Download Synthesis, Characterization of Chiral metal chelates, Immobilised

Synthesis, Characterization of Chiral metal chelates, Immobilised enzymes and their application in the synthesis of
various biologically active stereo selective compounds or Drug intermediates:
a. Present research related to research plan: During my previous work, I have synthesized heterogeneous catalysts and
used for synthesis of various biologically active compounds and screened for anti-neuroinflammatory studies and some
compounds are submitted for anticancer studies. In the continuation of the earlier work, in the present research plan I want
to synthesize chiral metal chelates and immobilized enzymes to explore in the synthesis of biologically active compounds
or drug intermediates.
b. Purpose of proposed research: To synthesize some stereo selective compounds or drug intermediates using chiral
catalysts and immobilised enzymes to cure some terrific diseases like cancer, AIDS and neuroinflammatory.
c. Proposed plan: In the continuation of my research work I want to synthesize various metal complexes to explore them
in the synthesis of active stereo-selective organic compounds or drugs. We want to synthesize various d-block metal
complexes with such as Ruthenium, Rhodium, Osmium, Palladium, Nickel, Cobalt and Copper. We want to study the
catalytic activities of these catalysts in the synthesis of various biologically active organic compounds. We also want to
immobilize different metal catalysts on various silica materials to explore those catalysts in various organic reactions. We
want to use these catalysts in the synthesis of Multifunctionalised/ stereo-selective compounds such as amino acids,
peptides, and some heterocyclic compounds such as BDPs, DHPMs, Triozoles, Triones, propargylamines, benzimidazoles
and knoevengel derivatives etc.
Proposed Ligands: (1)2-hydroxy ethyl benzimidazoles (2)2-(N-alkylaminomethyl) –benzimidazoles (3)1,2-Diphenyl
ethylenediamine 4).BINOL 5).BINAP
Chiral catalysts1-2:Benzimidazoles are simple compounds to synthesize and we want to use 2-hydroxy ethyl
benzimidazole and 2- (N-alkylaminomethyl)–benzimidazoles as chiral ligands which can be synthesized from ophenylenediamine (OPDA) and L-lactic acid/ L-Alanine. We want to synthesize various chiral ligands by changing Llactic acid or aminoacid. As shown in the scheme we want to synthesize various metal chelates using Pd, Ni, Co, Cu, and
other divalent metals. Similarly with Ru, Rh and Osmium metal ions to synthesize chiral metalchelates. Unfortunately, 2hydroxy ethyl benzimidazole, and 2-amino benzimidazoles are not explored much till now as chiral ligands to synthesize
the metal chelates.
R
R
H
N
+ MX
N
Z
R=H,Me,Ph
CH3
NH2
NH2
H
N
C
X
M
+ M-X2
Base
C
Ethanol,Reflux
CH3
NH2
X
NH2
N
O
Z=OH or NH2
(1S,2S)-(-)-1,2-Diphenyl
ethylenediamine
M
X
M= Pd,Ni,Cu,Co,Ru, Rh and Os metal ions. X=Anion
X
M=Divalant metals like
Pd,Ni,Co, Cu
X= Chloride
Fig.a: Metal chelates of 2-(α -hydroxyalkyl)-benzimidazoles
Fig.b.1,2-diphenylethylenediamine complex with divalent metals.
and of 2- N-alkylaminomethyl) –benzimidazoles
(alkyl = H,CH3,CnH5,n-CsH.i,n-C4H9,and n-CjHI1) are presented.
(1S,2S)-(-)-1,2-Diphenylethylene
diamine complex with metal
S
S
S
Pd complex/silica
S
BOC-HN
N-H
NO2 Methanol
N-methylmorpholine,DPPA
COOH
O
Mol.Wt = 376.6
(2S, 6R)
BOC-HN
Proposed work: Use of Pd or Nickel complexes in the following
reactions.
a. a. Heck reactions b. Suzuki couplings c. Sonagashira reactions.
b. Use of Pd or Ni complex in Temocapril drug intermediate (Fig.c) synthesis3-4: Temocapril is an antihypertensive drug
which is very expensive (5million dollars/kg). Previously they used to get racemic mixtures and chiral catalysts are not
developed till now for resolution. So we want to explore Pd or Nickel chiral catalyst in the following scheme to get the
chiral intermediate.
Fig.c. synthesis of temocapril drug intermediate
Some of the proposed schemes using Cu, Co:
NH2
NH2
Ru(III) or Cu or Co (II)chelates H
N
R
+
H
Ethanol, R.T
N
O
R +
N
R
N
+
N
Copper cat.
Cl
O
Copper catalyst
H
+ NaN3
Water
N
N
N
+
+
N
H
Ethanol
Scheme 1: Synthesis of various benzimidazole Scheme 2: Synthesis of Triazole derivatives Scheme 3: Synthesis of
propargyl amine
derivatives using Ru(III) or Cu(II) or Co(II)
using copper complex catalyst
derivatives using copper complex
catalyst
chelates.
Similarly we can apply immobilised enzymes in the chemoenzymatic synthesis of other chiral drugs.
Bio Catalysts5-7: The majority of synthetic chiral drugs are now marketed as race mates. This situation is rapidly due to
the recent advances in asymmetric chemical synthesis and biocatalytic methods. The use of the enzymes in the synthesis
and modification of optically pure drugs is an important task. Special attention is focused on the synthesis of new
pharmaceuticals which may require efficient procedures for large scale synthesis in the future. Bio catalysts are very
important tools in making chiral molecules for life.
Enzymes display three major types of selectivities:
1. Chemoselectivity: Since the purpose of an enzyme is to act a single type of functional group other functionalities, which
would normally react to a certain extent under chemical catalysis, survive. As a result, biocatalytic reactions tend to be
“cleaner” and laborious purification of product(s) from impurities emerging through side-reactions can largely be
omitted.
2. Regioselectivity & Diastereo selectivity: Due to their complex three-dimensional structure, enzymes may distinguish
between functional groups which are chemically situated in different regions of the substrate molecule.
3 .Enantio selectivity: Since almost all enzymes are made from L-amino acids, enzymes, are chiral catalysts. As a
consequence, any type of chirality present in the substrate molecule is “recognized” upon the formation of the enzymesubstrate complex. Thus a prochiral substrate may be transformed in to an optically active product and both enantiomers
of a racemic substrate may react at different rates.
Proposed work: Synthesis of various important chiral drug intermediates by chemoenzymatic methods.
Scheme 1: CRL mediated synthesis of enantiomerically pure(s) –1-(3-Dimethyl aminopropyl)-1-(4-Fluoro phenyl)-1,3dihydro isobenzofuran-5-carbonitrile hydrobromide. (S-Citaloform hydrogen bromide).
Scheme 2: Application of immobilized enzymes in the synthesis of S-form Hydroxy ester.
Scheme 3: Chemo Enzymatic synthesis of S - Clopidogrel bisulphate by using enzyme/SBA15.
Scheme4: Kinetic resolution of racemic 2-amino-1-butanol with penicillin G acylase enzyme immobilised on mesoporous
SBA15.
Scheme 5: Oxidation of biphenyls using aceticacid bacteria.
Scheme6: Enantiomeric separation of Lipoic acid using CRL lipase immobilized on silica materials (SBA-15, KIT6,MCM-41 and KIT-5).
Scheme7: Chemo enzymatic synthesis of CBZ-D-Proline using immobilized lipase enzyme on SBA-15, KIT-6, MCM41and KIT-5.
Scheme8: Synthesis of (S-Hydroxy ethyl Benzimidazoles by using immobilized enzymes on silica materials(SBA-15,
KIT-6,MCM-41 and KIT-5)
O
OH
COOK
O
CH2
C
H
O
H+
OH
CH2
CH2
CH3
CH3
N
CH2
H3C
+
C
KOH/MeOH
COOH
Br
(RS)
NaBH4/H2O
DCM
Trityl Chloride
Pyridine (2 moles)
addition at 0oc
F
X
C6H5
Cl
C
NH2
C6H5
C6H5
OH
O
COOK
Penicillin G
acylase
pH 7.8
CH3
CH2
CH2
(RS)
CH2
N
CH3
Acidify & extract with
E.A
Acetylation in DCM
(Ac)2O in DCM
Piridine 1 moles
X
CH2
CH2
HC
H
C
CH3
CH2
CH2
N
OH
NHCOCH2 Ph
24h
OH
+
OH
NHCOCH2 Ph
(R)
NH2
(S)
Scheme 4
O
O
OAc
140oC
(RS)
CH2
OH
OH + PhCH2COO
Me
C6H5
CH2
O
OH
COOH
H
DCM/Pyridine/DMAP
COOH
CH3
(RS)
CRL
(RS)
X
immobilised
Lipase
enzyme
X
O
CN
O
CH2
OAc
CH2
CH2
CN
CH3
CH2
CH2
N
HO
CH3
CH3
CH2
+
CH2
CH2
N
CH3
C
H
(R)-FORM
(S)-FORM
OH
OH
H
C
(S)
H
CH2
Pd/Charcoal
CH2
H
COOH
COOH
H2
(S)
Scheme 2
Scheme: 1
OH
COOCH3
+
S
HN
S
Cl
OH
immobilised Gluconobacter strain,
acetic acid bacteria
COOCH3
H2N
OTS
Cl
COOCH3
OH
N
OH
.SO3H
S
Scheme: 5
Cl
immobilised enzymes
COOCH3
COOH
N
N
.SO3H
S
.SO3H
+
S
Cl
Scheme 3
Cl
CRL
COOH+ R1-OH
SS
Hexane
COOR1
COOH
SS
+
SS
1
R = Me, Et, Pr,Bu, Hex,Octyl etc
(R)
(S)
Scheme 6
O
OH
+ R-OH
O
N
O
Immobilised Hydrolytic O
OH
Enzyme
+
N
O
Toulene, R.T.
O
+
_ - Carbobenzyloxy-D-Proline
O
OR
O
N
O
+
-
Scheme 7
H
N
N
OH
CH3
H
H
N
Immobilised CRL
Acyl donor
Toulene
(RS)
N
(S)
OH
CH3
+
H
H
N
N
OAc
CH3
H
(R)
Scheme 8
Similarly we can apply immobilised enzymes in the chemoenzymatic synthesis of other chiral drugs.
d. Expected results and impacts: In the proposed work we want to synthesize chiral metal chelates and immobilized
enzymes to use them as heterogeneous catalysts in the synthesis of some active chiral compounds, which may lead for new
drug discovery. Our main aim is to synthesize the novel chiral molecules to cure some terrific diseases such as anticancer,
AIDS and anti-neuroinflammatory. At present chiral drugs are anti cancer and key medicines for terrific diseases in the
world. So we are planning to immobilize the enzymes, to use in the synthesis of biologically active chiral molecules or
drugs. Our proposed research, which helps to the science to make new molecules or new drugs for society needs to lead
comfortable life. In conclusion, we want to explore here attractive catalysts that are chiral metal complexes or immobilized
enzymes and to apply in the synthesis of various biologically active compounds or drugs.
References :
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Complexes” Acc. Chem. Res., Vol.30.No.2, pp. 97–102, 1997.
2. Ryoji Noyori; “Asymmetric Catalysis: Science and Opportunities (Nobel Lecture)’’Angew. Chemie. Vol.41.No.2,
pp.2008-22, 1997.
3. Eugene P. Boden, Gary E. Keck “Proton-Transfer Steps in Steglich Esterification: A Very Practical New Method for
Macrolactonization” J. Org. Chem. Vol.50, pp.2394-2395, 1985.
4. Jagabandhu Das, Jeffrey A. Robl, Joyce A. Reid, Chong_Qing Sun, Raj N. Misra, Baerbel R. Brown, Denis E. Ryono,
Magdi M. Asaad, J. Edeen Bird, Nick C. Trippado, Edward W. Petrillo, Donald S. Karanewskyg “Dual Metalloprotease
Inhibitors. Iv. Utilization Of Thiazepines And Thiazines As Onstrained Peptidomimetic Surrogates In Mercaptoacyl
Dipeptides” Bioorganic & Medicinal Chemitry Letters. Vol. 4. No. 18. pp. 2193-2198, 1994.
5. R.A.Sheldon; R.Schoevaart, Cross-linked enzyme aggregates (CLEAs): A novel and versatile method for enzyme
immobilisation method for enzyme Immobilization (a review), vol.23,No.3-4,p.141-147, 2005.
6. R.A.Sheldon; Designing economic chiral syntheses;Journal of Chemical Technology&Biotechnology” vol.67, p.114,1996.
7. Alexey L. Margolin “Enzymes in the synthesis of chiral drugs” Enzyme in microbial technology Vol.15, pp. 266-280,
1993.