Open Access Repository of Indian Theses

R., RAVI

                              
                              
 
 
 11
ABSTRACT 
The thesis entitled “Total synthesis of quaternary alkaloid-cotarnine; formal 
synthesis of carbohydrate unit of varitriol and multicomponent construction of 
novel heterocyclic scaffolds” has been divided into three chapters. 
Chapter I: Synthesis of quaternary alkaloid-cotarnine and formal synthesis of 
carbohydrate unit of varitriol. 
           This chapter is further divided into two sections. 
Section A: Synthesis and process route of quaternary alkaloid-cotarnine from  
3,4,5-trimethoxy benzaldehyde. 
Section B: Synthesis of 5-deoxy-2,3-O-isopropylidene-β-D-allonitrile from D- 
ribose. 
Chapter II: Multicomponent construction of novel heterocyclic scaffolds. 
         This chapter is further divided into three sections. 
Section A: Synthesis of 1,2,4,5-tetra substituted imidazoles under conventional    
heating and microwave irradiation. 
Section B: Synthesis of novel C-linked glycosylated tetra substituted imidazoles. 
SectionC: Synthesis of polyhydroquinolines via Hantzsch reaction under solvent- 
free conditions. 
Chapter III: Synthesis of 1-amino-1-phenyl butane and 1-chloro-2-methyl-2-propanol. 
          This chapter is further divided into two sections. 
Section A: Synthesis of 1-amino-1-phenyl butane from n-butyl benzene. 
Section B: Synthesis of 1-chloro-2-methyl-2-propanol from chloroform and  
acetone.  


English

RHEOLOGY OF CHICKPEA (Cicer arietinum L.) FLOUR SUSPENSIONS AND CHARACTERISATION OF FRIED PRODUCT - BOONDI

Snigdha, -

Impact of dredging on water quality and group diversity of marine zooplankton during construction and reclaimation activities of new berths at Mormugao Harbour, Goa.

P., Swapna

Dynamics of large scale 3-dimensional circulation of the Indian Ocean

MURTHY, K.N.CHIDAMBARA

ABSTRACT OF THESIS
Nonlinear optis and ferroeletris have been reognized for several deades
as promising elds with important appliations in the area of opto-eletronis,
memory devies, ampliers, frequeny onverters et. High performane eletro-
optial swithing elements for teleommuniations and optial information pro-
essing are based on the material properties. Hene, there is always a ontinuous
searh for better materials. The development of materials exhibiting large opti-
al nonlinearities and satisfying tehnologial requirements suh as wide trans-
pareny range, fast response, proessibility, adaptability and interfaing with
other materials et. is ever-growing. Present thesis reports the growth and har-
ateristis of the properties of doped and undoped LiNbO
3
rystals. LiNbO
3
, has
several interesting aousto and eletro-optial properties and is used for making
various nonlinear and linear devies. LiNbO
3
rystal, doped with MgO, Cr, Nd
and other dopants are regularly being used for various high tehnology applia-
tions in nonlinear optis.
The thesis onsists of seven Chapters. The rst Chapter gives an overview of
historial perspetives of nonlinear optial materials, origin of nonlinear optis,
seond harmoni generation, nonlinear refrative index and nonlinear absorption
oeÆient. A brief review of the work done so far in this area has been presented
in this Chapter. The seond Chapter desribes the experimental tehniques of
rystal growth, utting, polishing and lapping of the rystals. Preliminary hara-
terization tehniques like powder X-ray diration, High-resolution X-ray dira-
tion, optial transmission et. are desribed briey. Maker fringe and Z-san
tehniques for haraterizing nonlinear optial properties of the rystals are also
disussed in the same Chapter.
Chapter 3 deals with the study of X-ray powder diration, High resolution X-
1
ray diration (HRXRD), Optial transmission in transparent and rak free Mg
doped, Cr doped, Mg-Nd odoped and Mg-Cr odoped LiNbO
3
single rystals.
X-ray powder diration analysis onrmed the desired phase and found that the
rystal struture of LiNbO
3
remains same after doping. The rystalline perfe-
tion of as-grown rystals was monitored using HRXRD tehnique. The roking
urve for undoped LiNbO
3
suggests the presene of low angle grain boundary in
the rystal. However, in ase of doped LiNbO
3
rystals the rystalline perfe-
tion is better due to the overall redution in Li vaanies. Optial transmission
study shows the red shift in absorption edge in Cr doped rystals. The divalent
magnesium ions aet the
4
T
2
and
4
T
1
exited state levels of Cr
+3
ions, pro-
duing a red shift in the
4
A
2
!
4
T
1
and
4
A
2
!
4
T
2
absorption bands. The red
shift explains the hange observed in the olor of Mg doped rystals. The blue
shift in absorption edge is observed in Mg doped and Mg-Nd odoped LiNbO
3
rystals as ompared to undoped LiNbO
3
rystal. The optial absorption spetra
of Mg:Nd:LiNbO
3
onsist of ve absorption peaks orresponding to transitions
from the
4
I
9=2
ground state of Nd
3+
ions to the dierent exited states.
These results have been published in Solid State Communiations, 140, 120
(2006) and Physia B: Condensed Matter Physis, 393, 37 (2007).
Chapter 4 reports the infrared transmittane and UV-VIS absorption study
in Mg doped, Cr doped and Mg-Cr odoped LiNbO
3
single rystals. Infrared
optial absorption for OH
 
ion has been used to study the eet of impurities
on the rystals. The peak position of OH
 
ions shift to 3535 m
 1
for Mg-Cr
odoped rystals ompared to 3484 m
 1
for undoped and Cr doped rystals.
Red shift in absorption edge is observed in Cr doped LiNbO
3
rystals. Optial
absorption studies show prominent absorption bands in the visible region of the
spetrum entered at 480 nm and 653 nm in Cr doped rystals while Mg-Cr
odoped LiNbO
3
rystals these bands red shifted to 517 nm and 678 nm.
These results have been published in Crystal Researh Tehnology, 42, 718,
(2007).
2
In Chapter 5, omparative study of the optial properties of undoped and 3,
5, 7 mol% MgO doped LiNbO
3
rystals was undertaken. The eet of doping
on refrative indies as well as seond-order suseptibility has been experimen-
tally analyzed. The omparison of 3, 5, 7 mol% MgO doped LiNbO
3
rystals
show that the seond-order suseptibility has minimum at 5 mol% MgO doping.
The refrative indies of ongruent as well as doped samples were measured by
Brewster's angles at 532 nm and 1064 nm wavelength. We also found that both
the refrative indies (n
o
and n
e
) derease due to MgO doping. It is observed
that the blue shift in the ut o frequeny ourred with inreasing MgO doping
onentration.
The details of this work is reported in Optial Materials, 28, 467, (2006).
Chapter 6 deals with the study of nonlinear refrative index and nonlinear
absorption oeÆient using Z-san tehnique in undoped, 5 and 7 mol% MgO
doped LiNbO
3
rystals. We have also alulated real and imaginary parts of
the third-order nonlinear suseptibility using experimentally obtained values of
nonlinear refrative index and nonlinear absorption oeÆient. We found the
hange in sign of the real part of the suseptibility by doping the LiNbO
3
rystal
while the imaginary part of suseptibility is found to minimize at 5 mol% doping
onentration. The absolute values of third-order suseptibility dereases with
inreasing doping onentration.
This part of the thesis is reported in DAE-BRNS National Laser Symposium,
M.S. University of Baroda, Vadodara, 305 (De. 17-20, 2007).
The general onlusions are given in Chapter 7 along with possible future
sope of work that ould be performed on these rystals.
Ravikant Choubey
Candidate
3


PRODUCTION OF b-CAROTENE FROM CULTURED DUNALIELLA sp. AND EVALUATION OF BIOLOGICAL ACTIVITIES

T., Jeyarani

Studies on preparation and physico-chemical characterization of speciality fats

BISWAS, SUNIT KUMAR

Quaternary Sedimentation History and Neotectonism of Lower Tapi Basin, South Gujarat

AVULA, RAMESH YADAV

  iii 
Abstract 
In the present work, lithium bis(oxalate)borate (LiBOB), lithium fluoroalkylphosphate (LiFAP) 
and lithium difluoro(oxalato)borate (LiDFOB) identified as suitable novel lithium salts which 
were synthesized by a solid-state reaction method. These synthesized salts (and chemically 
modified) were incorporated into polymer host and subjected to various physico-chemical 
studies to optimize the ionic conductivity of the prepared membrane by varying filler/plasticizer 
ratio for all the novel salts synthesized while keeping the polymer host content as constant 
without compromising the electrochemical, mechanical and thermal stabilities. These 
membranes were prepared by either conventional or phase inversion technique with and without 
fillers. The fillers used were nanosized TiO2, ZrO2, SiO2, Sb2O3 and AlO(OH)n pseudo-boehmite 
and nanoporous Al2O3. The cycling performances of membranes fabricated by later technique 
were studied as electrolytes in coin cell configurations with lithium as an anode and LiFePO4 as a 
cathode.  
  The chapter 1 covers the general introduction of electrochemical power sources and the 
materials in search of synergic activity and their important features. The classification of battery 
systems, i.e., primary and secondary is briefly described. Rechargeable battery systems such as 
lead-acid, Ni-Cd, Ni-MH and lithium-ion batteries are compared with the slowly emerging 
chemistries based on magnesium as an anode. State-of-the-art battery active materials for the 
lithium-based rechargeable batteries included. The platforms for the possible application avenues 
for solid, gel and composite polymer electrolytes are also discussed. 
The chapter 2 focuses on the synthesis of environment-friendly and cost-effective 
LiBOB by a solid-state reaction method and subsequent use of it in polymer membranes with 
suitable nanofillers. TiO2 and ZrO2 were used nanofillers with the polyvinylidene difluoride / 
polyvinylchloride blend as a host. The membranes were subjected to a.c. impedance, X-ray 
diffraction and morphological studies. 
 The chapter 3 elucidates the electrochemistry of LiFAP based polyvinylidene difluoride-
hexafluoropropylene (PVdF-HFP) host with nanoporous Al2O3 (activated, acidic) and 
nanoparticulate SiO2 fillers and ethylene carbonate / diethyl carbonate as plasticizers. The 
membranes were subjected to a.c. impedance, differential scanning calorimetry, Fourier 
transform infrared spectroscopy, photoluminescence and scanning electron microscopy.  
 
  iv 
The chapter 4 presents the synthesis of LiDFOB and discusses the various physico-
chemical characterizations of membranes based on it. Nanoparticles of TiO2 and Sb2O3 were 
consumed for the selected host of PVdF-HFP. The high resolution FT-Raman confirmed the 
conformational change of α to β phase of VdF crystals of the said host.  
 The chapter 5 commences with phase inversion technique, a novel way of preparing the 
nanocomposite polymer electrolytes. As such the synthesis of PVdF-HFP microporous 
membranes by phase inversion technique is presented in this chapter. The nanopartilces of 
AlO(OH)n was used as a filler. These prepared membranes were soaked in 0.5 M LiX (X=BOB, 
FAP and DFOB) in 1:1 v/v EC:DEC. The physico-chemical observation in the present work 
identifies that long-term storage led to surface crystallization of the salts with those membranes 
containing LiBOB and LiDFOB. Consequently, the freshly prepared membranes were only 
subjected to charge-discharge studies in Li/LiFePO4 coin cells. The membranes were also 
subjected to mechanical stability, a.c. impedance, differential scanning calorimetry and scanning 
electron microscopy. The physical properties like liquid uptake, porosity, surface area, 
percentage of crystallinity, etc of these membranes were also carried out. 
 Chapter 6 summarizes salient futures of LiBOB, LiFAP and LiDFOB based 
nanocomposite polymer membranes. The perspectives of current status of research of lithium 
battery technology are also enlightened in this chapter.   
 
 
 
 
 
 
 


RHEOLOGICAL AND FUNCTIONAL PROPERTIES OF POTATO AND SWEET POTATO FLOUR AND EVALUATION OF ITS APPLICATION IN SOME SELECTED FOOD PRODUCTS

MATHEW, SIJO

ABSTRACT

Proteases are the most studied microbial enzymes at commercial, industrial, pharmaceutical, analytical, diagnostic, effluent abatement, etc sectors.  Their application web is increasing day by day as the newer functional roles of these enzymes are discovered.  Proteases represent 40% of world enzymes market and expected to reach 22 billion US$ market by 2009.  Among all proteases, alkaline proteases revealed highest industrial application potential with 60% of market share of world protease sales. 
 
More than 110 different bacterial strains capable of producing protease enzyme were isolated using casienolytic technique.  One of them showing high protease activity was designated as RSP12.  The strain was characterized for its physico-chemical, biochemical and growth characteristics.  Based on biochemical properties the strain was identified as Bacillus circulans, however, 16s rRNA analysis revealed that this strain showed the similarity of 0.9985 with Bacillus anthracis and Bacillus thurengenesis.  Hence, it was referred as “Bacillus sp. RSP12” in this study. 

The strain, Bacillus sp.RSP12, showed the maximum growth at 33 oC with alkaline protease production of 2915 U/ml in 24 hrs of incubation at pH 10 and at rpm 150 with 3.0 % inoculum.  Several carbon and nitrogen sources were screened to understand their impact on growth and subsequent production of enzyme using Plackett-Burman design.  Maximum protease production of 3145 U/ml was achieved with glucose and soyabean meal as carbon and nitrogen source, respectively.  Further optimization experiments were performed using a hybrid system of feed-forward neural network (FFNN) and genetic algorithm (GA) to optimize the fermentation conditions and enhance the alkaline protease production by Bacillus. sp. RSP12. A ‘6-13-1’ topology of the FFNN was constructed based on different microbial metabolism regulating fermentation factors. FFNN predicted values were further optimized for alkaline protease production using GA. The overall mean absolute predictive error and the mean square errors were observed to be 0.0048, 27.9, 0.001128 and 22.45 U /ml) for training and testing, respectively. The goodness of the neural network prediction (coefficient of R2) was found to be 0.9993. A significant improvement (>2.5-fold) in the alkaline protease yield was achieved with the use of FFNN–GA hybrid methodology.
To understand the relationship between the Bacillus sp. RSP 12 growth and enzyme production in a continuous stirred tank fermenter, an unstructured mathematical model was developed based on logistic and Luedeking-Piret equations, respectively.   A carbon source concentration specific growth curve and enzyme production variation was noticed.  
All immobilization studies were performed using sodium alginate as immobilization matrix material.  An overall evaluation criterion was used for improving the immobilized bead reusability and extracellular enzyme production by immobilized cells by assigning relative weightage to bead-reusability, enzyme production and cell leakage using different (L-18 and L-9) Orthogonal Arrays (OAs).  All selected parameters showed the influence on enzyme production either at individual or interactive level.  Glucose concentration contributed the major influence on protease production followed by matrix material and incubation time at the individual level and at the interactive level; matrix concentration played a vital role by interacting with incubation time, inoculum and CaCl2 concentration. Significant improvement, approximately 147%, in enzyme yield was observed. SEM analysis showed bacterial morphology variation with variation of matrix concentration. 
Alkaline protease production by Bacillus RSP12 under solid-state fermentation was investigated using locally available agro-industrial waste materials.  Green gram husk supported maximum protease production (35,000 U/gram material) among different materials tested at pH 9.0 with 140% moisture content in 60 hrs of incubation. Supplementation of 1.5% maltose and 2.0% yeast extract to the solid medium improved the enzyme production to the tune of 371% than control. Further optimization studies with respect to fermentation (temperature, particle size, moisture content and pH), nutrition (yeast extract and maltose), and biomaterial-related (inoculum size and incubation time) factors based on Taguchi orthogonal array showed significant variation in enzyme production levels (32000-73000 U/ gram material). 

The crude extracellular protease was purified using ammonium sulphate precipitation and Sephadex G-100 column chromatography.  SDS-PAGE, native gel and zymography analysis revealed that this protease was monomeric in nature and has molecular weight of 39.5 kDa.  More than 90 % of the enzyme activity was inhibited by phenyl methyl sulphonnyl fluoride (PMSF) and diisopropyl flurophosphate (DFP) indicating the protease produced by Bacillus RSP12 belongs to serine-type.  This protease has high specificity for casein compared to BSA, egg albumin and gelatin.  The enzyme is thermostable and revealed optimum activity at 70oC with Km and Vmax values of 0.597 µmol.min-1 and 13825 mg/ml, respectively and retained 100% activity up to 10 hours of incubation at 70oC.  The enzyme showed half-life of 150 and 26 min at 75oC and 90oC.  The enzyme revealed excellent stability and compatibility towards the detergents, oxidizing, reducing, and bleaching agents containing different additives. Dehairing studies revealed effective dehairing within 12 hrs with out supplementation of sulphate ions and lime indicating its application potential in leather processing industry in eco-friendly manner. 




EFFECT OF SELECTED PRE TREATMENTS DURING FROZEN STORAGE ON THE PROPERTIES OF PROTEINS FROM INDIAN OIL SARDINE 

(Sardinella longiceps

)

DAVOODI, MEHDI GHIAFEH

			Abstract 



Organocatalysts and Transition Metal Complexes Catalyzed C-O, C-C and C-N Bond Forming Reactions and Mechanistic Investigations Using Computational Analysis

The thesis is divided into five chapters and covers three broad areas of chemistry: (a) organic transformations catalyzed by small organic molecules (Organocatalysis) and (b) organic transformations catalyzed by metal-ligand systems and (c) computational analysis of the metal-ligand interactions to gain structural insights and the reaction mechanism. The thesis, which begins with an introduction (Chapter 1), followed by 4 chapters is outlined here.


                                        Organization of the thesis



The aim of the research is described in chapter I. Chapter II describes D-proline catalyzed pharmaco-divergent synthesis of biologically active molecules. D-Proline is employed as an organocatalyst for asymmetric α-aminoxylation of phenylacetaldehyde with nitrosobenzene, to obtain highly enantioselective 2-phenyl-2-hydroxyethanol. This serves as a common intermediate for synthesis of biologically active molecules of diverse functionalities and pharmacological properties. The molecules synthesized are Levamisole, (R)-fluoxetine, (R)-norfluoxetine, (R)-atomoxetine, and κ-opiod receptor precursor (CJ-18,027). In Chapter III(A), chiral benzimidazole derivatives of proline were synthesized. The ability of these derivatives in promoting both Aldol and Michael addition reactions were also presented. In Chapter III(B), various achiral benzimidazoles were synthesized and applied for the Pd catalyzed Heck reaction of aryl halides and acrylates. Chapter IV describes N-arylation reaction of aryl halides with azaheterocycles catalyzed by preformed (-)-sparteine/CuI dimeric halo bridged complexes. Further, computational analysis of the metal-ligand interactions were carried out using Density Functional Theory using ADF package to gain structural insights and explore probable role of the ligand in promoting the N-arylation reaction. In chapter V, a computational study of ligand interactions with hafnium and zirconium metal complexes which occur in the liquid-liquid extraction of these metals from their aqueous solutions is presented. Gaussian 98 and Amsterdam Density functional software programs were applied for the study. 
CHAPTER-I
This chapter describes the importance of catalysis in industrial processes to effect various organic transformations. It includes a brief introduction to homogeneous and heterogeneous catalysis. The chapter introduces the concepts of chirality, various natural and unnatural sources of chiral building blocks for the synthesis of biologically active molecules. The chapter also discusses the concepts of asymmetric synthesis and various means of achieving the enantiomerically pure products. Further, the role of nitrogen ligands in effecting a variety of organocatalytic and transition metal catalyzed organic transformations is presented. This chapter also describes the importance of copper in effecting various C-C, C-N, and C-O bond organic transformations. 

CHAPTER-II

D-Proline catalyzed Stereoselective Synthesis of Levamisole, (R)-Fluoxetine, (R)-Tomoxetine, (R)-Nisoxetine, (R)-Norfluoxetine, and κ-Opioid receptor precursor (CJ-18,027) via Common Chiron Strategy.
This chapter deals with the application of D-proline catalyzed α-aminoxylation method in the synthesis of various biologically active drug molecules. Recently C2-Chirons having chiral 1,2-diol moieties turned out to be of considerable interest of research, since this structural moiety is widely found in biologically active natural products and synthetic pharmaceuticals. It is a versatile and efficient starting material for synthesis of molecules of high biological importance. This is the only organocatalytic approach leading to α-hydroxyaldehydes in high enantiomeric purity, while methods are shown where the oxidation of preformed enolates are performed from aldehyde-derivatized with chiral auxiliaries. Recent advances in the chemistry of enamines has emerged as a powerful alternative for the ubiquitous carbanion chemistry, where chiral amines were employed to mimic enzymatic catalysis leading to the utilization of aldehydes as donors to form C-O bonds. 



Scheme 1: D-proline catalyzed α-aminoxylation.
The targeted the C2-chiron, (S)-1-phenyl-2,3-ethanediol, was synthesized in high enantiomeric purity by D-proline catalyzed α-aminoxylation of phenylacetaldehyde under mild reaction conditions (Scheme 1). This was then used as a chiron to demonstrate simple and elegant method of “common precursor strategy” for the synthesis of series of stereochemically related and biologically divergent pharmaceutically active block buster drug candidates like: levamisole having a fused ring system; (R)-fluoxetine and it’s analogs (R)-norfluoxetine, (R)-nisoxetine, (R)-atomoxetine which share 1,3-aminoalcohol as a common structural motif, and opioid receptor precursor (CJ-18,027). All the products were obtained with high enantiomeric excess (Scheme 2).

 













Scheme 2: Synthesis of biologically active drug molecules from C2-chiron diol using a common precursor strategy.
CHAPTER-IIIA
Synthesis of Chiral Benzimidazole-Pyrrolidine Derivatives and their Application in Organocatalytic Aldol and Michael Addition Reactions.
β-Hydroxy carbonyl and 1,3-diol units are frequently found in complex polyol architectures of natural products and have attracted a great deal of attention from synthetic organic chemists. The aldol reaction is a useful and concise method for preparing these units from two carbonyl compounds such as a ketone and an aldehyde or an aldehyde with an aldehyde. Over the past half decade, rapid progress has been made in the development of enantioselective aldol reactions: from the utilization of “preformed and stereo defined stable enolates” (e.g., irreversibly generated metal enolates such as silyl, borane, titanium, and tin enolates) to “in situ formed labile enolate synthons” There have been numerous reports on small-molecule catalyzed direct aldol reactions using the latter enolate equivalents. In particular, “the discovery of the versatile catalytic nature of proline occurring via enamine intermediates” has undoubtedly been the biggest breakthrough in this field of research.
Michael addition is another important reaction which generally proceeds via carbon nucleophiles attack on the electrophiles and unsaturated carbonyl compounds. The carbonyl nucleophile that generated from active methylene centre such as malonic acid esters, -ketoesters or nitroalkanes have been studied in Michael addition reactions. Much progress has been made in the development of asymmetric variants of this reaction, providing the high enantiopurity. Carbonyl compounds which are converted into a more reactive species such as enol or enamine equivalents are generally used as donors. Among the various Michael acceptors, nitroalkenes are very attractive candidates.
In this regard, various chiral benzimidazole-pyrrolidine derivatives (Figure 1) are synthesized and preliminary investigations on organocatalytic aldol and Michael reactions are presented.




Figure 1: Pyrrolidine-benzimidazole ligand.
The synthesis of pyrrolidine-benzimidazole was readily performed by the reaction of N-benzylproline and aromatic diamine using ethyl chloroformate to give an amide. The amide could be cyclized to benzimidazole in acetic acid at room temperature. Pd(OH)​​2 debenzylation of the cyclized product under hydrogen atmosphere proceeded smoothly to afford the target molecule. All the three ligands were prepared according to the common general procedure. The scope of these ligands was then evaluated by their application in direct asymmetric aldol and Michael addition reactions. The aim of the study is to investigate the effect of R-group of the benzimidazole ring on the yields and enantioselectivities of the reaction.








Scheme 3: General procedure for the synthesis of pyrrolidine-benzimidazole ligands.
From the results of aldol reaction, it was concluded that the efficiency of the organocatalysts depends on the R-group of the benzimidazole. The benzimidazole ligand with ester group has shown positive effect which might be due to the electron withdrawing property of the ester, which makes the imidazole N-H proton more acidic compared to 3a and 3b, resulting in the stronger H-bond with the aromatic aldehyde in the transition state.




Scheme 4: Aldol reaction of acetone and arylaldehydes catalyzed by pyrrolidine-benzimidazole ligands.
In case of Michael addition reaction the ligand 3a was found to be more effective.




Scheme 5: Michael addition of various aromatic nitrostyrenes with cyclohexanone catalyzed by pyrrolidine-benzimidazole ligands.

One of the significant findings of these studies is the scope for the development of the pyrrolidine-imidazole catalysts with tunable electronic properties. This property in turn paves way for the further development for achieving good enantioselectivities by changing the substitutions of the benzimidazole moiety and also holds scope for the heterogenization of the ligand.


CHAPTER IV
Bis(μ-iodo)-bis((-)sparteine))dicopper(I): A Versatile Catalyst For Direct N-Arylation Of Diverse Nitrogen Heterocycles With Haloarenes.
Over past few decades there have been significant advances in metal catalyzed cross-coupling reactions for the formation of aryl-carbon and aryl-heteroatom bonds, which have led to more efficient synthetic protocols for compounds like N-arylheterocycles that have important biological, pharmaceutical, and material properties. A significant number of N-arylimidazole derivatives have been reported to have biomedical applications.  The key to the success in this area has been the in situ utilization of special nitrogen ligand additives along with copper (I) precursor salts as catalysts. Although the methods are versatile and applicable to variety of heterocycles such as azoles, indoles, pyrroles, and pyrazoles, the scope is limited to the use of expensive arylating agents, such as aryl iodides and aryl bromides.
The present work is focused on developing a versatile catalyst system which can overcome the above limitations and promote the reaction of aryl halides with imidazole, pyrazole and benzimidazole. For this purpose, easy-to-prepare dimeric bis(μ-iodo)bis((-)-sparteine)dicopper(I) complex has been used as a versatile catalyst for N-arylation of number of HN-heterocycles with structurally divergent aryl halides including activated aryl chloride substrates under mild conditions. To better understand the mechanistic aspects of the N-arylation reaction with the present system, Density Functional Theory based ab initio calculations was executed using ADF package. The DFT studies not only provide structural insights into square-pyramidal Cu(III) intermediate complexes derived from (-)-sparteine, but also highlight the important role of sterically demanding (-)-sparteine ligand framework in promoting activation of aryl-chlorine bonds for N-arylation of imidazoles.  





Scheme 6: N-arylation of NH-heterocycles with various haloarenes catalyzed by preformed bis(μ-iodo)bis((-)-sparteine)dicopper(I)
In the hope of broadening the scope of N-arylation protocol, it was decided to check efficiency of the catalyst system with a wide range of aryl iodides, aryl bromides and aryl chlorides substrates. A plausible mechanism for N-arylation is proposed to account for the experimental observation that aryl chlorides form excellent substrates for cross-coupling with imidazole with Cu/(-)-sparteine catalyst system. As seen in Figure 1, first an oxidative addition of aryl chlorides to Cu(I)/(-)-sparteine complex occurs, and that results in square-pyramidal Cu(III) intermediate A. 











Figure 2. Proposed pentacoordinate Cu(III) intermediates in the mechanistic scheme for bis(μ-iodo)bis((-)-sparteine)-dicopper(I) catalyzed N-arylation of imidazole using aryl chlorides. 
This intermediate, upon nucleophilic displacement reaction of iodide ion by imidazole anion, could result in intermediate B.  It is to be noted that the structural features of Xifra’s pentacoordinate [CuIII(L)Cl]+ [ClO4]- complexes are very similar to the proposed Cu(III) intermediate, B in particular, without counter anions. 

CHAPTER V
A Computational Study of Ligand Interactions with Hafnium and Zirconium Metal Complexes in the Liquid-Liquid Extraction Process.
The design of new ligands for efficient separation of cations in general, and metal cations in particular, is very important and challenging task given the heavy emphasis placed on decreasing the environmental problems present in the existing cation extraction technologies. One of the most widely used technologies for these metal ion separations is the liquid-liquid extraction from their aqueous solutions with an organic solvent.  The better understanding of information concerning the both the nature of guest-host interactions and their binding (or interaction) energies as well as their conformational features of metal-ligand complexes are of paramount importance from the viewpoint of designing new extractants or improving the existing ones, particularly, with emphasis on green technologies.  In this regard, theoretical studies using quantum chemical principles has been shown to be very promising for the quantitative predictions of the stability and geometrical parameters of extractant-metal complexes, particularly, for the lanthanide and other metal series.
In the second and third transition series, the separation of Hf and Zr presents a challenging task due to the near similar chemical and physical properties of the two metals. There are three widely used processes for the separation of these metals out of which two of them, namely the MIBK and TBP processes, are based on liquid-liquid extraction (Scheme 7).









Scheme 7: Extraction process for Hafnium and Zirconium.

With the general view of understanding the interactions of these metal complexes with the solvents and with the more specific aim of developing an efficient extractant, the theoretical studies have been conducted. The aim was to obtain the quantitative picture of the interaction energies (primary interactions), which will give an insight into the nature of Zr/Hf interacting with TBP/MIBK. While the intention of the work was not to explain the exact extraction sequence, but address some questions like: what are the molecular level interactions (gas phase) of Zr and Hf complexes with the P=O group and the C=O groups, and what conformations do these complexes adopt with the ligands. For this some energy terms were defined, which were useful for understanding the difference in the stability of Hf and Zr complexes. 
Utilizing many experimental observations such as neutrality of the complex, tetravalency, and disolvation, the problem of Hf and Zr separation was studied using the ab initio Hartree-Fock method and the density functional method (DFT). For the DFT method both Gaussian 98(G98) software, which uses Gaussian orbitals, and also the Amsterdam Density Functional package (ADF), which is based on the Slater-type orbitals were used. In this study the gas-phase interaction energy of the Hf/Zr complex interacting with the ligands was used as the model for understanding the extractions and stabilities. The relative energies of the stabilization in Hf and Zr complexes at their lowest energy conformations have been calculated, which turn out to be similar geometries, and thus compared stabilizations of Hf and Zr having equal nonbonded interactions. These studies show that at the molecular level (primary interaction), it is the Hf complex that has larger stability in acetone and TMP solvents, thus indicating that in Hf and Zr solutions which are not complicated by aggregation and polymerization of the metal complexes, Hf would be extracted preferably into the organic solvent. It is concluded from this study that the gas-phase interaction energies are sufficient to significantly discriminate Hf and Zr complexes and thus can be used to explain Hf and Zr separation.

Significant Achievements
	C2-chiron, 1-phenyl-2,3-ethanediol, synthesized in high enantiomeric purity by D-proline catalyzed α-aminoxylation of phenylacetaldehyde under mild reaction conditions and its utility demonstrated by the viability of “common precursor strategy” to synthesize a series of stereochemically related and biologically divergent target molecules of high commercial value.
	Evaluation of benzimidazole ligands with tunable electronic properties for Heck, asymmetric aldol and Michael addition reactions. 
	Bis(μ-iodo)-bis((-)sparteine))dicopper(I) for highly efficient N-arylation reaction of aryl halides and azoles, and valuable insights into the mechanism of the reaction using computational analysis.
	Explanation of the process of separation of Hafnium and Zirconium metal salts form aqueous media using computational studies, providing scope for the development of more selective extraction processes. 



Thesis

Chapter II

Chapter I

Chapter III

Chapter IV

Chapter V

Chapter IIIA

Chapter IIIB



















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STUDIES ON EXTENSION OF SHELF LIFE AND DEHYDRATION OF TOMATO

KULKARNI, ANAND

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	                                                                                                                                                                                    	                                                                XI                                                  Abstract


       
ABSTRACT
      The thesis entitled “Development of novel synthetic methodologies and its application for the total synthesis of scytophycin-C” is divided into three chapters.

CHAPTER I: Chapter I deals with the introduction to cancer and earlier synthetic approaches of scytophycin C.
CHAPTER II:  Chapter II is divided into two sections.
Section-A:  This section describes the stereoselective synthesis of trans-2,6-disubstituted 3,6-dihydro-2H-pyrans by using InBr3  as a catalyst.
Section-B:  This section describes the formation of C-(alkynyl)-pseudoglycals from δ-hydroxy-α,β-unsaturated aldehydes and alkynyl silanes using InBr3.
CHAPTER III:  Chapter III is divided into two sections.
Section-A:  This section describes the stereoselective synthesis of C6-C18 fragment of scytophycin-C. 
Section-B:  This section also describes the synthesis of C6-C18 fragment of scytophycin-C by a different approach.





CHAPTER I: Chapter I deals with the introduction to cancer and earlier synthetic approaches of scytophycin C.
The scytophycins are novel series of polyoxygenated 22-membered macrolides isolated from the cultured terrestrial blue-green algae Scytonema pseudohofmanni, first reported by Moore et al in 1986.  They exhibit potent cytotoxicity against a variety of human carcinoma cell lines, as well as broad-spectrum antifungal activity. Among them, scytophycin-C (fig.1) has been demonstrated to exhibit significant activity against solid tumors in vitro.                                                                   
They act as cytotoxic agents by microfilament depolymerization and have been show to circumvent P-glycoprotein medicated multidrug resistance in tumor cells, which gives them therapeutic potential for cancer patients.  

                                         Figure 1
Extensive research has been carried out worldwide by the legions of organic chemists in past few years. Some of the important earlier contributions and recent developments in this area are outlined in this chapter.


CHAPTER II:  This chapter is divided into two sections.
Section-A: This section describes the stereoselective synthesis of trans-2,6-disubstituted 3,6-dihydro-2H-pyrans by using InBr3  as a catalyst.
Substituted pyrans are a common structural motif of many natural products. The dihydropyran skeleton is a particularly attractive target since it occurs in many natural products such as swinholide, scytophycin C and laulimalide and furthermore the olefin function is a synthetically useful handle for further functionalization, making it a key intermediate to many polysubstituted tetrahydropyrans. They are also synthetically useful intermediates in the preparation of polysubstituted tetrahydropyran ring systems, such as those found in the pseudomonic acids. Some of the approaches for the preparation of dihydropyrans, and some of the more varied methodologies include electrophile-initiated alkylation of glycals, hetero-Diels-Alder cycloadditions, olefin metathesis, Prins cyclizations of cyclopropyl carbinols, or homoallylic alcohols, and an intramolecular silyl-modified Sakurai reaction (ISMS). Many of these reactions have limitations, such as the need for strictly anhydrous conditions, stoichiometric quantities of Lewis acid initiator, or delivery of a strong Lewis acid at low temperature.
	 Recently, indium tribromide has received increasing attention as a water-tolerant green Lewis acid catalyst for organic synthesis demonstrating highly chemo-, regio- and stereoselective results. Compared to conventional Lewis acids, it has advantages of water stability, recyclability, operational simplicity, strong tolerance to oxygen and nitrogen-containing substrates and functional groups, and it can often be used in catalytic amounts.
	

A new method has been developed for the synthesis of trans-2,6-disubstituted 3,6-dihydro-2H-pyrans of a variety of substitution patterns. This method involves Lewis acid induced a tandem allylation or cyanation/cyclization of δ–hydroxy-α,β-unsaturated aldehydes to produce dihydropyrans in good yields and with trans-selectivity (scheme 1). 




No cis-isomer was observed in the 1H NMR spectrum of the crude products obtained in the C-allylation of δ-hydroxy-enals. This result provided the incentive for further study of reactions with various δ-hydroxy-enals. Like allylsilane, trimethylsilyl cyanide also participated effectively in this reaction (scheme 2).



	 The present method provides good yields of products with high regio- and stereoselectivity   affording C-(allyl)-dihydropyrans of synthetic and biological importance.
                                                      






















Section-B: This section describes the formation of C-(alkynyl)-pseudoglycals  from δ-hydroxy-α,β-unsaturated aldehydes and alkynyl silanes using InBr3.
C-Glycosidation is of great significance in the organic synthesis of optically active materials, since it allows the introduction of carbon chains into sugar chirons and the use of sugar nuclei as a chiral pool as well as a carbon source.  Many biologically attractive C-glycosides such as aryl C-glycoside antibiotics have already been found in nature, and several types of C-glycosides such as alkyl and allyl C-glycosides are well recognized to be useful chiral building blocks for the synthesis of optically active natural products.  
The ever-increasing importance of the role of carbohydrates in biological processes relating to immunology, virology, cancer, antibiotic action, and a host of life-threatening diseases has heightened the interest in the accessibility of specific sugar-based molecules. Furthermore, carbon-linked glycosides, stable analogues of naturally occurring O- and N-glycosides, have become the subject of considerable interest in bioorganic and medicinal chemistry. 
       The synthesis of optically active compounds has posed challenges directed towards new methodologies with more practical sources.  The development of effective C-glycoside syntheses depends on the selective formation of only one anomer as the major reaction product in good to excellent yield. 
     


In recent years, indium reagents have emerged as mild and water-tolerant Lewis acids imparting high chemo-, regio-, and stereoselectivity in various organic transformations.  
     



       A novel protocol has been developed for the synthesis of C-glycosides from δ-hydroxy-α,β-unsaturated aldehydes and silylacetylenes using a catalytic amount of indium tribromide (scheme 3). The treatment of δ-hydroxy-α,β-unsaturated aldehydes with alkynylsilanes in the presence of indium tribromide in DCM under mild reaction conditions lead to formation of the corresponding C-(alkynyl)-pseudoglycals (Table 2) in excellent yields with high -selectivity.  The predominant formation of the -anomer arise from a thermodynamic anomeric effect.
           The present method provides high yields of products in a shorter periods with greater -selectivity, which makes it a useful and attractive process for the synthesis of C-glycosides of synthetic and biological importance.        







                                               





















Chapter-III:  This chapter is further divided into two sections.
Section-A: This section deals with the present work wherein the stereoselective synthesis of C6-C18 fragment of scytophycin-C applying a novel synthetic protocol, is described. The high potent activity combined with unique and challenging structure has made this compound an exciting target for total synthesis.  Retrosynthetic analysis for this approach is illustrated in scheme 4.
Retrosynthetic analysis:















The synthesis of fragment 4 began with the commercially available (+) 2-methyl 3-hydroxy propionate commonly called as Roche ester.  Our approach for the synthesis of fragment 4 is linear. 
The free OH of the (+) 2-methyl 3-hydroxy propionate 9 is protected as its benzyl ether 10 using silver oxide and benzyl bromide which is reduced to alcohol 11 using LAH.   This alcohol 11 is oxidized to aldehyde 12 under swern conditions using oxalyl chloride, DMSO, and triethylamine.






The aldehyde 12 was subjected to Marouka  allylation  with allyltributyltin in the presence of Ti(OiPr)4,  TiCl4, Ag2O and (R)-BINOL in CH2Cl2 to afford corresponding homoallylic alcohol 8 in 78% yield as shown in scheme 5.  Osmylation of the terminal vinyl group in alcohol 8 using OsO4 and NMO and subsequent oxidation with sodium periodate produced the β-hydroxy aldehyde, which was then subjected to wittig olefination reaction with (ethoxycarbonylmethylene)triphenyl phosphorane to produce δ-hydroxy-α,β-unsaturated ester 14 in 93% yield for three steps. Subsequent conversion of ester 14 into benzylidene acetal 15 via oxy-Michael addition reaction namely, by treatment with benzaldehyde and pot.tert.butoxide in THF at 0°C, in 70% yield with 9:1 

syn:anti diastereomeric ratio.  This ester was then reduced to alcohol 16 using LAH in THF under anhydrous conditions (scheme 6).




                                                            
                                                      

The alcohol 16 upon oxidation with  IBX in DMSO and THF, afforded aldehyde 17 which was then subjected to wittig olefination reaction with (ethoxycarbonylmethylene)triphenyl phosphorane to furnish the desired trans-unsaturated ester 7 exclusively. The key intermediate 7 was selectively reduced to α,β-unsaturated alcohol 18 using DIBAL-H at -78°C.  This benzylidene acetal with allylic alcohol was then deprotected using pTSA in MeOH to produce triol 19 as shown in scheme 7.








This reaction was slow and took longer time to give triol.  The regioselective oxidation of compound 19 using MnO2 in CH2Cl2 afforded α,β-unsaturated aldehyde 6 as shown in scheme-6 which was the substrate for formation of trans-disubstituted dihydropyran. 
 Although the formation of substituted dihydropyrans seems very difficult, this key step was carried out by the lewis-acid promoted, nucleophile inducing formation of dihydropyrans, using the methodology recently developed by us.  Thus, on treatment of the δ-hydroxy-α,β-unsaturated aldehyde 6 with allyl trimethylsilane, in the presence of lewis acid InBr3, gave rise to the compound 5 in 83% yield with 2:8 syn:anti diastereomeric ratio which are separated by column chromatography. 







                                                  
 The secondary hydroxyl of 5 was then protected as its methyl ether using NaH and methyl iodide in dry THF to give the methyl ether 20.  The benzyl group of 20 is selectively deprotected using Li and Naphthalene in THF to afford primary alcohol 21 without disturbing the double bonds in the dihydropyran ring as shown in scheme 8.








                                                          



The alcohol is then oxidized to aldehyde 22 using Dess-Martin Periodinane in CH2Cl2 which was subjected to methylation using CeCl3 and MeLi in THF to give compound 23 this on oxidation with Dess-Martin Periodinane in CH2Cl2 furnished compound 4, which was the C6-C18 fragment of scytophycin-C as shown in scheme 5.
	The stereoselective synthesis of C6-C18 fragment of scytophycin-C illustrates the dynamic utility of the method developed by us and in this approach four required stereocentres are fixed.
Section B: This section deals with an alternate and better approach of stereoselective synthesis of C6-C18 fragment of scytophycin-C and present work.
The synthesis of C6-C18 fragment was started with cheaply available propane diol.   The propane diol 24 was monoprotected selectively as its benzyl ether 25 using NaH and BnBr in THF and was subsequently oxidised to aldehyde 26.   Aldehyde 26 was 

then subjected to asymmetric allylation namely, Marouka allylation using allyltributyltin, Ti(OiPr)4,  TiCl4, Ag2O and (R)-BINOL in CH2Cl2 to produce homoallyl alcohol 27.



.  


Osmylation of the terminal vinyl group in alcohol 27 using OsO4 and NMO and subsequent oxidation with periodate produced the β-hydroxy aldehyde 28 in 90% yield for two steps. The aldehyde was then subjected to to wittig olefination reaction with (ethoxycarbonylmethylene)triphenyl phosphorane to produce δ-hydroxy-α,β-unsaturated ester 29 as shown in scheme 11 in 92% yield. 







This ester is reduced to α,β -unsaturated alcohol 30 using DIBAL-H in CH2Cl2 at -78°C which was regioselectively oxidized using MnO2 in CH2Cl2 to afford δ-hydroxy α,β-

unsaturated aldehyde 31 which on further treatment with allyltrimethylsilane and InBr3 in CH2Cl2 afforded trans-2,6-disubstituted dihydropyran 32 exclusively with required stereocenters at C9 and C13 based on methodology developed by us.
 The benzyl group in compound 32 is deprotected using Li and naphthalene in THF to afford primary alcohol 33.  This alcohol 33 was then oxidized to aldehyde 34 using IBX in DMSO and THF and was used for furthur reaction without purification as shown in scheme-7. 





 

                                                                  
                                                                    
 Ti(IV) mediated diastereoselective aldol reaction upon using 2-oxazolidinethione based chiral auxillary, fixed C15-C16 centres.  Propanoyl oxazolidenethione in CH2Cl2, TiCl4 and diisopropylethylamine were added to the crude aldehyde 34 to afford the aldol product 35. 
The chiral auxillary of aldol product 35 was removed by reductive method using NaBH4 in dry ethanol to afford the diol 36 along with chiral oxazolidinethione auxillary.  

The diol 36 was converted into its benzyl ether using benzyl bromide, NaH to give the benzyl ether 5 as shown in scheme 8.  
The compound 5 was further maneuvered to get the fragment 4 as shown in scheme 8 and 9 in previous section. The present synthetic sequence provides an easy access to the construction of the key fragment 4 of scytophycin-C.  
	In conclusion, we have developed two linear approaches for the synthesis of key intermediate 4 towards the total synthesis of scytophycin-C.  Further extension of this project towards total synthesis of Scytophycin-C is under progress.














































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