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Combinations of Enzymatic Procedures with Multicomponent Condensations Ryszard Ostaszewski a,b a...
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Combinations of Enzymatic Procedures with Multicomponent Condensations Ryszard Ostaszewski Ryszard Ostaszewski a ,b ,b a Faculty of Chemistry, Warsaw University of Technology, Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warszawa Noakowskiego 3, 00-664 Warszawa b Institute of Organic Chemistry, PAS, Kasprzaka 44/52, 01-224 Institute of Organic Chemistry, PAS, Kasprzaka 44/52, 01-224 Warszawa, Poland Warszawa, Poland
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Transcript of Combinations of Enzymatic Procedures with Multicomponent Condensations Ryszard Ostaszewski a,b a...
Combinations of Enzymatic Procedures with
Multicomponent Condensations
Ryszard OstaszewskiRyszard Ostaszewskiaa,b,b
aa Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 WarszawaFaculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warszawa
bb Institute of Organic Chemistry, PAS, Kasprzaka 44/52, 01-224 Institute of Organic Chemistry, PAS, Kasprzaka 44/52, 01-224 Warszawa, PolandWarszawa, Poland
General concept. CClassical processes:lassical processes:
Substrate(racemic)
Resolution of enantiomers
Substrate (optically
active)
Reaction 1
Product Reaction 2
Final product
Combination of Enzymatic Procedures with multicomponent condensation.
Substrate(meso)
Enzymatic Reaction (1)
Product Multicomponent condensation. (2)
Final product
General requirements for whole processes:General requirements for whole processes: - possibility to perform both reaction as a two - step one - pot procedure,- possibility to perform both reaction as a two - step one - pot procedure, - economy and simplicity,- economy and simplicity, - easy control of the stereochemical course of reactions. - easy control of the stereochemical course of reactions.
Multicomponent Condensations Ugi reactionUgi reaction
Bu NH2
O
H CNN
O
N
O
HO
OH
+ + +
Passerini reaction
O
H CNN
O
O
O
HO
OH+ +
Petasis reaction
R1
O
OHO
N
OH
O
RR
R1BOH
OH
RN
R
H+ +
EtO OH
O O
Cl
Cl
Holmann, M. J.; Vail, R.; Morgan, B., Sebesan, V.; Levy, C.; Dodds D. R.; Zaks, A.; Adv. Synth. Catal. 2001, 343, 744
ParoxetinParoxetin Yu, M. S.; Lantos, I.; Zhi-Qiang Peng, Yu J.; Cacchio T. Yu, M. S.; Lantos, I.; Zhi-Qiang Peng, Yu J.; Cacchio T. Tetrahedron Lett.Tetrahedron Lett. 20002000, 41, , 41,
5647.5647.
EtO OH
O O
F
Synthetic strategy.
OO O
R
O OH
O O
R
R'
O X
O O
R
R'
R
O
NR
H+ ROH
Enzyme UGI (X= NR)
Passerini (X= O)
The synthesis of 3-phenylglutaric anhydrides
R
O
O O
O
OO
Et
Et
HO OH
OO
R
OO O
R
HO OR'
O O
R
O
H
RO O
OEt
1a R=H1b R=Cl1c R=OMe
2 3
R'OH, Py
reflux, 2h
4
+piperidine
KOH
85-90oC
AcCl
5 R' =, Me, Et, Bu, Bn
Desymmetrization of 3-phenylglutaric anhydrides
OO O
R
O OH
O O
Et
R
+ EtOH
R = H R = Cl R = Me
Solvent Time(h)
Er Time (h/days)
Er Time (days)
Er
1 diethyl ether 114 7,2 -/17 2,5
2 diisopropyl ether 43 8,2 120/- 5,2 22 5,4
3 di-n-propyl ether 177 8,0 -/17 5,3
4 di-n-butyl ether 73 6,9 72/- 5,1
5 tertbutyl methyl ether 43 7,3 120/- 3,6 14 5,6
6 Cyclohexane 20 4,3 72/- 1,1
The influence of enzyme type on desymmetrization reaction.
R = H R = Cl R MeOLipase Time
(h/days)Er Time
(h/days)Er Time
(h/days)Er
Novozyme 435 61/- 8,5 120/- 5,2 -/22 5,4Chirazym A 19/- 10,8 -/4 5,9 -/12 6,4
Chirazym B -/9 0,80 -/4 0,7
Chirazym C -/18 5,2
Amano PS -/16 0,13
Amano PS imm. 19/- 0,13 -/4 1,4 -/7 267
SP 430 67/- 5,4 -/5 2,6
Candida cylindracea imm. -/46 1,62
Pseud. capacia imm. -/46 0,29
hog pancreas imm. -/18 0,88
Mucor miehei imm. -/46 0,35
The results of combination of enzymatic desymmetrization with Ugi Four-Component Condensation.
OO O
R
O OH
O O
R
R'O N
O O
R
R'
R
R
O
NR
H+ ROH
EnzymeRNH2
RCHO
RNC
O
O
N
OO
N
O
EtO
H
O
O
N
OO
N
O
EtO
H
O
O
N
OO
N
O
EtO
H
Entry Product Solvent Yield (%)
1
i-Pr2O
0
2 i-Pr2O/MeOH, 2:1,
v/v
6
3
i-Pr2O/MeOH
2:1, v/v
4
4
i-Pr2O/MeOH
2:1, v/v
6a
5
i-Pr2O/MeOH
2:1, v/v
13a
O
O
N
OO
N
O
EtO
H
O
O
N
OO
N
O
EtO
H
Entry Product
Solvent Yield (%)
1
i-Pr2O/MeOH
2:1, v/v
82
2
i-Pr2O/MeOH
2:1, v/v
81a
3
i-Pr2O/MeOH
2:1, v/v
70 a
4
i-Pr2O/MeOH
2:1, v/v
72 a
5
i-Pr2O/EtOH
2:1, v/v
80 a
N
OO
N
O
EtO
H
N
OO
N
O
EtO
H
N
OO
N
O
EtO
Cl
H
N
OO
N
O
EtO
OMe
H
N
O
NO
O O H
Passerini Reaction of 3-phenylglutaric monoesters
OO O
O OH
O O
RO O
O O
R
R1
O
NR
1
HROH
Lipase
1 2 3
R1CHO, R2NC
Entry Product Solvent Yield (%)
1 i-Pr2O/EtOH
2:151
2
i-Pr2O/EtOH
2:1
46a
3 i-Pr2O/EtOH
2:135
4i-Pr2O/EtOH
2:1
56 a
5
i-Pr2O/EtOH
2:135
6 i-Pr2O/EtOH
2:1
50a
7
i-Pr2O/EtOH
2:118%
O O
O O
NH
O
O O
O O
NH
O
O O
O O
NH
O
O O
O O
NH
O
O O
O O
NH
O
C7H15
O O
O O
NH
O
C7H15
O O
O O
NH
O
enzymatic reactions can be used with multicomponent Ugi and enzymatic reactions can be used with multicomponent Ugi and Passerini condensations as a two-step one-pot processesPasserini condensations as a two-step one-pot processes..
Summary
Acknowledgments
This work was supported by the State Commitee for Scientific Research (Grant 3 TO9A 081-19).
Katarzyna Jeziorska, Anna Fryszkowska, Marta Głażewska Katarzyna Jeziorska, Anna Fryszkowska, Marta Głażewska
