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Mike DeMartino
Group Meeting: August 27, 2003
Overview
• How these reactions are related
• The Biginelli Reaction
– Mechanism
– Modifications and chemical manipulation
– Biology
– Synthetic examples
• The Passerini Reaction
– Mechanism
– Synthetic examples
• The Ugi Reaction
– Mechanism
– Synthetic Reactions
• Concluding Remarks
Similarities
EtOH,
H+ heat
Ph
=> Biginelli-type
EtO2C compounds
NH
Me N O
H
The Mechanism: a Century of
Uncertainty
• First proposal in 1933
» Folkers, K., Johnson, T.B. J. Am. Chem. Soc. 1933, 55, 3784.
EtO2C
O
O O HN NH2 O
2X + R
H2N NH2 R H HN NH2
O
O HO Me
Ph
CO2Et
HN N EtO2C
H NH
R
HN NH2 H2O
Me N O
H
O
The Mechanism: a Century of
Uncertainty
• Second proposal in 1973
» Sweet, F., Fissekis, J.D.. J. Am. Chem. Soc. 1973, 95, 8741.
O EtO2C H
+ H+
H O O HO O
O O
O
OEt OEt OEt
H2N NH2
Ph
CO2Et O
HN H
HN
O N Me OEt
H H2O O
NH2 O
The Mechanism: a Century of
Uncertainty
• Latest proposal in 1997
» Kappe, C.O. J. Org. Chem. 1997, 62(21), 7203.
O Ph OH Ph H
O H+
H + HN NH2 N NH2
H2N NH2 -H2O H
O O
O
HN NH2
R
HN NH2
O
Ph
Ph Ph
EtO2C
EtO2C
NH NH EtO2C
NH
O O
H2N Me N O H2O O O
Hu, E.H., et.al. H Me
H2N
J. Org. Chem. 1998. 63, 3454.
The Atwal* modification
• Brought about by the need for better yields:
• Ortho-substituted aryl aldehydes
• Aliphatic aldehydes
R1 R1 H R1 H
RO2C NH2 RO2C
H + NaHCO3 RO2C N
Deprotect NH
HN X DMF R 2 Mostly 60-91%
Me O Me N X yield Me N X
R2 H H
X = O, S (With an appropriate protecting group)
O O
• Fluorous-Phase modifications
– Studer, A., et. al. J. Org. Chem., 1997, 62, 2917.
Ar
O H O Ar
O
NH2 1. HCl, THF/BTF, 50°C R
R + O NH
O TAG
HN O 2. Extract w/FC-72
R N O
R1 O 3. TBAF, THF/BTF 1
O O
O O
Tag = Si(CH2CH2C10F21)3
Synthetic Examples
• Synthesis of rac-Monastrol
• Mitosis blocker by kinase Eg5 inhibition
• Utilization and extension (to thioureas) of the
Yb(OTf)3 catalysis work
» Dondoni, A., et. al. Tet. Lett. 2001, 43, 5913
OH
HO
O O
H
EtO H Yb(OTf)3 EtO2C
+ NH
Me O S THF, reflux,
12 h Me N S
H2N NH2 H
(+/-) Monastrol
Synthetic Examples
• Inorganic catalysis
– Indium(III) Chloride mediated Biginelli reactions
» Brindaban, C. R., et. al. J. Org. Chem. 2000, 65, 6270
R2
O H O R2
X InCl3, THF
O O + R1 NH
H2N NH2 81-95 %
R R 1 R N X
X = O, S H
• Heavy-Metal catalysis
» Ma, Y., et. al. J. Org. Chem. 2000, 65, 3864
R2
O H O R2
O Yb(OTf)3 (5 mol %)
O O + R1 NH
H2N NH2 100°C
R R 1 81-99% R N O
H
Synthetic Examples
• Natural Product Synthesis
– The use of tethered Biginelli condensations for syntheses
of structurally diverse guanidine alkaloids
O O
• (–)-Ptilomycalin A: H H
N O N NH2
14
NH2
N N
OH H O
Overman, L., et. al. J. Am. Chem. Soc. 1995, 117, 2657
H H
R3O2C
N
R1
R3O2C R1 A: Morpholinium Acetate
CF3CH2OH, 60°C, 48 hr R2 N X
H H syn
+ HO N
B: Polyphosphonate ester +
R2 O
H2N X CH2Cl2, 23°C, 48 hr
H H
R3O2C
N
R1
O NH2
H H
N NH
H2N
N N NH2
H
HO
OH
Key Step:
H O
MeO2C Me
MeO2C Me ether NH2 MeO2C
NH NH
+ RT N O
NH C N O
O
The Passerini Reaction
Details of the Passerini Reaction
• Discovered in 1921 by Passerini
» Passerini, M. Gazz. Chim. Ital. 1921, 51, 126.
2 2
1 1
R R R R H 3
3 Acyl Group C C N R
C C N R
OH OCMe Rearrangement OCMe O
O O
Details of the Reaction
O
NHCbz
CH2Cl2 FmocHN N CO2Bn
H H
+ + FmocHN 0°C ->RT, O
CN CO2Bn O 3-5 days O
BocHN CO2H BocHN
O O CbzHN
HN
HN
O
O NH
s!
s tep
NH ~ 9
O Eurystatin A
Synthetic Examples
• Total synthesis of hydrastine, a
phthalideisoquinoline alkaloid, using a an
intramolecular Passerini reaction
» Zeigler, T., et. al. Tet. Lett. 1981, 22, 619
O
O NC + H O
CH2Cl2
OH NH
O O O
O
O O
O O
O O
O
O N
Me
Hydrastine O
O
O O
The Ugi Reaction
Details of the Ugi Reaction
• Discovered in 1959
» Ugi, I., et. al. Angew. Chem. 1959, 71, 386
• Four component condensation involving:
– Amine (secondary or primary)
– Aldehyde (or ketone)
– Carboxylic Acid
– Isocyanide
• Generally: 1 4
O R R
O O
+ 2 NH2 + + 4 NC 3 NH
1
R 3 R R N
R H R OH
R2 O
O H O
1 + 1
R N R N + 3
R 2
HO
3
R R2 O R
4
H R
1
N
R N 2 R
1
R + R4NC O
3
R O 3 HN 2
R O R
O
4
R 1 4
N O R R
1 Rearrangement
R 3 NH
O R N
3 HN 2 R2 O
R O R
Generally Observed Properties of
the Ugi Reaction
• Rxn is exothermic and usually complete in seconds-
minutes at room temperature
• Aprotic, polar solvents are best, though the low-
molecular weight alcohols have been used
• Can be performed in biphasic media
• High (0.5-2M) reactant concentrations are best
• By virtue of the mechanism, Lewis acids can accelerate
the reaction
• Precondensation of the amine and the carbonyl
(preformation of the Schiff base) can increase yields.
Synthetic Examples of the
Ugi Reaction
• The Ugi reaction can be utilized to make peptides
and peptoids
– Tripeptides in one pot
– Couple two peptide fragments
» Waki, M., Meienhofer, J. J. Am. Chem. Soc. 1977., 99, 6075
R2CHCONH
Z-Gly-Ala-OH
O Condensation
+ CN +
Z-Gly-Ala-NCHCO-Gly-OtBu
H-Leu-Gly-Ot Bu R H
CH2CH(CH3)2
Cleavage
Z-Gly-Ala-Leu-Gly-OR
by hn
Synthetic Examples of the
Ugi Reaction
• Synthesis of non-natural amino acids
– Yamada, T. et. al. Synthesis. 1998, 991
BocHN COOH CN O
+ H
COOCH3 CH2Cl2, RT N
BocHN N COOCH3
14 days H
O
NH
Synthetic Examples
• Concise synthesis of benzodiazepines
» Hulme, C., et. al. J. Org. Chem. 1998, 63, 8021
H 1
O 1
R O R
H
O N
4 OH 2 MeOH 4 N
R + R NH2 R 2
R O
NBoc 3N
R3 R Boc
NC
O 2
R
AcCl/MeOH N
4 1
R R
Heat
N
O
R3
Synthetic Examples
• Synthesis of the carbacephems containing a b-
lactam moiety commonly found in antibiotics
» Neyer, G., Achtaz, J., Danzer, B. Ugi, I. Heterocycles, 1990, 30, 863
O
DPO
H H
DPO O Ethylene Glycol/
+ O
Glycerol N
NH3 O O
NC N
H
Ph N
DPO = *
Ph O
N
O X
CO2H
Carbacephems
(X = OR, SR, Cl)
Synthetic Examples of the
Ugi Reaction
• Total synthesis of the cyclopeptidic alkyloid
natural product: Nummularine - F
» Bowers, M.M., et. al. J. Chem. Soc. Perkin Trans. 1, 1989, 857
CN
O
CN COOCH3 O O
O
+ + COOCH3
OH N HN
N O
O
O O
NH
N N
H
N O
Nummularine-F
Synthetic Examples of the
Ugi Reaction
OAc
OAc H AcO
AcO EtO2CO
+ H N Pr + + CN Pr O
2 O O
CO2H H2O Pr N
N Pr
H
CO2Et
HO
HO
Pr O
N
O
N HN
O Pr O NH
O O
R
HO H
HO H
R= or
HO CH2OH
CO2Et
Bicyclomycin
1 1
R 2 R
R 2
O O R
TiCl4 + (RNC, R1R2CO) Ti Ti
Cl
L N L Cl N
R R
1
R
2
O O R
R OH Ti
N L N
H R1 R2
R