The thesis entitled “Studies directed towards the total synthesis of polypropionate
natural products (–)-Ebelactone-A and (–)-Maurenone” is divided into three
chapters.
CHAPTER I: This chapter deals with the introduction and earlier synthetic
approaches of (–)-Ebelactone-A and a small review on
desymmetrization.
CHAPTER II: This chapter describes the stereoselective synthesis of C1-C6 and C7-
C14 fragments of (–)-Ebelactone A.
CHAPTER III: This chapter divided into two sections.
Section A: This section deals with the introduction and earlier synthetic approaches of
(–)-Maurenone.
Section B: This section describes the formal stereoselective synthesis of (–)-
Maurenone.
This chapter describes the β-lactones which are having enzymatic inhibitory
activity and also describes the introduction and previous synthetic approaches of
ebelactones, having proven esterase inhibitor activity. Also a brief literature survey on
“desymmetrization technique” a strategy used for introducing chirality into the target
(–)-Ebelactone-A is described.
This chapter describes the stereoselective synthesis of C1-C6 and C7-C14
fragments of (–)-Ebelactone A.
CHAPTER-I
CHAPTER-II
SYNOPSIS
15
In 1980 Umezawa and co-workers first reported the isolation of (–)-Ebelactone
A 1, a β-lactone enzyme inhibitor from the cultured strain of soil actinomycetes (mG7-
G1 related to streptomyces aburaviensis). The Ebelactones show structural
characteristics in common with macrolide antibiotics and butyrate precursors indicate
that they are like polyketide in origin. The Ebelactones act as potent inhibitors of
esterases, lipases and N-formylmethionine aminopeptidases located on the cellular
membrane of the various kinds of animal cells and they have shown to produce enhance
immune responses. They are also reported to inhibit cutinases produced by fungal
pathogens. Due to its biological activity combined with unique and challenging
structure have made this compound an exciting target for total synthesis (Figure 1).
Some of the synthetic approaches for the synthesis of (–)-Ebelactone A have
been disclosed in literature. As part of our program towards the synthesis of Ebelactone
A, we chose to adopt a highly convergent strategy, disconnecting the carbon back bone
at C6-C7 trans alkene, thus dividing the target into two key fragments 2 and 3. The
synthesis of fragments 2 and 3 were envisaged from common precursor lactone 6 which
was generated from bicyclic ketone 7 (Scheme 1).
O O OH
O
Figure 1
(−)-Ebelactone A
1
16
Synthesis of lactone intermediate 6:
The synthesis of lactone intermediate 6 was achieved from bicyclic ketone 7,
which was inturn synthesized from furan and 2,4-dibromo-3-pentanone. Accordingly,
the acid catalyzed dibromination of 3-pentanone 8 afforded the dibromo compound 9.
The dibromo compound 9 when treated with furan in the presence of Zn-Cu couple
O O OH
O
O OH
O
O
O
O
OBn
O
OBn OH OH
BnO
MeO
OBn
O
O
O
(−)-Ebelactone A
1
2 6
7
14
C1-C6 Fragment C7-C14 Fragment
7
6 14
1
6
1
7 14
1
2 3
4
5
6
7
Scheme 1: Retrosynthetic Analysis
17
underwent a (3+4) cycloaddition reaction to afford the compounds 7, 10 and 11 in the
ratio 8:1:1. These bicyclic ketones on selective reduction with DIBAL-H gave the
corresponding alcohols (Scheme 2).
The required alcohol 12 was isolated from the other isomers using column
chromatography and the structure was confirmed from spectral studies. The hydroxyl
group of compound 12 was protected as its benzylether 13 using NaH and
benzylbromide. Asymmetric hydroboration of olefin 13 using (–)-
diisopinocampheylborane (Ipc2BH) proceeded smoothly gave the alcohol 14 with high
enantiomeric purity. The alcohol 14 was converted to the lactone 16 by a two step
sequence, PCC oxidation of alcohol 14 followed by Baeyer-Villiger oxidation afforded
the lactone 16. The lactone 16 was subjected regioslective methylation using LDA and
methyl iodide to afford the methylated lactone 6 (Scheme 3). Thus the lactone
compound 6 was employed as a common precursor for both the key fragments.
O O
Br Br
Br O 2 / AcOH
Zn-Cu couple
O
O
O
O
O
O
O
OH
DME, -10 OC
DiBAL-H
THF, -10 oC
+ +
+
8 9
10 11
12
Scheme 2
7
mixture of isomers
18
Synthesis of C1-C6 fragment:
The synthesis of C1-C6 fragment 2 was started from lactone intermediate 6
which is having three stereogenic functionalized carbons which serves as the C-2, C-3
and C-4 carbons of the (–)-Ebelactone A. Accordingly, reductive opening of bicyclic
lactone 6 with LiAlH4 afforded the triol 17, which was further treated with 2,2-DMP
and PTSA (cat.) to give acetonide compound 18 (Scheme 4).
O
OH
O
OBn
(-) -Ipc2BH
O
OBn
HO
O
O OBn
PCC / CH2Cl2
O
O
O
OBn
O
O
O
OBn
NaH / BnBr
THF, reflux
12 13
(+)-α-pinene
14
r.t,
15
m-CPBA, NaHCO3
DCM, 25 0C
16
Scheme 3
6
LDA/MeI
90% 95%
90%
90%
92%
THF, -78 oC.
O
O
OBn
O OH OBn OH OH
OH OBn O O
6
LiAlH4, THF
0 0C-25 0C.
17
2,2-Dimethoxypropane
p-TSA (cat), acetone
18
Scheme 4
85%
81%
19
The hydroxyl group of compound 18 was protected as benzyl ether 19,
followed by cleavage of the acetonide group in 19 using 2N HCl in THF/H2O (1:1)
afforded diol 4. Selective protection of primary hydroxyl group was achieved in diol 4
as its tert-butyldiphenylsilyl ether with TBDPSCl and imidazole to give 20 (Scheme
5).
Next aim was deoxygenation of the hydroxyl group at C-5 carbon of compound
20. Accordingly the secondary hydroxyl group of compound 20 was converted as its
xanthateester derivative 21 using NaH, CS2 and MeI in dry THF, followed by
deoxygenation using n-Bu3SnH and cat. AIBN as a radical initiator in toluene to give
deoxygenated product 22. Deprotection of TBDPS group in 22 with TBAF in THF
afforded corresponding primary alcohol 23 (Scheme 6).
OH OBn O O OBn O O
BnO
OBn OH OH
BnO
OBn OH OTBDPS
BnO
NaH, Bn-Br
THF, reflux, 85%
2N HCl, THF/H2O
25 0C, 90%
TBDPS-Cl
18 19
4 20
Scheme 5
imidazole, 88%
OBn OH OTBDPS
BnO
OBn O OTBDPS
BnO
S
SMe
OBn OTBDPS
BnO
OBn OH
BnO
CS2, MeI, NaH
nBu3SnH, AIBN
THF, reflux, 80%
Toluene, reflux,
75%
TBAF, THF
0 oC-25 0C,
90%
20 21
22 23
Scheme 6
20
The hydroxyl group of compound 23 was treated with tosylchloride,
triethylamine and cat. amount of DMAP in DCM to afford the tosylate compound 24,
compound 24 was treated with DBU and NaI in glyme to afford the terminal olefin 25
(Scheme 7).
Primary and secondary benzyl protecting groups of compound 25 was removed
using Li-Naphthalenide in dry THF to provide the 1,3-diol 26. Compound 26 was
subjected to chemoselective oxidation using TEMPO/BAIB and subsequently
converted to β-hydroxy carboxylic acid 27 under Pinnik’s conditions. β-hydroxy
carboxylic acid 27 was treated with benzenesulphonylchloride in dry pyridine to afford
the β-lactone fragment 2 (C1-C6 fragment) (Scheme 8).
OBn
BnO
OBn
BnO OH
OBn
BnO OTs
25
DBU, NaI
glyme, reflux
Scheme 7
23
TsCl, Et3N
CH2Cl2, 25 0C
24
95%
90%
OBn
BnO
OH
HO
OH
HO
O O
O
25 26
Li-Naphthalenide
THF, -30 oC
Scheme 8
27
2) NaClO2, NaH2PO4
t-BuOH-H2O
PhSO2Cl
Pyridine, -20 oC.
2
78%
70% for 2 steps
85%
1) TEMPO, BAIB
CH2Cl2
21
Synthesis of C7-C14 fragment:
The lactone intermediate 6 contained four stereoselectively functionalized
carbons to serve as the C8, C10, C11 and C12 carbons of the (–)-Ebelactone A and
further functionalisations were carried out on the compound 6 to give corresponding
fragment 3. Accordingly hydrolysis of the bicyclic lactone 6 with catalytic amount of
sulphuric acid in methanol afforded acetal 28 along with a minor amount of the α-
isomer (at C-1 center). The compound 28 was treated with LiAlH4 in dry THF to give
the alcohol 29. The alcohol 29 was converted to methylated product 5 by a two step
sequence, tosylation of the alcohol 29 followed by alkylation with
dimethyllithiumcuperate of the resulting tosylated compound 30 (Scheme 9).
Hydrolysis of acetal 5 in AcOH/water (2:1) at 50-55 °C afforded the lactol 31
which was further subjected to reduction with sodiumborohydride in methanol to give
diol 32. The diol 32 was converted to alcohol 35 by a three step sequence, initially
primary hydroxyl group of the compound 32 was selectively protected as its pivalate
ester 33 and then secondary hydroxyl group of 33 protected as its triisopropyl silyl
ether 34 followed by reduction with DIBAL-H to give alcohol 35 (Scheme 10).
MeO OH
OBn
O
MeO OTs
OBn
O MeO
OBn
O
O
O
O
OBn
O
COOMe
MeO
OBn
LiAlH4, THF
0 0C-25 0C
29
TsCl, Et3N
DMAP/CH2Cl2
0 0C-25 0C,
30
Scheme 9
Me2LiCu, Ether
-30 0C-0 0C
5
6
cat. H2SO4
MeOH
28
86% 90%
95%
92%
22
The primary hydroxyl group of compound 35 was oxidized using Dess-Martin
periodinane to corresponding aldehyde, which was subsequently converted to olefin 36
by Wittig olefination. Compound 36 was treated with Li-Naphthalenide to provide the
hydroxy compound 37. Dess-Martin periodinane mediated oxidation of compound 37
provided the keto compound 38. Silyl protecting group of compound 38 was removed
using aqueous-hydrofluoric acid (40 %) in acetonitrile at ambient temperature to furnish
the C7-C14 fragment 3 in good yield (Scheme 11).
MeO
OBn
O HO
OBn
O
OBn
HO
OH OBn
PivO
OH
OBn
PivO
OTIPS OBn OTIPS
HO
5 31
AcOH/H2O (2:1)
50-55 0C
NaBH4
MeOH, 0 0C
32
Piv-Cl, DMAP
pyridine:CH2Cl2
0 0C-r.t.
33
CH2Cl2, 0 0C
34
DIBAL-H, CH2Cl2
-78 0C
35
TIPSOTf,
2,6-lutidine
Scheme 10
60% 85%
95%
90%
90%
O OTIPS
O OH
OBn OTIPS
HO
OBn OTIPS
OH OTIPS
DMP
DCM, 90%
HF-aqueous (40%)
38
3 Scheme 11
35
1. DessMartin Reagent,
DCM
2. LiHMDS, PPh3=CH2
-78 oC - r.t
36
Li-Naphthalenide
THF, - 35 0C
37
78% for 2 steps
78%
Acetonitrile, 20 oC
95%
23
Coupling of C1-C6 fragment with C7-C14 fragment:
Finally fragments 2 and 3 were planned to couple using olefin cross metathesis
approach29 to construct tri-substituted olefin as well as finish the total synthesis of
target molecule (–)-Ebelactone-A 1. For this crucial transformation we selected the
Grubbs second generation catalyst 39 according to literature procedures. Initially we
tried the cross metathesis reaction between fragments 2 and 3, the cross-metathesis
reaction was not succeeded (Scheme 12).
The cross-metathesis reaction was performed between compounds 2 and silyl
protected compound 38 with Grubbs second generation catalyst 39 in dichloromethane
at reflux temperature about 15 h, the reaction was not proceeded both starting materials
were recovered completely (Scheme 13).
O
O
O OH
O
O
O OH
MesN NMes
PCy Ph 3
Cl
Cl
+
Grubbs 2nd generation
Catalyst, 15 mol%
(−)-Ebelactone-A
CH2Cl2, 40 oC
X
Scheme 12
2nd generation
Ru Grubbs catalyst
2
3
1
39
O
O
O OTIPS
Grubbs 2nd generation
Catalyst
X No Product
2 38
39
+
Scheme 13
24
By the observation of above results we assumed that homoallylic keto group of
C7-C14 fragment 3 is responsible for failure of cross metathesis, then we planned the
cross metathesis reaction between compound 2 and homo-allylalcohol 37 with the same
Grubbs catalyst 39, in this reaction also no cross metathesis product was observed
(Scheme 14).
In conclusion synthesis of fully functionalized C1-C6 Fragment and C7-C14
fragments of (–)-Ebelactone-A has been achieved. This involved a novel strategy in
which bicyclic intermediate has been elaborated in a stereo controlled manner by using
desymmetrization of meso-bicyclic compound by using asymmetric hydroboration.
O
O
OH OTIPS
Grubbs 2nd generation
Catalyst
X No Product
2 37
39
+
Scheme 14
25
This chapter divided into two sections.
Section A: This section deals with the introduction and earlier synthetic approaches of
(–)-Maurenone.
The natural product maurenone was isolated by Faulkner et al. in 1986 from
specimens of the pulmonate mollusc Siphonaria maura, collected from Jaco Beach,
Costa Rica. In this section briefly discussed about the diverse polyketide natural
products from marine pulmonates of the genus Siphonaria.
Section B: This section describes the formal stereoselective synthesis of (–)-Maurenone.
The natural product maurenone was isolated by Faulkner et al. in 1986 from
specimens of the pulmonate mollusc Siphonaria maura, collected from Jaco Beach,
Costa Rica (Figure 1).
Marine pulmonates of the genus Siphonaria are rich sources of diverse
polyketide-derived natural products. There are some examples on polyketide natural
products which include siphonarin A and B, muamvatin, denticulatin A and B,
membrenone A–C, and vallartanones A and B. All species examined are the
metabolites of polypropionate origin that appear to share a common biosynthesis with
macrolides and polyether antibiotics.
O
OH
O
1
(−)-Maurenone
Figure 1
CHAPTER-III
26
In continuation of our interest on the total synthesis of polypropionate natural
products, and extreme scarcity of the natural material together with the novel structure
prompted us to attempt the total synthesis of (–)-maurenone.
The formal synthesis of (–)-Maurenone 1 was achieved via stereoselective
construction advanced intermediate 2, which was synthesized by coupling of fragments
3 and 4. The two key intermediates 3 and 4 were synthesized by silyl triflate mediated
opening of epoxy alcohol 5 and desymmetrization of the meso-bicyclic dihydrofuran 7
by an asymmetric hydroboration (Scheme 1).
O
OH
O
OTBSO
H
O OTES
O
OBn
O
OH O
O
O
OBn
OTBSOH O OTES
+
1
2
3 4
5 6 7
(−)-Maurenone
Scheme 1: Retrosynthetic strategy.
27
The synthesis of fragment 3 began with α,β-unsaturated ester 9, which was
synthesized from n-propanal 8 using stabilized three-carbon Wittig olefination to give
exclusively the E-isomer in 70% yield. Reduction of 9 with DIBAL-H furnished the
allylic alcohol 10 in 80% yield, which on Sharpless asymmetric epoxidation gave the
chiral epoxy alcohol 5. Upon treatment of epoxy alcohol 5 with tert-butyldimethylsilyl
triflate (TBSOTf) at –42 °C gave the syn-aldol product 3 in 85% yield (Scheme 2).
Synthesis of fragment 4 began with bicyclic olefin 7. Asymmetric
hydroboration of olefin 7 using (+)-diisopinocampheylborane (Ipc2BH) proceeded
smoothly to give the alcohol 11 with high enantiomeric purity. The alcohol 11 was
converted to the lactone 6 by a two step sequence, PCC oxidation of alcohol 11
followed by Baeyer-Villiger oxidation afforded the lactone 6. Triol compound 12 was
prepared by the reductive opening of lactone 6 with LiAlH4. Compound 12 was
protected as its acetonide 13 using 2,2-DMP/CSA(cat.). The primary hydroxyl group of
13 was tosylated with TsCl/Et3N and then treated with dimethyllithiumcuprate to afford
the compound 14 in good yield. Acetonide deprotection of compound 14 gave the 1,3-
diol, which was further converted into mono tosylated compound 15 in 85% yield.
Reductive elimination of tosyl group of 15 with LAH gave the secondary alcohol 16
(Scheme 3).
H
O O
OEt
OH
OH
O OTBS
H
O
OTBSO
H
CH2Cl2, 0-25 oC.
DIBAL-H
CH2Cl2, 0- 25 oC.
(-)-DET, TBHP,
CH2Cl2, -23 oC, CH2Cl2, MS oA, -42 oC,
85%.
TBSOTf, EtNiPr2
Ph3P=C(Me)CO2Et
8 9 10
5 3
=
Scheme 2
28
Compound 16 was then subjected to IBX oxidation to furnish keto compound
17 in good yield. Hydrogenolysis of benzyl ether 17 followed by TES protection with
TESOTf afforded the fragment 4 in 92% yield (Scheme 4).
O
OBn
O
O
OH OH OBn OH
O O OBn OH O O OBn
OTs OH OBn OH OBn
O
OBn
(+) -Ipc2BH
O
OBn
HO PCC / CH2Cl2
LiAlH4, THF
0 0C-25 0C, 4h, 85%
2,2-Dimethoxypropane
CSA (cat), DCM, 80%
2. Me2CuLi, Ether
1. TsCl, Et3N,
00C-250C, CH2Cl2
0 0C to -25 0C, 90%
2. TsCl, Et3NH,
0 0C-25 0C, CH2Cl2
1. 2N HCl, THF-H2O
LiAlH4, Ether
0 0C-25 0C, 90%
6 12
13 14
15
Scheme 3
16
7
(-)α-pinene
11
r.t
m-CPBA, NaHCO3
96% DCM, 25 0C
1)
2)
O OBn
O OTES
OH OBn
IBX
DMSO -THF, 88%
1. Pd/C,H2
Ethylacetate,95%
TESOTf
2,6-Lutidine
-78 0C, 92%
2.
17
4
Scheme 4
16
29
The coupling of compounds 3 and 4 gave the key fragment 2 as diastereomeric
mixtures which was consistent with literature (Scheme 5).
In conclusion, the formal synthesis of (–)-Maurenone has been achieved in a
stereocontrolled manner by silyl triflate mediated opening of epoxy alcohol and
desymmetrization of the meso-bicyclic dihydrofuran using an asymmetric
hydroboration. This synthetic sequence provides an easy access to the construction of
the key fragments of maurenone.
O OTES OTBSOH O OTES
O
OH
O
LiHMDS, Et2O
-78 to -50 oC
Fragment-3, -78 oC
(−)-Maurenone
Scheme 5
4 2
1