Abstract
ABSTRACT
This thesis entitled “Development of some important synthetic methodologies and
their applications in the synthesis of biologically important compounds” is divided
in to three chapters.
Chapter-I: This chapter deals with the “Stereoselective synthesis of (-)- pestalotin”.
Chapter-II: This chapter deals with the “TEMPO-oxidation of alcohols to aldehydes on
solid-phase”.
Chapter-III: This chapter divided in two sections.
Section-A: This section deals with the “A versatile and efficient synthesis of (2S)-2(hydroxylmethyl)-N- Boc-2, 3-dihydro-4-pyridone”.
Section-B: This section deals with the “Studies directed towards the synthesis of (+)-5epi-tashiromine”.
CHAPTER-I: Stereoselective synthesis of (-)-pestalotin.
Pestalotin 1, a gibberellin synergist, was first discovered by Kimura et al from a
culture broth of Pestalotia cryptomeriaecola Sawada, which is a fungus pathogenic for
the Japanese cedar, Cryptomeria japonica. Later Ellestad et al., also isolated 1 as a
minor metabolite from the fermentation culture P880, an unidentified penicillium species
and gave the code LLP-880α. The 6-substituted 5,6-dihydro-2-pyrone skeleton in
pestalotin 1 which also occurs in many natural products show diverse biological activity.
Especially those with oxygen function on the pyrone ring and C6-side chain are known
to exhibit plant growth inhibitory, antifungal, and antitumor activities.
Fig. I
OMe
O
OH
1
I
O
Abstract
The presence of two contiguous stereogenic centers in (-)-pestalotin 1 has made it
an attractive synthetic target since its discovery. Several synthesis of racemic and
optically active forms of pestalotin have been reported. In most of these syntheses the
two chiral centers were built stepwise and also in some cases low stereoselectivity was
observed.
In connection with our interest in utilizing substituted aromatic system as
masked, 1,3-dione or 1,3-diol and 1,5-dione in the synthesis of natural products, we
report here a facile synthesis of (-)-pestalotin where the m-methoxy substituted benzene
was utilized as masked -ketoester in turn to obtain pyranone skeleton of compound 1.
Also in our approach the asymmetric dihydroxylation (AD) developed by Sharpless was
used to get the two chiral centers present in 1.
Our synthesis commenced with the Wittig homologation of 1-pentanal 2 with
(carbethoxy ethylidene) triphenyl phosphorane to afford the --unsaturated ester
[diastereomeric ratio (trans: cis = 91.37:6.7) ] as a colourless liquid in 74%(trans)
isolated yield .
Scheme-I
O
H
O Ph3P=CHCO2Et
CH2Cl2, 16h, rt
2
O
H
O
3
trans
+
O
H
H
cis
4
Sharpless asymmetric dihydroxylation reaction of (E)-ethyl-2-heptenoate 3 using
(DHQ)2PHAL as the chiral ligand, catalytic OsO4, and methanesulfonamide at 0 C for
16 h provided the corresponding ethyl- 2, 3- dihydroxy-(2R, 3S)-heptanoate 5 in 71%
yield, ( Scheme-II) [97.35% ee, determined by chiral HPLC analysis].
II
Abstract
Scheme-II
OH
(DHQ)2 PHAL
O
O
OsO4, 0oC, 16 h
O
OH O
5
3
O
2,2-DMP
O
PTSA (cat)
CH2Cl2, rt, 16 h
O
O
LiBH4, THF
0oC to rt, 16 h
O
O
7
6
O
1. PTSA, MeOH : H2O
(4:1), rt, 20 h
TsCl, Et3N
DMAP (cat)
CH2Cl2, 0oC to rt, 4 h
O
OH
O
2. K2CO3, MeOH : H2O
rt, 19 h
OTs
OH
8
9
Compound 5 when exposed to 2, 2-dimethoxy propane in the presence of
catalytic PTSA gave 6. The ester 6 was smoothly reduced by LiBH4, generated in situ, to
afford the alcohol 7. The sulfonate ester 8 was readily prepared from 7 using p-toluene
sulfonyl chloride, triethylamine and DMAP (catalytic). Deprotection of the
isopropylidene moiety of 8 in acid medium followed by basification with K2CO3 in
MeOH/H2O afforded the epoxy alcohol 9. When compound 9 was subjected to
nucleophilic epoxide ring opening with m-methoxyphenyl magnesium bromide in the
presence of catalytic CuI, gave 10 (Scheme III).
Scheme-III
MeO
MgBr
OH
O
Li/Liq. NH3
OMe
THF, CuI (cat)
-20oC, 3.5 h
OH
9
THF, -78oC, 3 h
OH
10
OH
OH
OMe
O3, Me2S, CH2Cl2, MeOH, Pyridine
OH
12
11
OMe
O
Me2SO4, K2CO3
acetone
aq. NaOH
THF, rt, 1.5 h
O
OH
O
O
rt, 14 h
OH
1
13
III
O
OMe
Sudan-III, -78oC, 0.5 h
OH
O
O
Abstract
The crucial intermediate, β-keto ester 12 was unmasked from 10 via Birch
reduction-ozonolysis sequence. Accordingly, when 10 was treated with Li/liq.NH3,
EtOH the dihydroanisole intermediate 11 was produced. Ozonolytic cleavage was
performed on the unpurified Birch product to give the β-keto ester 12, which was carried
to the next step without any purification. The δ- lactone 13 was obtained from 12 by
treatment with 1N aqueous NaOH solution which was subsequently methylated using
dimethyl sulphate to furnish, the (-)-pestalotin 1 as a white solid after recrystallization
[hexane:benzene (1:1)]. The NMR (1H, and
13
C) spectral data of the synthetic sample
were consonant with those of the reported product.
In summary, we have accomplished the synthesis of (-)-pestalotin 1 using
asymmetric dihydroxylation and Birch reduction-ozonolysis sequence of m-substituted
anisyl ring as latent β-keto ester synthons for generating the 6-substituted 5,6-dihydro-2pyrone unit. Use of m-anisole unit as a masked form of -ketoester has an advantage, it
can be introduced easily in to the skeleton and can be converted to -keto ester at an
appropriate stage in two step sequence.
CHAPTER-II: TEMPO-oxidation of alcohols to aldehydes on solid-phase.
The solid-phase organic synthesis (SPOS) has been developed for the synthesis of
chemical libraries in solid-phase using an excess of reagents, which can be removed by
simple filtration and washings without the need for a chromatographic work up. Several
functional group transformation have been developed on solid phase to conduct SPOS.
One of the important transformations is oxidation of alcohol to aldehyde. Although
several reagents are known to oxidize alcohol to aldehyde in solution phase chemistry,
but there are several limitations to adopt these reagents on to solid phase.
So far only three approaches are known on solid-phase for oxidation of alcohol to
aldehyde. (i) TPAP (tetra-n-propyl ammonium perruthenate)/NMO in DMF (ii) Pyr.SO3.
DMSO, NEt3 (iii) Dess-Martin periodinane
Herein we report a convenient method of oxidizing alcohol to aldehyde using
TEMPO conditions. Though there are many reports where TEMPO-free radical was used
IV
Abstract
for oxidation reactions (solution phase) the one particularly attracted us is the work of
Jacques Einhorn et al., where they used NCS (1-3eq), TEMPO (0.1eq), TBACl (0.1eq)
and aqueous solution of NaHCO3 (0.5M) and K2CO3 (0.05M) in DCM at r.t for oxidizing
primary alcohol to aldehyde. Under these conditions alcohol gives good yields of
product and over oxidation product was not obtained even with slight excess NCS.
Therefore it was thought to adopt these conditions on solid-phase for oxidation of
alcohol to aldehyde. Though water is used in slight amounts in the reaction, but it is
required only for maintaining PH, mostly oxidation is taking place in CH2Cl2 medium.
Scheme-IV
OH
P
condition
O
O
TEMPO
O
TFA-CH2Cl2
P
O
14
HO
15
wang resin
16
As a first example Wang resin was taken in CH2Cl2 and is subjected to TEMPOoxidation conditions, after filtration and drying the resin, Magic angle NMR of the solid
showed clean formation of aldehyde. The resin aldehyde was cleaved under TFA/CH2Cl2
condition to give crude p-hydroxy benzaldehyde whose 1HNMR showed clear aldehyde
signal. Generally aldehydes may have unstability under cleavage condition therefore
product formation was conformed by 1HNMR of magic angle of the aldehyde on the
resin. Several examples (see the table-I) have been studied under the above conditions
the 1HNMR (magic angle) clearly showed aldehyde formation (δ 9.5- 10.0).
Thus simple general and useful method for the conversion of alcohol to aldehyde on
solid-phase was developed using TEMPO-oxidation condition.
V
Abstract
TEMPO-oxidation of alcohols to aldehydes on solid support
O
P
O
O
X
P
OH
X
O
X = aryl
Table –I
Entry
Substrate
Resin
Time
Product
R=
P
MeO
1
Merrifield
OH
24h
O
P
MeO
O
RO
17b
17a
2
OH
Chlorowang
24h
O
P
O
RO
18a
18b
3
Chlorowang
O
P
24h
OH
7
RO
7
4
Merrifield
24h
RO
O
O
OH
20b
20a
5
Merrifield
P
O
19b
19a
P
P
24h
O
OH
O
RO
21b
21a
CHAPTER-III: Section-A: A versatile and efficient synthesis of (2S)-2(hydroxymethyl)-N-Boc-2, 3-dihydro-4-pyridone.
2, 3-Dihydro-4-pyridones and their N-acyl derivatives are interesting building
blocks for a large variety of nitrogen-containing heterocycle syntheses. The amino-enone
moiety can be used in various reactions leading to key intermediates and is also
particularly useful in the synthesis of biologically active compounds and alkaloids. In
particular, the chiral dihydropyridones of type-28 (Fig.II) have been utilized for the
VI
Abstract
synthesis of some chiral piperidine skeletal natural products e.g. (+)-dienomycin C, (+)deoxoprosopinine, and 1-deoxynojirimycin.
O
Fig. II
N
Boc OH
28
Herein we report a novel and simple method for the synthesis of 28 starting from
3-aryl-2-aminopropanol 25 (obtained from aryl amino acid) in three steps, using Birch
reduction and ozonolysis.
Compound 25 is commercially available and can also be easily prepared from L(-)-phenylalanine in three steps. L-(-)-phenylalanine 22 was converted to N-Boc-methyl
ester 24 in the presence of acetyl chloride and methanol followed by treatment with
(Boc)2O. The resultant ester 24 was reduced to alcohol 25 using LiBH4.
Scheme-V
O
O
OH
NH 2
AcCl, MeOH
OMe
NH 2.HCl
reflux, 3 h
22
23
LiCl, NaBH4
O
(Boc)2O, Et3N
OMe
NHBo c
THF, 0oC to rt
8 h, 95%
24
OH
NHBo c
EtOH, THF
0oC to rt, 16 h, 82%
25
Birch reduction of 25 gave the corresponding dihydro derivative 26 which on
ozonolysis followed by quenching the resultant ozonide with H2/Pd(OH)2 yielded the keto aldehyde 27. Compound 27 without isolation was subjected to acid catalysed
cyclisation to give the dihydro-4-pyridinone 28.
VII
Abstract
Scheme-VI
OH
NHBo c
Li / liq. NH3
i. O3, EtOAc
OH
NHBo c
THF, EtOH,
-78oC 1h
25
-78oC, 1.5 h,
then
H2, Pd(OH)2
rt, 3 h
26
O
OH
O
O
NHBoc
27
PPTS (cat)/THF
-20oC, 1h, 43%
(overall yield for
three steps)
N
Boc OH
28
This method is novel and general in nature to obtain the skeleton of a 2,3dihydro-4-piperidinone, by using an appropriate amino-aryl precurser.
Section-B: Studies directed towards the synthesis of (+)-5-epi-tashiromine.
(+)-5-epi-tashiromine is an indolizidine alkaloid isolated from subtropical asian
deciduous shrub, “maackia tashiroi”. It is interesting from the perspective of both
chemotaxonamy and biosynthesis maackia species. Indolizidine alkaloids have been
isolated from poison dart frogs and may have neurological properties.
Fig. III
OH
OH
H
H
N
N
29
30
(+)-5-epi-tashiromine
(+)-tashiromine
Our synthesis of 33 and 36 commenced with the mono benzyl protection of the
commercially available butane- 1, 4- diol 31 and pentane- 1, 5- diol 34 (Scheme-VII).
One of the hydroxyl of 31 and 34 was protected as benzyl ether by using BnBr, NaH, in
DMF at 0 0C to room temperature for 12 h to afford compound 32 and 35 in 66% and
67% yield. TEMPO oxidation of the free hydroxyl in 32 provided the required aldehydes
33 in 82% yield, which without further characterization was taken forward for the next
reaction.
VIII
Abstract
Scheme- VII
HO
OH
31
HO
OH
34
NaH, BnBr
DMF, 12 h,
00C to rt
66%
BnO
TEMPO, NaBr, H2O
NaHCO3, NaOCl,
EtOAc : toulene
00C, 1h
OH
32
NaH, BnBr
DMF, 12h,
00C to rt, 67%
OH TEMPO, NaBr, H2O
BnO
TBAI (cat), NaOCl,
EtOAc : toulene
00C to rt, 16 h
35
BnO
O
33
BnO
OH
36
O
The compound 35 under goes TEMPO oxidation of free hydroxy provided the
required carboxylic acid 36 in 70% yield, which was taken forward to couple with
oxazolidinone 39 to get 40. The two chiral centers in (+)- 5- epi- tashiromine were
planned to generate by an Evan’s aldol reaction between the aldehyde 33 and the chiral
oxazolidinone 40, which in turn can be prepared from L- phenyl alanine 37, using a
known procedure. Accordingly, L- phenylalanine 37 was reduced to phenylalaninol 38
using sodium borohydride and iodine in THF (Scheme- VIII).
The amino alcohol was protected as a carbamate 39 using diethyl carbonate and
catalytic amount potassium carbonate at 135 0C. The analytical data of compound 39
matched with the reported value.
Scheme-VIII
O
NH 2
Ph
CO2H
NaBH4, I2, THF
NH 2
Ph
OH
HN
O
0
Reflux, 18 h, 72%
135 C, 2 h
37
38
BnO
Bn
39
O
O
36, Piv-Cl,
(EtO)2CO, K2CO3
N
O
LiCl, Et3N, THF
- 20 0C to rt, 4 h, 62%
Bn
40
In presence of 1.6 eq. of LiCl and 2.0 eq. of Et3N in dry THF, acid 36 (1.1eq.)
reacted with the amide nitrogen of 39 to give 40 in 62% yield. Dibutyl boryl
trifluromethane sulphonate mediated Evans aldol reaction between chiral oxazolidinone
40 and the aldehyde 33, gave the syn aldol product 41 in 73% yield.
IX
Abstract
Scheme-IX
O
O
O
N
OBn
O
1) n-Bu2BOTf, Et3N, CH2Cl2,
-78 0C to 0 0C
O
O
OBn
N
2) Re-cooled to - 780C then 33 in
CH2Cl2, -78 0C to 0 0C, 5 h, 73%
Bn
40
OH
Bn
OBn
41
OH
LiBH4, Et2O, H2O (cat),
41
00C, 0.5 h, 72%
OBn
BnO
OH
NaBH4,
THF-H2O
00C to r.t, 3 h
42
OH
OBn
BnO
OH
43
Our next objective was the non-destructive removal of the chiral oxazolidinone
without recemization to get enantiomercally pure primary alcohol 42 (Scheme- XI). To
realise this we initially treated compound 41 with NaBH4 in THF- H2O at 0 0C to r.t for
3 h. The -position to the carbonyl carbon in 41 under went recemization when
subjected to reduction with NaBH4 furnishing 43. To circumvent the possibility of
recemization at -position to the carbonylcarbon 41 was treated with LiBH4/Et2O in the
presence of cat.amount of water at 0 0C to furnish 42 in 72% yield and the recovery of
oxazolidinone 39. Selective protection of primary hydroxyl group of compound 42 was
then subjected to TBDMS protection, provided 44 in 87% yield.
Scheme-X
OH
OH
OBn
BnO
TBDMSCl, Imidazole
OBn
BnO
0
CH2Cl2, 0 C to rt, 2 h,
OH
OTBDMS
87%
42
44
OMs
MsCl, CH2Cl2,
0
Et3N, 0 C to rt, 3 h
N3
OBn
BnO
NaN3, DMF
0
80 C, 2.5 h
OBn
BnO
OTBDMS
OTBDMS
45
46
X
Abstract
NHBo c
46
1) TPP, THF- H2O
600C, 19 h
OBn
BnO
OTBDMS
2) (Boc)2O
47
The hydroxy group in 44 was converted to its azide via mesylation. The reduction
of azide functionality of 46 treated with TPP/THF-H2O and reflux at 60 0C for 19 h gave
the amine, which was subsequently Boc protected using (Boc)2O to give 47. Carbonate
47 was debenzylated under the Li/ liq NH3 conditions in THF at -78 0C to afford the
compound 48.
Scheme-XI
XI
Abstract
The diol 48 was then convert to corresponding ditosylate 49 which after
subsequent deprotection of the N- Boc followed by nutralization should afford the
cyclized product. Accordingly the ditosyl was subjected to N-Boc deprotection protocol
using TFA/CH2Cl2. Treatment of 51 with Et3N in CH2Cl2 at r.t did not realise the
cyclization, then the reaction mixture was subjected to reflux condition, however, we
failed to obtain the cyclized product. We then thought of changing the leaving group
ability. Thus we converted the diol 48 into the corresponding di-mesylate 50 using
MsCl, Et3N in CH2Cl2 and DMAP(catalytic) at 0 0C for 3h. The compound 50 was
subjected to amine deprotection with TFA/CH2Cl2 to give salt 52. The expected salt
failed to under go cyclisation with Et3N in CH2Cl2 at r.t., even after changing the solvent
system to CH3CN and DMF did not afford the cyclization product 30.
The steric hinderence executed by the hydroxyl methyl group in 51/52 during
cyclization could be a reason for the unsuccessful cascade cyclization to form
the indolizidine skeleton.
XII