Abstract
The thesis entitled “Studies Directed Towards the Total Synthesis of Ionomycin and
Development of Novel Methodologies” has been divided into three chapters.
Chapter I: This chapter deals with introduction to Polyether Antibiotic, including some of
potent antibiotic marine macrolide and the approaches cited in the literature towards the
synthesis of Antibiotic Ionomycin, including the total synthesis.
Chapter II: This chapter describes the deals with present work of Ionomycin.
Chapter III: This chapter describes the development of novel methodologies, which is
further subdivided into two sections.
Section A: This section describes LiClO4-catalyzed highly diastereoselective synthesis of
cis-aziridine carboxylates.
Section B: This section describes enzymatic resolution of N-aryl aziridine carboxylates.
I
Abstract
CHAPTER I: Introduction and previous approaches of Ionomycin.
Ionomycin, (Fig. 1) was first isolated from the fermentation broths of Streptomycin
congoblatus1 in 1978. Ionomycin is distinct from the other members of the polyether
antibiotic family in several important ways. Firstly, it is doubly charged, and therefore
highly selective for divalent ions. This property is in direct contrast to the monobasic
chelating effects of other polyether antibiotics and allows ionomycin to chelate divalent
ions as adibasic acid in an octahedral coordination system, as a 1:1 charge-neutral
complex.2 Calcimycin is the only other ionophore to similarly distinguish between
monovalent and divalent cations, differentiating between calcium and magnesium as its 2:1
Ligand/metal complex.3 a second anomaly is present in the P-dicarbonyl functionality at
C9-C11, a rarity in natural products.
23
O
H
22
H
O
OH
OH
O
OH
17
16
OH O
3
11 10
1
Ionornycin 1
Fig. 1
II
HO
Abstract
CHAPTER II: Stereospecific synthesis of C3-C10, C11-C16 and C17-C23 fragments of
Ionomycin.
Retrosynthetic stategy of Ionomycin:The successful synthesis of a complex molecule
depends upon the analysis of the problem to develop feasible scheme of synthesis
generally consisting of a pathway of synthetic intermediates connected by possible
reactions for the required interconversions. We chose to adopt a highly convergent
strategy for the synthesis of Ionomycin disconnecting the carbon backbone at C (10-11)
and C (16-17) E-alkenes thus dividing the target into three key subunits 2, 3 and 4.
23
O
H
22
H
O
OH
OH
O
OH
17
HO
OH O
16
3
11 10
1
O
O
O
+
I
S
S
H
OBn
+
4
3
2
OBn
O
O
5
6
O
O
5
7
OBn
Scheme 1
III
4
1
2
3
O
6
Abstract
The advantages of making use of such a common bicyclic precursor 5 are
manifold. The inherent rigidity of bicyclic intermediate 5 facilitates functionalisation in a
stereo controlled fashion. The bicyclic compound 5 has five stereogenic centers and two
prostereogenic sp2 sites, which could facilitate further functionalisation.
Synthesis of common bicyclic precursor (6):
The initial attempts toward the synthesis of Ionomycin began with the synthesis of
bicyclic precursor 6, which is common starting material for fragments C3-C10, C11-C16
and C17-C23. The bicyclic ketone 6 was prepared by employing the [3+4] cycloaddition of
oxyallyl cation and furan 9 as reported by Hoffman and co-workers.4 The oxalyl cation,
generated from 2,4-dibromopentanone 8 with Zn-Cu couple at –10 oC, when treated with
furan undergo [3+4] cycloaddition to afford 6, 10 and 11 in the ratio 8:1:1. The stereo
selective reduction of these ketones with DIBAL-H exclusively gave the corresponding
endo alcohol 12 and two other isomers.
Br
Br
Br2 / AcOH
O
7
O
8
O
Br
O
Zn-Cu couple,
+
O
O
O
-10oC,
Br
6
9
8
+
DME
O
+
10
O
O
O
DIBAL-H,
-10oC,
11
O
+ mixture of isomers
DCM
12
NaH, BnBr
THF, reflux, 6 h
13
OH
Scheme 2
IV
OBn
Abstract
The required alcohol 12 was separated from the other isomers by column
chromatographic technique and the structure was confirmed from spectral studies. The
hydroxyl group of compound 12 was then protected as its benzyl ether 13 using NaH and
benzyl bromide. Asymmetric hydro boration of olefin13 using (+)-diisopino camphenyl
borane 5 proceeded smoothly to give the alcohol 14 with high enantiomeric purity in 96%
yield. The alcohol 14 was converted to the lactone 5 by a two-step sequence, PCC
oxidation of alcohol 14 followed by Baeyer-Villiger oxidation of the resulting ketone 15
(Scheme 3).
O
O
[(-)--IPc2BH]
13
O
HO
PCC
CH2Cl2,
OBn
OBn
14
O
15 OBn
O
m-CPBA, NaHCO3
CH2Cl2, r.t.
O
O
5
OBn
Scheme 3
Synthesis of C17-C23 fragment of Ionomycin (3):
Acetylinic C17-C23 fragment of Ionomycin achieved in 9 steps from known
bicyclic precursor, which was obtained from [4+2] cyclo addition of 2, 4 dibromo-3pentanone and furan. The key feature of the strategy is the generation of 3-stereogenic
centers from a single bicylic precursor, which has been utilized as a chiral building block
for the synthesis of various natural products.
V
Abstract
O
LAH
O
OH
THF
O
OTPS OBn OH
OBn OH OH TBDPS-Cl, imid.
CH2Cl2, r.t.
OBn
5
Dess-Martin
17
16
OTPS OBn O
CH2 Cl2, r.t.
OTPS
OTPS
NaBH4
OTPS OBn OH
OTPS
TBAF/THF
OH
OBn OH OH
MeOH/THF
19
18
20
Scheme 4
Having synthesized the bicyclic lactone 5 with all the functionalities for elaboration
of the C3–C9 fragment, attention was directed to the opening of lactone ring. Accordingly
lactone 5 on treatment with LAH in dry THF gave a polar compound in 80% yield, which
was found to be the expected triol 16 (Scheme 4). The primary hydroxyl groups of
compound 16 were selectively protected as TBDPS ether. Some more steps and the low
yield of the expected product forced us to abandon this route.
Since the Mitsunobu protocol for the inversion at C-5 centre failed it was decided to
explore the oxidation reduction strategy. Oxidation of compound 17 using Dess-Martin
periodinane afforded the keto compound 18 in 95% yields. It was found that the reduction
of keto compound 18 using NaBH4 in MeOH:THF (4:1) afforded the required -isomer 19
as the major product (19:17 = 9:1).
VI
Abstract
OH
OBn OH
OH
OH
OBn O
O
Cat.PTSA
DMSO/DCM,
1h, rt
20
CBr4,
TPP,Et3N,
Dry DCM
O
IBX
DMP, acetone
21
OBn O
O
Br
EtMgBr
OBn O
OBn O
O
H
22
O
Dry THF
Br
Scheme 5
23
2
The deprotection of TBDPS group of compound 19 with TBAF in THF afforded the
triol 20 and the resultant triol 20 was protected as its monoacetonide 21 using
dimethoxypropane and catalytic amount of PTSA in acetone as shown in scheme 5. The
hydroxyl group in acetonide compound 21 was transformed into aldehyde 22
6
using o-
iodoxybenzoic acid, DMSO in DCM at room temperature. The aldehyde 22 was
transformed to acetylenic compound 2 7 by Corey-Fuchs protocol. The aldehyde 22 was
transformed to dibromo compound 23 by treatment with CBr4, TPP and triethylamine in
dry DCM (yield 85%) and When the dibromo compound 23 was treated with EtMgBr (in
situ generated from EtBr and Mg in dry THF at 0 oC) gave the acetylene compound 2 in
75% yield. (Scheme 5)
Synthesis of C11-C16 fragment of Ionomycin (3):
Synthesis of C11-C16 fragment began using common by cyclic precursor that was
utilized in first fragment synthesis. This fragment was achieved in 14 steps. The synthesis
of C11-C16 fragment of Ionomycin began with known common bicyclic precursor, which
was synthesized in Chapter I. Alkylation at the -position of the lactone 5 was achieved
by treating it with methyl iodide in the presence of LDA in dry THF at –78 0C to give a
compound 25 in 85% yield (Scheme 6).
VII
Abstract
Having synthesized the bicyclic lactone 24 with all the functionalities for
elaboration of the C3 – C9 fragment, attention was directed to the opening of lactone ring.
It was felt that reduction of lactone 24 would be the most ideal strategy. Accordingly
lactone 24 on treatment with LAH in dry THF gave a polar compound in 80% yield, which
was found to be the expected triol 25 (Scheme 6). The triol 25 was protected as its
monoacetonide 26 using 2, 2-dimethoxy propane and catalytic amount of PPTS in DCM in
80% yield and the primary alcohol 26 was treated with 1.1 eq of TBDPSCl and 1.5 eq of
imidazole in DCM afforded the protected compound 27 in 92% yield (Scheme 6)
O
O
LDA,, -78 0C,
Methyl iodide
O
O
OH
OBn O
O
O
OBn
5
24
O
OH
LiAlH4,
TBDPS-Cl, Imidazole
OH
dry THF,
OBn
OTPS OBn O
O
Napthalene,
OTPS O
dry THF,0oC-rt
O
O
O
OH
OH
28
S
NaH, CS2, MeI
OTPS OH
dry THF, -20oC, 5h
27
SMe
2,2-DMP, PPTS
,
TBDPSCl,
Imidazole
25
dry DCM, 0oC-rt, 3h
26
OBn OH
O n-Bu3SnH, AIBN OTPS
O
O PPTS, MeOH
OTPS
0oC-rt, 1 h
Toluene,
30
29
31
Scheme 6
Further goal at this stage was to knock out the OBn group from compound 27. In
that consequence benzyl group of compound 27 as deprotected using Li in Naphthalene to
give compound 28 8 in 78% yield and next we moved to knock out the 2o-hydroxygroup,
which was done via. xanthate 29. Compound 28 reacted with CS2 in standard conditions 9
VIII
Abstract
to obtain xanthate 29, which was subjected to reductive elimination using Bu3SnH to give
compound 30.10
OTPS
OH
OH
3.5 eq. IBX
OTPS
OTPS
O
MeOH
DMSO, THF, r.t.
31
NaIO4
O
32
OTPS
THF:H2O
O
1,3-propanedithiane
H
S
S
H
33
OTPS
OH
TBAF, dry THF
S
30 min, BF3. OEt2
S
H
34
OH
OH
NaBH4
0oC -rt,3 h
35
TPP, I2, imidazole
I
S
CH3CN : Et2O (1:3)
0oC - rt, 1 h
S
H
36
3
Scheme 7
Compound 30 was treated with catalytic amount of PPTS in methanol to afford diol 31 and
subsequent oxidation with 3.5 eq of IBX and DMSO in THF afforded diketo 32 (Scheme
7). The 1, 2-diketo group in compound 32 was reduction with sodium borohydride in
methanol afforded 1, 2 diol 33 in 82 % yield (Scheme 7). Oxidative cleavage of compound
33with sodium periodate in THF-water (8:2) at room temperature afforded the aldehyde
and the aldehyde 35 was converted to dithiane 35 through carbonyl protection by 1,3
propane dithiol under acidic condition according to Scheme 7. Thus, when aldehyde 34
was allowed to react with 1, 3-propane dithiol in the presence of catalytic amount of
BF3.OEt211 in dry DCM afforded the dithiane 35 in yield 94%.
IX
Abstract
Next goal of the programme was to introduce iodo functionality at the primary hydroxyl
group. Compound 35 was treated with TBAF to obtain compound 36 12 in 85 % yield and
13
the iodination
of hydroxyl group of 36 using I2, TPP and imidazole in acetonitrile and
diethyl ether mixture at room temperature afforded the iodo compound 37 in yield 85%,
which is corresponding to C11-C16 fragment of Ionomycin.
Synthesis of C3-C10 fragment of Ionomycin
Synthesis of C3-C10 fragment of Ionomycin began with diol 31, which was
utilized in the synthesis of C11-C16 fragment of Ionomycin of using common bicyclic
precursor that was utilized in first and second fragment. Synthesis of this fragment
achieved in 15 steps.
SMe
OTBDPS
OH
OH
OTBDPS
NaH, BnBr
n-Bu3SnH, Cat. AIBN
OBn
OTBDPS
OBn
TBAF, dry THF
OH
OBn
IBX
DMSO, DCM,
00 C -rt,3 h
OBn
40
OH
OBn
MeMgI,
H3 C
DMP, NaHCO3
O
OBn
dry DCM, 0oC-rt H3 C
Ether
41
OBn
38
39
H
O
THF,0oC-rt
37
dry Toluene, 80o C
3h
O
NaH, CS2, MeI
dry
TBAI (Cat),
THF
31
OH
S
OTBDPS
4
42
Scheme 8
One of the two hydroxyl groups of 31 was protected as its mono benzyl ether using 1.1 eq
NaH and BnBr in the presence of catalytic amount TBAI in dry THF at room temperature
to furnish 37 in 90% yield. Next we moved to knock out the 2o-hydroxygroup, which was
X
Abstract
done via. xanthate 38. Compound 37 reacted with CS2 in standard conditions to obtain
xanthate 38, which was subjected to reductive elimination using Bu3SnH to give
compound 39 (Scheme 8). Compound 39 was treated with TBAF to obtain compound 40
in 86 % yield. Compound 40 which on oxidation using IBX and DMSO in DCM afforded
aldehyde 41 (Scheme 8). Further aldehyde 41 was exposure to Grignard reaction. The
methylene alcohol could be easily obtained by reaction of aldehyde 41 with MeMgI in
ether at room temperature in 89% yield and the compound 42 was oxidized with DesMartin periodinane 14 to give methyl keto 4 in 88% yield, which is corresponding to the
C3-C10 fragment of Ionomycin.
In conclusion, these stereospecific C3-C10, C11-C16 and C17-C23 fragments
synthesis illustrates the dynamic utility of the common bicyclic precursor 5 and its
desymmetrisation approach to fix nine required stereo centers. Thus we have demonstrated
three key fragments of Ionomycin in very efficient manner.
CHAPTER III: Development of new methodologies. This chapter further divided into
two sections.
Section A: LiClO4-catalyzed highly diastereoselective synthesis of cis-aziridine
carboxylates
Aziridines are useful building blocks for the synthesis of many biologically active
compounds such as amino alcohols, unnatural amino acids and nitrogenous heterocycles.15
Aziridines are carbon electrophiles capable of reacting with various nucloephiles and their
ability to undergo regioselective ring opening contributes to their synthetic value. The
nucleophilic ring-opeing of aziridines leads to many biologically active compounds such as
,-unsaturated amino esters, -lactam antibiotics and alkaloids.16
XI
Abstract
In recent years, LiClO4 in diethyl ether (LPDE) has emerged as a mild Lewis acid
imparting high regio-, chemo- and stereoselectivity in various organic transformations.17
Lithium perchlorate is found to retain its activity even in the presence of amines and has
also been found to activate effectively nitrogen-containing compounds such as imines.18
NH2 + N2 CHO2 Et
H + Ar
R
1
Ar
Ar
O
2
LiClO4
CH3 CN, r.t.
N
N
+
COOEt
R
3 (cis)
EDA
R
COOEt
4 (trans)
Scheme 9
In this part of work we explored the facile synthesis of highly diastereoselective cisaziridine carboxylates by the reaction of aldimines generated in situ from aldehydes and
amines in the presence of a catalytic amount of lithium perchlorate. Accordingly, treatment
of benzaldehyde and aniline with ethyl diazoacetate in the presence of 10 mol% of lithium
perchlorate gave the corresponding ethyl 1,3-diphenylaziridine-2-carboxylate (3a) in 87%
yield with high cis-selectivity (Scheme 9). The cisstereochemistry of the aziridine 3a was
confirmed by the large coupling constant (J=6.9 Hz) of the aziridine ring hydrogens at _
3.20 and 3.59 (the ring protons of trans-3a appear at 3.20 and 3.80 with a smaller coupling
constant, J=2.0–3.0 Hz).In summary, acetonitrile solutions of lithium perchlorate were
found to be a highly efficient and convenient catalytic media for the synthesis of cisaziridine carboxylates from aldehydes, amines and ethyl diazoacetate in a single-step
operation. In addition to its simplicity and milder reaction conditions, this method provides
high yields of products with high cis-selectivity which makes it a useful and attractive
strategy for the preparation of cis-aziridine carboxylates of synthetic importance.
XII
Abstract
Table 1 LiClO4-catalyzed synthesis of cis-aziridne carboxylates from imines
Entry
Aldehyde
R
CHO
Producta
Amine
R'
Time (h)
Yield (%)
Cis-trans
R'
N
NH2
R
COOEt
a
R = Ph
R' = Ph
3a
4.5
89
cis only
b
R = 4-Me-Ph
R' = 4-Cl-Ph
3b
5.0
91
cis only
c
R = 2-Naphthyl
R' = Ph
3c
6.5
84
cis only
d
R = Ph
R' = 4-F-Ph
3d
5.5
87
cis only
e
R = 4-NO2-Ph
R' = Ph
3e
6.0
75
85:15
f
R = 3-NO2-Ph
R' = 4-Br-Ph
3f
6.5
79
82:18
g
R = 4-Cl-Ph
R' = 4-Cl-Ph
3g
5.0
86
cis only
h
R = 4-Me-Ph
R' = Ph
3h
4.5
90
cis only
i
R = 4-Me-Ph
R' = 4-Br-Ph
3i
5.5
85
cis only
j
R = 4-HO-Ph
R' = Ph
3j
6.0
80
cis only
k
R = Ph
R' =
3k
5.0
87
97:3
3l
5.5
89
95:5
O
l
R = 4-Cl-Ph
R' =
O
CH2
CH2
m
R = Ph
R' = PhCH2-
3m
6.0
85
cis only
n
R = 4-Cl-Ph
R' = Ph
3n
4.5
90
cis only
o
R = 4-MrO-Ph
R' = Ph
3o
5.0
86
cis only
p
R = n-C5H11-
R' = Ph
3p
6.0
78
92:8
q
R = n-C9H19-
R' = Ph
3q
7.5
75
89:11
r
R = PhCH2CH2-
R' = Ph
3r
5.5
80
87:13
a. All products were charcterized by 1H NMR, IR and mass spectroscopy.
b. Yield refers to pure products after column chromatography
XIII
Abstract
Section B: Enzymatic resolution of N-arylaziridine carboxylates.
Candida rugosa lipase (CRL) is an extracellular protein, inexpensive and accepts a
broad range of substrates. It is extensively used for the hydrolysis and esterification of
organic compounds
19
and the knowledge
20
of its crystal structure has greatly contributed
to understanding the mechanism of its selective recognition of substrates.21 In order to
improve the chemo-, region- and diastereoselectivity of the enzyme, commercial CRL as
well as conventional purifications, 22 have been subjected to several treatments that cause
molecular or conformational changes. Structural analysis reveals that the catalytic traid is
not exposed to the reaction medium, and the polypeptide lid, which covers the active site
of the native enzyme, is displaced before the substrate approaches the active site.23
Scattered data indicate that the method of CRL purification and the reaction medium
24
strongly influence the activity and selectivity of lipase but systematic studies in this area
are rare. 25
In this part of work we report the kinetic resolution of racemic N-arylaziridine-2carboxylates via enantioselective hydrolysis by C. rugosa lipase (CRL).
MeO2 C
HO2 C
MeO2 C
N
N
N
Candida rugosa
+
R
ph 7.5 phosphate buffer
S
5
6
Scheme 10
XIV
R
R
R
7
Abstract
Hydrolysis was conducted in PH 7.5 phosphate buffer (0.1 M) and due to the low
solubility of the substrates in buffer solution, dioxane was used as the co-solvent. The
hydrolysis was terminated at around 45–50% conversion by extraction with EtOAc. The
crude optically active esters obtained after evaporation of the solvent were flash
chromatographed on silica gel (EtOAc/n-hexane gradient) to afford pure N-arylaziridine
carboxylates. The enantiomeric purity was determined by chiral HPLC and 1H NMR-shift
reagent methods. Moderate to high enantiomeric purity (70–99%) was observed among the
substrates (see Table 1) studied. The absolute configuration of all the unhydrolyzed Narylaziridine carboxylates was determined as S by comparing the sign of the specific
rotation, based on a literature precedent.
We have successfully demonstrated herein, the kinetic resolution of synthetically
important N-arylaziridine-2- carboxylates in moderate to high enantiomeric purity using
Candida rugosa lipase. All the unhydrolyzed esters were found to be of an (S)configuration. (Scheme 10)
XV
Abstract
Table 1. Enantioselective hydrolysis of aziridine-2-carboxylates by C. rugosa
Entry
Substrate (Ar)
3
4
5
Conversion (%)
t (h)
E/Sa
4
1/2
48
-173.2
84
S
Br
5
1/2
50
-156.7
99
S
O2 N
3
1/2
45
-40.3
12
S
4.5
1/2
48
-195.5
70
S
5.5
1/4
44
-18.4
7
S
5.5
1/4
46
-15.9
15
S
5
1/2
46
-184.3
79
S
1
2
Unchanced ester
Reaction conditions
H3 C
F
[]D25 CHCl3b
Ee (%)c
Absolute configuration
Br
6
7
a E/S
b+
c
H3 C
MeO
refers to enzyme, substrate (wt/wt) ratio.
or - refers to the sign of the specific rotation.
Determined by chiral HPLC conditions: Chiracel ODTM, Daicel, Japan; 5  250mm,  330 nm;
10% isopropanol in hexane; .flow rate 0.6 mL/min and
by 1H NMR with Eu(hfc)3 in CDCl3.
XVI
Abstract
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XVII
Abstract
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XVIII
Abstract
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