Open Access Repository of Indian Theses

SARNAIK, ADITYA PANDHARINATH

 
5 
 
ABSTRACT 
Cyanobacteria are photosynthetic prokaryotes and important primary producers which 
can directly convert atmospheric CO2 into economically viable biochemicals using solar 
energy. Owing to their efficient photosynthesis ability than other photoautotrophs including 
plants, simple prokaryotic cell organization and natural competency to uptake extracellular 
DNA; cyanobacteria have been widely explored as cyanofactories for production of value-
added compounds and hydrocarbons. Engineering these cells for chemical synthesis has been 
potential green bioconversion approach, whereby more than 20 chemicals have been 
successfully produced by engineered cyanobacteria. In light of this perspective, we have 
exploited cyanobacteria Synechococcus elongatus PCC 7942 (fresh water strain) and 
Synechococcus sp. PCC 7002 (marine strain) for both; improving biomass productivities as 
well as hydrocarbon production under natural light conditions. Therefore, the work has been 
broadly categorized into two sections; cyanobacterial growth studies and cyanobacterial 
genetic engineering for hydrocarbon production. 
Preliminary light acclimation studies have been performed to comprehend the effect of 
natural light on cyanobacterial growth and photosynthetic pigment profiles. These studies 
showed that cyanobacteria could efficiently grow under natural diurnal light conditions. This 
improved growth rate is concurrent with reduced photo-toxicity by decreasing photosynthetic 
antenna density. This pigment modulation ability helps the cells in faster acclimatization to 
dynamic light alterations. Therefore, further investigations were performed under sunlight. To 
increase biomass productivity, we examined ability of various cyanobacteria to uptake 
extracellular organic C. PCC 7942 and PCC 7002 which cannot naturally uptake extracellular 
sugar, were engineered to display heterologous sugar transporters and perform mixotrophy. 
Integrative plasmid for PCC 7942 was commercially available, however we constructed an 
indigenous plasmid vector pUKD6 for genetic engineering of PCC 7002 cells and could 
successfully demonstrate mixotrophy in the strain. 
Efforts have been made to genetically engineer PCC 7942 cells for heterologous 
production of isoprene where we could produce 14 µg/L.h bioisoprene. Moreover, PCC 7942 
cells were also modified for improving the flux towards value-added xanthophyll zeaxanthin, 
where our engineered cells exhibited 2.5 times improved yield over wild type culture. 
Simultaneously, we engineered these cells for mixotrophy as already explained above. 
Conjoining these strategies was found to increase the yield of lutein-free zeaxanthin while 
improving cyanobacterial biomass productivity, thereby escalating the product titer thrice over 
wild type. In addition, we explored PCC 7942 chassis for production of novel 
 
6 
 
biopharmaceutical molecule heparosan through metabolic engineering. Our studies 
demonstrated for the first-time engineered cyanobacteria for the photoautotrophic production 
of this high-value polysaccharide.  
Collectively, our work provides insights to cyanobacterial growth and genetic 
engineering for production of hydrocarbons under natural light conditions. 
 
Keywords: Algae, Cyanobacteria, Hydrocarbons, Carotenoids, Genetic engineering, Value-
added biochemicals, Photochemistry 
 
Classification: Biotechnology, Molecular Biology, Algal Biotechnology, Cyanobacteria 
Genetic Engineering  
 
Abbreviations:  
Auto, Autotrophy  
EC/EL, Environmental chamber/ laboratory (State of the art glass house facility at DBT-ICT 
Centre for Energy Biosciences) 
IC, Incubator  
Tr, transformant 
WT, Wild Type 
 
 
 
 
 
 


English

Genetic and Growth Engineering of Cyanobacteria for Production of Hydrocarbons

G., HANUMANTHA RAO

                                                                                                   Abstract 
 
 Page i 
 
Abstract: 
The present thesis entitled ‘Design and Synthesis of Near-Infrared Functional Dyes 
for Optoelectronic Applications’ focuses on the design, synthesis and characterization of novel 
squaraine (SQ) dyes for solar cell applications. In solar cell devices, sensitizer plays an important 
role in determining photovoltaic performance of the device. The optical and electrochemical 
properties were investigated by using absorption, luminescence spectroscopy, cyclic 
voltammetry (CV) and differential pulse voltammetry (DPV). The thesis consists of five 
chapters. The first chapter deals with the introduction to Dye Sensitized Solar cells (DSSCs), 
while consequent chapters deal with the detailed work. 
Introduction: 
The inadequate quantity of our present energy supplies desires an inexhaustible source, i.e. solar 
energy, which is a clean and unlimited energy source. The main challenges associated with this 
energy is converting it into a form that solar energy can be utilized for various applications. In 
this regard, dye sensitized solar cells (DSSCs) cells, which directly convert solar energy into 
electricity, have been well established as a promising long-term solution for harvesting solar 
energy. In particular, DSSCs have attracted a lot of attention because of their lower production 
cost as well as their flexible and large panels with high photovoltaic performance.1 In DSSCs 
metal-free organic light absorbers have advantage as promising class of sensitizers because their 
molar absorptivities are often higher than those of the metal containing dyes and versatile 
molecular design. Even though metal containing dyes reached efficiencies >13%, they are 
limited due to their expense, toxicity in nature and low molar extinction coefficients.2 Recently, 
organic dyes have drawn immense interest owing to their high molar extinction coefficient, ease 
of purification, structural diversity and ease of fabrication.3 Among all organic sensitizers, near-
IR sensitizers exhibit a strong absorption in the visible and near-IR regions and include 
porphyrins,4 arylamines,5 indolines,6 coumarins,7 phthalocyanines8  and squaraines.9 
Squaraine dyes are an old class of organic dyes and are divided into symmetrical and 
unsymmetrical dyes. Symmetrical dyes can be prepared via a condensation reaction of squaric 
acid and electron rich compounds. While unsymmetrical squaraine dyes are prepared via a 
condensation reaction of an indolium salt and squaric acid followed by treatment with another 
indolium salt to obtain the squaraine dyes.10 In point of their synthesis, symmetrical dyes are 
                                                                                                   Abstract 
 
 Page ii 
 
easily synthesized when compared to unsymmetrical dyes. Squaraine dyes have drawn immense 
attention in the field of optoelectronics owing to their sensitizing abilities in the near-IR region 
of solar flux. Due to its Donor–Acceptor–Donor (D-A-D) type molecular structure, they have 
wide potential applications in organic solar cells, field-effect transistors, fluorescence probes, 
bio-sensing applications, photodynamic therapy and non-linear optics. To date, cis configured 
squaraine dyes are the most promising candidates for DSSC and result in high efficiency when 
compared to symmetrical and asymmetrical squaraine dyes. At present, different types of 
architectures of organic dyes have been developed, which can be divided into acceptor–donor 
(A–D) type, donor–acceptor–spacer–donor (D–A–π–D) type, acceptor–donor–acceptor (A–D–A) 
etc. Metal-free systems were strategically synthesized to increase the intramolecular charge 
transfer and extend the absorption from visible to NIR region, respectively. However, majority of 
these dyes were efficient sensitizers in the NIR region, but photocurrent response in the NIR 
region needed to be improved for better PCE. 
Statement of Problem: The power conversion efficiencies currently oscillating around 25% 
for crystalline Si based cells and of 28% for thin film cells. The silicon based solar cells are very 
high cost and their tedious production process has forced researcher across the globe to think and 
develop alternate technologies with easy and cheap production. In this context, excellent 
progress has been made on DSSCs, organic field effect transistors (OFETs), small molecule 
organic photovoltaic (OPV) and perovskite solar cells technologies. Further research and 
development is needed to improve the device efficiency and stability/lifetime in order to compete 
favorably with inorganic PV cells. Materials with both high and broad absorption are still 
lacking. In order to harness solar energy cheaply and efficiently, molecular design plays an 
important role for tuning of the molecular energy levels, red-shift of the charge-transfer 
absorption band, and distinct improvement of photovoltaic performance and stability. 
Methodology(s) used: The designed and synthesized molecules including squaraine 
sensitizers and small organic molecules were prepared by alkylations, condensation, 
bromination, Miyaura borylation, Suzuki, and Stille couplings. The prepared intermediates and 
final compounds were purified by column chromatography, systematically characterized by 1H, 
13C NMR, and Mass. Furthermore, the HOMO/LUMO frontier orbital energy levels are 
determined by cyclic voltammetry, differential pulse voltammetry (DPV) to know the essential 
                                                                                                   Abstract 
 
 Page iii 
 
information about the electronic properties and charge transfer processes. This method allows for 
the selection of the most promising candidates, which can be employed for the fabrication of 
efficient PV devices. 
Sample results with interpretation: The results are presented in five individual chapters, 
first chapter deals with the introduction to DSSCs, organic field effect transistors (OFETs) while 
2, 3, 4 and 5 chapter’s deals with detailed work. A brief, chapter-wise account of the results is 
presented below. 
In the first chapter of this thesis, we have discussed about the importance of solar energy and 
conversion of solar radiation into electricity using various generations of devices, like DSSCs 
and Thin Film Transistors. Literature survey on development of squaraine dyes as 
photosensitizers and thin film transistors materials are also discussed. 
Chapter 2 is divided in two parts, in chapter 2 A, two novel panchromatic asymmetrical 
squaraine sensitizers (SPSQ1 and SPSQ2 shown in figure 1) have been synthesized, 
characterized and effectively used for TiO2-based dye sensitized solar cells. In a solution, both 
dyes display a highly intense near-IR absorption (SPSQ1; 651 nm and SPSQ2; 692 nm), the red 
shifted absorption of SPSQ2 was attributed to the incorporation of the auxiliary acceptor 
dicyanovinyl unit on the squaraine moiety. Interestingly, the dicyanovinyl unit lowered the 
LUMO level of SPSQ2, which decreased the band gap and red shifted the absorption when 
compared to SPSQ1. These dyes possess suitable HOMO and LUMO levels to work as efficient 
sensitizers in DSSCs. Under standard global AM 1.5 G solar conditions, the DSSC based on 
SPSQ2 exhibited a high-power conversion efficiency of 3.1% with a high short circuit current 
density (JSC) attributed to the broadening of the IPCE spectra in the UV-vis and near-IR regions 
when compared to SPSQ1 (2.5%). 
 
 
 
 
Figure 1. Molecular structures of SPSQ1 and SPSQ2 dyes. 
                                                                                                   Abstract 
 
 Page iv 
 
 
In chapter 2 B, A combination of squaraine-based dyes (SPSQ1 and SPSQ2) and a 
ruthenium-based dye (N3) (Figure 2) were chosen as co-sensitizers to construct efficient dye-
sensitized solar cells. The co-sensitization of squaraine dyes with N3 enhanced their light-
harvesting properties as a result of the broad spectral coverage in the region 350–800 nm. The 
co-sensitized solar cells based on SPSQ2+N3 showed the highest short circuit current density of 
17.10 mA cm-2, an open circuit voltage of 0.66 V and a fill factor of 0.73, resulting in the highest 
power conversion efficiency of 8.2%, which is higher than that of the dye-sensitized solar cells 
based on the individual SPSQ1 and SPSQ2 dyes.  
 
 
 
 
Figure 2. Molecular structures of SPSQ1, SPSQ2 and N3 dyes. 
In chapter 3, we have designed, synthesized and characterized a novel metal free near infrared 
panchromatic asymmetrical squaraine sensitizers (SQ-SPS) (Figure 3) with thienothiophene as 
π-spacer, dicyanovinyl and cyanoacrylic acid unit as acceptor and successfully used for DSSC 
application. In contrast, Squaraine dyes generally display a strong narrow half-bandwidth spike 
like absorption peak in NIR region, beside this they also consist the weak absorption in the 
visible region, which help in matching the band gap and the energy levels for DSSC. Under AM 
1.5 G solar conditions, the isolated SQ-SPS shows the power conversion efficiency of 5.86 %, 
Voc 0.564 mV, Jsc 15.00 mA cm-2 after co-sensitization with N3 dye there is a tremendous 
increase in PCE to 8.84%, Voc 0.650 mV, Jsc 15.00 mA cm-2. The increase in efficiency is 
mainly due to entire spectral coverage of IPCE spectra after co-sensitization. 
 
 
                                                                                                   Abstract 
 
 Page v 
 
 
 
 
 
Figure 3. Molecular structure of SQ-SPS dye. 
In chapter 4, we report synthesis and characterizations of two novel small molecules namely 
SQ-BEN-THI and SQ-BEN-FUR (Figure 4) with D-A-D molecular structure consists of 
squaraine as central unit, benzothiophene and benzo furan as end groups for organic field effect 
transistor (OFET) devices. The photophysical, electrochemical and density functional theory 
(DFT) results were combined to elucidate the structural and electronic properties of two 
squaraine derivatives. Organic field-effect charge transport properties were carried out using 
bottom gate top contact devices, showed field-effect mobility of 4.0 × 10-5 and 5.4 × 10-5 
(cm2/VS) for SQ-BEN-THI and SQ-BEN-FUR, respectively. After thermal annealing at 130°C 
the field-effect mobility would slightly increase up to 7.4 × 10-5 (cm2/VS) for SQ-BEN-FUR and 
5.0 × 10-5 for SQ-BEN-THI. 
 
 
 
 
Figure 4. Molecular structures of SQ-BEN-FUR, SQ-BEN-THI dyes. 
 
In chapter 5, we have synthesized three new small molecules squaraine based functional π-
conjugated molecules considering core and wings concept. The molecule SQDICN, SQDIEt-RH, 
SQDICN-RH were ended caped with three different wings such as malononitrile, 2-(3-hexyl-4-
oxothiazolidin-2-ylidene) malononitrile and 3-Ethyl rhodamine. Among all the three dyes 
                                                                                                   Abstract 
 
 Page vi 
 
SQDICN-RH shows the high molar extinction coefficient other than two dyes. The 
photoluminescence of all the SQ dyes contrary to the absorption maximum trend. Further, we 
carried out solvatochromism to observe the effect of solvent with our dyes. The optical and the 
electrochemical results of all the SQ dyes are in good agreement with the theoretical studies. 
 
Figure 5. Molecular structures of SQ-DICN, SQ-DICN-Rh and SQ-DIEt-Rh dyes. 
 
A-π-D-A-D- π -A
SQ-DICN-Rh
SQ-DICN
SQ-DIEt-Rh
SQ-DICN-Rh
SQ-DICN
SQ-DIEt-Rh Extending π
-conjugation
Increases
solubility


Design and Synthesis of Near-Infrared Functional Dyes for Optoelectronic Applications

DEV, JITENDER

Synopsis 
 
i 
 
The thesis entitled “Studies on synthesis of novel quinoline derivatives and their 
biological activity” has been divided into four chapters. 
Chapter-I: Introduction 
In ancient days to cure diseases, our ancestors used nature as the best remedy and 
compounds which are isolated from natural sources were used. The present modern 
lifestyle lead to deadly diseases like cancer, HIV, T.B., etc. and prompt innovative 
research is necessary to deal with resistance and side effects associated with current 
therapies. Natural compounds like alkaloids as well as synthetic drug candidates which 
have nitrogen atom at unique position exhibit various biological properties and among 
them quinoline ring system shown diverse application in pharmaceuticals. Aim of this 
work is to synthesize a new variety of quinoline analogues and screen against various 
diseases in order to find promising molecules. Fluoro or trifluoromethyl substituted 
compounds are of great interest due to strong electron-withdrawing effect which adds to 
high pharmacokinetic properties. Aim of this work is to synthesize a new variety of 
quinoline with substituted fluoro or trifluoromethyl analogues and screen against various 
diseases in order to find promising molecules. In this research program, efforts have been 
initiated towards the investigation of more potent molecules based on structural features. 
Thus, synthesized a number of new analogues of quinolin-2(1H)-one and its fused 
heterocycles like pyrazolo[3,4-b]quinolinyl acetamide and pyrazolo[3,4-b]quinolin-1-yl 
derivatives and subjected to activity screening.  The research work is pursued in four 
chapters which include introduction and work of each chapter is briefly outlined below.  
Chapter-II 
Statement of the problem: 
Functionalized quinolin-2(1H)-one derivatives are attractive compounds for drug 
discovery as many of them found to show promising biological activities. Some of them 
are considered as receptor antagonists for angiotensin II, glycine NMDA, endothelin , 
antiplatelet and antitumor agents. Ciprofloxacin and Oflaxacin, a large group of quinoline 
derivatives and 1,2,3-triazoles/isoxazole derivatives are considered as one of the most 
important scaffolds  embedded in many biologically active compounds and attracted 
attention. These findings encouraged us and increasing interest in structural modification 
of the antitumor properties containing both quinolin-2(1H)-one and 1,2,3-
triazole/isoxazole pharmacophores in a compact system. 
Methodology: A series of novel N-triazole alkyl quinolin-2(1H)-one derivatives 6a-m 
and 9a-d were prepared starting from 2-amino aceto/benzophenone 1 via cyclization, 
propargylation to form compound 4 followed by reaction with different azides under 
Sharpless conditions obtained triazole alkyl tagged quinolin-2(1H)-one derivatives 6a-m 
and 9a-d. Compound 4 on reaction with aryl aldoximes through 1,3-dipolar cycloaddition 
resulted isoxazole alkyl quinolin-2(1H)-one derivatives 7a-r. 
Synopsis 
 
ii 
 
Synthesis and Anticancer Activity of Novel N-triazole/isoxazole Alkyl 
Functionalized Quinolin-2(1H)-one Derivatives 
 
 
Scheme 1: Synthetic pathways for compounds 4a-c, 5a-c and 8
 
Scheme 2: Synthetic pathways of compounds 6a-m, 7a-r and 9a-d 
Result: A series of novel N-triazole/isoxazole alkyl quinolin-2(1H)-one derivatives 6a-
m, 7a-r and 9a-d were synthesized and all these analogs were screened for anticancer 
activity against four human cancer cell lines.  Compounds 6d, 6k which showed 
promising activity at micro molar concentration have been identified. 
Synopsis 
 
iii 
 
Chapter III 
Statement of the problem: Bacterial and fungal infections became a threat and a major 
cause of deaths in immune compromised persons. Cancer is the second most leading and 
debilitating disease all over the world. Recently, substituted quinolines at 2 and 3 position 
exhibited excellent pharmacological properties such as antimicrobial, antifungal and 
antitumor activities. Similarly, some natural products like ellipticine and camptothecin 
type of core moieties with small alterations have resulted in promising quinoline fused 
pyrazole hybrids which showed good anxiolytic and neuroprotective activities. Pyrazolo 
fused quinoline analogs were used to kill microorganisms (as antimicrobial agents) and 
also inhibits uncontrolled cell division (as anticancer agents) both properties in a single 
molecule which drags us to develop a new series of analogs of these derivatives.  Based 
on the importance of fused heterocyclic compounds, we have focused our attention to 
synthesis of novel trifluoromethyl substituted pyrazolo[3,4-b]quinolinyl acetamide 
derivatives, screened for antimicrobial, antifungal and anticancer activity.  
Methodology: A series of novel pyrazolo[3,4-b]quinolinyl acetamide analogs 5a-r, 6a-h 
and 7a-f were prepared starting from quinolin-2(1H)-ones 1a-c on chlorination with 
POCl3 resulted in 2-chloroquinolines 2a-c followed by reaction with hydrazine hydrate 
resulted in 2,3-pyrazole fused quinoline derivatives 3a-c. Compounds 3a-c further 
reacted with 2-bromoethylacetate to form N-alkylated ester of 2,3-pyrazole fused 
quinoline derivatives 4a-c. Compounds of series 4 were reacted with primary aliphatic 
amines, cyclic amines and secondary amines to obtain amide derivatives 5a-r and 6a-h 
respectively. Similarly, compounds of the series 4 on reaction with primary aromatic 
amines did not result in the products of series 7. An alternate approach has been 
developed to obtain products 7a-f by reaction of 2,3-pyrazole-fused quinoline derivatives 
3 with chloroacetyl aniline derivatives under basic conditions as they are not easily 
accessible by reaction of 4 with aromatic primary amines due to their less nucleophilicity. 
 
 
 
 
 
 
 
 
Synopsis 
 
iv 
 
Synthesis of novel pyrazolo[3,4-b]quinolinyl acetamide analogs, their evaluation for 
antimicrobial and anticancer activities 
 
Scheme 1: Synthesis of 1o and 2o alkyl amide tagged pyrazolo quinoline derivatives 5a-r 
and 6a-h. 
 
Scheme 2: Synthesis of 1o aryl amide tagged pyrazolo quinoline analogs 7a-f. 
 
Result: A series of novel alkyl amide functionalized 2,3-pyrazole fused quinoline 
derivatives were prepared and screened for antibacterial activity and the promising 
compounds identified were further evaluated for antifungal and antibio-film activities. 
Compound 5r exhibited MIC values ranging between 3.9-7.8 µg/mL against different 
bacterial strains and was identified as a promising lead. Compound 5r also showed good 
antifungal and anti bio-film activities against various fungal and bacterial strains. 
Compound 5r when treated on mature S. aureus MLS16 biofilms showed increased 
levels of intracellular ROS accumulation which may be contributing to the bactericidal 
activity. Further, the cytotoxicity evaluation against four human cancer cell lines revealed 
that the compounds 5c, 5d, 5r and 7f exhibited promising cytotoxicity. Based on these 
assays, the lead compound 5r was identified. 
Synopsis 
 
v 
 
Chapter-IV 
Statement of the problem: Triazole and isoxazole tagged pyrazoloquinoline which 
contain five membered ring systems, enough nitrogen and oxygen atoms they can 
contribute substantially in increasing pharmacological activity by participating in 
hydrogen bonding interactions with the receptors. 1,2,3-Triazoles are useful building 
blocks in organic synthesis because of their wide range of biological activity, and are 
stable to moisture, oxygen, light and also metabolism in the body. Moreover, these 
moieties can be tuned to form powerful pharmacophores and also plays an important role 
in bio-conjugation. Introduction of pyrazolo[3,4-b]quinoline moiety to the triazole core 
will increase the hydrophilicity of the molecule, which promotes biological activity. 
Recent literature reveals that, a pyrazoloquinoline scaffold identified to display 
significant role as various pharmaceutical agents, especially antitumor agent, 
antimicrobial agent, PDE10A inhibitory activity, etc. Based on the above findings, 
encouraged us to predict the combination of both pharmacophores in a compact system 
and synthesized new series of hybrids novel 3,4 substituted 1-N-alkyl tagged 
triazole/isoxazle and pyrazolo[3,4-b]quinoline derivatives. 
Methodology: A series of novel pyrazolo[3,4-b]quinolinyl triazole and isoxazole analogs 
7a-m and 8a-i were prepared starting from quinolin-2(1H)-ones 3a-d on chlorination 
with POCl3 resulted in 2-chloroquinoline derivatives 4a-d followed by reaction with 
hydrazine hydrate resulted 2,3-pyrazole fused quinoline derivatives 5a-d. Compounds 
5a-d further reacted with propargyl bromide to form N-alkylated 2,3-pyrazole fused 
quinoline derivatives 6a-d. Compounds of series 6 were reacted with different azides 
under Sharpless conditions obtained 1,2,3-triazole alkyl tagged pyrazolo[3,4-b]quinoline 
derivatives 7a-m. Similarly, compounds of the series 6 on reaction with aryl aldoximes 
through 1,3-dipolar cyclo addition resulted products of series 8a-i.  
 
 
 
 
 
 
 
 
 
Synopsis 
 
vi 
 
Sec A:  Synthesis of novel N-triazole/ isoxazole alkyl functonalized pyrazolo 
quinoline derivatives 
 
Scheme 1: Synthetic pathways for N-alkylated pyrazoloquinoline derivatives 6a-d. 
 
Scheme 2. Synthetic pathways for formation of compounds 7a-m and 8a-i derivatives 
Results: A series of novel N-alkyl pyrazoloquinoline derivatives 6a-d and 1,2,3-
triazole/isoxazole functionalized pyrazoloquinoline derivatives 7a-m and 8a-i were 
prepared in series of steps. All the compounds were screened for anticancer activity 
against human cancer cell lines and potent compounds have been identified.  
Sec B: Synthesis of novel 4,4-disubstituted-5-alkyl/aryl substituted 1H-
[1,3]oxazino[4,5-b]quinolin-2(4H)-one derivatives 
Statement of the problem: HIV is uncurable disease till now as no clearcut drug was 
invented, however there are some drugs sold in combo to treat patients adequately. Some 
of them are listed here as Abacavir, Efavirenz, Emtricitabine, Tenofovir disoproxil, 
Synopsis 
 
vii 
 
Zidovudine, etc. Among them, Efavirenz is considered as promising molecule and some 
structural modification may lead to an interesting result for synthetic as well as 
medicinal. We took this challenge and synthesized few analogs which structurally mimic 
with Efavirenz skeleton. 
Methodology: A series of novel 4,4-disubstituted-5-alkyl/aryl substituted 1H-
[1,3]oxazino[4,5-b]quinolin-2(4H)-one derivatives 3a-c were prepared starting from 
substituted 2-chloroquinolinones 1a-c on nucleophilic addition with in-situ generated 
lithium cyclopropylacetylide resulted 2-chloroalcohol 2a-c followed by reaction with 
NaOCN resulted substituted 1H-[1,3]oxazino[4,5-b]quinolin-2(4H)-one derivatives 3a-c. 
 
Scheme 1. Synthesis of substituted 1H-[1,3]oxazino[4,5-b]quinolin-2(4H)-one 
derivatives (3a-c) 
Result: A series of novel 4,4-disubstituted-5-alkyl/aryl substituted 1H-[1,3]oxazino[4,5-
b]quinolin-2(4H)-one derivatives 3a-c were synthesized starting from 2-chloro quinoline 
derivatives 1. 


STUDIES ON SYNTHESIS OF NOVEL QUINOLINE DERIVATIVES AND THEIR BIOLOGICAL ACTIVITY

JARAUT, PRAVEEN

Abstract
Each generation of wireless communication systems is evolving to provide higher data rates
with more services and accommodate more users within a limited radio-frequency (RF)
spectrum. The wireless technologies, such as worldwide interoperability for microwave
(WiMAX), Long Term Evolution (LTE), and Long Term Evolution-advanced (LTE-A) are
being used to provide higher data rate wireless services. However, this places very challeng-
ing requirements for RF front-end specifications in terms of power efficiency and bandwidth
for both base stations and hand-held devices. As the RF spectrum nowadays is shared by
many users. Therefore, spectral efficient complex modulation schemes, such as orthogonal
frequency-division multiplexing (OFDM), have to be used. In order to access these various
schemes and services, the multi-band/multi-standard transceiver designs are used and get-
ting enhanced in order to reduce power consumption, physical size and cost. The RF power
amplifier (PA) is the main power consuming device in the multi-band and multi-input-multi-
output (MIMO) transceivers and generates unwanted nonlinear distortion while operating
close to the saturation region. The most optimum PA linearization technique is Digital Pre-
distortion (DPD). The complexity and numerical stability of the DPD model is still a huge
challenge.
The thesis investigates the issue of implementation complexity, numerical stability and
feasibility of DPD model adaptation for low cost FPGAs for single band, multi-band and
multi-channel transmission. Principal Component Analysis (PCA) based DPD technique
is investigated as a solution to the numerical stability problem arising in lower-bits fixed-
point digital signal processor/FPGA. It is reported with measurement results that PCA based
model provides better linearization performance than memory polynomial (MP), orthogonal
memory polynomial (OMP), and generalized memory polynomial (GMP) models in 16-bit
fixed-point DSP operation.
Further, to enhance numerical stability of the state-of-the-art models, Independent Com-
i
Abstract
ponent Analysis (ICA) as a novel algorithm level solution is proposed for different carrier ag-
gregated (intra-band contiguous, intra-band non-contiguous and inter-band noncontiguous)
LTE signals. ICA technique is proposed for 12-bit fixed-point digital signal processor/FPGA
implementation of DPD for intra-band and inter-band CA signals. The application of the
ICA technique upon MP model reduces model complexity and improves numerical stabil-
ity of the DPD model for CA LTE signals. The proposed MP-ICA requires lesser memory
requirement as compared to the state-of-the-art low complexity models such as MP model,
OMP model and PCA-based memory polynomial (MP-PCA) model for CA LTE signals.
A novel two-dimensional curtailed harmonic memory polynomial (2D-CHMP) model to
capture harmonic interferences, cross-modulation distortions (CMDs) and intermodulation
distortions (IMDs) in concurrent dual-band PA operating at harmonic frequencies is further
purposed to reduce the complexity of the state-of-the art models. The 2D-CHMP model is
constructed by simplifying the envelope terms of the state-of-the-art two-dimensional har-
monic memory polynomial (2D-HMP) model. The model complexity and memory require-
ment of 2D-CHMP are very less as compared to the 2D-HMP model. In addition, the novel
DPD models is proposed for linearization of a previously uninvestigated case of concurrent
tri-band PA at harmonic frequencies. This work analyzes the IMD terms which are pro-
ducing harmonic distortions and proposes three-dimensional harmonic memory polynomial
(3D-HMP) and harmonic Volterra spline (3D-HVS) models for mitigation of in-band inter-
ferences, CMDs, and IMDs.
As an integral solution to compensate for crosstalk, PA nonlinearity, I/Q imbalance and
dc offset imperfections simultaneously in MIMO transmitters, a neural network (NN)-based
DPD models has been investigated. The proposed NN DPD model provides a single-model
digital mitigation solution to multi-branches of MIMO transmitters, which is suitable for
higher order MIMO operation. A less complex, novel polynomial-based DPD model is also
proposed for linearizing higher dimension MIMO transmitters along with its characterization
procedure. The proposed model performs comparably to the state-of-art DPD model parallel
Hammerstein (PH) with lower number of coefficients and floating point operations (flops).
ii


DIGITAL PREDISTORTION LINEARIZATION FOR MULTI-BAND/MULTI- SOFTWARE DEFINED TRANSMITTERS

Baddi, Sravan

 
 
Ph.D. Thesis, Mr. Sravan Baddi, 2017 Page i 
 
Abstract 
 
Gel forming materials have extended much consideration over the last few decades because of 
their ability to form supramolecular architectures as well as their potential applications in various 
fields from biomedical research to advanced functional materials. Thrust is more on stimuli 
induced gelation and multi stimuli responsive gels for functional applications.  Most of the 
gelators were discovered through serendipity and their structural requirements are somewhat 
ambiguous. This is due, in part, to the fact that the supramolecular gelation phenomenon is not 
yet fully understood, though many structural classes have been found to be excellent 
organogelators. The aim of this thesis was to develop new thermoreversible organogelators 
(materials which can form gels in organic solvent upon stimulation), both low molecular weight 
compounds and polymers. The study also includes investigations on the gelation mechanism, 
structure-property relationship of the gels and their potential applications.  
To begin with, we have synthesized a novel class of aromatic bis(acyl-semicarbazides)  
carrying aromatic core and alkyl side chains of varying length. The compounds were exhibiting 
thermoreversible gelation at concentrations below 10 mg/mL in common organic solvents. The 
effect of the chain length variation of fatty acid units on gel properties like gelation 
concentration, gelation time and gel melting temperatures were studied. In addition, when the 
gelator-solvent mixture was subjected to sonication, they underwent gelation. A high degree of 
inter-molecular H-bonding existed in the gel state between the semicarbazide moieties as 
confirmed by IR and XRD (WAXS) studies.  Gelator with a specific spacer length was chosen to 
study the effect of stimuli (i.e. heat and ultrasound) on gel strength, mode of interaction and 
morphology. DSC, dynamic oscillatory studies, FT-IR and XRD revealed a difference in the 
modes of aggregation in the two cases. The gels could be tuned in the presence of anions at 
different concentrations – addition of 5 equivalents of F− and AcO−  induced gel-sol transition. 
In addition, these organogels adsorbed dyes such as crystal violet and rhodamine-B from water 
every effectively. 
As a next step, gelators carrying cycloaliphatic moiety in the core (instead of aromatic group) 
and hydrophobic side chains of varying length (C8-C18) were synthesized.   The gelation 
occurred in the organic solvents with both heat and ultrasound as stimulus. The gels exhibited 
thermoreversibility and could be tuned in the presence of anions at different concentrations. IR 
 
 
Ph.D. Thesis, Mr. Sravan Baddi, 2017 Page ii 
 
and WAXS studies were carried out to propose a suitable mode of aggregation and mechanism 
of gelation. Experimental and computational studies on these gels revealed that the balance 
between two non-covalent interactions, viz., hydrogen bonding between the amide groups in 
acyl-semicarbazide moieties and Van der Waals forces between long hydrocarbon tails, is found 
to be the determining factor for self-assembly and hence organogelation and both intermolecular 
and intramolecular hydrogen bonding stabilize the aggregate structures. Viscoelastic properties 
of the gels were investigated by rheological studies and dependence of gel strength on length of 
alkyl substitutes/ concentrations of gel were also explained. 
In the next phase, polymeric gelators were developed by incorporating LMWG aromatic and 
cycloaliphatic moieties in the polyurethane backbone. Segmented poly(urethane acyl-
semicarbazides) carrying aromatic groups in the hard segments were synthesized by  two step 
polymerization technique using polypropylene glycol (Mn~1000 and 2000), hexamethylene 
diisocyanate and terephthalic dihydrazide. The resulting polymers with specific ratios of 
NCO/OH were found to gel organic solvents like dimethylformamide, dimethylacetamide and N-
methylpyrrolidone at a concentration of 170 mg/mL and their corresponding gels were 
thermoreversible. Tuning of the gelation behaviour and gel properties have been achieved by 
varying the polyol molecular weight (Mn1000 and 2000) and NCO/OH ratio.  Films of xerogels 
reflected a network kind of structure due to physical crosslinks in the self-assembled state in 
SEM analysis and PPG1000 based polymers exhibited higher tensile strength but lower elongation 
than PPG2000 based systems. Viscoelastic nature of the supramolecular elastomeric gels was 
confirmed by dynamic oscillatory studies and stability of the gel was found to increase with 
increase in hard segment content. H-bonding between the urethane moieties and hydrophobic 
interactions between the PPG units in the soft segments lead to a phase separated structure. A 
phase separation induced gelation mechanism has been proposed and supported by SEM images 
and SAXS data.   Both the gelators and xerogels had capability of adsorbing crystal violet from 
their aqueous solutions and desorbing in organic solvents like acetone and methanol.  
To investigate polymers carrying cycloaliphatic moieties in the backbone, linear segmented 
poly(urethane acylsemicarbazides) of different compositions were synthesized from 
polypropylene glycol (Mn~1000 and 2000), hexamethylene diisocyanate and 
cyclohexanedicarboxylic acid-1,4-dihydrazide. The polymers exhibited thermoreversible 
gelation at a minimum gelation concentration of 25 mg/mL in DMSO in about 25 minutes. 
 
 
Ph.D. Thesis, Mr. Sravan Baddi, 2017 Page iii 
 
Among the compositions of varying NCO/OH ratios, PPG1000 based polyurethanes with 
NCO/OH ~ 2.5 and 3 and PPG2000 based systems with NCO/OH ~ 3.0 and 3.5 exhibited gelation. 
IR studies on the solutions and gels (in DMSO) revealed the extensive H-bonding between the 
chains in gel state. Scanning electron micrographs of the xerogel exhibited a 3D-network 
structure wherein higher hard segment content (P1000-1:3.5) led to a fibrous morphology and 
lower hard segment content (P2000-1:3) led to a microsphere like architecture. The phase 
separation induced gelation mechanism of self-assembly and effect of the stoichiometry on the 
morphology were explained based on the correlation between DSC, WAXS and FE-SEM data. 
The xerogels of the self-assembled polymers described in this work demonstrated a remarkable 
ability to remove dye molecules selectively, rapidly and efficiently. The xerogels retained their 
original structure and performance even after they are recycled several times. 
  


MULTI-STIMULI-RESPONSIVE LOW MOLECULAR WEIGHT BIS(ACYL-SEMICARBAZIDE) GELS AND THERMOREVERSIBLE POLY(URETHANE ACYL-SEMICARBAZIDE) GELS - FUNCTIONAL APPLICATIONS

Patel, Javed Sardar

Synopsis 
 
 
Synopsis 
 
Chapter-I: Total synthesis of (-) cephalosporolide E and (+) cephalosporolide F  
 
Introduction: Cephalosporolide E (1) and F (2) Figure 1, isolated from the fungus 
Cephalosporium aphidicola ACC 3490
1
 in 1985 and subsequently from Cordyceps militaris 
BCC 2816
2
 in 2004 belong to a small group of natural products possessing [5,5]-spiroketal 
moiety that is fused to the lactone ring. Their novel structure added to the fact that several 
members of the family possess anti-inflammatory activity and ability to treat Alzheimer’s 
disease has attracted the attention of synthetic chemists. 
 
 
 
 
Fig 1. Structures of (-) Cephalosporolide E and (+) Cephalosporolide F. 
Statement of problem: Even though the synthesis of cephalosporolide E and cephalosporolide F 
have been reported by a few groups, there still remains a need for a general, efficient and short 
approach to the its synthesis. Herein, is described the synthesis of cephalosporolides E and F by 
taking advantage of a vinylogous silylketene acetal addition to an α-chloro sulfide to introduce 
the butenolide ring eventually the C3 and C4 stereocenters and Noyori reduction of a propargylic 
ketone to create the stereocenter at C6. 
Results & discussion: The synthesis of the targets began with the protection of commercially 
available alcohol 8 to yield the silyl ether 10. Reaction of the lithium acetylide of 10 with 
phenylthio acetaldehyde 11, obtained by oxidation of phenylthio ethanol 9 with IBX, furnished 
an inseparable equimolar mixture of alcohols 12. Oxidation of 12 afforded ketone 13 which on 
reduction using (S,S)-Noyori catalyst
 
furnished alcohol 14 (dr 98:2). Protection of the carbinol 14 
as its TBS ether afforded compound 7.Treatment of sulfide 7 with N-chlorosuccinimide in 
Synopsis 
ii 
 
benzene afforded an epimeric mixture of α-chloro sulfides which without isolation was reacted 
with siloxyfuran 6 in the presence of zinc bromide to furnish a mixture of all possible 
diastereomers 15-18 in a 10:2:1:1 ratio respectively. Further deprotection using buffred TBAF 
led to concomitant epimerization followed by oxy-Michael reaction to afford compound 4 as the 
sole product as shown below in Scheme 1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Scheme 1. Synthesis of Bicyclic Lactone 4. 
Synopsis 
iii 
 
                The synthesis of the targets was accomplished in two steps. Thus, the sulfanyl group 
and triple bond in lactone 4 was reduced by treatment with Ra-Ni under a hydrogen atmosphere 
using buffered conditions to furnish alcohol 3. The key oxidative radical cyclization of alcohol 3 
using iodobenzene diacetate and iodine afforded a 1:1 mixture of cephalosporolide E and F, 
Scheme 2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Scheme 2: Completion of Total Synthesis of Target Compounds 1 and 2. 
Conclusion:  In conclusion, a short, highly flexible synthesis of cephalosporolides E and F is 
disclosed. The configuration at C9 and the length of the side chain (n-heptyl for cephalosporolide 
H) can be varied by an appropriate choice of propargylic alcohol (obtained by reduction of the 
corresponding propargylic ketone using the Noyori’s catalyst). The configuration at C6 that 
translates into C3 and C4 stereogenic centers can be varied by the appropriate choice of 
enantiomeric Noyori catalyst. The vinylogous Mukaiyama type reaction with the chloro sulfide, 
reported for the first time and oxidative cyclization are other key steps in the disclosed route. It is 
noteworthy that related members of the family will be readily accessible by modification of the 
disclosed strategy. 
Chapter-II: Experimental procedure for the total synthesis of (-) cephalosporolide E and 
(+) cephalosporolide F 
 
               This chapter deals with detailed experimental procedure for the synthesis of each 
compound and its characterisation data. 
Synopsis 
iv 
 
Chapter-III: Studies towards the synthesis of phoslactomycin-B 
 
Introduction: Phoslactomycins A-F were isolated in 1989 from the culture broth of a soil 
bacteria species Steptomyces nigrescens. Phoslatomycin B, 20 (Figure-2) was also isolated from 
fermentation broth of a strain of Streptomyces hygroscopicus. Phoslatomycin B exhibits potent 
activity against L1210, P388 and EL4 murine cancer cell lines. Its antitumor activity is a 
consequence of it being a highly potent and selective inhibitor of protein serine/threonine 
phosphatase 2A (PP2A), an enzyme involved in the regulation of many crucial biological events. 
 
 
 
 
 
 
Figure-2. Phoslatomycins, phosphazomycins, leustroduscin and fostriecin. 
Statement of problem: Phoslactomycin B 20 has attracted a great deal of attention in the 
chemical and biological communities due to its intriguing molecular architecture and its potential 
as a lead compound for anticancer drugs as well as its importance as a biological tool. The 
structural features include an -unsaturated -lactone, a disubstituted alkene of (E)-
configuration (C6-C7), a tertiary alcohol at C8 substituted by a 2-aminoethyl chain, a phosphate 
at C9, a secondary alcohol at C11, a conjugated (Z,Z)-diene (C12-C15) and a cyclohexane ring. 
 
Results & discussion: The synthesis of sulphide 25 constituting the C1-C6 fragment 
commenced with the Crimmins aldol reaction of thiozolidinethione 21 with 2-phenyl 
Synopsis 
v 
 
thioacetaldehyde 11 to give aldol 22. Protection of the hydroxyl group as its TBS ether using 
TBS-triflate afforded compound 23. DIBAL-H reduction resulted in the formation of aldehyde 
24 with the recovery of the chiral auxiliary. Treatment of aldehyde 24 with the anion generated 
from Ando’s reagent gave the cis ester 25 selectively as shown in the Scheme 3. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Scheme 3. Synthesis of Sulphide 25. 
 
               The aldehyde 30 constituting the C9-C12 subunit was synthesized from commercially 
available chloro keto ester 26 as depicted in Scheme 4. The chlorine in compound 26 was 
displaced by p-methoxybenzyl alkoxide to afford the -keto ester compound 27. The keto group 
of 27 was selectively reduced using Ru-Binap catalysed hydrogenation at 80 
o
C and 50 psi 
hydrogen pressure in pressure reactor to afford -hydroxyester 28 with excellent selectivity. The 
free hydroxy group was protected as its methoxy methyl ether 29 under standard conditions. 
Finally ester group was subjected to controlled reduction with DIBAL-H to afford aldehyde 30, 
Scheme 4. 
 
 
 
 
Synopsis 
vi 
 
 
 
 
 
 
 
 
 
 
 
 
 
Scheme 4. Synthesis of Aldehyde 30. 
               The C8 tetrasubstituted stereocenter was envisioned to be introduced by a 
regioselective enyne coupling following Trost’s protocol followed by Mislow-Evans 
rearrangement of an allylic sulfoxide. The requisite alkyne was imagined to be obtained by 
coupling the chloro sulfide 25 with an alkyne derived from aldehyde 30. However, it was 
thought that to test the feasibility of the proposal on a simpler substrate which was prepared as 
depicted in Scheme 5. The synthesis of the model fragment started from the resolution of 
epichlorohydin 31 using (R,R) Jacobsen’s catalyst to afford enantiomerically pure diol 32.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Scheme 5. Synthesis of Terminal Alkyne 38.  
 
Synopsis 
vii 
 
               Selective monoprotection of the primary hydroxyl group using TBDPSCL furnished 
siliyl ether 33 in excellent yield. Nucleophilic substitution of chlorine by using thiophenol and 
DBU yielded hydroxy sulphide 34. The free secondary hydroxyl was protected as its TBS ether 
under standard conditions to give sulphide 35. Reaction of sulfide 35 with N-chlorosuccinimide 
afforded the chlorosulfide 36 which on reaction with zinc acetylide prepared from TMS-
acetylene furnished propargylic sulfide 37 with excellent selectivity. Base catalyzed deprotection 
of the TMS group yielded terminal alkyne 38 Scheme 5. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Scheme 6. Synthesis of Tertiary Alcohol 45. 
Synopsis 
viii 
 
               The lithium acetylide generated from alkyne 38 using n-BuLi was reacted with 
aldehyde 30 to afford an epimeric mixture of propargylic alcohol 39 which was subsequently 
oxidized using DMP to furnish the corresponding ketone 40. Stereoselective reduction using 
Noyori’s asymmetric transfer hydrogenation conditions delivered alcohol 41. Alcohol 41 was 
subjected to enyne coupling with homoallyl alcohol using Trost’s catalyst to afford readily 
separable regioisomers 42 and 43 in (2:1 ratio) a combined yield of 30%. The predominant 
isomer 42 was assumed to be the desired regioisomer and taken ahead to the next step. Thus 
oxidation of sulfide to sulfoxide 44 followed by Mislow-Evans rearrangement yielded diol 45, 
Scheme 6. The selective functionalization of the disubstituted alkene in substrate 42 or 45 would 
provide a suitable handle for the introduction of the amino ethyl side chain, Scheme 6. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Scheme 7. Synthesis of Lactone 52. 
Synopsis 
ix 
 
                Though the regioselectivity of enyne coupling had to be addressed, attempts were 
made on a more complex substrate. Thus the chlorosulfide intermediate obtained from sulfide 25 
was treated with the zinc acetylide prepared from TMS-acetylene furnished propargylic sulfide 
46. C-TMS group of 46 was selectively deprotected in presence of TBS group using TBAF-
AcOH to afford the terminal alkyne 47. Lithium acetylide generated from alkyne 47 was reacted 
with aldehyde 30 to give an epimeric mixture of propargylic alcohol 48 which on oxidation using 
Dess-Martin periodinate provided propargylic ketone 49.Stereoselective reduction following 
Noyori’s protocol afforded alcohol 50 in good yield. The secondary TBS ether was deprotected 
under standard TBAF conditions to give diol 51 which on treatment with titanium 
tetraisopropoxide in benzene delivered the -unsaturated lactone 52, Scheme 7. 
                After having experience of enyne coupling on simpler substrate, enyne coupling was 
attempted on propargylic alcohol 52 was not forwarded after many trials in different solvents, 
Scheme 8.  
 
 
 
 
 
 
Scheme 8. Attempt of Enyne Coupling. 
                 Thus the enyne coupling failed on substrate 52. With compound 52 in hand, it was 
decided to check the feasibility of the Stille coupling for the introduction of the (Z,Z) moiety. 
Thus the free secondary hydroxyl group of 52 was protected as its TBS ether under standard 
conditions to afford the TBS ether 53. The lactone 53 was reduced to an epimeric mixture of 
lactols using DIBAL-H and further reacted with i-prOH and PPTS to yield hemiacetal 54. The 
Synopsis 
x 
 
PMB ether in 54 was deprotected using DDQ to furnish the primary alcohol 55 in excellent 
yield. Dess-Martin periodinate promoted oxidation of 55 alcohol to aldehyde and further wittig 
reaction afforded vinyl iodide 56. With vinyl iodide 56 in hand the Stille coupling with vinyl tin 
57 was attempted. Unfortunately, the reaction failed after several trials using different catalysts 
in many solvents and reaction conditions. Due to the curiosity about enyne coupling reaction we 
had attemped  Trost’s protocol on hemiacetal internal alkyne 54 with 3-butenol but the reaction 
was unsuccessful under various conditions, Scheme 9. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Scheme 9. Synthesis of Vinyl Iodide and Attempted Stille Coupling. 
 
                 Having been unsuccessful in the Stille coupling in the previous attempt, it was decided 
to introduce the conjugated Z,Z-diene even at an earlier stage in the synthesis. The synthesis 
commenced from compound 60 which was obtained from ethynylcyclohexane 59 following 
procedures reported in the literature. The lithium anion of 60 was quenched with ethyl 
choroformate at low temperature to afford compound 61. To the lithium enolate of ethyl acetate, 
Synopsis 
xi 
 
compound 61 was added to afford -keto ester 62. Enatioselective reduction of the keto carbonyl 
in 62 using (R,R)-Noyori catalyst yielded -hydoxy ester 63. The conjugated alkyne of 63 was 
chemoselectively reduced by applying Hansen’s modification to the Boland protocol for Z 
stereoselective semi reduction of alkynes to afford diene 64. The free hydroxyl group in 64 was 
protected as its TBS ether under standard conditions to furnish compound 65. Contolled 
reduction of ester to aldehyde 66 was carried out using DIBAL-H at low temperature, Scheme 
10.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Scheme 10. Synthesis of Aldehyde 66. 
 
                  The propargylic sulfide 46 was subjected to treatment with TBAF which resulted in 
the deptotection of TBS and TMS in one step to afford terminal alkyne 67, Compound 67 
underwent intramolecular lactonisation in the presence of titanium tetraisopropoxide to afford 
lactone 68. The lactone 68 was reduced to the corresponding lactol using DIBAL-H and 
subsequently converted to hemiacetal 69. The lithium anion of terminal alkyne 69 was reacted 
Synopsis 
xii 
 
with aldehyde 66 to furnish compound 70. Dess-Martin periodinane oxidation of alcohol 70 
afforded propargylic ketone 71, which on Noyori’s asymmetric transfer hydrogenation afforded 
alcohol 72 as shown in Scheme 11.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Scheme 11. Synthesis of Propargylic Alcohol 72.  
                 Propargylic alcohol 72 on treatment with triethylsilyl chloride and imidazole in 
anhydrous DCM afforded TES ether 73 Scheme 11. The sulfide in compound 73 was oxidized to 
sulfoxide 74 using mCPBA in chloroform. The sulfoxide 74 was subjected to Milsolw-Evans 
rearrangement in the same pot to afford -unsaturated ketone 75. The amino ethy side chain 
was introduced by the reaction of anion of acetonitrile with ketone 75 to furnish a mixture of 
Synopsis 
xiii 
 
tertiary alcohols 76 & 77 in a 4:1 ratio which can be easily separated by column 
chromatography, Scheme 12. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Scheme 12. Synthesis of Tertiary Alcohol 76. 
 
 
 
 
 
 
Synopsis 
xiv 
 
 
 
 
 
 
Scheme 13: Confirmation of Stereochemistry of Tertiary Alcohol. 
                 Moving ahead towards target our next attention was to confirm the stereochemistry at 
newly generated tertiary alcohol for that reason TES group of major compound 76 was 
selectively deprotected by using PPTS in iso-propanol to afford diol in good yield which was 
subsequently protected as its acetonide under 2,2-DMP condition to furnish  protected diol 78. 
As expected in compound 78 NOE was observed between –CH2CN and methine proton at C9 
thus confirmed stereochemistry at tertiary alcohol center as required in the target compound 
phoslactomycin B Scheme 13. 
 
 
 
 
 
 
Scheme 14. Towards Synthesis of Phoslactomycin-B. 
                   In the next step compound 76 was subjected to LAH reduction in which cyanide 
group was reduced to primary amine and also nearby TES group was deprotected in same pot. 
Obtained amino diol was used without further purification and amino group was protected as a 
allyloxy carbonyl to give protected amino diol 79. Scheme 14. 
Synopsis 
xv 
 
Conclusion:   The hydroxyl ester was prepared by Noyori’s asymmetric hydrogenation of -keto 
ester, other key reactions include C-C bond formation using -chloro sulfide, asymmetric 
transfer hydrogenation, witting olefination to prepare iodo alkene, Ando’s cis olefination, Evans-
Mislow rearrangement and Hansen’s modification of Boland protocol for Z selective semi 
reduction of alkynes. 
Chapter-IV: Experimental procedure for the studies towards the synthesis of 
phoslactomycin-B. 
               This chapter deals with detailed experimental procedure for the synthesis of each 
compound and its characterisation data. 
 
 
 
 
 
 
 


Total synthesis of Cephalosporolide (-) E, (+) F and Studies towards synthesis of Phoslactomycin-B utilising

alpha-Chloro sulfide as key intermediate

NEKKALA, NAGARAJU

Chapter 5 Summary & Conclusions 
Summary and Conclusions 
This thesis describes the preparation, characterization and catalytic evaluation of cerium, 
lanthanum and magnesium phosphates for the vapor phase catalytic dehydration of lactic 
acid to produce acrylic acid. 
Several catalysts containing tungsten oxide supported on Y-zeolites with different 
SiO2/Al2O3 ratio, mordenite and different metal oxides supported on Y-zeolite (CBV-
760) have also been synthesized for the vapor phase catalytic esterification of lactic acid 
with butanol to produce butyl lactate. 
> Chapter 1, gives the general introduction about the solid acid catalysts (metal 
phosphates and zeolite supported tungsten oxide catalysts) and an up-to-date literature 
survey on the applications and characterization of metal phosphates and zeolite 
supported metal oxide catalysts for various techniques have been provided. Importance 
of renewable source as an alternative to fossil fuels, biomass utilization, lactic acid and 
acrylic acid production and valorization of lactic acid to value added chemicals also 
briefly discussed. Finally, the aim of the thesis is given to check the catalytic 
performance of dehydration of lactic acid to acrylic acid and esterification of lactic 
acid to butyl lactate in the vapor phase conditioned fixed bed reactor over solid acid 
catalysts. 
> In chapter 2, a brief description of experimental techniques is given viz., the 
preparation of various metal phosphates and zeolite supported metal oxide catalysts 
and their characterization techniques like X-ray diffraction analysis (XRD), Fourier 
206 
Chapter 5 Summary & Conclusions 
transform infrared spectroscopy (FT-IR), Temperature programmed desorption (TPD) 
of ammonia, BET surface area, pore size distribution measurements, scanning electron 
microscope (SEM), EDAX, and Thermo gravimetric analysis (TGA). This section 
also consists of the flow diagram of catalytic experiments for the valorization of lactic 
acid to value added chemicals. 
> Section A of chapter 3, describes a series of cerium phosphate (CeP) catalysts 
synthesized by using a precipitation method with varying Ce/P mole ratio ranging 
from 0.5-3.0. The formation of cerium phosphate was confirmed by XRD and FT-IR 
techniques. The catalysts were further characterized to understand the morphology and 
surface area by using transmission electron microscopy (TEM) and N2-sorption 
measurements. The acidic and basic sites were measured by CO2-TPD, NH3-TPD and 
ex-situ pyridine FT-IR methods. The CeP catalysts were employed for the dehydration 
of lactic acid (LA) to acrylic acid (AA) under vapour phase reaction conditions. 
Among the catalysts examined, CeP catalyst with Ce/P mole ratio 2.5 (CeP(2.5)) was 
found to exhibit better catalytic performance with conversion of lactic acid ~100 % 
and 64 % selectivity towards acrylic acid at optimized reaction conditions. The 
catalytic performance depends strongly on the ratio of acidic/basic sites on the catalyst 
surface. AA selectivity was found to be highest at acid-base balance factor = 0.56. 
Time on stream experiments suggest that CeP(2.5) catalyst exhibited constant activity 
until 20 h after which a slight drop in conversion of lactic acid was noticed. The 
characterization studies of the spent catalysts using thermo gravimetric (TG), CHNS 
207 
Chapter 5 Summary & Conclusions 
and FT-IR analyses suggests the presence of carbonaceous species over the catalyst 
surface causing deactivation of the catalyst. 
> Section B of chapter 3, describes the synthesis and catalytic activity of a series of 
lanthanum phosphate (LaP) catalysts of varying La/P mole ratio (2.0, 1.0, 0.5, 0.35 & 
0.2) with different calcination temperatures (400, 500, 600 & 800 oC) for the 
dehydration of lactic acid (LA) to acrylic acid (AA). Al l the synthesized catalysts have 
been characterized to understand the physico-chemical properties like crystallinity, 
surface acidity, specific surface area and morphology. The NH3-TPD results suggest 
that all the catalysts consists weak acidic sites and the amount of acidity have been 
varied with the amount of phosphate loading. After the modification of lanthanum 
phosphate catalysts with suitable surface acidity (La/P mole ratio) can efficiently 
dehydrate the LA to produce AA. Not only has the metal-phosphorous mole ratio, 
calcination temperature also played a major role in AA selectivity and LA conversion. 
The catalytic performance is shown to correlate with the amount of total acidic sites 
present on the catalyst surface. Under the optimized reaction conditions (360 °C, 30 wt 
% LA flow rate = 1.5 mL/h, WHSV = 3.156 h -1), the LaP catalyst with La/P mole ratio 
= 0.35, calcined at 500 °C (LaP(0.35)[500]) was showed the better catalytic 
performance (~74 % AA yield) compared to other LaP catalysts prepared. 
Furthermore, the LaP(0.35)[500] catalyst was efficiently tested for three cycles with 
different time on steams and noticed a marginal drop in conversion up to 80 %. The 
deactivation studies revealed that the drop in conversion was caused by the deposition 
208 
Chapter 5 Summary & Conclusions 
of carbon/carbonaceous species on the catalyst surface but switch to the in situ air flow 
at 450 °C could regenerate the LaP catalysts for the LTA reaction. 
> Section C of chapter 3, describes a series of MgHP catalysts with different magnesium 
to phosphorous (Mg/P) mole ratio (2.0, 1.5, 1.0, 0.5, 0.35 & 0.2) at different 
calcination temperatures (400, 500, 600 & 800 oC) have been synthesized by using 
simple co-precipitation method. The physico-chemical properties of MgHP catalysts 
have been characterized by using various spectroscopic and adsorption techniques 
such as XRD, FT-IR, SEM-EDX, NH3-TPD, N2-physisorption, etc. Magnesium 
hydrogen phosphates (MgHP) have been set up to be highly effective and stable 
catalysts for acrylic acid production from lactic acid. The Mg/P mole ratio and 
calcination temperature were played a major key role in producing the high yield of 
AA. The Mg/P mole ratio affects the total amount of acidity which is a main 
determining factor for LTA reaction. The increase in calcination temperature affects 
the structure of magnesium hydrogen phosphate to form magnesium pyrophosphates 
which are inefficient to the LTA reaction. Under the optimized reaction conditions 
(360 °C, 20 wt % LA feed flow rate = 1.5 mL/h), the MgHP catalyst with Mg/P mole 
ratio = 0.5, calcined at 500 °C (MgHP(0.35)[500]) was showed the better catalytic 
performance (~82 % A A yield) compared to other MgHP catalysts prepared. The 
catalyst was tested for three cycles of 24 h each and observed that consistent acrylic 
acid selectivity with only a little drop in lactic acid conversion. Though magnesium 
hydrogen phosphate catalysts were also suffered with little deactivation but 
209 
Chapter 5 Summary & Conclusions 
comparable to the other catalysts studied in this reaction these catalysts are very less 
efficiently adsorbed the carbon/carbonaceous particles onto their surface. 
> Section A of chapter 4, describes the vapour phase esterification of lactic acid with 
butanol carried out over tungsten oxide supported on Y-zeolite catalysts. The degree of 
esterification depends on the type of zeolite with different SiO2/Al2O3 ratio, the 
amount of WO 3 deposited and the total amount acidity produced by the catalyst. There 
are two series of WO3 supported zeolite catalysts have been prepared. One is 10 wt % 
WO3 supported on Y-zeolites and mordenite namely 10W-400, 10W-720, 10W-760 
and 10W-20A having different SiO2/A^O3 ratio = 5.1, 30, 60 and 20 respectively. The 
second series is having various loadings of WO3 (5, 10, 15 and 20 wt %) supported on 
to CBV-760 (SiO2/Al2O3 ratio = 60) namely 5W-760, 10W-760, 15W-760 and 20W-
760. High dispersion of WO3 species on Y-zeolite was achieved, but at higher loading 
micro crystallites of WO3 was detected. Tungsten oxide species were deposited 
preferentially inside the zeolite structure and interacted with the Bronsted sites as well 
as on silanol surface groups with the formation of small aggregates. As seen by the 
differences in conversion over different zeolites, CBV-760 (with SiO2/Al2O3 ratio = 
60) and 10 wt % WO3 supported on it was favored the highest lactic acid conversion 
and butyl lactate selectivity. Under the optimized reaction conditions (175 °C, 1:3 LA-
BtOH feed flow rate = 1.0 mL/h), the 10W-760 catalyst produced an overall yield of 
67 % (80 % conversion and 84 % selectivity) towards butyl lactate. The better 
performance of the 10W-760 sample was attributed to a better distribution of strength 
of the acidic sites towards the selective esterification of lactic acid with butanol. 
210 
Chapter 5 Summary & Conclusions 
> Section B of chapter 4, describes the vapour phase esterification of lactic acid with 
butanol carried out over different metal oxides supported on Y-zeolite (CBV-760). A 
series of metal oxide supported zeolite catalysts (10 wt % of WO3 , MoO3 , Nb2O5 , 
V2O5 and SnO2 supported on CBV-760) have been synthesized and employed for the 
esterification of lactic acid (LA) with butanol to produce butyl lactate. Al l the 
synthesized catalysts have been characterized to understand the physico-chemical 
properties like crystallinity, surface acidity, specific surface area and morphology. The 
NH3-TPD results suggest that impregnation of the metal oxides on the Y-zeolite 
(CBV-760) catalysts enhances the total amount of surface acidic sites relative to that 
of pure Y-zeolite (CBV-760). The degree of esterification depends on the type of 
metal oxide deposited and the total amount acidity produced by the catalyst. Among 
the 10 wt % of WO3, MoO3, Nb2O5, V2O5 and SnO2 supported on CBV-760 catalysts 
10Sn-760 is favoring the highest lactic acid conversion with butyl lactate yield. Under 
the optimized reaction conditions (175 °C, 1:3 LA-BtOH feed flow rate = 1.0 mL/h) 
10Sn-760 catalyst calcined at 550 °C exhibited a maximum yield of butyl lactate ~85 
% (LA conversion ~95 % and butyl lactate selectivity ~90 % ) . 
> Finally, chapter 5 summarizes the summary and the conclusions drawn from this thesis 
work. 
211 
Chapter 5 Summary & Conclusions 
The most important conclusions that can be drawn from the present thesis are: 
1. The CeP, LaP and MgHP catalysts have been prepared by the co-precipation method 
using the metal nitrate precursor and ortho phosphoric acid using aqueous ammonia 
as the precipitating agent. 
2. The CeP, LaP and MgHP catalysts have been prepared by varying the metal to 
phosphorous mole ratios (M/P) to get different structural acid properties and with 
different calcination temperatures to vary the structure of the metal phosphate. 
3. These catalysts were employed for the vapour phase dehydration of lactic acid to 
produce acrylic acid. 
4. The physico-chemical characteristic properties of these metal phosphate catalysts 
have been determined by various spectroscopic and adsorption techniques. 
5. The formation of cerium phosphate was confirmed by X-ray diffraction and FT-IR 
techniques. TEM results clearly suggest that the formation of rod shaped like particles 
of single crystal. 
6. The catalytic performance CeP catalyst strongly depends on the ratio of acidic/basic 
sites on the catalyst surface. The density of surface acidic sites (surface acidity) and 
basic sites (surface basicity), which are obtained by normalizing to the sample surface 
area and measured from the NH3- and CO2-TPD peaks. Furthermore, the acid-base 
balance (acid to base atomic balance) was calculated by the ratio of total amount of 
acidity to total amount of basicity. AA selectivity was found to be highest at acid-
base balance factor = 0.56. 
212 
Chapter 5 Summary & Conclusions 
7. The XRD patterns of LaP catalysts resembles to rhabdophane lanthanum phosphate 
crystalline structure with phase transformation from rhabdophane to monoclinic 
lanthanum phosphate observed for LaP(0.35)[600] and LaP(0.35)[800] samples. 
8. The SEM images of LaP(0.35)[500], LaP(0.35)[UC] and LaP(0.35)[used] with 
different magnification suggesting all the LaP catalysts have a dandelion-like 
structure without disturbing any structure difference between the samples before 
calcination, after calcination and after the reaction. 
9. The catalytic performance of LaP catalysts was shown to correlate with the amount of 
total acidic sites present on the catalyst surface determined from NH3-TPD 
measurements. 
10. The formation of carbon / carbonaceous deposits on the LaP catalyst surface causes 
little deactivation in the LA conversion but switch to the in situ air flow at 450 °C 
could regenerate the LaP catalysts for the LTA reaction. 
11. The morphological features of the MgHP catalysts were assessed by SEM and 
depicted the flakes like morphology. Interestingly, the calcined (MgHP(0.5)[500]) 
and the used catalyst (MgHP(0.5)[Used]) samples also show a clear existence of 
flakes like morphology. 
12. Though MgHP catalysts were also suffered with little deactivation but comparable to 
the other catalysts studied in this reaction these catalysts are very less efficiently 
adsorbed the carbon / carbonaceous particles onto their surface. 
13. Among the three series of metal phosphates (CeP, LaP and MgHP) the MgHP 
catalysts showed the better catalytic performance towards the acrylic acid production. 
The order of performance of various catalysts is as follows CeP < LaP < MgHP. 
213 
Chapter 5 Summary & Conclusions 
14. Three series of zeolite supported metal oxide catalysts have been prepared to perform 
the esterification of lactic acid in vapour phase conditions. 
15. First series is 10 wt % WO3 supported on Y-zeolites and mordenite namely 10W-400, 
10W-720, 10W-760 and 10W-20A having different SiO2/Al2O3 ratio = 5.1, 30, 60 
and 20 respectively. The second series is having different weights of WO 3 (5, 10, 15 
and 20 wt %) supported on to CBV-760 (SiO2/A^O3 ratio = 60) namely 5W-760, 
10W-760, 15W-760 and 20W-760. The third series is different metal oxide (10 wt % 
of WO3, MoO3, Nb2O5, V2O5 and SnO2) supported Y-zeolite (CBV-760) catalysts. 
16. High dispersion of WO3 species on Y-zeolite was achieved, but at higher loading 
microcrystalites of WO3 was detected. Tungsten species were deposited preferentially 
inside the zeolite structure. 
17. The better performance of the 10 WO3/Y-zeolite (CBV-760) sample was attributed to 
a better distribution of strength of the acidic sites towards the selective esterification 
of lactic acid with butanol. 
18. The degree of esterification depends on the type of metal oxide deposited and the 
total amount acidity produced by the catalyst. Among the 10 wt % of WO3, MoO3, 
Nb2O5 , V 2 O 5 and SnO2 supported on CBV-760 catalysts 10Sn-760 is favoring the 
highest lactic acid conversion with butyl lactate yield. 
19. The NH3-TPD results suggest that impregnation of the metal oxides on the Y-zeolite 
(CBV-760) catalysts enhances the total amount of surface acidic sites relative to that 
of pure Y-zeolite (CBV-760) which enhances the degree of esterification of lactic 
acid to produce butyl lactate. 
214 


VAPOUR PHASE CONVERSION OF LACTIC ACID TO VALUE ADDED CHEMICALS USING SOLID ACID-BASE CATALYSTS

PAL, DHANANJAYA

Glioma Amplified Sequence 41(GAS41) Interconnects RNAi and Cancer via miRNA

Kommuru, Goutham

 
 
 
 
 
 
 
 
 
 
 
 
vi 
 
GOLD CATALYZED TRANSFORMATION OF N-PROPARGYLIC β-
ENAMINONES: SYNTHESIS OF 1-PYRROLINES, AZABICYCLO 
[4.1.0]HEPTA-2,4-DIENES, 1,4-OXAZEPINES AND 1,2-DIHYDRO 
BENZO[c][2,7]NAPHTHYRIDINES 
 
Chapter-I : 
This chapter describes about enaminones and applications of N-propargylic β-enaminones for 
the synthesis of various heterocyclic scaffolds and also discussed about gold-catalysis and its 
applications. 
 
Enaminones are known as versatile reactive intermediates for the synthesis of various 
heterocyclic compounds which exhibits broad range of applications in agrochemicals, medicinal 
chemistry and functional materials.  
Recent research outputs evidencing that there is an enhanced advancement by the utility 
of N-substituted β-enaminones and their synthetic transformations for generation of various 
useful heterocyclic scaffolds.  
Gold-catalysis emerged as an thriving field with numerous novel and unexpected 
discoveries every year. The advantageous features of organic transformations through 
homogenous gold-catalysis are high atom economy, high functional group tolerance, sometimes 
a tremendous increase in molecular complexity. Robust applications of homogeneous gold-
catalysis in asymmetric synthesis was also achieved. 
 
 
vii 
 
 
      
Chapter-II : 
This chapter deals with the synthesis of 1,2-diphenyl-1-pyrrolines and synthesis of 3-
azabicyclo[4.1.0] hepta-2,4-dienes. 
 This chapter was divided into two parts (A and B). 
In part A we have discussed the synthesis of 1,2-diphenyl-1-pyrrolines from N-propargylic 
β-enaminones and arynes under gold-catalysis.  
Gold-catalyzed reaction between N-propargylic β-enaminones and arynes was developed to 
access 3-methylene-1-pyrrolines. The title compounds were obtained in 55–78% yields. This 
reaction is useful for the generation of substituted 1-pyrrolines exhibiting significant molecular 
complexity with quaternary stereocenters and exocyclic double bonds. 
1-Pyrrolines (3,4-dihydro-2H-pyrrolines) have received considerable attention, they exhibit 
important roles in several applications such as semiochemicals, flavouring agents for various 
food products, natural products, alkaloids, and therapeutic compounds.  
 
viii 
 
In part B we have discussed the synthesis of azabicyclo[4.1.0]hepta-2,4-dienes from N-
propargylic β-enaminones and dialkyl acetylene dicarboxylates.  
 Cyclopropane fused aza-heterocyclic compounds represent a privileged class of structural 
motifs embeded in natural products and numerous biologically active agents. They have potential 
applications in pharmaceutical chemistry. 
3-Azabicyclo[4.1.0]hepta-2,4-dienes were efficiently synthesized in the reaction of N-
propargylic β-enaminones with acetylenedicarboxylates under novel and exceptional catalyst- 
and base-free conditions in a single step. 
 
 
 
Chapter-III: 
This chapter describes the synthesis of 1,4-Oxazepine derivatives by intramolecular cyclization 
of N-propargylic β-enaminones under gold-catalysis. 
 
 The 1,4- oxazepines are the parent core of medicinally important drugs like amoxapine, 
loxapine, and sintamil. 1,4-Oxazepine derivatives exhibiting biological properties such as histone 
deacetylase inhibitions and antitumor activity have been reported. 
An efficient and mild one-pot, gold-catalyzed intramolecular cyclization of N-propargylic 
β-enaminones has been achieved for the generation of 1,4-oxazepine derivatives. This synthetic 
transformation tolerates a range of substituted N-propargylic β-enaminones in moderate to good 
yields. It is noteworthy that N-propargylic β-enaminones undergo 7-exo-dig cyclization 
regioselectively to give the title compounds.  
 
ix 
 
 
 
Chapter-IV : 
In this chapter, we discussed the synthesis of 1,2-dihydrobenzo[c][2,7]naphthyridine 
compounds by employing gold / AcOH binary catalytic system on 2-aminophenyl substituted 
N-propargylic β-enaminones. 
 
 We focused on synthesis of poly heterocyclic systems by employing compatible binary 
catalytic system. An efficient gold catalysed domino, atom economical protocol for the 
construction of benzo fused dihydronaphthyridines nucleus has been achieved from 2-
aminophenyl substituted N-propargylic β-enaminones. In this organic transformation a new C-C 
and C-N bond formations occurred along with sp3-carbon centre. Substituted benzofused 
dihydronaphthyridines were obtained in good to excellent yields in one-pot fashion under mild 
reaction conditions. 
Benzo[c][2,7]naphthyridine derivatives are the basic structural skeleton of many alkaloids 
isolated from marine living organisms and also possess wide spectrum of biological activity.  
 
 


Gold Catalyzed Transformation of N-Propargylic β-Enaminones : Synthesis of 1-Pyrrolines, Azabicyclo[4.1.0]hepta-2,4-dienes, 1,4-Oxazepines and 1,2-Dihydrobenzo[c] [2,7]naphthyridines

KANUGULA, BHAVANI

Synopsis 
 
1 
 
The thesis entitled “Studies towards the synthesis of (-)-Ushikulide-A, (-)-Aspergillide-B 
and chiral β-hydroxy ketones” is divided into three chapters. 
Chapter I: This chapter deals with studies towards the synthesis of (-)-Ushikulide-A (1) 
 (-)-Ushikulide A (1) exhibits potent activity against murine splenic lymphocyte 
proliferation (IC50) 70 nM), rivalling that of the well-known cyclosporin A2 and FK506,3 
which revolutionized organ transplant therapy by suppressing rejection, was isolated from a 
culture broth of Streptomyces sp. IUK- 102 by Takahashi et al.,
1
 in 2005.  
Figure 1 
 
From the retrosynthetic analysis of 2 (Scheme 1), the formation of the spiroketal 
segment (2) of Ushikulide-A (1) was envisaged through an acid catalyzed one pot 
desilylation and spiroketalization via double intramolecular hetero Michael addition 
(DIHMA)
2 
on the linear ynone 3 as key step to construct the spiroketal moiety. In turn, 
ynone 3 was planned by the assembly of two fragments alkyne 4 and aldehyde 5, which in 
turn could be prepared from 6 and 7 respectively. The alkyne 4 serves as a stabilized anion, 
which undergoes addition with aldehyde 5. The alkyne in ynone 3 then acts as an 
electrophile in acid catalyzed DIHMA reaction.  
Scheme 1: Retrosynthetic analysis 
   
Synopsis 
 
2 
 
 Alkyne 4 has been synthesized from known  alcohol 6.
3
 Accordingly 6 on treatment 
with BnBr, NaH in THF gave corresponding benzyl ether  in 58% yield, which on 
ozonolysis in CH2Cl2 at -78 ºC gave aldehyde 8 in quantitative yield.  Aldehyde 8 on 
propargylation with 14a under Marshall conditions
 4
 furnished 9 in 78% yield (94:6 de) . 
The secondary hydroxy group in single diastereomer 9 was subsequently protected as silyl 
ether on treatment with TBDMS-Cl and imidazole to furnish 10 in 78% yield, which on 
formylation with para formaldehyde using  EtMgBr furnished propargyl alcohol 11(69%), 
which on hydrogenation with PtO2 in EtOAc gave saturated alcohol 12 in 91% yield.  
Oxidation of 12 with Dess–Martin periodinane
5 
gave the aldehyde in quantitative yield, 
which was subsequently treated with CBr4 and PPh3 to furnish dibromoolefin in good yield. 
Finally the dibromoolefin on treatment with n-BuLi under Coey-Fuchs conditions
6
 gave the 
alkyne 4 in 80% yield. 
 Aldehyde 5 has been synthesized from known epoxy alcohol 7, Accordingly epoxy 
alcohol under Gillmann
7
 condition gave 1,3 diol 15 in 66% yield, which on treatment with 
TBDMS-Cl, with imidazole gave Di –TBS protected compound 16 in 54% yield.  
  
Synopsis 
 
3 
 
 Selective deprotection of primary TBDMS ether with HF-Pyridine furnished 
primary alcohol 17 in 71% yield. Oxidation of 10 with Dess–Martin periodinane gave the 
aldehyde 5 in 96% yield (Scheme 3). 
 Synthesis of ynone 3 (Scheme 4) began with the coupling of lithium acetylide 
derived from 4 with 5 to afford a mixture of propargylic alcohol 18 in 54% yield, which on 
oxidation with Dess-Martin periodinane gave the ynone 3 in 84% yield. Cleavage of the 
TBDMS groups in 2 with CSA in MeOH and subsequent treatment with p-TsOH in toluene 
at room temperature for 24 h cleanly affected the spiroketal formation under DIHMA 
conditions and furnished diastereomeric spiroketal mixture 1 in 58% yield. 
 
 In summary synthesis of spiroketal fragment of ushikulide-A accomplished by a 
divergent route that involves Double Intramolecular hetero Michael addition for the 
construction of spiroketal fragment, Marshall propargylation for the creation of syn C24, 
C25 centers, Corey-Futch reaction for the synthesis of terminal alkyne. 
Chapter II: This chapter deals with studies towards the synthesis of Aspergillide-B 
 Aspergillides A-C (19a-c) were isolated from the marine fungus Aspergillus 
ostianus by Kusumi and co-workers.
8
 These natural products are characterized by a 14-
membered macrolactone core structure embedded with a 2,3,6-trisubstituted 
tetrahydropyran ring and the first examples of 14-membered macrolides that possess 
tetrahydropyran ring not forming part of a hemiacetal or acetal moiety. Compounds 19b 
Synopsis 
 
4 
 
have four stereocentres (3S, 4S, 6R, 13S) with a 2,6-trans tetrahydropyran, 6-hydroxy  and 
13-methyl moiety.  
Figure 2 
 
The macrolides 19a and 19b showed good cytotoxic activities against mouse 
lymphocytic leukemia cells
 
and five different human cancer cell lines: promyelocytic 
leukemia, breast carcinoma, fibrosarcoma, colon adenocarcinoma and osteosarcoma, as well 
as in a primary culture of non-transformed bovine aorta endothelial cells.  
 From the retrosynthetic analysis of 20 (Scheme 5), the formation of the 14- lactone 
moiety was envisaged through Yamaguchi macrolactonization on the seco acid 21, inturn 
seco acid envisaged by the cross metathesis of  fragments 22, known alcohol 23
9a
. 2,6 
dihydro-2H-pyran 22 was envisaged from  hydroxy ester 24, which inturn synthesized from 
known α, β-unsaturated-γ, δ-epoxy ester 25.  
Scheme 5: Retrosynthetic analysis 
 Pyran 22 was synthesized from known epoxy unsaturated ester 25,
9b 
opening of 
vinyl epoxides with retention of stereochemistry. Only one method that allows opening of 
trans vinyl epoxide with various alcohols with retention of stereochemistry developed by 
Synopsis 
 
5 
 
Miyashita et al.
10
 Accordingly palladium catalyzed regio- and stereoselective opening of 
epoxy unsaturated ester 25 with retention of configuration by using triphenyl borate and 
benzyl alcohol to give 24 as a single stereoisomer in 52% yield.  The selective reduction of 
olefin 24 by using Mg in MeOH gave 26 in 80% yield. Ester 26 was reduced by using 
DIBAL-H at -78 ᵒC to give lactol in 26a in quantitative yield. Next it was aimed to 
construct key fragment trans-2,6-disubstituted tetrahydro-2H-pyran ring by adopting the 
streategy developed by our group,
11
 Accordingly reaction of  26a with allyltrimethyl silane 
by using I2 in CH2Cl2 gave pyran 27 in 75% yield, which on reaction with DDQ in 
CH2Cl2:H2O (19:1) gave 28 in 81% yield. Isomerisation olefin of 22 was achieved by 
adopting the method developed by Hanessian et  al.
12
 Accordingly treatment of 28 with G-II 
catalyst in MeOH afforded isomerized olefin 22 in 73% yield as an 8:1: E/Z mixture. 
 
 
 The olefin 22 and known alcohol 23
13 
(Scheme 7) were subjected to cross metathesis 
in the presence of Grubbs second generation catalyst in CH2Cl2 at 60 C to give diol 29 in 
70% yield. A subsequent oxidation of the primary alcohol 29 with TEMPO and BIAB 
readily furnished the hydroxy aldehyde 29a in 88% yield, further oxidation of the aldehyde 
29a to the carboxylic acid 21 was accomplished in 68% yield, under the Lindgren-Kraus-
Pinnick condition.
14
 Macrolactonization of the resulting hydroxy-acid 21 was then realized 
under the Yamaguchi protocol. Activation of the acid functionality in 21 with 2,4,6-
tirchlorobenzoyl chloride, followed by cyclization in presence of base (DMAP) under high 
Synopsis 
 
6 
 
dilution conditions in toluene afforded the E-macrolactone 20 in 30% yield.  The spectral 
data and optical rotation of 20 in accordance with the reported
 
[α]D
25
 -59.22 (c 0.4, CHCl3); 
Lit.
 
[α]D -56.3 (c 1.5, CHCl3) by
 
Marco et al.
15 
 
 In summary formal synthesis of  the cytotoxic macrolide aspergillide-B 
accomplished by a divergent route that involves Yamaguchi macrolactonization for the 
construction of 14-membered lactone, I2 catalyzed synthesis of trans-2,6-disubstituted 
tetrahydro-2H-pyran sub unit, Pd(0)-triphenyl borate mediated stereoselective epoxide 
opening for the creation of  C4, C5 centers. 
Chapter III: This chapter deals with studies towards the synthesis of chiral β-hydroxy 
ketones 
 The stereoselective aldol is one of the most powerful synthetic methods for the 
synthesis of β-hydroxy carbonyl compounds,
16 
which are subunits of many natural products 
and it has also been utilized in the synthesis of polyoxygenated compounds. Since the first 
report of L-Proline catalyzed enantioselective C-C bond formation
 17
 via an intermolecular 
aldol reaction by List and co-workers,
 18
 there has been a tremendous progress in Proline 
catalyzed direct aldol
 
reactions. A number of catalysts were reported with modified acidic 
moiety of L-proline. The asymmetric direct aldol reaction
 19
 does not require preformed 
enolate thus makes it more atom economical. The major proline derived organocatalysts are 
4-substituted L-proline,
 20 
proline derived N-sulfonyl carboxamides,
21 
small peptides,   
different type of prolinamides
22 
and other chiral aminoacids. 
 A facile enantioselective direct aldol reaction of acetone with various aromatic 
aldehydes using a novel trifunctional L-prolinamide catalyst (30) was developed. 
Synopsis 
 
7 
 
 
Scheme 8. Direct asymmetric aldol reaction catalyzed by prolinamide A 
 The catalyst 30 was prepared
 
from 8-aminoquinoline (32) and N-Boc-L-proline(33) 
(Scheme 9). We envisaged that L-prolinamide (30) may induce the enantioselectivity owing 
to the stereorigidity within the catalyst (30). The quinoline ring of the catalyst could be 
anticipated to interfere in the transition state of aldol reaction in such a way that it manifests 
the enantioselectivity.  
 
Scheme 9: Synthesis of prolinamide (30) 
 Similarly, other prolinamide derivatives (35and 36) were prepared from N-Boc-L-
proline (33) and the corresponding amines respectively, according to synthetic route as 
shown in Scheme 9. Deprotection of Boc group by 5N HCl in THF:H2O (3:1) afforded the 
prolinamides 35 and 36 in good yields. Accordingly, the catalytic performance of 
prolinamide catalysts (30, 35, 36) were examined in direct aldol reaction between o-
nitrobenzaldehyde (31) and acetone in a variety of solvents without additives at different 
temperatures.  The results are summarized in Table 1. Among those catalyst 30 shown good 
‘ee’ values. Initially, the aldol reaction was performed at room temperature using the 
catalyst 30 under neat conditions.  
Synopsis 
 
8 
 
 
Figure 3. L-Prolinamide derivatives 
 
 Indeed the catalyst 30 (10 mol%) showed very high reactivity in the aldol reaction of 
acetone with 2-nitrobenzaldehyde (31). The reaction proceeded smoothly at room 
temperature in solvent free conditions. The reaction was completed within 2 h and the 
corresponding product 31a was obtained in 90% yield, but the enantiomeric excess was 
nonetheless low (65%). The reaction conditions were further optimized for catalyst 30 to 
increase the ee. The results, as depicted in Table 2, reveal that the aldol reaction occurs in 
many of organic solvents, but good yield and high enantioseletivity were observed in DMF 
only. Though slight difference in enantioselectivity was observed in THF and CHCl3, the 
reaction took longer reaction times. However, the enantiomeric excess was further 
decreased when water was used as a solvent. By further optimizing the reaction conditions, 
the enantioselectivity was increased to 78% at 0 ºC. By further decreasing the reaction 
temperature to -40 ºC, the product was obtained with 92% ee. It was found that the 
enantioselectivity was dependent on the reaction temperature. The best enantioselectivity 
was obtained in direct aldol reaction by catalyst 30, when temperature was lowered, though 
the reaction was sluggish   (6.5 h). 
Synopsis 
 
9 
 
 
 This result is presumably due to steric bulkiness in the catalyst, which may play an 
important role in stereoselectivity. Moreover, when the loading of catalyst was decreased 
from 10 mol% to 5 mol% there is no change in enantiomeric excess but the reaction time 
has increased (11 hrs). 
 Next, we examined the scope and generality of this process with various aldehydes 
under optimized conditions. The best results were achieved when  ortho–nitrobenzaldehyde 
was used. Similarly other nitro substituted benzaldehydes also produced the corresponding 
products in good yields with good enantioselectivities. The halo and cyano substituted 
benzaldehydes were also effective for this conversion. In the case of naphthaldehyde, both 
enantioselectivity and yields were moderate. Aliphatic aldehydes are not so effective. 
Therefore, the yields and enantioselectivity were low with aliphatic aldehydes. In the case 
of p-methoxybenzaldehyde, the enantioselectivity and yield were very low (Figure 4). 
Synopsis 
 
10 
 
Figure 4:Aldol derivatives from various aldehydes 
 The stereochemistry of the aldol products was assigned by comparing the data with 
the reported values.
20
 On the basis of experimental results, the high stereo control observed 
when using Prolinamide catalyst 30 can be rationalized by involving presumed transition 
state, steric crowding plays an important role in selectivity.  
 
  
 
 
Figure 5. Proposed transition state for the aldol reaction  
 In summary, we have synthesized a new prolinamide catalysts for enantioselective 
direct aldol reaction. This method shows moderate to good enantioselectivity at -40 ˚C. Of 
three catalysts, prolinamide 30 was the most efficient for the aldol reaction of acetone with 
various aldehydes. The corresponding β-hydroxy ketones were obtained in good yields (up 
to 90%) with excellent enantioselectivity (up to 92% ee).  
Synopsis 
 
11 
 
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