Synopsis
The Thesis entitled “
Synthetic efforts towards Eleutherobin, (6S)-5,6dihydro-6-[-(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one and development of one-pot reactions” has been divided into three chapters.
Chapter I : This chapter deals with the brief introduction to cancer and efforts towards the synthesis of Eleutherobin.
Chapter II : This chapter describes an efficient synthesis of (6 S )-5,6-dihydro-6-[-(2 R )-
2-hydroxy-6-phenylhexyl]-2 H -pyran-2-one.
Chapter III : This chapter deals with introduction to development of one-pot reactions.
This is further subdivided into two sections.
Section A: This section deals with a solvent and catalyst free one-pot synthesis of

amino phosphonates.
Section B: This section describes triethylborane triggered domino Michael-aldol three component coupling reaction.
Chapter I : Chapter I deals with a brief introduction to cancer and efforts towards the synthesis of Eleutherobin.
INTRODUCTION :
Eleutherobin is a toxin, which was isolated in 1995 by Fenical et al., from an
Eleutherobia species of marine soft corals ( Eleutherobia albiflora Alcynacea,
Alcyoniidea) collected in the Indian Ocean near Bennett’s Shoal in Western Australia.
The soft corals have tentacles, which are surrounded by needle tipped poison sacs called nematocysts. By injecting this nerve toxin into passing prey, they paralyse the creatures they intend to devour.
I

Synopsis
Eleutherobin is a diterpene glycoside (20 carbon core) and belongs to the family of 1,4-oxacladiellanes. It is a very complex molecule and more easier to look at it as a composition of three different parts. The carbon skeleton (the eleutherobin core), which contains a cyclohexene ring that is cis -fused to cyclodecane ring, an ester (can be derived from urocanic acid), and a sugar (that can be derived from D-arabinose).
Unfortunately this soft coral is a very rare species and produces only extremely small amounts of the toxin; therefore in order to obtain sufficient amounts for use as an anticancer drug it must be produced synthetically. Eleutherobin kills cells even if diluted to a million fold.
O
12
13
17
11
14
A
19
18
20
H
9
10
1
2
B
O
8
3
O
H
15
7
C
4
Me
16
6
5
OMe
O
OAc
N
O OH
N CH
3
OH
Eleutherobin 1
Retrosynthetic analysis for convergent approach for eleutherobin, and synthesis of compounds 3 and 4 is as outlined below. We envisioned that the ‘C’ (C3-C8) ring of eleutherobin could be formed by oxidation and Lindlar’s reduction of triol 6 . This intermediate, inturn, would be generated by Sharpless asymmetric dihydroxylation of enynol 13
. ‘A’ (C9-C14) ring would be synthesized from a MOM protected ketone
3 , which could be obtained by the modification of S -(+)-carvone 7 (Scheme 1).
II

Retro synthetic analysis:
H
H
1
O
O
Me
O
N
OMe
O
OAc
O OH
OH
N CH
3
H
OR
H
OMOM
3
H
O
OMOM
5
O
( S )-(+)-Carvone 7
+
H O
H O
Scheme 1
H O
Me
O
4
6
OH
8
OH
OH
H
H
2
OR
Me
O
OMe
COOR'
OTBDPS
OTPS
Synopsis
III

Synopsis
Initially synthesis of ‘C’ ring was started with a mono protection of 1,3propanediol 9 as the corresponding t butyldiphenylsilylether 10 using TBDPSCl and diisopropylethylamine in dichloromethane at 0 o C to afford 10 in 90% yield. The thusobtained monoprotected TBDPS ether 10 was subjected to ‘Parekh-Doering oxidation’ using SO
3
-pyridine complex in DMSO/CH
2
Cl
2
solvent system at room temperature to convert as corresponding aldehyde 11 in 93% yield (Scheme 2).
H O
9
OH
TBDPSCl, DIPEA
CH
2
Cl
2,
r.t., 90%
TBDPSO
10
OH
SO
3
.pyr
DMSO:CH
2
Cl
2
(1:4)
r.t., 93%
O
TBDPSO
11
H
Scheme 2
On the other side, to introduce a required alkyne moiety (C5-C8), initially the commercially available 2-methyl-3-butyn-2-ol 8 was subjected to dehydration process using acetic anhydride to afford a low boiling (b.p. 30 o
C) enyne 12 in 60% yield. The key union was achieved by addition of acetylide anion to aldehyde. Treatment of n
BuLi with alkyne 12 at –78 o C in THF for 1 h and followed by aldehyde 11 addition at the same temperature in THF afforded the enynol 13 in 94% yield (Scheme 3). i. n BuLi, -78 o C, THF H
3
C
H
3
C
OH
CH
Ac
2
O, H
2
SO
4
(cat) heat, 50 o C, 60%
H
2
C
H
3
C
12
CH ii.
TBDPSO
O
8
11
H
OH
H
2
C
H
3
C
OTBDPS
13
Scheme 3
IV

Synopsis
Thus, initially we concentrated on crucial element of stereochemistry at C7, which was established using ‘Sharpless asymmetric dihydroxylation’ method.
Treatment of enynol 13 with AD mix-

in t
BuOH:H
2
O in 1:1 ratio at 0 o
C for 24 h resulted in triol
6 in 90% yield with 76% ee . The stereo chemical assignments were supported by chiral
HPLC. The selective oxidation of C4-hydroxy group was achieved after protection of
C8-C7 triol 9 as its acetonide using 2,2-DMP and catalytic CSA in dichloromethane to give acetonide protected compound 14 in 95% yield (Scheme 4).
OH
13
ADmix-alpha t BuOH:H
2
O (1:1)
0 o C, 90%
H O
H O
6
OTBDPS
2,2-DMP, CSA
CH
2
Cl
2,
r.t., 95%
OH
O
OTBDPS
O
14 Scheme 4
Now oxidation at C4-carbon of triol 14 accomplished with mild oxidizing agent
MnO
2
in dichloromethane at room temperature, gave the keto compound 15 in 92% yield. With a required skeleton in hand, a hydrolysis reaction was carried out using
80% AcOH at room temperature to provide an alkynediol 16 requisite for cyclization after partial reduction.
O
14
MnO
2
CH
2
Cl
2,
r.t., 92%
O
O
15
OTBDPS
80% AcOH r.t., 82%
H O
H O
16
O
Pd/CaCO
3,
H
2
OTBDPS
Ethylacetate, r.t., 93%
H
3
C
H O
O
4
OH
OTBDPS
Scheme 5
V

Synopsis
The alkynediol 16 on partial reduction, after in situ cyclization yielded the ‘C’ ring skeleton 4 in 93% yield (Scheme 5).
Synthesis of ‘A (C9-C14)’ ring:
Since the carbon framework required for the ‘A’ ring of target compound 3 can directly be mapped onto S - (+)-carvone 7 and its hydroxymethylation makes it possible to obtain the two of the chiral centers, it was chosen as an ideal starting material. The selective hydrogenation of S - (+)-carvone 7 using Wilkinson’s catalyst in toluene afforded 17 in 92 % yield. Generation of a new chiral center by one carbon introduction at C1-carbon was accomplished with the treatment of TiCl
4
, DIPEA and MOMCl in dichloromethane from –78 o
C to 0 o
C to afford the hydroxy compound by in situ deprotection of methylether to yield 18 in 50% yield (Scheme 6).
O
(PPh
3
)
3
RhCl/H
2
PhCH
3,
r.t., 92%
O i. TiCl
4
, -78 o C ii. DIPEA, -78 o C iii. CH
3
OCH
2
Cl
CH
2
Cl
2
, 50%
7 17
18
Scheme 6
O
OH
Modifications at C10-needed chemical inactivity at C2-carbon, which was in turn, protected as corresponding MOMether using MOMCl and DIPEA in dichloromethane to give 5 in 95% yield. Olefination was affected with Tebbe’s reagent to give diene 19 in 82% yield (Scheme 7).
18
MeOCH
2
OCl,
DIPEA
CH
2
Cl
2
, 0 0 C, 95%
O
OMOM
Tebbe reagent
THF, r.t., 82%
CH
2
OMOM
5
Scheme 7
19
VI

Synopsis
A streoselective hydroboration of diene 19 was achieved with 9-BBN in THF resulting in hydroxy compound 3 in 58% yield (Scheme 8), which will act as ‘A’ ring synthon for coupling of ‘A’ and ‘C’ rings to obtain the tricyclic core of the target molecule.
OH
CH
2
OMOM i) 9-BBN, THF, reflux ii) 15% NaOH, H
2
O
2 ,
58%
OMOM
19 3
Scheme 8
VII

Synopsis
Chapter II : Chapter II describes an efficient synthesis of (6 S )-5,6-dihydro-6-[-(2 R )-2- hydroxy-6-phenylhexyl]-2 H -pyran-2-one.
Ravensara crassifolia DANGUY (Lauraceae) (syn. Cryptocarya crassifolia
Baker), a tree up to 18-20 m growing in the eastern region of Madagascar. The genus
Ravensara is considered as endemic to Madagascar. In a series of preliminary screenings, (6 S )-5,6-dihydro-6-[-(2 R )-2-hydroxy-6-phenylhexyl]-2 H -pyran-2-one 20 , isolated from the above natural source displayed antifungal activity against the phytopathogenic fungus cladosporium cucumerinum in a bioautographic TLC assay.
Pyranone 20 possesses a noncoplanar six membered

,

-unsaturated lactone chromophore, in addition to a monosubstituted benzene one with a four-C distance from the chirality center at C (2’).
The minimum amount of compound 20 required to inhibit C. cucumerimum fungal growth on TLC plates was 1
 g. These amounts were comparable to the minimum quantities in the same assays of miconazole (1
 g) and propiconazole (0.1
 g), two commercially available reference antifungal compounds.
5"
4"
6"
3"
1"
6'
2"
5'
4'
3'
O
OH O
1
6
5
2'
1'
2
4
3
20
The retro synthetic analysis for pyranone 20 may be represented as below. The key step was the ring closing metathesis reaction leading to the formation of the 5,6dihydro pyran-2-one which would be derived from the homoallylic alcohol. The MOM ether of homoallylic alcohol 22 would be established through an asymmetric allylation
VIII

Synopsis
(Marouka allylation) of phenylpentanal 23 , which inturn could be obtained from commercially available 3-phenylpropanol 24 (Scheme 9).
Retro synthetic analysis:
O
OMOM O
Keck allylation
20
RCM
21
OMOM
O
22
Marouka allylation
H
23
24
OH
Scheme 9
Initially, the requisite aldehyde 5-phenylpentanal 23 was synthesized in five steps from commercially available 3-phenylpropan-1-ol 24 . The oxidation of 24 was carried out using iodoxybenzoicacid in DMSO/THF yielded the 3-phenylpropanal 25 in
88% yield. A two carbon homologation was achieved by a simple Wittig reaction using carbomethoxymethylene triphenyl phosphorane in benzene to afford the

,

unsaturated ester 26 in 93% yield (Scheme 10).
Reduction of the olefinic functionality as well as ester functionality of unsaturated ester 26 in one step was unsuccessful with excess lithium aluminium hydride. Alternatively a sequential reduction of the olefin and ester was achieved.
Treatment of unsaturated ester 26 with Mg/methanol caused the selective reduction of the olefin resulting in saturated ester 27 in 93% yield. The ester 27 was then reduced to alcohol 28 using lithium aluminium hydride in THF at 0 0 C to room temperature.
IX

Synopsis
24
OH Iodoxybezoic acid
DMSO/THF, r.t., 88%
O
OMe
Mg/MeOH
r.t., 93%
25
O
H
Ph
3
P=CHCOOMe
Benzene, r.t., 93%
O
OMe
LiAlH
4
, THF
0 0 C - r.t., 90%
26 27
OH
28
Scheme 10
The required aldehyde 23, was prepared by oxidation of the 28 using iodoxybenzoicacid in DMSO/THF (Scheme 11). With the required aldehyde 23 in hand our aim was to introduce chirality at the C2’carbon using catalytic asymmetric allylation method. In general asymmetric allylation can be achieved using β -allyl diisocampheylborane or Keck stereoselective allylation reaction conditions. According to the recent report on modified Keck allylation by Marouka et al., a higher ee was observed. Accordingly we planned for a Marouka allylation on the aldehyde 23 .
Initially the Ti-BINOL complex was prepared as follows. Treatment of 5 mol% of
TiCl
4
and 15 mol% of Ti(O i Pr)
4
in dichloromethane at room temperature resulted in
TiCl(O i
Pr)
3
, which was dimerized using 10 mol% silver oxide at the same temperature.
Then the Ti-dimer was treated with 2 eq. of ( S , S )-BINOL to give the required catalyst for the asymmetric allylation. To the same reaction mixture at –15 o C was added 5phenylpentanal 23 , allyln -tributylstannane and allowed to stirr at 0 o
C for a period of
12 h to yield the homoallylalcohol 29 in 82% yield with 96% ee (based on chiral
HPLC).
X

Synopsis
28
OH Iodoxybenzoicacid
DMSO:THF, r.t., 88%
23
O
H
TiCl
4
(5 mol%),
Ti(O i Pr)
4
(15 mol%), r.t.,
Ag
2
O (10 mol%), r.t.,
S -BINOL (20 mol%), r.t.,
Allyltri n butyltin, 0 0 C, 82%
29
OH
Scheme 11
Choice of the protection at the hydroxyl group was a must to achieve a selective asymmetric allylation at C6’ carbon. According to earlier reported method silyl ether protection was unsatisfactory in diastereoselectivity of second asymmetric allylation.
Thus we planned to employ methoxymethylene protection for the hydroxy functional group. The hydroxyl functionality in 29 was protected as its methoxymethylene
(MOM) ether using methoxymethylene chloride and diisopropylethylamine in dichloromethane at 0 o
C resulting in MOM-ether 22 in 90% yield. Dihydroxylation using OsO
4
/NMO in t
BuOH/H
2
O resulted diol 30 in 90% yield. Cleavage of diol 30 using sodium metaperiodate (NaIO
4
) in THF/H
2
O resulted the aldehyde 31 in 85% yield
(Scheme 12).
29
MOMCl, DIPEA
CH
2
Cl
2
, r.t., 90%
22
OMOM
30
OMOM OH
OH NaIO
4
THF:H
2
O (1:1), 85%
Scheme 12
OsO
4
(2 mol%)
NMO.H
2
O
Acetone:H
2
O
r.t., 90%
31
OMOM O
H
XI

Synopsis
The asymmetric allylation on 31 using Keck approach resulted diastereomers in
9:1 (by NMR) of the alcohol 21 in 72% yield (Scheme 13). To construct the 5,6dihydropyran-2-one moiety, initially allylicalcohol 21 was converted into the acryloylester 32 using acryloyl chloride and diisopropylethylamine.
OMOM O
H
Ti(O i Pr)
4
(10 mol%)
S -BINOL (20 mol%), r.t., 1 h
Allyl tri n butyltin
CH
2
Cl
2
, r.t., 72%
OMOM OH
21
31
O
OMOM O
Acryloyl chloride,
DIPEA,
CH
2
Cl
2
, 0 o C, 85%
32
Scheme 13
At this stage, ring closure metathesis (RCM) of unsaturated ester 32 has been successfully used to achieve the target lactone moiety using Grubb’s catalyst, with the full carbon frame diene ester 32 using Ru-catalyst to afford the lactone compound 33 in
80% yield. Deprotection of the MOM ether with 6N HCl in THF resulted in the final target molecule 20 in 90% yield (Scheme 14).
32
OMOM O
O
6 N HCl:THF:H
2
O
(1:2:1) r.t., 90%
20
(Cy
3
P)
2
Cl
2
Ru=CHPh
(5 mol%)
CH
2
Cl
2
, r.t., 80%
Scheme 14
33
OMOM O
O
XII

Synopsis
Chapter III :
Introduction to one-pot reactions
Synthetic organic chemistry has always been a frontier area of research due to its impact on the materials and biological sciences. The scientific community in this area is constantly thriving to develop efficient methodologies, novel reactions and processes that will lead to the synthesis of desired target molecules and their derivatives with ease.
Synthetic organic chemistry is not only a tool for obtaining compounds that can be utilized for understanding biological functions or the behavior of materials, but it also leads to the creation of novel drug or drug like candidates and of novel materials with interesting properties.
Generally the targets are usually made via an elaborate chain of separate reaction steps that takes longer time to complete, and when that process is enlarged to industrial or large scale, it becomes an environmentally, economically and energetically non viable. These environmental and economical concerns have increased in the political and economic world over the last one or two decades because quality of life is strongly connected to a clean environment.
The reaction sequence should be designed in such a manner that the first step creates the conditions to trigger the next step, and so on. Chemists can put all the ingredients in together at the beginning. This type of multistage reaction has always been a part of organic synthesis, which is known as “one-pot reaction”, meaning
“chemical conversions consisting of a number of sequential transformations are brought about in one reaction step”. According to Tietze “ we are trying to copy nature by performing a reaction intermediate products and by retaining the same gentle reaction conditions through out
”. This approach is not only selective but also highly efficient,
XIII

Synopsis saving time, energy and raw materials, and adds chemists aim to use the mildest possible conditions, ideally a temperature of 25
0
C, atmospheric pressure, an environmentally safe solvent and finding suitable nontoxic catalyst.
This kind of organic synthesis not only promises diversity, it also copes well with one of the major concerns of the pharmaceutical industry getting shape right. The effectiveness of many compounds, particularly biological ones is critic.
‘One-pot’ reactions can be divided into two groups (i) Domino reactions and (ii)
Consecutive reactions. Domino reactions also described as tandem, sequential, iterative, zipper or cascade reactions, a process involving two subsequent reactions result as a consequence of the functionality formed by bond formation or fragmentation of a reactive intermediate is not counted here as a reaction step.
In consecutive reaction another reagent mediator, or catalyst is added after the first transformation without isolation of the first formed product or strictly speaking sequences in which the individual steps are carried out at different temperatures should also be included in this area.
XIV

Synopsis
Section A : It deals with a solvent and catalyst free one-pot synthesis of

-amino phosphonates.
Development of a reaction media, which is environmentally benign, is an important task for modern day synthetic chemistry. Organic solvents are the major concern as they occupy major volumes and their disposal and recycling has been a target of concern. Most of the organic reactions have been studied in solution phase.
One reason for this might be Aristotle’s famous philosophy, “No coopora nisi Fluida”, which means, “No reaction occurs in the absence of solvent”. This philosophy had a big influence on modern science. However, many biological reactions occur in absence of the solvent. Some approaches explored to minimize solvents, replace with more ecofriendly ionic liquids as solvents, water as solvent, as the reaction medium and multicomponent coupling in one-pot to avoid more steps in synthetic sequence. It is important that, if one could develop a simple procedure the synthesis of organic intermediates or targets using a one-pot, multicomponent, reagent or a catalyst free reaction will lead to a general method, useful to organic chemistry in economic and ecological aspects. Considering all these aspects, we have developed a first solvent and catalyst free one-pot multicomponent reaction for the synthesis of
α
-amino phosphonates using carbonyl compounds, amines and triethylphosphite. The present method describes a general procedure producing biologically important

-amino phosphonates (Scheme 15).
R
O
R 1
+ R 2 -NH
2
+ P(OEt)
3
No catalyst r. t., 15 min - 12 h
R, R 2 = aryl, alkyl
R 1 = H, alkyl
Scheme 15
R 1
HNR 2
R
P(OEt)
2
O
XV

Table 1. Solvent and catalyst free one-pot synthesis of
 aminophosphonates
Entry Carbonyl compound Amine
Time
(min)
Yield a
(%)
CHO 15 95 1
2 CHO
H
2
N
H
2
N OMe
15 93
3 CHO 8 b 93
4
5 H
3
C
6 MeO
CHO
CHO
CHO
7
13
Cl CHO
8 O
2
N CHO
9 O
2
N
10
CHO
O
CHO
11
12
CHO
CHO
CHO
14
CHO
15
CHO
H
2
N
H
2
N
H
2
N
H
2
N
H
2
N
H
2
N
CH
3
Ph
H
2
N
H
2
N OMe
OMe
H
2
N
H
2
N
H
2
N
H
2
N
H
2
N
12 b, c 85
15 94
20 90
30 89
30 93
15 95
20 94
60 92
45
60
60
60
93
91
93
90
CHO
16 45 95
H
2
N
17
CHO
H
2
N 45 94
18
19
20
O
O
CHO
H
2
N
H
2
N
H
2
N
60 84
12 b
12 b
80
85 a) Isolated after column chromatography and characterised by
and Mass spectroscopy.
1 H NMR b) Time in hours.
c) 86% de (HPLC).
XVI
Synopsis

Synopsis
Section B : Triethylborane triggered domino Michael-aldol three component coupling reaction.
Over the past two decades there has been a great demand to develop ‘one-pot’ procedures for successive reactions for the formation of several C-C bonds. The minimization of steps involved in multistep synthesis not only allows the reduction of waste but also results in the diminution of costs. The word ‘domino’ has been coined and extensively used by Tietze et al., for such classes of reactions. Of several such transformations described to date, most reactions concern radical or anionic processes and involve intramolecular reactions resulting in the formation of carbocycles. Metal catalysts are extensively used for these transformations. Three-component couplings involving the successive formation of two bonds preferably C-C bonds using a single catalyst are being seriously studied in several laboratories and Lewis acids are often used for this purpose. The most common Lewis acids include lanthanum and scandium triflate, BiCl
3
and others but most involve one C-C and one C-X bond where ‘X’ is a heteroatom.
Installation of two carbon chains in the

and

positions in enones has been studied to some extent using base or Cu(OTf)
2
and a chiral ligand.
While exploring this multicomponent “domino” reaction, we have observed serendipitously that no additional catalyst is required for the domino Michael-aldol reaction if the carbon nucleophile for Michael initiation is obtained from Et
3
B. In this section, the results pertaining to this very useful Michael-aldol reaction are described. In the design of the present protocol the following aspects were considered; a) Can one of the reagents add in a Michael fashion onto the enone without any external catalyst? b) Are functional groups tolerated? c) What is the role of substituents in the aldol reaction once the Michael reaction has been triggered, d) Can metal contamination be avoided? More
XVII

Synopsis important observation is that the Michael addition of Et
3
B onto methyl vinyl ketone and the subsequent aldol reaction between the

-carbon of the methyl vinyl ketone and aryl/alkyl aldehyde were very facile (Scheme 16).
Scheme 16
R-CHO +
R = aryl, alkyl
1
Entry
1
2
3
4
MeO
5
6
7
8
9
10
H
3
C
MeO
O
O
O
2
N
Cl
O
O
2
N
Et
3
B
THF, r.t.
R-CHO
CHO
( 1a )
CHO
( 1b )
CHO
( 1c )
CHO
( 1e )
8
CHO
( 1f )
4
CHO
( 1g )
Cl
CHO
( 1h )
4
CHO
( 1i )
O
CHO
( 1j )
R
OH O syn 2
+
R
OH O anti 2
Time
(h)
Product syn : anti
(%)
Yield
(%)
6
6
8
CHO
OMe
( 1d )
8
4
8
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
20 : 80 82
54 : 46 72
20 : 80 85
40 : 60 81
34 : 66 73
70 : 30 85
65 : 35 82
45 : 55 90
66 : 34 65
58 : 42 90
XVIII