Synopsis
The thesis entitled “Towards The Total Synthesis of Phorboxazole A, Synthesis
And Biological Evaluation of Coumarin Analogues As DNA Gyrase Inhibitors And
Development of New Synthetic Methodologies” is divided into three chapters.
CHAPTER I: This chapter further divided into two sections.
SECTION A: This section describes biological importance of some antitumor
molecules
and earlier synthetic approaches to C20-C32 fragment of the
phorboxazoles.
SECTION B: This section comprises present work, the stereoconvergent synthesis of C20C32 fragment of phorboxazoles.
Phorboxazole A and B (Scheme 1) rare marine macrolides isolated from the Indian
ocean sponge Phorbas sp. by Searle and Molinski.1 Both C13 epimers comprised of a 21membered macrolide ring that embodies three oxane rings, one oxazole and subtends a side
chain that contains a second oxazole and a hemiketal oxane ring. These are among the most
cytostatic natural products known, inhibiting the growth of tumor cells at nanomolar
concentrations with mean GI50 = 1.58 x 10-9 M against NCI panel 60 tumor cell lines. These
scarce natural products arrest cancer cell growth in S phase at low to subnanomolar
concentrations, making them promising candidates for therapeutic development. The
enormous biological activity and the fascinating molecule structure have stimulated synthetic
efforts by a number of research groups and seven elegant total syntheses have been reported
so far. The remarkable biological activities associated with the phorboxazoles make these
compounds important leads for biotherapeutic development.2
We have depicted our strategy in the Scheme 1, which reveals the disconnection
approach. The convergent synthesis of C20-C32 oxazole-oxane 1 achieved by coupling two
subunits, pentasubstituted oxane 2 and oxazole sulfone 3 via modified Julia olefination. The
oxane moiety 2 was synthesized from the bicyclic ketone 4.
i
Synopsis
46
Br
MeO
R1
O
OH
11
9
22
O
O
HO
O
20
37
33
15
N
19
MeO
R2
O
5
N 29
O
26
32
1
O
O
(+)-Phorboxazole A: R1 = H, R2 = OH
(+)-Phorboxazole B: R1 = OH, R2 = H
OBn
20
26
BnO
O
1
O
N
32
OBn
S
+
BnO
2
S
N
O
O
O
O
O
N
3
O
O
OMe
N
O
O
4
5
Scheme 1
The bycyclic alcohol 6 was prepared from the bycyclic ketone 4 in three step
sequence using (-) Ipc2BH asymmetric hydroboration3 as a key step. It was converted to keto
compound 7 by PCC oxidation in DCM in 85% yield (Scheme 2). Next task was to open the
bicyclic ketone 7. It was thought that the best way of opening the bicyclic ketone was by
ii
Synopsis
making the corresponding ester 8 and hydrolyzing it. Thus a Baeyer – Villiger oxidation of
the ketone 7 using m-CPBA and NaHCO3 in DCM yielded the ester 8 in 90% yield (Scheme
2).
O
O
O
HO
PCC
m-CPBA, NaHCO3
CH2Cl2, rt
CH2Cl2, rt
OBn
O
O
8
OBn
7
6
O
OBn
Scheme 2
Methanolysis of lactone 8 using catalytic amount of sulfuric acid in MeOH afforded the
acetal ester 9 in 85% yield with a minor amount of the -isomer (at C-1 center). This ester
consists of three stereocenters out of five in the central pyran moiety 1. Next we turned our
attention to obtain the stereocenters at C1 and C2 carbons of the pentasubstituted pyran ring
1. In that direction ester functionality of 9 was reduced with LAH in THF at ambient
temparature to the corresponding alcohol 10 in 90% yield. Then benzylation of the resulting
primary alcohol with BnBr, NaH, and TBAI (catalytic) in THF furnished dibenzyl acetal 11
in 95% yield (Scheme 3).
O
cat. H2SO4
O
O
MeOH, rt, 12h
8
O
MeO
OBn
OBn
4 3 2
5
LiAlH4, THF
1
O
9
rt, 3 h
OMe
OBn
OBn
BnBr, NaH, TBAI (cat.)
HO
O
OMe
THF, rt, 12 h
10
BnO
O
OMe
11
Scheme 3
Next the dibenzyl methyl acetal 11 was converted to lactol 12 under acidic conditions
AcOH/H2O (2:1) at 55-60 oC for 12 h with 55% yield. Then the lactol 12 was oxidized to
lactone 13 using PCC, CH3COONa, celite in CH2Cl2 for 3 h with 90% yield (Scheme 4).
iii
Synopsis
OBn
OBn
AcOH/H2O (2:1)
BnO
O
11
OMe
55-60 oC,15 h
BnO
O
OH
12
OBn
3 2
PCC, CH3COONa, celite
CH2Cl2, rt, 3 h
4
BnO
1
5 O
13
O
Scheme 4
Having made flat form to obtain the stereocenters at C1 and C2 of pentasubstituted
pyran moiety 1, we thought to epimerize the α-methyl at C2 of the lactone 13. For this
purpose we made experiments using MeONa/MeOH and refluxing KOH/EtOH which were
resulted in ring opening of the lactone to corresponding hydroxy ester and hydroxy acid
respectively. And acid catalyzed cyclization of hydroxy acid resulted in epimerized lactone
14, and base catalyzed cyclization of hydroxy ester also led to the same 14. To avoid ring
opening of lactone it was thought that to use mild base such as DBU. Epimerization was
successfully carried out with DBU in THF for 12 h with 85% yield with 100% conversion
(Scheme 5).4 Epimerization was confirmed by 1H NMR and NOE studies.
OBn
OBn
DBU, THF, 12 h
BnO
O
13
O
BnO
O
14
O
Scheme 5
Accordingly, nucleophilic addition of lithiumtrimethylsilyl acetylide which was
generated in situ from acetylenetrimethylsilane and n-BuLi at -78 oC to the resulting epilactone 14 at -78 oC in THF provided inseparable anomeric mixture of hemiketals 15 in 90%
yield. Reduction of hemiketal to pyran 16 was carried out with excess Et3SiH/BF3.Et2O in
CH2Cl2/CH3CN (1:1) at -40 oC.5 The reaction was proceeded to completion within 1 h,
furnishing exclusively pentasubstituted pyarn moiety 16 in which ether linkage between C1
iv
Synopsis
and C5 is in syn configuration (Scheme 6). The stereochemistry of 16 was confirmed by 1H
NMR and NOE experiments.
OBn
OBn
,n-BuLi
TMS
BnO
THF, -78 oC, 1.5 h
O
O
14
BnO
O
15
OH
TM S
OBn
HgO, H2SO4, acetone
Et3SiH, BF3.Et2O
CH3CN + CH2Cl2 (1:1), -40 oC, 2h
BnO
O
16
reflux, 2 h
TM S
OBn
BnO
O
2
O
Scheme 6
Desilylation and hydrolysis of the triple bond via oxymercuration in Markownikoff’s
fashion was effected in a single transformation using yellow HgO and aq.H 2SO4 in refluxing
acetone for 2 h with 70% yield to give keto oxane 2 (Scheme 6).6
O
OEt
+
HO
N
12 h, rt
CO 2Me
NH.HCl
17
OMe
NH 2.HCl Et3N, CH2Cl2
DBU, CH2Cl2, rt
O
19
18
CuBr2, HMTA
O
OMe
OH
DIBAL-H
N
N
CH2Cl2, -78 oC, 3 h
O
N
S
TPP, DEAD, THF, 4 h, rt
O
20
5
S
mercaptobenzothiazole
S
oxone
N
S
N
THF/H2O/MeOH
O
O
21
O
3
Scheme 7
v
O
N
Synopsis
Many attempts went in vain to make the desired oxazole 5. Finally we followed the
Conforth’s synthesis of oxazoline 19, which was prepared by employing ethyl acetimidate
hydrochloride 17 and DL-serine methyl ester hydrochloride 18 in CH2Cl2 in presence of Et3N
for 12 h. The resulting oxazoline 19 was oxidized to oxazole 5 by using CuBr2, HMTA and
DBU in CH2Cl2 for 2 h at ambient temparature in 75% yield. Further the ester functionality
in oxazole was reduced to alcohol 20 by employing DIBAL-H.7 Then the alcohol was made
into thioether 21 under Mitsnobu reaction conditions using mercaptobenzothiazole, DEAD
and TPP in THF for 4 h. Thioether was oxidized to oxazole sulfone 3 by oxone in
THF:H2O:MeOH (2:1:1) for 12 h in 90 % yield (Scheme 7).
OBn
OBn
S
+
BnO
O
2
S
N
O
O
O
O
NaHMDS, THF
N
-78 oC to rt, 4 h
BnO
3
O
1
O
N
Sc
heme 8
Coupling of oxazole sulfone and the ketone under the modified Julia olefination
reaction conditions gave the C20-C32 fragment as separable E:Z isomers in a ratio of 9:1 in
50% yield (40% conversion) based on recovered starting material (Scheme 8).
In conclusion, the practical synthesis of the penta substituted pyran C20-C32
fragment achieved from bycyclic ketone is described. Modified Julia olefination reaction
between sulfone and the ketone was also achieved.
CHAPTER II : This chapter again divided into two sections.
SECTION A: This section deals with introduction to coumarin and quinolone antibiotics and
dual action drugs.
SECTION B: This section deals with the present work, synthesis and biological
evaluation of coumarin linked fluoroquinolones, phthalimides and naphthalimides as potential DNA gyrase Inhibitors.
vi
Synopsis
Over the past decade, bacterial DNA gyrase has drawn much attention as a selected
target for finding potent antibacterial agents. Accordingly, a number of synthetic quinoline
antibacterial agents have been developed and are now widely used for treatment of bacterial
infectious diseases. Quinolones inhibit DNA gyrase and topoisomerase IV, and cause
bacterial cell death. Besides the quinolones, naturally occurring antibacterial agents, such as
novobiocin (NB; Fig. 1) have also been identified as bacterial DNA gyrase inhibitors. 8
Novobiocin inhibits ATPase activity of DNA gyrase by competing with ATP for binding to
the gyrase subunit B. Based on this background it was considered of interest to prepare new
type of dual-acting coumarin-linked hybrids possessing phthalimide, naphthalimide and
quinolone moieties to unravel their antibacterial activity and DNA gyrase inhibition
potential.
A hybrid molecule synthesis strategy was employed to develop new molecules with
potential antibacterial activity. Three types of coumarin-linked hybrids have been
synthesized. The coumarin ring system has been linked to phthalimido, naphthalimido and
quinolone moieties at 4-position through piperazino alkane spacers. These compounds have
been evaluated for their antibacterial activity. Some of these new hybrids particularly
phthalimido and naphthalimido ones have exhibited DNA gyrase inhibition activity.
O
R2
O
O
O
O
OH
O
O
O
OH
OH H
N
F
N
O
COOH
N
HN
R1
novobiocin R1 = Me, R2 = NH2
ciprofloxacin
Figure. 1
Chemistry
The coumarin precursors 4-(1-piperazinyl)-2H-1-benzopyran-2-one 25a and 25b
were synthesized9 from the starting materials o-hydroxy acetophenones 23a, 23b in two step
sequence. Compounds 23a, 23b were treated with diethylcarbonate in the presence of Na to
reflux for 4 h to obtain substituted 4-hydroxy coumarins 24a, 24b which
vii
Synopsis
inturn heated with piperazine at 160 oC for 1h to obtain the precursors 25a and 25b
(Scheme11).
CH 3
HO
CH 3
OH
alkyl iodide, K2CO3, acetone
CH 3
RO
CH 3
reflux, 6 h, 85%
O
reflux, 4 h, H3O+, 75%
O
22
23a,b
CH 3
RO
diethyl carbonate, Na
OH
CH 3
O
O
o
piperazine, 160 C
RO
O
O
1 h, 65%
OH
24a,b
N
25a,b
N
H
a = CH3, b = C2H5
Scheme 9
Quinolone precursors were obtained from substited anilines 26a and 26b by reacting
with diethylethoxymethylenemalonate at 110 oC for 1.5 h to give 2-(3,4-dihaloanilinomethylene)melonates 27a, 27b which upon heating with diphenylether at 250 oC for 1h
furnished 28a, 28b (Scheme 10).
X
diethylethoxymethylenemalonate
Y
NH 2
110 oC, 1.5 h, 98%
26a,b
X
EtO2C
Y
N
H
CO 2Et
27a,b
OH O
o
diphenylether, 250 C
X
1 h, 81%
Y
OEt
N
28a,b
a: X = F, Y = Cl; b: X = Y = F
Scheme 10
N-alkylbromoquinolones 32a-g were synthesized by reacting 28a, 28b with
dibromoalkanes 29a-d in acetone in the presence of potassium carbonate. The precursors Nalkylbromophthalimides 33a,b and N-alkylbromonaphthalimides 34a,b were prepared by
viii
Synopsis
reacting phthalimide 30 and naphthalimide 31 with corresponding dibromoalkanes 29a-d
(Scheme 11).
O
O
X
OH O
X
Y
OEt
Y
N
OEt
( )n
Br
32a-g
X = F, Y = Cl, F
n = 2, 3, 4, 6
i
N
28a,b
O
O
HN
Br
( )n
Br
ii
N
30
O
( )n
29a-d: n = 2, 3, 4, 6
Br
O
ii
33a, b: n = 2, 3
O
HN
O
O
31
N
( )n
Br
34a, b: n = 2, 3
O
Scheme 11. Reagents and conditions: (i) acetone, K2CO3, reflux, 24 h,
93-95% (ii) acetonitrile, K2CO3, reflux, 24 h, 80-85%.
Scheme 11
The new cross linked hybrids of coumarins with quinolones, phthalimides and
naphthalimides have been synthesized by coupling 4-(1-piperazinyl) coumarin 25a or 25b
with N-alkylbromo-6,7-dihaloquinolones 32a-g, N-alkylbromophthalimide 33a,b and Nalkylbromonaphthalimides 34a,b respectively. The reaction was carried out in the presence
of anhydrous K2CO3 at reflux in acetonitrile for 24 h to afford the coumarin-quinolone
hybrids 35a-k, the coumarin-phthalimide analogues 36a-d and coumarin-naphthalimide
analogues 37a-d (Scheme 12) in good yields.
ix
Synopsis
CH 3
RO
O
O
Y
N
X
N
32a-g
i
N
( )n
O
O
EtO
CH 3
RO
35a-k:
X = F, Y = Cl, F
R = CH3, C2H5
n = 2, 3, 4, 6
O
CH 3
O
33a, b
RO
O
O
i
N
N
25a, b
N
H
O
N
34a, b
i
( )n
O
CH 3
RO
N
36a-d
R = CH3, C2H5
n = 2, 3
O
O
N
O
N
( )n
N
37a-d
R = CH3, C2H5
n = 2, 3
O
Scheme 12. Reagents and conditions: (i) acetonitrile, K2CO3, reflux, 24 h, 70-87%.
Scheme 12
Antibacterial activity
The in-vitro antibacterial activity of the compounds was assessed along with
ciprofloxacin by Kirby-Bauer method on both Gram negative and Gram-positive bacteria.
The minimum inhibitory concentration of the compounds was determined by inoculating the
test organisms (E. coli MTCC 443, B. subtilis MTCC 736) on Mueller-Hinton agar plates
with different concentrations of compound (4 mg/mL, DMSO) followed by incubation at 37
x
Synopsis
o
C for 16-18 hrs. To ensure that the solvent had no effect on bacterial growth, a control test
with DMSO was also performed. Some of the compounds exhibited mild activity against E.
coli. (Table1). However, these compounds were almost inactive against B. subtilis (MIC >60
g/mL).
Inhibition of DNA supercoiling
The ability of the coumarin linked hybrids to inhibit the supercoiling activity of DNA
gyrase was tested. For this purpose very well studied E. coli DNA gyrase was employed.
Ciprofloxacin was used as positive control in these assays as it has been shown to be a potent
inhibitor of DNA supercoiling activity of the enzyme. Many of the compounds tested showed
dose-dependent inhibition of enzyme activity. From the data (Table 1) it is clear that some of
the compounds inhibit the DNA gyrase activity, particularly the phthalimido and
naphthalimido linked coumarin hybrids (36a-d, 37a-d). One of the molecules from the
quinolone linked coumarin series (35d) also exhibited promising DNA gyrase inhibition,
which could be considered as dual activity coumarin. Although compounds 36b,d and 37b-d
had good inhibitory activity against DNA gyrase, it did not show any antibacterial activity,
presumably because of low permeability through bacterial membrane. Compounds 35d, 36a,
36c and 37a had potent DNA gyrase inhibitory activity and showed moderate antibacterial
activity (Table 1). It is interesting to note that precursors 25a,b, 30 and 31 did not exhibit any
significant inhibition of DNA-gyrase up to 50ug/mL. The precursors 28a,b could not be
evaluated because of the insolubility in DMSO. Therefore, it appears that there is no intrinsic
activity for the precursor fragment in these hybrid molecules.
xi
Synopsis
Table 1. Minimal inhibitory concentrations (MIC) of coumarin hybrids against DNA
gyrase and bacteria
Sl.
No
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
a
Compound
R
X
Y
n
35a
35b
35c
35d
35e
35f
35g
35h
35i
35j
35k
36a
36b
36c
36d
37a
37b
37c
37d
Ciprofloxacin
CH3
CH3
CH3
CH3
C2H5
C2H5
CH3
CH3
CH3
C2H5
C2H5
CH3
CH3
C2H5
C2H5
CH3
CH3
C2H5
C2H5
F
F
F
F
F
F
F
F
F
F
F
-
Cl
Cl
Cl
Cl
Cl
Cl
F
F
F
F
F
-
2
3
4
6
2
3
2
3
4
2
3
2
3
2
3
2
3
2
3
MIC against E.
coli (g/mL)
>60
>60
>60
53
>60
>60
>60
>60
>60
>60
>60
35
>60
42
>60
40
>60
>60
>60
5
MIC against
DNA gyrase
(g/mL)
a
a
50
30
a
50
50
a
50
50
a
30
30
30
30
30
30
30
30
10
No inhibition was observed.
Conclusion
The present studies demonstrate the synthesis of these hybrid molecules and evaluate
their antibacterial activity as well as their ability to inhibit DNA gyrase. These new coumarin
based hybrids exhibit moderate antibacterial activity against E. coli. with promising DNA
gyrase inhibition activity and as such warrant further investigation by modulation of linker
spacers and functional groups in the coumarin ring system. It is anticipated that this structure
activity based approach could lead to the development of much improved inhibitors of DNA
gyrase with better in-vivo efficacy.
xii
Synopsis
CHAPTER III: This chapter describes new methodologies for the synthesis of 2deoxyglycosides and 2,3-unsaturated glycosides. This chapter again
divided into two sections.
SECTION A: This section describes the synthesis of 2-deoxyglycosides from D-glycals
using CeCl3.7H2O-NaI as a novel reagent.
Deoxyglycosides are well-known structural components of several biologically active
compounds, especially antitumor antibiotics such as anthracyclines, aureolic acids,
orthosamycins, angucyclins, and enediynes. In particular, 2-deoxy-α-glycosides are present
in many bioactive natural products including compactin, olivomycin, mithramycin,
daunomycin, calicheamicin and many others.10 In this context, several methods have been
developed for the preparation of 2-deoxy sugars in a multi-step sequence. Of these, the acidcatalyzed addition of an alcohol to acetylated glycals appears to be the most direct method
for the synthesis of 2-deoxy pyranosides. However, only a few methods have been reported
so far for the direct synthesis of 2-deoxy- α -glycosides from glycals. Thus the development
of a neutral alternative such as the CeCl3.7H2O– NaI reagent system would extend the scope
of this transformation.
AcO
CeCl3.7H2O-NaI
O
+ R'OH
AcO
CH3CN, reflux
AcO
O
O
R'
AcO
OAc
OAc
Scheme 13
This is a mild and efficient method for the synthesis of 2-deoxyglycosides from
glycals and alcohols using the CeCl3·7H2O–NaI reagent system. Thus, treatment of 3, 4, 6tri-O-acetyl-D-glucal with alcohols in the presence of cerium(III) chloride heptahydrate–
sodium iodide in acetonitrile afforded the corresponding 2-deoxyglycopyranosides in good
yields with high α-selectivity (Scheme 13). The α -anomer was obtained exclusively, the
structure of which was characterized by spectroscopic data (Table 2.).
xiii
Synopsis
Table 2.CeCl3.7H2O-NaI promoted synthesis of 2-deoxyglycopyranosides.
___________________________________________________________________________
Entry
Substrate
Product
Time (h) Yield (%)
___________________________________________________________________________
a
AcO
O
AcO
AcO
AcO
O
AcO
AcO
AcO
O
AcO
O
AcO
O
AcO
OAc
O
AcO
i
O
OAc
O
j
90
AcO
O
O
5.5
80
AcO
4.5
87
7.0
83
8.5
80
6.5
85
8.0
87
OAc
O
O
OAc
AcO
O
O
AcO
OAc
O
O
( )4
AcO
OAc
O
AcO
OAc
O
O
AcO
AcO
AcO
6.0
O
AcO
AcO
AcO
O
AcO
AcO
h
82
OAc
OAc
AcO
7.5
O
AcO
AcO
g
O
AcO
AcO
f
85
OAc
OAc
e
5.5
O
AcO
AcO
AcO
O
OAc
OAc
AcO
87
AcO
AcO
d
6.5
OAc
OAc
c
O
AcO
OAc
b
O
OAc
O
AcO
OAc
O
O
AcO
AcO
OAc
OAc
xiv
Ph
Synopsis
However, in the absence of NaI, the glycals underwent Ferrier rearrangement under
the influence of CeCl3·7H2O in refluxing acetonitrile to afford the corresponding 2,3unsaturated hexopyranosides in good yields (Scheme 14). The products were obtained as a
mixture of - α and β-anomers, favoring the α-anomer. The ratios of products were determined
by the examination of the 1H NMR spectra of the crude products.
AcO
O
CeCl3.7H2O
+ R'OH
CH3CN, reflux
AcO
AcO
O
O
R'
AcO
OAc
Scheme 14
SECTION B: This section describes the synthesis of 2,3-unsaturated C and O and Sglycosides from D-glycals using phosphomolybdic acid supported on
silica gel as an efficient catalyst.
The acid-catalyzed allylic rearrangement of glycals in the presence of nucleophiles
such as alcohols, thiols etc., and known as Ferrier rearrangement11 is widely employed to
obtain 2, 3-unsaturated glycosides. Allyl C-glycosides are attractive synthons due to the
presence of terminal double bond that is amenable to easy functionalization, for instance, by
hydroxylation, hydrogenation, epoxidation and amino hydroxylation. These glycosides or
pseudoglycals represent versatile chiral intermediates towards the synthesis of modified
carbohydrates and nucleosides with important pharmacological properties. This class of
compounds can be transformed in to 2-deoxy or 2, 3-dideoxy sugars, which are building
blocks for the total synthesis of many antibiotics.12 Due to its great significance in the area of
carbohydrate chemistry, there has been a growing interest in the improvement of the Ferrier
reaction by using a variety of catalysts.
Phosphomolybdic acid (PMA) belongs to the class of heteropoly acids (HPA).
Catalysis using HPAs and related polyoxometalate compounds is a field of growing
importance.13 HPAs are commercially cheap and environmentally friendly catalysts. They
exhibit high activities and selectivities and allow cleaner processes over conventional
xv
Synopsis
catalysts. HPAs are promising solid acids, redox and bifunctional catalysts in homogeneous
as well as in heterogeneous conditions. HPAs have a very strong, approaching the superacid
region, Bronsted acidity greatly exceeding that of ordinary mineral acids and solid acid
catalysts.
O
RO
1 mol % PMA-SiO2
acetonitrile, Me3Si
RO
RO
rt, 10-15 min
OR
O
RO
R = Ac, Piv
Scheme 15
In a typical experiment, a solution of triacetyl glucal and allyl trimethylsilane in
acetonitrile was stirred with 1 mol% PMA-SiO2 at room temperature. The reaction was
complete within 10 minutes to produce exclusively corresponding -4,6-di-O-acetyl-2,3unsaturated C-allyl glycoside with high yield (Table 3., Scheme 15). After the reaction the
catalyst was filtered and reused 5 times without any appreciable loss in catalytic activity and
yields.
RO
O
1 mol % PMA-SiO2
acetonitrile, R'XH
RO
OR
RO
O
X
R'
RO
rt, 10-15 min
R = Ac; X = O or S
Scheme 16
2,3-unsaturated glycopyranosides were successfully prepared with nucleophiles such
as alcohols and thiols. A mixture of two anomers of 2,3-unsaturated glycopyranosides ( and
) were obtained in the case of glucal and galactal when alcohol was the nucleophile, while
exclusively -anomers were obtained with thiols (Table 3., Scheme 16). The predominant
formation of this -anomer may arise from thermodynamic anomeric effect.
xvi
Synopsis
Table 3. Synthesis of 2,3-unsaturated glycosides by PMA-SiO2 catalysed Ferrier rearrangement.
_______________________________________________________________________________________
Yield (%)
Time (min)
Entry
Product
( 
Substrate
_______________________________________________________________________________________
a
O
AcO
AcO
AcO
O
10
89

15
90

15
87

10
90

15
93

10
92

10
89

15
85

15
84

AcO
OAc
b
O
AcO
AcO
AcO
O
AcO
OAc
c
O
PivO
PivO
PivO
O
PivO
OPiv
d
O
AcO
AcO
O
O
O
O
O
O
AcO
AcO
OAc
AcO
e
''
AcO
AcO
f
''
h
AcO
AcO
g
''
O
O
Ph
AcO
O
AcO
( )7
AcO
O
O
AcO
AcO
OAc
AcO
i
''
j
O
( )7
AcO
O
AcO
O
AcO
AcO
O
S
AcO
OMe
10
88

10
94

OAc
k
AcO
''
O
S
AcO
Br
_______________________________________________________________________________________
xvii
Synopsis
Table 3. continued..
_______________________________________________________________________________________
Entry
Substrate
Product
Time (min) Yield (%)
(  )
______________________________________________________________________________________
_
l
O
AcO
AcO
O
S
10
90

10
90

10
92

10
90

10
94

AcO
AcO
OAc
m
O
AcO
AcO
O
S
AcO
AcO
OMe
OAc
n
AcO
O
S
''
AcO
o
''
AcO
Br
O
S
AcO
p
AcO
O
S
"
AcO
_______________________________________________________________________________________
xviii
Synopsis
References
1. (a) Searle, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1995, 117, 8126; (b) Searle, P.
A.;
Molinski, T. F.; Brzezinski, L. J.; Leahy, J. W. J. Am. Chem. Soc. 1996, 118, 9422.
2. Forsyth, C. J.; Ying, L.; Chen, J.; La Clair, J. J. J. Am. Chem. Soc. 2006, 128, 3858.
3. (a) Yadav, J. S.; Rao, C. S.; Chandrasekhar, S.; Ramarao, A.V. Tetrahedron
Lett. 1995,
36, 7717; (b) Rama Rao, A.V.; Yadav, J. S.; Vidyasagar, V. J. Chem. Soc.,
Chem.
Commun. 1985, 55; (c) Brown, H. C.; Varaprasad, J. N. V. J. Am.
Chem. Soc. 1986,
108, 2049.
4. (a) Bernsmann, Heiko.; Gruner, M.; Frohlich, R.; Metz, P. Tetrahedron Lett. 2001,
42,
5377-5380; (b) Klotz, P.; Mann, A. Tetrahedron Lett. 2003, 44, 1927- 1930.
5. Bolitt, V.; Mioskowski, C.; Kollah, R. O.; Manna, S.; Rajapaksa, D.; Falck, J. R.
J.
Am. Chem. Soc. 1991, 113, 6320-6321.
6. Potman, R. P.; Janssen, N. J. M. L.; Scheeren, J. W.; Nivard, R. J. F. J. Org.
Chem.
1984, 49, 3628-3634.
7. Entwistle, D. A.; Jordon, S. I.; Montgomery, J.; Pattenden, G. Synthesis 1998, 603.
8. (a) Kim, O. K.; Ohemeng, K. A. Exp. Opin. Ther. Patents 1998, 8, 959; (b) Maxwell, A.
Mol. Microbiol. 1993, 9, 681.
9. Roma, G.; Braccio, M. D.; Carrieri, A.; Grossi, G.; Leoncini, G.; Signorello, M. G.;
Carotti, A. Bioorg. Med. Chem. 2003, 11, 123.
10. Sabesan, S.; Neira, S. J. Org. Chem. 1991, 56, 5468.
11. (a) Ferrier, R. J. J. Chem. Soc. (C) 1964, 5443; (b) Ferrier, R. J.; Ciment, D. M. J. Chem.
Soc. (C) 1966,441.
12. (a) Holder, N. Chem. Rev. 1982, 82, 287; (b) Liu, Z. J.; Zhou, M.; Min, J. M.; Zhang, L.
H. Tetrahedron: Asymmetry. 1999, 10, 2119.
13. (a) Kozhevnikow, I. V. Chem. Rev. 1998, 98, 171. (b) Mizuno, N.; Misono, M. Chem.
Rev. 1998, 98, 199.
xix