I
Abstract
ABSTRACT
The thesis entitled “Development of novel synthetic methodologies and its
application for the total synthesis of scytophycin-C” is divided into three chapters.
CHAPTER I: Chapter I deals with the introduction to cancer and earlier synthetic
approaches of scytophycin C.
CHAPTER II: Chapter II is divided into two sections.
Section-A: This section describes the stereoselective synthesis of trans-2,6-disubstituted
3,6-dihydro-2H-pyrans by using InBr3 as a catalyst.
Section-B: This section describes the formation of C-(alkynyl)-pseudoglycals from δhydroxy-α,β-unsaturated aldehydes and alkynyl silanes using InBr3.
CHAPTER III: Chapter III is divided into two sections.
Section-A: This section describes the stereoselective synthesis of C6-C18 fragment of
scytophycin-C.
Section-B: This section also describes the synthesis of C6-C18 fragment of scytophycinC by a different approach.
II
Abstract
CHAPTER I: Chapter I deals with the introduction to cancer and earlier synthetic
approaches of scytophycin C.
The scytophycins are novel series of polyoxygenated 22-membered macrolides
isolated from the cultured terrestrial blue-green algae Scytonema pseudohofmanni, first
reported by Moore et al in 1986. They exhibit potent cytotoxicity against a variety of
human carcinoma cell lines, as well as broad-spectrum antifungal activity. Among them,
scytophycin-C (fig.1) has been demonstrated to exhibit significant activity against solid
tumors in vitro.
They act as cytotoxic agents by microfilament depolymerization and have been
show to circumvent P-glycoprotein medicated multidrug resistance in tumor cells, which
gives them therapeutic potential for cancer patients.
Scytophycin-C
OMe
O
O
OMe OMe
N
O
OH
OH
O
OMe
H
Me
O
Figure 1
Extensive research has been carried out worldwide by the legions of organic
chemists in past few years. Some of the important earlier contributions and recent
developments in this area are outlined in this chapter.
III
Abstract
CHAPTER II: This chapter is divided into two sections.
Section-A: This section describes the stereoselective synthesis of trans-2,6-disubstituted
3,6-dihydro-2H-pyrans by using InBr3 as a catalyst.
Substituted pyrans are a common structural motif of many natural products. The
dihydropyran skeleton is a particularly attractive target since it occurs in many natural
products such as swinholide, scytophycin C and laulimalide and furthermore the olefin
function is a synthetically useful handle for further functionalization, making it a key
intermediate to many polysubstituted tetrahydropyrans. They are also synthetically useful
intermediates in the preparation of polysubstituted tetrahydropyran ring systems, such as
those found in the pseudomonic acids. Some of the approaches for the preparation of
dihydropyrans, and some of the more varied methodologies include electrophile-initiated
alkylation of glycals, hetero-Diels-Alder cycloadditions, olefin metathesis, Prins
cyclizations of cyclopropyl carbinols, or homoallylic alcohols, and an intramolecular
silyl-modified Sakurai reaction (ISMS). Many of these reactions have limitations, such as
the need for strictly anhydrous conditions, stoichiometric quantities of Lewis acid
initiator, or delivery of a strong Lewis acid at low temperature.
Recently, indium tribromide has received increasing attention as a water-tolerant
green Lewis acid catalyst for organic synthesis demonstrating highly chemo-, regio- and
stereoselective results. Compared to conventional Lewis acids, it has advantages of water
stability, recyclability, operational simplicity, strong tolerance to oxygen and nitrogencontaining substrates and functional groups, and it can often be used in catalytic amounts.
IV
Abstract
A new method has been developed for the synthesis of trans-2,6-disubstituted 3,6dihydro-2H-pyrans of a variety of substitution patterns. This method involves Lewis acid
induced a tandem allylation or cyanation/cyclization of δ–hydroxy-α,β-unsaturated
aldehydes to produce dihydropyrans in good yields and with trans-selectivity (scheme 1).
OH
Ph
InBr3
CHO
O
+
Si
Ph
O
O
CH2Cl2, r.t.
Scheme 1
No cis-isomer was observed in the 1H NMR spectrum of the crude products obtained in
the C-allylation of δ-hydroxy-enals. This result provided the incentive for further study of
reactions with various δ-hydroxy-enals. Like allylsilane, trimethylsilyl cyanide also
participated effectively in this reaction (scheme 2).
OH
Ph
O
( )3
CHO
InBr3
+ TMSCN
Ph
O
( )2
O
CN
CH2Cl2 , r.t.
Scheme 2
The present method provides good yields of products with high regio- and
stereoselectivity
importance.
affording C-(allyl)-dihydropyrans of synthetic and biological
V
Abstract
Table 1: InBr3-catalyzed stereoselective synthesis of trans-2,6-disubstituted 3,6-dihydro-2H-pyrans
Entry
Nucleophile
Time (h)
Producta
Substrate
Yield (%)b
OH
Si
a
CHO
BnO
BnO
b
Si
CHO
BnO
O
BnO
O
OH
1.0
82
0.5
85
0.5
88
0.5
70
2.0
85
2.0
70
1.5
85
1.0
75
1.5
70
2.0
70
1.0
82
1.0
72
OAc
Si
c
AcO
AcO
CHO
OH
AcO
OAc
Si CN
d
AcO
O
AcO
CHO
OH
O
CN
AcO
OH
e
O
CHO
Si
OH
f
O
CHO
Si
OH
Si
g
BnO
CHO
OH
Si
h
CHO
PMBO
BnO
PMBO
O
O
OH
CHO
O
Si
i
OH
j
Si
k
Si
OH
CHO
BnO
OH
Si CN
l
aThe
O
CHO
BnO
BnO
BnO
CHO
products were characterized by 1H NMR, IR and mass spectrometry.
refers to pure products after chromatography.
bYield
O
O
CN
VI
Abstract
Section-B: This section describes the formation of C-(alkynyl)-pseudoglycals from δhydroxy-α,β-unsaturated aldehydes and alkynyl silanes using InBr3.
C-Glycosidation is of great significance in the organic synthesis of optically
active materials, since it allows the introduction of carbon chains into sugar chirons and
the use of sugar nuclei as a chiral pool as well as a carbon source. Many biologically
attractive C-glycosides such as aryl C-glycoside antibiotics have already been found in
nature, and several types of C-glycosides such as alkyl and allyl C-glycosides are well
recognized to be useful chiral building blocks for the synthesis of optically active natural
products.
The ever-increasing importance of the role of carbohydrates in biological
processes relating to immunology, virology, cancer, antibiotic action, and a host of lifethreatening diseases has heightened the interest in the accessibility of specific sugarbased molecules. Furthermore, carbon-linked glycosides, stable analogues of naturally
occurring O- and N-glycosides, have become the subject of considerable interest in
bioorganic and medicinal chemistry.
The synthesis of optically active compounds has posed challenges directed towards
new methodologies with more practical sources.
The development of effective C-
glycoside syntheses depends on the selective formation of only one anomer as the major
reaction product in good to excellent yield.
VII
Abstract
In recent years, indium reagents have emerged as mild and water-tolerant Lewis acids
imparting high chemo-, regio-, and stereoselectivity in various organic transformations.
R
R"
H
R'
OH
+
SiMe3
R
O
InBr3
DCM, rt
O
R'
R"
Scheme 3
A novel protocol has been developed for the synthesis of C-glycosides from δhydroxy-α,β-unsaturated aldehydes and silylacetylenes using a catalytic amount of
indium tribromide (scheme 3). The treatment of δ-hydroxy-α,β-unsaturated aldehydes
with alkynylsilanes in the presence of indium tribromide in DCM under mild reaction
conditions lead to formation of the corresponding C-(alkynyl)-pseudoglycals (Table 2) in
excellent yields with high -selectivity. The predominant formation of the -anomer
arise from a thermodynamic anomeric effect.
The present method provides high yields of products in a shorter periods with
greater -selectivity, which makes it a useful and attractive process for the synthesis of
C-glycosides of synthetic and biological importance.
VIII
Abstract
Table 2: Formation of C-(alkynyl)-pseudoglycals from hydroxy enals and silyl acetylenes.
Entry
H
Me3 Si
AcO
AcO
Ph
O
1a
OH
O
Me3 Si
SiMe3
AcO
AcO
1a
O
H
Me3 Si
AcO
O
1a
OAc
AcO
AcO
1a
OH
O
O
( )2
AcO
AcO
1a O
OH
O
AcO
AcO
3
1a
OH
O
AcO
H
Me3 Si
OTBDPS
AcO
AcO
1a
OH
O
H
Me3 Si
OTBDPS
AcO
AcO
OH
i
Me3 Si
j
Me3 Si
OH
( )6
Me3 Si
Ph
OH
aThe
1b
Ph
3.5
75
O
1c
1c
1.0
78
5.5
70
7.0
65
7.0
67
( )3
O
()
( )6
3
O
O
Ph
( )6
O
products were characterized by 1H NMR, IR and mass spectrometry.
refers to pure products after chromatography.
bYield
85
O
H
( )6
3.5
OTBDPS
AcO
H
( )3
90
O
H
OH
k
1a
Ph
( )3
3.0
OTBDPS
O
AcO
OAc
h
( )2
O
OAc
g
89
( )3
H
()
2.0
AcO
OAc
Me3 Si
90
AcO
H
f
2.0
O
OAc
Me3 Si
85
AcO
H
Me3 Si
e
1.0
AcO
OH
d
O
AcO
OAc
c
91
SiMe3
H
OH
0.5
AcO
OAc
b
Yield (%)b
Ph
OAc
a
Time (h)
Producta (2)
Substrate (1)
Nucleophile
O
IX
Abstract
Chapter-III: This chapter is further divided into two sections.
Section-A: This section deals with the present work wherein the stereoselective synthesis
of C6-C18 fragment of scytophycin-C applying a novel synthetic protocol, is described.
The high potent activity combined with unique and challenging structure has made this
compound an exciting target for total synthesis. Retrosynthetic analysis for this approach
is illustrated in scheme 4.
OMe
Me
Me
Retrosynthetic analysis:
Me
O
Me
MeO MeO
N
OH
Me
Me
O
Me
OMe
O
Me
OH
O
1
OMe
O
Me
Me
Me
Me
OMe
Me
O
Me
O
O
OMe
O
CHO
Me
OP
+
OP
O
O
Me
2
3
O
OBn
H
O
OMe
H
O
H
OH
BnO
CHO
OH
OH
H
6
4
5
BnO
COOEt
O
O
Ph
HO
BnO
7
8
Scheme 4
OH
OMe
O
9
X
Abstract
The synthesis of fragment 4 began with the commercially available (+) 2-methyl 3hydroxy propionate commonly called as Roche ester. Our approach for the synthesis of
fragment 4 is linear.
The free OH of the (+) 2-methyl 3-hydroxy propionate 9 is protected as its benzyl
ether 10 using silver oxide and benzyl bromide which is reduced to alcohol 11 using
LAH. This alcohol 11 is oxidized to aldehyde 12 under swern conditions using oxalyl
chloride, DMSO, and triethylamine.
OMe
HO
9 O
Ag2O, BnBr,
Et2O, rt, 72%
(COCl)2, DMSO, Et3N,
CH2Cl2, -78 oC, 93%
LAH, THF,
BnO
COOMe
10
BnO
H
O
12
0
oC,
BnO
92%
TiCl4, Ti(OiPr)4
R-BINOL, Ag2O
12 h, 0 oC, 78%
95% de
OH
11
BnO
8
OH
Scheme 5
The aldehyde 12 was subjected to Marouka allylation with allyltributyltin in the
presence of Ti(OiPr)4, TiCl4, Ag2O and (R)-BINOL in CH2Cl2 to afford corresponding
homoallylic alcohol 8 in 78% yield as shown in scheme 5. Osmylation of the terminal
vinyl group in alcohol 8 using OsO4 and NMO and subsequent oxidation with sodium
periodate produced the β-hydroxy aldehyde, which was then subjected to wittig
olefination reaction with (ethoxycarbonylmethylene)triphenyl phosphorane to produce δhydroxy-α,β-unsaturated ester 14 in 93% yield for three steps. Subsequent conversion of
ester 14 into benzylidene acetal 15 via oxy-Michael addition reaction namely, by
treatment with benzaldehyde and pot.tert.butoxide in THF at 0°C, in 70% yield with 9:1
XI
Abstract
syn:anti diastereomeric ratio. This ester was then reduced to alcohol 16 using LAH in
THF under anhydrous conditions (scheme 6).
8
OsO4, NMO,
Acetone:H2O, 88%
a) NaIO4, THF:H2O
r.t., 97%
BnO
OH
OH OH
13
PhCHO, tBuOK, BnO
O
OEt
OH
b) Ph3P=CHCO2Et,
C6H6, rt, 4h, 93%
O
14
BnO
OEt
O
0 oC, 2h, 70%
BnO
OH
LAH,THF
O
O
0 oC, 90%
O
Ph
Ph
15
16
Scheme 6
The alcohol 16 upon oxidation with IBX in DMSO and THF, afforded aldehyde 17
which
was
then
subjected
to
wittig
olefination
reaction
with
(ethoxycarbonylmethylene)triphenyl phosphorane to furnish the desired trans-unsaturated
ester 7 exclusively. The key intermediate 7 was selectively reduced to α,β-unsaturated
alcohol 18 using DIBAL-H at -78°C. This benzylidene acetal with allylic alcohol was
then deprotected using pTSA in MeOH to produce triol 19 as shown in scheme 7.
a) IBX, DMSO,
THF, rt, 89%
16
BnO
O
b) Ph3P=CHCO2Et
C6H6, rt, 92%
BnO
O
Ph
OH
O
O
Ph
DIBAL-H, CH2Cl2,
OEt
-78 oC, 2h, 87%
O
7
BnO
OH
p-TSA, MeOH,
rt, 12h, 76%
OH
OH
19
18
Scheme 7
XII
Abstract
This reaction was slow and took longer time to give triol. The regioselective oxidation of
compound 19 using MnO2 in CH2Cl2 afforded α,β-unsaturated aldehyde 6 as shown in
scheme-6 which was the substrate for formation of trans-disubstituted dihydropyran.
Although the formation of substituted dihydropyrans seems very difficult, this
key step was carried out by the lewis-acid promoted, nucleophile inducing formation of
dihydropyrans, using the methodology recently developed by us. Thus, on treatment of
the δ-hydroxy-α,β-unsaturated aldehyde 6 with allyl trimethylsilane, in the presence of
lewis acid InBr3, gave rise to the compound 5 in 83% yield with 2:8 syn:anti
diastereomeric ratio which are separated by column chromatography.
OBn
MnO2, CH2Cl2
19
BnO
rt, 3h, 87%
H
OH OH
OH
ATMS, InBr3,
CH2Cl2, rt, 1h, 83%
O
O
6
5
OBn
OMe
NaH, MeI,
O
THF, 0 oC, 92%
OH
OMe
Li, Naphthalene,
THF, -78 oC, 83%
20
O
21
Scheme 8
The secondary hydroxyl of 5 was then protected as its methyl ether using NaH
and methyl iodide in dry THF to give the methyl ether 20. The benzyl group of 20 is
selectively deprotected using Li and Naphthalene in THF to afford primary alcohol 21
without disturbing the double bonds in the dihydropyran ring as shown in scheme 8.
XIII
Abstract
O
H
OMe
21
DMP, CH2Cl2,
rt, 1h, 92%
O
CeCl3, MeLi, THF
-78 oC, 2h, 76%
22
O
OH
OMe
DMP, CH2Cl2,
rt, 1h, 90%
O
O
23
OMe
Scheme 9
4
The alcohol is then oxidized to aldehyde 22 using Dess-Martin Periodinane in CH2Cl2
which was subjected to methylation using CeCl3 and MeLi in THF to give compound 23
this on oxidation with Dess-Martin Periodinane in CH2Cl2 furnished compound 4, which
was the C6-C18 fragment of scytophycin-C as shown in scheme 5.
The stereoselective synthesis of C6-C18 fragment of scytophycin-C illustrates the
dynamic utility of the method developed by us and in this approach four required
stereocentres are fixed.
Section B: This section deals with an alternate and better approach of stereoselective
synthesis of C6-C18 fragment of scytophycin-C and present work.
The synthesis of C6-C18 fragment was started with cheaply available propane
diol.
The propane diol 24 was monoprotected selectively as its benzyl ether 25 using
NaH and BnBr in THF and was subsequently oxidised to aldehyde 26. Aldehyde 26 was
XIV
Abstract
then subjected to asymmetric allylation namely, Marouka allylation using allyltributyltin,
Ti(OiPr)4, TiCl4, Ag2O and (R)-BINOL in CH2Cl2 to produce homoallyl alcohol 27.
O
HO
OH
24
.
(COCl)2, DMSO, Et3N,
NaH, BnBr
THF, 0 oC, 89%
BnO
CH2Cl2, -78 oC, 91%
25
BnO
H
26
OH OH
OH
Ti(OiPr)4, TiCl4,
(R)-BINOL, ATBT,
CH2Cl2, 0 oC, 12h, 77%
OH
OsO4, NMO
BnO
Acetone:H2O
27
OH
BnO
28
Scheme 10
Osmylation of the terminal vinyl group in alcohol 27 using OsO4 and NMO and
subsequent oxidation with periodate produced the β-hydroxy aldehyde 28 in 90% yield
for two steps. The aldehyde was then subjected to to wittig olefination reaction with
(ethoxycarbonylmethylene)triphenyl phosphorane to produce δ-hydroxy-α,β-unsaturated
ester 29 as shown in scheme 11 in 92% yield.
28
a) NaIO4, THF, H2O
b) Ph3P=CHCO2Et,
C6H6, rt, 92%
OH
OH
O
BnO
DIBAL-H, CH2Cl2
OEt
BnO
OH
-78 oC, 2h, 90%
30
29
OBn
OH
MnO2, CH2Cl2
rt, 3h, 89%
CHO
BnO
ATMS, InBr3,
CH2Cl2, rt, 90%
O
31
32
Scheme 11
This ester is reduced to α,β -unsaturated alcohol 30 using DIBAL-H in CH2Cl2 at -78°C
which was regioselectively oxidized using MnO2 in CH2Cl2 to afford δ-hydroxy α,β-
XV
Abstract
unsaturated aldehyde 31 which on further treatment with allyltrimethylsilane and InBr3 in
CH2Cl2 afforded trans-2,6-disubstituted dihydropyran 32 exclusively with required
stereocenters at C9 and C13 based on methodology developed by us.
The benzyl group in compound 32 is deprotected using Li and naphthalene in
THF to afford primary alcohol 33. This alcohol 33 was then oxidized to aldehyde 34
using IBX in DMSO and THF and was used for furthur reaction without purification as
shown in scheme-7.
O
OH
H
Li, Naphthalene,
32
THF, -78 oC, 84%
IBX, DMSO,
O
O
THF, rt, 93%
TiCl4, DIPEA,
CH2Cl2, -78 oC, 72%
34
33
Ph
O
N
OH S
O
OH
O
OBn
OH
NaBH4, EtOH
O
0 oC, 3h, 88%
36
OH
NaH, BnBr
THF, 0 oC, 84%
O
5
35
Scheme 12
Ti(IV) mediated diastereoselective aldol reaction upon using 2-oxazolidinethione
based chiral auxillary, fixed C15-C16 centres. Propanoyl oxazolidenethione in CH2Cl2,
TiCl4 and diisopropylethylamine were added to the crude aldehyde 34 to afford the aldol
product 35.
The chiral auxillary of aldol product 35 was removed by reductive method using
NaBH4 in dry ethanol to afford the diol 36 along with chiral oxazolidinethione auxillary.
XVI
Abstract
The diol 36 was converted into its benzyl ether using benzyl bromide, NaH to give the
benzyl ether 5 as shown in scheme 8.
The compound 5 was further maneuvered to get the fragment 4 as shown in
scheme 8 and 9 in previous section. The present synthetic sequence provides an easy
access to the construction of the key fragment 4 of scytophycin-C.
In conclusion, we have developed two linear approaches for the synthesis
of key intermediate 4 towards the total synthesis of scytophycin-C. Further extension of
this project towards total synthesis of Scytophycin-C is under progress.