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Transcript of Peptidomimetics and Mimicry of -Strand / Sheets and -Sheet Sandwiches Jian Liu Merck & Co., Inc....
![Page 1: Peptidomimetics and Mimicry of -Strand / Sheets and -Sheet Sandwiches Jian Liu Merck & Co., Inc. Rahway, NJ 07065.](https://reader036.fdocuments.net/reader036/viewer/2022062713/56649f575503460f94c7baa1/html5/thumbnails/1.jpg)
Peptidomimetics and Mimicry of -Strand / Sheets and -Sheet Sandwiches
Jian Liu
Merck & Co., Inc.
Rahway, NJ 07065
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Research Summary
Pyrrolinone -Strand Peptidomimetic
HIV-1 Protease Inhibitor
1999-presentUPenn
NH
HN
O
NHCH3
OPh
CbzHN
BnO
O
OHN
O
OH
PhO
HN
O
O NH2
OPh
Ph
-Sheet Sandwich
1998-1999UC Irvine
ON
CN
NO
O
(CH2)2
HN
O
O
NH
CH3
HNN
O
ON
H
Hi-Pr
O
Me
NH
RAla
RLys
N
CN
NO
O
(CH2)2
HN
O
O
NH
CH3
HN
N
O
ON
H
Hi-Pr
O
Me
NH
ROrn
RVal
Cycloaddition of Enol Ethers
1994-1998UCLA
Enantioselective Epoxidation
RR
O
O
R
O R
X
O
O
R
X
O
O R
s-transGround state of enol etherss-cis
s-transs-cis
Transition States
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Part I
a. Computational Study on Epoxidation Reactions
b. Conformational Switch for Enol Ethers in Cycloaddition Reactions
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Reaction Path Investigation by Computational Methods
R
TS1*
TS2*
Ea1
Ea2
Ea
k1/k2 = e -Ea/RT
P1
P2
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Epoxidations of Unfunctionalized Olefins
Liu, J., Houk, K. N. et. al. J. Am. Chem. Soc. 1997, 119, 3385-3386; J. Am. Chem. Soc. 1997, 119, 10147-10152; J. Am. Chem. Soc. 1997, 119, 12982-12983; J. Org. Chem. 1998, 63, 8565-8569
O
OO
H
R'
R O
O
H
R'O
R
R O
R"R' O
R
R N R"
R'O
R
OO
NO
R'R"
R'
R"
R N+ R"
R'O
RN+
O
R'
R"R"'
R"'+
+ +(1)
+
+
+
+
(2)
(3)
+(4)
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Part I
a. Computational Study on Epoxidation Reactions
b. Conformational Switch for Enol Ethers in Cycloaddition Reactions
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Conformational Switch in Cycloaddition of Enol Ethers
s-cis in ground state s-trans in transition state
Liu, J.; Niwayama, S.; You, Y.; Houk, K. N. J. Org. Chem. 1998, 63, 1064.
O
R
N
O
O R
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Stereoselective Cycloaddition Reactions of Chiral Enol Ether
Denmark, S. E. et. al. J. Org. Chem. 1994, 59, 5672; 1995, 60, 3205; 1995, 60, 3574.
Reissig, H. U. et. al. SYNLETT 1990, 514; Angew. Chem. Int. Ed. Engl. 1992, 31, 1033.
O2N
O
O
Ph
Ph
HO
H
N+ O-O
H
O
O
Ph
O
Ph
+Ti(O-i-Pr)2Cl2CH2Cl2
13 : 1
NO
Ph
O
O O
OO
OO
NO
R*
+
Diastereomerically pure
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Ground State Conformations of Chiral Enol Ethers
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Conformations of Vinyl Methyl Ether in Ground and Transition States
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Design of Conformation Fixed Enol Ethers
trans cis trans cis
O O
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Designed Diels-Alder Reactions with the Conformation Fixed Enol Ethers
Y NO Y
ON Y NO
Y
ON
Ph
Ph Ph
Ph
ON
Ph
ON
Ph
O
O
1
13.5
b: +33.5
+Y= CH2 : yield = 14%
Y= O : yield = 84%(1)
(2)Y= CH2 : yield = 90%
Y= O : yield = 95%
(3) Competitive Reactions:
a: +
Product Ratio
1
+
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Designed 1,3-dipolar Cycloaddition With the Conformation Fixed Enol Ethers
N+
COPh
O-Ph Y ONPh
COPh
Y
N+
COPh
O-PhY O
NPh
COPh
Y
N+
COPh
O-Ph
N+
COPh
O-PhO
O 12.2
Y = CH2: yield= 85%
Y = O, endo : yield= 72%
exo : yield= 23%
(1)
Product Ratio
+
1
(2)
+
(3) Competitive Reactions:
a:
b:
Y = CH2, endo : yield= 46%
exo : yield= 38%
Y = O, endo : yield= 51%
exo : yield= 47%
+
+
1
10.0
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Comparison of the Calculated and Experimental Results
k1/k2 = e -Ea/RT
Diels-Alder of Enol Ethers
Calculated Ea (kcal/mol) Experimental Ea (kcal/mol)
Diels-Alder of Alkenes
1,3-Dipolar of Enol Ethers
1,3-Dipolar of Alkenes
2.4 2.1 ( 33.5 : 1)
1.0 1.5 (13.5 : 1)
3.0 1.5 (12.2 : 1)
1.4 1.4 (10.4 : 1)
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Rationalization of Conformation Switch
OR
O R
s-transGround state of enol etherss-cis
s-transs-cis
Transition States
XO
OR
XO
O
R
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Summary for Ph.D Research at UCLA
RR
O
a. Computation study on epoxidation reaction:
b. Conformation switch of enol ether in cycloaddition reaction:
O
R
NO
O R
s-cis s-trans
O O
O
R
O R
X
O
O
R
X
O
O R
s-transGround state of enol etherss-cis
s-transs-cis
Transition States
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Part II
Design, Synthesis and Structure Study of Artificial -Sheet Sandwiches
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Previous Study on Artificial -Sheet Structures
Nowick, J. S. et al J. Org. Chem. 1997, 62, 7906-7907.Nowick, J. S. et al Chem. Soc. Rev. 1996, 25, 401-415. Nowick, J. S. Acc. Chem. Res. 1999, 32, 287-296.
-Sheet Mimic
NH
HN
NH
HN
CH3O O
O OCH3 CH3
NH
HN
NH
HN
CH3O
O
O
PhO
N
N
O
Ph
NC
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The Importance of the -Sheet Sandwich in Nature
Definition: The -Sheet sandwich is a structure motif in proteins in which two -sheets face each other to form a sandwich. The -sheet sandwich can act as a binding pocket.
Goal of building the artificial -sheet sandwich: To build a chemical model to mimic the three dimensional structures of globular proteins.
Lipid binding protein: 1lif
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Design of an Artificial -Sheet Sandwich
Hydrophilic Back
Hydrophobic Face
ON
CN
NO
O
(CH2)2
HN
O
O
NH
CH3
HNN
O
ON
H
Hi-Pr
O
Me
NH
RAla
RLys
N
CN
NO
O
(CH2)2
HN
O
O
NH
CH3
HNN
O
ON
H
Hi-Pr
O
Me
NH
ROrn
RVal
Artificial -Sheet Sandwich
Xanthene Template
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Synthesis of a Model with one Template Holding two -Turn Scaffold Structures
O
N
N
N
NC
N
NC
NH
OPh
NH
PhO
HN
PhO
O
HN
Ph
SO2Cl
NO2
DPPA, Et3N
BnOH, Tolune (80°C)
H2, Pd/C
MeOH
( 78 % )
Collidine, CH2Cl2
( 80 % )
O
CO2H
CO2H
O
NHCbz
NHCbz ( 95 % )
O
NH2
NH2
O
NHSO2Ar
NHSO2Ar
1. PPh3, DEAD, THF HOCH2CH2NHBoc
2. HSCH2CH2OH, LiOH DMF ( 85 %, two steps )
O
NH
NH
NHBoc
NHBoc
Xanthene Diacid
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Synthesis of a Model with One Template Holding Two -Turn Scaffold Structures (Cont.)
CN
2) NaHCO3
80°C
3) MeOH,
PhCNO
Template with Two Scaffolds
O
NH
NH
NHBoc
NHBoc
1) TFA/CH2Cl2
( 70 % )
O
NH
NH
HN
NH
CN
CN
( 95 % )
O
N
N
N
NC
N
NC
NH
OPh
NH
PhO
HN
PhO
O
HN
Ph
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Crystal Structure of the Model with a Template Holding Two -Turn Scaffolds
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Synthesis of the Designed -Sheet Sandwich
O
NH
NH
NH
NH
NC
NC
OCNO
HN
OCH3
NH
O
NH
NH
N
N
NC
NC
O
HN
OCH3
NHN
H
O
O
HN
OCH3
NH
NH
O
OCNO
HN
ROrn(Z)
O
N
NH
N
N
NC
NC
O
HN
OCH3
NH
NH
O
O
HN
OCH3
NH
NH
O
NH
HN
O
O
ROrn(Z)
O
O
O
N
O
O
N
O
O
RVal
( 94% )
THF, 30 min
( 95 % )
THF, rt, 19 hr
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Synthesis of the Designed -Sheet Sandwich (Cont.)
O
N
NH
N
N
NC
NC
O
HN
OCH3
NH
NH
O
O
HN
OCH3
NH
NH
O
NH
HN
O
O
ROrn(Z)
H2N
HN
O
RAla
O
N
O
O
O
N
N
N
N
NC
NC
O
HN
OCH3
NH
NH
O
NH
HN
O
O
ROrn(Z)
O
N
O
Cl
O
HN
OO
NH
HN
O
O
CH3
N
O
RLys(Z)
RVal
O
N
N
N
N
NC
NC
O
HN
OCH3
NH
NH
O
NH
HN
O
O
ROrn(Z)
O
N
O
HN
O
HN
OO
NH
HN
O
O
CH3
NH
N
O
O
RAla
RLys(Z)
RVal
RVal
COCl2, CH2Cl2
NaHCO3 ( sat ), 0 °C, 15 min
•HCl
TEA, THF, rt, 19 hr
-Sheet Sandwich
( 90 %, two steps )
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Two Dimensional TLC Test on the Interconvergenceof Different Conformations for -Sheet Sandwich 11
Solvent 10 % MeOH / CHCl3 1D TLC 2D TLC
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Possible Conformations for -Sheet Sandwich
Back - Face Face - Face
Back - Back Face - Back
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New Design for -Sheet Sandwich with an Additional Linkage between -Sheets
ON
CN
N
O
O
HN
O
O
N
H
NN
O
O
N
H
H
O
Me
NH
RTyr
N
CN
N
O
O
HN
O
O
N
H
NN
O
O
N
H
H
O
Me
NH
ROrn
S
S
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Synthesis of -Sheet Sandwich with S-S Linkage
O
N
N
N
N
NC
NC
O
HN
OCH3
NH
NH
O
NH
HN
O
O
ROrn(Z)
O
N
O
HN
O
HN
OO
NH
HN
O
O
CH3
NH
N
O
O
RCys(Acm)
RTyr(Bn)
RCys(Acm)
2. Dithiothritol
1. NPSCl, AcOH
O
N
N
N
N
NC
NC
O
HN
OCH3
NH
NH
O
NH
HN
O
O
ROrn(Z)
O
N
O
HN
O
HN
OO
NH
HN
O
O
CH3
NH
N
O
O
RCys
RTyr(Bn)
RCys
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Synthesis of -Sheet Sandwich with S-S Linkage (Cont.)
O
N
N
N
N
NC
NC
O
HN
OCH3
NHN
H
O
NH
HN
O
O
ROrn(Z)
i-Pr
O
N
O
HN
O
HN
OO
NH
HN i-Pr
O
O
CH3
NH
N
O
O
RCys
RTyr(Bn)
RCys
ON
CN
NO
O
HN
O
O
N
HN
N
O
ON
H
Hi-Pr
O
Me
NH RTyr
N
CN
NO
O
HN
O
O
N
HNN
O
ON
H
Hi-Pr
O
Me
NH
ROrn
S
S50%
(1) O2, MeOH, Cu
(2) HBr/AcOH
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Synthesis of -Sheet Sandwich with C-C Linkage
Metathesis Product: ( 3 : 1, trans to cis )
O
N
N
N
N
NC
NC
O
HN
OCH3
NHN
H
O
NH
HN
O
O
ROrn(Z)
O
N
O
HN
O
HN
OO
NH
HN
O
O
CH3
NH
N
O
O
RAllyl
RTyr(Bn)
RAllyl
ON
CN
NO
O
HN
O
O
N
HN
N
O
ON
H
H
O
Me
NH RTyr
N
CN
NO
O
HN
O
O
N
HNN
O
ON
H
H
O
Me
NH
ROrn
1. Grubbs Ru Catalyst CHCl3, 48 hrs, 70%
2. Pd/C, H2, MeOH
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NMR Study of the -Sheet Sandwiches with C=C Linkage
No Inter Sheet NOEs Observed Inter Sheet NOEs: H15 - H18; H15 - H20; H18 - H19;
H23 - H27; H26 - H21; H27 - H21.
O
Me5
Me6N
CN
NO
O
H28N
O
O
NMe
H11
NN
O
O
N
H26
H27
O
Me22
NH12
RTyr
N
CN
NO
O
H25N
O
O
NMe
H9
NN
O
O
N
H23
H24
O
Me21
NH10
Bu7
Bu8
H4
H1
H2
H3
H13H14
H15
H16H17
H18
ROrn
H31
H32
H19
H20
H30
H29 Me
Me
Me
MeH
MeMe
H
O
Me5
Me6N
CN
NO
O
H28N
O
O
NMe
H11
NN
O
O
N
H26
H27
O
Me22
NH12
RTyr
N
CN
NO
O
H25N
O
O
NMe
H9
NN
O
O
N
H23
H24
O
Me21
NH10
Bu7
Bu8
H4
H1
H2
H3
H13H14
H15
H16H17
H18
ROrnH19
H20
H30
H29 Me
Me
Me
MeH33
MeMe
H34
H31
H32
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Summary of Postdoc Research at UC Irvine
a. Designed and synthesized the artificial -sheet sandwich:
b. Designed and synthesized the -sheet sandwich with homogenous conformation:
ON
CN
NO
O
(CH2)2
HN
O
O
NH
CH3
HNN
O
ON
H
Hi-Pr
O
Me
NH
RAla
RLys
N
CN
NO
O
(CH2)2
HN
O
O
NH
CH3
HNN
O
ON
H
Hi-Pr
O
Me
NH
ROrn
RVal
Artificial -Sheet Sandwich
ON
CN
NO
O
HN
O
O
N
HNN
O
ON
H
Hi-Pr
O
Me
NH RTyr
N
CN
NO
O
HN
O
O
N
HNN
O
ON
H
Hi-Pr
O
Me
NH
ROrn
S
S
Artificial -Sheet Sandwichwith a Second Linkage
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Part III
Design, Synthesis and Structure Study of -Strand Peptidomimetic Based on Pyrrolinone Backbone
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Concept for the Design of -Strand Peptidomimetic Based on Pyrrolinone Backbone
NH
HN
NH
O
O
O
O
HN
R H
R H
R H
R H O
O
O
OR
R
R
R H
NH
O
R
HN
O
R
NH
O
R O
R H
NH
O
R
HN
O
R
NH
O
R O
R H
Nitrogen-Displaced Pyrrolinones
NH
NH
HN
Peptide -Strand ConformationDisplaceNitrogens
CyclizePyrrolinone
Rings
IncorporateEnaminone
Functionality
NH
OR
NH
ORH
N
OR
HN
RH O
NH
HN
NH
O
O
O
O
HN
H R
H R
H R
H R
NH
HN
NH
O
HN
NH
OR
NH
ORH
N
OR
HN
RH O
R
R
R
RH
O O
ODisplace
Carbonyls
CyclizePyrrolinone
Rings
IncorporateEnaminone
Functionality
Carbonyl-Displaced Pyrrolinones
Peptide -Strand Conformation
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Precigoux, G et. al. J. Am. Chem. Soc. 1987, 109, 7463.Smith, A. B. III; Hirschmann, R. et. al. J. Am. Chem. Soc. 1994, 116, 9947.
Peptides and Peptidomimetics Which Forms -Strand/Sheets
CO2Me
NH2
Ph
N
N
N
O
O
O
CO2Me
NHBocPh
N
N
N
O
O
O
NH
HN
O
NH
CH3
OPh
CbzHN
BnO
O
H2NNH
HN
NH
OHO
O
O
O
OH
Parallel-Sheet in Solid State
Anti-parallel -Sheet in Solid State
Parallel-Sheet in Solid State
What Kind of Conformation?
H
H
H
H
HH
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Retrosynthesis of Tris Carbonyl Displaced Pyrrolinone
NH
O
HN
O
NH
CH3
OPh
CbzHN
BnO
HN
O
NH
CH3
OPhCbzHN
BnO
O O
TeocHN
HN
O
NH
CH3
OPh
H
O
TeocHN
CH3
OCbzHN
BnO
TeocHN CHO
BnO CH3
OBocHN
BnOH
O
NHCbz
CH3
Ph
A B C D
+
NH
O
CH3Ph
BocHN
O
+
A
B
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Synthesis of Fragment A and B
HO2C
NH2 NO
O
AllocN
O
O
AllocOBn
NHO
O
O
OBn NH2OBn
HO
CbzNHOBn
HO
TeocNHOBn
HO
CbzNHOBn
H3C
O
TeocNHOBn
H
O
( 88 %, three steps )
CbzCl, TEA, CH2Cl2
( 61 % )
3. Alloc-Cl, CH2Cl2
( 60 %, three steps )
1. NaOH, EtOH, H2O
2. t-BuCHO, pentane reflux, 3d
L-Leu 0 °C, 14d
KHMDS, BnOCH2Cl
THF, -78°C
1. 1N NaOH, MeOH
2. (COCl)2, PhH, reflux
NaBH4, MeOH 0 °C
( 65 % )
1. TPAP, NMO MS 4Å, CH2Cl2
3. TPAP, NMO MS 4Å, CH2Cl2
2. MeMgBr, THF - 78 °C
A
TPAP, NMOMS 4Å, CH2Cl2
B
Teoc-succimide, TEA, CH2Cl2
( 85 % )
( 94 % )
( 72 %, three steps )
over 20 : 1 cis : trans
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Synthesis of Fragment D
S. Knight
HO2C
NH2
Ph NO
O
Alloc
PhN
O
O
Alloc
PhCH3
NHO
O
O
CH3
Ph HOCbzHN CH3
Ph
CbzHN CH3
O
H Ph
D
KHMDS, CH3I
D-Phe
2. t-BuCHO, pentane reflux, 3d
3. Alloc-Cl, CH2Cl2THF, -78 °C
1. NaOH, EtOH, H2O
1. 1N NaOH, MeOH
2. NaBH4, MeOH MS 4Å, CH2Cl2
Et3N, THF, 0 °C
( 44 %, five steps )
TPAP, NMO
2. (COCl)2, PhH, reflux
1. Cbz-Cl, DMAP
( 81 % )
( 74 %, three steps )
0 °C, 15d
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Synthesis of Fragment C
S. Knight
HO2C
NH2
ON
O
Alloc
ON
O
Alloc
OBn
ONH
O
OBn
O
HO
NHBocOBn
H
NHBocOBn
O
H3C
NHBocOBn
OH
H3C
NHBocOBn
OO
BocHN
BnO
C
L-Val
1. NaOH, EtOH, H2O
2. t-BuCHO, petane, reflux, 3d
3. Alloc-Cl, CH2Cl2 0 °C, 14d
( 84 %, three steps )
KHMDS, BnOCH2Cl
THF, -78 °C
( 84 % )
1. 1N NaOH, MeOH
2. (COCl)2, PhH, reflux1. Boc2O, DMAP Et3N, THF
2. NaBH4, MeOH 0°C,
( 61 %, four steps )
TPAP, NMOCH2Cl2, MS 4Å
MeMgBrTHF, -78 °C
( 60 % )
TPAP, NMOCH2Cl2, MS 4Å
( 99 % )
( 96 % )
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Synthesis of Mono Pyrrolinone
S. Knight
MeOH, rt
CH2Cl2
Dess-Martinperiodinane
H2, Pd/C
( 86% )
1. HCO2H, Pd black MeOH
1. MeMgBr, THF
( 81% )
2. Dess-Martin
( 60 %, for two steps )
+
( 98% )
LiHMDS
THF, -78 °C
2. TPAP, NMO
( 70 %, two steps )
C D
BocHNO
BnOH
O
NHCbz
CH3
PhBocHN
O
BnO
OH
NHCbz
CH3
Ph
BocHNO
BnO
O
NHCbz
CH3
Ph
NH
CH3
OPh
BocHN
BnO
NH
CH3
OPh
BocHN
H
O
NH
CH3
OPh
BocHN
O
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Synthesis of Bis Pyrrolinone
N CH3
OPh
BocHN
OBoc
THF, -78 °C - 0 °C
KHMDS (1.1 eq),Boc2O ( 2.5 eq )
( 85 % )
NH
CH3
OPh
BocHN
O TeocHN CHO
BnO
N CH3
OPh
BocHN
OBoc
OHTeocHN
BnO
LiHMDS ( 5 eq ), THF, -78 °C
B ( 2 eq )
( 60 - 85 % )
NH
CH3
OPh
BocHN
OTeocHN
BnO
O2. Dess- Martin, Pyr, CH2Cl2, rt
( 76 % )
1. NaHSO4 ( sat ), THF, rt, 24 hr
HN
O
NH
CH3
OPh
TeocHN
BnO
TsOH ( 4 eq ), EtOH 85 °C, 25 min
( 82 % )
HN
O
NH
CH3
OPh
H2N
BnO
( 0 - 5 % )
+
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Synthesis of Tris Pyrrolinone
HN
O
NH
CH3
OPh
TeocHN
BnO HN
O
NH
CH3
OPh
TeocHN
HOHCOOH, Pd Black
MeOH
( 91 % )
HN
O
NH
CH3
OPh
TeocHN
TMSO
TMSCl ( 2 eq ), TEA (4 eq)
( 89 % )
HN
O
N CH3
OPh
TeocHN
TMSO
Boc
KHMDS(1.1 eq),Boc2O (3.0 eq)
THF, -78 °C - 0 °C
( 85 % )
HN
O
N CH3
OPh
TeocHN
HO
Boc
4 % AcOH / MeOH
( 95 % )
HN
O
N CH3
OPh
TeocHN
H
Boc
ODMSO, DCC
Pyridine, TFA, PhH
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Synthesis of Tris Pyrrolinone (Cont.)
HN
O
N CH3
OPh
TeocHN
H
Boc
O
CH3
OCbzHN
BnO
TeocHN
HN
O
N CH3
OPh
Boc
CbzHN
BnO
O OHLiHMDS, THF, -78 °C
( 23 %, two steps )
A
TeocHN
HN
O
N CH3
OPh
Boc
CbzHN
BnO
O OH
Retro Aldol Reaction:
CbzHN
BnO
O O
HTeocHN
HN
O
N CH3
OPh
Boc+
H
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Synthesis of Tris Pyrrolinone (Cont.)
TeocHN
HN
O
N CH3
OPh
Boc
CbzHN
BnO
O OH
NH
HN
O
NH
CH3
OPh
CbzHN
BnO
O
1. Dess-Martin, Pyr, CH2Cl2
2. TFA, rt, 15 min( 18 %, two steps )
H2, Pd/C
NH
HN
O
NH
CH3
OPh
H2N
BnO
O
74 %
+
N
HN
O
NH
CH3
OPh
CbzHN
BnO
X - Ray Crystallography and NMR Study
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Part IV
Design and Synthesis of Pyrrolinone Based HIV-1 Protease Inhibitor
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Previous Peptidomimetic HIV-1 Protease Inhibitors
OHN NH2
OPh
OH N
N O
PhPh
O O
O
IC50 1.3 nM, CIC95 800 nM
OHN
OPh
OH NPh
O O
OH
IC50 2 nM, CIC95 100 nM
OHN
O
OH
Ph
HN
O
Ph
NH
O
CH3
Ph
10 % inhibition at 3 M
OHN
O
OH
PhO
HN
O
O NH2
OPh
Ph
HH
H
Smith, A. B., III, Pasternak, A., Hirschmann, R. et. al. J. Med. Chem. 1997, 40, 2440-2444
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Retrosynthesis of Second Generation Carbonyl Displaced Pyrrolinone HIV-1 Protease Inhibitor
OHN
O
OH
PhO
HN
O
O NH2
OPh
Ph
BocNO
H
OPh
Ph
O
NHCbz
OBn
Ph
+
BocHNO
O
Ph
BocHNOH
O
Ph
ON
O
Alloc
Ph
BocHNOH
O
Ph
L-Phe
D-Phe
Available from PreviousCarbonyl-Displaced PyrrolinoneHIV-1 Inhibitor Project
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Synthesis of Carbonyl Displaced Pyrrolinone HIV-1 Protease Inhibitor
1. Dess-Martin Periodinane Pyr, CH2CL2
2. H2, Pd(OH)2, MeOH, Overnight
( 72 %, two steps )
BocNO
Ph
PhHN
O Ph
OHa. Cl3CCON=C=O, CH2Cl2
b. K2CO3, MeOH / H2OBocN
O
Ph
PhHN
O Ph
O NH2
O
1. 1N HCl / MeOH
2. O
O OO
N
O
O Et3N, CH2Cl2
OHN
O
OH
PhO
HN
O
O NH2
OPh
Ph
( 54 % )
( 62 %, two steps )
O
NHCbz
OBn
Ph
a. LiHMDS, THF, -78 °C
b.BocN
OH
OPh
Ph
( 35 - 43 % )
BocNO
OH O
NHCbz
Ph OBnPh
Ph
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X-Ray Crystal Structure of HIV-1 Protease Complexed with Inhibitor
H2O
Asp29
Asp25
Asp225
H2O
Ile250 Ile50
Gly27
A. Pasternak
OHN
OPh
OH N
Ph
O O
OHH
IC50 2 nM, CIC95 100 nM
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X-Ray Crystal Structure of HIV-1 Protease Complexed with Inhibitor
Asp29
Asp25
Asp225
H2OIle250
Ile50
Asp230
Gly227
L. Zawaki
OHN
O
Ph
OH N
Ph
O O
O NH2
OH
IC50 2.1 nM, CIC95 250 nM
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Design of New Carbonyl Displaced Pyrrolinone HIV-1 Protease Inhibitor
Asp230
Gly227
Asp225
Asp25
Asp29
Ile250Ile50
OH
Ph
PhHN
OPh
NH2OH
HNO
OO
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Summary of Postdoc Research at UPenn
a. The tris carbonyl-displaced pyrrolinone was synthesized and the structure is being studied:
b. A carbonyl-displaced pyrrolinone HIV-1 protease inhibitor was designed and synthesized. A new design was made based on modeling:
NH
HN
O
NH
CH3
OPh
CbzHN
BnO
O
NH
HN
O
NH
CH3
OPh
H2N
BnO
OOH
Ph
PhHN
OPh
NH2OH
HNO
OO
OHN
O
OH
PhO
HN
O
O NH2
OPh
Ph
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Acknowledgements
Professor Ken N. Houk (UCLA)
Professor James S. Nowick (UC Irvine)
Professor Amos B. Smith, III (UPenn)
Professor Ralph Hirschmann (UPenn)
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Thank You