

R

C O

H

R

Cl

Cl

O

R

B:

Zn

OR

R

R

CO

R

R

R

h!

or "

ElectrocyclicRing Opening

R

H

O

N2

C O

H

Ror !

h"

R

H

O

R

H

O

O

[!2s!

2a]

!

C

O

R R

C

R

R

R

R

Antarafacial Suprafacial

Cycloaddition: FMO Analysis

R

R

HOMO

R

R

LUMO

C

C

RR

O

bondingbonding

Cycloaddition Reactions-3 Chem 30D. A. Evans

[2+2]: Stepwise Versus Concerted

H R

H R

C C O

R'

H

RH

H R

CR'

HO

OR'

R Rleast hinderedbond rotation

• Very large polar effects

• E olefins yield a mixture of cis and trans products

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

• KIE seen for many reactions support stepwise mechanism

• Calculations show a highly asynchronus transition state.

• Stereochemical consequence can be rationalized by stepwise mechanism

Stepwise

Concerted • Ketenes add stereoselectively to Z alkenes.

• Z olefins are much more reactive than E olefins

O

C

Me Me

O

C

Me Me

Me Me

OMe

Me

Me Me

OMe

Me

Me Me

OMe

Me

Me Me

+

Fast

1 : 2

!

!

Me

Me

+

+

Ketene-Alkene [2+2]

OCMe

Me

Me+

C

Me

Me

CHMe

MeH

O

C

Me

Me

CMeH

MeH

O

Me

O

CMe3

CO2H

1. (COCl)2, PhH, !

2. NBu3, toluene, !

O

CMe3

H

O H

CH2COCl

HNEt3

O

CO

H

MeO

C

O

ClCl

O

Cl

Cl

C

O

ClCl

Cl

Cl

Zn+

O

H H

O

C

H H

OO

H HH H

OO

HHH

H

OO

+

38 kcal/mol

32 kcal/mol

Ketenes + Aldehydes Afford !-Lactones

path A

path B

ab initio Calulations

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

favored

Cycloaddition Reactions-4 Chem 30D. A. Evans

Transformations of !-Lactones

O

R2

R1

O R2

R1

O

O

S O

O

_+

" or BF3

-CO2

Me2S

O

R2N O R2N CO2H

R'CuCN

R'Li (2eq)

Vederas et al JACS 1987, 107, 4649.

Most soft Nuattack Csp3

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.

N

S

O

HHR

N

S

C

O

HREt3N

O

R

Cl

NR

R

O

HHR

NR

R

(1)

(2)

H

H

(Z)

(E)

The stepwise mechanism,,,,

C

O

HR

NR

R HN

R

H

RR

O

H

NR

R

O

HHR

(E) Imine ! Cis Product

conrotatoryclosure

N

R

H

R

R

O

H

NR

R

O

HHR

NS

HR

O

H

C

O

HR

N

SH

N

S

O

HHR

conrotatoryclosure

NS

HR

O

H

N

S

O

HHR

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

(Z) Imine ! Trans Product

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

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

NBn

Ar

O

HHN

O

Ph

O

O Cl

NBn

ArH

N

O

Ph

O

Et3N

NBn

Ar

O

HHN

O

Ph

O

diastereoselection > 95:580-90% yields

+

Cycloaddition Reactions-5 Chem 206D. A. Evans

Me

O

Br H R

O OO

R

O

C

CH2

N

N

NF3CO2S SO2CF3

Bn

Al

R

i-Pr i-Pr

5a: R = Me5b: R = Cl

+catalyst (10 mol%)

i-Pr2NEt

[RCHO • cat.]R3N

cat. =

Enantioselective Ketene-Aldehyde Cycloaddiitons

R3NH•Br

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

Me3C

BnOCH2

a

b

c

d

92 (R)

Aldehyde 2 (R)entry % yield

CH2CH(CH2)8—

% ee 3(configuration)

91

89 (R)74

92 (S)93

91 (S)91

91 (S)90

54 (R)56

e

93 (S)80

f

catalyst[time (h), temp (°C)]

5b (8, -40)

5a (16, -50)

95 (S)895a (72, -78)

5b (16, -50)

5b (16, -40)

5a (24, -50)

5b (16, -40)

5b (24, -40)

93 (R)86g 5a (16, -50)

85 (R)91h 5a (16, -50)

i

BnOCH2—

C6H11—

PhCH2CH2—

BnOCH2CH2—

TBDPSOCH2—

Me2CHCH2—

PhCH2CH2—

O

Me3SiH

O

O

OEt+ 1 mol%, THF, 3Å MS

-78 °C, 24 h

C

77% yield, 93% ee

NCu

N

O O

Me3C CMe3H2O OH2OTf

Me Me +

OTf_

H

3: >99% yield, 92% ee

O

O

EtO2C

KF, CH3CN

O

OPhMe2Si

EtO2C

1)

O

OPhMe2Si

EtO2C

N CuN

O

OO

OR2

Me

RR

H

H

O

Me3Si

H

O

CC

R1

Me

observed productO

O

OR2O

R1

Me3Si

2+

Cu

OH2

Me

NN

CMe3Me3C

Me

OO

H2O

+ 2 CF3SO3–

2+

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

The Diels-Alder Reaction Chem 206D. A. Evans

! Representative natural products displaying the Diels-Alder retron:

+

‡! The Reaction:

Articles and monographs of Significance

"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)

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

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

Catalytic Enantioselective Diels–Alder Reactions: Methods, Mechanistic

Fundamentals, Pathways, and Applications, E. J. Corey, Angew Chem. Int.

Ed. 2002, 41, 1650-1667 (pdf)

Chemistry and Biology of Biosynthetic Diels–Alder Reactions

Emily M. Stocking and Robert M. Williams, Angew Chem. Int. Ed. 2003, 42,

3078-3115 (pdf)

Recent Advances in Natural Product Synthesis by Using Intramolecular

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

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

Endiandric Acid B

(Syntheses) Nicolaou, JACS 1982, 104, 5555-5562

Endiandric Acid C

HO2CH

H PhH

H

H

H

Ph

CO2HH

HH

H

X-14547A

Hirama, JACS 1982, 104, 4251

Girotra, Tet. Let. 1983, 24, 3687

Heathcock, JACS 1985, 107, 3731

Grieco, JACS 1986, 108, 5908

Keck, JOC 1986, 51, 2487

Kozikowski, JOC 1987, 52, 3541

Clive, JACS 1988, 110, 6914

Ley Chem. Commun. 1983, 630

Nicolaou JOC 1985, 50, 1440

Roush JOC 1984, 49, 3429

(Biosynthesis) JACS 1985, 107, 3694

Mevinolin: R = Me

Compactin: R = H

(Synthesis) JACS, 1993, 115, 4497

Lepicidin

O

H

O

MeOMe

MeOOMe

NMe2

O

O

O

O

MeEt

H

O

H

HHH

H

H

Me

H

H

H

H

R

Me

O

OHO

HO

Et

H

O

Me

OMe

Me

Et

Et

HN

O

COOH

H

H

H

H

ent-FR182877 (WS9885B)

H

OH

HO

Me

Me

OO

O

Me

Me

H

H

J. Antibiotics 2000, 53, 204

CO2Et

Me

TBSO

MeTBSO

OTBS

MeO

Br

Sorensen, JACS 2003, 125, 5393Evans, JACS 2003, 125, 13531

DAHet DA

O

Br

TBSO

TBSO

OTBS

Me

Me

Me

H H

H

CO2Et

H

Diels-Alder Reaction-Orbital Symmetry ConsiderationsD. A. Evans Chem 206

En

erg

y

disfavored favored

The Alder Endo RuleThe following observation illustrates an example of the Alder Rule which will be defined below.

+

"Endo product""Exo 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.

2

Exo TS ‡

Endo TS ‡

H

HH

H

H

H

HH

If the symmetries of the frontier MO's of reacting partners are "properly matched" thereaction 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.

Orbital Symmetry Considerations for Diels Alder Reaction

LUMO-!3

HOMO-!2CC

C C

C

CC

C

LUMO-!3

HOMO-!2

CC

C C

C

CC

C

! 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:

LUMO-!3

HOMO-!2

Frontier MO Explanation for the Endo Rule

C

CC

C

CCC C

! Note that the termini only match at one end for theHOMO-LUMO pairing. Hence we say that the symmetryrequirements 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 reactionsare called "symmetry-forbidden". LUMO-!3

HOMO-!2

Does the possibility for the followingconcerted dimerization exist?

The Other Dimerization Possibility for Butadiene

C C

C C

C

C C

C

"

Chem 206D. A. Evans Diels-Alder Reaction: The Transition Structure

Houk, Jorgensen, JACS 1989, 111, 9172

Jorgensen, JACS 1993, 115, 2936-2942leading references:

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

Transition State Modelling is Coming of Age

Transition Structures of Hydrocarbon Pericyclic ReactionsHouk Angew. chem. Int. Ed. 1992, 31, 682-708

‡

+

! Diene Reactivity as measured against Maleic anhydride

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

log k = 4.96 log k = 1.83log k = 2.12log k = 2.19log k = 2.36

Me

Me

Dienophile

E(LUMO1) - E(HOMO2)or

E(LUMO2) - E(HOMO1)

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

LUMO1LUMO2

HOMO2

HOMO1

Diene

The Critical Energy Difference:

en

erg

y

! Lewis Acid Catalysis of the reaction is possible: Yates & Eaton, JACS 1960, 82, 4436

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

it also improves reaction regiochemistry & endo diastereoselectivity

Ethylene & Butadiene Vs Butadiene & Acrolein

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

+

LUMO1

HOMO1

+

E

HOMO3

LUMO3

HOMO2

LUMO2

H

O O

H

Diels-Alder Reaction: RegiochemistryD. A. Evans Chem 206

Orientation of Reacting Partners

favored disfavored

4.5 : 01 @ 100 °C

CO2HCO2H

CO2H CO2H CO2H

CO2H

disfavoredfavored

toluene, 120 °C 59 : 41

96 : 04C6H6, SnCl4, 25 °C

Lewis acid catalysis improves orientation

In general, 1-substituted dienes are more regioselective than their 2-substituted counterparts: Sauer, Angew. Chem. Int. Ed., 1967, 6, 16-33

COX

Me

MeCOX

Me

COX

favored disfavored

C6H6, SnCl4, 25 °C 95 : 05

80 : 20CH2Cl2, 0 °C

Lewis acid catalysis improves endo diastereoselection

DA Reactions Part II: The Reaction Mechanism, Sauer, Angew. Chem. Int. Ed., 1967, 6, 16-33

CO2Me

CO2Me

H CO2Me

H

Here is an interesting problem in reaction design

favored disfavored

However, what if you need the disfavored product?

COX

RO

COX RO

RO

COX

disfavored favored

Ni(Raney)

Trost, JACS 1980, 102, 3554

PhS PhS

AcOAcO

COMe

AcOCOMe

PhS

COMe

MgBr2

By employing a removable substituent, it is possible to access the normallydisfavored product diastereomer

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

CO2Me RO

NO2

RO

O2N

CO2Me

–NO2–

baseIt then can be removed by elimination

or by reductionOno, Tet. 1985, 4013

83%

86%

mixture of ring-fusionisomers

Ono, Chem. Commun. 1982, 33-34

CO2Me RO

CO2Me

NO2

RO CO2Me

RO

NO2

ROCO2Me

NO2

O O

O2NMe

H

Me Me

H

H

O

R3SnH

R3SnH

Chem 206D. A. Evans Diels-Alder Reaction: Regiochemistry

Instructive Issues of Regiocontrol with Quinone Dienophiles

Orientation of Reacting Partnerscontrolled by Lewis acid structure

Conditions Ratio

thermal (100 °)

SnCl4 (-20 °)

50 : 50

<5 : 95

80 : 20BF3•OEt2 (-20 °)Reusch JOC 1980, 45, 5013

O

O

MeO

Me Me Me

MeO

O

O

H

Me

MeH

O

O

MeO

Me

!+ selection 80 : 20

selection >95 :5

!+

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

Me

O

O

O

Me

Me Me

H

O

O

MeO

Me

MeH

O

O

MeO

Me

MeOSn

Cl4

OMe

O

Me

F3B

0.5 equiv

0.4 equivselection >95 :5

selection >95 :5

Kelly Tet. Let. 1978, 4311

O

OOH

RO

OMe

Me

OMe

Me

RO

OH O

O OMe

Me

Me

OMe

O

OOH

ROMgI2

BF3•OEt2

Corey, JACS 1969, 91, 5675 Ratio: 90 : 10

0 °CCN

CN

Cl Cl

CN

CH2OMe

Cl

MeOCH2 H H CH2OMe

Cu(BF4)2

25-50 °C

4.1 Intermolecular Diels-Alder Reactions, W. Oppolzer, See page 347

Comprehensive Organic Synthesis, Vol. 5, Trost, Ed. 1991

83 : 17

>97 : 3

36 : 64

Ratio

–OH

–OMe

–Me

X =

Overman, JACS 1988, 110, 4625

X

Ph–N

X

H

O

O

H

O

O

X

Ph–N

H

HO

O

N–Ph

Diels-Alder Reactions with Chiral Dienes

25-50 °C

Franck, Tet. Lett. 1985, 26, 3187

Franck, JACS 1988,110, 3257

R = Me: Ratio; 83 : 17

R = Me3Si: Ratio; 88 : 12

N–Ph

O

OMe

ORMe OR

Me

Me Me OR

O

O

N–Ph

Me O

O

N–Ph

better than

Comments on the Transition State

! Avoid Eclipsing allylic substituents

! better donor (Me) anti to forming bond

! avoid gauche OR interactionPhN

O

OMe

Me

ORH

PhNO

O

ROH

Me

Me

Chem 206D. A. Evans Diels-Alder Reaction: Selected Problems from the Database

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.

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

N NN

NCO2Me

N

NCO2Me

heat, 48 h

–N2

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

OOH

CMe3

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

(1)

OOH

CMe3

ZnCl2

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.

–45 °C

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

Me

MeR

Me

O MeAlCl2CH2Cl2

Me

RMe

Me

O

diastereoselection >99:1

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.

Me

SMe Me

OO

heat

A

O

+

Lewis acid

O

MeMe

Me

❊❊

❊

OEtO

OH

EtO

C7H15

OO

HO

HH

C7H15

O

160 oC

1 3

MgBr2•Et3N

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.

O

H

OEtC7H15

OOH2

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

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)

300 °C

1 2