Intramolecular Diels-Alder Reactions
Rebecca Wilson
MacMillan Group Meeting
January 24, 2001
I. Introduction
II. Simple Diastereoselectivity
III. Transfer of Stereochemistry
IV. Heteroatoms
V. Removable Tethers
VI. Chiral Auxiliaries
VII. Enantioselective Catalysis
Introduction: Intramolecular Diels Alder
Type I vs. Type II
Type II: Tether is attached at 3- position of diene.
Type I: Tether is attached at 4- position of diene.
R
R
+
H
cis fused
trans fused
Type II IMDA's always cyclize to syn product.
References for Type II IMDA:
bridged
Bridged products rarely observed (tether must be >9 atoms).
Shea, KJ Tetrahedron Lett. 1994, 35, 7311.
Shea, KJ J. Am. Chem. Soc. 1988,110, 860.
Fused products usually have 3 or 4 atom tethers
Syn vs. Anti Transition State
Representative Transition States for E- diene
R
R'
R
R
R
R'
R'
R'
7
H
H
anti TS
trans fused
products
4
syn TS
cis fused
products
With E- diene, anti TS is sterically favored. Syn TS experiences nonbonding interactions between C4-C7.
A combination of steric and electronic factors determine IMDA stereochemistry.
Diastereoselectivity in the IMDA: Z - Dienes
Representative Transition State for Z -Diene.
R'
R'
R
R
anti TS
cis fused
product
R
R'
H
Regardless of the length or nature of the tether, Z - dienes always cyclize to give cis- fused products
CO2Me
AcO
230°C, 32 hr
O
Me
O
OAc
80 % yield
OAc
CO2Me
O
O
+
O
Me
CO2Me
O
Reaction time for corresponding E,E-diene is 0.5 h
Due to steric congestion, Z - dienes often cyclize more slowly than E - dienes.
Boeckman, RK J. Am. Chem. Soc. 1982, 104, 3216.
Diastereoselectivity in the IMDA: Unactivated trienes
250°C, 1-5h
+
95%
27%
73%
220°C, C6H12
+
7 h , 90%
55%
45%
In both nonatriene and decatriene systems, there is a some preference for cis fused cycloadducts
Product ratios can be enhanced or reversed through the use of substituents on the triene
Concept of Asynchronous Transition State and Twist Asynchronicity
Although the IMDA is concerted, bond formation is asynchronous in the transtion state
Internal bond formation is more advanced in the TS
anti TS, trans product
External bond formation is more advanced in the TS
syn TS, cis product
R'
R
R
R'
7
H
H
Effects of asynchronicity are less pronounced for decatriene systems
anti TS
4
syn TS
Houk, KN, Tetrahedron Lett., 1985, 26, 2269.
Diastereoselectivity in the IMDA
Terminally Activated Dienophiles- [4.3.0] Bicycles
E- dienophiles
CO2Me
CO2Me
O
CO2Me
+
MeO
anti TS
trans
150°C, 24 hrs.
EtAlCl2, 23°C, 36 hrs.
endo
cis
60
:
40
100
:
0
Trans product is favored sterically and electronically with terminally activated E-dienophiles.
Z- dienophiles
O
CO2Me
CO2Me
OMe
+
anti TS
exo
CO2Me
trans
cis
150°C, 24 hrs.
65
:
35
EtAlCl2, 23°C, 36 hrs.
52
:
48
O
syn TS
endo
MeO
H
H
Trans product is favored sterically and cis product is favored electronically with terminally activated Z-dienophiles.
Roush, WR J. Am. Chem. Soc. 1982, 104, 2269
Diastereoselectivity in the IMDA
Terminally Activated Dienophiles- [4.4.0] Bicycles
E- dienophiles
CO2Me
CO2Me
+
MeO2C
CO2Me
trans
cis
150°C, 24 hrs.
50
:
50
EtAlCl2, 23°C, 36 hrs.
88
:
12
anti TS, endo
trans
Z- dienophiles
CO2Me
CO2Me
CO2Me
CO2Me
+
trans
150°C, 24 hrs.
EtAlCl2, 23°C, 36 hrs.
55
:
cis
45
8
:
92
syn TS, endo
cis
Lewis Acid- promoted terminally activated [6.4.0] IMDA's give endo product.
Roush, W.R. J. Org. Chem., 1982, 47, 4825.
Diastereoselectivity in the IMDA
Internally Activated Dienophiles- [4.3.0] Bicycles
180°C, 51%
+
O
O
O
13
:
87
Unless other steric factors intervene, internally activated trienes give cis-fused products.
Roush, W.R. J. Am. Chem. Soc. 1981, 103, 6696
Internally Activated Dienophiles- [4.4.0] Bicycles: Carbonyl Coplanarity Effect
MeO
O
O
O
O
23°C, 60%
+
CO2Me
CO2Me
:
86
14
O
MeO2C
syn boat
major product
H
syn chair
O
H
MeO2C
minor product
Decatrienes with internal carbonyls adjacent to dienophile cyclize through boat TS to give cis-fused products.
Zschiesche, R. Angew. Chem. Int. Ed. Engl. 1986, 25,1086.
Diastereoselectivity in the IMDA
Internally Substituted Dienes- [4.3.0] Bicycles
150°C, 3 h
O
O
92%
O
O
O
O
+
O
O
:
O
0
O
syn TS
100
cis
O
H
O H
O
O
Sakamura, S. J. Am. Chem. Soc. 1980,102, 6353.
Internally Substituted Dienes- [4.4.0] Bicycles
160°C,
+
Me
95%
Me
0
syn TS
H Me
trans
anti TS
O
cis
Me
100
:
Me
anti TS
trans
H
Internally substituted dienes give trans fused products for steric reasons.
Wilson, S.R. J. Am. Chem. Soc. 1978,100, 6289
Diastereoselectivity in the IMDA
Substitution adjacent to diene- [4.4.0] Bicycles
Me
O
MeO
O
OMe
O
60%
Me
Me
Me
150°C, 100h
Me
CO2Me
Me
O
O
anti TS
trans products
carbonyl coplanar with diene
MeO
H
OMe
OMe
Me
150°C, 19h
O
Me
Me
Me
CO2Me
CO2Me
Me
MeO
71 %
MeO
OMe
Me
MeO
syn TS
cis product
alleviate nonbonding interaction
If oxygenation is desired adjacent to diene, alter product stereochemistry by choosing between ketal and ketone.
Roush, WR J. Am. Chem. Soc. 1981, 103, 5200.
Diastereoselectivity in the IMDA
Disubstitution on tether- [4.3.0] Bicycles
!"Disubstitution
PhMe, 170 C
MeO
OMe
OMe
OMe
24 hr.; 98%
OMe
OMe
anti TS
72:28 trans
alleviate nonbonding interaction
Nonbonding interactions in syn TS give predominantly trans product
Jung, M.E. Tetrahedron Lett. 1981, 22, 3929.
#"Disubstitution
MeO2C
O
O
CO2Me
CO2Me
O
155 C, 10 hr.
O
Me
Me
85 % yield
O
O
trans only
Dialkyl Substitution on tether- [4.4.0] Bicycles
Oppolzer W. Helv. Chim. Acta. 1981, 64, 2002.
CO2Me
CO2Me
toluene, 100 C
CO2Me
CO2Me
CO2Me
CO2Me
trans only
Trost, B.M.
J. Am.
Chem. Soc.usually trans.
Thorpe-Ingold effect: Dialkyl Substitution gives enhanced reaction rates. IMDA products
1985, 106,
7641.
Relay of Stereochemistry in the IMDA
Stereocenters adjacent to dienophile
Me
Me
CO2Me PhMe, 240C
CO2Me
CO2Me
Me
Me
OBn
11h, 67%
OBn
+
40%
Me
Me
Me
10h, 80%
OBn
30%
30%
CO2Me
PhMe, 220C
Me
cis fused
products
OBn +
OBn
CO2Me
+
cis fused
products
OBn
O
80%
OMeH
20%
A1,3 - minimized anti TS
Allylic strain dictates orientation of tether. Z- Dienophile experiences A1,3 strain---products obtained with good diastereocontrol
Roush, WR J. Am Chem. Soc. 1981, 103, 6696.
Stereocenters adjacent to diene
Me
Me
O2N
SO2Ph
Me
H
25h, 77%
SO2Ph
H
+
PhMe, 90C
NO2
H
NO2
NO2
PhO2S
PhO2S
10%
90%
A1,3 - minimized anti TS
Oppolzer, W. Helv. Chim. Acta 1975, 587.
Relay of Stereochemistry in the IMDA
Stereocenters adjacent to diene: [4.4.0]
R
Me
TMS OTBS
CHO
R
OTBS
180°C, 24h
OHC
89%
Me
CHO
TMS
TMS H
A1,3-minimized anti TS
TBSO
only product
Minimize A1,3 strain in both syn and anti transition states
Boeckman, RK J. Org. Chem. 1985, 50, 3241.
Nonallylic tether stereocenters: [4.4.0]
OH
Me
H
PhCH3, 190°C
Me
HO
69%
Me
Me
Me
OH
82:19
Me
Me
Taber, DF Tetrahedron Lett. 1982, 23, 2361.
St Bu
O
Me
Me
O
O
O
StBu
LiClO4, 25°C, 18h
70%
Me
Me
Me
O
StBu
Zn O
Me
Place stereocenter equatorial in chair transition state when not in conjugation
90% de
Me
Dixon, D.J. Org. Lett. 2000,2, 3611.
Heteroatoms in Diene
Most substrates with diene heteroatoms cyclize according to the same rules of diastereoselectivity as all-carbon dienes.
Enone Diene
Me Me
O
100 ºC
O
O
Me
65 %
Me
Me
Me
O
O
O
Me
only product
substituent in 3-position of diene promotes anti TS
stereocenter placed equatorial in chair-like TS
Jung, ME J. Org. Chem. 1982,47, 1084
Oxazole Diene- Total Synthesis of (-)-Stemoamide
O
O
N
MeO
Me
DEB
182ºC
O
MeO
Me
N
O
O
O
Retro
N
Me
Me
N
[4+2]
O
MeO
N
N
O
O
53% yield
Oxazoles are very reactive dienes. Retro [4+2]- eliminate MeCN and form furan
Jacobi, P.A. J.Am.Chem.Soc. 2000, 122, 4295.
Heteroatoms in Dienophile
Substrates with dienophile heteroatoms often have different electronic properties than all-carbon dienophiles.
This can have large effects on stereoselectivity of IMDA
Acyl-amine IMDA
AcO
MeO2C
CO2Me O
O
H
N
O
200°C
MeO2C
N
O
syn TS
N
one
diastereomer
O
ester exo
O
opposite diastereomer as when
all-carbon triene is used
Weinreb, SM J. Am. Chem. Soc. 1981, 103, 7573
Imino IMDA
Me
Me
H2O 70°C
Me
N
N
Me
48 hrs; 80%
H
one
diastereomer
N
Me
Me
Grieco, P.A. J.Org.Chem. 1999, 64, 6041-8.
Acylnitroso IMDA
BnO
N
O
O
H2O/ DMF (50:1)
0°C; 90%
OMOM
BnO
R
O
OBn
O
H
N
N
H
O
5.5:1 dr
O
OMOM
Kibayashi, C. Org. Lett. 2000, 19, 2955-8.
Heteroatoms in Tether- Esters
Amines, ethers, and thioethers in the linker:
Usually react to produce IMDA adducts with stereoselectivities similar to those seen in all-carbon tethers.
Ester conjugated to dienophile: [4.4.0]
Me
O
O
150°C ; 10 days
O
O
i Pr
76%
iPr
Me
Me
Me
Me
O
O
H
Me
i Pr
syn boat TS
Carbonyl coplanarity effect: Ester reacts through boat TS to give [4.4.0] bicycles
Jung, M.E. Org. Lett. 2000, 2, 1835-7.
Kurth, M.J. Org. Lett. 2000, 2 , 1831-4.
Ester conjugated to dienophile: [4.3.0]
R
OTBS
R
O
R
toluene, BHT,
250°C, 55 hr.
O
O
O
O
H
O
TBSO
OTBS
Me
anti TS
Sterically favored trans product predominates
White, J.D. Org. Lett. 2000, 2, 3313-6
Esters not in conjugation with dienophile:
Often exhibit low reactivity due to poor overlap of nonbonding ethereal electrons with carbonyl in TS
Heteroatoms in Tether- Amides
Amide conjugated to diene: [4.4.0]
Me
O
Me
Ph
190°C
Me
Me
H
Ph
81%
N
Ph
N
Me
O
Me
Ph
O
N
Me
O
N
Me
trans only
Carbonyl coplanarity: Amide reacts through chair TS when in conjugation with diene to give trans products
Diastereoselectivity of IMDA for [4.4.0] Amides varies greatly, depending upon position/ orientation on chain.
Handa, S. J. Chem. Soc. Chem. Commun. 1985, 1362.
Amide conjugated to diene: [4.3.0]
Amide conjugated to dienophile: [4.3.0]
Ar
Ar
Ph
Ph
80°C
O
190°C
H
80%
NMe
NMe
84%
N
O
cis only
88:12
Sterically favored trans product predominates
N
MeO2C
MeO2C
H
anti TS
Ester and C7-H experience
eclipsing intrxns in anti TS
MeO2C N
Gschwend, HW Angew. Chem. Int. Ed. Engl. 1975, 11, 294.
Oppolzer, W. Helv. Chim. Acta. 1975,58, 590.
Removable Tethers for IMDA: Vinyl Sulfonates
O
13 kbar, CH2Cl2
O
S
O
Me
25°C, 79%
Me
SO2
O
H
S
anti- selective because of
substitution on 3- position of diene.
R
anti TS
13 kbar, CH2Cl2
O
S
O
O
O
H
R'
3.6:1 (anti)
O
O
SO2
25°C, 88%
O
H
2.3: 1 (syn)
Me
O
O
H
O
13 kbar, CH2Cl2
S
O
S
R
O
H
O
R'
25°C, 92%
O
S
O
O
highly syn- selective because bridgehead methylenes
experience nonbonding interactions in anti TS.
syn TS
Me
Metz, P. Tetrahedron 2000, 56, 873-9.
Metz, P. Tetrahedron Lett. 1996, 22, 3841-4.
54.6:1 (syn)
Removal of sulfonate tether:
TBAF
1. n-BuLi
Me3Si
O
S
O
2. I
O
Me
SiMe3
65%
O
S
70%
O
O
HO
Me
Me
Removable Tethers for IMDA: Boron
Alkenyl Boronate Tethers (C-B-O)
Me
Ph
B(OiPr)2
1.
Me
Me
OH
Me3N(O), C6H6,80 C, 24 hrs;
Ph
PhMe; 5 mol% BHT, 190
B
3 hrs
OiPr
Ph
H2O, 60 C, 0.5 hrs.
O
OH
HO
90:10 (trans:cis)
83% yield
When three-atom linker is used, trans fused product formed
OH
1.
Ph
Ph
B(OiPr)2
PhMe; 5 mol% BHT, 190
3 hrs
B
OiPr
Me3N(O), C6H6,80 C, 24 hrs;
Ph
H2O, 60 C, 0.5 hrs.
OH
O
OH
When four-atom linker is used, cis fused product formed
80:20 (cis:trans)
85% yield
Batey,R.A. J. Am. Chem. Soc. 1999, 121, 450-1.
Removable Tethers for IMDA: Magnesium and Silicon
Magnesium Tethers (C-Mg-O)
OH
O
Me
Mg
1. nBuLi (-78°C )
OH
2.
130 C, 3 hrs
Me
Me
MgBr
60% yield
4:1 dr
Me
Me
Me
OH
1. nBuLi (-78°C )
Me
130 C, 2 hrs
O
OH
60% yield
9:1 dr
Mg
2.
Me
MgBr
Me
Me
Me
Me
Stereochemistry of Diels-Alder adducts dependent upon geometry of vinyl magnesium bromide.
Stork, G. J. Am. Chem. Soc. 1995, 117, 6595-6.
Silicon Tethers (C-Si-O)
O
EtO2C
Me
OH
SiMe2
SiMe2Cl
TBAF
OH
OH
Et3N
CO2Et
160 C; 3.5 hrs.
Me
H2O2
Tamao Oxidation
80% yield
CO2Et
Me
trans only
IMDA of silyl ethers gives trans fused products
Stork, G. J. Am. Chem. Soc. 1992, 114, 7578-9.
Removable Tethers for IMDA: Silicon
N
N
HH
(+)-aloperine
Silicon Tethers (C-Si-N)
First example of a diastereoselective nitrogen-silicon tethered IMDA
CO2Me
TfOMe2Si
N
H
H
Et3N, CH2Cl2
Me
N
Ts
N
N
Si
Me Si
Me
N
Ts
Me
MeO2C
Co2Me
SiMe2F
1.HF-pyridine
2. mesitylene, reflux
OH
KF, KHCO3, H2O2
N
N
HH
O
H N
Ts
MeOH, THF, reflux
(+)-aloperine
N
N
HH
O
63% yield (major)
5:1 dr
Overman, L.E. J. Am. Chem. Soc. 1999, 121, 700-9
Internal Chiral Auxiliaries: Chiral Amides
Phenylglycinol-Derived Carboxylic Amides
OH
Ph
O
Me
N
Me
1. BuMgBr
2. !
3. H+
Me Me
OH O
N
OH O
N
O
O
Ph
Ph
O
Me Me
88%
12%
Rationale for observed stereoinduction:
Magnesium chelates alcohol and amide carbonyl
O M
O
Me
N
Me
Furan approaches top face of dienophile to avoid
steric interactions with phenyl
O
Removal of Chiral Auxiliary
OH O
N
Me Me
O
Na, NH3
O
HN
Ph
Me Me
Me Me
1. NaNO2/AcOH
2. KOH/EtOH
EtO2C
3. H+
HO
O
O
Mukaiyama, T. Chem. Lett. 1981, 29-32.
External Chiral Auxiliaries: "-Hydroxy Ketones
n
O
O
O
OH
ZnCl2, CH2Cl2
Xc
Xc
0-23 C, 24 hrs.
n=1
70% yield
endo only
94% de
n=2
82% yield
endo only
92% de
Stereochemical Rationale:
Zinc chelates hydroxy ketones
Tether wraps around to bottom face of dienophile to avoid
steric interaction with cyclohexyl.
R
O
O
Zn
Endo TS yields trans fused product
Drawback of hydroxyketone is the harsh conditions required to remove the auxiliary.
O
O
NaIO4
OH
OH
Masamune, S. J. Org. Chem.. 1983, 48, 1137-9.
Roush, Comprehensive Organic Synthesis; Trost, B.M, Fleming, I.,Eds.; Pergamon Press: Oxford,1991; v.5, Chapter 4.4.
External Chiral Auxiliaries: Acyl Sultams
N-Acyl sultam gives trans-fused (endo) adducts with excellent diastereoselectivity and good yields.
Me
Me
O
O
1. Cl
NH
SO2
Me
n
Me
Xc
O
2. EtAlCl2, -20C, 4hrs.
n
N
SO2
n
O
O
n=1
75% yield
endo only
95% de
Xc
n=2
53% yield
97:3 endo: exo
91% de
Xc
Stereochemical Rationale:
Me
Me
Aluminum chelates sulfonyl and carbonyl.
R
N
O
S
Tether wraps around to bottom face of
dienophile to avoid steric interaction with camphor.
O
O
Endo TS yields fused product
Al
Oppolzer, W. Tetrahedron Lett. 1985, 26, 5437-40.
External Chiral Auxiliaries: Oxazolidinones
Trienes with oxazolidinone auxiliary exhibit high reactivity and endo:exo selectivity
O
O
Xc
O
Xc
O
N
Me2AlCl (1.4 eq.)
O
>100:1 endo: exo
73 % yield
90% de
CH2Cl2, -30°C, 5h.
:
95
Ph
O
O
O
5
Xc
O
Xc
Me2AlCl (1.4 eq.)
N
>30:1 endo: exo
88 % yield
94% de
O
CH2Cl2, -30°C, 5h.
Ph
:
97
3
Rationale for observed stereoinduction:
Aluminum chelates imide carbonyls.
Al
O
O
N
O
Pi- stacking interactions believed to exist with phenyl ring and dienophile.
Diene approaches from top face to avoid steric interactions with phenyl
Endo transition state yields trans fused products
Evans, D.A., Tetrahedron Lett. 1984, 25, 4071-4.
Evans, D.A., J. Am. Chem. Soc. 1988, 110, 1238-56.
Evans, D.A., J. Am. Chem. Soc. 1984, 106, 4261-3.
Enantioselective Catalysis: Ti-TADDOL
Ph
Narasaka's Titanium TADDOL Catalyst
O
n
N
30 mol%cat., 4A mol. sieves
O
Ph
O
O
Me
O
O
Ti
O
O
Ph
Ph
X
Ph
Catalyst
CH2Cl2, 25C, 256 hrs
n
O
O
87 % yield
endo only
87% ee
X
X
no
reaction
O
S
O
S
O
N
n
X
10 mol%cat., 4A mol. sieves
O
CH2Cl2, 25C, 68-120 hrs
n
S
S
O
O
X
62 % yield
endo only
95% ee
X
S
S
S
64 % yield
endo only
86% ee
S
Moderate reactivity: Geminal dialkyl substituents required for [6.4.0] bicycles.
Narasaka, K. Chem. Lett.. 1989, 62, 1947-50
Narasaka, K. Tetrahedron: Asymm 1991, 12, 1305-18.
Enantioselective Catalysis: Bis(oxazoline)
O
Evans' C2- symmetric Cu(II) tert-butylbis(oxazoline) catalyst:
N
[4.3.0] systems readily synthesized, but unactivated [4.4.0] substrates are unreactive.
O
n
R
O
N
R
2+
2SbF6
O
Cu
N
O
5-10 mol% cat.
O
X
CH2Cl2
Catalyst
n
Ph
O
O
X
86 % yield
endo only
92% ee
(5 hrs)
Ph
X
O
O
89 % yield
endo only
86% ee
(24 hrs)
X
X
97% yield
84:16 dr
97% ee
(24 hrs)
no
reaction
Application towards the total synthesis of (-)-Isopulo'upone
TBSO
O
X
O
Me
O
O
5 mol% cat., 25 CTBSO
N
N
CH2Cl2, 24 hrs
81% yield
endo only
96% ee
(-)-Isopulo'upone
Evans, D.A. J. Org. Chem. 1997, 62, 786-7.
Application of Asymmetric IMDA: Evans Oxazolidinone
O
Total synthesis of (-)-Stenine
Me
O
S
S
S
Me
S
O
1.3 eq. Me2AlCl
-20ºC, 72h, 85%
O
N
Me
O
O
MPMO
(-)-stenine
O
N
O
N
endo only
10:1 dr
Ph
Me
MPMO
Ph
Morimoto, Y. Ang. Chem. Int. Ed. Engl. 1996, 35, 904.
Total synthesis of (+)-Lepicidin A
OH
OTIPS
O
OTIPS
Et
OTES
Et
Me
H
O
O
OTES
O
O
Et
4.6 eq. Me2AlCl
N
O
Bn
O
Me
0ºC, 74%
endo only
10:1 dr
O
O
O
H
Me
H
O
H
Xc
H
OH
(+)-lepidicin aglycone
OTBS
H
OTBS
Able to overcome inherent stereochemical bias for opposite endo stereosisomer
Evans, D.A.. J. Am. Chem. Soc. 1993, 115, 4497
Enantioselective Catalysis: Chiral Acyloxyborane (CAB)
Me
O
84% yield
99:1 dr (endo)
92% ee
First Generation Catalyst requires !-Substituent on dienophile
O
O
OMe
H
CH2Cl2, -40°C
Me
O
O
10 mol% cat.I
H
CO2H O
OMe O
Yamamoto's First Generation CAB Catalyst:
B
H
Catalyst I
Yamamoto, H. Tetrahedron Lett. 1989, 30, 7231-2.
O
O
CF3
30 mol% cat. II
H
CH2Cl2, -40°C
H
95% yield
99:1 dr (endo)
80% ee
O
O
Second Generation Catalyst allows cycloaddition of non-substituted dienophiles.
B
CF3
HO
Proposed Mode of Stereoinduction:
F3C
CF3
Catalyst II
Aldehyde coordinates with boron.
O
B
O
O
O
Dienophile rests over phenyl, forcing chain to wrap
around to top face.
Anti TS
Trans Product
Yamamoto, H. J. Am. Chem. Soc. 1996, 118 , 3049-50.
Enantioselective Catalysis in the IMDA: MacMillan Imidazolidinone Catalyst
R
CHO
R
CHO
n
O
Me
20 mol % cat.
N
4-25°C; 5% H2O
N
H
n
X
Stereochemical Rationale:
catalyst
O
Me
N
Iminium ion forms cis to benzyl group.
N
R
Tether wraps around to top face of dienophile to avoid steric interactions with pheny.
Reaction is endo -selective.
R
Ph
CHO
CHO
n
n
Challenges:
Diels-Alder adducts can epimerize under reaction conditions.
Less reactive substrates can polymerize or undergo
amine-catalyzed intermolecular Diels-Alder/aromatization sequence.
CHO
When R=Ph, the olefin can isomerize into conjugation with phenyl.
Enantioselective Catalysis in the IMDA: MacMillan Imidazolidinone Catalyst
20 mol% cat. II-TFA
Ph
CHO
CHO
Ph
94% ee
16:1 dr
90% yield
-10°C, nBuOH; 5% H2O
O
Me
N
CHO
Ph
O
20 mol% cat. I-HClO4
CHO
Ph
O
-20°C, nBuOH; 5% H2O
OHC
Ph
30 mol % cat. I-HCl
CHO
Ph
N
H
HX
catalyst I
Me
95% ee
20:1 dr
90% conv.
25°C, CH3CN; 2% H2O
Me
94% ee
>100:1 dr
79% yield
CHO
Me
20 mol % cat.I-HClO4
CHO
Me
89% ee
20:1 dr
50-60% conv.
-20°C, nBuOH; 5% H2O
CHO
20 mol % cat.I-HClO4
CHO
CHO
Ph
CHO
20 mol% cat. I-HClO4
4°C, nBuOH; 5% H2O
Ph
N
N
H
HX
93% ee
7:1 dr
50-60% conv.
4°C, CH3CN; 5% H2O
O
Me
98% ee
100:1 dr
50-60% conv.
catalyst II