Peptide Catalyst in Synthetic Organic Chemistry 2011.11.08

24 Pages·2012·1.79 MB·English

Peptide Catalyst in Synthetic Organic Chemistry 2011.11.08
M2 S. Majima
Contents
1. Introduction
4. Artificial Metalloenzymes
2. Design of Peptide
3. Miller's Works
5. Summary
Wikipedia: Amino acid: http://en.wikipedia.org/wiki/Amino_acid
Arginine Histidine Lydine Aspartic acid Glutamic acid
(Arg, R) (His, H) (Lys, K) (Asp, D) (Glu, E)
Serine Threonine Asparagine Glutamine Cysteine Glycine Proline
(Ser, S) (Thr, T) (Asn, G) (Gln, Q) (Cys, C) (Gly, G) (Pro, P)
Alanine Valine Isoleucine Leucine Methionine Phenylakanine Tyrosine Tryptophan
(Ala, A) (Val, V) (Ile, I) (Leu, L) (Met, M) (Phe, F) (Tyr, Y) (Trp,W)
1. Introduction
1-1. Outline of Idea
review: Itsuno, S. et al. Polymeric Chiral Catalyst Design and
Chiral Polymer Synthesis, 2011, Wiley. ISBN-10: 0470568208
efficientry
Life
• High selectivity
Catalyze substrate specificity
• Mild condition
Enzymes • In water.
R
Many chemical reactions By using artificial peptide,
N high performance reaction can
H be achieved?
O n
Amino acids
1-2. Typical Works in the Peptide Catalyst Field in 20th Century
Wiechert, R. et al. ACIE, 1971, 10, 496.
" Amino acid catalyzed asymmetric Robinson annulation"
O L-Proline O
1NHClO
4
CH CN
3
O
O O
87%,84%ee.
Inoue, S. et al. Die Mukromolekulure Chemie, 1975, 176, 2751.
" Poly(amino acid)-catalyzed asymmetric protonation"
PBLG(8mol%)
C H SH +
12 25 O C H S O
20-68days,50-98%conv. 12 25
up to47%ee.
CH CO Bn
2 2
H
N
H
O
n
PBLG:poly(5-benzylL-glutamate),n=1- 20
Ohkubo, K. et al. J. Chem. SOC. Chem. Commun. 1980, 637.
" Enantioselective hydroysis of ester by amino acid dimer"
C H CO(L-His)(L-Leu)H,
11 23
N Ph
C H
O 18 37 O
H Br H
R N R N
O OH
CH CN/H O
3 2
O Bn C H -p-NO buffer pH7.61,25°C O Bn
6 4 2
kL/kD=upto5.7
(ca. 70%ee.)
Julia, S. et al. ACIE, 1980, 19, 929.
" Asymmetric epoxidation (Julia-Colonna reaction)"
poly(L-Ala), O
Ph Ph H O ,NaOH Ph Ph
2 2
toluene/H O,rt.
O 2 O
Miller, S. J. et al. Chem. Rev.
2007, 107, 5759.
85%,93%ee.
Miller, S. J. et al. JACS. 1998, 120, 1629.
" Kinetic resolution in the acetylation of alcohols"
O
peptide
OH OAc N
Ac O
2 N H O
toluene,0°C BocHN HN
NHAc NHAc
O
racemic >90%,84%ee. Ph
N
N
peptide
List, B. et al. JACS. 2000, 122, 2395.
" Asymmetric aldol reaction"
O O OH
O L-Pro(30mol%)
+
H DMSO,rt.
97%,96%ee.
1-3. Features of Peptide Catalyst
Advantages
• Tolerances of oxygen ansd water: easy handling.
• Easy synthesis and valious amino acid monomers are available: high diversity.
Disadvantages
• Reaction forms are limited to organocatalytic reactions.
• Tremendous screenning is requiered to optimize catalyst.
2. Design of Peptide
2-1. Basic Structure of Peptide Catalyst
chiral backbone (steric, hydrogen bond, - stacking)
active site
2-2. Active Site review: Miller, S. J. et al. Chem. Rev. 2007, 107, 5759.
Peptide catalized reactions are organocatalyst.
Base or nucleophile:
O O O
RHN RHN RHN
NHR NHR NHR
N S S
N HN NH N N
R R R :
NH via
2
application: conjugate addition (-> protonation), MBH reaction, protonation of silyl enorl
ether, hydrolysis of ester, Strecker reaction, Stetter reaction, acylation, phosphorylation
Enamine/ iminium formation:
O O
H
N H N
2
NHR NHR
R
application: aldol reaction, conjugate addition (epoxidation).
Oxidant
O I O O
RHN RHN
NHR NHR OH
R
N
Br O
O
I O
OOH
NR
via
application: oxidation. via
Ligand
O O O
RHN RHN
NHR NHR NR
Ph P
2
R
X PPh
2
N
H PPh
2
application: metal catalyzed reaction.
2-3. Chiral Backbone
2-3-1. Structure of Peptide
review: Balaram, P. et al. Chem. Rev. 2001. 101. 3131.
~ 1960's
Area of peptide catalysts.
~ 2000's
Enzyme's area.
Hard to design.
Artificial metalloenzymes.
Fig. 2-1: Various levels of structural organization observed in protein structures.
Main structures of paptide cataysts are showed in the circles.
2-3-2. Helices
Berkessel, A. et al. Org. Lett. 2001, 3, 3839. Also see above Julia-Colonna reaction.
Fig. 2-2: A interactoin of peptide and substrate. left: Org. Lett.
right: Hughes, R, M. Design Strategies for Peptide-Based Asymmetric Catalysis,
http://images.dcheetahimages.com/www.organicdivision.org/ama/orig/
Fellowship/2005_2006_Awardees/Essays/Hughes.pdf
Construction of helices (see also Mr. Sakaoka's literature seminar in 2010/7/14.)
1. Residues with large helix-forming propensities.
-> Leu, Val, Phe, Met, etc... (hydrophobic side chains.)
It seems that the electrostatic (i, i + 4) interactions eg) Gln•Asp, Glu•Asn) are rare
in peptide catalyst field. Maybe ionic functional groups give wrong effect to reaction.
2. Covalent helix-stabilization.
-> Linking (i, i + 3 or 4) residues.
Kurihara, M. et al. Tetrahedon Lett. 2011, 52, 798.
Arora, P. S. et al. ACIE. 2005, 44, 6525.
Kuroda, R. et al. JACS. 2008, 130, 12266.
3. Aib type peptide.
-> Aib: -aminoisobutyric acid; one of the ( , )-dialkylglycines.
Fig. 2-3: Chemical structures of some
representative ( , )-dialkylglycines.
much
glycine L-alanine
R
DL-alanine Both of DL-alanine NHR
RHN
Fig. 2-4: Ramachandran maps of amino acids.
O
Tanaka, M. et al. Org. Lett. 2010, 12, 3564.
DMF*2
X-ray
higher selectivity and substrate
scope than original reaction.
2-3-3. -turns
Hydrogen bond between (i, i + 3) ( < 7 Å). Desighned from three amino acid.
1. Proline.
R
O H
R N R
N
R
O HN O
NHR R
compatible with the i + 1 position
of type I/III and type II turns.
Fig. 2-5: Crystallographically observed values of L-Pro residues
from 538 independent protein crystal structures.
These two are very
2. Aib type peptide. important elements
for peptide catalysts!
R R O
O H O H
R
N N
HN R HN NHR
VS
R R R R
O HN O O
NHR R NHR
-> When dialkyl amino acid is i + 3 position, -turn is stabilized.
2-4. How to Screening?
Target reaction
Active site type Backbone type
Screening
base, enamine, etc... helix or turn
The sequences of amino acides are infinite, so huge screenings are required for
development of peptide catalyst.screening methods.
Fluoresence Assey in Enantioselective Acyl Transfer Reaction.
Miller, S. J. et. al. JACS. 1999, 121, 4306.
ivid. 2000, 122, 11270.
ivid. 2001, 123, 6496.
Miller, S. J. et al. JACS. 1998, 120, 1629.
see also Miller, S. J. et. al. J. Org. Chem. 1998, 63, 6784. (N-Me His as a active site.)
O
peptide
OH OAc
Ac O
2
N
toluene, 0 °C N H O
NHAc NHAc
BocHN HN
O
racemic > 90%, 84% ee.
Ph
N
When the reaction is faster, it is more selective.
N
-> By measure reactivity, good catalyst can be found.
peptide
PET PET X
OAc
Ph
OH
+
Ph OH
resign
Fig. 2-6: Mechanisum of fluorescence. Ph
Split & pool
method Assey
Amino acids Catalyst library
24 h
1000 cat.
Pick up
in 60 min!
Flu
Edman sequence
Fig. 2-7: Outline of catalyst development.
Reason of this choice is not written in the paper.
D-Pro(L-His + D-Pro is better than L-Pro, JOC.) and Aib are turn elements.
Gly is less hinder, Val, Ile, Phe, Ala is middle hinder, trt or tBu protected
amino acid and Trp is higher hinder amino acid.
How do we choose amino acid monomer in library synthesis?
1. Choose -turn element.
-> It seems -turn ( -hairpin) type peptide catalysts more effective than helix type one.
ex) Pro, Aib, Ach, etc.
2. Choose aliphatic amino acids.
ex) Val, Leu, Ile, Chg, Cha, etc.
3. Choose aromatic amino acids.
ex) Phe, His, Trp, Bn-Asn, Bn-Ser, Bn-His, trt-Asn, trt-His, Pya, etc.
4. Choose bulky side-cained amino acids.
ex) tBu-Asn, tBu-Ser, trt-Asn, trt-Gln, trt-His, Pya, etc.
0,1
NH
2
H N CO H
2 2
CO H
2
Chg = cyclohexyl glycine
Pya = 1-pyrenyl alanine
Cha = cyclohexyl alanin
How do we set amino acid monomer in library synthesis?
-> Absolute randam screening gives us too large library (see after the next page.)
The reasonable sequence methodology is desirable.
Miller, S. J. et al. JACS. 2006, 128, 16454.
Structural correlation
long range
95 % ee
Fig. 2-8: Substrate form (MM calc.)