hathi ram thesis final pdf

Glycolate Alkylation Reactions and its application in the total synthesis of Ligraminol E
Contents
1. Introduction....................................................................................................................... 1
2. Classification..................................................................................................................... 1
3.Biological Activity of Lignans............................................................................................ 3
4. Oxyneolignans .................................................................................................................. 5
4.1.Oxyneolignans having anti-protozoal activity .............................................................. 5
5. Objectives ......................................................................................................................... 8
Objective 1........................................................................................................................ 8
Objective 2........................................................................................................................ 8
6. Retrosynthetic analysis:..................................................................................................... 8
7. Work plan : ....................................................................................................................... 9
8. Result and discussoin: ..................................................................................................... 10
8.1. Synthesis of chiral auxiliary:..................................................................................... 10
8.2 Glycolate alkytion reaction of N-acetyl-(S)-4-isopropyl-1-[(R)-1-phenylethyl]
imidazolidin-2-one .......................................................................................................... 10
8.3 Hydrolysis of aldol adduct :....................................................................................... 12
8.4. Synthesis of substituted benzyl bromide: .................................................................. 13
8.5. Synthesis of 4-(3-hydroxypropyl)-2-methoxyphenol:................................................ 15
9. Summary and Conclusion:............................................................................................... 16
10. Experimental Section: ................................................................................................... 17
11. References..................................................................................................................... 25

Page 1
1. Introduction
Harworth introduced the term “lignan” to describe a group of phenolic compounds
extracted from plants. These compounds represent the fusion of two phenylpropanoid
units through (ß-ß') carbons of side chain.
Lignans are defined as compounds in which the two C6-C3 units are linked to each
other via the C8 and the C8. Neolignans on other hand, are composed of two C6-C3 units,
which are linked via other carbon atoms than C8. Within the neolignans, three subgroups
are distinguished, which are oxyneolignans, sesquineolignans and dineolignans.
Oxyneolignans have their C6-C3 units linked via an ether linkage. Sesquineolignans are
composed of three C6-C3 units and dineolignans of four C6-C3 units. Lignans have been
identified in many plants, while neolignans are less abundant.
Figure 1. General structure of lignans and neolignans.
These share basic C6 -C3 skeleton along with lignins, coumarins, flavonoids etc. Phenyl
propanoids are aromatic compounds, with a hydroxyl group in the para position.1
Neolignans are compounds formed from fusion of phenylpropanoid units by bonds other
than a (ß-ß')
2. Classification
Lignans are Product of shikimic acid pathway. Lignans are formed from units of the
hydroxycinnamic alcohols, p- coumaryl alcohol, coniferyl alcohol, and sinapyl alcohol.2
They are the product of stereoselective coupling of two hydroxyl cinnamic alcohols units.
Lignans are divided into several subgroups with the general structures shown in the
following figures. In spite of recognizing the distribution of lignans in plants, the exact

Page 2
biological function is still unclear in most cases. However the accumulation of lignans in
the core of trees enhances the durability and longevity of the plant.
Lignans also function as phytoalexins, which are compounds providing protection to sthe
plants from various diseases and pests. With their diverse biological activities, the lignans
have attracted the attention of the pharmaceutical industry and have been the target of
intensive synthetic and pharmacological studies.
Classification of Lignans
S. No. Class Sub Class Example Structure
1. 1,4-Diarylbutane
derivative
Guaiaretic
acid
2. 2,3-Dibenzyl
butyrolactone
derivative
Hinokinin
3. Tetrahydro-
furan
derivative
i)2,5-Diaryl
tetrahydrofuran Olivil
ii)2-Aryl-4-benzyl
tetrahydrofuran Lariciresinol
4. Tetrahydrofurofuran
derivative Pinoresinol
5. 4-Aryltetrahydro
napthalenederivative
i)1-Hydroxy-2-
Hydroxymethyl
-3-Carboxylic
acid lactones
Podophylloto
-xin
ii)2-Hydroxy
methyl-3-
Carboxylic acid
lactones
Peltatins

Page 3
iii) 3-Hydroxy
methyl-2-
Carboxylic acid
lactones
Conidendrin
iv)2,3-Bis
(Hydroxymethy
l)derivatives
Isoolivil
v)2,3-Dimethyl
derivatives
Galbulin
3.Biological Activity of Lignans
Lignans and neolignans possess large variety of structures, enabling them to exhibit a
broad range of biological activities. Among these most important are antiviral and
anticancer. These have been used in traditional medicines in China and India. Some
examples are:
Figure 2. Podophyllotoxin and etoposide.
Initial search for anti-cancer natural products showed that the alcoholic extract of the
dried roots and rhizomes of Podophyylum exhibited significant destructive effect on
animal cancer cells. The main compound responsible for this activity is Podophyllotoxin,
a powerful microtubule inhibitor mainly obtained from Podophyllum peltatum and

Page 4
Podophyllum hexandrum. The group of lignans in these plants have an aryltetralin
general structure. Podophyllotoxin inhibits assembly of tubulin proteins to form
microtubules. These are needed during cell division to pull apart the duplicated
chromosomes. Thus Podophyllotoxin inhibits the process of cell division. However it is
not much selective and kills normal cells as well, which limits its use to topical treatment
of warts. Semisynthetic analogues of Podophyllotoxin have been developed e.g.
Teniposide and etoposide.3
These inhibit topoisomerase II (an enzyme involved in DNA
replication) These are used for treating testicular cancer, lung cancer, and certain forms of
leukemia. Many other lignans also show antitumour activity but their potency is not
comparable to podophyllotoxin e.g.Stegnacin and Burseran.
Figure 3. Stegnacin and Burseran.
Manganone A and B have been found to be antagonist of Phospholipid PAF (Platelet
activating factor) involves in Haematological disturbances and Asthma. Enterodiol is a
mammalian lignan and has cancer protective activities.
Figure 4: Manganone A and Enterodiol

Page 5
Diphyllin and justicidin are isolated from Jusiicia procumbenr, and inhbit growth of
Sindbis viruse at concentration of 1.0 μg/ml. Retrojusticidin B and Phyllamycin B
isolated from Phyllanthus myrtifolius have strong inhibitory activity on reverse
transcriptase of HIV-1.
4. Oxyneolignans
Oxyneolignan are subclass of neolignans in which two C6C3 units are linked by an ether
oxygen atom and not directly bonded together the parent structure. The locants of the two
positions linked by the ether oxygen are cited in front of the name with the second
number primed.4
Figure 5: General structure of oxyneolignan
Oxyneolignans have potent and varied biological activity, like anti-leishmanial, anti-
malarial and anti-parasitic to anti-fungal and anti-oxidant.
4.1.Oxyneolignans having anti-protozoal activity
Viroline, polysphorin are isolated from plant Acorus gramineus, the level of substitution
on the A-ring was found to directly inﬂuence the activity against Leishmania donovani
while the activity against Plasmodium falciparum was inﬂuenced by numerous
substitutions and stereochemical factors.5

Page 6
Figure 6: Oxyneolignan molecule having antioxidant activity
1-(4-((1,3-dihydroxy-1-(4-hydroxy-3-methoxyphenyl)propan-2-yl)oxy)-3-methoxy-
phenyl)propane-1,2,3-triol derivatives have antioxidant activity. The antioxidant potential
of the sap samples were determined on the basis of their ability to scavenge the 2, 2- O-
diphenyl-1-picrylhydrazyl (DPPH) radical6
as previously reported that they have ability
to scavenge the DPPH radical, like ascorbic acid and synthetic commercial antioxidant
BHT7
. The asymmetric glycolate alkylation offered an attractive solution to both these
needs. As such, we required a highly diastereoselective asymmetric glycolate enolate
which allowed for easy interchange of the hydroxyl protecting group. The well
documented Evans alkylation of N-acyl 4-substituted oxazolidinones seemed a logical
choice. A survey of the literature uncovered only a single, fairly complex of a glycolate
oxazolidinone alkylation with methallyl bromide. This was surprising given the extensive
application of 4-substituted oxazolidinone auxiliaries in asymmetric synthesis. They are
readily available (both commercially and synthetically), easily removed, and can be
recovered and recycled. We have previously reported the use of asymmetric glycolate
alkylations for some specific applications here, we report on the utility and generality of
asymmetric alkylations of sodium enolates of numerous glycolate oxazolidinones with a
variety of allylic iodides for the preparation of R-hydroxy carboxylic acids and 1,2-diols
with selective protection of the secondary alcohol.
The wide spread use of α-hydroxy acids and their derivatives as chiral synthons in
organic synthesis has grown collaterally with advances in methodology for their

Page 7
asymmetric synthesis.7
Various methods including asymmetric dihydroxylations,8
symmetric enolate hydroxylation,9
and asymmetric glycolate alkylation10
have been used
to prepare α-hydroxy acid. Asymmetric glycolate alkylation is a straightforward approach
because of the relative ease of changing the alkyl group and the protecting group of the
glycolate hydroxyl.11
Several Chiral auxiliary-derived asymmetric alkylations have been
studied extensively and are now important and general methods for asymmetric carbon–
carbon bond formation.11
Chiral auxiliaries attached to the carbonyl, the hydroxyl group,
and to both have been employed in diastereoselective alkylations of chiral glycolates.11
The asymmetric glycolate alkylation is an attractive approach because of the relative ease
of interchanging the alkyl group as well as the protecting group on the glycolate
hydroxyl. Chiral auxiliaries attached to the carbonyl, the hydroxyl group, and to both
have been employed in diastereoselective alkylations of chiral glycolates
To employ the application of asymmetric glycolate alkylation to synthesize natural
products and compounds of medicinal and industrial importance, we plan to synthesize
oxyneolignans (Ligraminol E)12
using N-acetyl-(S)-4-isopropyl-1-[(R)-1-phenylethyl]
imidazolidin-2-one13
as chiral auxiliary.
In our lab we have already designed imidazolidinone type chiral auxillary by the scheme
presented below. It has shown good enantioselectivity for the synthesis of various
molecules. N-acetyl-(s)-4-isopropyl-1-[(r)-1-phenylethyl]imidazolidin-2-one has shown
reversal of selectivity in acetate aldol reactions. It forms anti acetate aldol with lithium
enolate and syn acetate aldol with titanium enolate. Here we are exploiting this auxiliary
for the glycolate alkylation reaction and for the total synthesis of ligraminol E.

Page 8
5. Objectives
Objective 1: Standardization of the glycolate alkylation reaction of N-acetyl-(S)-4-
isopropyl-1- [(R)-1-phenylethyl]imidazolidin-2-one
Objective 2: Total synthesis of Ligraminol E.
6. Retrosynthetic analysis:
The retrosynthetic analysis were based on asymmetric glycolate alkylation as the main step of the
synthesis. In scheme 1 compound 3 undergo glycolate alkylation reaction with the substituted
benzyl bromide and finally the reduction and deprotection will give the final natural products.
Compound 3 will be synthesized starting from ferulic acid and its esterification and reduction
finally the alkylation by bromoacetylated auxiliary will give the compound 3.

Page 9
7. Work plan :
Scheme 2: Work plan for the total synthesis of Ligraminol E.

Page 10
8. Result and discussoin:
8.1. Synthesis of chiral auxiliary:
In our lab we have already designed imidazolidinone type chiral auxillary by the scheme
presented below. It has shown good enantioselectivity for the synthesis of various
molecules. N-acetyl-(s)-4-isopropyl-1-[(r)-1-phenylethyl]imidazolidin-2-one has shown
reversal of selectivity in acetate aldol reactions. It forms anti acetate aldol with lithium
enolate and syn acetate aldol with titanium enolate. Here we are exploiting this auxiliary
for the glycolate alkylation reaction and for the total synthesis of ligraminol E.
Scheme 3: Synthesis of chiral auxiliary12
8.2 Glycolate alkytion reaction of N-acetyl-(S)-4-isopropyl-1-[(R)-1-phenylethyl]
imidazolidin-2-one
Scheme 4: Glycolate alkylation reaction

Page 11
Table 2:
S.No. Reagent Temperature ( 0
C) Yield (%) De
1 LiHMDS -78 to 0 NA NA
2 NaHMDS -78 to 0 trace NA
3 KHMDS -78 to 0 NA NA
4 LDA -78 to 0 NA NA
5 TiCl4, DIPEA -78 to 0 NA NA
6 LiHMDS, TMEDA -78 to -40 90 >99:01
The alkylation reaction on the (R)-3-(2-(benzyloxy)acetyl)-4-isopropyl-1-((S)-1-
phenylethyl)imidazolidin-2-one was tried with different bases. Initially LiHMDS was
tried and enolization was done at -78 0
C and benzyl bromide was added at the same
temperature but the reaction did not proceed at all, then we increase the temperature to -
40 0
C and stir for few hours and then at 0 0
C but the reaction did not work at all and
starting material was recovered as such. Then we tried the reaction using different bases
like NaHMDS, KHMDS, LDA but still the reaction is not going. We also tried with lewis
acid TiCl4 with DIPEA as base but the reaction did not work under this condition also.
Then we use better electrophile and perform the same set of conditions using methyl
iodide as electrophile but the reaction still did not work. Then we add 1 equivalent of
TMEDA and LiHMDS as base at -78 0
C and benzyl bromide as electrophile, the reaction
is going under these conditions but the reaction was very slow at this temperature and
after 12 hours more than half of the starting material remains as such so we increase the
temperature to -40 0
C, at this temperature the reaction proceed smoothly and after 6 hours
all of the starting material was consumed and the product was purified using column
chromatography giving product with high yield ( 90% isolated yield) confirmed by 1H
and 13C NMR spectroscopy and HRMS. The diastereomeric excess was confirmed by
1H NMR spectroscopy and it shows >99:01 de.
The absolute configuration was confirmed by cleaving the auxiliary using NaOH in
THF:Water under reflux conditions giving the (R)-2-(benzyloxy)-3-phenylpropanoic acid
and its specific rotation matched with the literature value giving it the R stereochemistry.
The chiral auxiliary was recovered after hydrolysis.

Page 12
8.3 Hydrolysis of aldol adduct :
Scheme 5: Hydrolysis of aldol adduct
Table 3:
S.No. RBr Product Time(h) Yield(%) dr(R:S)
1 3 >90 99:01
2 3 88 99:01
3 3 85 99:01
4 4 88 98:02
5 4 92 98:02
All reaction were performed under nitrogen with 1.1 eq of LiHMDS and 1.05 eq TMEDA at -780
C to400
C
Diastereomeric excess was determined from the 1
H NMR of crude product.

Page 13
8.4. Synthesis of substituted benzyl bromide:
Scheme 6: Synthesis of 3,4 dimethoxy benzylbromide
S. No. Reagent Solvent Yield
1 PBr3 Et2O NA
2 PBr3 DCM NA
3 CBr4, PPh3 DCM NA
3,4-Dimethoxybenzaldehyde was converted into the 3,4-dimethoxybenzylalcohol using
NaBH4 in MeOH at room temperature. Then we tried to convert alcoholic group to
bromide group under different conditions. First we use PBr3 in solvents like Et2O and
DCM but reaction did not work then we use CBr4 in DCM the reaction did not work also.
Scheme 7: Synthesis of (4-(bromomethyl)-2-methoxyphenoxy)(tert-butyl)dimethylsilane
Then we tried to convert the TBS protected vallinol under same conditions used above
but the reaction either gave degraded product or the reaction did not work.
S.No. Reagent Solvent Yield
1 PBr3 Et2O NA
2 PBr3 DCM NA
3 CBr4, PPh3 DCM NA
All reactions are performed at 0 0
C to rt
All reactions are performed at 0 0
C to rt

Page 14
Assuming that the problem was due to the more acid labile TBS group we then tried the
more bulky and stable TBDPS group. Then under the PBr3 in Et2O the reaction perform
well and gave good yield in 1h.
Scheme 8. Synthesis of (4-(bromomethyl)-2-methoxyphenoxy)(tert-butyl)diphenylsilane
Scheme 9. Synthesis of ferulic ester
Esterification of ferulic acid was done using cat.H2SO4 in EtOH under reflux conditions
for 12h giving product in 95% yield.

Page 15
8.5. Synthesis of 4-(3-hydroxypropyl)-2-methoxyphenol:
HO
MeO
OEt
O
LaH, BnCl, THF
0 0
C to rt
HO
MeO
OH
N
(S)
N
(R)
O
O
Br
K2CO3, cat. KI,
acetone, rt
O
MeO
OH
Xc
O
O
MeO
OTBS
Xc
O
LiHMDS, -78 0
C to -20 0
C
Br
OTBDPS
OMe
OTBS
O
MeO
Xc
O
OTBDPS
OMe
OTBS
O
MeO
OH
OTBDPS
OMe
OH
O
MeO
OH
OH
OMe
NaBH4, MeOH, rt
1. Pd/C, EtOAc, rt
2. TBAF, THF, rt
dr 95:05
Ligraminol E
TBSCl, imidazole
DCM, 0 0
C
33 34
35
36
37
38
39
1
31
Scheme 10. Synthesis of 4-(3-hydroxypropyl)-2-methoxyphenol
The ferulic ester was then reduced in the presence of LaH and BnCl in THF at 0 0
C to
give α,β unsatured alcohol. The phenolic group of ferulic ester was alkylated with
bromoacetylated auxiliary using K2CO3 as base and cat.KI in acetone to give product in
90% isolated yield. The glycolate alkylation was first tried with the already standardised
conditions at -78 to -40 ºC but we get very low yield even after long reaction times so we
increase the temperature to -78 to -20 ºC and then we get good yield and
diastereoselectivity in 4h. We then reductively removed the chiral auxiliary with NaBH4
in MeOH and then reduce the double bond in side chain and finally deprotect the silyl
protection with TBAF in THF to get the Ligraminol E.

Page 16
9. Summary and Conclusion:
We successfully standardised the glycolate alkylation reaction of N-acetyl-(S)-4-
isopropyl-1- [(R)-1-phenylethyl]imidazolidin-2-one using LiHMDS and TMEDA in THF
to give the product in >90% yield and >99% diastereomeric excess. Total synthesis of
Ligraminol E has been done.

Page 17
10. Experimental Section:
All the reagents required for this study were purchased from commercial sources and
used as such without further purification. Solvents were distilled and dried before use. 1
H
and 13
C NMR spectra were recorded at 400 and 100 MHz, respectively, on a Bruker
Avance DPX 400 (400 MHz) spectrometer in CDCl3/CD3OD using TMS as an internal
standard. The chemical shifts (δ) for 1
H and 13
C spectra are given in ppm relative to
residual signals of the solvent. Coupling constants are given in Hz. The following
abbreviations are used to indicate multiplicity: s, singlet; d, doublet; t, triplet; td, triple
doublet; dt, double triplet; q, quartet; m, multiplet; brs, broad signal. HRMS were
recorded on a Bruker Maxix TOF mass spectrometer. Melting points are uncorrected.
Synthesis of (S)-3-[2-(benzyloxy)acetyl]-4-isopropyl-1-[(R)-1-
phenylethyl]imidazolidin-2-one (18)
To a stirred solution of (S)-4-isopropyl-1-[(R)-1-phenylethyl]imidazolidin-2-one (8 g,
34.4 mmol, 1.0 equiv) in dry THF (100 mL) under N2 environment was added n-BuLi
(1.7 mL, 41.3 mmol, 1.2 equiv, 60%) in portion at –78°C. After 1h the benzyloxyacetyl
chloride (3.2 mL, 41.3 mmol, 1.2 equiv) was added drop wise and stirred another 1h. The
reaction mixture was quenched with aq NH4Cl, further washed with aq NaHCO3 and
dried over anhydrous sodium sulphate further evaporated under vacuum to give desired
compound.
Yield 95%; gummy; [α]D
20
+ 89.1 (c 1, CHCl3); 1
H NMR (400 MHz, CDCl3) δ 0.81 (d, J
= 6.8 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H), 1.55 (d, J = 7.1 Hz, 1H), 2.42–2.50 (m, 1H), 2.96
(t, J = 9.6 Hz, 1H), 3.10 (dd, J = 3.0, 9.6 Hz, 1H), 4.18–4.22 (m, 1H), 4.66 (q, J = 11.7
Hz, 1H), 4.76 (d, J = 1.9 Hz, 1H), 5.28 (q, J = 7.1 Hz, 1H), 7.28–7.7.36 (m, 8H), 7.40–
7.42 (m, 2H); 13
C NMR (100 MHz, CDCl3) δ 14.39, 16.12, 18.01, 28.48, 37.81, 50.32,
54.87, 70.03, 73.41, 127.15, 127.78, 128.00, 128.07, 128.41, 128.77, 137.70, 138.83,
154.40, 170.47; HRMS (ESI-TOF) calcd for C23H28N2O3Na [M+Na]+
: 403.1998; found:
403.1998
General procedure for glycolate alkylation reaction using (S)-3-((R)-2-(benzyloxy)-3-
phenylpropanoyl)-4-isopropyl-1-((R)-1-phenylethyl)imidazolidin-2-one
To the solution of (S)-3-[2-(benzyloxy)acetyl]-4-isopropyl-1-[(R)-1-phenylethyl]
imidazolidin-2-one (3) (0.6 g, 2.2 mmol, 1.0 equiv) in freshly dried THF (5 mL) under N2
environment was cooled to –78°C and added LiHMDS solution (2.4 mL, 2.4 mmol, 1.1
equiv; 1M in THF) and TMEDA (1.05 equiv.) at ‒78°C, and stirred for 1 h then the

Page 18
benzyl bromide or other bromides (1.1 equiv) was added to the reaction mixture and
further stirred for 30 min and then the temperature was increased to -40 0
C and stir for
another 2 h. The reaction was quenched by saturated aq NH4Cl solution, and extracted
with EtOAc which was further washed with brine and dried over anhydrous sodium
sulphate. The crude was purified by flash column chromatography using silica gel (60-
120 mesh) eluting with petroleum ether/EtOAc (9:1) to afford desired product (85 - 92%)
(S)-3-((R)-2-(Benzyloxy)-3-phenylpropanoyl)-4-isopropyl-1-((R)-1-phenylethyl)
imidazolidin-2-one (19)
1
H NMR (400 MHz, CDCl3) 0.77 (d, J = 6.9 Hz, 3H), 0.89 (d, J = 7.0 Hz, 3H), 1.61 (d, J
= 7.2 Hz, 3H), 2.29-2.37 (m, 1H), 2.92-2.99 (m, 2H), 3.11 (dd, J = 2.9, 9.6 Hz, 1H), 3.27
(dd, J = 3.2, 13.4 Hz, 1H), 4.19 (dt, J = 3.1, 9.4 Hz, 1H), 4.36 (d, J = 11.8 Hz, 1H), 4.53
(d, J = 11.7 Hz, 1H), 5.40 (q, J = 7.1 Hz, 1H), 5.52 (dd, J = 3.2, 9.6 Hz, 1H), 7.11-7.19
(m, 5H), 7.25-7.37 (m, 6H), 7.40-7.46 (m,4H)
13C 14.58, 16.13, 17.99, 28.69, 37.49, 39.98, 50.38, 54.84, 72.54, 78.94, 126.34, 127.27,
127.38, 127.95, 128.04, 128.15, 128.77, 129.78, 137.91, 138.04, 138.94, 153.99, 172.78
HRMS (ESI-TOF) calcd for C30H34N2O3Na [M+Na]+
: 493.2467; found: 493.2453
(S)-3-((R)-2-(Benzyloxy)-3-(p-tolyl)propanoyl)-4-isopropyl-1-((R)-1-phenylethyl)
1
H NMR (400 MHz, CDCl3) 0.74 (d, J = 6.9 Hz, 3H), 0.85 (d, J = 7.0 Hz, 3H), 1.58(d, J
= 7.2 Hz, 3H), 2.27-2.33 (m, 4H, peak merged of methyl and H of auxiliary), 2.87-2.93
(m, 2H), 3.07 (dd, J = 2.9, 9.5 Hz, 1H), 3.19 (dd, J = 3.2, 13.5 Hz, 1H), 4.15 (dt, J = 3.2,
9.5 Hz, 1H), 4.34 (d, J = 11.8 Hz, 1H), 4.49 (d, J = 11.8 Hz, 1H), 5.37 (q, J = 7.1 Hz,
1H), 5.47 (dd, J = 3.2 Hz, 1H), 7.09-7.17 (m, 6H), 7.28-7.34 (m, 6H), 7.36-7.40 (m, 2H)
13
C NMR (400 MHz, CDCl3) 14.55, 16.14, 18.00, 21.15, 28.69, 37.45, 39.57, 50.36,
54.82, 72.56, 79.01, 127.20, 127.28, 127.36, 127.99, 128.03, 128.77, 128.84, 129.65,
134.89, 135.73, 137.97, 138.95, 153.99, 172.87
: 507.2624; found: 507.2608
(S)-3-((R)-2-(Benzyloxy)pent-4-enoyl)-4-isopropyl-1-((R)-1-
phenylethyl)imidazolidin-2-one (22)
1
= 7.2 Hz, 3H), 2.27-2.35 (m, 1H), 2.51-2.59 (m, 1H), 2.65-2.71(m, 1H), 2.93 (t, J = 9.5
Hz, 1H), 3.09 (dd, J = 2.8, 9.6 Hz, 1H), 4.16 (dt, J = 3.3, 9.4 Hz, 1H), 4.46 (d, J = 11.5

Page 19
Hz, 1H), 4.60 (d, J = 11.4 Hz, 1H), 5.08-5.12 (m, 1H), 5.15-5.19 (m, 1H), 5.32-5.38 (m,
2H), 5.94-6.01 (m, 1H), 7.21-7.26 (m, 3H), 7.30-7.40 (m, 7H)
13C NMR 14.58, 16.15, 18.00, 28.67, 37.45, 38.04, 50.41, 54.83, 72.38, 77.30, 117.48,
127.25, 127.57, 128.04, 128.16, 128.19, 128.77, 133.88, 138.02, 138.98, 153.98, 172.54.
(S)-3-((R)-2-(Benzyloxy)-5-methylhex-4-enoyl)-4-isopropyl-1-((R)-1-phenylethyl)
1
= 7.2 Hz, 3H), 1.67 (s, 3H), 1.74 (s, 3H), 2.29-2.36 (m, 1H), 2.52-2.68 (m, 2H), 2.93 (t, J
= 9.5 Hz, 1H), 3.09 (dd, J = 2.8, 9.6 Hz, 1H), 4.16 (dt, J = 3.0, 9.4 Hz, 1H), 4.51 (d, J =
11.7 Hz, 1H), 4.62 (d, J = 11.6 Hz, 1H), 5.33-5.40 (m, 3H), 7.22-7.24 (m, 3H), 7.32-
7.42(m, 7H)
13
C NMR (400 MHz, CDCl3) 14.50, 16.16, 17.97, 18.08, 25.89, 28.74, 32.68, 37.47,
50.43, 54.83, 72.41, 77.52, 119.43, 127.26, 127.48, 128.03, 128.08, 128.13, 128.76,
134.17, 138.23, 139.03, 154.01, 173.08
: 443.2311; found: 443.2290
(S)-3-((R)-2-(Benzyloxy)-3-(4-bromophenyl)propanoyl)-4-isopropyl-1-((R)-1-
phenylethyl)imidazolidin-2-one (24)
1
H NMR (400 MHz, d6
-DMSO) 0.72 (d, J = 6.9 Hz, 3H), 0.85 (d, J = 7.0 Hz, 3H), 1.53
(d, J = 7.2 Hz, 3H), 2.11-2.18 (m, 1H), 2.79 (dd, J = 9.3, 13.6 Hz, 1H), 2.98 (t, J = 9.6
Hz, 1H), 3.10 (dd, J = 3.1, 13.7 Hz, 1H), 3.27 (dd, J = 2.5, 9.9 Hz, 1H), 4.17 (dt, J = 3.0,
9.2 Hz, 1H), 4.23 (d, J = 12.0 Hz, 1H), 4.43 (d, J = 12.0 Hz, 1H), 5.18 (q, J = 7.1 Hz,
1H), 5.35 (dd, J = 3.1, 9.2 Hz, 1H), 7.06 (dd, J = 1.7, 7.7 Hz, 2H), 7.17-7.21 (m, 2H),
7.28 (d, J = 8.4 Hz, 2H), 7.33-7.42 (m, 6H), 7.49 (d, J = 8.4 Hz, 2H)
13C NMR (DMSO), 14.27, 16.38, 17.47, 28.41, 37.41, 38.42, 50.17, 54.42, 70.93, 77.64,
119.36, 127.05, 127.20, 127.31, 127.83, 128.47, 130.79, 131.45, 137.39, 137.88, 139.25,
153.43, 171.16
: 449.2804; found: 449.2789
Synthesis of 4-((tert-butyldiphenylsilyl)oxy)-3-methoxybenzaldehyde (29)
To a stirring solution of vanillin (3g, 1equi) in DCM was added imidazole (2.5 equi) at 0
0
C and stir for 30 min. TBDPSCl (1.1 equi) dissolved in 20ml DCM was then added and
stirring continued for another 2 h at 0 0
C. After the reaction completed (monitored by
TLC) water was added and two layer separated, organic layer was washed with brine,
dried over sodium sulphate and concentrate in rotary evaporater. The crude was purified

Page 20
by flash column chromatography using silica gel (60-120 mesh) eluting with petroleum
ether/EtOAc (19:1) to afford desired product (92%)
(4-((tert-butyldiphenylsilyl)oxy)-3-methoxyphenyl)methanol (30)
To a stirring solution of 4-((tert-butyldiphenylsilyl)oxy)-3-methoxy benzaldehyde (3g,
1equi) in methanol at 0 0
C was added sodium borohydride (4 equi) and the reaction was
slowly allowed to come at rt and stir for another 2h. After the reaction was complete
(monitored by TLC), methanol was evaporated using rotary evaporater and ethyl acetate
and water was added. Organic layer was then separated, washed with water, dried over
sodium sulphate and concentrate in rotary evaporater. The crude was purified by flash
column chromatography using silica gel (60-120 mesh) eluting with petroleum
ether/EtOAc (19:1) to afford desired product (95%)
(4-(bromomethyl)-2-methoxyphenoxy)(tert-butyl)diphenylsilane (31)
To a stirring solution of (4-((tert-butyldiphenylsilyl)oxy)-3-methoxyphenyl)methanol (2.5
g, 1 equi) in dry Et2O at 0 0
C was added PBr3 (0.5 equi) and stir for 20 min and after the
completion of reaction (monitored by TLC) water was added to the reaction mixture, the
organic layer was separated, washed again with saturated solution of NaHCO3 3 times
and again with water, dried over sodium sulphate and concentrate using rotary evaporater.
The crude product was used as such without column chromatography (95%).
1
H NMR (400 MHz, CDCl3 ) 1.14 (s, 9H), 3.61 (s, 3H), 4.45 (s, 2H), 6.66 (d, J = 9.1,
1H), 6.71 (dd, J = 2.0, 8.1m 1H), 6.82 (d, J = 2.0, 1H), 7.35-7.46 (m, 6H), 7.72- 7.74 (m,
4H).
Synthesis of (E)-ethyl 3-(4-hydroxy-3-methoxyphenyl) acrylate (33)
To a solution of ferulic acid in 120ml of ethanol, 2-3 drops of cconc. H2SO4 was added
and refluxed for 4 h. After the completion of the reaction (monitored by TLC) the
solvent was evaporated and ethylacetate was added. The organic layer was washed 2-3
times with saturated olution of aq.NaHCO3 and then with brine. The organic layer was
separated and solvent was evaporated under the vacuum to give white solid compound
(yield 98 %).
Synthesis of (E)-4-(3-hydroxyprop-1-en-1-yl)-2-methoxyphenol (34)
To a stirred suspension of LiAlH4 (67.36 mmol) in freshly dry THF (200 mL), a solution
of BnCl (67.36 mmol) in dry THF (20 ml) was added dropwise through dropping funnel
at 0 0
C.After the addition of BnCl the solution was alllowed to warm to room temperature
and let it stir for 15-20 min at room temperature, then solution of (E)-ethyl 3-(4-hydroxy-

Page 21
3-methoxyphenyl) acrylate (45 mmol) in 40 ml THF was added dropwise to the
suspension.
The reaction mixture was allowed to stir at room temperature for 2 hrs. There after it was
cooled and slowly quenched with water, aq.NaOH and again washed with water to form
slurry which was filtered through celite bed. The filtrate was taken in ethylacetate,
washed with brine,and dried over anhydrous sodium sulphate. It was evaporated under
vaccum. Crude product was purified by column chromatography over silica gel (60-120)
merck using hexane/ethylacetate as eluent to afford the desired product (yield 80%).
1
H NMR (400 MHz,CDCl3 ) δ 3.92(s, 3H), 4.32 (dd, J = 1.24, 5.96 Hz, 2H), 5.78 (s,
1H), 6.24 (dt, J = 6.0, 15.8 Hz, 1H), 6.55 (d, 15.84 Hz, 1H), 6.87-6.94 (m, 3H).
13
C NMR (100 MHz, CDCl3 ) δ 55.88, 63.87, 108.33, 114.49, 120.31 ,126.13, 129.13,
129.24, 131.39, 145.58, 146.65.
Systhensis of (S)-3-(2-(4-((E)-3-hydroxyprop-1-en-1-yl)-2-methoxyphenoxy) acetyl)-
4-iopropyl-1-((R)-1-phenylethyl)imidazolidine-2-one (36)
To a solution of of (E)-4-(3-hydroxyprop-1-en-1-yl)-2-methoxyphenol (11.10 mmol) in
25ml Acetone at room temperature was added K2CO3 (27.74 mmol) and KI (1.109 mmol)
and stir for 15 min. A Solution of (S)-3-(2-bromoacetyl)-4-isopropyl-1-((R)-1-
phenylethyl)imidazolidine-2-one (12.20 mmol) in acetone was added to the reaction
mixture.The reaction mixture was allowed to stir overnight at room temperature,after the
completion of the reaction (monitored by TLC) water was added and organic layer was
separated,washed with brine.The solvent wass evaporated under vaccum. Crude product
was purified by column chromatography over silica gel (60-120) merck using
hexane/ethylacetate as eluent to afford the desired product.(yield 95%).
Sticky liquid;(α)25
D +136.87 (c 0.5 in CHCl3 );1
H NMR (400 MHz, CDCl3 ) δ 0.84 (d, J
=6.88 Hz, 3H ), 0.87 (d, J =7.0 Hz, 3H), 1.6 (d, J = 7.16 Hz, 3H), 2.46 -2.50 (m, 1H),
3.01 ( t, J = 9.6 Hz, 1H), 3.15 (dd, J =3.02 Hz, 9.70), 3.90 (s, 3H), 4.22 (dt, J = 9.44, 3.32
Hz,1H), 4.30 (dd, J = 5.86, 1.3 Hz, 2H), 5.33 (q, J = 7.10 Hz, 1H), 5.37 (d, J = 3.6 Hz,
2H), 6.24 (dt, J = 15.8, 5.88 Hz, 1H), 6.53 (d, J = 15.84 Hz, 1H), 6.79 (d, J = 8.28 Hz,
1H), 6.67(dd, J = 8.3, 1.86 Hz, 1H), 6.69 (d, J = 1.8 Hz, 1H), 7.31-7.41 (m, 5H).
13
C NMR (100 MHz, CDCl3) δ 14.31, 16.16, 17.94, 37.90,50.49,54.96, 55.90, 60.46,
63.73, 68.42, 109.59, 113.57, 119.39, 126.87, 127.17, 128.09, 128.52, 130.72,130.98,
138.72, 147.45, 149.45, 154.47, 168.40.
HRMS (ESI-TOF) calcd for C26H34N2O5Na (M+Na )+
: 475.2209; found: 475.2219

Page 22
Synthesis of (S)-3-(2-(4-((E)-3-((tert-butyldimethylsilyl)oxy) prop-1-en-1-yl)-2-
methoxyphenoxy)acetyl)-4-iopropyl-1-((R)-1-phenylethyl)imidazolidine-2-one (37)
To a solution of (S)-3-(2-(4-((E)-3-hydroxyprop-1-en-1-yl)-2-methoxyphenoxy)acetyl)-4-
isopropyl-1-((R)-1-phenylethyl)imidazolidine-2-one (6.629 mmol) in 40 ml DCM was
added imidazole (16.57 mmol) at 0 0
C and stir for 30 min. Then the solution of TBSCl
(6.629 mmol) in 10 ml DCM was added to the reaction mixture. The reaction mixture
was allowed to warm to room temperature and stir for another 2 hr. Afer the completion
of the reaction (monitored by TLC ) water was added to the reaction mixture, organic
phase was separated and dried over anhydrous sodium sulphate. Solvent was evaporated
and crude product was purified by column chromatography (60-120) to give product as
sticky liquid (yield 94%).
Sticky liquid; [α]25
D + 131.21 (c 0.5 in CHCl3); 1
H NMR (400 MHz,CDCl3) δ 0.13 (s,
6H), 0.85 (d, J = 6.88 Hz, 3H), 0.89 (d, J = 7.04 Hz, 3H), 0.96 (s, 9H), 1.61 (d, J = 7.16
Hz, 3H), 2.46 -2.53 (m, 1H), 3.02 (t, J = 9.58 Hz, 1H), 3.16 (dd, J = 9.66, 3.02 Hz, 1H),
3.75-3.79 (m, 1H), 3.93 (s, 3H), 4.23 (dt, J = 9.54,3.34 Hz, 1H), 4.35 (dd, J = 5.24, 1.6
Hz, 1H), 5.36 (q, J = 7.16 Hz, 1H), 5.38 (d, J = 2.32 Hz, 2H), 6.17 (dt, J = 15.72, 5.24
Hz, 1H), 6.52 (d, J = 15.8 Hz, 1H), 6.80 (d, J = 8.28 Hz, 1H), 6.88 (dd, J = 8.32, 1.84 Hz,
1H), 6.96 (d, J = 1.84 Hz, 1H), 7.33-7.42 (m, 5H).
13
C NMR (100 MHz, CDCl3 ) δ 5.03, 14.39, 16.23, 18.02, 18.56, 26.08, 28.37, 37.95,
50.52, 55.01, 56.00, 64.10, 68.52, 109.68, 113.68, 119.29,127.25, 127.56, 128.14, 128.89,
129.47, 131.24, 138.85, 147.31, 149.53, 154.55, 168.48.
HRMS (ESI-TOF) calcd for C32H46N2O5SiNa [M+Na]+
: 589.3074; found:589.3075
Synthesis of (S)-3-((R)-2-(4-((E)-3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-2-
methoxyphenoxy)-3-(4-((tert-butyldiphenylsilyl)oxy)-3-methoxyphenyl)propanoyl)-
4-isopropyl-1-((R)-1-phenylethyl)imidazolidin-2-one (38)
To the solution of (S)-3-(2-(4-((E)-3-((tert-butyldimethylsilyl)oxy) prop-1-en-1-yl)-2-
methoxyphenoxy)acetyl)-4-iopropyl-1-((R)-1-phenylethyl)imidazolidine-2-one (0.6 g, 1.0
equiv) in freshly dried THF (5 mL) under N2 environment was cooled to –78 °C and
added LiHMDS solution (1.1 equiv; 1M in THF) and TMEDA (1.05 equiv.) at ‒78°C,
and stirred for 1 h then the (4-(bromomethyl)-2-methoxyphenoxy)(tert-
butyl)diphenylsilane (1.1 equiv) was added to the reaction mixture and further stirred for
30 min and then the temperature was increased to -20 0
C and stir for another 4 h. The
reaction was quenched by half saturated aq NH4Cl solution, and extracted with EtOAc

Page 23
which was further washed with brine and dried over anhydrous sodium sulphate. The
crude was purified by flash column chromatography using silica gel (60-120 mesh)
eluting with petroleum ether/EtOAc (9:1) to afford desired product
1
H NMR (400 MHz, CDCl3) 0.13 (s, 6H), 0.76 (d, J = 6.9 Hz, 3H), 0.86 (d, J = 7.0 Hz,
3H), 0.96 (s, 9H), 1.12 (s, 9H), 1.61 (d, J = 7.1 Hz, 3H), 2.26 – 2.34 (m, 1H), 2.97 (t, J =
9.5 Hz, 1H), 3.09 (t, J = 10.1 Hz, 1H; merge with doublet at 3.11), 3.11 (d, J = 9.4 Hz,
1H; merge with triplet at 3.09), 3.27 (dd, J = 3.3, 13.7 Hz, 1H), 3.59 (s, 3H), 3.68 (s, 3H),
4.26 (tt, J = 3.1, 9.4 Hz, 1H), 4.34 (dd, J = 1.6, 5.2 Hz, 2H), 5.39 (q, J = 7.1, 1H), 6.10 –
6.15 (m, 1H), 6.18 (dd, J = 3.7, 9.5 Hz, 1H), 6.48 (d, J = 15.8 Hz, 1H), 6.57 (d, J = 8.3
Hz, 1H), 6.65 (d, J = 8.1 Hz, 1H), 6.72 (dd, J = 1.9, 8.3 Hz, 1H), 6.78 (dd, J = 2.0, 8.2
Hz, 1H), 6.86 (d, J = 1.9 Hz, 1H), 7.00 (d, J = 2.0 Hz, 1H), 7.31 – 7.35 (m, 7H), 7.37 –
7.41 (m, 4H), 7.70 – 7.74 (m, 4H)
13
C NMR (400 MHz, CDCl3) -5.09, 14.58, 16.07, 17.96, 18.48, 19.79, 26.01, 26.72,
28.73, 37.56, 39.42, 50.33, 54.79, 55.35, 55.96, 64.02, 78.44, 110.38, 114.49, 116.26,
119.35, 119.69, 120.31, 121.65, 127.04, 127.15, 127.42, 128.00, 128.39, 128.76, 129.40,
129.47, 129.54, 130.48, 131.29, 133.83, 133.88, 135.39, 138.95, 143.64, 147.40, 149.97,
150.04, 154.05, 171.39.
Synthesis of (R,E)-2-(4-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-2-
methoxyphenoxy)-3-(4-((tert-butyldiphenylsilyl)oxy)-3-methoxyphenyl)propan-1-ol
(39)
To a solution of (S)-3-((R)-2-(4-((E)-3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-2-
methoxyphenoxy)-3-(4-((tert-butyldiphenylsilyl)oxy)-3-methoxyphenyl)propanoyl)-4-
isopropyl-1-((R)-1-phenylethyl)imidazolidin-2-one 38 in MeOH was added NaBH4 (4
equi) at rt and stir for 2 h. After the completion of the reaction monitored by the TLC,
MeOH was evaporated using rotary evaporater and water and ethyl acetate was added,
organic layer was separated and washed with brine and dried over sodium sulphate.
Solvent was evaporated and crude product was purified by column chromatography (60-
120) to give product as sticky liquid.
1
H NMR (400 MHz, CDCl3) 0.14 (s, 6H), 0.97 (s, 9H), 1.13 (s, 9H), 2.82 (dd, J = 6.9,
13.9 Hz, 1H), 2.94 (s, 1H), 3.01 (dd, J = 6.7, 13.8, 1H), 3.56-3.67 (m, 5H; OMe, 3H & q,
2H, merged), 3.89 (s, 3H), 4.17 – 4.19 (m, 1H), 4.36 (dd, J = 1.6, 5.12, 2H), 6.20 (dt, J =
5.1, 15.8 Hz, 1H), 6.65-6.69 (m, 3H), 6.86 (dd, J = 1.8, 8.2 Hz, 1H), 6.94 (d, J = 1.8, 1H),
7.34-7.44 (m, 6H), 7.73 (d, J = 6.6 Hz, 4H)

Page 24
13
C NMR (400 MHz, CDCl3) -5.13, 18.48, 19.78, 26.00, 26.70, 37.32, 55.43, 55.84,
63.61, 63.87, 85.31, 109.70, 113.74, 119.77, 119.82, 120.15, 121.38, 127.46, 128.38,
129.03, 129.56, 130.97, 132.70, 133.67, 135.40, 143.74, 147.03, 150.42, 151.10.
Synthesis of Ligraminol E
To a solution of 39 in MeOH was added Pd/C and the reaction mixture was then degassed
and subjected to hydrogenolysis at a pressure of 5 atm for 3 h on a parr reactor. After
completion of the reaction, the reaction mixture was filtered through celiteR
-545 pad and
the filtrate thus obtained was evaporated in vacuum to get the crude mixture. Crude
mixture was then taken in THF and add TBAF (2.2 equi) at 0 0
C and stir for 1h. Water
was added to the reaction mixture, ethyl acetate was added and the organic layer was
separated washed with brine and dried over sodium sulphate and solvent was evaporated
and crude product was purified by column chromatography (60-120) to give product as
colourless oil.
1
H NMR (400 MHz, CDCl3): 1.83 (m, 2H), 2.62 (t, J = 7.8 Hz, 2H ) 2.90 (dd, J = 2.1, 6.7
Hz, 2H), 3.59 (t, J = 6.8 Hz, 2H) 3.62 (dd, J = 6.5, 11.5 Hz, 1H), 3.64 (dd, J = 3.5, 11.5
Hz, 1H), 3.79 (s, 3H), 3.82 (s, 3H), 4.36 (m, 1H), 6.69 (m, 2H) , 6.72 (dd, J = 1.5, 8.2 Hz,
1H), 6.82 (d, J = 1.6 Hz, 2H,), 6.83 (d, J = 8.2 Hz, 1H),
13
C NMR (400 MHz, CDCl3) 31.6, 34.4, 36.7, 55.4, 55.4, 61.2, 62.9, 82.5, 113.1, 113.3,
114.9, 117.6, 120.7, 121.8, 129.7, 136.8, 144.8, 145.7, 147.6, 150.7,

Page 25
11. References
1. Xia, Y.; Chang, L.; Ding, Y.; Jiao, B. Asymmetric synthesis of erythro-8-O-4'-
neolignan Machilin C. Mendeleev Commun. 2010, 20, 151-152.
2. Curti, C.; Zanardi, F.; Battistini, L.; Sartori, A.; Rassu, G.; Pinna, L.; Casiraghi, G.
Streamlined, asymmetric synthesis of 8, 4'-oxyneolignans. J. Org. Chem. 2006, 71, 8552-
8558.
3. Nie, G.; Cao, Y.; Zhao, B. Redox Rep. 2002, 7, 171-177.
4. G. P. Moss. Nomenclature of lignans and neolignans. Pure Appl. Chem., 2000, 72,
1493-1523.
5. C.E. Rye,; D. Barker. Asymmetric synthesis and anti-protozoal activity of the 8,40-
oxyneolignans virolin, surinamensin and analogues. Eur. J. Med. Chem. 2013, 60, 240-
248.
6. Tao Yuan,; Liya Li,; Yan Zhang,; Navindra P. Seeram.. Journal of functional foods
2013, 5, 1582 –1590.
7. Liya Li and Navindra P. Seeram. Further Investigation into Maple Syrup Yields 3 New
Lignans, a New Phenylpropanoid, and 26 Other Phytochemicals. J. Agric. Food Chem.
2011, 59, 7708–7716.
8. ) Kelly, T.R.; Arvanitis, M. Tetrahedron Lett 2000, 41 1793–1796
9. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483–
2547.
10. (a) Frater, G. Y.; Muller, U.; Gunther, W. Tetrahedron Lett. 1981, 22, 4221–4224;
(b) Angelo, J.; Pages, O.;Maddaluno, J.; Dumas, F.; Revial, G. Tetrahedron Lett.1983,
24, 5869–5872; (c) Helmchen, G.; Wierzchowski,
R.Angew.Chem.,Int.Ed.Engl.1984,23,60–61;
(d) Kelly, T.R.; Arvanitis, A. Tetrahedron Lett. 1984, 25, 39–42;(e) Enomoto, M.; Ito,
Y.; Katsuki, T.; Yamaguchi, M.Tetrahedron Lett. 1985, 25, 1343–1344;(f) Ludwig,
J.W.; Newcomb, M.; Bergbreiter, D. E. Tetrahedron Lett.1986, 26, 2731–2734;(g)
Pearson, W. H.; Cheng, M.-C. J.Org. Chem. 1986, 51, 3746–3748;(h) Cardillo, G.;
Orena,M.; Romero, M.; Sandri, S. Tetrahedron 1989, 45, 1501–1508; (i) Chang, J.-W.;
Jang, D.-P.; Uang, B.-J.; Liao,F.-L.; Wang, S.-L.Org. Lett.1999,1, 2061–2063(j) Jung,J.

Page 26
E.; Ho, H.; Kim, H.-D. Tetrahedron Lett. 2000, 41,1793–1796;(k) Crimmins,M.;
Emmitte, K.A.; Katz, J.D.Org. Lett. 2000, 2, 2165–2167; (l) Yu, H.; Ballard, E.;Wang,
B. Tetrahedron Lett. 2001, 42, 1835–1838;
11 . Yu, H.; Ballard, C. E.; Boyle, P. D.; Wang, B. Tetrahedron 2002, 58, 7663–7679
12. Khatik G.L; Kumar V.; Nair V.A. Org. Lett. 2012, 14, 2442–2445

hathi ram thesis final pdf

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Viewers also liked

Viewers also liked (6)

Similar to hathi ram thesis final pdf

Similar to hathi ram thesis final pdf (20)

hathi ram thesis final pdf