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Enantioselective Diels-Alder Reactions

D. A. Evans

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 (pdf)

Chemistry 206
Advanced Organic Chemistry
Lecture Number 18

Cycloaddition Reactions-3
! The Diels-Alder Reaction
Enantioselective Processes

! Reading Assignment for week:


Carey & Sundberg: Part A; Chapter 11
Concerted Pericyclic Reactions
Carey & Sundberg: Part B; Chapter 6
Cycloadditions, Unimolecular Rearrangements
Thermal Eliminations
"Chiral Bis(oxazoline) Copper (II) Complexes: Versatile Catalysts for
Enantioselective Cycloaddition, Adol, Michael and Carbonyl Ene
Reactions". Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325335. (handout)

The formyl CHO hydrogen bond as a critical factor in enantioselective


Lewis-acid catalyzed reactions of aldehydes, Corey, Lee, Chem Commun.
2001, 1321 (handout)
New Strategies for Organic Catalysis: The First Highly Enantioselective
Organocatalytic Diels-Alder Reaction, MacMillan, D. JACS 2000, 122, 4243
(handout)

D. A. Evans

Chem 206

Monday
October 30, 2006

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


Int. Ed. 2002, 41, 1668-1698 (pdf)
Catalytic Enantioselective DielsAlder Reactions: Methods, Mechanistic
Fundamentals, Pathways, and Applications, E. J. Corey, Angew Chem. Int.
Ed. 2002, 41, 1650-1667 (pdf)
Chemistry and Biology of Biosynthetic DielsAlder Reactions
Emily M. Stocking and Robert M. Williams, Angew Chem. Int. Ed. 2003, 42,
3078-3115 (pdf)
Chiral Lewis Acids in Catalytic Asymmetric Reactions, Narasaka, Synthesis,
1991, 1-11 (pdf)
Carbonyl-Lewis Acid Complexes Schreiber, Angew. Chem. Int. Ed., 1990, 29,
256-272 (pdf)
Problem 363. The C2-symmetric cationic Cu(II) complex 1 is a chiral Lewis
acid catalyst that exhibits good chelating potential. Palomo has reported the
utilization of 1 in the catalyzed Diels-Alder reaction is illustrated below (JACS,
2003, 125, 3943). Provide the absolute stereochemistry of the product of this
reaction. Provide a 3-dimensional drawing of the transition state for this
reaction.
O
HO
Ph
Me

10 mol% 1

+ C5H6

Ph
Me

rt, 8 h

Me

O
N

Cu
Me3C

OH

2+

Me Me

CMe3

Me

OTf

O
99% ee, 90% yield
endo/exo: 91:9

The Diels-Alder Reaction: Enantioselective Catalysis

D. A. Evans

Chem 206

Problem B: Design of a well-defined Dienophile-LA Complex

The Design of Enantioselective Diels-Alder Catalysts


R'

Early Empirical Studies

Chiral Lewis Acids in Catalytic Asymmetric Reactions


Narasaka, Synthesis, 1991, 1-11 (pdf)

X
R

O
X

chiral Lewis acid


catalyst

Me

R'

O
EtAlCl2

R'

Chiral
complex

X
OH

16 mol%

Me

Me
O

Problem A: Reacting conformation of the dienophile


The S-cis versus S-trans dienophile conformation is coupled to the
geometry of the Lewis acid-dienophile complex & both issues
determine face selection
M

L
S

R'
O

re-face

O
X

re-face

R
M
O

L
M

si-face
R

(Z) s-cis

O
X
R

si-face

CHO

78 C

72% ee

Me

Me

L
M

M
M

toluene

OtBu

Me
+

L
R'

(E) s-cis

K. Koga, Chem. Commun. 1979, 437

TMSO

Ph

10 C

Me

55-58% ee
Ph

O
R

C3F7

Danishefsky, Tetrahedron Lett. 1983, 24, 3451

hfc ligand

Theoretical Studies on Conformations of Acrolein & Methyl


Acrylate & their Lewis Acid Complexes
Houk, JACS, 1987, 109, 14-23

Eu(hfc)3

O
O

Eu

The Diels-Alder Reaction: Enantioselective Catalysis

D. A. Evans

Chem 206

Transition from Chiral Auxiliary Control to Asymmetric Catalysis


with Chapman, Bisaha, JACS, 1984, 106, 4261, JACS, 1988, 110, 1238

Me

Me
Al

O
R

Relocate
chirality

Ph

Ph

Ph

Me Me

Ti

Ph

N
M

Bn
R

s-cis conformation
strongly favored

Narasaka JACS, 1989, 111, 5340


O

O
N

R
H

Me

Ph

Ph

Ph

Ph

Ph

OH HO

TiCl2(OiPr)2
molecular
sieves

"Endo 4"

10% cat

The hunt for the "best" catalytic metal center has begun!

Ox

Me

Ph

O
Ph

Ph
Ph

O
Cl

Ti

O
Cl

O
O

10 mol % cat

-50 C
O

Ph
Me

+ 2 i-PrOH

O
N

Ph

Me

Me

76% ee

Ph

Me

Me

N
FeI3

Me

O
N

Ph

N
MgI2

Me
Me

Ph

86% ee

Fe(3+) Corey JACS, 1991, 113, 728; Mg(2+) Corey Tet. Lett. 1992, 45, 6807

These catalysts are superior for unsubstituted dienophiles

The Diels-Alder Reaction: Enantioselective Catalysis

D. A. Evans

Cu(II) Lewis Acids: Evans, Miller, Lectka, JACS 1993, 115, 6460.
Me
O

O
N

Me

Cu(OTf)2

HO

-78 C

10 % Cu(II) catalyst

Catalyst (R) Endo ee


R = Ph

30%

R = CHMe2

58%

R = CMe3

>98%

Temp

50 C
0 C
25 C

Endo ee
98%
92%
86%

Chem 206

Metal-Box Complexes: A Comparison

D. A. Evans

O
O

10 mol % catalyst

50 C
Endo-1

Endo/Exo = 94:6
Endo ratio = 88:12 (Endo-2)
Me

Endo ratio = 99:1 (Endo-1)

Ph

Ph

Me

Me

t-Bu

Ph

Me +

Cu(OTf)2

t-Bu

Endo/Exo = 96:4

Endo/Exo = 80:20
Endo ratio = 50:50

Endo ratio = 98:2

O
N

N
MgI2-I2

Me

O
N

Endo/Exo = 76:24
Endo ratio = 66:34

Endo ratio = 93:7 (Endo-2)

FeI3-I2

Endo-2

Endo/Exo = 97:3

Me
O

Endo/Exo = 95:5

Me

Ph

Chem 206

Me

10 mol % catalyst

H
Me

-15 C

with S. Miller, JACS 1999, 121, 7559-7573

D. A. Evans

Torsional Rigidity of Catalyst-Substrate Complex

Me

Me

O
N

C5H6, -78 C

Cu
Me3C

Expected Outcome

O
N
O

steric bulk
on same face

Matched case if Cu center


square-planar

O
N

N
Cu

C5H6, -78 C

CMe3

O
N

steric bulk
on opposite faces

catalyst control

Me

Me3C

Bn

Bn
Me

highly
diastereoselective

HO

CMe3

Chem 206

Mismatched case if Cu center


square-planar

Bn

poorly
diastereoselective

H O
N

slow reaction

Bn

torsional pressure
C5H6, -78 C

H O

Tetrahedral Complex

Matched case if Cu center


Tetrahedral

substrate control

Bn

This test for torsional rigidity may be applied to any catalyst-substrate complex

D. A. Evans

Torsional Rigidity of Catalyst-Substrate Complex


Me

Me

O
N
O

C5H6, -78 C

Matched case if Cu center


square-planar

Endo(1): Endo(2) ! 99:1


O

100% conversion

Me

O
N

N
Cu

Me3C

N
Bn

Bn

Me

CMe3

O
N

steric bulk
opposite faces

HO

CMe3

O
N

steric bulk
same face

Outcome

N
Cu

Me3C

Chem 206

Bn

C5H6, -78 C

Endo(1): Endo(2) = 68:32

HO

Mismatched case if Cu center


square-planar

20% conversion
Catalyst control

Bn

Cu(II) strongly resists distortion from square planar to tetrahedral.


Other metals such Mg(II), Fe(III), and Zn(II) succumb to internal
stereochemical "pressure."
JACS 1999, 121, 7559-7573; JACS 1999, 121, 7582-7594

Diels-Alder Reaction Scope: (Box)Cu(SbF6)22H2O Catalyst

D. A. Evans

R = Me
+25 C
O
R

O
N

H
H

10 mol% cat.
CH2Cl2

O
N

counterion

time

endo ee

yield

X = TfO
X = SbF6

8h
8h

94% ee
96% ee

95%
98%

counterion

time

endo ee

yield

X = TfO
X = SbF6

24 h
24 h

90% ee
96% ee

counterion

time

endo ee

X = TfO
X = SbF6

24 h
18 h

53% ee
94% ee

R
O

R = Ph

+25 C

R = Cl
O

O
N

2-5 mol% cat.


CH2Cl2

+25 C

counterion
+25 C

R = Ph
-20 C

R = OAc
0 C

time

endo ee

X = TfO
X = SbF6

12 h
12 h

86% ee
94% ee

counterion

time

endo ee

X = TfO
X = SbF6

12 h
24 h

86% ee
97 % ee

counterion

time

endo ee

X = SbF6

24 h

97 % ee

85%
95%
yield
---95%

O
O

R = Me

Chem 206

yield

O
N

72%
89%

10 mol% cat.
CH2Cl2 +25 C
O

yield
72%
95%

counterion

time

endo ee

X = TfO
X = SbF6

48 h
5h

82% ee
93% ee

yield
90%
90%

yield
100%

JACS 1999, 121, 7559-7573; JACS 1999, 121, 7582-7594

Extensions may be made to other Dienophiles

Me

Me

C. Palomo et al., JACS 2003, 125, 13942-13943

O
N

O
OH

R'
Me

Me

Me3C

OH

10 mol% cat 1a (X = OTf)


rt, CH2Cl2

Cu

H Me

CMe3

catalyst 1a: X = OTf


catalyst 1d: X = SbF6

Me

endo: exo >99:1


>98% ee, 93% yield

Stereochemical Model
Me

Me

O
Me3C

O
N

O-H

CMe3

Cu
H

H
R'

Me
Me

Diene Approach

Chiral Cu(2+) Complexes as Chiral Lewis Acids

D. A. Evans

Chem 206

Cu(box) and Cu(pybox) catalyst-substrate complexes implicated in enantioselective reactions.


"Chiral Bis(oxazoline) Copper (II) Complexes: Versatile Catalysts for Enantioselective Cycloaddition, Adol,
Michael and Carbonyl Ene Reactions". Johnson, Evans, Acc. Chem. Res. 2000, 33, 325-335. (pdf)

Me

2+

Me

Me
O

O
N

Me

Me3C

CMe3

O
N

RO2C

O
N

CMe3

O
N

2+

O
N

Cu

2+

Me

2 X

Cu
Me3C

2+

Me

2 X

Cu
Me3C

N
O

MeO

CMe3

Cu
O

Ph

OMe

2 X

N
N
OBn

Ph

Cycloaddition Reactions
Michael Reactions

Me

2+

Me

Enol Amination Reactons

Me

2+

Me

2X

Cu
Me3C O

CMe3

Me

CMe3

2 X

Me3C O

CMe3
Bn

OR'
OR'

Hetero Diels-Alder Reactions

N
Cu

P
R

2+

2 X

Aldol Reactions

2+

Me

Cu
Me3C

OR'
R

Michael Reactions

N
N

Cu

N
Bn

OR'

R = H, Cycloaddition Reactions
Ene Reactions
R = Alkyl, Cycloaddition Reactions
Aldol Reactions

Diels-Alder Reactions

2 X

Chiral Boron Lewis Acids

DA. Evans

Chem 206

Boron-Based Catalyst: Hawkins JACS 1991, 113, 7794

10 mol %
H

H
BCl2

OMe
R

re-face

Temp (C)

Endo ee

-78

97 %

Me

-20

91 %

CO2Me

-78

92 %

Endo/Exo Ratios not provided.


R
CO2Me

The pragmatic Issue:


The cost of producing the chiral
catalyst

Chiral Boron Lewis Acids

DA. Evans, E. P. Balskus

Chem 206

A New Hydrogen Bonding Motif


F
B

O
R

F
R

2.352.36

O R
2.412.59

sum of the van der Waals radii:


2.72 (H = 1.20 and O = 1.52 ).

sum of the van der Waals radii:


2.67 (H = 1.20 and F = 1.47 ).

The formyl CHO hydrogen bond as a critical factor in


enantioselective Lewis-acid catalyzed reactions of aldehydes,
Corey, Lee, Chem Commun. 2001, 1321 (pdf)

"There may also be a contribution from an anomeric


effect in which electrons from the noncomplexed lone
pair on aldehyde oxygen delocalize into the !*orbital of
the eclipsed BF or BO bond. The authors of one
study1 attributed a value of 6 kJ mol to the anomeric
effect and 9 kJ mol21 to the formyl hydrogen bond.4
(1) M. D. Mackey and J. M. Goodman,
Chem. Commun., 1997, 2383

!* BX
B
O
R

X
H

A possiible anomeric effect


Yamamoto et al. J. Org. Chem. 1992, 57, 1951-1952

Furuta, K.; Miwa, Y.; Iwanaga, K.; Yamamoto, H. JACS 1988, 110, 6254.

PriO
OMe O

78 C, 6 h

CO2R'
O

OMe O

Me

Me
89:11(exo:endo)
96% ee

CHO

40 C, 11 h

Me

Me

CHO

10% cat
91% ee

MeO

OiPr O

Note modifications to catalyst

OMe

OMe
Me

R' = H or Alkyl
X = H or Acyloxy
Me

CO2R'

CHO

10% cat

B X

PhCHO
20 mol% cat

TMSO
Me

Me

Me

OR

TFA

Ph

O
O

Ph
Me

Me
97% ee, 95% yield

Chiral Boron Lewis Acids

DA. Evans, E. P. Balskus

Chem 206

Oxazaborolidine Catalysts: Corey JACS 2002, 124, 3808.


H Ar
N

H Ar

H Ar

Ar
O

N
H

Me

H
OTf

OTf
Me

COR
R= H, alkyl OH, OR

Ar

Ar

TfOH

dienophile =

R'

O
Alkene CH - O interaction may organize complex

Me

Aryl groups screen back face of dienophile


!" stacking may also be involved

active catalyst

Ar = Ph or 3,5- Me2-Ph

Me

endo product is observed* Note the opposite facial

6 mol% cat.
CH2Cl2, -95 C
1-2 h

CHO

Me

selectivity

O
R'

OTf

CHO
Me
99% yield 89:11(exo:endo) 96% ee

Examples: Corey JACS 2002 124, 9992.


O

Organized formyl CHO hydrogen bonded complex


Aryl groups screen back face of dienophile
!" stacking may also be involved
exo or endo selectivity varies with the diene

Stereochemical
Model:

H
n

H
O
Me
Me

time

endo ee

yield

n=1

14 h

96% ee

92%

n=2

15 h

96% ee

95%

n=3

22 h

94% ee

93%

O
Me

Me

Me

20 mol% cat.
_20 C

Me
O

Me
10 mol% cat.
_78 C, 1h

80% yield
> 98:2 endo:exo
92% ee

Switching the counterion from triflate OTt() to triflamide (Tf)2N()


expands dienophile scope: Corey JACS 2003, 125, 6388.

Hetero-Diels-Alder Reactions Enantioselective Catalysis

E. P. Balskus

Chromium (III) Schiff-Base Catalysts:


Jacobsen Angew. Chem. Int. Ed. 1999, 38, 2398.
Me
RO

R'

Stereochemical Model:
Me
OR

1. 3 mol% catalyst
4 sieves, rt, 16 - 40h

Me

2. TBAF, AcOH, THF

Me

> 95% de
(all cis)
90-99% ee
72-97% yield

R' = aryl, alkyl, heteroaromatic

Me

N
O

The catalyst is a water-bridged dimer

O
R
H

O Cr O
H2O
Cl

Single-point binding to the aldehyde


X

O
Cr

Cr
H

O
Me

Sieves may be needed to open up a


binding site for the aldehyde
N

Me

H Cl

R'

Me
R = TMS, TES, TBS

Me

+
O

Chem 206

A variety of mono- and di-oxygenated


dienes are good substrates

X = Cl, SbF6

HDA

Catalyst-Controlled Diastereoselective HDA:

Hetero-Ene Reaction:

t-Bu

O
TMSO

O
+
OMe
catalyst
achiral catalyst
(1R,2S)-Cl
(1S,2R)-Cl

Me
OTBS
yield
81%
96%
97%

t-Bu

1. catalyst (5 mol%)
EtOAc, BaO
2. TFA

OTBS
dr
1:2.0
1:12
15:1

OR

Me

ee
nd
>99%
>99%

Org. Lett. 2002, 4, 1795.

Me
R = TMS, Me

5 mol%

Cr

R'

R' = Ar, alkyl

OR

OH

Cl

R'
BaO or4 sieves
base, acetone, 4C

JACS, 2002,124, 2882.; Angew. Chem. Int. Ed. 2003, 42, 4771.

70 - 96% ee
77 - 97% yield

Organo-Catalysis:The Diels-Alder Reaction

DA. Evans

MacMillan introduces a new catalyst:

Chem 206

The Catalytic Cycle

MacMillan, D. JACS 2000, 122, 4243.


R
! C=X Polarization

R
C

LUMO Lowering
C

R
C

! + 0.33

! + 0.51

R
C

! + 0.54

R
! + 0.61 (R = H)
! + 0.63 (R = Me)

Diels-Alder Catalysis via chiral Iminium Ions


Me

Me

N
Me
Ph

N
H

N
Me

Me
N

Me
N
Ph

Me

Me

1
R
O
H
R
LUMO of imminium
intermediate lower than that
of corresponding aldehyde.

Me
H

!-stacking
?

dienophile

Me
N

Bn

Me
N
H

Me
H

R'
N
H

electrophilic reactivity

R
R

H
R

R
Partial Charge: As the familiar polar resonance structure above indicates, the
carbonyl carbon supports a partial positive charge due to the polarization of the sigma
and pi system by the more electronegative heteroatom. The partial charges for this
family of functional groups derived from molecular orbital calclulations (ab initio, 321(G)*, HF) are illustrated below:

R'

R"

R"