1
SYNOPSIS
SYNOPSIS
The thesis entitled “Studies directed towards the total synthesis of
Constanolactone A, B and development of novel synthetic methodologies” is divided
into three chapters i.e., chapter I, II and III.
Chapter- I: This chapter is further divided into two sections i.e., section A and section B
Section A: This section deals with the introduction to Oxylipins and the approaches cited
in the literature towards the synthesis of Constanolactone A, B.
Section B: This section deals with the present work wherein the synthesis of the C1-C9 and
C10-C20 fragment of the Constanolactone A, B is described.
Chapter II: This chapter is further divided into three sections i.e., section A, section B,
and section C, each one deals with the development of new synthetic methodologies.
Chapter III: This chapter deals with Regioselective synthesis of -alkoxy alcohols and 1,
2- diols
Chapter I: This chapter is further divided in to two sections i.e., section A and B.
Section-A
It is relatively a recent development in the study of marine derived natural products,
to recognize the creatures inhabiting the world’s oceans that are rich with eicosanoids and
related fatty acid derivatives collectively known as oxylipins. Interest in the structural
chemistry, biosynthesis and pharmacological activities of these marine products has
intensified, because this class of compounds play a crucial role in both mammalian
physiology and disease.
2
SYNOPSIS
Constanolactone 1 belongs to the class of oxylipin possessing a cyclopropane ring
and a lactone moiety. Nagle et al., have carried out the isolation, structural elucidation and
stereochemical assignment of constanolactone by using a combination of spectroscopic
and degradation studies.
19
15
17
R1
R2
14 10
20
18
12
5 O
9
16
13
7 H
11
1 O
8 6
H
2
4
3
OH
1
R1 = H, R2 = OH Constanolactone A
R1 = OH, R2 = H Constanolactone B
The structural ensemble and stereochemical features of Constanolactone are
decorated with dense functionalities that include a six membered lactone, trans-fused
cyclopropane ring, and a Z-olefinic bond. With its five stereocentres and two geometrical
elements, Constanolactone a considerable challenge as synthetic target, particularly with
respect to stereochemistry and functional group sensitivity.
Section-B
Retrosynthesis: A careful retrosynthetic study reveals that disconnection at C9-C10 of
Constanolactone 1 provides two crucial intermediates 2 and 3, which can be obtained from
(S)-p-methoxyphenylmethyl epoxide 4a and (R)-p-methoxyphenylmethyl glycidol 4b
respectively.
3
SYNOPSIS
Retro synthesis
R1
H
R2
O
O
H
1
OH
R1=H, R2=OH Constanolactone A
R1=OH, R2=H Constanolactone B
O
OBn
H
O
+
H
O
H
3
2
O
O
OMPM
OMPM
4b
4a
O
OMPM
4c
Scheme-1
4
SYNOPSIS
Protected glycidol (±) 4c was subjected to Jacobsen’s resolution to furnish the (S)glycidol 4a and (R)-diol 5.
O
Cl
NaH,MPMOH
THF
O
OMPM
R,R-Jacobsen's catalyst
O
OMPM
4a
4c
+
OH
Scheme-2
OMPM
HO
5
The enantio purity of the chiral epoxide 4a was further confirmed by its synthesis
from L-ascorbic acid. L-ascorbic acid 6 was treated with acetone and catalytic amount of
acetyl chloride to afford the acetonide 7 which was oxidized with H2O2 in the presence of
potassium carbonate to furnish it’s potassium carboxylate salt. The salt was subsenquentlly
converted to ethyl ester 8 by refluxing with ethyl iodide in acetonitrile. The ester 8
underwent reduction with lithium aluminium hydride (LAH) in ether at 0oC to yield the
diol 9. The diol 9 was oxidatively cleaved with NaIO4 to provide the L-glyceraldehyde 10.
The aldehyde 10 was reduced to the alcohol 11 and protected with paramethoxybenzyl to
furnish the substrate 12. Substrate 12 was converted to epoxide 4a by the sequential
treatment with catalytic PTSA in methanol, tosylchloride and triethylamine in DCM
followed by K2CO3 in methanol.
5
SYNOPSIS
HO
O
O
HO
HO
OH
acetone
O
O
O
O
COOEt
HO
OH
LiAlH4, Et2O
O
NaIO4
O
OH
OH
OH
9
NaBH4, MeOH
O
2)EtI, CH3CN
7
8
O
1) H2O2 , K2CO3,H2O
Acetyl chloride
6
O
O
MPMBr
O
O
H
OH
NaH, THF
11
O
10
PTSA
O
O
OMPM
O
OMPM
MeOH
12
1) TsCl, TEA, CH2Cl2
HO
HO
13
2) K2CO3, MeOH
OMPM
4a
Scheme-3
The synthesis of 2 started with the metallation of 1-heptyne (n-BuLi, THF,
-78oC) followed by the addition of BF3.Et2O and (S)-paramethoxybenzyl protected epoxide
4a to provide the secondary alcohol 14. Benzylation of the free hydroxyl group with NaH
and benzylbromide in THF at 0oC yielded 15. Compound 15 was subjected to DDQ
(DCM: H2O; 17:3 rt; 15 min) which gave compound 16 in 90% yield. The alcohol 16 was
converted to dibromo compound 17 by the sequential treatment with IBX in a mixture of
6
dimethylsulfoxide-diethyl
ether,
and
SYNOPSIS
triphenylphosphine-carbontetrabromide
in
dichloromethane. The geminal dibromo olefine 17 was treated with EtMgBr in THF to
afford the alkyne 2 in 80% yield.
OH
O
OMPM
BuLi, BF3.Et2O
+
4a
THF, -780c
OBn
OMPM
NaH,BnBr, THF
OMPM
14
DDQ, DCM:H2O(17:3)
15
OBn Br
I). IBX, DMSO:Ether
OBn
OH
Br
II) TPP, CBr4, DCM
16
17
OBn
EtMgBr, THF
2
Scheme-4
The aldehyde 3 was prepared from (R)-p-methoxyphenylmethyl glycidol 4b.The
(R)-diol 5 was treated with triethyl amine p-toluenesulphonylchloride in dichloromethane
to obtain the primary alcohol protection followed by treatment with potassium carbonate in
methanol yielded 4b in 85% yield.
7
OH
OMPM
HO
OH
TEA, TsCl ,
TsO
CH2Cl2
5
O
SYNOPSIS
OMPM
K2CO3, MeOH
18
Scheme-5
OMPM
4b
The enantio purity of the chiral epoxide 4b was further confirmed by its synthesis
from D-mannitol. D-mannitol was protected with 2,2 DMP followed by cleavage with
NaIO4 to give the aldehyde 19. The aldehyde 19 was reduced to the alcohol 20 and
protected with MPMBr to give the substrate 21. Substrate 21 was converted to epoxide 4b
by the sequential treatment with catalytic PTSA in methanol, tosylchloride and
triethylamine in DCM followed by potassium carbonate in methanol.
2,2,-DMP
Mannitol
D-Mannitol
DMSO
diacetonide
NaIO4
O
O
H
MeOH, H2O
19 O
NaBH4
MPMBr
O
O
OH
MeOH
MeOH
1) TsCl, TEA
HO
HO
OMPM
NaH, THF
20
PTSA
O
O
21
O
OMPM
OMPM
2) K2CO3
5
Scheme 6
4b
8
SYNOPSIS
(R)-p-methoxyphenylmethyl glycidol 4b was treated with allylmagnesiumchloride,
in diethyl ether to afford the terminal olefinic compound 22.
MgCl
O
OMPM
OMPM
4b
THF
22
THF, NaOH
IBX, DMSO/THF
OMPM
OMPM
O
HO
RT
OH
OH
BH3.DMS, H2O2
OH
24
23
DDQ, DCM/ H2O
NaH, MeI, THF
O
O
OMPM
(17:3)
25
i) (COCl)2 DMSO,TEA
O
OH
O
O
O
DCM, -780c
O
O
27
26
ii) Ph3P=CHCO2Et, Benzene
Et2Zn, CH2I2
DIBAL-H,DCM,-780c
O
O
OH
CH2Cl2, -230c
28
H
O
O
HO
O
O
H
H
H
Dess-Martin reagent
CH2Cl2
29
H
3
SCHEME-7
O
9
SYNOPSIS
The terminal olefinic compound 22 was subjected to hydroboration with BH3.DMS
to obtain the diol 23. Diol 23 was oxidized with one equivalent of IBX in a mixture of
dimethylsulfoxide and THF to furnish lactol 24. Lactol 24 was protected as methoxy by
treating with methyl iodide, NaH in THF at 0oC to obtain the compound 25. Deprotection
of MPM from compound 25 was accomplished with DDQ (DCM: H2O, 17:3: rt; 18 min)
in 85% yield. The alcohol 26 was then oxidized to aldehyde by following Swern oxidation
and subsequently, the aldehyde was subjected to Wittig reaction in benzene to yield 27.
The ester 27 was reduced to alcohol 28, by treatment with DIBAL-H in dichloromethane.
The trans olefinic alcohol 28 was treated with diethylzinc, diiodomethane in DCM at –
23oC which yielded trans cyclopropane compound 29. The alcohol 29 was oxidized with
desmartinperiodinane in dichloromethane to obtain the aldehyde 3.
Conformation and the absolute stereochemistry of compound 3 was established by
converting the compound 3 into known carboxaldehyde 30, by subjecting it, to
deprotection of methyl group using acetic acid, followed by oxidation with
desmartinperiodinane in dichloromethane. Proton NMR of the aldehyde 30 showed that the
aldehyde proton appeared at 9.15 ppm and cyclopropyl protons at 1.4-1.10 ppm integrating
for four protons and the optical rotation of the compound 30 was found to be in agreement
with literature, D 38.3o (C 1.0, CHCl3): lit. D 41.50 (C 0.83, CHCl3) conforming the
absolute stereochemistry of cyclopropyl group as (S, S) and hydroxyl as (R).
H
O
HO
OMe
1) AcOH
O
2) Dess Martin reagent
H
29
H
O
CH2Cl2
Scheme-8
H
H
30
O
10
SYNOPSIS
Chapter-II
Section-A
Aziridines react smoothly with carboxylic acids in the presence of a catalytic
amount of indium triflate at ambient temperature to afford the corresponding aminoacetate and benzoates in high yields with high regioselectivity.
NTs
R
+
R1COOH
In(OTf)3
CH2Cl2
1
NHTs
OCOR1
+
R
R
OCOR1
NHTs
3
2
Scheme-9
NTS
+
R1COOH
In(OTf)3
NHTs
CH2Cl2
OCOR1
1
4
Scheme-10
Aziridines are versatile synthetic intermediates for the synthesis of many
biologically interesting molecules such as amino acids, heterocycles and alkaloids. They
are well known carbon electrophiles. They are capable of reacting with various
nucleophiles and their ability to undergo regioselective ring opening reactions contribute
largly to their synthetic value. However, there are no reports on the regioselective ring
opening of aziridines with carboxylic acids.
-Amino acetates and benzoates so formed are very usefull synthetic intermediates
employed in the preparation of many biologically active compounds.
11
SYNOPSIS
Table 1. In(oTf)3-catalyzed ring opening of aziridines with carboxylic acids
Entry
Aziridines
Acid
2
1
a
Product
N-Ts
Acetic
acid
Yield
Ratio
(%)
2:3
3
NHTs
90
OCOCH3
b
Crotonic
acid
N-Ts
NHTs
92
OCOCH=CHCH3
c
N-Ts
Acrylic
acid
NHTs
85
OCOCH=CH2
d
Acetic
acid
N-Ts
NHTs
89
OCOCH3
NHTs
e
Crotonic
acid
N-Ts
92
OCOCH=CHCH3
NHTs
f
N-Ts
Cinnamic
acid
85
OCOCH=CHPh
NHTs
N-Ts Phenyl
g
acetic acid
OCOCH2Ph
NHTs
N-Ts
h
Acetic
acid
OCOCH3
OCOCH2Ph
NHTs
90
92:8
92
96:4
OCOCH3
NHTs
12
Entry
Aziridine
SYNOPSIS
Product
Acid
1
Yield
3
2
Ratio
2:3
(%)
NHTs
OCOCH=CH2
OCOCH=CH2
NHTs
N-Ts
Acrylic
acid
i
N-Ts
Cinnamic
j
97:3b
88
NHTs
OCOCH=CHPh
OCOCH=CHPh
NHTs
95:5b
90
acid
N-Ts
k
NHTs
OCOPh
OCOPh
NHTs
NHTs
OCOCH=CHCH3
OCOCH=CHCH3
NHTs
N-Ts
Crotonic
acid
l
N-Ts
m
Cinnamic
acid
Cl
N-Ts
n
NTs
o
NTs
p
aIsolated
cRatio
NHTs
OCOCH=CHPh
OCOCH=CHPh
NHTs
Crotonic
acid
Acetic
acid
87
94:7b
90
95:5b
Cl
Cl
NHTs
Acetic
acid
91:9b
89
Benzoic
acid
OCOCH3
89
NHTs
7:93c
OCOCH3
NHTs
OCOCH=CHCH3
OCOCH=CHCH3
NHTs
NHTs
OCOCH3
OCOCH3
NHTs
and unoptimized yield, bRatio of products from internal attack Vs terminal attack
of products from terminal attack Vs internal attack
90
10:90c
87
12:88c
13
SYNOPSIS
Section-B
Enantiomerically pure aziridines serve as versatile intermediates for the asymmetric
synthesis of biologically active compounds because they undergo highly regio and
stereocontrolled ring opening reactions with nucleophiles.
NTs
R
(R1CO)2O
+
Sc(OTf)3
CH2Cl2, r.t.
1
NHTs
OCOR1
+
R
R
OCOR1
NHTs
2
3
Scheme-11
NTs
+
(R1CO)2O
NHTs
Sc(OTf)3
CH2Cl2, r.t.
OCOR1
4
1
Scheme-12
Several procedures have been reported for the regioselective ring opening of
aziridines with various nucleophiles such as organometallic reagents silyl nucleophiles,
Wittig reagents, amines, halides, hydroxyl compounds and alkenes produce ring opened
products. However, there are no reports on the regioselective ring opening of aziridines
with acid anhydrides. To the best of our knowledge, this is the first report on the
regioselective ring opening of aziridines with acid anhydrides using a catalytic amount of
scandium triflate.
The treatment of styrene-N-tosyl aziridine with acetic anhydride in the presence of
5-mol%
14
SYNOPSIS
Sc (OTf) 3 at ambient temperature resulted in the formation of -amino acetate derivative
3g (Table-2) in 85% yield. In a similar fashion, aryl-N-tosyl aziridines reacted smoothly
with acid anhydrides to afford the corresponding -amino acetates, benzoates and
propionates. Furthermore, the treatment of cycloalkyl-N-tosyl aziridines with acid
anhydrides afforded the corresponding -amino esters in high yields. -Amino esters are
important moieties of many biologically active molecules.
15
SYNOPSIS
(Table-2) Sc(OTf) 3-catalyzed cleavage of activated aziridines with acid anhydrides
Entry Aziridine
Anhydride
Yielda
Product
3
1
(%)
2
NHTs
a
N-Ts
Ac2O
85
OCOCH3
NHTs
b
N-Ts
Bz2O
80
OCOPh
81
NHTs
c
N-Ts
(CH3CH2CO)2O
NHTs
(CH3CH2CO)2O
OCOCH2 CH3
NHTs
d
83
OCOCH2 CH3
NHTs
e
NHTs
Ratiob
2:3
87
Ac2O
OCOCH3
NHTs
f
NHTs
78
Bz2O
OCOPh
NHTs
OCOCH3
OCOCH3
NHTs
NHTs
OCOPh
NTs
Ac2O
g
NTs
h
87c
81
Bz2O
OCOPh
NHTs
95:5
90:10
16
Entry
Aziridine
1
Anhydride
Product
2
NTs
AC2O
i
SYNOPSIS
NHTs
OCOCH3
OCOCH3
NHTs
NTs
Ratiob
2:3
85c
NHTs
OCOPh
OCOPh
NHTs
80
Bz2O
j
85:15
H3 C
H3 C
H3 C
94:6
H3 C
H3 C
H3 C
Yielda
(%)
3
NHTs
OCOCH2 CH3
OCOCH2 CH3
NTs
k
(CH3CH2CO)O
83
92:8
78c
93:7
NHTs
H3 C
H3 C
NHTs
H3 C
OCOCH3
NTs
OCOCH3
AC2O
NHTs
l
NHTs
OCOPh
OCOPh
NTs
Bz2O
m
85c
NHTs
Cl
Cl
Cl
OCOCH2 CH3
NHTs
NTs
n
5
5
(CH3CH2CO)O
5
NTs
6
6
AC2O
OCOCH2 CH3
OCOCH3
6
p
7
NTs (CH3CH2CO)O
a Isolated and unoptimized yield.
b Ratio of products from internal attack vs. terminal attack.
c 7-10% Diamide derivative was also obtained.
OCOCH2 CH3
75c
12:88
82
14:86
NHTs
OCOCH2 CH3
7
10:90
OCOCH3
NHTs
-
80
NHTs
NHTs
o
95:5
7
NHTs
17
SYNOPSIS
Section C: This section describes the synthesis of -aminohalides and -azidoamines
Aziridines are the most versatile intermediates in organic synthesis. They can be easily
prepared from a variety of other functional groups. The strain of the ring makes them
prone to react with a large number of electrophiles, nucleophiles, acids,bases, reducing and
oxidizing reagents. Among the numerous transformations, the ring opening of aziridines to
the corresponding vicinal di amines are important because these are key intermediates in
the synthesis of halogenated marine natural products and also -blockers. The ring opened
products of aziridines, 1,2-azidoamines are compounds of synthetic interest because the
reduced products, vicinal diamines that are biologically important compounds and have
varied applications in organic synthesis.
NTs
+
CH3CN, r.t.
R= aryl, n-butyl, n-octyl ;
+
R
MX
R
NHTs
X
KSF or SiO2
X
NHTs
MX=LiI, LiBr, NaN3
Scheme-13
( )n
NTs
+
KSF or SiO2
MX
NHTs
( )n
CH3CN, r.t.
X
n=1,2
n=1,2
MX=LiI, LiBr, NaN3
Scheme-14
R
18
SYNOPSIS
Recently, the cleavage of aziridines with lithium halides has been reported using ionexchange resin as a catalyst. Aqueous acetonitrile is also known to promote the ring
opening of activated aziridines with sodium azide under refluxing conditions. In recent
years, the use of solid acidic catalysts such as clays and silica has attracted great attention
in different areas of organic synthesis. Indeed solid acids are advantageous as they can be
easily recovered from the reaction mixture by simple filtration and can be reused after
activation, thereby making the process economically viable. In many cases, heterogeneous
solid acids can be recovered with only minor change in activity and selectivity so that they
can be conveniently used in continuous flow reactions. Among various heterogeneous
catalysts, clays are most attractive because, of their reusability, environmental
compatibility, high selectivity, low cost, non-toxicity and operational simplicity. We
describe a simple and efficient approach for the synthesis of 2-halo and 2-azidoamines by a
regioselective ring opening of aziridines with lithium halides and sodium azide using an
inexpensive and reusable solid acid as novel promoters.
:
19
SYNOPSIS
Table-3
Solid acids-promoted synthesis of--amino azides and  -aminohalides
Entry
product a
Aziridine
KSF
Time(h)
NHTs
a
NHTs
Yield(%)b
SiO2
Time(h) Yield(%)b
6.5
85
8.0
90
7.0
83
8.5
85
6.0
86
7.0
89
6.0
89
6.5
92
87
7.0
85
N3
NHTs
b
NHTs
Br
c
NHTs
NHTs
I
NHTs
d
N-Ts
N3
NHTs
N-Ts
e
5.5
Br
NHTs
f
N-Ts
I
NTs
5.0
89
6.0
91
4.0
91
5.0
88
88
4.0
90
N3
NHTs
g
NTs
I
NHTs
h
3.5
20
Entry
SYNOPSIS
Producta
Aziridine
KSF
Time(h) Yieldb
N3
NTs
SiO2
Time(h) Yieldb
NHTs
4.0
93
4.5
89
NHTs
3.0
89c
4.0
91c
5.0
92
6.0
89
4.0
87c
4.5
84 c
4.5
90
5.0
92
i
H3 C
H3 C
I
NTs
j
H3 C
H3 C
N3
NHTs
NTs
k
Cl
Cl
I
NHTs
NTs
l
Cl
Cl
N3
NHTs
NTs
m
Br
Br
N3
n
5.5
85
7.0
87
5.0
88 c
6.5
85c
6.0
86
8.0
83
7.5
83 c
9.0
81c
NTs
NHTs
I
o
NTs
NHTs
p
N3
NTs
NHTs
Br
q
NTs
NHTs
a
All products were characterized by 1HNMR, IR and mass spectroscopy.
Yield refers to pure products after chromatography.
c 5-7% other regioisomer was NMR spectra of crude products.
b
21
SYNOPSIS
Chapter-III
This chapter deals with the regioselective synthesis of -alkoxy alcohols and 1,2diols.-Hydroxy ethers are important precursors for the preparation of -alkoxy ketones
and -alkoxyacids. -hydroxy ethers are also present in some naturally occurring
compounds.The simple and the straightforward method for the synthesis of -hydroxy
ethers is the ring opening of epoxides with an appropriate alcohol under acid conditions.
CBr4
O
R
R1-OH,
1
OH
OR1
OH
R
+
OR1
R
3
2
Scheme-15
OH
CBr4
O
R1-OH,
OR1
4
1
Scheme-16
Vicinal diols are present in many naturally occurring compounds. The ring opening
of epoxides with water in the presence of acid catalysts generates synthetically useful vicdiols. However, most of these epoxide ring opening reactions involve the use of strongly
acidic conditions, stoichiometric amounts of the reagents, extended reaction time, low
regioselectivity, unsatisfactory yields and also entail undesirable side products due to
rearrangement or polymerization of starting oxiranes. Subsequently, several methods have
been developed to perform these epoxide ring-opening reactions under mild conditions. In
22
SYNOPSIS
this respect, the use of Nafion-H appears to be of considerable importance, but its high
acidity still restricts its use with acid sensitive substrates. However, these methods are
described only for ring opening reactions of epoxide with primary alcohols. Furthermore,
many of these reagents are corrosive, moisture sensitive and are required in stoichiometric
amounts. Therefore, the development of simple and inexpensive reagents, which are more
efficient and provide convenient procedures with improved yields, is needed. In addition,
there is an advantage in developing a catalytic process for the synthesis of -hydroxy
ethers. Owing to its unique catalytic properties, CBr4 has been extensively used for a
plethora of organic transformations. However, there are no reports of the use of CBr4 for
the alcoholysis of oxiranes.
Regioselective ring opening reactions of oxiranes with alcohols and water using a
catalytic amount of CBr4 under mild conditions. Proceeds smoothly by a catalytic amount
of CBr4 in primary, secondary and tertiary alcohols to generate -hydroxy ethers in high
yields.
23
SYNOPSIS
Table4: Alcoholysis and hydrolysis of epoxides catalyzed by carbontetrabromide
Entry
Epoxide
O
a.
Reaction time
(h)
Yieldb
(%)
3.5
85
4.5
79
3.0
90
3.5
85
OH
2.0
95
OH
2.5
87
OH
3.5
72
OH
2.0
96
OH
2.5
93
( )5
OH
3.0
88
OH
2.5
90
OH
4.5
87
OMe
3.0
89
O
3.5
85
O
4.0
82
OMe
3.5
90
OH
4.0
85
O
3.5
89
Producta
Nucleophile
OH
H2O
OH
O
b
c
O
OH
PhCH2OH
OBn
OH
CH3OH
OMe
O
d
OH
H2O
OH
O
e
Ph
OMe
CH3OH
Ph
O
f
Ph
O
g
O
OH
Ph
O
OH
Ph
Ph
O
O
h
OH
Ph
Ph
O
i
Ph
O
OH
Ph
O
O
j
Ph
k
Ph
( )5 OH
Ph
O
O
OH
Ph
OH
O
l
H2O
Ph
Ph
O
m
PhOH2 C
OH
CH3OH
Ph
O
O
n
Ph-OCH2
o
OH
OH
Ph
O
O
p
O
( )3
CH3OH
Ph
O
( )3
OH
O
q
OH
OH
Ph-OCH2
H2O
OH
r
O
Cl
OH
Cl
OH
a: All products were characterized by 1H NMR, IR spectra and mass spectra
b: Yields refer after purification
24
SYNOPSIS