Abstract
The thesis entitled “TOWARDS THE SYNTHESIS OF C1-C14 FRAGMENT OF
VENTURICIDIN X, PONDAPLIN, (5S)-HEXADECANOLIDE AND (5R, 6S)ACETOXYHEXADECANOLIDE” has been divided into four chapters.
Chapter-I:
This chapter has been further divided into two sections.
Section A:
This section deals with the introduction and previous synthetic approaches of C1C14 fragment of Venturicidin X.
Section B:
This section deals with the present work of C1-C14 fragment of Venturicidin X.
Chapter-II:
This chapter has been divided into two sections.
Section A:
This section deals with the introduction, previous synthetic approaches of
Pondaplin.
Section B:
This section deals with the present work of Pondaplin.
Chapter-III: This chapter has been divided into three sections.
Section A:
This section deals with the introduction of insect pheromones (5S)Hexadecanolide, (5R, 6S)-Acetoxyhexadecanolide.
Section B:
This section deals with the previous synthetic approaches and present work of
(5S)-Hexadecanolide.
Section C:
This section deals with the previous synthetic approaches and present work of
(5R, 6S)-Acetoxyhexadecanolide.
Chapter-IV:
This chapter deals with the Bismuth(III) Chloride Catalyzed Efficient and
Selective Cleavage of Trityl ethers.
Chapter I: Towards the Synthesis of C1-C14 fragment of Venturicidin X.
The 20-membered macrolide antibiotics, venturicidins A and B were isolated from
several Streptomyces and their structures were elucidated by chemical degradations,
spectroscopic investigations and an X-ray crystallographic analysis. In addition, venturicidin X,
the aglycone of the venturicidins, (Fig. 1) was also isolated from Streptomyces, which was a
potent antibiotic.
Me
Me
OH
R=
27
Me
Me
Me
Me
Me
H2NCOO
14
RO
19
O
H
15
O
Me
O
O
OH
Venturicidin A :
1
O
3
7
H
OH
Me
R=
OH
OH
Me
Venturicidin X :
O
(aglycone of venturicidins)
R=H
Venturicidin B :
Fig. 1
Retro synthetic route for C1-C14 Segment of Venturicidin:
Our primary synthetic strategy divided the target macrolide Venturicidin X into two
fragments: acid 1 (C1-C14) and alcohol 2 (C15-C27) (Fig. 2).
Me
Me
Me
Me
Me
Me
14
27
19
RO
H
15
O
Me
O
OH
O
1
O
7
H
3
OH
Me
OPMB
OBn
Me
Me
Me
CO2H
Me
OH
H
Me
1
Me
Me
H
OP
O
Me
Fig. 2
OH
2
O
O
Me
Me
The C1-C14 fragment of Venturicidin X includes three chiral centers at C3, C7 and C13
positions along with two double bonds, cis olefin at C5 and trans olefin at C8 position. We
envisaged the synthesis of 1 by an aldol condensation approach between 3 and 4. Synthesis of 3
in turn is presumed from Wittig –Horner reaction between 6 and the resulting aldehyde through
Swern oxidation of 5 (Fig. 3).
OPMB
BnO
CO2 H
Me
O
OH
H
Me
1
OPMB
BnO
TBDPSO
CHO
O
O
4
O
3
OBn
MeOOC
PMBO
Ph3 P
OH
route b
route a
OPMB
OTHP
8
O
7
O
6
5
COOMe
O
10
9
Fig. 3
The compound 5 was synthesized in two different routes a and b by using two different starting
materials, 5-Hexen-1-ol and Propargyl alcohol respectively.
In route a, 5-Hexene-1-ol is protected as tetrahydropyranyl derivative 8 by treating with
an equimolar quantity of 3, 4-dihydro-2H-pyran and a catalytic amount of PTSA in dry
methylene chloride. The THP ether 8 was subjected to epoxidation using dry m-CPBA and
sodium bicarbonate in dry methylene chloride to afford epoxide 11 in 96% yield. The epoxide 11
was subjected to hydrolytic kinetic resolution (HKR) using 0.005eq of chiral Jacobsen’s (S,S)salenCo(III)
acetate
catalyst
(freshly
prepared
((S,S)-N-N1-bis3,5-di-tert-
from
butylicsalicylidene)-1,2-cyclohexanediamino Cobalt(III) chloride and acetic acid) to afford
enantioenriched (>96% ee) terminal diol 12 in 47% yield (Scheme 1). The primary hydroxyl
group of the diol 13 was protected as its p-methoxy benzyl ether using 1 eq of PMBBr and 1.5 eq
of NaH in dry THF at 0 oC to afford the compound 4 in 80% yield.
O
m-CPBA, NaHCO3,
OTHP
8
(S, S)-salen cobalt(III)
acetate(0.005eq),
OTHP
CH2Cl2,0 oC rt., 96%
11
OH
O
H2O(0.5eq),THF
47%
+
HO
OTHP
OTHP
12
13
OH
PMBBr,NaH,
dry THF, 0 oC-rt.,
80%
PMBO
OTHP
5
Scheme 1
In second route b, the starting material Propargyl alcohol was protected as its
p-methoxybenzyl ether by treating with 1.1 eq of PMBBr and 2 eq of NaH in dry THF at 0 oC to
afford the compound 9 in 92% yield. Treatment of 9 with ethyl magnesium bromide (prepared
from EtBr and Mg) followed by quenching with para-formaldehyde in dry THF afforded
compound 14 in 85% yield. Compound 14 was then converted into trans allylic alcohol 15 in
80% yield by reduction using 1.5 eq of LiAlH4 in dry THF for 4 h. Sharpless asymmetric
epoxidation of 15 gave the epoxy alcohol 16 in 75% yield. The epoxy alcohol 16 was converted
to the corresponding chloride 17 using TPP, dry CCl4 and NaHCO3 in 85% yield. The conversion
of epoxy chloride 17 to the substituted chiral acetylenic alcohol 18 in 70% yield was
accomplished by treating compound 17 with 6 eq of Li metal in liquid ammonia at
-78 oC and further treated with 2 eq of THP protected bromoethanol (Scheme 2). Reduction of
triple bond in compound 18 over 10% Pd/C and Na2CO3 in EtOAc furnished the corresponding
saturated compound 5 in 90% yield.
Mg, EtBr,
OPMB
PMBO
dry THF, 0 oC-rt.,
(CH2O)n, 85%
9
dry THF, 0 oC-rt.,
80%
14
O
Ti(OiPr)4, (+) DIPT,
PMBO
OH
PMBO
OH
Cumene hydroperoxide,
-25 oC, dry CH2Cl2, 75%
15
PMBO
Cl
NaHCO3,reflux,
85%
Br
OTHP
dry THF, -78 oC, 70%
17
OH
16
Li-liq NH3, Fe(NO3)3, then,
O
TPP, CCl4,
LiAlH4,
OH
OH
H2, Pd/C,
PMBO
PMBO
18
OTHP
OTHP
EtOAc, Na2CO3,
rt., 90%
15
Scheme 2
Accordingly, the secondary hydroxyl group of compound 5 was protected as its
benzylether using sodium hydride and benzyl bromide in dry THF at 0 oC- room temperature to
afford 19 in 96% yield.
NaH, BnBr,
dryTHF,
OH
OBn
PMBO
PMBO
OTHP
OTHP
0 oC-rt., 94%
5
19
OPMB
BnO
(COCl)2, dry DMSO,
-78 oC, dry CH2Cl2, Et3N,
OBn
PTSA,
PMBO
OH then,
MeOH, 84%
65%
Ph3 P
O
36
20
Scheme 3
3
O
Deprotection of the THP group in 19 using PTSA in MeOH resulted in alcohol 20 in 84%
yield. The alcohol 20 was oxidized to the aldehyde by Swern oxidation without isolation, it was
further treated with the Wittig ylide 6, to furnish the trans α, β-unsaturated keto compound 3 in
70% yield (Scheme 3).
MeOOC
Ethylene glycol,
PPTS, dry benzene
COOMe
O
MeOOC
COOMe
O
O
reflux, 80%
7
21
O
O
0 oC-rt., 80%
TBDPSCl,
Imidazole,
OH
HO
LiAlH4, dry THF
dry CH2Cl2, 75%
22
OH
TBDPSO
O
O
(COCl)2, dry DMSO,
Et3N, dry CH2Cl2,
TBDPSO
CHO
O
O
-78 oC, 70%
4
23
Scheme 4
The aldehyde 4 was prepared from dimethyl acetone dicarboxylate 7. The keto group of
dimethyl acetone dicarboxylate 7 is protected with ethylene glycol, followed by the reduction of
the ester groups to diol 22 by using 2 eq. of LiAlH4 in dry THF. Monoprotection of diol 22 by
using TBDMSCl and imidazole in dry dichloromethane to afford compound 23 which on
oxidation to give the aldehyde 4 (Scheme 4).
The Aldol condensation of compound 3 and 4 by using LiHMDS in dry THF at -78 oC to
afford compound 24 resulted in the formation of inseparable diastereomers. Reduction of
diastereomeric mixture 24 using sodium borohydride in methanol resulted in diastereomeric
mixture of 25 (Scheme 5). Hence, a different approach is to be followed to selectively synthesize
the required enantiomer of 24. Efforts are on in our group to complete the synthesis of C1-C14
fragment of Venturicidin X.
OPMB
BnO
3
LiHMDS, dry THF,
-78 oC, 1 h
OTBDPS
then, 4, 60%
O
OH
O
O
24
OPMB
BnO
NaBH4, MeOH, 60%
OTBDPS
OH
Scheme 5
OH
O
O
25
Chapter II: Total synthesis of Pondaplin analogues.
Pondaplin 26, a novel cyclic prenylated phenylpropanoid was recently isolated from
Annona glabra L (Annonaceae). It shows selective cytotoxicities against six human solid tumor
cell lines and particularly potent activity against MCF-7 breast and PC-3 prostate cancer cell
lines. Many related phenylpropanoids exhibit a broad range of biological activities such as
antimicrobial, anticancer, and hypotensive properties.
3
7
8
2
4
1
O
5
O
1'
6
4'
3'
O
2'
5'
26
Moreover, phenyl propanoid derivatives are known to inhibit enzymes such as cAMP
phosphodiesterase and prostaglandin synthetase.
Retro synthetic route for Pondaplin
Synthetic strategy for Pondaplin is outlined below in Fig 4.
OHC
O
OH +
OHC
O
Br
29
28
O
O
TrO
TrO
26
27
TrO
30
Fig. 4
Present Work
We
chose
a
strategy
for
the
synthesis
of
Pondaplin
26
starting
from
p-hydroxybenzaldehyde 28. Propargyl alcohol was protected as trityl ether 30 by treating with
triphenylmethyl chloride and triethyl amine. The compound 30 was subjected to
methoxycarbonylation to afford 31 in 86% yield. The conjugate addition of lithium
dimethylcuprate to 31 in dry THF at -100 to -85 oC provided Z-ester 32 as the sole product in
90% yield. The reduction of 32 with LiAlH4/AlCl3 at 0 oC in dry ether afforded the
corresponding Z-allylic alcohol 33 in 74% yield.
Standard bromination conditions furnished bromide 29 in 62% yield. Bromide 29 was
used in an alkylation reaction with 4-hydroxybenzaldehyde 28 to give O-alkylated compound 27
in
63%
4-substituted
yield.
benzaldehyde
Modified
27
Wadsworth-Emmons
using
NaH,
condensation
bis((2,2,2)-trifluoroethyl)
(methoxycarbonylmethyl)phosphonate in THF at –78 oC afforded Z-ethyl ester 34 in 88% yield.
Removal of the trityl group to afford Z-hydroxy ester 35 and followed by saponification afforded
the corresponding Z-hydroxy acid 36. Subjecting hydroxy acid 36 to intramolecular Keck
coupling
conditions
in
the
presence
of
1,3-dicyclohexylcarbodiimide and DMAP in dry methylene chloride at 0 oC did not give the
expected product 26, instead a dimer 37 was formed (Scheme 6).
Mg, EtBr,
dry THF, 0 oC
- rt,
ClCOOMe, 86%
TrO
TrO
Me2CuLi, dry THF,
COOMe
-100 oC to -85 oC, 90%
30
31
O
LiAlH4, AlCl3,
dry Ether, 0 oC,
TrO
OMe
MsCl, LiBr,
NEt3, MeCN,
TrO
OH
74%
32
0 oC, 62%
33
NaH, dry THF,
p-Hydroxybenzaldehyde (28),
TrO
Br
OHC
O
0 oC, 63%
29
27
TrO
NaH, dry THF,
(CF3CH2O)2P(O)CH2COOMe
,
-78 oC, 88%
O
PPTS, MeOH,
rt, 67%
OMe
TrO
O
34
O
aq.LiOH, MeOH,
O
rt.,99%
O
OMe
HO
OH
O
HO
35
36
O
O
DCC, DMAP,
dryCH2Cl2,
0 oC - rt., 55%
O
O
O
O
dimer 37
Scheme 6
We considered that the double bond reduction of the , -unsaturated ester might favor the
cyclization. To examine this, the hydroxy ester 38 was prepared from p-hydroxybenzaldehyde 28
in two steps. The two carbon Wittig olefination, followed by ester double bond reduction with
Mg/MeOH afforded 39 in 94% overall yield for the two steps. O-Alkylation of 39 with NaH and
bromide compound 29 afforded compound 40. Deprotection of trityl group to afford allyl alcohol
41 was achieved using PPTS in MeOH in 67% yield. Ester hydrolysis of 41 followed by
intramolecular cyclization using Keck coupling conditions allowed macrolactonization to give
the saturated analogue 43 of pondaplin in good yield (Scheme 7).
OHC
OH
OH Mg/ dry MeOH
Ph3P=CHCOOMe
90%
dry MeOH, 98%
28
O
38
OMe
NaH, dry THF,
OH
PPTS, MeOH,
O
rt., 67%
(29), 60%
O
39
OMe
OMe
TrO
O
40
aq.LiOH, MeOH,
O
O
rt., 96%
O
OMe
HO
O
OH
HO
42
41
DCC, DMAP,
O
dryCH2Cl2, 55%
O
O
43
Scheme 7
Another pondaplin analogue 47 was synthesized from saturated ester 39 in 4 steps.
Compound 39 was subjected to alkylation with NaH and prenyl bromide to afford O-prenyl ether
44 in 92% yield. Allylic oxidation if 44 was achieved using SeO2 to afford E-aldehyde 45 which
was further reduced to the corresponding E-allylic alcohol 46 by using NaBH4 in MeOH. Ester
hydrolysis followed by intramolecular cyclization with DCC/DMAP in CH2Cl2 at 0 oC afforded
the saturated analogue 48 of pondaplin (Scheme 8).
OH
Prenylbromide,
dry Acetone, K2CO3,
O
reflux, 50%
reflux, 92%
O
OMe
O
39
NaBH4, MeOH,
SeO2, dry EtOH,
OMe
44
aq.LiOH, MeOH,
Scheme 8
Chapter III: Total synthesis of insect pheromones (5S)-Hexadecanolide, (5R, 6S)Acetoxyhexadecanolide.
Lactonic functionality is present in a large number of natural products and biologically
active compounds. Lactone derivatives are very common flavor components used in the perfume
industry. They have also been reported to be sex attractant pheromones of different insects and to
be plant growth regulators and they are also useful intermediates in the synthesis of natural
products.
O
O
O
O
C10 H21
C11 H23
OAc
50
(5R, 6S)-Acetoxyhexadecanolide
49
(5S-Hexadecanolide)
Fig. 5
(5S)-Hexadecanolide 49 (Fig 5) a pheromone isolated from the mandibular glands of the
oriental hornet Vespa orientalis in 1969, has been proposed as a pheromone playing the role of a
queen substance.
(5R, 6S)-6-Acetoxyhexadecanolide 50 (Fig 5) is the major component of the apical
droplets that form on the eggs of the mosquito Culex pipens fatigans.
Retro synthetic route for 5(S)-Hexadecanolide
Synthetic strategy for (5S)-Hexadecanolide is outlined below in Fig 6.
O
OH
O
O
THPO
THPO
C11H23
C9 H19
51
49
OH
52
OH
53
Fig. 6
Present Work
Initially Homopropargyl alcohol 53 was treated with an equimolar quantity of
3,4-dihydro-2H-pyran and a catalytic amount of PTSA in dry methylene chloride gave its
tetrahydropyranyl derivative 54 in 80% yield. The compound 54 was treated with the Grignard
reagent prepared from ethyl bromide & magnesium followed by quenching with
paraformaldehyde in dry THF to afford acetylenic alcohol 55 in 85% yield. Acetylenic alcohol
55 was reduced with LiAlH4 in dry THF at room temperature to afford the trans-allylic alcohol
56 in 75% yield. The E-allyl alcohol 54 was subjected to the Sharpless asymmetric epoxidation
protocol to afford the epoxy alcohol 52 in 75% yield. The epoxy alcohol 52 was converted to
corresponding epoxy chloride 57 in 85% yield by using TPP and NaHCO3, in dry CCl4 on
refluxing for 4 h. Accordingly, compound 57 was subjected to LiNH2 in liquid ammonia and
further treated with 2eq of nonyl bromide to get the chiral propargyl alcohol 51 in 70% yield
(Scheme 9).
DHP, PTSA,
dry CH2Cl2,
OH
Mg, EtBr,
dry THF, 0 oC - rt.,
OTHP
0 oC - rt., 81%
54
53
OH
THPO
55
(CH2O)n, 85%
LiAlH4,
dryTHF,0 oC - rt.,
80%
THPO
OH
56
Scheme 9
The secondary hydroxyl group of the compound 51 was then protected as benzyl ether
using BnBr and NaH in dry THF at room temperature followed by deprotection of the THP
group by using PTSA in MeOH resulted in alcohol 59 in 84% yield. The alcohol 59 was oxidized
by Swern oxidation condition followed by insitu treatment with the two carbon Wittig ylide,
(ethoxy carbonyl methylene) triphenyl phosphorane to furnish the trans α, β-unsaturated ester 60
in 70% yield. Treatment of compound 60 over 10% Pd/C in ethanol yielded a target molecule 49,
by in situ removal of benzyl group, saturation of double and triple bonds followed by cyclization
in 70% yield (Scheme 10). The synthetic material showed IR, 1H,
13
C NMR spectral data and
optical rotation in good agreement with the natural lactone.
OH
OBn
NaH, BnBr,
THPO
51
C9 H19
THPO
dry THF, 0 oC-rt,
98%
58
OBn
PTSA, MeOH
(COCl)2, dry DMSO,
Et3N, -78 oC,
HO
96%
59
C9 H19
C9 H19
dryCH2Cl2, 70%,
PPh3=CHCO2Et
Scheme 10
Retro synthetic route for (5R, 6S)-6-Acetoxyhexadecanolide
Synthetic strategy for (5R, 6S)-acetoxyhexadecanolide 48 is outlined below in Fig 7.
O
O
OAc 50
OMOM
HO
OAc
61
OH
PMBO
OTHP
5
OPMB
Present Work
OTHP
8
9
Fig. 7
The intermediate 5 was synthesized in two different routes as shown in Scheme 1 and 2
(Chapter 1) and was further utilized for the synthesis of the target molecule 50. Accordingly the
secondary hydroxyl group of compound 5 was protected as its methoxy methyl ether using 3
equivalents of Hunig’s base (iPr2EtN) and 2 equivalents of MOMCl in dry DCM at room
temperature to afford 62 in 96% yield followed by deprotection of PMB group to afford
compound 63 in 83% yield. Oxidation of compound 63 using IBX (O- Iodoxy benzoic acid),
DMSO/
DCM
at
25 oC afforded aldehyde 64 in 73% yield.
OH
OMOM
MOMCl, iPr2EtN
PMBO
OTHP
5
PMBO
dry CH2Cl2, 0 oC-rt,
96%
OTHP
62
OMOM
OMOM
DDQ,
IBX, DMSO,
HO
DCM : H2O (9:1),
83%
OTHP dry CH2Cl2, 0 oC-rt,
80%
63
OHC
OTHP
64
OMOM
OMOM
Mg, C10H21Br,
Ac2O, Et3N,
C10 H21
dry Ether,
-10 oC, 78%
C10 H21
OTHP dry CH2Cl2,
0 oC-rt, 92%
OH
OTHP
OAc
65
66
OMOM
OMOM
IBX, DMSO,
PPTS,
C10 H21
OH
MeOH, rt,
90%
dry CH2Cl2,
0 oC-rt, 77%
OAc
CHO
C10 H21
OAc
61
67
O
OMOM
NaClO2, NaH2PO4,
dry DMSO, rt,
72%
C10 H21
COOH
PTSA,
dry benzene,
reflux, 76%
OAc
O
C10 H21
OAc
68
50
Scheme 11
The aldehyde 64 was treated with the Grignard reagent prepared from decyl magnesium
bromide followed by the protection of secondary hydroxyl group by using acetic anhydride and
triethylamine in dry dichloromethane to afford acetate 65. Deprotection of the THP group using
PTSA in MeOH followed by oxidation to afford the corresponding acid 68 in 72% yield. Finally
the synthesis of target molecule 50 was achieved in 76% yield by in situ deprotection of MOM
group and subsequent cyclization by using catalytic amount of PTSA in dry benzene in reflux
condition (Scheme 11. The synthetic material showed IR, 1H, 13C NMR spectral data and optical
rotation [[α]D25 : -35(c = 1.5, CHCl3)] in good agreement with the natural lactone.
Chapter-IV: Bismuth(III) Chloride Catalyzed Efficient and Selective Cleavage of Trityl ethers.
This chapter deals with the Bismuth(III) Chloride Catalyzed Efficient and Selective
Cleavage of Trityl ethers. The triphenylmethyl (trityl) group is a commonly used protecting
group for primary alcohols in carbohydrate and nucleoside chemistry due to its ease of
installation, removal and stability towards a variety of reagents. Most bismuth compounds are
relatively non-toxic, easy to handle and can tolerate small amounts of moisture. A simple, mild,
highly selective and efficient protocol has been developed for the detritylation using 5 mol%
Bismuth(III) Chloride in acetonitrile at room temperature. Several trityl ethers with different
protecting groups were subjected to deprotection using Bismuth(III) Chloride as a mild Lewis
acid (Scheme 12).
BiCl3/CH3CN
ROTr
r. t., 3-10 min
ROH
R = alkyl, aryl, terpenoid and carbohydrate units
Scheme 12
Trityl ethers containing acid sensitive THP and Boc group respectively underwent facile
cleavage of the trityl ether within 4 min, retaining the THP, Boc groups. Similarly, trityl ethers
having base sensitive Ac, Bz, Ts and Piv groups underwent smooth and selective deprotection of
the trityl group in 3 min to give the corresponding alcohols in good yields. In a further study,
sugar substrates possessing glycosidic linkages and O-prenyl, -allyl, and Bn groups were also
subjected to selective cleavage of trityl groups in 8-10 min to afford the corresponding alcohols.
Trityl ethers having acetonides derived from secondary alcohols underwent selective
deprotection of the trityl group leaving acetonides intact. The results show that the rate of
detritylation using our conditions is much faster (3-10 min) than those reported in the literature.
In addition the selectivity, for cleavage of trityl ethers in the presence of a variety of acid/base
sensitive groups and substrates such as carbohydrates, terpenes and amino acids makes this
procedure a valuable alternative to the existing procedures.