Abstract
This thesis entitled “Synthesis of New Glycosubstances, attempted
synthesis of Isoavenaciolide and New Reagents for the conversion of
alcohols into p-methoxybenzyl ethers” is divided into three chapters.
Chapter 1: Synthesis of New Glycosubstances
This chapter is divided into two sections.
Section A describes the synthesis of carbon-carbon linked disaccharides using
furan as masked sugar synthon and new furyl sugars as intermediates for ‘new
glycosubstances’.
Section B deals with the description on the synthesis of acetylenic new
glycosubstances, which are useful intermediates for the synthesis of New Chemical
Entities of therapeutic value.
Section A: This section is further divided into two parts.
Part I: Synthesis of C(4)-C(5) linked (L)- and (D)-disaccharides
from ‘diacetone glucose’
The role of carbohydrates in nature goes under the broad heading of
“Glycobiology”1, an eye-opening subject encompassing many areas of interest
particularly to the synthetic organic chemist and more recently receiving attention from
a therapeutic drug development aspect2.
OMe
OMe
AcO
OMe
AcO
O
AcO
O
O
AcO
O
O
H
OAc
MeO
1
O
O
AcO
O
O AcO
H
OAc
MeO
2
O
O
H
OAc
MeO
3
O
The C-glycosides3, where a methylene group replaces the interglycosidic oxygen
atom, are non-metabolisable analogues of natural disaccharides and represent an
interesting class of compounds for therapeutic studies. Synthetic C-glycosyl compounds
are starting chiral synthons, suitable for the synthesis of complex molecules, as they
contain a large number of chiral centres and functional groups. In a broader context, this
subclass also includes examples in which the monosaccharide units are connected either
directly or by way of more extended as well as substituted carbon spacers.
1
Abstract
In the present study, addition of 2-furyl lithium to the enantiopure aldehyde
template 4 obtained from DAG and further transformations was identified in offering a
direct access to the disaccharides 1, 2 and 3, where the new sugar unit has been
constructed from the furan moiety, while chirality was induced from the parent sugar
template.
Accordingly, addition of 2-furyl lithium to the known aldehyde 4 (Scheme 1)
afforded the derivatives 5a and 5b as a diastereomeric mixture separable by column
chromatography. However, this mixture was successively converted into the major
diastereomer 5a by a two step synthetic sequence viz a) oxidation of the diastereomeric
mixture under Swern oxidation conditions and b) subsequent reduction of the ketone 6
with NaBH4.
Scheme 1
OHC O
OM e O
4
OH
O
OH
O
O
OM
e O
H
5a
O
a
O
+
H
5b
O
OM e O
b
6
O
c
O
O
O
OM
e O
H
O
Reagents: a) 2-furyl lithium, THF, -780C; b) (COCl)2, DMSO, Et3N, CH2Cl2, -780C; c)
NaBH4, MeOH, 00C.
Oxidative unmasking of furan4 with Br2-pyridine in aqueous acetone gave the
lactols 7 (Scheme 2), which on reaction with Ag2O-MeI, was subsequently converted
into an inseparable mixture of -O-methyl pyranosides 8.
Scheme 2
OR
5a
OM e
O
a, b
OM e
O
O
c
O
O
O
H
OH
M eO
9
O H
O
M eO
7 R = H; 8 R = Me
OM e
OM e
O
+
O
O
+
O
O
O
H
OH
M eO
O
10
H
OH
M eO
O
O
11
OM e
RO
10
d
O
O
H
OAc
M eO
12
O
e, d
O
O
RO
O
H
OAc
O
M eO
13 R = H; 1 R = Ac
O
Reagents: a) Br2, pyridine, aqueous acetone; b) Ag2O, MeI; c) NaBH4, MeOH, 00C; d)
Ac2O, pyridine; e) OsO4, t-BuOH: THF.
2
Abstract
Stereoselective reduction of 8 using NaBH4 in MeOH afforded after
chromatographic purification, the two -glycosides 9 (minor) and 10 (major) in 3:5
ratio while the -anomers 11 were not separable. The major isomer 10 was subjected to
acetylation (Ac2O, pyridine) to give the acetate 12, which on selective5 cis
dihydroxylation of the double bond using OsO4-NMO in t-BuOH-THF gave the diol 13.
Finally, acetylation of the diol 13 (Ac2O, pyridine) gave the tri-acetate 1.
Similar functional group transformations performed on the minor isomer 5b
resulted in obtaining 2, the antipode of 1 and 3. Accordingly, oxidative ring opening of
5b gave the lactols 7a (Scheme 3), which were subsequently converted into the methyl
glycosides 8a. Reduction of the enones 8a with NaBH4 and chromatographic separation
gave the allylic alcohols 9a (major) and 10a (minor) in 2:1 ratio. Acetylation of 9a and
chromatographic purification afforded 11a (major) and 11b (minor). These were
subsequently submitted to catalytic osmylation to afford the diols 12a and 12b, which
on acetylation furnished the respective tri–acetates 2 and 3.
Scheme 3
OR
5b
O
a, b
OM e
OM e
O
O
c
O
H
O
+
O
O
H
OH
M eO
O
M eO
7a R = H; 8a R = Me
O
O
H
OH
M eO
O
9a
OM e
O
O
10a
OM e
RO
O
O
O
9a
d
OAc
M eO
O
e, d
O
OAc
O
M eO
12a R = H; 2 R =Ac
O
11a
OM e
O
RO
+
OM e
RO
O
O
OAc
M eO
O
e, d
O
O
RO
O
OAc
O
M eO
12b R = H; 3 R =Ac
O
11b
Reagents: a) Br2, pyridine, aqueous acetone; b) Ag2O, MeI; c) NaBH4, MeOH, 00C; d)
Ac2O, pyridine; e) OsO4, t-BuOH: THF.
3
Abstract
Part II: Synthesis of furyl sugars – intermediates for ‘new
glycosubstances’
In the preceding section, D-glucose was efficiently converted into furyl sugars
(Scheme 1).
Scheme 1
OH
OH
O
O
OHC
O
O
O
O
a
H
O
MeO 1
MeO 2a
O
O
O
+
O
H
O
MeO 2b
O
b
O
H
O
MeO 3
O
Reagents: a) 2-furyl lithium, THF, -780C; b) (COCl)2, DMSO, Et3N, CH2Cl2, -780C.
Similarly, galactose diacetonide 4 was subjected to oxidation to give 5, which on
reaction with 2-furyl lithium gave 6 (Scheme 2) as an inseparable mixture of isomers.
Further oxidation of 6 under Swern conditions gave the keto derivative 7.
Scheme 2
O
OH
O
HO
O
O
O 4
OHC
O
a
O
O
O
O
O
b
O
O
O
O5
O
O
H
O 6
a
O
O
H
O
O
O 7
Reagents: a) (COCl)2, DMSO, Et3N, CH2Cl2, -780C; b) 2-furyl lithium, THF, -780C.
In a further study, aldehyde 5 (Scheme 3) was converted into acetylene 9 through 8.
Reaction of 9 with 2-furaldehyde gave the furyl sugar 10.
Scheme 3
Reagents: a) PPh3, CBr4, CH2Cl2, 00C; b) n-butyl lithium, THF, -780C; c) n-butyl lithium,
2-furaldehyde, THF, -780C.
Likewise, the known olefin 11 (Scheme 4) was subjected to 1, 3-dipolar
cycloaddition reaction with the oxime derived from furaldehyde to give the adduct 12,
which on reduction using LAH afforded the furyl derivative 13.
4
Abstract
Scheme 4
HO
HO
O
OMe
O
O
OMe
H
a
NHR OR
N
O
12
O
11
O
O
b
O
O
OMe
c
O
OMe
H
O
O
O
13 R = H
O
O
0
Reagents: a) PPh3, I2, Imidazole, Toluene, 110 C; b) furaldoxime, NCS, Et3N, CH2Cl3,
RT; c) LAH, ether, 00C.
In a similar study, the known alcohol 14 (Scheme 5) on oxidation with DMSO(COCl)2 gave the aldehyde 15, which on reaction with 2-furyl lithium afforded 16a and
16b. Further oxidation of the isomeric mixture furnished the keto derivative 17.
Scheme 5
O
O
O
OH
O
O
O
a
O
O
OH
O
O
14
O
b
O
CHO
O
O
c
O
OH
O
O
H
O
O
+
O
OH
O
O
OH
16a
b
O
OH
H
O
H
O
O
OH
16b
15
O
O
O
d
O
O
17
Reagents: a) TMSOI, t-BuOK, DMSO; b) (COCl)2, DMSO, Et3N, CH2Cl2, -780C; c) 2furyl lithium, THF, -780C; d) NaBH4, MeOH.
The thus prepared furyl sugars are very useful intermediates for the synthesis of Cdisaccharides, glycosyl hydroxy, keto and amino acids, aza-C-disaccharides and others.
5
Abstract
SECTION
B:
Synthesis
fluorophenoxymethyl)-3,
of
(2R,
5R)-5-Ethynyl-2-(p-
4-O-isopropylidinetetrahydrofuran
from
mannose diacetonide:
Chiral tetrahydrofuran based compounds such as A and several 2, 5-disubstituted
tetrahydrofurans with biological activity were found in nature6. The research for the
development of new drugs based on such chiral tetrahydrofurans resulted in several
analogues having anti-inflammatory activity. Such a research resulted in a
therapeutically interesting tetrahydrofuran A and its stereoisomers as potent 5-LO
inhibitors7. In furthering the research on the development of new chiral furans with
potent activity, synthesis of 1 was reported starting from ‘mannose diacetonide’.
OH
HO
O
O
O
F
O
R
R
F
A R = CH2CH2N(OH)CONH2
1 R = CH2CH2N(OH)CONH2
1, is a tetrahydrofuran derivative related to A, with a dihydroxy group. The
synthesis of acetylene 2 would serve as a key intermediate for the synthesis of NCEs
and radio labelled compounds for the metabolic studies. As seen from the Scheme 1, it
was envisaged that 2 could be made from ‘mannose diacetonide’ 3 by the
transformations as indicated.
Scheme 1
F
introduce
CH2OAr
O
O
O
H
O
OH
O
O
convert to
acetylene
O
O
O
3
2
Accordingly, the known alcohol 4 (Scheme 2) was subjected to tosylation using pTsCl and Et3N in CH2Cl2 to give 5, which on etherification with p-fluorophenol using
NaH in dry DMF gave 6 in 53% yield. Deprotection of isopropylidene functionality in 6
with catalytic Conc. HCl in MeOH at room temperature afforded the diol 7, which on
oxidative cleavage with NaIO4 in the presence of aqueous NaHCO3 in CH2Cl2 gave the
corresponding aldehyde 8 (79%). Finally, aldehyde 8 on treatment with CBr4 and Ph3P
6
Abstract
in CH2Cl2 at room temperature afforded dibromo compound 9, which on further
reaction with n-BuLi gave 2 in 77% yield.
Scheme 2
O
O
O
O
O
O
OH
3
OR
O
b, c
a
O
F
HO
HO
d
O
O
O
O
O
5 R = Ts
4
OHC
7
6 R = 4-F-Ph
Br
F
Br
F
O
O
e
f
O
O
O
g
O
H
O
O 8
2
O 9
Reagents: a) TMSOI, t-BuOK, DMSO, 0ºC to RT, 1 h; b) p-TsCl, Et3N, CH2Cl2, RT, 4 h;
c) 4-F-C6H4OH, NaH, DMF, 80ºC, 5 h; d) Conc. HCl, MeOH, RT, 2 h; e) NaIO4, saturated
aqueous NaHCO3, CH2Cl2, RT, 6 h; f) CBr4, Ph3P, CH2Cl2, 0ºC to RT, 30 min; g) n-BuLi,
THF, -78ºC to RT, 2 h.
Thus, in the present study, the acetylene 2 was prepared by the introduction of
hydroxymethylene substituent at C-1 of mannose diacetonide while C-5 was converted
to acetylene moiety.
In a further study, the change of the sequence, i.e., introduction of -CH2OAr group
at C-5 position and acetylenic substituent at C-1 position results in a different isomer of
2. Accordingly, 3 (Scheme 3) was treated with diphenyldisulphide and TBP in
dichloromethane to afford the thioglycoside 10. 10 was hydrolysed with catalytic Conc.
HCl in MeOH for 2 h, to afford the diol 11, which on oxidative cleavage with NaIO4 in
aqueous dichloromethane afforded the aldehyde 12.
Scheme 3
O
O
O
OH
O
O
b
O
O
10
O
SPh
O
O
11
d
O
12
O
O
O
SPh g
O
O
OHC
SPh c
HO
O
RO
SPh e, f
HO
13
SPh
O
O
O
O
O
a
O
3
HO
O
O
SO 2Ph
O
F
16
14 R = Ts
15 R = 4-F-C4H4
O
O
F
O
O
R
17 R =
-CH2CH2OMPM
Reagents: a) PhSSPh, Bu3P, CH2Cl2; b) H+, MeOH; c) NaIO4, aqueous CH3CN; d) NaBH4,
MeOH; e) p-TsCl, Et3N, CH2Cl2; f) 4-F-PhOH, NaH, DMF, 80ºC; g) Ammonium
molybdate, H2O2, EtOH.
7
Abstract
Reduction of 12 with NaBH4 in MeOH gave the hydroxy compound 13. Tosylation
of the hydroxyl group in 13 using TsCl and Et3N in CH2Cl2 afforded 14, which on
reaction with 4-F-C6H4OH using NaH in DMF gave 15. The next step was to oxidise
thiophenyl substituent to sulfone funtionality, which can be substituted with the
required R-group through zinc mediated coupling. Oxidation of thiophenyl substituent
in 15 was achieved with ammonium molybdate and H2O2 in ethanol affording the
sulfone 16. However, efforts to substitute sulfone moiety in 16 with zinc mediated
alkynyl bromide coupling met with failure in offering 17.
CHAPTER 2: New reagents for the conversion of alcohols into pmethoxybenzyl ethers
This chapter is dealt with the description of development of new methodologies for
the conversion of alcohols into p-methoxybenzyl ethers using the lanthanide triflates
such as Yb(OTf)3 and Y(OTf)3 as Lewis acid catalysts and with newly developed
reagents.
This chapter is further divided into two sections.
SECTION A: p-Methoxybenzyl acetate (PMBA)- A new reagent for the
conversion of alcohols into p-methoxybenzyl ethers through Yb(OTf)3
catalysis
The p-methoxybenzyl group is frequently used for the protection of alcohols, which
is introduced by NaH and p-methoxybenzyl bromide in the conventional method where
base sensitive groups are not compatable. Herein, simpler method for the preparation of
PMB-ethers is described employing milder conditions wherein acid and base sensitive
groups do survive the reaction conditions.
A new reagent, p-methoxybenzyl acetate (PMBA) was prepared and developed as a
new and facile reagent for PMB protection. p-Methoxybenzyl alcohol was treated with
Ac2O in pyridine to give PMBA. Alcohol was subjected to reaction with PMBA and 5
mol% Yb(OTf)3 in dichloromethane at room temperature to give the PMB-ethers, where
both acid and base sensitive groups survive under the reaction conditions.
8
Abstract
ROH
Yb(OTf)3
MPMOAc
CH2Cl2, RT
ROMPM
eq (1)
R = alkyl, terpenoidal, sugar etc.
The generality of the reaction was established by studying the protection of a wide
variety of alcohols such as aliphatic, terpenoidal and sugar derivatives.
SECTION B: Y(OTf)3 mediated conversion of alcohols into pmethoxybenzyl ethers with PMBA and PMB-silyl ethers
Two new reagents, t-butyldimethylsilyl p-methoxybenzyl ether (PMB-OTBS) and
t-butyldiphenylsilyl p-methoxybenzyl ether (PMB-OTPS) were prepared and used for
the preparation of PMB-ethers. p-Methoxybenzyl alcohol was treated with TBS-Cl and
imidazole in CH2Cl2 to give PMB-OTBS, while treating PMB-OH with TPS-Cl under
same conditions furnished PMB-OTPS.
PMB protection of a variety of alcohols was performed using the rare earth triflate
Y(OTf)3 in catalytic quantity employing the newly developed reagents PMBA, PMBOTBS and PMB-OTPS, in an extension to the protocol developed in our group8,
wherein PMB-OH was employed as a reagent for the formation of PMB-ethers.
Comparative studies for better choice of the reagents and catalysts are recorded.
ROH
Y(OTf)3
MPMOR'
CH2Cl2, RT
ROMPM
eq (2)
R = alkyl, terpenoidal, sugar etc.
R' = Ac, TBS, TPS
The generality of the reaction was established by studying the protection of a wide
variety of alcohols such as aliphatic, terpenoidal and sugar derivatives.
9
Abstract
CHAPTER 3: Radical mediated approaches for the attempted
synthesis of isoavenaciolide
This chapter describes the synthetic efforts towards the synthesis of isoavenaciolide
and is further divided into two sections.
SECTION A: Attempted synthesis of isoavenaciolide starting from
‘Diacetone glucose’ (DAG)
Isoavenaciolide9 1, avenaciolide10 2 and ethisolide9 3 (Figure 1) are secondary
metabolites isolated fro Asperigillus and Pencillium fermentation broths, which inhibit
fungal growth. Carbohydrates are appropriate starting materials and intermediates for
the synthesis of enantiomerically pure compounds (chiron approach)11.
Figure 1. Metabolites isolated from Asperigillus and Pencillium fermentation broths
The apparent structural similarity of 1 to DAG and the presence of exo methylene
group in the unique bis-butyrolactone skeleton prompted us to evolve a strategy using
radical route for its synthesis. The utility of radical12 reactions on carbohydrate13
derived ‘chiral templates’, a fascinating protocol, particularly for the creation of cisfused bicyclic systems has been well documented in our group earlier, where the
syntheses14-16 of avenaciolide, discosiolide, 4-epi-ethisolide, sporothriolide and (-)canadensolide has been successfully achieved. From the antithetic analysis of 1
(Scheme 1), it was envisaged that the bicyclic system 4 would conveniently furnish 1,
and 4 in turn could be easily made by radical cyclisation of xanthate 5 that is obtained
from DAG.
Scheme 1
C8H17 O
1
OM e
H
H
C8H17 O
O
O
C8H17
O
O
H
O
4
OM e C8H17
M eS(S)CO
O
AcO
5
10
O
6
O
7
O
DAG
Abstract
Accordingly, the aldehyde 9 prepared from the triol 8 was converted to 10 (Scheme
2) through Wittig olefination and hydrogenation. Oxidation of 10 gave 7, which on
reaction with Ac2O/pyridine gave the enol acetate 11. Catalytic hydrogenation of 11
afforded the derivative 6. Deacetylation of 6 followed by treatment of 12 with PMB-Br
furnished 13. Methanolysis of 13 afforded 14, which on reaction with propargyl
bromide gave 15. Treatment of 15 with DDQ and subsequent reaction of 16 with CS2MeI-NaH gave 5. However, attempts to cyclise the xanthate 5 into the fused bicyclic
system 4 met with failure.
Scheme 2
H
HO
HO
OHC
O
O
H
HO
O
O
a
HO
O
C8H17
C8H17
O
O
d
C8H17
e
O
C8H17
g
O
PM BO
13
OM e
PM BO
O
C8H17
k
h
14
O
OH
i
PM BO
O
OM e
j
HO
O
O
16
OM e
O
H
H
O
5
O
12
C8H17
O
OM e
C8H17
H
O
HO
O
6
O
f
15
OM e
M eS(S)CO
O
10 R = C8H17
C8H17
C8H17
O
O
HO
O
AcO
O
c
O
O
c
11
O
H
C8H17
O
O
7
O
9a
AcO
O
O
R
O
HO
O
9
8
b C6H13
O
4
Reagents: a) NaIO4, aqueous CH2Cl2; b) C6H13P+Ph3Br-, n-BuLi, THF; c) H2, 5% Pd/C,
EtOAc; d) PDC, NaOAc, Ac2O, CH2Cl2, 40ºC; e) Ac2O, pyridine; f) Na, MeOH; g) NaH,
PMB-Br, THF; h) H+resin, MeOH, 40ºC; i) NaH, 1-bromopropyne, THF; j) DDQ, aqueous
CH2Cl2; k) NaH, CS2, MeI, THF.
SECTION B: Attempted synthesis of isoavenaciolide from ‘xylose
monoacetonide’
From the retrosynthetic analysis of 1 (Scheme 1), it was envisaged that a general
strategy could be arrived at where the alkyl chain could be incorporated at a later stage
on C-1 position i.e., after acquiring the required bicyclic system as in 3, while the C-5
carbon could be converted into lactone moiety. The bicyclic system 3 could be easily
11
Abstract
envisaged by radical cyclisation of xanthate 4, as is evidenced by the lack of steric
hindrance offered by the existing functional groups. Xanthate 4 could be obtained in
usual functional group manipulations of the xylose monoacetonide 5.
Scheme 1
OH HO
1
H
O
C8H17 RO
HO
H
OMe
TBSO
2
OMe HO
O
O
H
H
O
O
O
O
OCS2Me
4
3 R = -TBS
HO
O
5
Accordingly, 5 was monoprotected with trityl group to give 6 (Scheme 2), which
on reaction with NaH and 1-bromopropyne in THF gave 7, a crucial unit required for
the target molecule. Methanolysis of 7 with catalytic Conc. H2SO4 in MeOH gave the
diol 8, which was then selectively alkylated with TBS-Cl and imidazole in
dichloromethane to give 9. Further transformation of 9 into xanthate 4 using NaH, CS2
and MeI in THF and radical cyclisation of 4 using n-Bu3SnH and AIBN in benzene at
reflux for 24 h afforded 3. Having obtained the bicyclic system 3, next it was aimed at
incorporating the alkyl chain by performing Grignard reaction. To achieve this, 3 was
treated with aqueous TFA (5:1) to afford the required system 10, which on reaction with
C8H17MgBr in THF afforded 2. The triol 2 on oxidative cleavage with NaIO4 in
aqueous CH3CN resulted the lactol 11, which on oxidation with CrO3 and pyridine in
dichloromethane at 40ºC afforded the mono lactone 12. However, attempts were
unsuccessful in further oxidation of 12 to give 1.
Scheme 2
Reagents: a) TrCl, Et3N, CH2Cl2; b) NaH, 1-bromopropyne, THF; c) Conc. H2SO4,
MeOH, 50ºC, 2 h; d) TBS-Cl, imidazole, CH2Cl2; e) NaH, CS2, MeI, THF; f) n-Bu3SnH4,
C6H6, 80ºC; g) aqueous TfOH; h) C8H17MgBr, THF; i) NaIO4, aqueous CH3CN; j) CrO3,
pyridine, CH2Cl2, 40ºC.
12