RECENT ADVANCESIN 1,3-DIPOLAR CYCLOADDITIONS
OF AZOMETHINE YLIDES
Marina Tanasova
1,3-Dipolar Cycloadditions - the best and most convenient method for construction of five-member heterocycles.
BA
C
R2
R1
BA
C
R2
R1
+R3
R4
CB
AR2 R1
R4R3
Five-member heterocycles
Introduction
Five-member heterocycles - building blocks for a variety of biologically active molecules.
Possibility to construct different ring systems.
Formation of several contiguous stereocenters in one pot.
OH
MeON
O O
+TiCl4
4A MSDCE
ON
O O
H
O
O
NH
ON
O
H
HO
Endo Product
Tamura, O.; Okabe, T.; Yamaguchi, T.; Kotani, J.; Gotanda, K.; Sakamoto, M. Tetrahedron 1995, 51, 119-128.
Intramolecular 1,3-Dipolar Cycloaddition
o
O
O
H
Me
N COOMe
NH
O
CO2MeO
Me
Me
Me
AgOAc, Et3N
CH3CN, rt+
Subramaniyan, G.; Raghunathan, R. Tetrahedron 2001, 57, 2090-2013.
Synthesis of Spiro-Pyrrolidine
Only endo diastereomer is formed
Spiro-core with at least one heterocyclic ring,is found in various biologically active molecules.
Dipole precursor
O
HN
NN
O
OMeO
MeO O
HN
OCO2Me
N
MeMeO
MeSpirotryprostatin B
Formation of spiro-system by 1,3-dipolar cycloaddition
Synthesis of Spirotryprostatin B by 1,3-DipolarCycloaddition
Sebahar, P.R.; Hiroyuki, O.; Usui, T.; Williams, R.M. Tetrahedron 2002, 58, 6311-6322.
OPh
Ph
O
CO2MeH
HN
NN
O
OMeO
MeO O
Improved approach to the diastereocontrol of 1,3-dipolarcycloaddition of azomethine ylides with electron deficient mono- and di-substituted olefins.
Investigation and application of some chiral catalysts in order to increase enantiocontrol of cycloaddition.
Introduction of chirality through chiral vinyl sulfinyloxides. Recent approach to functionalized 2,5-dihydropyrroles.
Outline
Formation of substituted pyrrolidines through 1,3-dipolar cycloaddition of azomethine ylides.
1,3-dipolar cycloaddition of azomethine ylides with substituted imines, resulting in formation of different imidazo-compounds.
R3
R2 N
R1
O
OR
R3
R2 N
R1
O
OR
R3
R2 N
R1
O
OR
R3
R2 N
R1
O
OR
H
M
MX / Base
Generation of Azomethine Ylides
Grigg, R.; Kemp, J. J. Chem. Soc., Chem. Commun. 1978, 101,109-112. Kanemasa, S.; Yamamoto, H. Tetrahedron 1990, 113, 3633-3636. Padwa, A.; Burgess, E.M.; Gingrich, H.L.; Roush, D.M.J. Org. Chem. 1982, 47, 786-791.
R2 R3
O
H2N R1
O OR
+
R3
R2 N
R1
O
OR
H
∆
N
O
R1
R3
O
HON R1
O
R3 O
Ac2O
R2
R2
N CO2MePh
N
MeO2C
Ph
+R3
R4
NPh CO2Me
R3R4
Pyrrolidines
HN CO2MeAr
H
H
azomethine ylide
1,3-dipole
(generation in situ)
1,3-Dipolar Cycloaddition of Azomethine Ylide
∆
Simultaneous formation of both C-C bonds Concerted mechanism!
NH
Ph
X
HH
exo endo
Stereoselectivity
Regioselectivity
N
EDG
H
Ph N
H
Ph
EWGhead-to-head head-to-tail
General Approach to the Selectivityin 1,3-Dipolar Cycloadditions
N
H
Ph
X
H
HNH
Ph NH
Ph
X X
NH
Ph
EDG
NH
Ph
EWG
BnO
R
NOR1
N
ORBnO
O+
RO
O OAr
NH
RO2C
Ar CO2R1
NOR1
O
ArRO2C CO2R
NH
RO2C
Ar CO2R1
CO2R
+
+
Karlsson, S.; Hofberg, H.E. Tetrahedron: Asymmetry 2001, 123, 1977-1982.Chen, C.; Schreiberg, S.L. J. Am. Chem. Soc. 2003, 125, 10714-10715.Longmire, J.M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 13400-13401.
N
H
H
H
Substitution Pattern on Resulting Pyrrolidines
3
4
4
2
3
5
23
4 5
2
3 4
5
H
4 3
4
2
3
5
Formation through the concerted mechanism
NH
EtO2C
Ph
endo: 65%
NH
EtO2C
Ph
Ph N CO2Et
Me
+
+
Michael adduct: 10%
exo: 25%
Ph N CO2 Pr
Me
CO2Et
LiX / Base
1,3-Dipolar Cycloaddition of Azomethine Ylidewith Ethyl Acrylate
Ph N CO2 Pr
Me
M
i i
CO2 Pri CO2 Pri
CO2 Pri
Possible mechanism?
Vivanco, S.; Lecea, B.; Arrieta, A.; Prieto, P.; Morao, I.; Linden, A.; Cossio, F. J. Am. Chem. Soc. 2000, 122, 6078-6092.
NH
O
H
H
LiSingle Favorable Conformation
for Metal Complexed Azomethine Ylide
Computational and Mechanistic Studiesof Azomethine Ylide Cycloadditions
NH
H
H
O
LiX
H2C CH2 NH
O
NO
H
Li
+
Orientation Complex Concerted Interaction
Vivanco, S.; Lecea, B.; Arrieta, A.; Prieto, P.; Morao, I.; Linden, A.; Cossio, F. J. Am. Chem. Soc. 2000, 122, 6078-6092.
Concerted Mechanism for the Cycloaddition ofAzomethine Ylide with Ethylene
LiX / Base
34
Pyrrolidine
2534
25
O2NN
H
O
N
Li O
HN
Li O
H
O2NO2N
endo exo
+ +
Substitution Effect in 1,3-DipolarCycloaddition Reactions
Vivanco, S.; Lecea, B.; Arrieta, A.; Prieto, P.; Morao, I.; Linden, A.; Cossio, F. J. Am. Chem. Soc. 2000, 122, 6078-6092.
LiX / Base
A
O2NN
H
O
N
Li O
HN
Li O
H
O2NO2N
endo exo
+ +
2
3
4
Substitution Effect in 1,3-DipolarCycloaddition Reactions
Vivanco, S.; Lecea, B.; Arrieta, A.; Prieto, P.; Morao, I.; Linden, A.; Cossio, F. J. Am. Chem. Soc. 2000, 122, 6078-6092.
5
LiX / Base
C2 - C3 bond formationB
2
3
2
34
5
A
O2NN
H
O
N
Li O
HN
Li O
H
O2NO2N
endo exo
+ +
2
3
4
Substitution Effect in 1,3-DipolarCycloaddition Reactions
Li
Vivanco, S.; Lecea, B.; Arrieta, A.; Prieto, P.; Morao, I.; Linden, A.; Cossio, F. J. Am. Chem. Soc. 2000, 122, 6078-6092.
5
LiX / Base
C
4
5
2
34
5
C2 - C3 bond formationB
2
3
A
O2NN
H
O
N
Li O
HN
Li O
H
O2NO2N
endo exo
+ +
2
3
4
Substitution Effect in 1,3-DipolarCycloaddition Reactions
Li
Vivanco, S.; Lecea, B.; Arrieta, A.; Prieto, P.; Morao, I.; Linden, A.; Cossio, F. J. Am. Chem. Soc. 2000, 122, 6078-6092.
5
LiX / Base
C
4
5
2
34
5
C2 - C3 bond formation
B
2
3
Aendo
N
O
OR
EWG
N
O
OR
EWG
M
N
EWG
O
OR
M
NH
EWG
O
OR
R3N
Vivanco, S.; Lecea, B.; Arrieta, A.; Prieto, P.; Morao, I.; Linden, A.; Cossio, F. J. Am. Chem. Soc. 2000, 122,6078-6092.
ORN
OM
Stepwise Mechanism in Cycloadditions
N
O
OR
MXM
H
No change in mechanism was detected with N-protonated azomethine ylides.Equimolar endo/exo - 1:1 amounts of products were observed.Presence of metal in 1,3-dipolar cycloaddition reactions causes improvement of endo-exo selectivity and changes the mechanism to stepwise.!
N CO2MePh
NH
CO2MePh
MeO2C
+NH
CO2MePh
MeO2C
+
endo exo
CO2Me
Kanemasa, S.; Uchida, O.; Wada, E. J. Org. Chem. 1990, 55, 4411-4417.Barr, D.A.; Dorrity, M.J; Grigg, R.; Hargreaves, S.; Malone, J.F.; Montgomery, J.; Redpath, J.; Stevenson, P.; Tornton-Pett, M. Tetrahedron 1995, 51, 273-294.
Search for the Best Metal for Cycloaddition
+ MX / Base
LiBr / NEt3 - 81% yield for cyclized products; endo: exo - 3:1
N-protonated ylide - 41% yield, only cyclized products; endo : exo - 1:1
MgCl2, ZnCl2, MnCl2, NiCl2 and CoCl2 - gave the Michael adduct as the major product
Michael adduct
iN CO2 PrPh
Me
NH CO2
iPrPh
EtO2C
+
NH CO2
iPrPh
EtO2C
+
Ph N CO2Et
CO2iPr
endo exo Michael adduct
Solvents
Bases
AgOAc
20-25 oC
CO2Et
THF; Toluene; MeCN; CH2Cl2; MeOH
KOH; NaOH; K2CO3; LiOH; Et3N; DBU
Casas, J.; Grigg, R.; Najera, C.; Sansano, J.M. Eur. J. Org. Chem. 2001, 123, 1971-1982.
Application of Silver to the Cycloadditions
+
N CO2 PrPh
Me
NH CO2
iPrPh
EtO2C
+
NH CO2
iPrPh
EtO2C
+Ph N CO2Et
CO2iPr
endo exo Michael adduct
CO2Et
Casas, J.; Grigg, R.; Najera, C.; Sansano, J.M. Eur. J. Org. Chem. 2001, 123, 1971-1982.
Investigation of Better Conditions for Cycloadditions
+AgOAc -10 mol%KOH - 10 mol%
Toluene, CH2Cl2, THF - 100% conversion, but 75 - 80h, 88 - 92% yield of endo product
MeCN - 68% conversion, 90% - endo, 10% - exo
MeOH - 100% conversion, but 1:1:1 ratio of products
i
N CO2 PrPh
Me
NH CO2
iPrPh
EtO2C
+
NH CO2
iPrPh
EtO2C
+Ph N CO2Et
CO2iPr
endo exo Michael adduct
CO2Et
Casas, J.; Grigg, R.; Najera, C.; Sansano, J.M. Eur. J. Org. Chem. 2001, 123, 1971-1982.
Use of Silver Acetate under PTC Conditions
+
AgOAc -10 mol%KOH - 10 mol%
PTC
Toluene, TBAA - 51 - 73% conversion, 24 - 48 h.
TBAA, TBAH, TBAC - solid - liquid phase transfer catalysts
THF, TBAA - 100% conversion, 94% - endo product, 1% Michael adduct
i
Bu N
Bu
Bu
Bu
X
Ph N CO2 Pr
Me
NH
EtO2C
R
endo: 92-97% yield
Method ATHF
KOH (10 mol%)AgOAc (10 mol%)TBAC (10 mol%)
20-25 oC
Method BToluene
KOH (10 mol%)AgOAc (10 mol%)
20-25 oC
CO2Et
NH
EtO2C
R R N CO2Et
Me CO2iPr
++
Michael adduct: 3-4% yieldexo: 3-4% yield
Casas, J.; Grigg, R.; Najera, C.; Sansano, J.M. Eur. J. Org. Chem. 2001, 123, 1971-1982.
General Methods for AgOAc Catalyzed Cycloaddition
+i
CO2iPr
CO2iPr
Application of silver acetate (AgOAc) to the 1,3-dipolar cycloadditionreactions of azomethine ylides results in excellent diastereoselectivity of the process in favor of the endo product.!
Ph N CO2MeAgOAc / LigandiPr2NEt, Toluene
NH
CO2MeMeO2C
Ph CO2Me
endo
+ MeO2C CO2Me
NH
CO2MeMeO2C
Ph CO2Me
exo
+
Poor solubility of silver salts in organic solvents limits types of ligands.
Addition of PPh3 significally increases solubility of AgOAc.
Use of chiral phosphine ligands can improve optical purity of final products.
Enantiocontrol of Cycloaddition by Use of Chiral Catalysts
R-BINAP (1)
PPh2
PPh2HN O
Ph2P
(R,R)-Trost Ligand (2)
P P
(R,R)-Me-DuPhos (3)
NH
O
PPh2
P P
(R,S,R,S)-PennPhos (4)
H
H
PPh2PPh2
(R,R,R,R)-BICP (5)
NH HNOO
Fe PPh2 Ph2P
Fe
(S,S,Sp)-FAP (6)
Chiral Phosphine Ligands Screened forthe AgOAc Catalyzed Cycloaddition
Longmire, J.M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 13400-13401.Longmire, J.M.; Wang, B.; Zhang, X. Tetrahedron Lett. 2000, 41, 5435-5439.
13% ee, endo/exo = 3:123% ee
59% ee
27% ee 13% ee
Variation of the R-Substituents for the CycloadditionCatalyzed by Ag(I) - FAP
Longmire, J. M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 13400-13401.
R N CO2MeAgOAc / FAP
iPr2NEt, Toluene NH
CO2MeMeO2C
R CO2Me
endo
+
Entry yield, % ee, %
1
2
3
4
5
6
7
phenyl
p-anisole
p-chlorophenyl
p-cyanophenyl
2-naphthyl
i-propyl
cyclohexyl
MeO2C CO2Me
87
98
96
96
98
98
82
87
92
92
96
97
70
81
R
!
NH
MeO2C CO2Me
CO2MePh NH
MeO2C CO2Me
CO2MePhNH
PrO2C CO2iPr
CO2MePh
NH
MeO2C
CO2MePh NH
BuO2C
CO2MePhNH
CO2MePh
MeN OO
Cycloaddition with Various Dipolarophile SubstratesCatalyzed by Ag(I)-FAP
52% ee, 88% yield 87% ee, 87% yield87% ee, 85% yield
60% ee, 90% yield 79% ee, 87% yield60% ee, 90% yield
t
i
cis-olefintrans-olefin
Longmire, J. M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 13400-13401.
Ph NOMe
O+
CO2Me Base (Et3N)
M(II)-ligand NH
Ph CO2Me
MeO2C
A: (S)-t-Bu-BOX B: (R)-Ph-BOXN
O
But
N
O
But
N
O
Ph
N
O
Ph
Entry Lewis Acid SolventLigand Conversion, % ee, %1
2
3
4
5
Cu(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Cu(OTf)2
THF
THF
THF
THF
neat
95
10
95
95
50
rac
n.d.
78
79
n.d.
Gothelf, A.S.; Gothelf, K.V.; Hazell, R.G.; Jorgensen, K. A. Angew. Chem. Int. Ed. 2002, 41, 4236-4238.
Bisoxazolines as Chiral Catalysts for the Cycloadditions
A
A
A
B
B
Improved Results in Enantioselectivitywith Use of BOX - Catalyst
N
O
Bu
N
O
tBu
Ph NOMe
OZn
Gothelf, A.S.; Gothelf, K.V.; Hazell, R.G.; Jorgensen, K. A. Angew. Chem. Int. Ed. 2002, 41, 4236-4238.
t
Open face of Dipole
Ph NOMe
O
+
MeO2C Et3NZn(OTf)2,
(S)-t-Bu-BOXCO2Me
78% yield, 76% ee
with FAP - 88% yield, 52% ee
NH
Ph
MeO2C CO2Me
CO2Me
N
PPh2
(S)-QUINAP
Looking for an Alternative to FAP and BOX
P, N-ligand QUINAP along with silver acetate showed excellent levels ofdiastereo- and enantioselectivity.
Catalyst loading is reduced to 1 mol%.
Reactions proceed with good yield, de and ee even at -45oC or -20oC.
Chen, C.; Li, X.; Schreiber, S.L. J. Am. Chem. Soc. 2002, 125, 10174-10175.
NO
ArOMe
HOtBu
O
iPr2NEtAgOAc
(S)-QUINAPTHF, -45oC
20 hNH
Ar CO2Me
BuO2Ct
+
Exploration of the Reactivity of the Aromatic Moiety
Entry
1
2
3
4
5
Ar Yield, % ee, %
4-methoxyphenyl
4-bromophenyl
4-cyanophenyl
2-naphthyl
2-tolyl
93
89
92
89
95
95
95
96
94
89
N
PPh2
(S) - QUINAP
Chen, C.; Li, X.; Schreiber, S.L. J. Am. Chem. Soc. 2002, 125, 10174-10175.
NO
PhOMe
HOtBu
O
iPr2NEtAgOAc
(S)-QUINAPTHF, -45oC
20 hNR
Ph CO2Me
BuO2Ct
+
Cycloadditions with α-substituted 1,3-dipoles
Entry
1
2
3
R Yield, % ee, %
methyl
iso-butyl
benzyl
98
77
93
80
80
77
Chen, C.; Li, X.; Schreiber, S.L. J. Am. Chem. Soc. 2002, 125, 10174-10175.
R
Application of QUINAP with AgOAc to 1,3-dipolar cycloadditionreaction can provide excellent diastereo- and enantioselectivity. Obtained selectivity is comparable to results obtained with FAPand BOX catalysts.!
High degree of diastereoselectivity was achieved with use of silver acetate in presence of KOH, DBU or i-Pr2NEt.
Formation of endo diastereomer is preferable: 95% de.
Enantioselectivity can be controlled by use of chiral catalysts.
Application of FAP and QUINAP in presence of AgOAc and t-But-BOX in presence of Zn(OTf)2 provides 80-96% ee.
Summary
S
CO2MeTol
O
R1O2C N Ar
R+
NH
R1O2C
R
Ar
H
MeO2C SOTol
NH
R1O2CR
ArH
CO2Me
AgOAc, Base
Control of Enantioselectivity byUse of Chiral Sulfinyloxides
Ruano, J.L.G.; Tito, A.; Peromindo, T. J. Org. Chem. 2002, 67, 981-987.
(S)-2-(p-Tolylsulfinyl)acrylate
2,5-dihydropyrroles
S
O
p-TolH3CS
O
p-TolH3CO
O
S
O
p-TolH3CO
O
1: (R)-methyl p-tolyl sulfoxide
2: (R)-2-(p-tolylsulfinyl)acetate
3: (S)-2-(p-tolylsulfinyl) acrylate
97%ee
Ruano, J.L.G.; Tito, A.; Peromindo, T. J. Org. Chem. 2002, 67, 981-987.
Synthesis of (S)-2-(p-TolylSulfinyl)Acrylate
(a) LiHMDS, -78oC, THF
(c) HCHO, Me2NH, rt, 48 h
(d) MeI, CaCO3, MeCN, rt 76% yield
(b) ClCO2Me, -78oC, THF87% yield
Ar
PhPh
Nph
Nph
Solvent
THFTHF
THF
THF
T, oC
rt0
rt
0
1 26572
72
87
3528
28
13
S
CO2Mep-Tol
O
CO2MeNAr
NH
MeO2C Ar
MeO2CSOp-Tol
+AgOAC/DBU
1
2
+
Influence of the Solvent on Selectivity of the Cycloaddition
Ruano, J.L.G.; Tito, A.; Peromindo, T. J. Org. Chem. 2002, 67, 981-987.
Nph MeCN reflux 90 10
Yield, %
Ph MeCN reflux 70 30
Ph MeCN 0 27 73
(1.5/1.0 eq)NH
MeO2C Ar
CO2Mep-TolOS
Nph MeCN rt 19 81
S
p-TolO
OCH3
O
rotamer A
rotamer B
Facial Selectivity at Dipolarophile
in MeCN
in THF
Sp-Tol
O
OCH3
O
Ag
rotamer A
rotamer B
Facial Selectivity at Dipolarophile
in MeCN
in THF
Ag
syn-dipole
HN
H OCH3
O
AgAr
ArH
N
H
OCH3
O
Ag
anti-dipole
S
p-TolO
OCH3
O
Sp-Tol
O
OCH3
O
S
p-TolO
OCH3
O
rotamer A
rotamer B
Facial Selectivity at Dipolarophile
in MeCN
in THF
Sp-Tol
O
OCH3
O
Ag
syn-dipole
HN
H OCH3
O
AgAr
ArH
N
H
OCH3
O
Ag
anti-dipole
NH
MeO2C Ar
CO2Mep-TolOS
NH
MeO2C Ar
MeO2CSOp-Tol
2
1
Ruano, J.L.G.; Tito, A.; Peromindo, T. J. Org. Chem. 2002, 67, 981-987.
NH
MeO2C Ar
CO2Mep-TolOS
NH
MeO2C Ar
MeO2CSOp-Tol
NH
MeO2C Ar
CO2Me
NH
MeO2C Ar
CO2Me
Toluene
Toluene
Desulfination of Obtained Pyrrolidines
Optimal Conditions for Desulfination: Toluene, reflux for 3h - 86-89% yield
Ruano, J.L.G.; Tito, A.; Peromindo, T. J. Org. Chem. 2002, 67, 981-987.
∆
∆
NH
RO2C
H
H
Ar
CO2Mep-TolOS
NH
RO2C
H
H
Ar
CO2Me
NH
RO2C Ar
CO2Me
Toluene Toluene
O
N
Ph O
R
CO2Me
CO2Me O
NMe
Ph
R
CO2Me
CO2MeOMe
-CO2
NH
Ph R
CO2MeMeO2C
Advanced Ways for Construction of Functionalized Pyrroles
Ruano, J.L.G.; Tito, A.; Peromindo, T. J. Org. Chem. 2002, 67, 981-987.Peddibhotla, S.; Tepe, J.J. Synthesis 2003, 9, 1433-1440.
∆ ∆
NOMe
Ph
O
NArHN N
Ph
ArMeO2C
Sp-Tol
O
MeMe
Imidazolidine, 53%
+
LDA, THF -78oC 4oC
endo : exo = 95 : 5
S
p-Tol
O
Ruano, J.L.G.; Tito, A.; Peromindo, T. J. Org. Chem. 2002, 67, 981-987.Peddibhotla, S.; Jayakumar, S.; Tepe, J.J. Organic Letters 2002, 4, 3533-3535.
N
O
Ph Me
O NPhBn
TMSCl CH2Cl2
N
ON
O
Bn
Ph
MeH
TMS
Ph
N
N
Ph
Ph
MeCOOH
Bn
Imidazoline, 75%
Formation of Imidazo-Compounds throughCycloaddition Reactions
endo : exo = 95 : 5
NOMe
Ph
O
NS
Ar
p-Tol
HN N
Ph
PhMeO2C
S
Imidazolidine endo:exo - 95:9
only cyclized product
+
LDA, THF -78 oC 4oC
N
N
Ar
MeO2C
Ph
H
1. LDA, THF-78oC
2. BF3 Et2O -78oC to -20oC
NHN
Ph
ArCO2Me
0.1 M in CHCl3rt, 4-6 days
N
N
Ar
MeO2C
Ph
H
+
endo: 75% yield, (83 : 17) exo
Viso, A.; Garcia, A.; Alonso, M.; Guerrero-Strachan, C. Synlett 1999, 10, 1543-1546.Ruano, J.L.G.; Tito, A.; Peromindo, T. J. Org. Chem. 2002, 67, 981-987.
Influence of Lewis Acids on the Mechanism of Cycloaddition
O
p-Tol
O
S
p-Tol
Op-TolOS SOp-Tol
N
O
R1 R2
O
NR3
R4
TMSCl CH2Cl2
N
ON
O
R4
R1
R2H
TMS
R3
N
N
R1
R3
R2
COOH
R4
NR3
R4R1
O
HNC
O
R2
N
NH
R2
O
R1
O
R4R3
Ketene intermediate β-Lactam
Imidazoline
Generally: ~60-79% yieldendo:exo - 95:5%
Influence of TMSCl on Cycloadditions
Peddibhotla, S.; Jayakumar, S.; Tepe, J.J. Organic Letters 2002, 4, 3533-3535.Mukerjaa, A.K. Heterocycles 1987, 26, 1077-1097.
TolueneHeat
1,3-Dipolar cycloaddition of azomethine ylides can bediastereomerically and enantiomerically controlled by use ofmetal salts (AgOAc or Zn(OTf)2) in presence of a suitable base. Enantiocontrol can be provided by application of FAP, BOX orQUINAP as the chiral catalyst.
Use of chiral vinyl sulfinyloxides gives not only excellentenantiocontrol, but also has the potential to alterate theselectivity of cycloaddition by changing the solvent or reaction conditions.
Summary
1,3-Dipolar cycloaddition of aminoacid derived ylides andmuchnone ylides with substituted imines gives formation of different imidazo-compounds with good diastereo- andenantioselectivity.
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