Abstract
ABSTRACT
The thesis entitled “Stereoselective total synthesis of (-)-Aspinolide, Syributins, Ringclosing metathesis approach to the synthesis of Ilexlactone and synthesis of
structurally diverse compounds via Baylis-Hillman reaction.” is divided into three
chapters.
Chapter I: Stereoselective total synthesis of (-)-aspinolide B from (R)-2,3-Oisopropylidene glyceraldehyde
This chapter is dealt with the stereoselective total synthesis of (-)- aspinolide B from (R)2,3-O-isopropylidene glyceraldehyde and propylene oxide.
Aspinolide B (1) and the aspinonene/aspyrone co-metabolites, named trienediol,
isoaspinonene, dihydroaspyrone, and dienetriol were discovered by chemical screening
methods in the cultures of Aspergillus ochraceus1 (DSM-7428) under altered fermentation
conditions and the structures were established by detailed spectroscopic analysis. Other
representative members of the 10-membered lactones are decarestrictine D, phoracantolide
I and achaetolide with varied biological activities.
Figure 1
4'
10
9 O 1
3'
2'
2 3
8 O 54
1'
O
OH
O
7 6
OH
aspinolide B (1)
O
HO
OH
HO
O
OH
O
O
Aspyrone (3)
Aspinonene (2)
HO
O
HO
Isoaspinonene (4)
O
HO
HO
O
OH
Dihydroaspyrone (5)
Generally cyclizations of medium ring lactones with n = 8-11 (n = no. of atoms in
the macrolide) appear to be more difficult due to both enthalpic and entropic factors.2
1
Abstract
Notwithstanding the difficulty, to date, only one synthesis of (-)-aspinolide B (1) has been
reported by Pilli et al.3 through Nozaki-Hiyama-Kishi reaction as the key step albeit in low
stereoselectivity. As part of our interest in the synthesis of natural products, herein we
decided to synthesize of (-)-aspinolide B (1) by a convergent strategy wherein both the
intermediates are derived from common, inexpensive starting materials viz. (R)-2,3-Oisopropylidene glyceraldehyde and propylene oxide. The key steps involve Sharpless
asymmetric
epoxidation
on
the
chiron
derived
form
(R)-2,3-O-isopropylidene
glyceraldehyde, acetylenic addition onto a chiral aldehyde, 1,2-anti selective reduction and
Yamaguchi macrolactonization.
With an emphasis on convergent synthetic approach, our retrosynthetic analysis
revealed that the target compound 1 could be obtained from seco acid 6 by Yamaguchi
Scheme 1
OMOM
O
OBn
O
O
COOH
O
OH
1
OH
OBn
OH
6
OH
OBn
OTPS
OPMB
OBn
7
OPMB
OBn
OTPS
BnO
8
(R)-2,3-O-isopropylidene
glyceraldehyde
+
CHO
9
propylene oxide
macrolactonization and subsequent deprotection of MOM group followed by crotonylation
and deprotection of benzyl groups. Seco acid 6, in turn, could be obtained from chiral
propargylic alcohol 7 which could be traced back to two building blocks C1-C7 fragment
2
Abstract
(8) and C8-C10 (9). While C1-C7 fragment 8 (Scheme 2) could be realized from (R)-2,3-Oisopropylidene glyceraldehyde by simple chemical transformations, aldehyde 9 (Scheme 3)
could be derived from the chiral diol 21 which in turn could be easily obtained from
Jacobsen’s HKR (Hydrolytic Kinetic Resolution) of propylene oxide.
Accordingly, the known alcohol 104 (Scheme 2), prepared from a literature
procedure from D-mannitol, was silylated using TBDPSCl in the presence of imidazole in
CH2Cl2 at room temperature for 3 h obtained compound 11 in 90% yield. Then acetonide
deprotection in compound 11 on reaction with PTSA (catalytic) in MeOH at room
temperature for 10 min afforded the required diol 12 in 85% yield. Diol was firstly
protected using benzaldehydedimethyl acetal and PTSA (cat.) in dry CH2Cl2 at room
temperature for 3 h obtained 13 in 83% yield, which on subsequent regioselective
reductive ring opening with DIBAL-H (2M solution in toluene) at 0 °C to room
temperature for 6 h afforded primary alcohol 14 in 85% yield.
Scheme 2
O
O
a
OH
O
O
10
H
O
HO
OTPS
11
Ph
O
d
OH
OBn
HO
e
OTPS
OTPS
OHC
14
OBn
OTPS
OBn
h
HO
OTPS
HO
OBn
i
Cl
OBn
j
OTPS
OTPS
O
19
OTPS
O
17
16
f
15
OBn
g
MeO
c
12
OBn
13
O
OH
b
OTPS
OH
20
k
18
OBn
OTPS
OBn
8
Reagents and conditions: a) TBDPSCl, imidiazole, CH2Cl2, 0 oC-rt, 3 h; b) PTSA, MeOH, 10 min; c)
benzaldehyde dimethyl acetal, PTSA, CH2Cl2 , 0 oC-rt, 3 h; d) DIBAL-H, CH2Cl2, 0 oC-rt, 6 h; e) ( COCl)2,
DMSO, Et3N, CH2Cl2, -78 oC, 2 h; f) Ph3PCHCOOMe, CH2Cl2, 0 o C-rt, 4 h; g) DIBAL-H, CH2Cl2, 0 o C-rt, 4
h; h) (+)-DIPT, Ti(OiPr)4, cumene hydroperoxide, CH2Cl2, -20 o C 12 h; i) CCl4, Ph3P, NaHCO3, reflux, 1 h; j)
LDA, THF, -78 o C to -40 o C, 3 h; k) BnBr, NaH, THF-DMF, 0 oC-rt, 2 h.
3
Abstract
Later, oxidation of terminal alcohol of 14 in the presence of oxalyl chloride-DMSO
in dry CH2Cl2 at –78 °C, followed by treatment with triethyl amine furnished aldehyde 15
(Scheme 2) in 94% yield. Homologation of 15 with (methoxycarbonylmethylene) triphenyl
phosphorane in CH2Cl2 at 0 oC to room temperature for 4 h gave , -unsaturated ester 16
in 80% yield. Further, reduction of the ester 16 with DIBAL-H in dry CH2Cl2 at 0 °C to
room temperature for 4 h gave the corresponding allylic alcohol 17 in 86% yield. Then
exposure of the ensuing alcohol to Sharpless epoxidation with (+)-DIPT, Ti(OiPr)4 and
cumene hydroperoxide in the presence of MS 4 Å in dry CH2Cl2 at –20 °C for 12 h gave
18 in 84% yield. Later epoxy alcohol 18 was chlorinated with Ph3P and NaHCO3 in CCl4
under reflux conditions for 1h afforded chloro compound 19 (monitored by TLC,
comparatively faster Rf to epoxy alcohol 18) in 92% yield, followed by base induced
double elimination of compound 19 with LDA in dry THF at –78 oC to –40 oC for 3 h
afforded alkyne 20 (Scheme 2) in 85% yield. Further, propargylic hydroxyl group in 20
was protected on reaction with benzyl bromide in the presence of sodium hydride in dry
THF-DMF at 0 °C to room temperature for 2 h furnished 8 in 86% yield (Scheme 2).
Scheme 3
OMe
H
OH
OH
a
O
21
O
b
22
OPMB
OH
OPMB
c
CHO
9
23
Reagents and conditions: a) anisaldehydedimethyl acetal, PTSA, CH2Cl2, rt,
6 h; b) DIBAL-H, CH2Cl2, 0 oC-rt, 4 h; c) (COCl)2, DMSO, Et3N, CH2Cl2, -78 oC, 2 h.
For accessing aldehyde 9 (Scheme 3), known5 diol 21, obtained from Jacobsen’s
hydrolytic
kinetic
resolution
of
propylene
oxide,
was
converted
into
p-
methoxybenzylidene derivative in 82% yield, which on subsequent regioselective reductive
ring-opening reaction with DIBAL-H in CH2Cl2 afforded alcohol 23 in 84% yield.
Compound 23 on oxidation under Swern conditions gave aldehyde 9 in 90% yield.
Having prepared the key fragments i.e. alkyne 8 and aldehyde 9 respectively with
obligatory stereocenters in each segment, it was next aimed at their coupling and further
transformations towards our goal as aspinolide 6. Accordingly, to prepare propargylic
4
Abstract
alcohol 24, alkyne 8 was treated with n-BuLi in THF at –78 oC and the resulting acetylenic
anion was quenched with aldehyde 9 furnished 24 (Scheme 4) in 69% (with 20% de) yield.
In order to increase the diastereoselectivity in favor of the requisite stereocenter (anti to the
existing one), we reported to an oxidation-reduction protocol. Hence, propargylic alcohol
was oxidized with Dess-Martin periodinane in dry CH2Cl2 at 0 oC –room temperature for 4
h afforded 25 (Scheme 4) in 92% yield. Then selective reduction of keto with Zn(BH4)26
afforded alcohol 7 in 82% (74% de). Further, reaction of 7 with NaAlH2 (OCH2CH2OMe)2
in dry ether afforded allylic alcohol 26 in 90% yield. Followed by protection of compound
26 as MOM ether with MOM-Cl in the presence of DIPEA as a base and catalytic amount
of DMAP in dry CH2Cl2 at 0 oC to room temperature for 6 h gave compound 27 in 92%
yield.
Scheme 4
O
OH
8
OBn
a
OTPS
OPMB
OBn
b
OBn
OBn
24
c
OTPS
OPMB
25
OH
OH
OBn
OTPS
OPMB
OBn
OMOM
OPMB
OTPS
OPMB
OBn
OTPS
7
OBn
OBn
d
OBn
OMOM
f
e
26
OBn
OH
OPMB
27
OBn
28
Reagents and conditions: a) n-BuLi, 9, THF, -78 oC, 3 h; b) Dess-Martin periodinane, CH2Cl2, 0 oC-rt, 4 h;
c) Zn(BH4)2, ether, -30 oC, 4 h; d) Red-Al, ether, 0 oC-rt, 2 h; e) MOMCl, DIPEA, CH2Cl2, 0 oC-rt, 6 h;
f) TBAF, THF, 0 oC-rt, 8 h;
TBDPS protecting group in 27 was deprotected (Scheme 4) using TBAF at 0 °C to
room temperature for 8 h gave alcohol 28 in 92% yield. Oxidation of terminal alcohol in
28 with Dess-Martin periodinane in dry CH2Cl2 at 0 °C to room temperature for 4 h
furnished aldehyde 29 followed by oxidation of aldehyde 29 using NaClO2 and
NaH2PO4.2H2O in t-BuOH:2-methyl-2-butene (3:1) and few drops of water at room
temperature for 10 h furnished acid 30 in 85% yield. To make the seco acid 6, 30 was
5
Abstract
subjected to oxidative deprotection of PMB group using DDQ in CH2Cl2:H2O gave seco
acid 6 in 86% yield. Having prepared the key intermediate 6, it was next aimed at
macrolactonization and further transformations to aspinolide-B, by the use of Yamaguchi7
conditions gave 31 in 48% yield. Later, deprotection of MOM ether in compound 31 using
PPTS in n-BuOH under reflux temperature for 2 h afforded compound 32 in 87% yield.
Further, esterification of 2o-alcohol with trans-crotonic acid under Yamaguchi conditions
afforded crotonyl derivative 33 in 93% yield. Finally, global debenzylation of compound
33 with TiCl4 in CH2Cl2 at 0 oC- room temperature for 2 h gave target compound 1 in 69%
yield (Scheme 5) as a white solid.
Scheme 5
OMOM
a
28
OBn
OMOM
b
OBn
c
CHO
OPMB
OMOM
OBn
OBn
29
OBn
OBn
O
d
COOH
OH
COOH
OPMB
O
e
O
O
MOMO
OBn
6
HO
31 OBn
O
f
g
O
O
O
OBn
33
OBn
32 OBn
O
O
30
O
OBn
O
OH
1
OH
Reagents and conditions: a) Dess-Martin periodinane, CH2Cl2 , 0 oC-rt, 4 h; b) NaClO2, NaH2PO4.2H2O,
t-BuOH:2-methyl-2-butene (3:1), 0 oC-rt, 10 h; c) DDQ, CH2Cl2:H2O (19:1), 0 oC-rt, 2 h;
d) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, 0 oC-rt, 4 h, then DMAP, toluene, reflux, 12 h;
e) PPTS, n-BuOH, reflux, 2 h; f) trans- crotonic acid , 2,4,6-trichlorobenzoyl chloride, Et3N, THF, 0 oC-rt, 2 h,
then 32, DMAP, toluene, rt, 6 h; g) TiCl4, CH2Cl2, 0 oC-rt, 2 h.
The 1H and
13
C NMR data and optical rotation value of synthetic 1 were in good
accordance with those of the natural product.1,3
Chapter II: Section A: Stereoselective total synthesis of syributins 1 and 2
This section dealt with the stereoselective total synthesis of syributins using Baylis-Hillman
reaction and Grubbs’ catalyst
6
Abstract
The syributins along with secosyrins were isolated by Sims and co-workers8 as the
co-isolates of syringolide elicitors from pseudomonas syringea pv. tomato expressing
virulence gene D (avrD-genes). While syringolides are of interest due to their unusual
response to resistant soyabean plants, syributins.8-11 and secosyrins8,10,11 gained importance
owing to their interesting structural features and their potential properties of providing vital
clues to the biosynthesis of syringolides.
Figure 2
OHH
O
O
n
OH
(CH2)nCH3
O
34 : Syributin 1 (n = 4)
35 : Syributin 2 (n = 6)
O
O
O
O
OH
O
n
H
O
O
HO
HO
36 Syringolide 1 (n=4)
37 Syringolide 2 (n=6)
O
O
O
38 Secosyrin 1 (n=4)
39 Secosyrin 2 (n=6)
Although structurally related they do not display the same activity profile as
syringolides. Recently, a diastereoselective Baylis–Hillman reaction using sugar-derived
aldehydes as the chiral electrophiles was developed in our laboratories.12 The total
synthesis of syributins 34 and 35 was undertaken to exemplify the synthetic utility of one
such Baylis–Hillman adduct. Herein we describe the total synthesis of syributins 34 and 35
using the Baylis–Hillman adduct of (R)-2,3-O-isopropylidene glyceraldehyde-ethyl
acrylate as the starting material and RCM of the monoacrylate of the ensuing diol as the
key step for the construction of the lactone ring. Retrosynthetic analysis of 34 and 35 as
delineated in (Scheme 6) revealed that the lactone 40 is an appropriate intermediate for
further manipulation to the target compounds.
Lactone 40 in turn could be envisaged from the monoacrylate 41 by RCM and 41
could be readily accessed from 42, a Baylis–Hillman adduct obtained by the reaction
between (R)-2,3-O-isopropylidene glyceraldehyde 43 and ethyl acrylate.
7
Abstract
Scheme 6
O
O
O
OH
O
O
O
(CH2)nCH3
O
OH
O
34 : Syributin 1 (n = 4)
35 : Syributin 2 (n = 6)
OH
40
O
O
O
O
OH
O
OEt
42
41
Accordingly,
O
O
the
Baylis–Hillman
OH
O
reaction
O
CHO
43
of
(R)-2,3-O-isopropylidene
glyceraldehyde 43 with ethyl acrylate was performed in 1,4-dioxane:water13 as solvent and
DABCO as catalyst (Scheme 7). The reaction was complete in 24 h affording 42 (72%).
The de of adduct 42 was found to be 80% by 1H NMR and HPLC analysis. Although the
Baylis–Hillman reaction of (R)-2,3-O-isopropylidene glyceraldehyde 43 with ethyl
acrylate has been performed14 at high pressure (4 kbar), no diastereoselectivity was
obtained. Thus the use of 1,4-dioxane:water not only facilitates the Baylis–Hillman
reaction at normal atmospheric pressure and temperature but also resulted in adduct 42
with 80% de. The absolute stereochemistry of the major isomer of 42 was assigned as S
based on literature evidence. The observed stereoselectivity of 42 can be explained by the
favorable attack of the carbanion from the si-face of the sugar aldehyde leading to the ‘S’
isomer as the major product at the newly created center according to the Felkin–Anh
model15 by a non-chelation protocol. Adduct 42 was reduced with LAH and AlCl3
furnished diol 44, which on acryloylation (acryloyl chloride, N-ethyldiisopropylamine,
CH2Cl2, rt) afforded monoacylate 41 as the major product (75%) along with 10%
diacrylate.
Monoacrylate 41 was subjected to RCM with Grubbs’ catalyst16 (standard
ruthenium complex A, 30mol %, CH2Cl2, reflux) furnished 40 and 45 in a moderate yield
(62%, 1:9), which were separated by column chromatography.
8
Abstract
Scheme 7
O
a
O
O
b
O
OEt
CHO
43
O
HO
42
O
O
O
O
O
O
O
HO
O
g
41
OH
44 HO
O
O
d
c
O
O
O
40
OH
O
+
45
OH
e
O
O
O
f
O
O
O
O
O
O
O
47 n = 4
48 n = 6
O
h
O
(CH2)nCH3
Cl
O
34 n = 4
OH
OH
O
35 n = 6
(CH2)nCH3
PCy3
Ru
Cl
46
Ph
PCy3
A
O
Reagents and conditions ; (a) ethyl acrylate, DABCO, 1, 4 dioxane:H2O (1:1), rt, 24 h, 72%; b) LAH, AlCl3, ether, 0 oC,
2h, 65%; c) acryloyl chloride, N-ethyldiisopropylamine, CH2Cl2, 0 oC to rt, 10h, 75%; d) Grubbs' catalyst (A, 30
mol%), CH2Cl2, reflux, 48h, 62%, (40/45, 1:9); e) PDC, CH2Cl2, rt, 12h, 95%; f) LiEt3BH, THF, -78 oC, 1.5h, 100%;
g) 47: CH3(CH2)4COCl, Et3N, CH2Cl2, rt, 0.5 h, 87%; 48: CH3(CH2)6COCl, Et3N, CH2Cl2, rt, 0.5 h, 90%; (h) TsOH,
MeOH, rt, 2 h, 34 (90%); 35 (86%).
The major isomer 45 on oxidation with PDC afforded ketone 46, which on
reduction with super-hydride10 gave the required isomer 40. Interestingly, lactone 40 is an
important advanced intermediate used in the total synthesis of several natural products
such as syringolides, spyhydrofurans, and secosyrins. Upon acylation of 40 with hexanoyl
chloride and octanoyl chloride, 47 (87%) and 48 (90%) were obtained, respectively.
Deprotection of the acetonide group (PTSA in Methanol) in 47 and 48 afforded syributins
34 and 35 via a simultaneous 1,3-acyl migration. Additionally, the total synthesis of
syributins 34 and 35 unequivocally confirmed the stereochemistry at the newly created
center of the major isomer of 42 as S.
9
Abstract
In conclusion, the total synthesis of syributins 34 and 35 was successfully
accomplished in seven steps starting from the Baylis–Hillman adduct of (R)-2,3-Oisopropylidene glyceraldehyde -ethyl acrylate followed by RCM as the key step.
Section B: Studies directed towards the stereoselective total synthesis of ilexlactone
via a tandem ring-closing enyne metathesis protocol
This chapter dealt with the synthesis of the bicyclic systems through tandem ring-closing
enyne metathesis, Sharpless asymmetric epoxidation and 1,3-syn selective reduction as the
key steps.
The ruthenium carbenes developed by Grubbs in early 1990s aroused considerable
attention because of their functional group tolerance and alkene chemoselection in alkene
metathesis. During this time Mori and Kinoshita17 et. al reported ring-closing enyne
metathesis with high catalytic efficiency using Grubbs’ catalyst. After thorough
investigations on enyne metathesis, Grubbs’ group introduced tandem enyne metathesis in
1994.18 In this process various dienynes were subjected to ring-closing enyne metathesis to
produce an array of bicyclic systems as well as the highly complex natural products. Thus,
tandem ring-closing enyne metathesis gained much prominence in the synthetic organic
chemistry. In recent years we became interested in the synthesis of the natural products as
well as in the synthesis of diverse compounds using Grubbs’ catalyst. Consequently we
have chosen natural product ilexlactone,19 isolated from Ilex aquifolium whose structure
was determined as a 3-(3-hydroxycyclopent-1-enyl)-Z-propenic acid-1,5-lactone, as the
synthetic target. Though the absolute configuration at C-3 and C-5 not exactly determined,
their relative configuration was assigned as syn to each other. So it was decided to
synthesize both the enantiomers of ilexlactone simultaneously. Indeed to the best of our
knowledge there is no report on the synthesis of this molecule. The synthesis of all
possible isomers for 49 was initiated with commercially available L-malic acid and 1,3propane diol independently via tandem enyne metathesis as the key step. A glimpse at the
previous reports20 on tandem ring-closing enyne metathesis was considered; it indicated
that the substrates so far chosen substantially possessed either alkene or alkyne being
electron rich or sterically less crowded. The substrate chosen herein is unprecedented.
10
Abstract
Thus, retrosynthetic analysis (Scheme 8) revealed that the target compound 49
could be obtained from 50 by tandem ring-closing metathesis using Grubbs’ II catalyst (B)
and subsequent deprotection of MOM group. Compound 50, in turn, could be obtained
from propargyl alcohol 51 which could be realized from L-malic acid. While the
retroanalysis of other isomer ent-49 revealed that here the crucial substrate 52 could be
realized from chiral aldehyde 53, which in turn could be accessed from 1, 3-propane diol.
Scheme 8
Hg
HO
HfH
d
O
O
O
OR
O
O
He
OH
O
Hb
Hc
Ha
50
51
L- Malic acid
49
Hg
HO
HfH
d
1, 3- propane diol
O
O
O
OR
He
OPMB
O
OHC
Hb
Hc
Ha
ent-49
53
52
The synthesis began with known allylic alcohol 5421 which was subjected to
Sharpless epoxidation with (Scheme 9) (-)-DIPT, Ti(OiPr)4 and cumene hydroperoxide in
dry CH2Cl2 at -20 oC afforded epoxy alcohol 55, which was chlorinated using CCl4 and
Ph3P under reflux conditions gave 56. Followed by a base induced double elimination
compound 56 with LDA in dry THF at -78 C to -40 C furnished propargylic alcohol 51
(85%). Later, the propargylic hydroxyl group was protected as its p-methoxy benzyl ether
with PMBBr and NaH in dry THF at 0 oC to room temperature furnished alkyne 57 (86%).
Then removal of cyclohexanone protection with CSA in MeOH for 2 h gave 58. To this
end, selective formation of the primary silylation with TBDMSCl and imidazole in dry
CH2Cl2 afforded 2o alcohol 59 followed by protection of compound 59 as a MOM ether
using MOMCl, DIPEA and catalytic amount of DMAP in dry CH2Cl2 gave compound 60
and removal of silyl group with TBAF in THF provided the desired primary alcohol 61,
which on exposure to Swern oxidation afforded 62. Further Wittig olefination reaction
with Ph3PCH3I and t-BuOK in THF at 0 oC for 6 h then added aldehyde 62 furnished
11
Abstract
alkene 63 followed by deprotection of PMB-ether with DDQ in CH2Cl2-H2O afforded
propargylic alcohol 64 which was treated with acryloyl chloride and DIPEA in dry CH2Cl2
afforded compound 50.
Scheme 9
a
O
O
O
O
O
OH
Cl
O
O
OPMB
OH
e
f
TBSO
OH OPMB
59
58
OPMB
TBSO
h
g
HO
57
OR
OPMB
OH
O
51
56
55
d
O
O
OH
54
60
c
b
O
O
OR
OPMB
OR
i
HO
OPMB
j
OHC
62
61
R=MOM
O
OR
OPMB
OR
k
OH
OR
l
O
RO
65
O
n
m
50
64
63
O
O
O
Mes N
Cl
HO
N Mes
Ph
Ru
Cl PCy
3
Mes = C6H2-2,4,6-(CH3)3
B
49
Reagents and conditions: a) (-)-DIPT, Ti(OiPr)4, cumene hydroperoxide, CH2Cl2, -20 oC, 12 h; (b) CCl4, Ph3P,
NaHCO3, reflux, 1 h; c) LDA, THF, -78 oC to -40 oC, 3 h; d) PMBBr, NaH, THF, 0 oC-rt; (e) CSA, MeOH, 2 h; f)
TBSCl, imidazole, CH2Cl2, rt; (g) MOMCl, DIPEA, DMAP, CH2Cl2, 0 oC-rt, 6 h; (h) TBAF, THF, 0 oC-rt, 8 h; i)
(COCl)2, DMSO, Et3N, CH2Cl2, -78 oC; (j) PPh3CH3I, t-BuOK, THF, 0 oC, 6 h then added aldehyde; k) DDQ,
CH2Cl2:H2O (19:1), 0 oC-rt, 2 h; (l) acryloyl chloride, DIPEA, CH2Cl2, 0 oC-rt, 1 h; m) Grubbs' catalyst IInd generation
(B), 5 mol%, CH2Cl2, 12 h; n) PPTS, n-BuOH, reflux, 2 h;
Pleasingly, the critical tandem ring closing enyne metathesis of compound 50 with
catalyst B in dry CH2Cl2 under reflux conditions for 12 h led to bicyclic system 65.
Finally deprotection of MOM ether of compound 65 under basic condition with
PPTS in n-BuOH afforded required target molecule 49.
12
Abstract
As planned, the enantiomeric synthesis of ent-49 was initiated with commercially
available 1,3-propane diol (Scheme 10) that was selectively monoprotected with TBDPSCl
and imidazole in CH2Cl2 rt for 6 h gave monosilylated alcohol 66, which was oxidized
under Swern conditions gave aldehyde 67 followed by a Wittig olefination reaction with
Ph3PCHCOOEt in dry CH2Cl2 at 0 oC to room temperature afforded a chromatographically
separable trans-,-unsaturated ester 68 and its cis isomer in a
9.5:0.5 ratio (80%
combined yield). The reduction of the trans ester 68 with DIBAL-H in CH2Cl2 at 0 oC to
room temperature for 4 h gave 69 and then treating the ensuing allylic alcohol to Sharpless
epoxidation with (+)-DIPT, Ti(OiPr)4 and cumene hydroperoxide in CH2Cl2 at -20 oC
afforded epoxy alcohol 70.
Scheme 10
a
1,3-propane diol
TPSO
OH
b
TPSO
66
c
CHO
67
O
TPSO
O
e
d
O
TPSO
TPSO
OH
68
69
f
TPSO
OH
71
OPMB
OPMB
h
TPSO
TPSO
Cl
i
70
g
O
OH
73
72
j
OPMB
OHC
HO
74
53
Reagents and conditions: a) TBDPSCl, imidazole, CH2Cl2, 0 oC-rt, 6 h; b) (COCl)2, DMSO, Et3N, CH2Cl2, -78 o
C, 2 h; (c) Ph3PCHCOOEt, CH2Cl2, 0 o C, 4 h; d) DIBAL-H, CH2Cl2, 0 o C-rt, 4 h; e) (+)-DIPT, Ti(OiPr)4, cumene
hydroperoxide, CH2Cl2, -20 o C, 12 h; f) CCl4, Ph3P, NaHCO3, reflux, 1 h; g) LDA, THF, -78 o C to -40 o C, 3 h; h)
PMBBr, NaH, THF, 0 oC-rt, 2 h; i) TBAF, THF, 0 oC-rt, 8 h; j) (COCl)2, DMSO, Et3N, CH2Cl2, -78 o C, 2 h.
Epoxy alcohol 70 was chlorinated with CCl4 and Ph3P under reflux conditions gave
71 followed by a base induced double elimination with LDA in dry THF -78 C to -40 C
furnished propargylic alcohol 72 (85%). Later, the propargylic hydroxyl group was
protected as its p-methoxy benzyl ether (PMBBr/NaH/THF/0 oC to room temperature)
13
Abstract
furnished alkyne 73 (86%). TBDPS deprotection of alkyne 73 with TBAF in THF at rt
afforded primary alcohol 74, which was oxidized under Swern condition gave aldehyde 53.
Exposure
of
aldehyde
53
(Scheme
11)
with
vinyl
magnesium
bromide
(vinylbromide/Mg/THF) afforded mixture of allylic alcohol 75 (80%) as a diastereomeric
mixture in 1:1 ratio. The mixture of allylic alcohol 75 was protected as their MOM-ether
with MOMCl, DIPEA and catalytic amount of DMAP in dry CH2Cl2 at 0 C to room
temperature gave 76 followed by deprotection of PMB-ether with DDQ in CH2Cl2-H2O
afforded a mixture of propargylic alcohols 77 (86%), which upon acryloylation with
acryloyl chloride and DIPEA in CH2Cl2 afforded acrylate ester 52 (90%).
Scheme 11
OH
a
OPMB
OR
b
OPMB
OR
c
OH
53
75
O
OR
77
76 R= MOM
O
O
d
e
RO
52
O
HO
O
+
f
O
O
RO
ent-65
65a
O
g
f
O
O
h
O
O
HO
78
49a
O
ent-49
Reagents and conditions: a) vinyl bromide, Mg, THF, then added 53; b) MOMCl, DIPEA,
DMAP, CH2Cl2, 0 oC-rt, 6 h; c) DDQ, CH2Cl2:H2O (19:1), 0 oC-rt, 2 h; d) acryloyl chloride,
DIPEA, CH2Cl2, 0 oC-rt, 1 h; e) Grubbs' catalyst IInd generation (B), CH2Cl2, 12 h; f) PPTS,
n-BuOH, reflux, 2 h; g) Dess-Martin periodinane, CH2Cl2, 0 oC-rt, 4 h; h) NaBH4, CeCl3.7H2O,
EtOH.
Treatment
of
compound
52
with
Grubbs’
catalyst
(B)
furnished
chromatographically separable bicyclic systems 65a and ent-65. Then deprotection of
MOM ether of 65a and ent-65 with PPTS in n-BuOH afforded undesired isomer 49a and
required target molecule ent-49. To recycle the undesired isomer we have used oxidation–
reduction protocol. Accordingly, 49a was oxidized with Dess-Martin periodinane in
CH2Cl2 at 0 oC to room temperature gave its corresponding keto compound 78 and
14
Abstract
selectively reduced22 with NaBH4 and CeCl3.7H2O in EtOH obtained required target
molecule ent-49 exclusively.
The spectroscopic data (Table 1) of structures 49 and ent-49 were found to be
different from that of ilexlactone reported in the literature.
Table1. Comparative 1H NMR (300 MHz, CDCl3) data of ilexlactone and compounds
49/ent-49 and 49a
Position
1
Ha
Hb
Hc
Hd
He
Hf
Hg
Ilexlactone (reported)
H NMR (multi, J = Hz)
6.65 (dd, 10.0, 2.0)
6.37 (dt, 10.0, 1.5)
5.87 (s)
4.93(ddd, 12.5, 5.0, 2.0)
4.67(m)
2.97 (m)
1.68 (m)
Compound 49/ent-49
1
H NMR (multi, J =
Hz)
7.17 (d, 9.6)
6.02 (d, 9.6)
6.10 (br. s)
5.16 (dis. t, 7.55)
4.83-4.79 (m)
3.09-2.97 (m)
2.11-1.88 (m)
Compound 49a
1
H NMR (multi, J =
Hz)
7.19 (d, 9.63)
6.02 (d, 9.73)
6.10 (br.s)
5.67 (t, 6.79)
5.04-5.01 (m)
2.49-2.42 (m)
2.36-2.27 (m)
It maybe concluded that the structure proposed for ilexlactone is incorrect. Out of
all the proposed four isomers, three synthesized herein do not correspond to the proposed
structure.
Figure 3
O
HO
O
Probable structure 79
Hence it may be deduced that the correct structure of the compound could be
imagined as the one given above 79 (Figure 3), since the reported 1H NMR values are
likely to match with this structure.
15
Abstract
Chapter III: Section A: Diversely Substituted Sugar-linked ,  -Unsaturated Lactones from Sugar-derived Baylis-Hillman Adducts via a RCM
This chapter dealt with the synthesis of sugar-linked ,  -unsaturated -lactones with
stereochemical and functional group diversity starting from sugar-derived Baylis-Hillman
adducts via ring-closing metathesis.
The Baylis-Hillman reaction is one of the most well studied C-C bond formations.
It is also well documented in the literature that Baylis-Hillman adducts serve as advanced
key intermediates in the synthesis of many biologically active natural products. Likewise
the transition metal catalyzed ring-closing metathesis has been the subject of much
attention in the recent years, and the development of ruthenium carbene complexes by
Grubbs’ and co-workers is particularly notable because of the functional group tolerance,
operational simplicity, and ready availability of the catalyst. In the recent years, we have
been involved in expanding the horizon of the asymmetric Baylis-Hillman reaction and
also in elaborating the ensuing adducts in the synthesis of bioactive natural products. , Unsaturated -lactone scaffolds rank among the most ubiquitous structural motifs found in
naturally occurring organic molecules. Many of these compounds exhibit a variety of
properties such as antifungal, insecticidal, antibacterial, phytotoxic, or anti-inflammatory
activities, and some are antibiotics, potential anticancer agents, and cyclooxygenase or
phospholipase A2 inhibitors23. Because of the wide prevalence of ,  -unsaturated lactone skeletons in natural products24, the regio- and stereoselective synthesis of this
compound has been a focus of intensive efforts to help speed up the drug discovery
process. Furthermore, a combination of the Baylis-Hillman reaction, which produces an
olefin en route, and ring-closing metathesis (RCM) protocol is envisioned to be a means of
ready access to , -unsaturated -lactones as products. Toward this endeavor, the results
obtained are discussed in this section for the conversion of sugar-derived Baylis- Hillman
adducts via a RCM into diversely substituted sugar-linked , -unsaturated -lactones.
Consequently, to introduce diverse stereochemical and functional group elements into the
end products, we have chosen sugar-derived aldehydes, such as 1,2-O-isopropylidene- 3O-methyl-R-D-xylo-pentodialdo-1,4-furanose (80a), 2,3-O-isopropylidene-1-O-methyl-R16
Abstract
D-xylo-pentodialdo-1,4-furanose (80b), and 2,3-O-isopropylidene-1-O-methyl-R-D-ribo-
pentodialdo-1,4-furanose
(80c), as chiral electrophiles in Baylis-Hillman reactions to
derive chiral adducts as products which could further be extrapolated to diverse , unsaturated -lactones via RCM of the ensuing acrylates in solution phase. These end
products, in addition to retaining the stereochemical integrity of the starting materials,
possess newer structural motifs in the form of butenolides.
Scheme 12
O
O
OH
a or b
R CHO +
OCH2CH3
DABCO
81
O
R
O
80a
O
OCH3
O
R=
OCH3
H3CH2CO
82a =
82b, 82c =
82b', 82c' =
O
OH
c
OH
OH
OH
HO
83a =
83b, 83c =
83b', 83c' =
OCH3
Cl
O
O
80b
O
R
O
80c
PCy3
Ru
Cl
OH
OH
OH
Ph
PCy3
A
Reagents and conditions: a) 1,4 dioxane:H2O (1:1), rt, 24 h; b) DMSO, rt, 15 h; c) LAH, AlCl3, ether, 0 °C, 2 h
Results and Discussion
Accordingly, the reaction of aldehyde 80a (Scheme 12) and ethyl acrylate 81 in the
presence of DABCO in 1,4-dioxane/water (1:1) at room temperature for 24 h yielded the
adduct 82a as a mixture of inseparable diastereomers (36% de). Aldehydes 80b and 80c
were reacted, in a similar manner, with ethyl acrylate in the presence of DABCO in DMSO
medium at room temperature for 24 h gave adducts 82b, 82b', 82c and 82c,' respectively,
in good yields as separable diastereomers. The absolute stereochemistry of major isomer in
82a was assigned as S on the basis of literature evidence.25 The S stereoselectivity can be
explained by the favorable attack of the carbanion from the Si face of the sugar-derived
aldehyde leading to the S isomer as the major product at the newly created center,
according to the Felkin-Anh model, by a non-chelation protocol.
17
Abstract
Scheme 13
OH
O
OH
OH
a
HO
b
R
O
OH
OH
83a =
83b, 83c =
83b', 83c'=
OH
R
R
O
84a, 84b, 84c =
84a', 84b', 84c'=
O
OH
85a, 85b, 85c
=
OH
OH
85a', 85b', 85c' =
OH
Reagents and conditions: a) acryloyl chloride, N-ethyldiisopropylamine, CH2Cl2, 0 °C to rt,10 h;
b) Grubb's catalyst (A, 10mol%), CH2Cl2, 36 h.
Similarly, the stereochemistry of the major isomers 82b and 82c is expected to be
the same because they are derived from D-sugars. As depicted in Scheme 12, the ester
functionality in adducts 82a, 82b, 82c, 82b' and 82c' was reduced with LAH/AlCl3
obtained diols 83a, 83b, 83c, 83b' and 83c' which upon acryloylation with acryloyl
chloride and N-ethyldiisopropylamine in dry CH2Cl2 at rt yielded monoacrylate esters 84a,
84b, 84c, 84a', 84b' and 84c' where 84a and 84a' were separated by column
chromatography. Monoacrylate esters 84a, 84b, 84c, 84a,' 84b' and 84c' were subjected to
RCM with Grubbs’ catalyst (standard ruthenium complex A, 10 mol%, CH2Cl2, reflux)
gave 4-substituted , -unsaturated--lactones 85a, 85b, 85c, 85a', 85b' and 85c’ in
moderate yields (Scheme 13).
Scheme 14
O
OH
OH
O
O
a
HO
83a =
83b, 83c =
83b', 83c'=
R
R1O
OH
OH
OH
R
86a, 86b, 86c =
86a', 86b', 86c'=
R1 = TBS
R1O
R
O
R
OR 1
OH
87a, 87b, 87c
=
OH
88a, 88b, 88c
=
OH
OH
87a', 87b', 87c' =
OH
88a', 88b', 88c' =
OH
Reagents and conditions: a)TBSCl, imidazole, CH2Cl2, rt, 10 h; b) acryloyl chloride,
N-ethyldiisopropylamine, CH2Cl2, 0 °C to rt, 1 h; c) Grubbs' catalyst (A, 10mol%), CH2Cl2, 48 h.
18
Abstract
Table 2. A series of sugar-derived lactones.
Entry
Product
Time(h)
Yielda(%)
OH
O
O
85a
1
O
85a'
O
O
O
36
68
48
62
48
62
O
OH3CO
O
3
68
O
OH3CO
OH
O
2
36
O
O
88a
O
TBSO H3CO
O
O
4
O
O
88a'
O
TBSO H3CO
OH
O
5
85b
O
O
O
OCH3
36
67
O
OH
6
O
85b'
O
O
O
O
O
7
TBSO
65
48
62
48
61
36
66
OCH3
36
64
OCH3
48
60
48
61
O
O
88b
36
OCH3
O
OCH3
O
O
O
8
O
88b'
TBSO
O
OCH3
O
OH
9
O
OCH3
85c
O
O
O
O
OH
10
O
85c'
O
O
O
O
O
11
O
O
88c
O
TBSO
O
O
O
12
OCH3
88c'
TBSO
a
O
O
O
Isolated yields for final step
19
Abstract
Subsequently, diols 83a, 83b, 83c, 83b' and 83c'were protected as TBDMS ethers
by treatment with TBDMSCl and imidazole in dry CH2Cl2 at room temperature for 10 h
yielded 86a, 86b, 86c, 86a', 86b' and 86c'. Then reaction of 86a, 86b, 86c, 86a', 86b' and
86c' with acryloyl chloride and N-ethyldiisopropylamine in CH2Cl2 provided the acrylate
esters 87a, 87b, 87c, 87a', 87b' and 87c'. Finally, ring-closing metathesis on 87a, 87b, 87c,
87a', 87b' and 87c' using Grubbs’ catalyst (standard ruthenium complex A, 10 mol%) in
refluxing CH2Cl2 for 48 h gave the 4,5-disubstituted , -unsaturated--lactones 88a, 88b,
88c, 88a', 88b' and 88c' in moderate yields (Scheme 14).
Scheme 15
OH
OH
O
O
O
O
OCH3
O
O
O
TBSO
O
O
O
O
O
O
O
dr 67:33 (syn:anti)
85b'
O
OCH3
a
OCH3
O
O
a
O
HO
88b'
O
89b'
OCH3
O
dr 67:33 (syn:anti)
90b'
Reagents and conditions: a) H2, Pd-C, MeOH, 6 h
In total, a small library of 12 different lactones with stereochemical and
regiochemical diversity was prepared starting from 3 different sugars; their yields and
reaction times are shown in Table 2.
Sugar is used as a template for the creation of a new chiral center on the
butyrolactone skeleton. Additionally, the hydroxyl functional group at C-5 can act as the
diversity point both stereochemically and functionally, and the chirality can be extended
through the butyrolactone moiety by induction26. To demonstrate this possibility, 85b' and
88b' (Scheme 15) were subjected to hydrogenation in presence of Pd-C at room
temperature gave 89b' and 90b' in quantitative yields as an inseparable mixture in a 6.7:3.3
20
Abstract
ratio. It is interesting to note that both 89b' and 90b' are indeed stereochemically diverse
sugar-linked butenolides possessing chiral tertiary stereocenters.
Diversity-oriented synthesis (DOS) is a preferred technique in the development of
focused libraries. In conclusion, we have prepared a series of structurally diverse , unsaturated--lactones from sugar-derived Baylis-Hillman adducts via a RCM protocol.
These lactones not only serve as useful intermediates in the synthesis of many bioactive
natural products but also are also suitable for biological screening because of their natural
product like profiles.
Section B: Novel protocol for the generation of -branched Baylis–Hillman adducts
from ethyl sorbate and aryl aldehydes
This chapter dealt with the generation of -branched Baylis–Hillman adducts in moderate
yields (52–68%) as E/Z mixtures
The construction of C–C bonds is an important task in the field of synthetic organic
chemistry. The Baylis–Hillman reaction is recognized as a versatile and economically
favorable C–C bond forming reaction for generating multifunctional adducts as useful
synthons. Because synthesis of multi-functionalized alkenes is an important goal in organic
chemistry, Lewis acid catalyzed -halo Baylis–Hillman adducts27 gained prominence and
were synthesized from propargylic acids or ketones and aldehydes, but less importance has
been attached to ,-disubstituted28 or -branched adducts. As part of our continued
interest in the Baylis–Hillman reaction, herein we describe a practical protocol for the
preparation of -branched adducts for the first time using the commercially available
dienoate, ethyl sorbate, as a Michael acceptor and various aldehydes in the presence of
DABCO in DMSO at room temperature (Equation1). To optimize the reaction conditions,
91 was treated with 101 in DMSO, sulfolane, 1,4-dioxane/H2O (1:1), dimethylformamide,
tetrahydrofuran, and in the presence of a variety of bases such as DABCO, DBU, DMAP,
Et3N and N-ethyldiisopropylamine. The optimum results were obtained when the reaction
was conducted in DMSO and catalyzed by DABCO obtained adduct 91a (65%) at ambient
temperature in 72 h. The adduct 91a was isolated as an E/Z mixture presumably because of
free rotation prior to elimination of DABCO in the product-forming step. The scope of this
21
Abstract
reaction was extended when aryl aldehydes 92-98 were reacted with 101 under optimized
reaction conditions obtained adducts 92a-98a, respectively, in moderate yields (Table 3).
The yields of all the products are reported as the combined yield of both geometrical
isomers. However, an attempt to extrapolate the protocol to less reactive aldehydes was not
fruitful.
Equation 1
O
R
CHO
+
O
OCH2CH3
101
DABCO
DMSO, rt
72 h, 52-68%
OCH2CH3
OH
R
The major product was unambiguously proved to be an E,E-isomer from NMR
studies. In all cases, the olefinic proton signals for E,Z and E,E isomers were clearly
distinguishable in their 1H NMR spectra, with all the olefinic protons for the E,E-isomer
resonating relatively downfield compared with the E,Z-isomer.29 The geometry of the
diene system was proved conclusively using separated pure isomers. For instance, the
major isomer of 91a was proved to be E,E based on a strong NOE between the benzylic
proton and Hγ, as well as between Hβ and Hδ which means that the propenyl chain and the
α-hydroxy benzyl moiety are in a cis-orientation (Fig. 4).
Figure 4
H
H
O
OH OCH2CH3
H
H
NO 2
Diagramatic representation of the NOEs of major isomer of
(E, E) compound 91a.
The minor isomer did not show these effects. However, the separation of the E/Z
mixtures present in all the adducts by chromatography was not an easy task. Hence, the
major isomer in all other adduct mixtures were assigned as E,E by analogy and the ratios
22
Abstract
were determined by the relative integration of the clearly distinguishable protons.
Additionally, the point of attachment was proved unambiguously by a chemical method
(Scheme 16).
Scheme 16
O
O
OCH2CH3
OH
H2/Pd-C
OCH2CH3
OH
EtOAc, rt, 4 h
R
R
99a, 99b ( Two sets of separable diastereomers)
91a, R =
NO 2
R=
NH 2
92a, R =
Cl
100a, 100b ( Two sets of separable diastereomers)
Cl
R=
Cl
Cl
Thus, 91a and 92a were subjected to exhaustive reduction (Pd–C/H2/EtOAc/rt)
obtained two sets of separable diastereomers 99a, 99b (84%, 1:1) and 100a, 100b (81%,
1:1), respectively, in good yields. 1H NMR analysis of each compound revealed that in
99a, Hα appeared at  2.60 and the benzylic proton at  4.73 integrating for one proton
each; while the same protons appeared at  2.62 and at  4.62 for compound 99b.
Similarly, the 1H NMR spectrum of 100a revealed the Hα proton at  2.78 and the
benzylicproton at  5.32; correspondingly, its diastereomer 100b showed the same protons
at  2.80 and  5.20, respectively. Though these experiments do not predict the initial site
of attack of DABCO onto the dienoate, nevertheless they unambiguously prove the site of
aldol reaction of the dienoate (-carbon) and the aldehydes. Subsequent elimination of
DABCO regenerates the olefin obtained -branched Baylis–Hillman adducts.
23
Abstract
Table3. Baylis-Hillman reaction of various aryl aldehydes with ethyl sorbate
catalyzed by DABCO in DMSO at room temperaturea
Entry
Productb
Substrate
1
91
O2N
2
92
Cl
CHO
CHO
Yieldc
E,E/E,Zd
91a
65
65/35
92a
68
70/30
93a
66
70/30
94a
61
65/35
Cl
3
93
4
94
CHO
CHO
NO 2
5
95
Cl
CHO
95a
64
70/30
6
96
F
CHO
96a
54
70/30
7
97
Ph
CHO
97a
52
70/30
8
98
NC
CHO
98a
65
70/30
a. All the reactions were conducted as described in the general experimental procedure in
the reference section.
b. All the products were thoroughly charectarized by their spectral data.
c. Isolated yields are mentioned as the combined mixture of geometrical isomers.
d. E,E/E,Z ratio was determined based on the 1H NMR spectra.
In summary, an efficient yet simple protocol for ready access to -branched
Baylis–Hillman adducts using ethyl sorbate as the Michael acceptor is reported for the first
time. The resulting adducts may find broad utility in the synthesis of bioactive compounds.
24
Abstract
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