Embed Size (px)
Citation preview
Development and Advancement of the Stetter Reaction
Christopher D. HuppMichigan State University
December 8, 2004
Path of PresentationDevelopment of Stetter reaction
•Umpolung reactivity•Methods of umpolungreactivity
•Heteroatom exchange•Benzoin condensation•Stetter reaction
ConclusionsAcknowledgements
Advances in Stetter reaction•Intramolecular reactions•Enantioselective reactions•Stetter reactions withacylimine acceptors•Sila-Stetter reactions•Stetter reactions usingROMPgel
Michael Addition
O+
OCH3
O
Nucleophile
Electrophile
OCH3
O OM
R1 H
O
R2 R3
O+
?
Electrophile
Electrophile
R1 R3O
OR2
How do we couple two centers of identical polarity or affinity?
Definition of SynthonSynthons are “structural units within a molecule which are related to
possible synthetic operations”E. J. Corey
+
Synthon 2Synthon 1
O+
OCH3
O
OCH3
O OM
Donor Synthon Acceptor Synthon
Corey, E. J. Pure Appl. Chem. 1967, 14, 19Seebach, D. Angew. Chem. Int. Ed. 1979, 18, 239
Nomenclature for Synthonsan = Acceptor Synthon
dn = Donor Synthon
O+
OCH3
O
Nucleophile
Electrophile
OCH3
O OM
R1 H
O
R2 R3
O+
?
Electrophile
Electrophile
R1 R3O
OR2
d2
a1
a3
a3
Seebach, D. Angew. Chem. Int. Ed. 1979, 18, 239
Nature Gives an Example
+CO2
OCO2
O
OHPyruvate Acetolactate
Acetolactate SynthaseEnzyme-Bound
ThDP2 + Enzyme-Bound
ThDPa1
AcetolactateSynthase
N
N
NH2N
S
3-O6P2O
ThDP = Thiamine (Vitamin B1) Diphosphate
Pang, S. S.; Duggleby, R. G.; Schowen, R. L.; Guddat, L.. W. J. Biol. Chem. 2004, 279, 2242
Acetolactate Synthase
S
NR2
R1
CO2
O
a1Base
S
NR2
R1S
NR2
R1 S
NR2
R1OH
OO
S
NR2
R1 OHd1
S
NR2
O
HOCO2
HCO2
O
OHR1 CO2
O
a1
+ Enzyme-Bound ThDP
CO2B
Pang, S. S.; Duggleby, R. G.; Schowen, R. L.; Guddat, L.. W. J. Biol. Chem. 2004, 279, 2242
Umpolung Reactivity
R1 H
O
R2 R3
O+
?
a1
a3
R1 R3O
OR2
Umpolung reactivity is present in a reagent in which an a or d center is reversed.
R1 H
O
R2 R3
O+
R1 R3O
OR2d1
a3
Seebach, D. Angew. Chem. Int. Ed. 1979, 18, 239
Methods of Umpolung Reactivity
• Heteroatom exchange• Homologation
Heteroatom Exchange• Use of a 1,3-dithiol
OMe
O
O
SH SHTsOH (cat.), Benzenereflux 12 h
1 eq. OMe
O
S S
LDA, -78°CTHF
OMe
O
S S
-78°C to R.T., 15 h
Ph
O
Ph 1 eq., THF
70%S S
CO2MePh
O
PhS S
Ph
Ph
OOH
H H Lia1 d1
Griera, R.; Rigat, L.; Alvarez, M.; Joule, J. A. J. Chem. Soc., Perkin Trans 1, 1992, 10, 1223Wadi, A.; Calahorra, F. L. Tetrahedron Lett. 1992, 33, 3679
Methods of Umpolung Reactivity
• Heteroatom exchange– additional synthetic steps are needed ⇒ more chances
to lose potentially valuable material
• Homologation– aldehyde – aldehyde coupling
• Benzoin condensation
– aldehyde – α, β-unsaturated carbonyl coupling• Stetter reaction
Benzoin Condensation
a1
d1
a1
C NHO
CN
H
HO CN-H
HO CNPhCHO
Proton Transfer
- CN
OH
O
HO CN
O CN
H
O CN
H
H H+
O Ocat. CN
O
OHMeOH
Lapworth, A. J. Chem. Soc. 1903, 83, 995
Path of Benzoin Condensation
Cyanide catalyzedbenzoin condensation
Proposed mechanism forcyanide catalyzed benzoincondensation
Thiazolium salt catalyzed benzoincondensation
Catalytic activity ofnatural thiamine isbased on thiazolium unit
Ukai et al., 1943Mizuhara et al., 1954
Lapworth, 1903
Proposed mechanism forthiazolium salt catalyzed benzoincondensation
Breslow, 1958
Ukai, T.; Tanaka, R.; Dokawa, T. J. Pharm. Soc. Jpn. 1943, 18, 239Mizuhara, S.; Handler, P. J. Am. Chem. Soc. 1954, 76, 571
Thiazolium Salt-Catalyzed Benzoin
Breslow Intermediate
S
NR1
R2
H
R
-H
S
NR1
R2
R
S
NR1
R2
R
PhOH
H
PhCHO, H
S
NR1
R2
ROH
Ph
S
NR1
R2
R
PhO
OHPh
PhCHO-H
O
OHS
NR1
R2
RS
NR1
R2
R
S
N R1
R2
R
Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719
Alternative Mechanistic Model
S
NR1
R2
R
HBase
S
NR1
R2
R
S
NR1
R2
R
S
N R1
R2
PhCHO
S
NR1
R2
R
S
N R1
R2
R
Ph HO
S
NR1
R2
R
S
N R1
R2
R
PhOH
PhCHOS
NR1
R2
R
S
N R1
R2
R
PhHO
O HPh
S
NR1
R2
R
S
N R1
R2
R
PhOHO H
Ph
O
OH
AA
R
Castells, J.; Lopez-Calahorra, F.; Domingo, L. J. Org. Chem. 1988, 53, 4433
Methods of Umpolung Reactivity
• Heteroatom exchange– additional synthetic steps are needed ⇒ more chances
to lose potentially valuable material
• Homologation– aldehyde – aldehyde coupling
• Benzoin condensation
– aldehyde – α, β-unsaturated carbonyl coupling• Stetter reaction
Stetter Reaction
R H
O
R = Aromatic or Heterocyclic
R1 R2
O
RR2
O
OR1
CNDMF, 35°C
(10 mol%)
48-98%
(1 eq.)(1 eq.) +
• Reaction does not work with aliphatic aldehydes• Reaction does work with α, β-unsaturated ketones, esters, and nitriles
R H
O
R1 R2
O
RR2
O
OR1
S
NMeBn
HO
Cl
Et3N, DMF, 70°C
(10 mol%)
20-95%
(1 eq.)(1 eq.) +
• Reaction does work with aliphatic, aromatic, and heterocyclic aldehydes• Reaction does work with α, β-unsaturated ketones, esters, and nitriles
Stetter, H. Angew. Chem. Int. Ed. 1976, 15, 639
Mechanism of Stetter Reaction
R H
O
S
NR2
R3
R1
S
NR2
R3
R1
O
RH
S
NR2
R3
R1
OH
R
R1 R2
O
S
NR2
R3
R1
R2OHR
R1 OS
NR2
R3
R1
R2OR
R1 O
RR2
O
OR1
S
NR2
R3
R1
Base
X
ProtonTransfer
a1d1
S
NR2
R3
R1
OH
R
Stetter, H. Angew. Chem. Int. Ed. 1976, 15, 639
Scope of the Stetter Reaction
Stetter, H. Angew. Chem. Int. Ed. 1976, 15, 639
R H
O
R1 R2
O
RR2
O
OR1
A
BO
R R
O O
O
E
R1 OR2
OR
OR2O
OR1
D
R1 CN
R CN
O
R1
C
R1
OH3CO R1
O
O
O
First Application of the Stetter Reaction
CN
H3CO2C OHC
N
S
CH3H3C
HO
Cl
Et3N, i-PrOH, 80°C, 67%
CN
OH3CO2C
OO
CN
HO2C
H
H
O
OH
(±) - Hirsutic Acid C
(2.3 eq.)
Trost, B.M.; Shuey, C. D.; DiNinno Jr., F.; McElvain, S. S. J. Am. Chem. Soc. 1979, 101, 1284
Comparison of Benzoin and Stetter Reactions
Benzoin reaction• Reversible reaction• Products only include benzoin adducts
Ph H Ph H+
O O cat. CNPh
PhO
OHMeOH
Stetter reaction• Irreversible reaction• Products include Stetter adducts as well as benzoin adducts• Benzoin products can be used as substrates
Ph H+
O
Ph Ph
OThiazolium cat.
Base, DMF PhPh
O
OPh
Path of PresentationDevelopment of Stetter reaction
•Umpolung reactivity•Methods of umpolungreactivity
•Heteroatom exchange•Benzoin condensation•Stetter reaction
ConclusionsAcknowledgements
Advances in Stetter reaction•Intramolecular reactions•Enantioselective reactions•Stetter reactions withacylimine acceptors•Sila-Stetter reactions•Stetter reactions usingROMPgel
Intramolecular Stetter Reactions
O
CHO
CO2MeO
O
CO2Me
N
S
H3C Bn
HOCl
DMF, reflux
10 mol%
39%
Ciganek, E. Synthesis 1995, 1311
The Problem Using Cyanide
“tandem vicinal difunctionalization”
R1O
CHO
CO2R2NaCN (2 eq.), DMF
25°C O
O
CO2R2
R1
NaCN (2 eq.), DMF25°C, 58%
O
OHCO2CH3
CN
Ciganek, E. Synthesis 1995, 1311
Tandem Vicinal Difunctionalization
O OMe
OCHO
CN
OOMe
OO
CN
O
OHCO2Me
CN
Chapdelaine, M. J.; Hulce, M. Org. React. 1990, 38, 225
Intramolecular Stetter Reactions
O
CHO
CO2Me
N
S
H3C Bn
HOCl
DMF, reflux
10 mol%
O
O
CO2Me
39%
O
CHO
CO2Me
N
S
H3C Bn
HOCl
DMF, Et3N, 25°C orDMF, 120°C
10 mol%
O
CO2Me
O
86%
Ciganek, E. Synthesis 1995, 1311
Importance of Benzopyranones• Potential intermediates for the synthesis of heterocyclic
analogs of steroids• Important building blocks for the preparation of
pterocarpans and isoflavanones ⇒ strong fungicidal activity
O
O
HO
O
O
Pterocarpan
O
O OH
OMe
HOIsoflavanone
O
CO2Me
O
Benzopyranone
Morand, P.; Lyall, J. Chem. Rev. 1968, 68, 85Ozaki, Y.; Mochida, K.; Kim, S. W. J. Chem. Soc., Perkin Trans 1 1989, 1219
Vicario, J. L.; Badia, D.; Carrillo, L. Tetrahedron: Asymm. 2003, 14, 489
Path of PresentationDevelopment of Stetter reaction
•Umpolung reactivity•Methods of umpolungreactivity
•Heteroatom exchange•Benzoin condensation•Stetter reaction
ConclusionsAcknowledgements
Advances in Stetter reaction•Intramolecular reactions•Enantioselective reactions•Stetter reactions withacylimine acceptors•Sila-Stetter reactions•Stetter reactions usingROMPgel
First Asymmetric Intermolecular Stetter Reaction
H
O O O
O
N
S
MeMe
Me
*+ 20 mol % cat.
Catalyst
DMF, HMPA, Et3N,60°C
Cl
Yield = 30% ee = ≤ 40%
Enders, D. Enzymemimetic C-C and C-N Bond Formations. In Stereoselective Synthesis; Ottow, E.;Schoellkopf, K.; Schulz, B. G., Eds.; Springer-Verlag: Berlin-Heidelberg, 1994; pp 63-90.
First Asymmetric IntramolecularStetter Reaction
CHOR1
O CO2R2
1 (20 mol%),K2CO3 (10 mol%), THF
O
O
HCO2R2
R1
NN
N
Ph
O O
Ph
CH3H3C
ClO4
1
Yield = 44-73% ee = 41-74%
Enders, D.; Breuer, K.; Runsink, J. Helv. Chim. Acta 1996, 79, 1899
Transition State Model• Attack occurs from the si face of
the Breslow intermediate
• Attack to the si face of the α, β-unsaturated carbonylNN
N
Ph
R1
O
CO2R2
OO
CH3
CH3
HO sisi
Enders, D.; Breuer, K.; Runsink, J. Helv. Chim. Acta 1996, 79, 1899
Advancement ofEnantioselective Reactions
Substrate Product Cat. Yield(%) ee(%)
O
CO2EtO
O
O CO2Et
1 94 94
X
CO2MeO
X
O CO2Me1 63 96
1 64 82
CO2EtO O CO2Et 1
2
35 94
90 92
X = S
X = NMe
NN
NO
BF4
NNN
BnPh
BF41 2
OMe
CHO
X CO2R1 20 mol % KHMDS, xylenes, 25°C, 24 hX
O
20 mol % catalyst
CO2R1
Kerr, M. S.; de Alaniz, J. R.; Rovis, T. J. Am. Chem. Soc. 2002, 124, 10298
Stereochemical Reasoning
• Attack from the si face of the Breslow intermediate, to the si face of the α, β-unsaturated carbonyl
NN
N
Ph
CO2Et
OH
O
re
re
O
H
CO2Et
NN
N
Ph
OH
O
OEt
OH
• Attack from the re face of the Breslow intermediate, to the re face of the α, β-unsaturated carbonyl
What about racemization?
NN
N
Ph
O
CO2Et
HO
Osi
si
O
OHEtO2CNN
N
Ph
O
HO
O
OEt
O
H
Racemization with Benzofuranones
O
OCO2CH3 20 mol%
20 mol% KHMDS, xylenes, 25°C, 24 h
NNN
BnPh
BF4
O
O
CO2CH3
90% yield<5% ee
O
O
CO2CH3
O
OCO2CH3
Or
Kerr, M. S.; de Alaniz, J. R.; Rovis, T. J. Am. Chem. Soc. 2002, 124, 10298
Effect of Michael Acceptor
Kerr, M. S.; Rovis, T. Synlett, 2003, 12, 1934
CHO
O EWG 20 mol % KHMDS, xylenes, 25°C, 24 h O
O
EWG Time Yield (%) ee (%)
Triazolium catalyst 20 mol %
NN
NO
BF4
Catalyst
24 h
1 h
24 h
24 h
24 h
0
90
78
0
0
--
92
75
--
--
Et
O
H
O
NH2
O
NO2
CN
EWG
Aliphatic Enantioselective ReactionsO
CO2Et 20 mol%
20 mol% KHMDS, xylenes, 25°C, 24 h
NNN
BnPh
BF4 OCO2Et
81% yield95% ee
O20 mol%
20 mol% KHMDS, xylenes, 25°C, 24 h
NNN
BnPh
Cl O
CO2Et
CO2Et
O
CO2Et
CO2Et20 mol%
20 mol% KHMDS, xylenes, 25°C, 36 h
NNN
BnPh
Cl O CO2Et
CO2Et
97% Yield82% ee
Kerr, M. S.; Rovis, T. Synlett, 2003, 12, 1934
Synthesis of Quaternary Stereocenters
X
OEWG
R1 2 eq. Et3N, PhMe, 25°C, 24 h
20 mol % catalyst
X
OR1
EWG
ON
NN
F F
F
FF
BF4
Catalyst
Kerr, M. S.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 8876
Aromatic Substrates
O
OCO2Me
Et 2 eq. Et3N, PhMe, 25°C, 24 h
20 mol % cat.
O
OEt
CO2Me
Yield = 96% ee = 97%
OCO2Me
Et 2 eq. Et3N, PhMe, 25°C, 24 h
20 mol % cat.
OEt
CO2Me
Yield = 95% ee = 99%
O
O
2 eq. Et3N, PhMe, 25°C, 24 h
20 mol % cat.Me
PhO O
OPh
Me
O
Yield = 55% ee = 99%
Kerr, M. S.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 8876
Aliphatic Substrates
Me
O
Ar
O
20 mol% cat.
20 mol% KHMDS, PhMe, 25°C, 24 h
O
Me
Ar
O
Ar = 4-Py Yield = 85% ee = 96%Ar = p-NO2Ph Yield = 90% ee = 84%
Me
O
R
O 20 mol% KHMDS, PhMe, 25°C, 24 h
O
Me
R
O20 mol% cat.
R = Me Yield = 81% ee = 95%
Kerr, M. S.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 8876
Stereochemical Reasoning
• Attack from the si face of the Breslow intermediate, to the si face of the α, β-unsaturated carbonyl
NN
N
Ph
OH OMe
O
NN
N
Ph
OH OMe
O
O
Me
resi
C(O)Ph
NN
N
Ph
FO
CO2Me
HO
O
sisi
Me
F
F F
O
O
Me
MeO2C
NN
N
Ph
FO
HO
O
Me
F
F F
Me O
• Attack from the re face of the Breslow intermediate, to the si face of the α, β-unsaturated carbonyl
Path of PresentationDevelopment of Stetter reaction
•Umpolung reactivity•Methods of umpolungreactivity
•Heteroatom exchange•Benzoin condensation•Stetter reaction
ConclusionsAcknowledgements
Advances in Stetter reaction•Intramolecular reactions•Enantioselective reactions•Stetter reactions withacylimine acceptors•Sila-Stetter reactions•Stetter reactions usingROMPgel
Stetter with Acylimine Acceptors
R1 H
O+
R2 NH
R3
OSO2
TolR2 H
N R3
OR1O
N
S
Bn
OHCl
10 mol%
Et3N (5-15 eq.), CH2Cl2, 35°C
R1 R2 R3 Yield (%)
4-pyridyl
4-pyridyl
Ph
CH3
Ph
Ph
Ph
Ph
cyclohexyl
OBn
OtBu
OtBu
98
96
75
62
Murray, J. A.; Frantz, D. E.; Soheili, A.; Tillyer, R.; Grabowski, E. J. J.; Reider, P. J.J. Am. Chem. Soc. 2001, 123, 9696
The Problem with Aliphatic R2
H
O
+ NH
OSO2
Tol
HN
OO
10 mol% Cat
Et3N, CH2Cl2, 35°CNN
H
Et3N
NH
O
very low yields
Murray, J. A.; Frantz, D. E.; Soheili, A.; Tillyer, R.; Grabowski, E. J. J.; Reider, P. J.J. Am. Chem. Soc. 2001, 123, 9696
Proposed Mechanism
R2 NH
R3
R2 N R3
O
O
SO2
Tol
NS
RR
R
X
+R1 H
O
N
S
R
R
R
R1
HO
N
S
R
R
R
R1
HO
+R3 N
HR2
O OHR1
NS R
RR
R1HN R3
O
OR2
A
B
C
D
E F
G
Murray, J. A.; Frantz, D. E.; Soheili, A.; Tillyer, R.; Grabowski, E. J. J.; Reider, P. J.J. Am. Chem. Soc. 2001, 123, 9696
Data to Support Mechanism1. Mimic of intermediate
H NH
O OSO2
Tol
+ 10 mol% 1Et3N, CH2Cl2, 35°C
HN
OO
85%
S
N
OH
I
≡N
S
R
R
R
R1
HO
D
1
Murray, J. A.; Frantz, D. E.; Soheili, A.; Tillyer, R.; Grabowski, E. J. J.; Reider, P. J.J. Am. Chem. Soc. 2001, 123, 9696
Data to Support Mechanism2. Deuterium incorporation experiment
H NH
HN
O O
O
SO2
O
Tol
+
S
N
I10 mol%
Et3N, CH2Cl2, 35°C
>95% with D
OH
D
D
• Consistent with the acylimine operating asan electrophile
Murray, J. A.; Frantz, D. E.; Soheili, A.; Tillyer, R.; Grabowski, E. J. J.; Reider, P. J.J. Am. Chem. Soc. 2001, 123, 9696
Data to Support Mechanism3. Crossover experiment
R1 H
O+
R2 NH
R3
OSO2
Tol
10 mol% catalyst
Et3N, CH2Cl2, 35°C
R5 HN R6
OR4O R2 H
N R3
OR1O
R5 HN R6
OR4O
+
• No crossover products were observed
Murray, J. A.; Frantz, D. E.; Soheili, A.; Tillyer, R.; Grabowski, E. J. J.; Reider, P. J.J. Am. Chem. Soc. 2001, 123, 9696
Stetter vs. Stetter with AcylimineStetter reaction
• Products include Stetter adducts as well as benzoin adducts• Benzoin products can be used as substrates
Ph H+
O
Ph Ph
OThiazolium cat.
Base, DMF PhPh
O
OPh
R1 H
O+
R2 NH
R3
OSO2
TolThiazolium Cat.
Base, DCM R1HN R3
R2
O
O
Stetter with acylimine acceptor reaction• Products include only Stetter adducts • Benzoin products can not be used as substrates
One-Pot Synthesis of Substituted Imidazoles
R H R1 NH
R2
OO SO2
N
NR2
R3R
R1
Tol
R1 HN R2
R OO
+ 5-20 mol% Cat.Et3N, DCM,35-60°C
R3NH2AcOH
N
S OHI
Cat.
Frantz, D. E.; Morency, L.; Soheili, A.; Murray, J. A.; Brabowski, E. J. J.;Tillyer, R. D. Organic Letters, 2004, 6, 843
One-Pot Synthesis ofDi-substituted Imidazoles
HN
NH
O OSO2
Tol
+
1. 10 mol% catalystEt3N, CH2Cl2, 35°C
2. NH4OAC (15 eq.)reflux 12 h
N
HN
N 76%
H NH
O OSO2
Tol
+
1. 10 mol% catalystEt3N, CH2Cl2, 35°C
2. NH4OAC (15 eq.)reflux 12 h
NH
N
82%F
F
Frantz, D. E.; Morency, L.; Soheili, A.; Murray, J. A.; Brabowski, E. J. J.; Tillyer, R. D. Organic Letters, 2004, 6, 843
One-Pot Synthesis of Tri-substituted Imidazoles
HN
NH
O OSO2
Tol
+
1.10 mol% catalystEt3N, CH2Cl2, 35°C
2. NH4OAc (15 eq.)reflux
PhNH
N
N82%
H NH
O OSO2
Tol
+
1.10 mol% catalystEt3N, CH2Cl2, 35°C
2.Phe (5 eq.)Acetic Acid (5 eq.)reflux
Ph N
N
73%>98%ee
Ph
HO2C
Frantz, D. E.; Morency, L.; Soheili, A.; Murray, J. A.; Brabowski, E. J. J.; Tillyer, R. D. Organic Letters, 2004, 6, 843
Importance of ChiralTri-substituted Imidazoles
• Implicated as an angiotensin II receptor antagonists
• Syntheses have traditionally involved multistep sequences or resolutions
N
N
Ph
HO2C
Palkowitz, A. D. et al. J. Med. Chem. 1994, 37, 4508
One-Pot Synthesis ofTetra-substituted Imidazoles
HN
NH
O OSO2
Tol
+
1. 20 mol% catalystEt3N, CH2Cl2, 35°C
O2. EtOH, Acetic Acid(5 eq.),
H2N Ph
N
NO
N
Ph
76%(5 eq.)
HN
NH
O OSO2
Tol
+
1. 20 mol% catalystEt3N, CH2Cl2, 35°C2. EtOH, Acetic Acid(5 eq.),
H2NOMe
N
N
N
80%OMe
OMe
OMe(5 eq.)
Frantz, D. E.; Morency, L.; Soheili, A.; Murray, J. A.; Brabowski, E. J. J.; Tillyer, R. D. Organic Letters, 2004, 6, 843
Importance ofTetra-substituted Imidazoles
N
NO
N
Ph
• Representative of a class of highly potent p38 kinase inhibitors ⇒ helps to suppress a biological pathway that leads to inflammation
N
N
NOMe
OMe
Liverton, N. J. et al. J. Med. Chem. 1999, 42, 2180
One-Pot Synthesis ofTri-substituted Oxazole and Thiazole
HN
NH
O OSO2
Tol
+
1. 5 mol% catalystEt3N, PhMe, 35°C
2. Ph3P, I2O
N
N77%
HN
NH
O OSO2
Tol
+
1. 5 mol% catalystEt3N, PhMe, 35°C
2. Lawesson's reagent(1.5 eq.)
S
N
N
50%
Frantz, D. E.; Morency, L.; Soheili, A.; Murray, J. A.; Brabowski, E. J. J.; Tillyer, R. D. Organic Letters, 2004, 6, 843
Path of PresentationDevelopment of Stetter reaction
•Umpolung reactivity•Methods of umpolungreactivity
•Heteroatom exchange•Benzoin condensation•Stetter reaction
ConclusionsAcknowledgements
Advances in Stetter reaction•Intramolecular reactions•Enantioselective reactions•Stetter reactions withacylimine acceptors•Sila-Stetter reactions•Stetter reactions usingROMPgel
Sila-Stetter Reaction
R1 SiX3
O+
R2 R3
O
R1 R3O
OR2
1. cat. A, DBU2. THF, i-PrOH
SN Et
CH3
H
HO
Br
Cat. A
Mattson, A. E.; Bharadwaj, A. R.; Scheidt, K. A. J. Am. Chem. Soc. 2004, 126, 2314
Proposed Mechanism
S N R
H
DBUBr
S N R
R1 SiX3
O
S
NR
R1
OSiX3
ROH S
NR
R1
OH
ROSiX3
R1 SiX3
OR2 R3
O
R2 R3
OOH
R1N
S
R
R1 R3O
OR2
Brook rearrangement
Benzoin Product
S N R
Mattson, A. E.; Bharadwaj, A. R.; Scheidt, K. A. J. Am. Chem. Soc. 2004, 126, 2314
Scope of Sila-Stetter Reaction
Ph SiMe3Ph
OO
PhPh
O
O
+
30 mol% cat., DBU (30 mol%)
84%
i-PrOH, THF
H3C Si Ph Ph
OO
H3CPh
O
OPh
+Me
Me Ph
70%
30 mol% cat., DBU (30 mol%)
i-PrOH, THF
Ph SiMe3 H3CO2C OCH3
OOPh
OCH3
O
O
+
72%H3CO O
30 mol% cat., DBU (30 mol%)
i-PrOH, THF
Mattson, A. E.; Bharadwaj, A. R.; Scheidt, K. A. J. Am. Chem. Soc. 2004, 126, 2314
Stetter vs. Sila-Stetter Reaction
Ph H+
O
Ph Ph
OThiazolium cat.
Base, DMF PhPh
O
OPh
Stetter reaction• Products include Stetter adducts as well as benzoin adducts
Sila-Stetter reaction• Products include only Stetter adducts
R1 SiX3
O+
R2 R3
O
R1 R3O
OR2
Thiazolium cat., Base THF, i-PrOH
One-Pot Synthesis of Pyrroles
R1 SiX3 R2 R4
O
R3
O+ 20 mol% cat.
DBU, THFi-PrOH
R2 R4
R1 OO
R3
R5NH2TsOH4Å sieves
NR5
R1
R2 R3
R4
N
S
Et
HOBr
Catalyst
Bharadwaj, A. R.; Scheidt, K. A. Org. Lett. 2004, 6, 2465
One-Pot Synthesis of Pyrroles
SiPhMe2 Ph Ph
OO+
1. 20 mol% cat.DBU, THF,i-PrOH2.TsOH,4Å sieves,PhNH2
NPh
Ph
Ph
71%
Ph SiMe3Ph
OO
+1. 20 mol% cat.DBU, THF,i-PrOH2.TsOH,4Å sieves,PhNH2
NPh
Ph Ph
70%
Ph SiMe3
Ph
OO
+
1. 20 mol% cat.DBU, THF,i-PrOH2.TsOH,4Å sieves,PhNH2
NPh
Ph
PhCl
Cl
80%
Bharadwaj, A. R.; Scheidt, K. A. Org. Lett. 2004, 6, 2465
One-Pot Synthesis of Pyrroles
Ph SiMe3 Ph Ph
OO+
1. 20 mol% cat.DBU, THF,i-PrOH2.TsOH,4Å sieves,
NR
Ph
Ph
Ph
Amine
Br NH2
CH3(CH2)2NH2
H3CCH3
NH2
Amine Yield(%)
71
82
56
NH4 OAc 62
Bharadwaj, A. R.; Scheidt, K. A. Org. Lett. 2004, 6, 2465
Importance of Chiral Pyrrole Compounds
NMe
• Related chiral pyrroles have been identified as highly selective potential treatments for diabetes
Liu, K. G.; Lambert, M. H.; Ayscue, A. H.; Henke, B. R.; Leesnitzer, L. M.; Oliver, W. R.; Plunket, K. D.; Xu, H. E.; Sternbach, D. D.; Willson, T. M. Bioorg. Med. Chem. Lett. 2001, 11, 3111
Microwave Assisted Synthesis
Ph SiMe3Ph
OO+
20 mol% cat.DBU, THF, i-PrOH
Ar Ph
Ph OO
PhNH2, TsOH, 4Å sievesNPh
Ph Ph
µW (300 W), 160°C
µW (300 W), 160°C
55%
• Using conventional heating, rxn takes 16hr• Using microwave heating, rxn takes 30min
Bharadwaj, A. R.; Scheidt, K. A. Org. Lett. 2004, 6, 2465
Path of PresentationDevelopment of Stetter reaction
•Umpolung reactivity•Methods of umpolungreactivity
•Heteroatom exchange•Benzoin condensation•Stetter reaction
ConclusionsAcknowledgements
Advances in Stetter reaction•Intramolecular reactions•Enantioselective reactions•Stetter reactions withacylimine acceptors•Sila-Stetter reactions•Stetter reactions usingROMPgel
Stetter Reaction Using ROMPgel
R1 H
O
R2 R3
O
R1 R3O
OR2
Phn
S
NMe
Me I+
DMF, Et3N, 80°C
• ROMPgel = Ring Opening Metathesis Polymerization gel, which is a general class of high loading polymer supportedreagents, catalysts, or scavengers
Barrett, A. G. M.; Love, A. C.; Tedeschi, L. Organic Letters, 2004, 6, 3377
Preparation of ROMPgel-supported Thiazolium Iodide
N
S
180°C, 53%
N
S
MeI (1.5 eq.)n-BuOH, 80°C,87%
N
S
I
A (0.11 eq.),B (0.8 mol%),ClCH2CH2Cl,50°C, 94%
Phn
S
NMe
Me I
A B
RuPh
PCy3Cl
ClNMesMesN
(10 eq.)
Barrett, A. G. M.; Love, A. C.; Tedeschi, L. Organic Letters, 2004, 6, 3377
Stetter Reaction with ROMPgel
Phn
S
NMe
Me I
R2 R3
O
R1 H
O
R1 R3O
OR2
ROMPgel 4x
Synthesis of 1,4-Diketonesusing ROMPgel
n-Dec H
OPh
O
+DMF, Et3N, 80°C
Cl
Ph
O n-DecO
Cl99% yield
ROMPgel (16 mol%) Catalyst
O O+
DMF, Et3N, 80°C
ROMPgel (16 mol%) Catalyst
O
86% yieldN
H
OMe4
NMe
4
+Ph H
O
DMF, Et3N, 80°C Ph Ph
O PhO
Ph Ph
O
68% yield
ROMPgel (16 mol%) Catalyst
Barrett, A. G. M.; Love, A. C.; Tedeschi, L. Organic Letters, 2004, 6, 3377
Path of PresentationDevelopment of Stetter reaction
•Umpolung reactivity•Methods of umpolungreactivity
•Heteroatom exchange•Benzoin condensation•Stetter reaction
ConclusionsAcknowledgements
Advances in Stetter reaction•Intramolecular reactions•Enantioselective reactions•Stetter reactions withacylimine acceptors•Sila-Stetter reactions•Stetter reactions usingROMPgel
Conclusions
• The Stetter reaction is only one way to make 1,4-dicarbonyl compounds
• Utilizes umpolung reactivity to react two synthons of identical polarity
• The Stetter reaction can be used to make various substituted heterocycles
• Although enantioselective intramolecularreactions have been explored, there is still the need to develop the corresponding intermolecularreactions
Acknowledgements
• Dr. Babak Borhan• Dr. Jetze Tepe• Dr. Greg Baker• Adam Mosey• Jason Fisk• Mahesh Peddibhotla• Manasi Keni• Sam Frawley• Vasudha Sharma
• Amber Terry• Kyoungsoo Lee• Soong-Hyun Kim
