Myers

Asymmetric Diels!Alder Reactions

Reviews:

Chem 115

• The stereochemical model for chiral induction by the 8-phenylmenthol controller has been
applied in the design of a practical auxiliary for asymmetric Diels!Alder reactions:

Corey, E. J. Angew. Chem. Int. Ed. 2002, 41, 1650–1667.
Evans, D. A.; Johnson, J. S. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N.; Pfaltz, A.;

O

Yamamoto, H., Eds.; Springer: New York, 1999; Vol III, pp. 1177!1235.

S

Reilly, M.; Oh, T. Org. Prep. Proceed. Int. 1994, 26, 131!158.

, BCl3

O

O

OR

O

O

Kagan, H. B.; Riant, O. Chem. Rev. 1992, 92, 1007!1019.

99% yield, 98.5 : 1.5 endo : exo,
97% de

H

PhCH3, –78 °C
product

diene

yield (%)

endo : exo

de (%)

94

> 99 : 1

97

97

--


94

98

--

94

Applications in Total Synthesis:
Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G. Angew. Chem. Int. Ed. 2002,
41, 1668–1698.

H
O

OR
H OR

Chiral Auxiliaries – Dienophiles:
O

(–)-8-Phenylmenthol:

H OR
H3C
H3C

Ph
O

CH3
O

AlCl3, CH2Cl2

H3C
H3C

CH3

O
CH3

–55 °C

O

CH3

Corey, E. J.; Sarakinos, G. Org. Lett. 1999, 1, 1741!1744.
O
AlCl3

Dimenthyl Fumarate:
O

O

BnO


OR Et2AlCl

H3C
O
CH3

RO

I

O

O

CH3
toluene
–78 °C

• Lewis Acid(s?)

CO2R
CO2R
100%, 99% de

BnO
• The menthyl auxiliaries exhibit cooperative asymmetric induction in the case of the fumarate ester,
resulting in excellent selectivity for cycloaddition from the back face.

HO
OBn

(Intermediate in prostaglandin synthesis)

CH3

O

O

CH3

O
H3C

O

OR

Diene

89%, 97% de

• Endo-selective cycloaddition is proposed to occur from the unblocked "-face of the s-trans
acrylate-Lewis acid complex.
• A favorable #-stacking interaction is proposed to enhance the stereoselectivity of this process.
(Acrylates derived from menthol afford lower diastereoselectivity – ca. 40%).
• (–)-8-phenylmenthol, derived from (–)-pulegone, is commercially available. Recovery of the
auxiliary was accomplished in 94% yield following reductive removal.
Corey, E. J.; Ensley, H. E. J. Am. Chem. Soc. 1975, 97, 6908!6909.
Ensley, H. E.; Parnell, C. A.; Corey, E. J. J. Am. Chem. Soc. 1978, 43, 1610!1612.


Lewis Acid

Temperature (°C)

Yield

de (%)

i-Bu2AlCl

–40

56

95

i-Bu2AlCl

–20

94

95

Et2AlCl

–20

70


96

AlCl3

25

92

99

CH3
CH3
CH3

From: Furuta, K.; Iwanaga, K. Yamamoto, H. Tetrahedron Lett. 1986, 27, 4507!4510.

Kent Barbay

1


Myers

Asymmetric Diels"Alder Reactions

N-Acyloxazolidinone Dienophiles:
O

• Diene scope: includes dienes less reactive than cyclopentadiene (e.g. acyclic dienes). In this case,
imide 2 afforded uniformly higher diastereoselectivities than 1 or 3.

O
CH3

O
N

R'

O

1 R = CH(CH3)2
2 R = CH2Ph

R'

R

O
O

Et2AlCl (1.4 equiv)

CH3 O

CH3

Bn

XP
R


R'

Et2AlCl (1.4 eq)
Ph –100 °C, CH2Cl2
2–5 min.

3

R

COXC

diene

dr

isolated yield (%)

isolated dr

H

isoprene

95 : 5

85

> 99 : 1


H

piperylene

>100 : 1

84

> 99 : 1

endo dr

isolated yield

isolated dr

CH3

isoprene

94 : 6

83

> 99 : 1

>100 : 1

93 : 7


81

>99 : 1

CH3

piperylene

95 : 1 : 2 : 2

77

> 99 : 1

>100 : 1

95 : 5

78

97 : 3

dienophile

endo : exo

1, R' = H
2, R' = H


100 : 1

5 : 95

82

<1 : 99

1, R' = CH3

48 : 1

95 : 5

82

>99 : 1

2, R' = CH3

55 : 1

97 : 3

83

99 : 1

3, R' = CH3


60 : 1

Pha

b

2 : 98

88

<1 : 99

83

93 : 7

XC

O

Et2AlCl2

O

Al
N

Et2AlCl2

Et

O

O
O

H3C

Al
N

n

H3C

Et

XC

O

O
O

• (Z)-unsaturated imides and !,!-disubstituted imides have limited applicability due to competing
isomerization or low reactivity.
Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc. 1984, 106, 4261"4263.
Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc. 1988, 110, 1238"1256.

O


O
H

+

–30 °C, 5 h
H
Endo I
n

N

O

Ph

R
• cycloaddition occurs from the less sterically encumbered face
• the reactive dienophile is a chelated cationic species
• the s-cis conformation of chelated acyl oxazolidinones is assumed to be favored

O
N

XC

O
H

Me2AlCl


XC

• The stereochemical results are consistent with the following models:
Et

H3C

Et2AlCl2

Al

• The oxazolidinone auxiliaries have been applied to asymmetric intramolecular Diels"Alder reactions:

• The high reactivity of the unsaturated carboximides is highlighted by tolerance of !-substitution
on the dienophile, which is not typically the case for chiral ester dienophiles.

Et

O

Evans, D. A.; Chapman, K. T.; Hung, D. T.; Kawaguchi, A. T.
Angew. Chem., Int. Ed. Engl. 1987, 26, 1184"1186.

Et

Et

• The enhanced stereoselectivity of dienophile 2 is attributed to #-stacking:


>99 : 1

a. Reaction run at –20 °C, 2.5 h.
b. Exo product not observed by 500 MHz 1H-NMR.

H3C

R

H3C

N
2

O

H3C

1, R' =

O

O
N

3, R' = H

XP

R'

COXC

Et2AlCl (1.4 eq)
–100 °C, CH2Cl2
2–5 min.

R

O

Chem 115

dr
(Endo I : Endo II)

n

H
Endo II

n

Isolated yield (%)a

1

95 : 5

73


2

97 : 3

88

Bn
O
O

N

1

3 : 97

65

2

6 : 94

70

C6H11
a. Refers to purified products, de >99%.
Evans, D. A.; Chapman, K. T.; Bisaha, J. Tetrahedron Lett. 1984, 25, 4071"4074.

Kent Barbay


2


Myers

Asymmetric Diels#Alder Reactions

• The stereochemical outcome is rationalized by the following model, involving a chelated complex:

Camphor-derived N-Enoyl Sultams:

H3C

CH3

H3C

CH3

R

R

Temperature (°C)

H

N

R


Time (h)

endo : exo

endo dr

yield

–130

6

99.5 : 0.5

97.5 : 2.5

83a

–78

18

96 : 4

99 : 1

91b

CH3


O

R
O

R

Temperature (°C)

Time (h)

H

–78

6

98.5 : 1.5

81

CH3

–94

6

97 : 3


64

MLn

• The camphor-derived sultam auxiliary has also been applied to intramolecular reactions:

H3C

XC

CH3

H
Endo I

n
XC

H
Endo II
XC

O
H

H
Exo I

n


dr
(Endo I : Endo II :
[Exo I + Exo II])

1

>97.4 : 2.5 : <0.1

75

2

94.0 : 2.6 : 3.4

53

• The cycloadducts tend to be crystalline solids, facilitating purification.

Oppolzer, W. In Comprehensive Organic Synthesis; Trost, B.M. and Fleming, I. Eds.; Pergamon:
Oxford, 1991, Vol. 5, pp. 315–399.

+

n

n

O
H


+

• Both antipodes of the chiral auxiliary are available; they are synthesized in two synthetic
steps from camphor-10-sulfonyl chloride.

Oppolzer, W.; Chapuis, C.; Bernardinelli, G. Helv. Chem. Acta. 1984, 67, 1397–1401.

O
H

+

–20 °C, 5h

a. Recrystallized yield, de ≥ 99%.

• Recovery of the auxiliary is possible after reductive or hydrolytic removal.

XC

O
H

EtAlCl2

O
SO2

yielda


O

C(!)-Re face

TiCl4 Complex (X-ray)

N

dr

COXC

O

Oppolzer, W.; Rodriquez, I.; Blagg, J.; Bernardinelli, G. Helv. Chem. Acta. 1989, 72, 123–131.

R

EtAlCl2 (1.5 equiv)
CH2Cl2

S
O

Ground state (X-ray):
C=O/C=C s-cis,
NSO2/C=O s-trans

XC


N
SO2

CH3

H3C

H

N

Montaudo, G.; Librando, V.; Caccamese, S.; Maravigna, P. J. Am. Chem. Soc. 1973, 95, 6365–6370.

• Acyclic dienes are suitable substrates in the case of (unsubstituted) N-acryloyl sultams:
CH3

Lewis Acid

s-cis conformer
CH3

• !,"-unsaturated amides display a general preference for the s-cis conformer.

a. Recrystallized yield, de ≥ 99%.
b. Crude yield of material with indicated isomeric purity.

H3C

H


CH2Cl2

SO2

COXC

EtAlCl2 (1.5 equiv)

CH3

H3C
O

O
N
SO2

Chem 115

n

H
Exo II

n

Isolated yield (%)a

a. Refers to crystallized Endo I, de >99%.
Oppolzer, W.; Dupuis, D. Tetrahedron Lett. 1985, 26, 5437–5440.


Kent Barbay
3


Myers

Asymmetric Diels"Alder Reactions

Chiral Auxiliaries – Dienes:

Chem 115

• 1-Alkoxy-3-silyloxy-1,3-butadienes (auxiliary-modified analogs of Danishefsky's diene):

Review: Barluenga, J.; Suárez-Sobrino, A.; López, L. A. Aldrichimica Acta. 1999, 32, 4–15.
TBSO

Ph

TBSO

Chiral 1-heterosubstituted dienes:
• 1-O-methylmandeloxy substituted dienes (Trost's dienes):

CH3

O
CH3


CH3

CH3

CH3

O

PhCHO, (+)-Eu(hfc)3
O

CH3

–78 ! 23 °C

CH3

Ph
CH3

CHO

O

O

CH2Cl2

75% yield


Ph

92% de

BF3•OEt2
toluene

O

Ph

O

TFA

O

CHO
O

Bednarski, M.; Danishefsky, S. J. Am. Chem. Soc. 1986, 108, 7060–7067.
• 1-amino-3-silyloxy dienes:

Ph

CH3O

CH3O

Ph


O

H

B(OAc)3

+
O

O

OH

Ph

H3CO

O
Ph

O

H

O

1. LiAlH4
COX


toluene

O
Ph

N

Ph

Ph

dienophile
O

R

TBSO

X

CHCl3
O

R

TBSO

endo only
60% de, 92% yield


N

endo only
> 97% de, 98% yield

Ph

product

yield (%)

ee(%)

79

88

87

88

86

98

66

96

OH

OH

82

92

OH
OH

64

98

O

CH3

CH3
OH

CHO
O

CH3

Trost, B. M.; O'Krongly, D.; Belletire, J. L. J. Am. Chem. Soc. 1980, 102, 7595–7596.

OH

2. 10% HF


OH

OCH3

R

O

CHO

CH3
OH

O
• A stereochemical model rationalizing these results has been presented by Thornton:

CO2t-Bu

OH

CHO
H
• a transition state conformation in which the phenyl substituent
O
O
MeO

Ph


CO2Me

O

Ph
OH

is perpendicular to the plane of the diene is proposed, favoring
H

approach from the top face.

Siegel, C.; Thornton, E. R. Tetrahedron Lett. 1988, 29, 5225–5228.
Tripathy, R.; Carroll, P. J.; Thornton, E. R. J. Am. Chem. Soc. 1991, 113, 7630–7640.

EtO2C

MeO2C

CO2Et

CO2Me

O

O

Kent Barbay

4



Myers

Asymmetric Diels"Alder Reactions
• These cycloadditions are proposed to proceed by a stepwise mechanism:

• Stereochemical Model:
L

CH3O

TBSO

s

Ph

endo TS

L

OTBS

N

(L = COX)

Ph


N

Ph

TBSO

N

s
Ph

R3

Ph

exo TS

L
s

OTBS

Ph

s

N

Ph


Barluenga, J.; Aznar, F.; Ribas, C.; Valdés, C. J. Org. Chem. 1997, 62, 6746–6753.
Enders, D.; Meyer, O.; Raabe, G. Synthesis 1992, 1242–1244.
NaHMDS
OTMS
CH3

exo

N

TMS

+

• Both endo and exo cycloadducts are transformed to the same enantiomer of the cyclohexenone
product, allowing the use of dienophiles that do not undergo cycloaddition with high endo/exo
selectivity.

Ar

N

H

• 2-amino dienes:

R1

N


CH3

NO2
R2

N

R3

R1
HOAc

Ar

combined
yield (%)

R3

yield (%)

ee (%)

H

H

Ph

48


98

CH2OTBS

H

Ph

63

94

CH2OTBS
CH2OTBS

H

Me
i-Pr

48
56

95
92

70

94


CH2OTBS

H

-(CH2)4-

CH3

NH
Ar

O
B

ee (%)
(pdt A)

51

> 98

43

90

Ph

65


95

H3C

NO2
R2

O

R3

• Sulfinyl-substituted dienes:
O
S

CO2Me
OCH3

R2

+

Ar

O

3-furyl

OCH3


R1

OH

Barluenga, J.; Anzar, F.; Ribas, C.; Valdés, C.; Fernández, M.; Cabal, M.-P.; Trujillo, J. Chem.
Eur. J. 1996, 2, 805–811.

*R
OCH3

NH

4-MeOPh

Review: Enders, D.; Meyer, O. Liebigs Ann. 1996, 1023–1035.

NO2

CH3

–80 ! 23 °C
2. NaHCO3, H2O

OCH3

Chiral 2-heterosubstituted dienes:

R2
+
R3


OH
1. ZnCl2, THF

A

Kozmin, S. A.; Rawal, V. H. J. Am. Chem. Soc. 1999, 121, 9562–9573.

R1

R1

• Alkyl substitution at C3 of the diene appears to be required, probably to restrict the conformation
of the prolinol group as shown.

s
Ph

L

CH3

CH3

L

N

(L = COX)


O

TBSO

Ph

H
H

• Large group on dienophile occupies an
open quadrant of diphenylpyrrolidine auxiliary
in either endo or exo TS's.

s

L

N
NO2

R2
H

endo

+

Ph

Chem 115


R* =

LiClO4, CH2Cl2
25 °C
CH3

CH3

*R

O
S
CO2Me
OCH3

70% yield, 92% de
endo only

OH

Aversa, M. C.; Barattuci, A.; Bonaccorsi, P.; Giannetto, P.; Jones, D. N. J. Org. Chem. 1997, 62,
4376–4384.
Kent Barbay

5


Myers


Asymmetric Diels#Alder Reactions

Chiral Auxiliaries for Asymmetric Diels-Alder Reations – Applications in Synthesis:

(–)-Bilobalide:

(+)-Lepicidin A:
OTIPS
H3C

H3C
O

OTIPS

OTES

H3C

H

O

O

O

H3C
O


Me2AlCl

N

O

CH3

OTES

O

H

H3C

CH3

O
O

CH2Cl2
0 ! 23°C

Bn

H

71%, 10 : 1 diastereoselectivity


H

XP

O

(i-Bu)2AlCl
CH2Cl2/hexane

H3C

H

H3C
O

NaHMDS
OH

H

OTBS

H3C
O

O
O

Corey, E. J.; Su, W.-G. Tetrahedron Lett. 1988, 29, 3423–3426.


H
OTBS

Pulo'upone:

NMe2
TBSO

H
OH
HH

O H

H3C

CH3

XC
O

N
(+)-Lepicidin A

H

O

Me2AlCl


TBSO

CH2Cl2
–20 °C

SO2

Me
OMe
OMe
OMe

H3C
O
O

OTIPS

OTES
H

H3C
O

O

O

Me2AlCl


H3C
O

N

2. LiH, DMF

O
H

H3C
N

H

H

H

O
N

H
OTBS

89%

O
H


H

O

Evans, D. A.; Black, W. C. J. Am. Chem. Soc. 1993, 115, 4497–4513.

O

OTES
O

74%, 6 : 1 diastereoselectivity

1. BF3•OEt2

63%, ca. 100% de
(Crude de = 93%)

• A control experiment showed the auxiliary overcame inherent stereochemical bias in the substrate:
OTIPS

O
H

H

O

H3C


(–)-Bilobalide

H

O
H

t-Bu

O

H3CO

H

Me
O

H3C

OH
OH

O

O

O


12 : 1 diastereoselectivity
H

MenO2C

O

THF, –78 °C

HH

O
H

3. KHMDS, THF, –48 °C

O H

MenO2C
MenO2C

OTIPS

CO2Men

O

t-Bu

(CH3O)2HC


t-Bu

CO2Men

1. LDA, THF –78 °C
2.
t-Bu
CO2Ph

["]23D +25.5°
(c 8.0, CHCl3)

OTBS

O

O H

CH3

CH3

OTIPS

H

H3C
O


MenO2C

H3C

O

O

H

OTBS

H3C

Chem 115

OTBS

O

(+ 90% recovered sultam)

H
(–)-Pulo'upone

Oppolzer, W.; Dupuis, D.; Poli, G.; Raynham, T. R.; Bernardinelli, G. Tetrahedron Lett. 1988, 29,
5885–5888.
Kent Barbay

6



Myers

Asymmetric Diels!Alder Reactions

Chem 115

• Both antipodes of the 1,2-diaryl-1,2-diaminoethane ligands are available, via resolution employing
tartaric acid: Corey, E. J.; Lee, D.-H.; Sarshar, S. Tetrahedron: Asymmetry 1995, 6, 3–6.

Catalytic, Asymmetric Diels!Alder Reactions:
• The first reported catalytic, asymmetric Diels!Alder reaction:

• Proposed transition-state assembly:

CH3

O
N

OAlCl2

+

H3C

CHO

Tf


H3C
CH3
(15 mol%)
toluene, –78 °C

CH3
69%, 72% ee
exo : endo = 98 : 2

• Non-chelated binding mode
• s-trans dienophile conformer

O

N
Al
N
CH3
Tf

• Phenyl blocks front face

CHO

O

• The exo selectivity of "-substituted acroleins is general.

• This model is supported by 1H, 13C, and 1H NOE data for the 1 : 1 dienophile : catalyst complex,

as well as X-ray diffraction analysis of the catalyst dimer.

Hasimoto, S.; Komeshima, N.; Koga, K. J. Chem. Soc., Chem. Commun. 1979, 437–438.

Corey, E. J.; Sarshar, S. J. Am. Chem. Soc. 1992, 114, 7938–7939.

C2-symmetric Diazaaluminolidine Catalysts:

Chiral (Acyloxy)borane (CAB):

Ph

Ph

F3CO2SN
R

O
+

R'

O
N

R

NSO2CF3

+


R

Al
CH3

R'
O

(10-20 mol%)
O

R'

H

H

H

CH3

CH2OBn

H

CH2Cl2, –78 °C
endo : exo

ee (%)


O

91

92

96 : 4

94

88

R3
+
O

Corey, E. J.; Imwinkelried, R.; Pikul, S.; Xiang, Y. J. Am. Chem. Soc. 1989, 111, 5493–5495.
• A modified catalyst expanded the scope of this system to include maleimide dienophiles:
Ar

F3CO2SN

NSO2CF3
Al
CH3
Ar = 3,5-dimethylphenyl
(20 mol%)

O

+
H3CO

N
O

toluene, –78 °C
CH3

R2
R1

CHO

R4

94

95

Ar

CHO

OR O

CHO
R1

CH2Cl2, –78 °C

R3

CH2Cl2, –78 °C

R4

O

O

R2

1 or 2 (10 mol %)

CO2H

OR

R1

B H
O

O

1 R = Me
2 R = i-Pr

CHO
R2


yield (%)

>50 : 1

–

N

1 or 2 (10 mol %)

R2
R1

H O
N
H3CO

H O

R1

R2

R3

1

H


H

–

–

88 : 12

84

90

1

H

H

CH3

CH3

–

84

53

1


H

CH3

–

–

11 : 89

96

85

1

H

CH3

CH3

CH3

–

97

61


1

H

CH3 CH3

H

–

91

65

1

CH3

CH3

–

3 : 97

90

91

2


H

Br

–

–

6 : 94

95

100

2

H

Br

CH3

CH3

–

95

80


2

CH3

Br

–

–

>99 : 1

98

100

–

R4

endo : exo ee (%) yield (%)

• "-substituted ",#-unsaturated aldehyde dienophiles give optimal selectivities.
CH3

98%, 93% ee
Corey, E. J.; Sarshar, S.; Lee, D.-H. J. Am. Chem. Soc. 1994, 116, 12089–12090.

catalyst


• Both enantiomers of the CAB catalyst are available, from (+) and (–)-tartaric acid.
Furuta, K.; Shimizu, S.; Miwa, Y.; Yamamoto, H. J. Org. Chem. 1989, 54, 1483–1484.
Ishihara, K.; Gao, Q.; Yamamoto, H. J. Org. Chem. 1993, 58, 6917–6919.

Kent Barbay
7


Myers

Asymmetric Diels#Alder Reactions

• Yamamoto's CAB catalyst has been applied to intramolecular reactions:
MeO

O

CHO
CH3

• Lewis acids complex aldehydes syn with respect to the formyl proton – for a review on the
conformations of carbonyl-Lewis acid complexes, see: Shambayati, S.; Crowe, W. E.;
Schreiber, S. L. Angew. Chem., Int. Ed. Engl. 1990, 29, 256–272.

CO2H
O

Chem 115

O

B H

O
OMe O
(10 mol%)

• Formyl CH--O hydrogen bonding is proposed as an additional organizational element leading to
the excellent enantioselectivities observed. For the application of the formyl CH--O hydrogen bond
postulate to the understanding of enantioselective reactions involving chiral boron Lewis acids and
aldehydes, see: Corey, E. J.; Rohde, J. J. Tetrahedron Lett. 1997, 38, 37–40.

CHO
CH3

CH2Cl2, –40 °C
84%, 92% ee
99 : 1 endo : exo

• A modified oxazaborolidine catalyzes cycloadditions to furan:

Furuta, K.; Kanematsu, A.; Yamamoto, H.; Takaoka, S. Tetrahedron Lett. 1989, 30, 7231–7232.
NH

Oxazaborolidine Catalysts:
Br
+

Br
CHO


3 (5 mol%)
CHO

CHO

CH2Cl2, –78 °C

CHO

Br
+

3 (5 mol%)
CHO

O

4 (10 mol%)

+

Br

CH2Cl2, –40 °C H3C

H

O

CHO


CH2Cl2, –78 °C

NH

Br
95%, 99% ee
96 : 4 exo : endo

CH3

O

H3C

Br
>98%, 92% ee

O

Ts N B O
n-Bu

O
N B
n-Bu
Ts
4

H


Corey, E. J.; Loh, T.-P. Tetrahedron Lett. 1993, 34, 3979–3982.

3

76%, 92% ee

• Corey has demonstrated the synthetic versatility of the 2-bromoacrolein/cyclopentadiene
cycloaddition adducts:

• !-substitution on the aldehyde component is required for high enantioselectivity.
• The tryptophan-derived ligand was efficiently recovered.
Corey, E. J.; Loh, T.-P. J. Am. Chem. Soc. 1991, 113, 8966–8967.

CO2H

OH

Br
O

• Physical and chemical studies of this system led to the following transition-state model:
O

H
N

Br

H


H

Br

H
O

O

CHO

O
N B n-Bu
H O
S O

• The complex of the s-cis conformer is proposed
to be the reactive species.
• Attractive "-stacking interactions between the indole and
the dienophile organize the TS, and result in reaction from
the unblocked (back) face.

CH3
Corey, E. J.; Loh, T.-P.; Roper, T. D.; Azimioara, M. D.; Noe, M. C. J. Am. Chem. Soc. 1992,
114, 8290–8292.

CH3

O


CO2Et

O
Br

CH3

Corey, E. J.; Loh, T.-P. J. Am. Chem. Soc. 1991, 113, 8966–8967.

Kent Barbay
8


Myers

Asymmetric Diels"Alder Reactions

• Catalysts 1, 2, and 3 exhibit broad substrate scope and predictable selectivities.
Enantioselectivities are typically >90%; endo:exo ratios are uniformally high (4:1!>99:1).

Cationic Oxazaborolidine Catalysts:
H Ph Ph

O

+

catalysta
2

3

1 or 2 (20 mol%)

CH3
CO2Et

CH2Cl2

CH3

diene

dienophile

product

O

O
N B
X– H Ar
OEt

Chem 115

CH3

CH3


CH3

CH3

Ar = o-tolyl

O

H

yield, ee (%)

16, 20

99, 64

24, 4

99, 77

48, –78

97, 91

2, –95

98, >99

24, –78


85, 94

16, –20

97, 93b

H
O

H

CH3

time (h), temp (°C)
O

CH3

2
catalyst

X

1
2

OTf
NTf2

temp (°C) time (h)

4
20

yield (%)

endo:exo

ee (%, endo)

46
94

91:9
89:11

>98
97

72
16

CH3

CH3

O
O

O


H

CH3

O
CH3

2
CH3 TIPSO

TIPSO

• The neutral oxazaborolidine catalyst does not exhibit catalytic activity in the Diels"Alder reaction
of cyclopentadiene with methacrolein.

O

• Early experiments were conducted with catalyst 1; it was subsequently shown that the triflimideactivated catalyst 2 exhibits greater thermal stability and higher catalytic activity.

H

N B
Tf2N H Ar1
3

1

O
CHO
CH3


H

O
Ar1 = o-tolyl
Ar2 = 3,5-dimethylphenyl

O
1
a

20 mol% catalyst. bendo:exo = 91:9.

• Corey has proposed the following pre-transition-state complexes:

O
OCH2CF3

+

CH3

Ar2

O

H

O


• When using less reative dienes, the related 3,5-dimethylphenyl catalyst 3 is often superior to 2.
Ar2

CH3

H

2 or 3
(20 mol%)

Ar1

CO2CH2CF3

solvent, 20 °C

H
X

catalyst

solvent

time (h)

yield (%)

ee (%)

2

3

toluene
neat

40
24

78
96

88
95

Corey, E. J.; Shibata, T.; Lee, T. W. J. Am. Chem. Soc. 2002, 124, 3808.
Ryu, D. H.; Lee, T. W.; Corey, E. J. J. Am. Chem. Soc. 2002, 124, 9992.
Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 6388.
• A useful set of predictive selection rules has been developed for the oxazaborolidinium-mediated
Diels"Alder reaction of substituted quinones:
Ryu, D. H.; Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 4800.

N B

Ar1

Ph
O
H

H


O

X

R

enals

R'

N B

O
R

Ph
O

H

R'

quinones, enones, and
#,$-unsaturated esters

• The phenyl [or 3,5-dimethylphenyl in the case of 3 (not shown)] substituent is proposed to engage
in %-stacking with the dienophile.
• The diene approaches the catalyst–dienophile complex from the face opposite the phenyl group.
• The existence of an O—HC interaction is supported by studies of enal-, and enone-BF3 complexes.

• Note the sense of stereoinduction for enals is opposite that of quinones, enones, and #,$unsaturated esters.
Seth B. Herzon

9


Myers

Asymmetric Diels#Alder Reactions

Alkyldichloroboranes:

Chem 115

Titanium-TADDOL:
• Narasaka's Ti complex catalyzes a wide variety of Diels#Alder reactions with high selectivities:
Ph

BCl2
Ph
Me
R

CO2Me +

n

(10 mol%)

n


CH2Cl2
–78 ! –20 °C

Ph

O

O

O

O

TiCl2

Ph Ph
R
CO2Me

+ R2

5
(10 mol %)

O

O
N


O

R2
O

4Å MS, –23 ! 23 °C

6
R

n

O

ee (%) yield (%)

H

1

97

97

CH3

1

93


91

CO2Me

1

90

92

H

2

86

83

O

O

R1

+ R
2

N

R1


5 (10 mol %)
O

N

O

R2
N

4Å MS, 0 ! 23 °C

7

O

O

O
• The catalyst was prepared by resolution with (–)-menthone.
O
• The adjacent figure illustrates the approximate conformation of the catalyst•
methyl crotonate complex (X-ray).
Cl B Cl
O
H3C

H3CS


N

O

toluene/pet. ether
4Å MS, –5 °C

O

R2

CH3S

O

N

O

8

• NMR studies suggest this conformation is retained in solution.
CH3

O

+ R2

5 (10 mol %)


O

O

O

• The s-trans crotonate conformer is observed.
• The carbonyl is positioned over and parallel to the naphthylene,
within van der Waals contact (3.2 Å) ("-stacking interaction).
• Complexation of Lewis acids anti to ester C–O bonds
appears to be a general phenomenon.

• The absolute stereochemical configuration of the products is consistent with a transition-state
model closely related to the observed ground state complex:

Cl B Cl
R

O
H3C

O

R
CO2Me

Diene

R1


R2

6

–

H

6

–

6

–

endo : exo

ee (%)

yield (%)

reference

n.d.

88

81


2

CH3

87 : 13

94

91

1

Ph

92 : 8

80

76

1

7

H

H

–


93

81

2

7

H

CO2Me

–

91

84

1

7

CH3

H

–

>96


93

2

7

CH3

CO2Me

–

94

94

1

8

–

H

85 :15

87

97


3

8

–

CO2Me

78 : 22

86

99

3

1. Narasaka, K.; Iwasawa, N.; Inoue, M.; Yamada, T.; Nakashima, M.; Sugimori, J.
J. Am. Chem. Soc. 1989, 111, 5340–5345.
2. Narasaka, K.; Tanaka, H.; Kanai, F. Bull. Chem. Soc. Jpn. 1991, 64, 387–391.
3. Narasaka, K.; Yamamoto, I. Chem. Lett. 1995, 1129–1130.

• The naphthalene substituent forces the dienophile to approach from the front face.
Hawkins, J. M.; Loren, S. J. Am. Chem. Soc. 1991, 113, 7794–7795.

• A number of transition-state models have been proposed; the analysis is complicated by the
number of coordination possibilities available in octahedral complexes.
Kent Barbay

10



Myers

Asymmetric Diels!Alder Reactions

Bis(oxazoline) Copper Complexes:

• The stereochemical results are in all cases consistent with the following model:

• Evans' copper (II) catalysts have been successfully applied to a wide array of cycloaddition
substrates:

O

+

Cu

N

CH2Cl2

6
O
X +

O
N

CMe3

O

Si face
R

• Acyclic dienes unsubstituted at the 1-position afforded lower enantioselectivities:

O
O

N

Catalyst
O

Diene

O

N

CH2Cl2
O

+

O
N

yield (%)


–

59

81

–

65

78

98

57a

CH3

CH3

O
O

10
CH3

O
O


ee (%)

X

10 (1–5 mol%)

11

O

endo : exo

10

O
N

O

R

9 or 10
(5–10 mol%)

O

+ 2 SbF6–

N
Cu


Me3C

CMe3
9 X = OTf
10 X = SbF6

O

R

N
+2

N

• Square planar geometry about Cu
• Imide binds in a bidentate fashion
• s-cis dienophile configuration
• diene approaches from the back face;
the front face is blocked by the t-Bu group

O

O
N

Me3C

O


X–

+2

H3C CH3

+2

H3C CH3

O

Chem 115

CH3

10 (5 mol %)
O

O

12

10

O

CH2Cl2, –78 °C
N


O

OAc

27 : 73

a. Isolated yield of enantiomerically and diastereomerically pure material.
• These dienes (substituted at C3) are proposed to approach via an exo transition state. The exo
transition state is apparently only selective in the case of 1-substituted dienes.

R

endo : exo

–

H

98 : 2

>98

86

–

CO2Et

94 : 6


95

92

96 : 4

97

85

Catalyst

Diene

X

9

6

9

6

ee (%)

yield (%)

9


6

–

CH3

10

6

–

Ph

91 : 9

96

96

10

6

–

Cl

86 : 14


95

96

10

11

OAc

–

85 : 15

96

75

10

11

SPh

–

98 : 2

98


10

11

NHCbz

–

72 : 28

90

10

12

–

–

80 : 20

97

• Calalyst 10 is also effective for intramolecular Diels!Alder reactions:
R
O

O

N

n

10
(5-10 mol%)
O

R
H

CH2Cl2, 25 °C

N
H
n

R

n

84

H

1

>99 : 1

86


89

54

Ph

1

>95 : 5

92

86

97

Ph

2

97

97

• Catalyst 10 (X = SbF6) uniformly provides higher reactivity and higher levels of asymmetric
induction than 9 (X = OTf), which was reported earlier.
Evans. D. A.; Murry, J. A.; von Matt, P.; Norcross, R. D.; Miller, S. J. Angew. Chem., Int. Ed. Engl.
1995, 34, 798–800.


endo : exo

84 : 16

ee (%)

O

O
O

yield (%)

Evans, D. A.; Miller, S. J.; Lectka, T. J. Am. Chem. Soc. 1993, 115, 6460–6461.
Evans, D. A.; Miller, S. J.; Lectka, T.; von Matt, P. J. Am. Chem. Soc. 1999, 121, 7559–7573.
Evans, D. A.; Barnes, D. M.; Johnson, J.; Lectka, T.; von Matt, P.; Miller, S. J.; Murry, J. A.;
Norcross, R. D.; Shaughnessy, E. A.; Campos, K. R. J. Am. Chem. Soc. 1999, 121, 7582–7594.

Kent Barbay
11


Myers

Asymmetric Diels"Alder Reactions

Asymmetric Catalysis of the Diels–Alder Reaction with a Chiral Amine through Reversible
Iminium Ion Formation:
O
N


R

• Stereochemical model:

CH3

O
N

CH3
N CH3
H
• HCl
13
5 mol %

Ph

Chem 115

Ph

CH3

N

• Selective formation of the (illustrated) (E)-iminium isomer is

CH3

CH3

proposed, avoiding unfavorable interactions between the
substrate olefin and the geminal dimethyl substituents.

H

O

+

R
CHO
endo

• The benzyl substituent shields the !-face of the dienophile.

CHO
R

Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4243–4244.

exo

5% H2O–MeOH
23 °C
Jacobsen's Catalyst:
R

exo : endo


yield

exo ee (%)

endo ee (%)

Me

75

1:1

86

90

n-Pr

92

1:1

86

90

i-Pr

81


1:1

84

93

Ph

99

1.3 : 1

93

93

Furyl

89

1:1

91

93

• Jacobsen's Cr (III) salen complex 14 catalyzes highly enantioselective Diels–Alder reactions of
1-amino-3-silyloxydienes and acroleins:


H
N

H
N
Cr

t-Bu

R

O
SbF6
t-Bu
t-Bu
14

CHO

13 (20 mol %)
R

O

O
5% H2O–MeOH
23 °C

X
R2


TBSO

endo

14 (5 mol %)

t-Bu

R2

TBSO

+
R1
product

R

diene

yield endo : exo ee (%)

Ph

N

CHO

CO2Me


4Å MS, CH2Cl2
–40 °C

Ph

N

R1
CHO
CO2Me

endo
H

82

14 : 1

94

CHO
CH3

CH3
H

84

–


89

CHO
H

Ph

Ph

CH3
CH3

CH3

R
CHO

CH3

90

–

75

–

90


75

5:1

90

83

R1

R2

yield

ee (%)

Me

H

93

97

Et

H

91


97

i-Pr

H

92

>97

TBSO(CH2)2

H

93

95

TBSO

H

86

>97

76

96


–(CH2)3–

CH3

H
CHO

• No exo products were observed in these cycloadditions.
Huang, Y.; Iwama, T.; Rawal, V. H. J. Am. Chem. Soc. 2000, 122, 7843–7844.
Kent Barbay

12


Myers

Asymmetric Diels!Alder Reactions

• X-ray analysis of the (1R, 2R)-salen–Co(III)-SbF6•2PhCHO complex suggested that replacing the
t-butyl groups with bulkier trimethylsilyl substituents might create a steric interaction (between
the trimethylsilyl groups) that would twist the aromatic rings out of plane.
• This modification has resulted in an exceptionally selective and active Diels–Alder catalyst:

H
N

H
N
Co


t-Bu

t-Bu

O

O
SbF6
TMS
TMS

R2

N

Ph

CH2Cl2
room temp.

N

Ph

CO2Me

R1

R2


1

CH3

H

2

CH3

3
4

1

98

98

H

0.05

72

93

98

CH2CH3


H

0.1

30

93

>97

TBSO(CH2)2

H

0.5

18

100

>97

5a

H

H

0.1


18

100

85

6b

H

H

2

40

90

>97

2

72

78

>95

b


TBSO

CH3

Reaction performed at –78 °C.

CH3

N

CH3

82

91

80

83

88

4

i-Pr

77

81


92

5

Bn

84

82

89

6

CH2CH2OTBS

80

80

86

N

CH3

R

Ar

CH3
CH3

O
Ar

R
N

CH3CN

CH3

Ar

1. LAH, Et2O

OH
OH

2. HF, CH3CN

Ar

H

R

O


R

TBSO
O

toluene, –40 °C

2.0 equiv

CH3

N

CH3

R

O

AcCl

O
CH2Cl2
–78 °C

OCH3
O

O


O

O
R CHO
1
O

68%, 94% ee

68%, 94% ee

O

69%, >98% ee

97%, 94% ee

O

O
O

O
O

O

70%, >98% ee

HF


2.0 equiv
O

H O

catalyst
(20 mol%)

CF3
CHO

toluene, –80 °C
2 days

• The diene approaches from the
face opposite the napthyl group.

O

• Products:

TBSO

CH3

catalyst:

85


CH2CH3

O

catalyst
(20 mol%)
CHO

CH3

3

H
+

O

R

2

The same TADDOL derivative catalyzes hetero-Diels–Alder reactions:

Catalysis via Hydrogen Bonding

+

73

Catalytic, Asymmetric Hetero-Diels–Alder Reactions:


• Entry 2 represents the lowest substrate/catalyst ratio (s:c = 2000) reported for an asymmetric
Diels–Alder reaction.
Huang, Y.; Iwama, T.; Rawal, V. H. J. Am. Chem. Soc. 2002, 124, 5950.

TBSO

77

Thadani, A. N.; Stankovic, A. R.; Rawal, V. H. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5846.

4

performed at 0 °C.

—

CO2Me
ee (%)

–(CH2)4–

H

R1
CHO

yield

7


1

CH3
O
O O

time (h)

a Reaction

mol % cat.

% yield 1

CH3

endo
entry

% ee of 2

R

R2

+
CHO

% yield 2


entry

•The following stereochemical model has been proposed:

catalyst

R1

Chem 115

O
O
67%, 92% ee

Ph

O
O
64%, 86% ee

O
52%, >94% ee

Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V. H. Nature, 2003, 424, 146.
R

2

OH


• A 2nd-generation catalyst was developed, expanding the substrate scope. See: Unni, A. K.;
Takenaka, N.; Yamamoto, H.; Rawal, V. H. J. Am. Chem. Soc. 2005, 127, 1336.
Seth B. Herzon

13


Myers

Asymmetric Diels!Alder Reactions
OTES
CH3

+ RCHO

H3C

2. TBAF, AcOH,
THF

Inverse Electron Demand Hetero-Diels!Alder Reactions catalyzed by Bis(oxazoline)

O

1. 14 (3 mol%)
4Å MS, 23 °C

CH3
O


H3C

Chem 115

Copper(II) Complexes:
+

H3C CH3

R

O

O
–

R
Ph
CH2OTBS
CH2OBn

ee (%)

yield (%)

90

72


>99

97

94

94

98

85

(CH2)4CH=CH2 98

78

CH2CH2Ph

98

78

2-furyl

95

77

n-C5H11


N

CH3

N

O
X

X

hetero
diene

• Excellent enantioselectivities were maintained with several other dienes in reactions catalyzed
by 15:

ee (%)

H3C

O

O

3Å MS, THF, 0 °C

hetero
dienophile


O

EtO

91

C
O

O

H3CO

O

endo

yield (%)

ee (%)

R = Me

24 : 1

87

97

R = Ph


> 20 : 1

93

97

R = i-Pr

22 : 1

95

96

R = OMe

59 : 1

90

98

R = Ph

16 : 1

96

97


R = i-Pr

16 : 1

94

95

R = Et

> 20 : 1

94

97

R = Ph

> 20 : 1

91

99

OEt
EtO2C

O


R

O

EtO2C

50

Ph
H3CO

Y

R

OTBS

>99

O

endo : exo

product

78

OTBS

X

O

R

CH3
H3C

+
O Y

yield (%)

O

OTES
CH3
H3C

C
O

O
98

H3C

C
O

R


EtO

OTES

R
2 mol% 16

14 X = SbF6
15 X = Cl

Product

• air-stable, solid catalyst

R

• The diastereoselectivity was >95% in all cases, favoring the illustrated endo product.
• Use of acetone as solvent in the cycloaddition generally improves enantioselectivities, and is
critical in the case of aromatic aldehydes.
• Both enantiomers of the aminoindanol ligand are commercially available.

Diene

OTf

Cu
Me3C H2O OH2 CMe3
OTf
16


Cr
O

N

O

OEt

H

H

O

Ph

91

OTBS

• This is the first effective method for the asymmetric HDA reaction between dienes with less than
two oxygen substituents and unactivated carbonyl compounds.
Dossetter, A. G.; Jamison, T. F.; Jacobsen, E. N. Angew. Chem., Int. Ed. Engl. 1999, 38, 2398!2400.

EtO

C
O


O

SR
EtO2C

O

SR

Kent Barbay

14


Myers

Asymmetric Diels!Alder Reactions
Catalytic, Asymmetric Diels!Alder Reactions – Applications in Synthesis:

R1

R1
R2

Gibberellic Acid:

R2

5 mol% 16


Chem 115

NH

+
O

(MeO)2P
O

3Å MS, THF, 0 °C

X

(MeO)2P
O

X

O

O

endo

O
N B
Ts
n-Bu


H
R1

R2

X

yield (%)

endo : exo

ee (%)

Me

H

OEt

84

36 : 1

93

Ph

H


OEt

95

22 : 1

97

i-Pr

H

OEt

92

22 : 1

95

OEt

H

OEt

92

44 : 1


97

Me

Me

OEt

98

25 : 1

≥90

H

Me

16 : 1

75

SEt

Br

CO2Me

Br


96

CHO

OTMS
• The hetero-Diels!Alder reactions catalyzed by 16 have a favorable temperature-enantioselectivity
profile, affording dihydropyrans with high enantioselectivities even at 0 °C.
• Stereochemical Model:
H3C CH3
O
Me3C

Gracilin B:

R1

CMe3
O
P OCH3

R2

O

H

1. "

CO


2. NaCl,
DMSO, "

(20 mol %)

TMS

• attack of heterodienophile occurs from the less
hindered #-face

O

Br

Ar

NSO2CF3
Al
TMS
CH3
Ar = 3,5-dimethylphenyl

t-Bu

R2 = H

H2, Pd/C
or Rh/C
R1


(MeO)2P
O

CH3

O

R2 = H
O

X

dr > 20 : 1

COOH

OsO4, NMO
t-BuOH, H2O

O

CH3
R2

TMS

H OCH3

H


HO2C
OHC

H OCH
3

RuCl3•(H2O)3
NaIO4

Evans, D. A.; Johnson, J. S.; Olhava, E. J. J. Am. Chem. Soc. 2000, 122, 1635–1649.

H

H
H

O
H
O

H OCH
3
H3CO

CH3
O
O

HO
O

OEt
(MeO)2P
O OH
dr > 20 : 1

MeSO3H

O

CH3

R2 = H

O

H OCH3

H3C

OEt

t-Bu

O
89%, 95% ee
O

O

R1 = CH3

O
OEt
(MeO)2P
R2 = H or CH3
O
dr > 20 : 1

O
N

O

R2

HO

H

toluene, –78 °C

1. HCl, MeOH
2. PPTS
CHO

H3C

OH
H

Ar


• The product dihydropyrans are synthetically versatile:

MeO2C

HO

O

N

+

OCH3

R1

H

F3CO2SN

• heterodiene binds in a chelated fashion

Cu
XO

81%, 99% ee,
99 : 1 exo : endo

Gibberellic Acid


• square planar transition structure

2 –OTf

N

Br

CH2Cl2, –78 °C

Corey, E. J.; Guzman-Perez, A.; Loh, T.-P. J. Am. Chem. Soc. 1994, 116, 3611!3612.
+2

O
N

CHO

Br

(10 mol %)

Br +

Gracilin B

H

H

H
AcO

O
H
O

AcO

Corey, E. J.; Letavic, M. A. J. Am. Chem. Soc. 1995, 117, 9616!9617.

Kent Barbay

15


Myers

Asymmetric Diels!Alder Reactions

Estrone
Ph

H

Tf2N–

CH3

CHO


N B
H

O
CH3

CH3
CHO

(20 mol%)

Chem 115

The application of the oxazaborolidinium catalysts to once racemic syntheses has been
demonstrated:
H Ph Ph
O
O
H
i-Pr
i-Pr
O
N B
Tf2N– H Ar
OCH3
OCH3
H
O
O

toluene, –50 °C, 48 h
Ar = o-tolyl

99%, 99% ee

CO2Et
EtO2C

CH3O

H

CH2Cl2, –78 °C, 8 h

H

CH3O
92%, 94% ee
recryst.
100% ee

O

5 steps

CH
H N 3

62%
CH3 O


CH3 O
three steps†

H

O

H

CH3
(–)-dendrobine

H

H NCH3
CH3

H

racemic synthesis: Kende, A. S.; Bentley, T. J. J. Am. Chem. Soc. 1974, 96, 4332.

HO

H

CH3O

Hu, Q.; Rege, P. D.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 5984.
†


i-Pr

Hu, Q.; Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 13708.

H

(+)-estrone

H3CO2C

H

i-Pr
O

Tf2N–

Ph

Ar = o-(CF3)C6H4

(a). Ananchenko, S. N.; Torgov, I. V. Tetrahedron Lett. 1963, 4, 1553.
(b) Quinkert, G.; Grosso, M. D.; Dõring, A.; Döring, W.; Schenkel, R. I.; Bauch, M.; Dambacher, G. T.;
Bats, J. W.; Zimmermann, G.; Dürner, G. Helv. Chim. Acta 1995, 78, 1345.

O

H


O
N B
H Ar

(10 mol%)
CH2Cl2, –50 °C, 16 h

H O
95%, 82/18 endo/exo
96% ee (endo)

• Both enantiomers of the catalyst are accessible.
• The following pre-transition-state assembly was suggested:
CO2Et
CH3
H O

H

H
H
H N B O
CH3

CH3

H3C

CH3


CH3O2C

H

H

CH3

silphinene

H

O

OCH3

O

racemic synthesis: Tsunoda, T.; Kodama, M.; Ito, S. Tetrahedron Lett. 1983, 24, 83.
Hu, Q.; Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 13708.

Seth B. Herzon

16