ABSTRACT
The thesis entitled “Studies towards the synthesis of fumagillin &
ovalicin and development of new synthetic methodologies” is divided into
three chapters.
CHAPTER I: This chapter is further divided into two sections.
Section A : This section describes introduction and previous synthetic
approaches for fumagillin.
Section B : This section describes introduction and previous synthetic
approaches for ovalicin.
CHAPTER II: This chapter includes our contribution for the synthesis of
fumagillin and ovalicin and is further divided into two sections.
Section A : This section describes the synthesis of a key intermediate for the
total synthesis of fumagillin .
Section B : This section describes the formal total synthesis of ovalicin.
CHAPTER III: This chapter deals with the development of new
methodologies and is further divided into two sections
Section A : This section describes introduction of α- amino phosphonates,
α- hydroxyl amino phosphonates and previous approaches for the synthesis
α- amino phosphonates
Section B : This section describes the present work for the synthesis αamino phosphonates and α- hydroxyl amino phosphonates.
1
Abstract
Chapter II.
Scection–A: This section describes the stereo selective sythesis of a key intermediate for
the total synthesis of fumagillin .
In 1990 Judah Folkman and co-workers discovered that fumagillin 1 isolated from
aspergilles fumigatus and its semi-synthetic drug TNP-470, 2 (also known as AGM
1470) have the remarkable capacity to inhibit the proliferation of endothelial cell in vitro
and tumor induced angiogensis in vivo (Fig 1).
Fumagillin and its less toxic semisynthetic derivative TNP-470 are potential antimalarial and anti-leishmaniasis drugs and are the only treatments for intestinal
microsporidiosis in HIV-infected patients
O
O
HO
O
O
O
OMe
O
N
H
OMe
Cl
O
O
O
O
Fumagillin-1
Me
AGM 1470. 2
Fig 1
Retro synthetic strategy :
The retro synthetic strategy was devised and outlined in Scheme 1. In this the main
core cylohexane moiety 3 could be obtained from 4 by extending the aldehyde group.
The compound 4 could be obtained from olefinic alcohol 5 which in turn could be
synthesized from our well known ring opening reaction of alcohol 6. It was also
envisioned that the alcohol compound 6 could be easily obtained from 7, which was
accessed from the Diels-Alder reaction of protected furfuryl alcohol 8 and bromo methyl
propiolate 9.
2
Abstract
OT BS
OH
OMe
OH
OMe
OMe
CHO
COOMe
Fumagillin-1
O
O
O
3
OMe
OMe
O
5
4
Br
O
COOMe
COOMe
OH
Br
R=TBDMS
R=PMB
8a-R=TBS
8b-R=PMB
OR
7a-R=TBS
7b-R=PMB
6
+
OR
O
COOM e
9
Scheme 1
Our first approach is outlined in Scheme 2. The Diels-Alder reaction of TBS
protected furfuryl alcohol 8a and bromo meyhyl propiolate 9 in refluxing benzene gave
the adducts 10 and 7a in 3:7 ratio. The regiochemistry of the two adducts was assigned
from their 1H -NMR spectroscopy. The adduct 7a when treated with NaOMe in MeOH
gave the dimethoxy compound 11 in good yields. Compound 11 on hydrogenation
followed by TBS deprotection with TBAF in THF gave the alcohol 6. Where as the
Diels-Alder reaction of PMB protected furfuryl alcohol 8b and bromo meyhyl propiolate
9 under similar conditions gave the adduct 7b as a single regioisomer. To check the regio
chemistry of the adduct, we applied the same set of reactions as above and obtained the
same alcohol 6.
Scheme 2
COOMe
Br
O
OTBS
COOMe
O
Br
COOMe
OMe
COOMe
OTBS
11
OMe
O
COOMe
THF,95%
OH
OTBS
6
OMe
OMe
Br
NaOMe, MeOH
O
Benzene, reflux,
OPMB
24 h, (58%).
1 h, (78%).
7a
TBAF
OMe
COOMe
12
O
OMe
OMe
12 h, (93%)
8b
COOMe
OTBS
10
H2, Pd/C, MeOH
NaOMe, MeOH
O
OTBS
8a
O
+
Br
Benzene, reflux,
24 h, (58%).
OMe
Br
O
COOMe
O
1 h, (78%).
COOMe
OPMB
OPMB
7b
13
3
OMe
H2, Pd/C, MeOH
OMe
O
12 h, (93%)
COOMe
OH
6
Abstract
The free 1o-alcohol was transformed to iodide using iodine, TPP and imidazole in
refluxing toluene. This iodo compound 14 when treated with TMSOTf in DCM gave the
keto compound 15. NaBH4 reduction followed by methylation resulted the iodo methoxy
compound 17. Zn mediated ring opening reaction of iodo methoxy compound 17 in
refluxing ethanol gave the olefinic alcohol 5. Protection of the sec-alcohol as TBS ether
by using TBS-Cl followed by dihydroxylation of the double bond with OsO4-NMO
resulted in diol 19. Acetonide protection of the diol followed by DIBAL-H reduction
gave the aldehyde compound 21 which is in contrast to desired aldehyde 4 from the noe
studies, which revealed that the two sec-hydroxyl groups were not in the same plane
which is mandatory for the target molecule, instead the methoxy group was in the same
plane with aldehyde (Scheme 3).
OMe
OMe
I2 , TPP,IMD.
OMe
O
toulene, ref,
2 h, (93%).
COOMe
O
I
15
I
6
14
OH
O
MeI, Ag2 O.
OMe
O
COOMe THF, 24 h, (87%).
OTBS
OH
OMe
Zn, Ethanol.
COOMe ref, 2 h, (88%)
OMe
TBS-Cl, IMD.
COOMe DCM, 1 h, (73%).
COOMe
I
I
16
OsO4 ,NMO,
Acetone:H2 O
NaBH4 ,MeOH.
COOMe r.t, 1 h, (80%).
0 0 C, 10 min, (60%)
COOMe
OH
O
TMSOTf, DCM
OMe
O
5
17
OMe
OMe
CSA, Acetone.
O O
19
20
DIBAL-H, DCM
4
4
CHO
CHO
O O
Scheme 3
OMe
OMe
COOMe -78 0 C, 1 h, (66%)
COOMe r.t, 30 min, (65%).
OHOH
OTBS
OTBS
OTBS
OTBS
24 h, (75%).
18
EXPECTED
O O
OBTAINED 21
Abstract
As the above synthetic route gave the unexpected and unwanted epi compound (at
the methoxy center) a small modification was applied in the retro synthetic strategy as
given in Scheme 4. In this the epoxide compound 3 could be obtained from the key inter
mediate 22 by extending the 10-alcohol. The key intermediate 22 could be obtained from
olefin 23 which in turn could be obtained from compound 6 in a similar manner as
mentioned above.
Modified retro synthetic strategy.
O
OH
OH
OMe
OH
O
OMe
OMe
OMe
O
O
COOMe
COOMe
O
OH
O
3
OMe
22
6
23
.
Scheme 4
The alternate strategy devised was delineated in Scheme 5. Zn mediated ring
opening reaction of iodo compound 14 gave the dimethoxy olefinic alcohol 23.
Dihydroxylation of the double bond followed by acetonide protection gave compound 25.
This compound 25 when subjected to either protection of the hydroxyl group or
deprotection of the dimethoxy ketal resulted in decomposition
OH
OMe
Zn, EtOH.
OMe
O
OMe
OMe
COOMe ref, 2 h, (87%).
OH
OsO4 , NMO,
Acetone:Water
CSA, Acetone
OMe
COOMe r.t, 30 min, (65%).
COOMe 24 h, (65%),
I
OHOH
14
23
24
OH
OMe
OMe
COOMe
Decomposed
subjected to any
reaction
O O
25
Scheme 5
5
OH
OMe
OMe
OMe
COOMe
O O
25
Abstract
As the above conversion was unsuccessful, we tried to synthesize the epoxide
intermediate 26 which may be converted to the target molecule 1 and also can be
converted to 27 which is biologically active (Fig-2). The details were outlined in Scheme
6.
OH
R= CH 2 Ph
OR'
OH
R= Allyl
OMe
R=
OT BDP S
OR
O
O
H
N
R'=
26
O
27
Cl
O
Fig-2
Reduction of the ester in 23 gave homoallylic alcohol 28. The m-CPBA epoxidation of
the homo allylic alcohol 28 gave the epoxide 29. This epoxide moiety decomposed when
subjected to any reaction i.e either protection of the 1o-alcohol or deprotection of the
ketal. Therefore the p-alcohol in 28 was first protected as its TBDPS ether using TBDPSCl followed by epoxidation of the double bond with m-CPBA afforded the epoxide
compound 31. Deprotection of the ketal to ketone 32 was carried out using CSA, acetone
and water in 9:1 ratio. Chelation controlled reduction of the ketone 32 with Et3B and
NaBH4 gave the syn diol 26. unfortunately the noe studies revealed that this epoxide
compound is epi at the epoxide center 33.
OH
OH
OMe
OMe
DIBAL-H, DCM
OH
OMe
OMe
OH
TBDPS-Cl, IMD.
O
29
OH
OMe
OTBDPS
m-CPBA, DCM.
O
31
OH
OH
OH
OH
Et3 B, NaBH4 .
OTBDPS
OTBDPS
THF, 1h, (87%).
O
26
EXPECTED
O
33
OBTAINED
Scheme 6
6
OH
OMe
O
CSA, Acetone:H2 O
OMe
OTBDPS 0-r.t, (65%).
1 h, (76%).
30
28
Decomposed when
subjected to any
reaction.
OMe
OH
1 h, (78%).
28
OH
OMe
DCM, 1 h, (73%).
OMe
m-CPBA, DCM.
OMe
OH
COOMe -780 C, 30 min, (66%).
23
OH
OMe
OTBDPS
O
32
Abstract
As the above synthetic route again gave the unexpected and unwanted epi compound (at
the epoxide center) the strategy was slightly modified as given in Scheme 7.
Dihydroxylation of the double bond in 28 with OsO4-NMO gave the tetrol 34.
Protection of the 1,2- di hydroxyl groups and deprotection of the ketal to ketone was
achieved in one pot by treating with CSA in acetone. The 1o-hydroxy group in 35 was
masked as its TBS ether and chelation controlled reduction of the ketone with Et3B and
NaBH4 gave the syn diol 37. Protection of the two sec-hydroxyl groups with 2,2 DMP
followed by deprotection of the TBS group with TBAF in THF resulted in required
cyclohexane moiety 22. The stereo chemistry of the key intermediate 22 was further
confirmed by the NOESY and COSY studies. Further Studies are under progress in our
lab to complete the total sythesis of fumagillin 1.
OH
OMe
OMe
OH
OH
OMe
OsO4, NMO,
Acetone:H2O
OMe
OH
24 h, r.t.(75%) .
OH
0 0C, 3 h, (78%).
OH
THF, (78%).
OTBS
O
O
37
OH
DCM, 1 h
O
O
CSA, 2,2-DMP.
Acetone,
r.t, (78%).
O
O
35
O
OH
Et3B, NaBH4,
O
O
O
TBS-Cl, IMD
CSA, Acetone
OHOH
34
28
OH
O
O
TBAF, THF
OTBS
O
O
38
r.t, (89%).
OH
O
O
22
Scheme 7
7
OTBS
36
Abstract
CHAPTER II, Section-B: This section describes the formal synthesis of ovalicin by
carbohydrate approach.
During recent years abnormal angiogenesis has been recognized as a common
feature for many proliferate diseases viz. diabetic retinopathy, psoriosis, rheumatoid
arthritis including cancer. Thus it has become increasingly importance to inhibit
angiogenesis as one of the alternative promising method for cancer therapy.
Towards these studies, ovalcin 3 isolated from cultures of Pseudorotium ovalis
stock was found to be non-toxic, non-inflammatory and stable at room temperature for
years bearing equal potency as AGM 1470 2 and enhanced potency compared to
fumagillin 1.
O
Me
O
OMe
O
O
O
O
OH
Me
O
OMe
N
Cl
O O
AGM 1470 2
O
Fumagillin 1
O
Me
O
OH
OMe
O
Ovalcin 3
Retro synthetic strategy:
Our synthetic approach towards the ovalcin is based on chiron approach and
utilizes two key steps, an olefin metathesis reaction and the zinc mediated ring-opening
reaction to afford the chiral olefinic alcohol.
Our retrosynthetic approach revealed a key intermediate 4 which is formed by the
disconnection of the side chain and our main target was to synthesise this fragment 4 as
the conversion of 4 to final target
was well documented in the literature. It was
envisioned that the key fragment 4 could be easily prepared by Grubbs RCM of 5, which
in turn is obtained from fragment 6. The fragment 6 is easily prepared from D-ribose via
a sequence of reactions (Scheme 1).
8
Abstract
Retro synthetic stategy:
O
Me
O
OH
OMe
O 3
O
O
OH
+
OMe
4 OTES
OH
OMe
4 OTES
OPMB
D(-)ribose
O
Me
OMe
OTES
5
O
I
OBn
OH
Br
O
Me
6
Scheme 1
Commercially available D(-)ribose was protected as its 2,3-O-isopropylidene
derivative and the primary hydroxyl group was protected as tert-butyldimethylsilyl ether
with TBDMSCl and imidazole in DCM. The resulting compound 8 was homologated to
compound 9 by using Corey-Chekoviskies reagent. The compound 9 was taken and
protected as its MPM ether 10 with para-methoxybenzyl bromide. Desilylation of
compound 10 with TBAF afforded free alcohol 11,which was further converted to iodide
6 with iodine, triphenyl phosphine and imidazole (scheme 2).
HO
O
OH
2, 2-DMP, acetone,
pTSA, r.t, 72%.
O
Me
OH OH
OH
O
TBDMSO
TBDMS-Cl, imidazole,
CH2Cl2, r.t., 98%.
O
TBDMSO
O
Me
O
Me
7
Me2SO=CH2,
O
TBDMSO
O
Me
DMSO, 20 0C, 60%.
OH
NaH, PMB-Br, Et2O,
0 0C-r.t., 3 h, 97%.
TBDMSO
O O
Me Me
10
O
Me
9
TBAF, THF,
30 min. 98%.
O
HO
O
Me
OPMB
O
Me
I2,TPP, imidazole,
toluene,
reflux, 2 h, 80%.
O
I
O
Me
9
OPMB
O
Me
6
11
O
Me
8
O
OPMB
OH
Scheme 2
Abstract
By applying the commonly used protocol for zinc mediated ring opening reaction
compound 12 was obtained in good yields. The resulting free alcohol in 12 was masked
with NaH and benzyl bromide as its benzyl ether 13. Deprotection of the acetonide group
from compound 13 was achieved using pTSA to give diol 14.
The diol 14 was
selectively protected as the corresponding TES ether 15 at the allylic position under
lower temperatures and simultaneously as methyl ether 16 with methyl iodide. The
compound 16 on PMB deprotection with DDQ provided primary alcohol 17 which was
oxidized to aldehyde 18 using TPAP and NMO conditions. Vinylation of the aldehyde 18
afforded allyl alcohol 5, which could be used for the metathesis reaction to get the
required basic skeleton (Scheme 3).
I
O
OBn
OH
OPMB
Zn, EtOH
OPMB
O
Me
reflux, 2 h, 95%.
O O
Me Me
6
OPMB
NaH, BnBr, THF,
O
Me
0 0C-r.t. 12 h, 85%.
O
Me
13
12
pTSA, MeOH,
r.t. 30 min. 98%.
OH
OH
TESCl, imidazole,
OH OBn
DCM, 00 C, 1 h, 84%.
OMe
DDQ, CH2Cl2:H2O (8:2),
r.t., 2 h, 61%.
16
vinyl magnesium bromide
THF, r.t., 90 min., 75%.
OTESOBn
NaH, MeI, THF,
0 0C-r.t., 4 h, 95%.
15
14
OTESOBn
OPMB
OPMB
OMe
OPMB
O
Me
TPAP, NMO, CH2Cl2,
OH
OTESOBn
17
OMe OH
OTESOBn
5
Scheme 3
10
r.t., 1 h, 80%.
OMe
CHO
OTESOBn
18
Abstract
Thus compound 5 was subjected to metathesis using Grubb’s 1st generation
catalyst to afford the compound 19.The allylic alcohol 19 was converted to enone 20 with
benzyl ether was achieved with Pd(OH)2 under hydrogen atmosphere to afford the
compound 21. One carbon Wittig reaction on ketone with methyltriphenylphosphonium
iodide yielded olefin 22. Epoxidation of the olefin with m-CPBA afforded the known
key intermediate 4 (Scheme 4).
OMe OH
OBn
CH2Cl2, r.t., 2 h, 98%
OTESOBn
5
O
OH
(Cy3P)2Cl2Ru=CHPh
10 mol%
OBn
IBX, DMSO, CH2Cl2
OMe
OTES
19
r.t., 1 h, 69%
OMe
OTES
20
O
OH
H2 atm. 87%
Pd(OH)2, THF
OMe
OTES
21
O
OH
CH3PPh3I, KOtBu
THF, 0 0C-r.t., 5 h, 87%
ref
OMe
OTES
0 0C-r.t., 3 h, 85%.
22
O
OH
OMe
OTES
mCPBA, CH2Cl2,
Me
O
OH
OMe
O
3
4
Scheme 4
This intermediate 4 was already converted to ovalicin in further few steps as
reported earlier by Barton et al.
Thus we have accomplished formal total synthesis of
ovalicin.
In conclusion, we have described an efficient formal total synthesis of ovalicin by
chiron approach. Since all the reactions are high yielding, this strategy could be applied
for multigram scale synthesis of the key intermediate, which can be derivatized further
for the synthesis of several other analogues for various biological activities.
11
Abstract
Chapter-III. Section-A: This section describes introduction -amino phosphonates,
-hydroxyl amino phosphonates and previous approaches to the synthesis of -amino
phosphonates.
Section-B: This section describes present work on -amino phosphonates and hydroxyl amino phosphonates.
The synthesis of -amino phosphonates has attracted much interest because of their
biological activity and structural analogy to -amino acids. As a result, a variety of
synthetic approaches have been developed for the synthesis of -amino phosphonates
during the past two decades.
Recently, ionic liquids have particularly gained recognition as possible
environmentally safe and alternative solvent to conventional molecular organic solvents
for the development of waste-free chemical processes. Ionic liquids are widely employed
as novel and recyclable reaction media for a variety of transformation including
asymmetric hydrogenation reaction, oxidation, Friedel-Crafts alkylation and acylation,
Diels-Alder reaction, esterfication reaction, Heck-reaction, Baylis-Hillman reaction,
Wittig
reaction,
aromatic
nitration,
Baker’s
yeast
reduction,
lipase
induced
transetserfication, acetylation reaction, alkene metathesis, asymmetric epoxidation, Oalkylation, hydroformylation, Fries rearrangement, allylation reaction, Pechmann
reaction, Knoevenagel condensation, single-electron transfer reaction, and polymerization
reaction, etc.
N
N
BF4-
N
Liquid (Hydrophilic)
N
PF6-
Liquid (Hydrophobic)
bmimPF6-
bmimBF4-
bmimBF4- : 1-Butyl -3-methyl imidazolium tetraflouroborate.
bmimPF6- : 1-Butyl -3-methyl imidazolium hexaflourophosphate.
12
Abstract
Herein, the ionic liquids (bmimBF4 & bmimPF6) have been proved as an efficient
catalyst and reaction medium for the three component coupling of a carbonyl compound,
amine and diethyl phosphite to yield various -amino phosphonates (Scheme 1). This
method describes a general procedure for producing biologically important -amino
phosphonates.
R-CHO + R'-NH2 +
bmimBF4
HOP(OEt)2
or
bmimPF6
r.t
HN
R'
OEt
R
P
O
OEt
Scheme 1
We first investigated the reaction between a simple, commercially available
benzaldehyde 1a, amine 2a and diethyl phosphite 3 by stirring equimolar quantities of the
three components in ionic liquids (ILs) for an appropriate time (Table-1) and isolated the
desired -amino phosphonate 4a in excellent yields (Table 1) (Scheme 2).
CHO
NH2
NH
+ (HO)P(OEt)
+
r.t., 5.0 h, 90%
2
1a
ILs
2a
3
P(O)(OEt)2
4a
Scheme 2
Similarly several aldimines (generated in situ from aldehydes and amines) reacted
with diethyl phosphite under similar reaction conditions to afford the corresponding amino phosphonates in high yields. In all cases, the reaction proceeded smoothly at
ambient temperatures with high selectivity (Table 1).
13
Abstract
Table-1
Aldehyde
Entry
NH2
CHO
a
bmimBF4
Amine
CHO
NH2
b
OH
bmimPF6
Time/h
Yieldb%
Time/h
Yieldb%
5.0
90
8.0
84
7.5
88
95
9.5
85
6.5
85
09
9.0
81
5.0
91
8.0
87
5.0
90
8.0
85
6.5
90
6.0
Cl
CHO
NH2
CHO
NH2
c
3.5
5.0
5.5
5.0
4.5
7.0
5.5
4.5
MeO
d
F
NH2
e
S
CHO
CHO
NH2
f
g
()
4
NH2
CHO
CHO
h
9.5
70
13.0
68
11.5
70
NH2
8.0
a
75
Products were characterized by 1H NMR, IR and mass spectroscopy
b
Isolated yields of products
14
Abstract
Both aromatic and aliphatic aldimines produced excellent yields of products.
However, the reactions of aliphatic aldimines took longer reaction time compared to
aromatic imines because of the low reactivity of aliphatic aldehydes than aromatic. The
reactions are clean and complete within 5-12 hours. The reaction conditions are very mild
and amino phosphonates are exclusively formed without the formation of any undesired
side products.
Encouraged by the above results, we tried to apply the same ILs system for the
synthesis of α-hydroxyl amino phosponates. Although a large number of methods is
available for the synthesis of -amino phosphonates, only few methods are reported for
-hydroxylamino phosphonates. Further more there are no examples on the use of ILs as
promoters for the three component coupling of aldehydes, hydroxylamines and diethyl
phosphite to produce -hydroxylamino phosphonates .
The treatment of benzaldehyde and phenyl hydroxylamine with diethyl
phosphite in ILs afforded the corresponding -hydroxylamino phosphonate in excellent
yield (Scheme 3).
HO
Ph-CHO + Ph-NH-OH +
HOP(OEt)2
bmimBF4 or
bmimPF6
r.t
N
Ph
OEt
Ph
P
O
OEt
Scheme 3
In a similar fashion, various aldehydes and aryl hydroxylamines reacted
smoothly with diethyl phosphite to give the corresponding -hydroxylamino
phosphonates in excellent yields (Table 2). The reactions proceeded efficiently at ambient
temperature with high selectivity. No trace amounts of -hydroxy phosphonates are
obtained as a result of the reaction between the aldehyde and diethyl phosphite. However
in the absence of ILs the reaction did not yield any product even after a long reaction
time.
15
Abstract
Table-2
Aldehyde
Entry
bmimBF4
Amine
Time/h
a
CHO
CHO
b
H
N OH
H
N
OH
bmimpF6
Yieldb%
Time/h
Yieldb%
3.5
89
2.5
92
3.5
90
4.0
87
4.5
90
5.0
85
2.5
92
92
3.5
87
3.0
89
4.5
85
3.5
92
4.5
90
3.0
95
4.0
89
MeO
MeO
CHO
H
N
c
OH
MeO
OMe
CHO
H
N
d
CHO
e
H
N
H
N
f
S
O
OH
OH
CHO
H
N
g
OH
OH
CHO
a
Products were characterized by 1H NMR, IR and mass spectroscopy
b
Isolated yields of products
16
Abstract
In addition to its simplicity and milder reaction conditions, this method is even
effective with aliphatic and unsaturated aldehydes which normally produce low yields.
The present method does not require any additives or promoters to proceed the reaction.
Another important feature of this reaction is the survival of a variety of functional
groups such as olefins, ethers, and halides under the reaction conditions. The advantage
of the use of ILs as novel reaction media for these two transformations is that these ILs
were easily recovered and reused.
In summary, we have demonstrated a novel and efficient protocol for the synthesis
of -amino phosphonates and -hydroxylamino phosphonates which can serve as peptide
mimetics by using ILs as efficient catalysts and reaction medium. The method is effective
for aromatic, aliphatic, unsaturated aldehydes and provides excellent yields of the
products, which makes it useful and attractive process for the synthesis of α-amino
phosphonates and -hydroxylamino phosphonates.
It is believed that this method presents a better and more practical alternative to the
existing methodologies for the synthesis of -amino phosphonates and -hydroxylamino
phosphonates.
17