Asymmetric Diels Alder ReactionsChiral Auxiliaries
(-)-8-Phenylmenthol
H3C
O
H3CCH3
O
AlCl3H3C
O
H3CCH3
O
AlCl3
s-transLewis-acidcomplex
favorable !-stacking
OBnfront-face approachof diene
O OR*
BnO
97%de
H3C
OH
H3CCH3
O
Cl
(-)-8-phenylmenthol=R*
LiAlH4
auxiliary recovery
JACS, 1975, 1610
Dimenthyl fumarate:
R*O2C
O
O
O
Et2AlCl
O
CH3
CH3
H3C
O
O
OR*
R'O
R'=
CH3
CH3
H3C
H3C
CH3
CO2R*
Et2Al
AlEt2
99%deTL, 1986, 4507Tetrahedron, 1963, 2333
Diene Lewis acid de%
OTMS
iBuAlCl
Et2AlCl
AlCl3
Et2AlCl
95
95
96
94
N-acyl oxazolidinone auxiliaries
ON
OO
R
Et2AlCl
COXc
R
tolerates !-substitutionon dienophile
-100°C
ON
OO
R
Et2AlCl
COXc
R
-100°CH3C Ph
ON
OO
R
Al
EtEt
+
chelated s-cis formof dienophile
front faceattack ofdiene
ON
OO
R
H3C Ph
Al
EtEt
back faceattack ofdiene
JACS, 1984, 4261JACS, 1988, 1238
1
2
dienophile endo:exo isolated dr
1, R=H >100:1 >99:1
1, R=CH3 >100:1 >99:1
1, R=Ph >100:1 >99:1
2, R=H >100:1 <1:99
2, R=CH3 >100:1 <1:99
imides and amides favor s-trans form of dienophile
ON
OO
R
Ph
Et2AlCl
-100°C
H3C R
COXc
CH3 R
COXc
CH3
R=H, dr=95:5
R=CH3, dr=94:6
R=H, dr=>100:1
R=CH3, dr=95:1
ON
OO
R
Al
EtEt
!-stacking enhances stereoselectivity
Asymmetric Intramolecular Diels-Alder
Xc
O
n
Me2AlCl
-30°C, 5h
diene and dienophilein the same molecule
H
H
OXc
n
H
H
OXc
n
+
Endo I Endo II
enantiomers
Diene Scope:
XC n Endo I : EndoII
O N
O
Ph
O N
O
C6H11
1 95:5
2 97:3
1 3:97
2 6:94
TL, 1984, 4071
ACIEE, 1987, 1184.
COXc
Camphor-Derived N-enoyl Sultams: Oppolzer
CH3H3C
N
S O
O
O
CH3H3C
N
S O
O
O
MLn
dieneR
EtAlCl2R
R endo:exo dr
H 99.5:0.5 97.5:2.5
CH3 96:4 99:1
CH3
H
H
s-cis conformer
!-faceapproach
Chelated ComplexHelv. Chim. Acta, 1989, 123.
(1.5 eq.)
Acyclic dienes:
CH3H3C
N
S O
O
O
R
R
O
Xc
R dr yield
H 98.5:1.5 81
CH3 97:3 64
for unsubstituted N-acyloyl sultams
Helv. Chim. Acta. 1984, 1397
Intramolecular Diels-Alder Reactions:
CH3H3C
N
S O
O
O
s-cis form of dienophilefavored for amides:JACS, 1973, 6365.
n
EtAlCl2H
H
OXc
n
H
H
OXc
n
+
Endo I Endo II
n EndoI:EndoII yield1 >97.4:2.5 752 94:2.6 53
TL, 1985, 5437
EtAlCl21.5 eq.
Catalytic Asymmetric Diels-Alder ReactionsAn Early Example
+
H3C
O
H
OAlCl2
(15 mol%)toluene, -78°C
CHO
CH3
72% eeexo:endo = 98:2
C2-symmetric Diazaaluminate Catalysis: Corey
Al
NN
Ph Ph
CH3
SS
F3CCF3
O O O O
J. Chem. Soc., Chem. Commun. 1979, 437.
RO
NR' O
O
+
10-20 mol%
CH2Cl2, -78°C
R'
R
O N O
O
JACS, 1989, 5493
R R' endo:exo ee%
H H >50:1 91
H CH3 96:4 94
CH2OBn H 95
N
N
Al
Tf
Tf
CH3
O
N
O
O
Phenylblocks frontface
•non-chelated binding mode•s-trans dienophile conformer
Proposed Transition-StateAssembly:
JACS, 1992, 7938.
•a modified version of this catalyst expands the scope to maleimide dienophiles: JACS, 1994, 12089.
Oxazaborolidine Catalysis:
+
Br
O
H
3 (5 mol%)
CH2Cl2, -78°C
O
H
Br
96:4 exo:endo, 92% eeO
O
B-n-BuNTs
HN
H
3, tryptophan-derived
+Br
O
H
3 (5 mol%)
CH2Cl2, -78°C
CHO
Br
92%ee!-substitution on aldehyde requiredfor high ee
O
O
BN
HN
H
SOO
Ar
O
H
Br
H
H
•exo-TS
•s-cis conformer isreactive species
•formyl C-H---Ohydrogen bond is proposedas an additional organizing element leading to excellentenantioselectivities : TL, 1997, 37.
•Attractive pi-stackinginteractions between indoleand dienophile organizethe T.S., resulting in reactionfrom the unblocked (back)face
ACIEE, 1990, 256
Lewis acids complex syn to the formyl proton:
JACS, 1992, 8290
A modified oxazaborolidine catalyzes cycloadditions to furan:
Br
O
H
+O 4 (10 mol%)
CH2Cl2, -78°C
O
CHO
Br
92% ee
O
O
B-n-BuNTs
HN
H
H3C4
Tetrahedron Letters, 1993, 3979
CHO
Br
CH3
CO2Et
CH2
O
CO2H
Br
O
Corey has demonstrated the utilityof the cycloaddition products:JACS, 1991, 8966.
Alkyl Dichloroboranes:
+ O
OMe
R
n
BCl2
(10 mol%)
CO2Me
R
nJACS, 1991, 7794
R n ee%
H 1 97
CH3 1 93
CO2Me 1 90
H 2 86
B
O
OCH3
CH3
ClCl
•s-trans crotonate conformation•pi-stacking of crotonate carbonylwith aromatic ring
•complexation of Lewis acid antito ester C-O bond.
•the napthalene substituent forces thedienophile approach from the front face.
Titanium TADDOL: TiCl2
O
O
O
O
Me
Ph
Ph
PhPh
Ph
5
+R2
O
N O
O
5, (10 mol%)
R2
O NO
O
R1
R2
O
N O
O
+5, (10 mol%) R1 R2
O
N O
O
JACS, 1989, 5340Chem. Lett. 1995, 1129.
R2 endo:exo ee%
H 88
CH3 87:13 94
Ph 92:8 80
R1 R2 ee%
H H 93
H CO2Me 91
CH3 H >96
CH3 CO2Me 94
A number of transition state models have been proposed; the analysis is complicated by the number of coordinationpossibilities available in octahedral complexes
Bull. Chem. Soc. Jpn. 1991, 387.
O
N N
O
Cu
H3C CH3
2+
9 2TfO-
or
10 2SbF6
+R
O
N O
O
9, (5-10 mol%)R
O NO
O
O
N O
O
+ 10, (1-5 mol%)X
O
N O
O
X
O
+
O
N O
O
10, (5 mol%)
O
O NO
O
6
11
12
Diene X R endo:exo ee%
6 H 98:2 >98
6 CO2Et 94:6 95
6 CH3 96:4 97
6 Ph 91:9 96
11 OAc 85:15 96
11 SPh 98:2 98
12 80:20 97
Evans Bis(oxazoline) CopperComplexes
ACIEE, 1995, 798note: catalyst 10 uniformly provides higher reativityand higher levels of asymmetric induction than 9.
note:exo product
O
N N
O
Cu
H3C CH3 2+
10 2SbF6
The stereochemical results are consistent with the following model:
O O
NOR
Si-face
• 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
note: acyclic dienes unsubstituted at the 1-position afforded lower enantioselectivities; these dienes are proposed to approach via an exo TS, and the exo TS is only selective in the case of 1-substituted dienes
Diene endo:exo ee% yield
CH3
CH3
CH3
CH3
59% 81%
65 78
98 57OAc27:73
Catalyst 10 also is effective for the intramolecular Diels-Alder reaction:
O
N O
O
10
5-10 mol% H
H
R
O
N O
O
R
n n
R n endo:exo ee yieldH 1 >99:1 86 89Ph 1 >95:5 92 86Ph 2 84:16 97 97
JACS, 1993, 6460JACS, 1999, 7559JACS, 1999, 7582CH2Cl2, 25°C
Recommended
