Abstract
ABSTRACT
The thesis entitled “Studies directed toward the synthesis of 2-epibotcinolide,
lycoperdinoside A and B and stereoselective synthesis of a δ-lactone” consists of three
chapters.
CHAPTER I: Studies directed towards the synthesis of 2-epibotcinolide. This chapter is
divided into two parts:
PART A: Stereoselective synthesis of the nonalactone ring of 2-epi-8-epibotcinolide.
PART B: Stereoselective synthesis of the tetrahydropyran core and fatty acid side chain
of newly revised 2-epibotcinolide.
CHAPTER II: Studies directed towards the synthesis of lycoperdinoside A and B.
CHAPTER
III:
Stereoselective
synthesis
of
(3R,4S,5S,9S)-3,5,9-trihydroxy-4-
methylundecanoic acid δ-lactone.
CHAPTER I
PART A: Stereoselective synthesis of the nonalactone ring of 2-epi-8-epibotcinolide:
Botcinolides belong to a family of novel phytotoxic metabolites isolated from a
strain of plant pathogen Botrytis cinerea, a fungus that is responsible for both the socalled noble and grey rot in fruits. The pronounced biological activities of botcinolides as
phytotoxins with relatively low acute toxicity and their structures with a
polyhydroxylated nonalactone ring acylated with a fatty acid side chain, make them
attractive targets to synthetic organic chemists. The relative configurations of these
molecules have been deduced by extensive spectroscopic methods. We concentrated here
only to the synthesis of nonalactone ring 2, of 2-epibotcinolide 1.
Retrosynthetically, the molecule can be divided into nonalactone ring 2 and fatty
acid side chain 3 (Scheme 1). The targeted core 2 could be prepared from the seco acid 4
which can be prepared from the chiral allylic alcohol 7 following some functional group
manipulation, TiCl4 mediated aldol to get 6, highly selective dihydroxylation to 5 and
finally Mitsunobu cyclization.
i
Abstract
O
O
PMBO
OH
OH
O
O
OH
O
+
OH
OTBS
OTES
OTBS
O
OH
1
3
2
OTES
OH
OH
HO
2
O
OTBS
O
BnO
O
OTBS OPMB
4
TBSO
OH
OH
O
PMP
5
OTBS
BnO
BnO
OH
7
O
OH
6
Scheme 1
Benzylation of commercially available methyl (S)-3-hydroxy-2-methylpropionate
(8) with O-benzyl-trichloroacetimidate under acidic condition was followed by reduction
of ester with LAH to provide the chiral alcohol 9. Oxidation of 9 gave an aldehyde, which
OH
MeO
O
OH
BnO
8
9
OTBS
O
12
BnO
OTBS
BnO
BnO
COOEt
10
11
CHO
OTES
BnO
6 OH
O
TIPSO
OTES
OTES
BnO
+
OH
TIPSO
O 13
BnO
TIPSO
14
OH
14a
Scheme 2
was subjected to Wittig olefination using the stabilized ylide Ph3P=C(CH3)CO2Et to
furnish the E-olefin 10 exclusively. Compound 10 was next transformed into the aldehyde
11 in two steps- reduction with LAH to an alcohol followed by oxidation to the aldehyde.
Aldol reaction of 11 with the titanium enolate derived from the chiral ketone 12 gave the
desired syn isomer 6 as the major product in 6:1 ratio. The product was purified and
silylation of the allylic hydroxyl was carried out followed by protective group
ii
Abstract
manipulation, necessitated in order to achieve selective deprotection at a later stage, to
furnish the intermediate 13 (Scheme 2). Diastereoselective 1,3-syn hydride reduction of
the β-alkoxy ketone 13 with DIBAL-H gave the all syn product 14 as the major isomer
and anti product 14a as the minor isomer. The stereochemistry of major isomer 14 was
determined after three more steps.
Compound 14 was next treated with CSA to deprotect selectively the TES-group
and the resulting 1,2-diol was protected as its p-methoxybenzylidene acetal. The 1H NMR
spectrum at this stage showed a 3J coupling of 5.3 Hz between C7-H and C8-H supporting
the structure assigned to the major product during the hydride reduction. Finally, TIPSdeprotection with TBAF furnished 15. Cis-hydroxylation of 15 with OsO4 gave an all syn
triol 5. Selective silylation of the two secondary hydroxyl groups of 5 was followed by
debenzylation to furnish 16. Reductive ring opening of 16 gave 17 and 17a in 3:2 ratio.
The requisite intermediate 17 was diacylated to give 18. The tert-hydroxyl group of 18
was next protected as its TES-ether and the hydride reduction was carried out to deprotect
the acetates to furnish 19 (Scheme 3).
OH
O
14
BnO
15 OH
OH
OH
PMP
O
O
OH
HO
OTBS O
PMP
OH
OPMB
+
TBSO
OH
OAc
AcO
TBSO
O
HO
PMP
16
17
OH
5
OH
HO
TBSO
O
BnO
OTBS OPMB
18
TBSO
OTBS OH
OTBS OPMB (3:2)
17a
17
OTES
OH
HO
TBSO
OTBS OPMB
19
Scheme 3
A two step oxidation protocol from 19 was then followed to give the keto acid 20.
Diastereoselective reduction of the keto group of 20 using DIBAL-H furnished the syn
product 4. Although the stereochemistry of the newly generated C 8-OH was not
determined in this stage, based on earlier work on the reduction of α-alkoxy ketones, it
was assumed to have the desired S stereochemistry. With the requisite seco acid 4 in
hand, the stage was set to carry out the crucial Mitsunobu macrolactonization reaction.
Unfortunately we were not successful to prepare the targeted lactone moiety 2. But the
iii
Abstract
same seco acid 4 in Yamaguchi macrolactonization reaction provided 21 (Scheme 4), the
nonalactone core of 2-epi-8-epibotcinolide.
OTES
OTES
O
HO
HO
19
O
OH
O
TBSO OTBS OPMB
20
OTBS OPMB
4
PMBO
TBSO
PMBO
OTBS
OTBS
O
19
O
X
OTES
OTBS
(Not formed)
2
OTES
OTBS
21
O
O
Scheme 4
PART B: Stereoselective synthesis of the tetrahydropyran core and fatty acid side
chain of newly revised 2-epibotcinolide:
The structure of 2-epibotcinolide was revised by Nakajima group and it was
revealed that the revised structure 22, had a highly substituted pyran moiety acylated with
a long chain fatty acid. Retrosynthetic analysis gave two segments- substituted tetrahydro
pyran 23 and fatty acid side chain 24. The intermediate 23 was prepared from the epoxide
26 and the compound 24 from the chiral epoxide 25 stereoselectively (Scheme 5).
OH
HO
HO
O
O
O
OH
TBSO
O
OTBS
OH
+
TBSO
O
OTBS 23
22
HO
24
O
O
HO
HO
O
OPMB
OBn
25
O
26
Scheme 5
Synthesis of tetrahydropyran moiety 23:
Aldol reaction of the commercially available aldehyde methacrolein 28 with the
titanium enolate derived from the chiral ketone 27 gave the desired syn isomer 29 as the
major product in 7:1 ratio. The products were purified and silylation of allylic alcohol 29
iv
Abstract
followed by functional group manipulation gave the intermediate 30. Diastereoselective
1,3-syn hydride reduction of 30 with DIBAL-H gave a mixture of all syn product 31 and
anti product 31a. The mixture of compounds 31 and 31a was treated with CSA to
deprotect selectively the TES-group to furnish diol 32 and diol 32a in major and minor
amounts, respectively. Compound 32 was converted to its PMP-acetal and followed by
dihydroxylation to produce the anti isomer 33. The free primary hydroxyl group of 33
was next protected as TBS-ether followed by reductive ring opening of the corresponding
p-methoxybenzylidine acetal to furnish selectively 34 (Scheme 6).
28
O
OTES
OTBS
OTBS
CHO
27
OH
30
OTES
TIPSO
OH
OH
+
OH
TIPSO
31 and 31a
(9:1)
OH
TIPSO
32
OH
32a
O
OH
32
O
TIPSO
O
29
OH
HO
OH
TBSO
TIPSO
O
PMP
TIPSO
33
OPMB
34
Scheme 6
The diol 34 was in our hand to carry out the crucial six member cyclization. The
secondary hydroxyl group was selectively mesylated followed by concomitant
cycloetherification to afford 35 in complete stereogenic manner. The selective TBS-group
deprotection of 35 was followed by two step reaction protocol- oxidation and Wittig
olefination with a stabilized ylide Ph3P=CHCO2Et to provide the α,β-unsaturated ester 36
exclusively in trans geometry. Next the reduction of ester functionality with DIBAL-H
and TBAF mediated TIPS deprotection gave the diol 37. Sharpless asymmetric
epoxidation of intermediate 37 furnished the epoxide 26 which on further treatment with
Me2CuLi, followed by NaIO4 mediated oxidative cleavage produced the triol 38. The triol
38 was persilylated and selective deprotection of PMB-group by DDQ provided the
tetrahydropyran moiety 23 (Scheme 7).
v
Abstract
TIPSO
TIPSO
EtO
34
TBSO
O
O
O
35
HO
HO
OPMB
OPMB
HO
OPMB
36
HO
OPMB
HO
HO
O
37
O
O
O
OH
26
TBSO
TBSO
OPMB
38
OH
O
OTBS
23
Scheme 7
Synthesis of side chain moiety 24:
Synthesis of fatty acid side chain 24 started from the commercially available
racemic epichlorohydrin 39. Benzylation was followed by Jacobsen’s hydrolytic kinetic
resolution of compound 39 to provide the required enantiomerically pure epoxide 25 and
Cl
O
39
+ HO
OBn
O
OBn
OH
40
25
OH
OBn
25
OTBS
OH
42
41
OTBS
OH
24
O
Scheme 8
diol 40. Cu(I)-mediated regioselective epoxide opening of 25 furnished the alcohol 41.
The compound 41 (Scheme 8) was converted to TBS-ether which on debenzylation gave
intermediate 42. Oxidation of primary alcohol and subsequent Wittig olefination gave
α,β-unsaturated ester which was saponified with LiOH to produce the required acid 24.
vi
Abstract
CHAPTER II
Studies directed towards the synthesis of lycoperdinoside A and B:
Lycoperdinoside A (1) and B (2) were isolated by Řezanka et al from the slime
mold Enteridium lycoperdon. Retrosynthetic analysis reveals that the aglycon part 3 can
be synthesized from the intermediates 4 or 7. It was seen that the important intermediates
4 and 7 could be synthesized by Negishi or Stille coupling reactions from the two pairs of
coupling partners 5, 6 or 8, 6 respectively. The key intermediate 4 alternatively could be
prepared from the fragments 9 and 10 in Suzuki approach (Scheme 1).
O
O
O
2
9
O
1: R=
O
OH
10
OR
O
21
O
O
O
O
2: R=
O
O
O
OH
O
3
OH
OR1
O
TBDPSO
O
OR1
I
5
OR2
4
+
OH
OR1 OR1
[R1, R2= protecting group]
O
TBDPSO
OH
7
O
O
TBDPSO
I
8
O
6
+
OH
OTBS
O
O 6
OTBS
4
OBn
I +
I
10 OTBS OTBS
9
Scheme 1
Synthesis of C3-C11 moiety 18:
Commercially available (S)-3-hydroxy-2-methylpropionate (11) was transformed
into two differently protected alcohols 12 and 13, which were then linked together
through an acetylene. Oxidation of 12 was followed by the conversion of the aldehyde
into an acetylenic group. The anion generated from this acetylenic intermediate was next
vii
Abstract
added to the aldehyde derived from the alcohol 13 to give the desired anti isomer 14 and
syn isomer 14a in almost equal amounts. Controlled hydrogenation of the acetylenic
moiety 14 was achieved using P2-Ni to give 15. Silylation of 15 was followed by
selective primary TBS-group deprotection to give 16. Tosylation of the free hydroxyl
group of 16 was followed by incorporation of cyano group to afford 17. The cyano
compound 17 was subjected to three consecutive reactions- reduction of cyano to
aldehyde, conversion of aldehyde to dibromo and finally exchange of bromo to acetyleneto produce compound 18. Unfortunately, acetylene 18 could not be converted to
intermediate 5 (Scheme 2) in Negishi reaction condition.
HO
MeO
OTBS
12
OH
O
HO
TBDPSO
14a
OTBS
(1:1)
OH
14
HO
+
14
OTBS
TBDPSO
OH
13
11
TBDPSO
12
TBDPSO
OTBS
OH
TBDPSO
16
15
OTBS
OTBS
CN
TBDPSO
OTBS
X
TBDPSO
5
18
17
Scheme 2
Synthesis of C7-C11 moiety 8:
Commercially available (R)-3-hydroxy-2-methylpropionate (19) was transformed
into protected alcohol 20. Almost following the same reaction sequences described for
MeO
OH
O
TBDPSO
19
TBDPSO
OH
21
20
TBDPSO
TBDPSO
I
8
22
Scheme 3
viii
CN
Abstract
synthesis of compound 18 from compound 16 (Scheme 2), the alcohol 20 was converted
to acetylene compound 22 which finally converted to the vinyl iodide 8 (Scheme 3)
following the Negishi protocol.
Synthesis of C12-C21 moiety 6:
Our synthesis started with the commercially available propane-1,3-diol 23.
Compound 24 was prepared from the diol 23 by standard chemical transformation. The
α,β-unsaturated ester 24 (Scheme 4) was reduced to an alcohol which further on oxidation
provided an aldehyde 25. Non-Evans aldol reaction between the Ti-enolate derived from
the thiooxazolidine chiral auxiliary 26 and the aldehyde 25 furnished compound 27.
Compound 27 was converted to epoxy alcohol 28 following three steps reaction
sequences- removal of chiral auxiliary, selective primary hydroxyl protection and finally
OH
HO
BnO
25
Bn
25
O
N
26
CHO
24
Bn
O
BnO
COOEt
23
N
BnO
OH O
27
S
O
O
BnO
S
28
OTBDPS + BnO
BnO
OH OH
29
OH
OTBDPS
OH OH
30
OTBDPS
OTBDPS
HO
30
O
O
O
O
32
31
OH
COOEt
O
OTBDPS
O
O
33
O
6
Scheme 4
Sharpless epoxidation. The trisubstituted chiral epoxy alcohol 28 was subjected to crucial
radical mediated epoxide opening reaction using Cp2Ti(III)Cl to give compounds 29 and
30. Compound 31 was prepared from compound 30 following routine functional groups
manipulation in four steps. The primary alcohol 31 was oxidized to its corresponding
aldehyde. The resulting aldehyde on reaction with CBr4 and Ph3P provided a dibromo
compound which was reacted with nBuLi and MeI to give the substituted acetylene 32.
ix
Abstract
Compound 33 was prepared from compound 32 in three steps- desilylation, oxidation and
finally Wittig olefination. The ester functionality as well as olefin moiety of compound 33
was converted to the saturated alcoholic product 6 (Scheme 4) using LiBH4 as the
reducing agent.
Synthesis of C1-C9 moiety 9:
Tosylation of 16 gave the primary tosylate, which was transformed into the iodide
34. Our failure to selectively desilylate the primary O-silyl group in 34 required us to
deprotect both silyl groups, reprotect them as TBS-ethers and then carry out the desired
selective desilylation to give 35. Oxidation of 35 was followed by selective Z-olefination
using the ketophosphonate, (CF3CH2O)2P(O)CH2CO2Me, to give 36 as major product in
ca 10:1 ratio. The minor isomer could be removed chromatographically after the
reduction step. Reduction of 36 with DIBAL-H was followed by silylation to furnish the
targeted intermediate 9 (Scheme 5).
OTBS
16
OTBS
I
TBDPSO
35
34
OTBS
OH
COOMe
OTBS
OTBS
OTBS
I
36
I
HO
I
I
37
9
Scheme 5
Synthesis of C10-C21 moiety 10:
Our synthesis of fragment 10 was started from the previously prepared alcohol 31.
Tritylation of 31 gave 38, which was converted to α,β-unsaturated ester 39 in three stepsdesilylation, oxidation and followed by Wittig olefination. Reduction of ester 39 provided
a saturated alcohol which was protected to Bn-ether 40. Acid treatment of 40 removed the
trityl as well as the acetonide protection to give the triol 41. Compound 41 was converted
to ester 42 following routine functional groups manipulations and standard chemical
conversions. Reduction of the ester group of 42 gave the alcohol 43, which was converted
to acetylene 44 (Scheme 6).
x
Abstract
TrO
OTBDPS
TrO
31
O
COOEt
O
O
39
38
O
OBn
HO
OBn
TrO
OH
O
40
OH
41
OBn
HO
OBn
EtOOC
TBSO
O
OTBS
OTBS
TBSO
42
43
OBn
OTBS
TBSO
44
Scheme 6
Methylation of the terminal acetylene moiety of 44 and conversion of the resulting
internal alkyne to the targeted 10 using hydrozirconation-iodine sequence failed to
provide the desired product. Even Pd(0)-catalysed hydrostannylation did not yield the
OBn
44
HO
TBSO
OTBS
45
AcO
OBn
AcO
OTBS
TBSO
46
AcO
OBn
Bu3Sn
OBn
I
OTBS
47
terminal:internal (3:1)
TBSO
TBSO
OTBS
48
Br
HO
OBn
I
TBSO
OBn
I
OTBS
10
OTBS
TBSO
50
49
Scheme 7
expected result. Hydroxymethylation of 44 gave the propargylic alcohol 45, which was
acylated next to give acetate 46. Hydrostannylation of 46 produced terminal stannylated
product 47 as the major product in 3:1 ratio. The minor product could be separated easily
by column chromatography after two steps. Iodination of 47 gave the vinyl iodide 48,
xi
Abstract
which required four more steps- deacylation, mesylation, bromination and finally
reduction with super hydride-to furnish the targeted fragment 10 (Scheme 7).
CHAPTER III
Stereoselective synthesis of (3R,4S,5S,9S)-3,5,9-trihydroxy-4-methylundecanoic acid
δ-lactone:
During the studies of the biosynthesis of spinosyn, a family of agriculturally
important molecule, a truncated version of the spinosyn polyketide synthase was
expressed in the heterologous host Saccharopolyspora erythraea JC2. This resulted in the
formation of a novel pentaketide lactone that was identified as (3R,4S,5S,9S)-3,5,9trihydroxy-4-methylundecanoic acid δ-lactone 1. Retrosynthetically, compound 1 could
be prepared from the suitably protected diol 2 having a ‘2-methyl-1,3-diol’ moiety. The
radical mediated anti-Markovnikov opening of trisubstituted chiral epoxy alcohol 3 using
Cp2Ti(III)Cl to construct the three stereocentres of 1. The trisubstituted syn epoxy alcohol
3, in turn, could be synthesized by mCPBA epoxidation of the unreacted R-allylic alcohol
obtained during a Sharpless kinetic resolution of compound 4 (Scheme 1).
OH
OBn
OH
O
O
OH
OTBDPS
O
2
1
OBn
OH
OBn
OH
OH
OTBDPS
OTBDPS
4
3
Scheme 1
Ethylation of commercially available propargylic alcohol 5 gave compound 6
which after three steps-RedAl reaction, Sharpless epoxidation and finally Red-Al
mediated epoxide opening, afforded the diol 7. Compound 8 was prepared from the diol 7
in three steps- protection of primary hydroxyl as TBDPS-ether, benzylation of the
secondary hydroxyl group and finally desilylation using TBAF. Swern oxidation of the
primary hydroxyl group of 8 furnished an aldehyde, which was reacted with stabilized
ylide Ph3P=CHCO2Et to give α,β-unsaturated ester 9. The ester 9 was reduced to the
saturated alcohol 10 using LiBH4, prepared in situ from NaBH4 and LiCl. Oxidation of 10
to an aldehyde and subsequent Horner-Wadsworth-Emmons olefination of the resulting
xii
Abstract
aldehyde with the Li-anion of ketophosphonate 11, furnished E-enone 12 with complete
selectivity. The enone 12 was reduced with NaBH4 to give the allylic alcohol 4. Sharpless
kinetic resolution of 4 furnished the chiral alcohol 13 and unrequired epoxide 14
(Scheme 2).
OBn
OH
5
OH
OH
6
OH
7
O
OBn
OBn
O
CO2Et
9
O
O
O
P
OBn
OH
OTBDPS
12
OTBDPS
4
OBn
OH
OTBDPS
11
OH
10
OBn
OH
8
OBn
O
OH
OTBDPS +
OTBDPS
13
14
Scheme 2
The diastereoselective epoxidation of 13 using mCPBA gave syn 3 as the major
product and anti 15 as the minor product. With the trisubstituted chiral epoxy alcohol 3 in
our hand, the stage was set to carry out the crucial Ti(III)-mediated epoxide opening
reaction. Treatment of 3 with Cp2Ti(III)Cl provided the expected all-syn ‘2-methyl-1,3diol’-containing intermediate 2. Protection of diol 2 as acetonide and followed by
OBn
O
13
OH
OBn
O
OTBDPS +
OTBDPS
3
OBn
OH
OH
15
OH
OBn
3
O
O
OTBDPS
OH
2
16
OH
OBn
O
O
O
OBn
1
OMe
O
O
18
17
Scheme 3
TBAF-mediated desilylation furnished the alcohol 16. Oxidation of the primary hydroxyl
of 16 in two steps gave the acid, which was esterified with CH2N2 to provide the methyl
xiii
Abstract
ester 17. Treatment of 17 with aqueous acetic acid led to deprotection of the acetonide
group with concomitant cyclization to furnish the six-membered lactone 18. Finally
hydrogenolysis of compound 18 using Pd-C as catalyst afforded the desired δ-lactone 1
(Scheme 3).
xiv