Open Access Repository of Indian Theses

DAPHNE, LEON

ABSTRACT











The thesis entitled “ Towards The Total Synthesis of Macrolactin-A and Synthesis of Furopyranones” is divided into four chapters.
CHAPTER I: Chapter I deals with the introduction and literature approaches towards the synthesis of macrolactin-A.
 The macrolactins1 are a structurally diverse class of secondary metabolites isolated from a deep-sea bacterium. The parent aglycone, macrolactin-A is representive. Some members of this class possess pendant glucose-β-pyrannosides, while others differ in the oxidation state and degree of unsaturation. Macrolactin-A exhibits a broad spectrum of activity with significant antiviral and cancer cell cytotoxic properties including inhibition of B16-F16 murine melanoma cell replication with invitro IC50 values of 3.5 µg/mL. Macrolactin-A also has implication for Herpes simplex type II and I. 
                                                                         A: X = β-H, α-OH, R=H
                                                                                        B: X = β-H, α-OH, R= β-glucosyl
     C: X = β-H, α-O- β-glucosyl, R=H
                                                                              D:X = β-H, α-OH, R=R(D)
                                                          E:X = O, R=H
                                                                                    F: X = O, R=H, 16.17 di hydro

                            Figure 1





CHAPTER II: Chaprter II is further divided into two sections.
Section A:  Section A deals with the present work wherein the synthesis of C1-C11 fragment of macrolactin-A is described. 
Synthesis of C1-C11 fragment of Macrolactin-A is presented in this section. The general retrosynthetic strategy of Macrolactin-A is shown in scheme 1.
 

















Synthesis of C1-C11 fragment:
Synthesis of C1-C11 fragment began with readily available 3-butyn-1-ol 7. Primary hydroxy group of 3-butyn-1-ol was protected as a PMB ether 9 using PMB-Br and NaH in 92% yield. Treatment of the compound 9 with EtMgBr and para formaldehyde afforded 10 in 75% yield. Compound 10 was converted to its allyl alcohol 11 by using LiAlH4.2 Sharpless asymmetric epoxidation3 (SAE) of compound 11 afforded epoxy allyl alcohol 12 in 83% yield. Swern oxidation4 of compound    12 followed by Wittig olefination gave the α, β-unsaturated ester 14. Reduction of ester group of compound 14 using DIBAL-H at -100 oC afforded the epoxy allyl alcohol 15 in 60% yield.5 Compound 15 was converted to its epoxy allyl chloride 16 by treating with TPP, NaHCO3 and CCl4 at reflux temperature in 77% yield.6 Treatment of 16 with LDA at -78 oC or LiNH2 at -33 oC gave the hydroxy enyne 17 in 80% yield (Scheme 2).7








Scheme 2
 


Secondary hydroxy group of 17 was protected as its silyl ether 4 using TBDMS-Cl and imdazole. Deprotection of PMB group of 4 in the presence of DDQ8 followed by IBX oxidation gave the aldehyde 19.9 Two-carbon extension was done to 19 by using formethylene triphenyl phosphorane to afford 20 in 72% yield. Applying Stille’s modified Wittig-Horner10 reaction to compound 20 completes the synthesis of C1-C11 fragment 2 using bis 2,2,2- trifluro methyl (methoxy carbonyl methyl) phosphonate in the presence of NaH at -78 oC in 80% yield (Scheme 3).










Scheme 3

Section B: Synthesis of C12-C24 fragment of macrolactin-A is described in this section. As accordingly C12-C24 fragment was again divided into two building blocks, C12-C17 and C18-C24.
Synthesis of C12-C17 fragment: The synthesis of C12-C17 fragment began with readily available starting material (R)-malic acid 8. Accordingly, (R)-malic acid 8 was converted to its dimethyl derivative 21, which was treated with BH3.DMS to afford 1,2,4-butane triol 22.11 1,2-diol protection of compound 22 as its cyclic ether 23 was achieved at r.t using cyclohexanone and catalytic amount of PTSA in 56% yield. One pot oxidation and Wittig olefination of compound 23 gave the α,β-unsaturated ester 24 in 89% yield. DIBAL-H reduction of compound 24 followed by SAE gave the epoxy alcohol 26. The epoxy alcohol 26 was converted to its epoxy chloride 27 by treating with TPP, NaHCO3 and CCl4 at reflux conditions. Treatment of compound 27 with LDA at -78 oC or LiNH2 at -33 oC afforded chiral propargyl alcohol 28, which upon doing acetylation in the presence of Ac2O, Et3N gave the acetate compound 5 (Scheme 4).












Synthesis of C18-C24 fragment:
Synthesis of C18-C24 fragment began with the solvent free kinetic resolution of racemic propylene oxide 29 with Jacobsen catalyst to afford chiral epoxide 30 and chiral diol 31 (99% ee).12 Enatiomeric purity of the epoxide 30 and diol 31 was confirmed by gas chromatography (Scheme 5).





Epoxide 30 was opened by Yamaguchi protocol with the compound 9 to produce the secondary alcohol 32.13 PMB group of compound 32 was deprotected using DDQ to afford 33. Tosylation of compound 33 in the presence of TsCl and Et3N at 0 oC afforded a tosyl derivative 34. Tosyl group of the compound 34 was converted to its methyl group by treating with LAH at 40oC to afford compound 35. Zipper isomerization of compound 35 in the presence of NaNH2 and 1,3 diamino propane gave the terminal alkyne 36.14 Protection of compound 36 as its TBDPS ether 37 was achieved using TBDPS-Cl and imidazole. Stannylation15 of compound 37 using n-Bu3SnH and AIBN followed by NBS treatment afforded bromo compound 6 as the mixture of trans and cis in 4:1 ratio (Scheme 6).16














Scheme 6

Synthesis of C12-C24 fragment:
 The Sonogashira coupling reaction between alkyne 5 and vinyl bromide 6 in the presence of a catalytic amount of Pd(PPh3)4, CuI and diethyl amine afforded eneyne 39 as an inseparable mixture of trans and cis  (trans as a major isomer) in an overall yield of 60% at r.t.17 Acetate hydrolysis of compound 39 using K2CO3 in MeOH at room temperature, followed by LAH reduction gave trans isomer 41. Hydroxy group of compound 41 was protected as PMB ether 42 using PMB-Br and NaH at reflux temperature. Deprotection of cyclohexane part of compound 42 in the presence of PTSA in MeOH afforded the diol 43, which on tosylation using TsCl, Et3N gave the tosyl compound 44. Finally tosyl compound 44 was converted to its corresponding epoxide in the presence of K2CO3 in MeOH at room temperature afforded C12-C24 fragment of Macrolactin-A 3 (Scheme 7).

 











Scheme 7







CHAPTER III:  A brief review on proline-catalysed reactions were described in this chapter. 
There are several reasons why proline has become an important molecule in asymmetric catalysis. Not least is the fact that proline is an abundant chiral molecule that is inexpensive and available in both enatiomeric forms. Additionally, there are various chemical reasons that contribute to role of proline in catalysis. Proline is bifunctional, with a carboxylic acid and an amine portion. These two functional groups can both act as acid or base and can also facilitate chemical transformations in consert, similar to enzymatic catalysis. While enzymes typically use several different functional groups in their catalytic machinery, bifunctional asymmetric catalysis has become a very successful strategy in the laboratory.18 Different modes of action in bifunctional asymmetric catalysis of proline are illustrated in fig 2. In adition, proline is a chiral bidentate ligand that can form catalytically active metal complexes.







Figure 2

CHAPTER IV: Chapter IV describes a D, L-Proline Catalyzed Diastereoselective Trimolecular Condensation: An approach to the one-pot synthesis of perhydrofuro[3,2-b] pyran-5-ones.
As synthetic targets increase in complexity, chemoselective transformations of poly functional compounds is a challenging problem in organic synthesis, especially in the cases where sensitive structural features limit with reagent choice. Although several recent methods and procedures are general and efficient enough to be employed across a wide range of substrate molecules, there is still a great need to develop new and milder methods. 
The furo-pyran nucleus is an important element in pharmacologically active compounds19 such as nucleotide antibiotics20 and carbohydrate derivatives.21Furthermore, Dysiherbaine22 and Neodysiherbaine23 (Figure3) which are recently isolated from a marine sponge having a furo-pyran core were found to be selective agonist of non-NMDA type glutamate receptors in the central nervous system. 




Figure 3
Multicomponent reactions (MCR’s) are of increasing importance in organic and medicinal chemistry for various reasons.24 MCR strategies offer significant advantages over conventional linear-type syntheses. MCR condensations involve three or more compounds reacting in a single event, but consecutively to form a new product, which contains the essential parts of all the starting materials. The search and discovery for new MCR’s on one hand, and the full exploitation of already known multicomponent reactions on the other hand, is therefore of considerable current interest.
We herein report a new, extremely facile and efficient proline catalysed one pot trimolecular condensation reaction between indoles 45a-g, sugar hydroxyaldehyde 46 (derived from D-glucose), and Meldrum’s acid (47) to furnish chiral 7-(1H-3-indolyl)-



Scheme 8
2,3-dimethoxyperhydrofuro [3,2-b] pyran-5-ones 48 as exclusive products. This reaction is highly diastereoselective affording exclusively cis-fused furo [3,2-b] pyranone derivatives with ‘R’ configuration at C-7. The stereochemistry of the product was established by exclusive NMR analysis and NOE studies (Scheme 8).25
When the same reaction was carried out using the O-protected sugar aldehyde 49 the reaction was found to give the adduct 50 exclusively as expected (Scheme 9). The structure of the product 50 was confirmed by exclusive NMR analysis and NOE studies (Scheme 9).



Scheme 9







































 EMBED ISISServer  

































English

PARTIAL PURIFICATION AND IMMOBILIZATION OF RNase T2

L., GURUCHARAN

Abstract
SIGNIFICANCE OF THE WORK
India is the 8th largest country having a total of around 47 thousand plant species, out of which more than 7,500 species are cited as medicinal plants. There are two main reasons for interest in natural products. Firstly the use of medicinal plants as such as phytomedicines, dietary supplements and traditional medicines. Secondly natural products continue to remain an important source of new drug discovery. There are many intrinsic factors which govern the growth and medicinal quality of herbs. This is largely due to change in their chemical constitution which often leads to change in their bioactivity. Due to these inherent uncontrollable variations standardization becomes extremely important. Standardization of natural products is a complex task due to their heterogeneous composition, which is in the form of whole plant, plant parts or extracts obtained thereof. To ensure reproducible quality of herbal products, proper control of starting material is utmost essential. The first step towards ensuring quality of starting material is authentication. Thus the problems faced in the standardization of crude drugs are numerous but one has to make a beginning somewhere. Keeping in mind that natural product quality control generally necessitates a multidisciplinary approach which requires resources and expensive equipments. For identification of the crude drug it is best to possess the authentic reference standard of that particular crude drug. Markers are compound (s) unique/characteristic to the plant in question and are preferably present in detectable amounts and can be easily isolated. A marker compound can be quantified when ever actual bioactive are not known. The concentration of markers in a particular drug could be appropriately fixed and each batch of the drug produced should adhere to these limits. The quantification can be carried out by high performance liquid chromatography (HPLC), high performance thin layer chromatography (HPTLC) and Supercritical fluid chromatography (SFC). There is a great market potential for medicinal plants and their value added products, both in the domestic as well as in the international arena. The global market demands superior quality of crude drugs, their semi-processed forms and their finished products. Towards this it is essential to ensure quality assurance at all levels for standardization, efficacy, safety and consistency. The present project is designed to study recent chromatographic techniques of analysis for quality assurance of Herbal and Herbo-mineral products from raw material to finished product. Recent developments in the field of analytical instrumentation and computational techniques along with systematic experimental designs can be exploited for analytical method development of herbal and herbo-mineral products. The recent chromatographic techniques of analysis such as High Performance Liquid Chromatography (HPLC), High Performance Thin Layer Chromatography (HPTLC), Supercritical Fluid Chromatography (SFC) coupled to photo diode array detector (PDA) are extremely useful for qualitative and quantitative evaluation of herbal and herbo-mineral drugs. Gas chromatography (GC) however is not suitable for herbal analysis as only substances that can be volatilized at higher temperatures and which are thermolabile can be analyzed. HPLC is slow, cannot produce visual images but is useful for quantification.  HPTLC is well suited to obtain a detailed fingerprint of herbal extract or product. Such a fingerprint comprises of scanning, in UV, fluorescence, UV spectra and photographic images in UV light (254 and 366 nm) and occasionally in visible light after derivatisation. HPTLC fingerprint is obtained at low cost and high speed and thus meets the need of a modern quality control method. HPTLC fingerprint serves a highly useful purpose in evaluating the changes in chemical composition during storage. The changes in HPTLC fingerprint pattern don’t necessary reflect appreciable change in bioactivity. Another approach of monitoring HPTLC fingerprinting includes assays of markers and generates data by determining the extent of bioactivity as a means of stability testing. Packed column SFC coupled to PDA detector is a promising novel chromatographic technique which can be employed for standardization of herbals having components with different λ values. Especially for herbals containing short wavelength components, the UV signal has to be recorded at low wavelengths (215 nm, e59200) in order to maximize sensitivity, requiring the use of solvent systems that are UV-transparent in this range. In LC methods, most solvents absorb strongly at the short wavelength required for sensitive detection. Excellent transparency of supercritical carbon dioxide at short UV wavelengths compelled us to investigate the analysis of these compounds by PC-SFC-DAD method. Among the published methods there are no integrated experimental design based fingerprint development studies, which include development, optimization and validation of the method. In this work we describe a strategy for method development, optimization and validation of HPTLC and PC-SFC-DAD methods for fingerprint development studies of herbal extract as well as commercial formulations. Some controllable parameters and the range of the factors, which need to be optimized, were selected. Optimization was performed using a uniform design, which is very useful when a large number of levels are evaluated. The use of this approach in the context of herbal analysis problem where the components have more or less similar chemical structure and their separation remains still a challenging task for the pharmaceutical analyst. It is therefore necessary to establish universal and systemized approach to conveniently develop reliable chromatographic fingerprints of herbal medicines. The last step was method validation as per the recommendations laid down by ICH guidelines [52-54] consisting of injection precision, repeatability, reproducibility and sample stability test. The present study is also an effort to evaluate temperature dependence of the enantioselectivities for dextro and levo- herbal optical isomers under PC-SFC-DAD conditions from a thermodynamic point of view






A sensitive, selective, precise and robust high-performance thin-layer chromatographic method of analysis of E and Z stereoisomers of guggulsterone (the hypolipidemic agent in the gum-resin exudates of Commiphora mukul) both as a bulk drug and in formulations was developed and validated. The method employed TLC aluminium plates precoated with silica gel 60F-254 as the stationary phase. The solvent system consisted of toluene- acetone (9:1, v/v). Densitometric analysis of guggulsterone was carried out in the absorbance mode at 250 nm. This system was found to give compact spots for E- and Z- guggulsterone, (Rf value of 0.38 ± 0.02 and 0.46 ± 0.02 respectively) following double development of chromatoplates with the same mobile phase. The linear regression analysis data for the calibration plots for E- and Z- guggulsterone showed good linear relationship with r2 = 0.9977 ± 0.054 and r2 = 0.9975 ± 0.068 respectively  in the concentration range of 100 ng/spot to 6000 ng/spot. The mean value of slope and intercept were 0.11 ± 0.006 and 0.11 ± 0.005, 14.26 ± 0.56 and 10.92 ± 0.76 respectively for E- and Z- guggulsterone. The method was validated for precision, robustness and recovery. The limit of detection and quantitation were 12 ng/spot, 10 ng/spot and 24 ng/spot, 20 ng/spot respectively for E- and Z- guggulsterone. Statistical analysis proves that the method is repeatable and selective for the estimation of the said drug. Since the proposed mobile phase effectively resolves the E- and Z- isomers of guggulsterone, this HPTLC method can be applied for identification and quantitation of these isomers in herbal extracts and pharmaceutical dosage form.
Key words: Guggulsterone; E and Z stereo isomers; Commiphora mukul; HPTLC


Stress degradation studies were carried out on guggulsterone (the hypolipidemic agent in the gum-resin exudates of Commiphora mukul) following the conditions prescribed in the parent drug stability testing guideline (Q1AR) issued by International Conference on Harmonization (ICH). The present study describes degradation of guggulsterone under different ICH prescribed stress conditions (acid and base hydrolysis, oxidation, dry and wet heat degradation and photodegradation) and establishment of a stability indicating HPTLC assay. The method employed TLC aluminium plates precoated with silica gel 60F-254 as the stationary phase. The solvent system consisted of toluene- acetone (9:1, v/v). Densitometric analysis of guggulsterone was carried out in the absorbance mode at 250 nm. This system was found to give compact spots for E- and Z- guggulsterone, (Rf value of 0.38 ± 0.02 and 0.46 ± 0.02 respectively) following double development of chromatoplates with the same mobile phase. The drug undergoes degradation under acidic and basic conditions, oxidation, dry and wet heat treatment and photodegradation. All the peaks of degraded products were resolved from the standard guggulsterone with significantly different Rf values.  As the method could effectively separate the drug from its degradation products, it can be employed as a stability indicating one.
 Key words: Guggulsterone; Commiphora mukul; HPTLC; Stability indicating; Stress degradation.

Two chromatographic techniques are described for the separation and quantitative determination of azadirachtin A and B, salannin, and nimbin present in the crude extract of neem seed kernels and commercial neem based formulations. The high performance thin-layer chromatography (HPTLC) separation of markers was carried out on Merck TLC aluminium sheets of silica gel 60 F254 using ethylacetate-benzene (7.0: 3.0, v/v) as mobile phase. The other technique was based on extended length packed column supercritical fluid chromatographic (PC-SFC) separation of the markers using Cyano column (250 mm × 4.6 mm I.D, S-5.0 µ) and Kromasil 100 NH2 column (250 mm × 4.6 mm I.D, 5.0 µ) connected in series. The detection was carried out using photodiode array detector at 338 K using methanol-modified carbon dioxide (10 %) as the mobile phase at flow rate of 2.0 mL min-1. The current study assesses the effect of extending column length during PC-SFC experiment to obtain maximum resolution between a number of unknown components and known markers present in neem seed extracts. Both the chromatographic methods were validated in terms of precision, robustness, recovery, limits of detection and quantitation. The analysis of variance (ANOVA) and Student’s t-test were applied to correlate the results of quantitative determination of markers by means of HPTLC and PC-SFC method.
Key words: Thin layer chromatography; Supercritical fluid chromatography; Method validation; Azadirachtin A and B, salannin and nimbin.





IMMOBILIZATION OF ENZYMES: PURIFICATION AND IMMOBILIZATION

RAMSWARUP, YOGESH

Abstract

Ecology and Biodiversity of Branchiopods with special reference to Cladocerans from Pune region

Branchiopoda are a group of primitive and primarily freshwater (​http:​/​​/​en.wikipedia.org​/​wiki​/​Fresh_water" \o "Fresh water​) crustaceans (​http:​/​​/​en.wikipedia.org​/​wiki​/​Crustacean" \o "Crustacean​). The current number of species of branchiopods is 1180. Knowledge of the distribution and ecology of large branchiopods of India is in a poor state. Studies pertaining to Indian branchiopods have been few and scattered. Same scenario persists for Maharashtra and Pune as well. Data on branchiopods is meager with few checklists and inventories which include very little information about their identification, distribution and habitats. Therefore, main aim of the study was to document the Branchiopod diversity from a specific region of Northern Western Ghats with best taxonomic resolution along with few ecological and distributional observations as well. A special emphasis has been given to Cladocera as the available literature is relatively better than for large branchiopods.
Work generated 156 samples from over 70 habitats from which 7 species of large branchiopods from all extant large branchiopod families and 42 species of cladocerans from 7 different families were found. Molecular taxonomic analysis of of collected Triops granarius using COI gene sequences along with conspecific downloaded sequences from Genbank showed monophyly of T. granarius supporting the sister relationship of Indian lineages with African and Japanese populations though within this clade, a separate clade of the specimens from this study was seen thus representing a distinct lineage.

 Nearly fifty percent of Cladoceran fauna described by Michael and Sharma in 1988 from India was found in the study from one district. Report of 42 species of cladocerans from a single study is the highest record from Maharashtra state till date. The species number calculated by using Chao2 analysis showed that expected species number was 50. Fifty percent of the samples had less than 4 species in them. Ilyocryptus spinifer was the most abundant cladoceran seen. All the ‘very common’ species were found at slightly alkaline pH and a median temperature value between (27°C-28°C). Salinity ranges too were similar for most of the abundantly occurring species with medial values just above or below 100 ppm. Correspondence Analysis showed that temporary water bodies and permanent water bodies were quite distinct when their fauna was considered. 




STUDIES ON CEREAL STORAGE PROTEINS WITH A SPECIAL REFERENCE TO RICE

KUMAR, LALITHA

Abstract

Fluorescent Dissolved Organic Matter (FDOM) studies in the western Bay of Bengal.

After the International Indian Ocean Expedition (IIOE) during 1959-1965, many studies have been done on the physical and biochemical aspects of the Bay of Bengal. There, however, exists a gap in the study of the optical properties.  The Bay of Bengal, the largest Bay of the world, is a tropical semi enclosed basin to the north-east of the Indian Ocean and receives a large freshwater influx ca.1,600 km3 yr-1, i.e., ~50,000 m3sec-1 from the rivers draining India, Bangladesh, Nepal and Myanmar.  For an oceanic surface area of only 1.13%, this influx constitutes 6.6% of the global river flux.  The Bay of Bengal experiences seasonally reversing monsoon winds, the south-westerly wind during summer monsoon (June to September) and north easterly wind during winter monsoon (November to February). Rivers bring together with fresh water, large amounts of organic matter in dissolved as well as particulate form into the coastal waters primarily during the monsoon season. 
The dissolved organic matter (DOM) of natural waters comprises carbohydrates, amino acids, hydrocarbons, phenolic acids, and other identified molecules, adding up only to <7% of the total DOM.  About 15-20% of DOM is made of oligomers and polymers dominated by carbohydrate, aminoacid and lipid structural moieties.  A majority ca 70% of DOM is chemically unclassified and called variously as humic substances, gelbstoff, fulvic acids, gilvin etc.  Colored dissolved organic matter (CDOM) is a variable fraction of DOM.   The definition and quantification of CDOM is in terms of optical absorption.  The absorption of CDOM increases exponentially from the visible (700 nm) to the UV region (200 nm). A sub-fraction of CDOM say ~5% is fluorescent and emits blue radiation when excited with UV-light.  
In this Thesis, measurements of fluorescent dissolved organic matter (FDOM), to my knowledge, for the first time for the Bay of Bengal are reported.  Fluorescence method is a relatively recent technique for the characterization of DOM.  The technique received two breakthroughs, the first one when the Excitation Emission Matrix (EEM) Spectra were introduced by Coble and her co-workers for a simultaneous characterization of various fluorophoric components of DOM.  The second breakthrough was the introduction of parallel factor (PARAFAC) analysis of the EEM spectra, a statistical method of data reduction by Stedmon and his co-workers by which the overlapping fluorophores are resolved and precisely quantified.  These methods were adopted in my Study of marine samples collected for over 2 years from the mid-western Bay of Bengal.   
The objectives of the Thesis were:
	To examine the utility of fluorescence (and absorbance) as a tool for identifying different water types (regions) along a major part of the east Indian coast, 
	To identify and quantify different fluorophores in a smaller continental shelf area of the western Bay Bengal with data collected at higher resolutions of time and space, and to examine their utility as descriptors of season / region,
	To examine the ability of phytoplankton as source of different fluorescent compounds during its life cycle, in culture, so that this result can be useful in distinguishing internal inputs (primary production) to fluorescence from external inputs (discharges).




PARTIAL DNA ANALYSIS OF MILLETS WITH SPECIAL REFERENCE TO THAT OF GREAT MILLET

Shinde, Ramesh Fakira

STRUCTURAL INVESTIGATIONS IN OXIDE CERAMICS

MULLA, IMTIYAZ S.

iii 
 
 
ABSTRACT 
 
 Multicore processors have become the defacto standard today and 
this has led to renewed interest in multiprocessor scheduling. There are many 
factors that need to be considered while designing scheduling algorithms for 
multicore processors. These factors include reduction of overheads due to task 
migration / preemption, effective slack utilization and appropriate handling of 
task dependencies. This will lead to effective resource utilization and 
improved task schedulability. This thesis work has proposed four different 
scheduling algorithms that tackle these issues and aim at effective resource 
utilization. 
 Several researchers, as a means of avoiding wastage of resources, 
have looked at fairness strategies that grant resources to tasks based on their 
actual requirement. Proportionate fairness is one such strategy that grants 
resources to tasks based on the minimal resource requirement. However, the 
proportionate fairness approach is rigid as it does not allow subtasks to be 
scheduled if they miss their respective slots and keeps the processor idle when 
subtasks await execution. Further, the proportionate fairness approach also 
incurs overheads due to migration and preemption. The overheads incurred 
affect resource allocation and hence task schedulability. To make the 
proportionate fairness approach more flexible, this thesis work has modified it 
and has incorporated a migration window to accommodate all subtasks of a 
iv 
 
particular task on the same core as far as possible. EDF constraints have been 
appended to ensure that all critical tasks are scheduled. The execution times 
of subtasks have been approximately estimated and a worst / best heuristic 
function has been appended to define the objective of the scheduler. The 
modified proportionate fairness approach is simulated using Cheddar, a real 
time scheduler and SESC, an architectural simulator. The simulated results 
show that resource utilization and task schedulability are improved, compared 
to the proportionate fairness approach.  
 The modified proportionate fairness strategy schedules tasks with a 
small quantum of resource, cumulating the unutilized resource as slack.  The 
cumulated slack is used to schedule tasks that arrive at a later point of time 
with inadequate resources. The second approach proposed in this work uses a 
new slack distribution measure, non-uniform laxity, to handle slack 
effectively. The non-uniform laxity distributes slack based on the minimum 
execution time, worst case execution time, computation cost and laxity of a 
task. The simulated results indicate improved resource utilization and task 
schedulability, compared to existing laxity based approaches. 
 The third approach proposed in this work handles task 
dependencies.  Dependent tasks are grouped as clusters by constructing a 
Directed Acyclic Graph (DAG). The clusters are partitioned as coarse and 
fine grain clusters based on granularity and are scheduled by computing a 
ranking parameter, which is based on granularity and non-uniform laxity. The 
fine grain clusters are scheduled followed by the coarse grain clusters. Parent 
tasks of clusters with high communication cost are scheduled by a selective 
v 
 
duplication strategy. The results show a reduction in communication cost and 
improvement in resource utilization and task schedulability. 
 A comparative study of all the proposed approaches has been 
carried out and the approaches have been evaluated against each other. The 
results indicate that the non-uniform laxity based approach yields better 
resource utilization and task schedulability, compared to the modified 
proportionate fairness and non-uniform laxity scheduling heuristic with 
selective duplication. 
 Further, in situations when the scheduling parameters are not 
precisely available, they can be specified as linguistic variables. This thesis 
work has incorporated a fuzzy inference engine that takes in the scheduling 
parameters as linguistic variables and produces a revised priority based on 
which a scheduling algorithm is developed. Thus, all the four proposed 
approaches work towards minimization of wastage of resources and 
improvement of task schedulability.  


SYNTHESIS AND STUDIES ON NEW RARE-EARTH COPPER OXIDE SYSTEMS

VAIDYA, UTPAL

ABSTRACT
A proposal on atomic parity violation experiment & a study on parametric
resonances with trapped ions
by Pintu Mandal
Supervisor:Dr. Manas Mukherjee
Motivated by the challenges and limitation of existing experimental techniques, the
thesis introduces and elaborates a proposal for the precision measurement of atomic
parity violation by quantum metrology with an entangled pair of trapped ions. Al-
though the technique is fundamentally based on an existing proposal, it can poten-
tially reach a figure of merit twice as high for an exceedingly tiny observable, yet to
be measured in any ion trap experiment. The systematic of the technique have been
shown to be better controlled as compared to other experiments. Since the goal of the
experiment is to test the Standard Model of physics, the measured parity violating
transitional dipole matrix element has to be compared with the theory of competitive
precision. The choice of the element therefore plays an important role for the success
of the experiment. From this perspective, barium and radium ions have been com-
pared. The thesis presents the theoretical study on nuclear spin dependent atomic
parity violation and nuclear anapole moment in different isotopes of these ions and
proposes specific transitions that are experimentally feasible. The analysis has been
specifically performed to observe the nuclear anapole moment which is still illusive.
The second part of the thesis studies the behaviour of non-ideal geometry of linear ion
trap in order to understand possible systematic and prepare an endeavour to measure
atomic parity violation with it. Experiments have been carried out to characterise
the field imperfections and their origins in a linear trap setup. The axial coupling into
the radial plane, a common problem in this trap geometry, has been systematically
studied by employing electric dipole excitation of the trapped ions. The thesis reports
a geometric loss factor in the radial plane of this setup which is consistent with
simulated result. The space charge effect on the parametric resonance has been
studied and the observation has been modelled. The signature of collective oscillation
and its behaviour with increasing space charge density are presented here. The line
shape of the parametric resonance has been conclusively studied with asymmetric
radial trap geometry and its importance in the field of mass spectrometry has been
analysed.


SYNTHESIS, KINETICS AND CHARACTERIZATION OF NOVEL UNSATURATED POLYESTERS AND POLYURETHANES

PAWAR, HEMANT S.

MICROBIAL GLUCOSE ISOMERASE

MAMMAN, A. S.

                                                                                                                                 Abstract                                                                                                                                                                                                                                                                                                       


                                                ABSTRACT
Electrophilic Iodination of Electron rich Aromatics and Alkynes their Application in the Synthesis of Heterocycles and C-C bond formation
The present thesis primarily deals with the utilization of iodine or iodides in substitution reactions or in catalytic organic transformations. 

Figure 1
Major part of the work deals with the electrophilic or oxidative iodination of electron rich organic moieties like phenols, anilines, indoles and alkynes their further application in the synthesis of heterocyclic compounds as well as in C-C bond formations. The other part of the work is on exploring the possibility of iodide mediated catalytic organic transformations under oxidative conditions. Schematic representation of the thesis is presented (Fig 1) above and which is further followed by a brief description of each chapter. 
Chapter I. Introduction  
	This chapter describes the general features of halogens and their reactivity towards organic compounds viz., fluorination, chlorination and bromination using different halogen based reagents. More emphasis is laid on iodination of various organic compounds and their application in the synthesis of heterocycles and in the formation of C-C bond via metal catalyzed reactions.
Chapter II. Mild and efficient Oxy-iodination of Alkynes and Phenols with Potassium iodide and tert-butyl hydroperoxide
Iodoalkynes are useful precursors in synthetic organic chemistry. These iodoalkynes have been utilized in the synthesis of asymmetric acetylenes, enynes and enediynes and also for construction of C-C bonds. These motifs play a significant role in pharmaceuticals and natural products. Similarly, iodophenols are used as building blocks for the synthesis of various organic compounds that have importance in medicine, bio-chemistry and pharmaceutics and they were also useful for C-C, C-N and C-O bond forming reactions.
Numerous methods have been appeared in the literature for the preparation of 1-iodoalkynes employing various metal catalysts, anodic oxidation, hypervalent iodonium salts, ionic liquids, bases, phase transfer catalysts (PTC), ultrasound, iodine oxide, Grignard reagent and n-BuLi. Similarly, several reports have been developed for the iodination of phenols using iodinating agents such as, N-iodosuccinimide (NIS), bis(pyridinium)iodonium(I)tetrafluoroborate (IPy2BF4), iodochloride (ICl) and potassium iodide (KI).
However, these procedures have disadvantages like, involving the complex synthetic processes, use of expensive reagents such as hypervalent iodine reagents, metal iodides and moreover generates considerable amount of waste materials. In order to overcome some of the disadvantages associated with the above synthetic procedures in preparation of iodoalkynes and iodophenols, we were interested in developing mild and efficient methods.
The present chapter deals with the development of new methodology for the synthesis of 1-iodoalkynes and iodophenols via oxy-iodination route. A simple treatment of terminal alkynes and phenols at room temperature in the presence of potassium iodide as iodinating source and tert-butyl hydroperoxide (TBHP) as an oxidant provided selectively 1-iodoalkynes and iodophenols respectively. Further these iodo compounds were used for synthesis of 5-iodo-triazoles and 2-substituted benzofurans (Scheme-1, 2).

Scheme 1



Scheme 2
Key feature of this chapter:
	This is one of the mild and efficient routes for the synthesis 1-iodo-alkynes, avoiding the use of external base, additives and air sensitive reagents.
	The present methods also do not require any expensive metal catalysts or hypervalent iodine reagents, which are generally used for iodination. 
	In this method 100% iodine atom-economy was achieved
	Application of iodo-alkynes and iodo-phenols were shown by synthesizing 5-iodo-1, 4-disubstituted-1, 2, 3-triazoles and 2-arylbenzofuran derivatives in high yields.
Chapter III. Synthesis of Iodo-Substituted Aromatic Nitro Compounds and Their Application in C-C Coupling Chemistry
Aromatic nitro compounds have greater importance in many industrial applications, such as in the preparation of explosives, dyes, perfumes, pharmaceutics and in plastic industries. Seebach quoted them as “ideal intermediates in organic synthesis” and introduction of halogen particularly iodine on the ring, which can facilitate the coupling chemistry will further expand the synthetic importance of these compounds. 
One can visualize three approaches for the synthesis of iodo-substituted aromatic nitro compounds (Scheme 3). One of the approaches is the direct iodination on the aromatic nitro compounds (A). However, it is known that the unlike chlorine and bromine, iodine is the least reactive halogen towards the electrophilic aromatic substitution and needs a more powerful iodinating species than iodine for direct aromatic iodination. Moreover, electrophilic iodination is even more difficult by the presence of electron withdrawing nitro group and needs harsh reaction conditions. Alternatively, direct nitration of aromatic iodo compounds (B) with classical methods which involves harsh reaction conditions results in a mixture of ortho- and para- compounds. Hence, an ideal and more practical approach could be an indirect two step method involving electrophilic iodination of anilines followed by selective oxidation of aromatic amines to nitro derivatives (C and D).
. 
Scheme 3
This chapter deals with the two step strategy for the synthesis of iodo-substituted aromatic nitro compounds. We have developed a mild procedure for the iodination of anilines with molecular iodine in 1N acetic acid to provide the iodo-substituted anilines in high yields. A novel method using catalytic amount of potassium iodide in combination of TBHP developed in our laboratory is efficiently utilized in selective oxidation of aromatic amines to corresponding nitro derivatives. These compounds are further successfully applied for C-C coupling chemistry. We have generalized the reactivities for Suzuki, Sonogashira and Heck reactions using different palladium catalysts (Scheme 4). 


Scheme 4
Key feature of this chapter:
	It avoids the use of expensive metal catalysts and hypervalent iodine reagents in iodination of anilines. 
	It avoids the use of strong acids as well as strong bases in iodinations as well as in oxidation of iodoaniline derivatives.
	An alternative route under milder conditions for the synthesis of iodo-nitro compounds is achieved by selective oxidation of anilines using KI-TBHP system.
	Iodo nitro compound which were prepared in high yields were further successfully utilized in various C-C coupling reactions.
Chapter IV. Mild and efficient synthesis of 2-Aryl-4H-3,1-Benzoxazin-4-ones via 2-substituted Indoles by using KI/TBHP system 
The indole ring system is probably the most ubiquitous heterocycle in nature. Owing to the great structural diversity of biologically active indoles, it is not surprising that the indole ring system has become an important structural component in many pharmaceutical agents. Substituted indoles have been referred to as “privileged structures” since they are capable of binding to many receptors with high affinity and several 2-substituted indole derivatives were useful in medicine and pharmaceutics.
Similarly, 4H-3,1-benzoxazin-4-one derivatives which were first synthesized in  1883. These compounds were used as precursors for the synthesis of biologically active compounds like antimicrobial and analgesics. Several synthetic routes are available in the literature for the synthesis of indoles and benzoxazinone.
In most of the cases, 2-substituted indoles were prepared by using o-alkynylaniline derivatives with transition metal catalysts like palladium and/or copper. This reaction follows two main steps (i) alkynylation of 2-bromo or iodoaniline derivative via Sonogashira coupling (ii) followed by cyclization with a base or catalyst. 
Regarding the synthesis of 4H-3, 1-benzoxazin-4-one derivatives several methods have been reported. Among one of N-anthranilic acid derivatives is the most preferred one. Other methods reported are, from isatoic anhydrides, from oxidation of 2-substituted indoles and indole derivatives and from other compounds.
In this chapter we have developed a new methodology for the synthesis of 4H-3, 1-benzoxazin-4-one derivatives via oxidation of 2-substituted indoles using KI-TBHP combination. Moreover, 2-substituted indoles were synthesized using 2-iodo-anilines which in turn synthesized from a mild iodination route developed as a part of the thesis work (Scheme 5, 6).

Scheme 5

                                                   Scheme 6
Key feature of this chapter:
	A new synthetic methodology is developed for the preparation of 2-aryl-benzoxazinone derivatives via oxidation of 2-aryl-indoles in the presence of KI-TBHP. The present procedure provides high yields of the desired products compare to previous reports. 
Chapter V. Oxy-iodination of Indoles by using KI/TBHP and its Application on C-C bond formation and Catalytic Oxidative Esterification of Aldehydes and Alcohols Using KI-TBHP
This chapter is divided into two sections.
Chapter V. Section A. Oxy-iodination of Indoles by using KI/TBHP and its Application on C-C bond formation
Iodo indoles are the best synthetic precursors for the synthesis of a wide range of 3-indole derivatives having biological and pharmaceutical importance. The general synthetic strategy involves the compounds of 3-iodoindoles using Heck, Suzuki, Sonogashira and other C-C coupling reactions. 
Few synthetic procedures for the preparation of 3-iodoindoles have been reported, by using molecular iodine or iodinating agents with base or acid. However, these procedures have disadvantages like, involving the moisture sensitive reagents, use of strong bases in stoichiometric or more than stoichiometric amounts, use of expensive reagents such as hypervalent iodine reagents and use of strong acidic media such as HCl, H2SO4 in 2-10 equivalents and moreover generates considerable amount of waste materials. 
This chapter deals with the development of mild and efficient method for the synthesis of 3-iodoindole derivatives (Scheme 7). We have shown that treatment of a variety of indoles with simple potassium iodide as iodinating source and tert-butyl hydroperoxide (TBHP) as an external oxidant at room temperature selectively provides 3-iodoindole derivatives respectively. These 3-iodo indoles are protected with Boc anhydride and further used in C-C coupling reactions.

Scheme 7
Key feature of this chapter:
	No need of any expensive metal catalyst or hypervalent iodine reagent, by using a simple KI is required as iodinating source.
	No need of strong basic media, in situ generated potassium hydroxide is enough.  
	Further iodinated compounds were utilized in the synthesis of C-C bond formation reactions like Sonogashira, Suzuki and Heck with palladium catalysts.
Chapter V. Section B. Catalytic Oxidative Esterification of Aldehydes and Alcohols Using KI/TBHP
Direct conversion of aldehydes to ester is one such reaction, which is often required in the synthesis of natural products. Traditional synthesis of esters generally involves the nucleophilic addition of an alcohol to activated carboxylic acid derivatives such as acid anhydrides or chlorides. Recently, several catalytic methods have been reported for the direct conversion of aldehydes to esters using different catalysts and reagents for example, MnO2-HCN, (Ipy2BF4), NIS, MTO-H2O2, Oxone, V2O5-SPB or SPC, Cu(ClO4)2–InBr3–TBHP, Pd-siloxane, and NaIO4-LiBr. Unfortunately, several of these methods have limitations in terms of cost, ready availability, safety and easy handling of the reagents and catalysts.
In this chapter a catalytic oxidative esterification of aldehydes and alcohols using KI-TBHP as an external oxidant is described (Scheme 8). The KI-TBHP catalyzed oxidative esterification occurred smoothly to provide the desired ester in good yields. The oxidative esterification reaction was amenable to both electron-rich and electron-poor aromatic aldehydes. Electron-withdrawing groups on the aromatic ring enhance the activity. More gratifying was the compatibility of the reaction to proceed successfully with hetero-aromatic and aliphatic aldehydes as substrates.

Scheme 8
Key feature of this chapter:
	It is a metal-free system.
	A catalytic amount of potassium iodide was required to promote the reaction, whereas an equivalent amount of iodine was used in earlier methods.
	It is a green process, where the by-products are water and t-BuOH. 
	This method does not require the use of any external base. 
Significant Achievements:
	The iodination of alkynes, phenols, anilines and indoles doesn’t require any external base, metal catalyst or hypervalent iodine reagent. By using KI-TBHP, we achieved the iodinated products in good to excellent yields.
	In oxidation reaction, catalytic amount of KI is required.
	Selectively para-iodo nitro compounds were prepared in good yields in two steps. 
	2-Aryl-benzoxazinones were prepared in good yields from 2-aryl-indoles.
	Iodinated products were further used in either synthesis of heterocycles or in C-C bond forming reactions.    




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DIFFUSION OF PURE LIQUID HYDROCARBONS IN HIGH SILICA PENTASIL ZEOLITES

SAHASRABUDHE, NIRMALA

Abstract

ISOLATION & CHARACTERIZATION OF BIOLOGICALLY ACTIVE COMPOUNDS FROM THE MEDICINAL PLANTS SALVINIA NATANS AND DECALEPIS HAMILTONII AND TOTAL SYNTHESIS OF CLEISTENOLIDE AND YASHABUSHIDIOL DERIVATIVES


CHAPTER – I
SECTION-A:  Describes the isolation and characterization of a an unusual novel anti-oxidant dibenzoyl glycoside from the plant Salvinia natans 
Salvinia natans, which belongs to the family of Salvinaceae, is a free floating, rootless aquatic fern. Despite the large number of fern-like plants, aqueous ferns of the Salvinia family have only ten species. They all grow in freshwater aquifers of tropical and subtropical countries, mainly in Africa and South America.

	The phytochemical investigation on Salvinia natans showed that it consists 96% of amino compounds. Though it is used in most of the systems of medicine including Homeopathy, no reports on medicinally important phytochemical compounds isolated from Salvinia natans. Several reports indicate that there is an inverse relationship between the incidence of human diseases and the dietary intake of antioxidant-rich foods. Hence, search for new synthetic and natural antioxidants is essentially important. For the present study, the plants were collected from the Chidambaram area of Tamilnadu, India.  
	In view of the isolation of an unusual novel anti-oxidant dibenzoyl glycoside found to have anti-oxidative properties from Salvinia natans and the previous literature on glycopyranosides along with a brief description have been discussed, whose structural studies are also explained in the section. 
 	The detailed chemical investigation of the plant Salvinia natans, (Salvinaceae) afforded three compounds SN-1 to SN-3 and a detailed extraction and isolation of these compounds from the plant material has been described in the experimental section. Out of all the isolated compounds, compound SN-3 was an unusual novel anti-oxidant dibenzoyl glycoside found to have anti-oxidative properties and the structure was confirmed by 1H, 13C and also from 2D-NMR spectroscopy.

Antioxidant activity of Natansnin:  Natansnin was screened for anti-oxidant activity using ascorbic acid as the standard. The IC50 value of natansnin is 25.28 µM, whereas for ascorbic acid, it is 25.89 µM. To the best of our knowledge very few free anomeric substituted sugars are available in nature, for example, ‘coyolosa’, a hypoglycaemic compound isolated from the methanol extract of the root of Acrocomia Mexicana. Coyolosa is comprised of two hexopyranose units joined through an ether link at their 6-positions. To the best of our knowledge, this is the first report of the existence α and β-3, 4-dibenzoyl D-glucopyranose which is separable in the NMR time scale.

Free radical scavenging activity on a DPPH radical of Natansnin:
Assay for the scavenging of the stable free radical, DPPH, was done as reported earlier. In brief, in a 96-well micro plate, 25 µL of the test sample dissolved in DMSO (1 mg/mL) and 125 µl of 0.5mM DPPH dissolved in absolute ethyl alcohol were added. The reaction mixture was shaken well and incubated in the dark for 30 min. The absorbance was read at 517nm spectrophotometrically (SPECTRAMAXPLUS384, Molecular Devices Corporation, Sunnyvale, CA, USA).

The free radical scavenging potential was expressed as the percent change in color of the DPPH solution due to the test sample, and calculated as (1-B/A) is the multiple of 100, where A represents absorbance of the DPPH solution without the test sample and B, the absorbance of the DPPH solution with the test sample. The SC50 values (50% free radical scavenging activity) of the test sample were calculated by regression analysis. Ascorbic acid was taken as the reference standard as a free radical scavenger. Measurements were performed in triplicate.












The following compounds were isolated from the plant Salvinia natans
SN-1 : Methylbenzoate
SN-2 : 3,4-dihydroxy methylbenzoate
SN-3 : Natansnin



                           

SN-1                                                               SN-2










SECTION-B:  Describes the isolation and characterization of new sources possess anti-inflammatory and anti-oxidant properties from the plant Decalepis hamiltonii
Decalepis hamiltonii (Asclepiadaceae) known as swallow in biotechnology root is a monogeneric climbing shrub and a native of the forests of Deccan Peninsula and Western Ghats of India. The extracts of these roots have also been shown to be potent antimicrobial agents as well further the roots of D. hamiltonii possess also antioxidant properties and hypothesized that antioxidants constituent present in the root extracts could contribute to the health-promoting potential.

In the present study, the plant  Decalepis hamiltonii yielded five new sources, out of which two new sources showing anti-inflammatory activities by down regulating TNF-α and IL-2 specific mRNA, besides up regulating the synthesis of mRNA of IL-10.

The following compounds were isolated from the plant Decalepis hamiltonii
DH-1 : Lupeol acetate
DH-2 : Sesamin
DH-3 : (S) - Naringenin
DH-4 : Milimorin
DH-5 : (S)-Naringenin 4'-O-β-glucopyranoside   
  

                                                                                                                                                      

                                            



                                                                       


Chapter II: Describes Total Synthesis of (-)-cleistenolide an α, β-unsaturated δ-lactone from the plant Cleistochlamys kirkii. (Annonaceae) starting from D-mannitol. 
Many natural products possessing α, β-unsaturated δ-lactone moiety which exhibit various biological activities such as antitumor, antibacterial, antifungal and immunosuppressive properties. A natural product (-)-cleistodienol 1 and (-)-cleistodienol 2 were isolated in 2007 by Nkunya et al., from the plant Cleistochlamys kirkii Oliver (Annonaceae), a plant species found in Tanzania and Mozambique.  






Extracts made from this plant are used in traditional medicine as a remedy for treatment of wound infections, rheumatism, and tuberculosis. Cleistenolide also reportedly exhibits in vitro antibacterial activity against Staphylococcus aureus and Bacillus anthracis, and antifungal activity against Candida albicans.

Owing to the importance of this cleistenolide regarding antimicrobial activity we planned a stereo selective synthesis of (-)-cleistenolide 1 starting from commercially available D-mannitol.

          Here, we described an efficient stereo-selective synthesis of α-pyrone 1, from (R)-2, 3-O-isopropylidine glyceraldehyde. Wittig reaction, ring closing metathesis (RCM) and one pot acetylation and benzoylation of compound 1 are the keysteps involved in our synthesis. The retro-synthetic analysis for (-)-5-acetoxy-6-(1-benzoyloxy-2-acetoxyethyl)-pyr-3-en-2-one 1 is represented as shown in (Scheme – 1).


      

 

	Initially, the D-mannitol 3 was reacted with 2,2-DMP in DMSO in presence of p-TSA to afforded the corresponding 1,2,5,6-diisopropylidene diol 4 as a white solid, which was further reacted with benzoyl chloride in the presence of Et3N in CH2Cl2 to afford 1,2,5,6- diisopropylidene-3, 4-dibenzoyl derivative 5  in 91% yield. Compound 5 was oxidized with H5IO6 in diethyl ether at room temperature to yield the corresponding primary diol (not isolated) in high yield in short reaction time which was reacted with NaHCO3 in same pot to afford aldehyde through oxidative cleavage of diol. The aldehyde was further converted into terminal alkene 6 using Wittig reaction with methyltriphenylphosphonium bromide salt in the presence of tert-BuOK. The dibenzoyl protecting groups in 6 were removed by reacting with K2CO3/MeOH to afford diol 7 in 91% yields. The sterically hindered allylic hydroxyl group in 7 was selectively protected as triethylsilyl ether by reacting 7 with TESCl and imidazole in CH2Cl2-DMF (1:1) at -780C to obtain the compound 8 as a colorless liquid in 90% yield. The mono triethylsilyl ether 8 was reacted with acryloyl chloride in presence of Et3N to give the corresponding acrylate ester 9 in 84% yields. 

Finally, the deprotection of the both acetonide and TES groups were done by DOWEX-50 (H+) resin in methanol  to afford the desired triol intermediate 10 in 94% yield. Compound 10 was reacted benzoyl chloride in pyridine followed by acetic anhydride in one pot to afford diene tetra ester intermediate 11 in 85% yield which was subjected to ring closing metathesis (RCM) by using Grubbs 2nd generation catalyst in dichloromethane to afford the natural product (-)-cleistenolide (1) in 85% yield as a colorless solid. The physical and spectroscopic data of the synthesized compound 1 was found to be identical with those of natural product (1) (Scheme – 2)

Scheme-2: Reagents and conditions: (a) 2,2-DMP, DMSO, p-TSA (cat), 6h, r.t, 79% (b) Et3N, BzCl, CH2Cl2, 500C, 6h, 91% (c) i) H5IO6, ether, rt, 6h, NaHCO3; ii) tBuOK, PPh3PCH2+Br-, THF, -100C, 4h, 71% (d) K2CO3, MeOH, rt, 3h, 91% (e) TESCl, imidazole, DMAP, CH2Cl2-DMF (1:1), -780C, 1h, 90% (f) Acryloyl chloride, Et3N, CH2Cl2, rt, 4h, 84% (g) i) DOWEX-50 (H+), MeOH, rt, 6h, 94% h) Benzoyl chloride, pyridine, followed by acetic anhydride, 00C to rt, 7h, 85% (i) Grubbs 2nd generation catalyst (5 mol%), CH2Cl2, reflux, 5h, 85%.


Chapter III: A Catalytic route to a concise stereoselective synthesis of cytotoxic Yashabushidiol derivatives, (3S,5S)-1-(4-Hydroxyphenyl)-7-phenyl-heptane-3,5-diol and its (3R,5S)-Isomer.
Diarylheptanoids constitute a distinct group of natural plant metabolites characterized by two aromatic rings linked by a linear seven-carbon aliphatic chain. Diarylheptanoids having 1,3-diol system are natural plant metabolites which exhibit good medicinal properties such as cytotoxic, antioxidative, hepatoprotective, anti-inflammatory and antiemitic activities. Among these compounds, 1a and 1b showed significant cytotoxic activity against cancer cell lines THP-1 (12.82 ± 0.89 g/ml for 1a, 12.62 ± 0.69 g/ml for 1b), U-937 (Leukemia) (31.09 ± 8.07g/ml for 1a, 32.99 ± 5.03g/ml for 1b) and A-375 (melanoma) (56.30 ± 3.88 g/ml for 1a, 57.78 ± 5.02 g/ml for 1b). This prompted us to establish a concise catalytic synthetic route for the synthesis of compounds 1a and 1b by employing the Maruoka asymmetric allylation and Jacobsen’s resolution to obtained the required chiral centers for construction of the syn & anti 1,3-diol systems in diarylheptanoids 1a, and 1b. By using this strategy other diarylheptanoid analogues(Fig.-1)  can also be prepared. 










Fig. - 1
Fig. - 1:  1a. (3S,5S)-1-(4-Hydroxyphenyl)-7-phenylheptane-3,5-diol 
               1b. (3R,5S)-1-(4-Hydroxyphenyl)-7-phenylheptane-3,5-diol  
               1c. (3S,5S)-1-(4-Hydroxy-3-methoxyphenyl)-7-phenylheptane-3,5-diol
               1d. (3R,5S)-1-(4-Hydroxy-3-methoxyphenyl)-7-phenylheptane-3,5- diol 
               1e. (3S,5S)-1,7-Diphenylheptane-3,5-diol 
               1f. (3R,5S)-1,7-Diphenylheptane-3,5-diol  

                
From the retro-synthetic analysis (Scheme-1), we envisaged that the target molecules can be obtained from the intermediate epoxide 5 via opening of kinetically resolved epoxide 6a with Grignard reagent, in turn intermediate epoxide 5 prepared from 3-phenylpropanal 2 via the Maruoka asymmetric allylation, tert-butyldiphenylsilyl (TPS) protection, and m-chloroperoxybenzoic acid epoxidation.


Scheme-1.  Retro-synthetic analysis

             
(R, R)-1                                                      (R,R)-Salen-Co(III)-OAc complex

Fig.-2

The readily commercially available 3-phenylpropanal 2 was subjected to Maruoka asymmetric allylation with titanium complex (R,R)-1 (Fig.-2) to furnish the homoallylic alcohol 3 in 83% yield with 97% ee. The secondary hydroxyl group in 3 was protected as its TPS ether using TPSCl and imidizole in dry DCM to yield compound 4, which was subjected to epoxidation using m-CPBA in DCM to afford diastereomeric mixture of epoxide 5. The epoxide of compound 5 was subjected to Jacobsen’s HKR using (R, R)-salen-Co- (OAc) catalyst (Fig.-2) to afford chiral epoxide 6a [α]D25 = +30.64 (c = 1.55, CHCl3); as a single isomer and (S,S)-diol 7 [α]D25 = + 39.7 (c =1.7, CHCl3);  which were separated by column chromatography.




Scheme-2: Reagents and Conditions: a) (R,R)-1(10 mol%), allyltrinbutyltin, CH2Cl2, -15 to 00C, 24h, 83% ; b) TBDPSCl, Imidizole, dry CH2Cl2, 4h, 87% ;c) MCPBA, CH2Cl2, r.t., 4h, 95% d) (R,R)-Salen-Co-(OAc) (0.5 mol %), distd H2O (0.55 equiv), 00C, 14 h, (46% for 6a, 42% for compound 7 e) p-Benzyloxybenzylmegnesiumbromide, THF, CuI, -200C, 1 h, 88% f) TiCl4, anhy CH2Cl2, 00C, 2 h, 73%.

Chiral epoxide 6a was reacted with 4-(benzyloxy)benzylmegnesiumbromide to afford compound 8a which on one-pot deprotection of tert-butyldiphenylsilyl and benzyl groups with TiCl4 in DCM to afforded (3S,5S)-1-(4-hydroxyphenyl)-7-phenylheptane-3,5-diol (1a) (Scheme-2). The physical and spectral data of synthetically prepared compound 1a (1H NMR and 13C NMR) were found to be in agreement with those of reported product {[α] D25 ​​-2.1 ​(c 0.25, CHCl3) lit.  [α]D25 -2.8 (c = 1, EtOH)}.

The Jacobsen’s resolved diol 7 was monotosylated using TsCl/Et3N to afford monotosyl compound 9 which was reacted with K2CO3 in methanol to afford (S)-epoxide 6b. The (S)-epoxide 6b was subjected to the same sequence of reactions followed in Scheme-2  to afford (3R,5S)-1-(4-hydroxyphenyl)-7-phenylheptane-3,5-diol (1b) (Scheme- 3).



Scheme-3: Reagents and conditions: a) TsCl, Bu2SnO, Et3N, 00C to rt, 4h, 89%              b) K2CO3, MeOH, rt, 1 h, 89% c)  1. Mg, 4-(benzyloxy)benzyl bromide, CuI, THF, r.t. 0.5 h, 2. 6a, 0 °C to r.t., 1 h, 85%; (d) TiCl4, anhyd CH2Cl2, 00C, 2 h, 87%.



The physical and spectral data of synthetically prepared compound 1b (1H NMR and 13C NMR) were found to be in agreement the reported product {[α] D25​​​ -1.1(c 0.5, Ethanol) lit. [α]D25 -1.9 (c = 1, EtOH)}. Utilizing the same strategy one can prepare other diarylheptanoid analogues. 






















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