Synopsis
SYNOPSIS
The thesis entitled “Synthesis of unusual amino acids as building blocks in
bioactive peptidomimetics” is divided into three chapters.
CHAPTER-I: This chapter deals with Introduction to -peptides and synthesis of linear
and cyclic peptides of cis--furanoid sugar amino acid and -hGly.
CHAPTER-II: This chapter describes the synthesis of protected (2R,3R,4S) 4,7-diamino
2,3-dihydroxy heptanoic acid, a constituent of Callipeltins A and D.
CHAPTER-III: This chapter deals with the introduction to antidepressants and the
synthesis of antidepressant ‘Glaziovine-Sertraline hybrid’.
CHAPTER-I: Introduction to -peptides and Synthesis of Linear and Cyclic
peptides of cis--furanoid sugar amino acid and -hGly.
The secondary structure of peptides, i.e. helices, turns, and sheet like
conformations are determinant factors of their biological properties, both in  and amino acid derivatives. -peptides are composed of amino acids with the carboxylic acid
functionality at C rather than C The difference in the chiral center allows the peptides to resist hydrolysis by proteases even though they are amide-linked oligomers
with the side chains similar to those in dietary proteins. Typically, -peptides make poor
drugs due to low bioavailability as the body readily breaks them by proteases. Thus,
biomimetic polymers hold promise for new biomaterials and therapeutics.
Originally, it was proposed that -peptides would be more flexible than peptides because they contain an additional CH2 between the amine and carboxylic acid
groups. Surprisingly, -peptides have exhibited greater conformational stability than peptides. -peptides can form stable helices with only four to six residues, where as a peptide of that length would be disordered. By understanding the conformational
behavior of these interesting molecules, we may develop a means of controlling their
structure. This would allow us to use -peptides as building blocks in new therapeutics to
target almost any protein recognition event (proteolysis, protein-protein association,
phosphorylation in signaling pathways, ribosomal translation, etc.). Recently, the relevant
antimicrobial and hemolytic activities of amphiphilic -oligomers have also been shown
I
Synopsis
thus prompting the research in this field. Thus, we have turned our attention towards the
design and synthesis of new class of -peptides using sugar amino acids.
The sugar amino acids are part structures of several natural products and very
important components. Importance of such unusual aminoacids and non-availability from
‘chiral pool’, prompted synthetic organic chemists to develop new and efficient strategies
for the synthesis of such amino acids enroute to the synthesis of both natural products and
peptidomimetics.
Synthesis of cis--furanoid sugar amino acid:
The synthesis of cis-f-SAA was started from cheap and commercially available
D-Glucose 1. It was protected by acetonide using H2SO4 in acetone. Inversion of
configuration at C-3 position was carried out by oxidation (PDC/CH2Cl2) followed by
reduction using NaBH4/MeOH. The inverted alcohol 3 was converted into its tosylate
using TsCl/Py. Tosylate was subjected to reaction with NaN3 at 135 oC in DMF for 6 h to
give azido derivative 4. The exocyclic hydroxylic groups of azide 4 are selectively
deprotected to diol 5 using 0.8% H2SO4 in methanol (Scheme 1). Subsequently, the diol 5
is oxidatively cleaved using NaIO4, followed by NaClO2, NaH2PO4, H2O2 oxidation to
afford azido acid 6. The azido acid 6 was converted to methyl ester 7 using ethereal
diazomethane followed by reduction with Pd/C 10% afforded free amine ester 8, which
was protected using di-ter-butyl dicarbonate to give Boc protected sugar monomer 9 in
96% yield (Scheme 2).
HO
OH
O
OH i) acetone, CuSO
4
OH
HO
O
H2SO4
O
O
O
HO
1
O
2
i) PDC, Ac2O,
CH2Cl2
ii) NaBH4,
MeOH, 0oC
O
O
O
O
3
ii) NaN3, DMF, 135
oC
O
O
HO
O
MeOH
O
N3
OH
0.8 % H2SO4
O
5
Scheme-1
II
O
O
N3
4
O
HO
D-Glucose
i) TsCl, Py, CH2Cl2
O
Synopsis
OH
HO
O
O
O
O
N3
5
i) NaIO4, THF-H2O
O
HO
ii) NaClO2, NaH2PO4
CH3CN
O
CH2N2
dry Ether
O
N3
6
O
O
O
O
MeO
O
O
MeO
EtOAc
O
N3
Pd-C/10%, H2
O
O
H2N
O
MeO
(Boc)2O
EtOAc
O
BocHN
9
8
Scheme-2
7
O
Having successfully synthesized new class of -amino acid monomer, cis-furanoid sugar amino acid (cis-fSAA or fSAA), the attention was then focused to
synthesize new class of -peptides using this monomer. Hence, homooligomers of cisfSAA were synthesized and their secondary structure pattern was studied.
Synthesis of homo oligomers of cis--furanoid sugar amino acid:
Homo oligomers of cis-furanoid sugar amino acid -peptides were prepared using
3-Azido–3-deoxy-1, 2-O-isopropylidene-α-D-xylo-furanoic acid 6 and free amine ester 8
by adopting segment condensation method. Dipeptides were prepared by condesation of
two monomers. Tetrapeptide was prepared by coupling of two dipeptides. Hexapeptide
was synthesized by condensing tetrapeptide acid with dipeptide amine, whereas
octapeptide was obtained by coupling of two tetrapeptides.
Coupling of azido acid 6 and free amine ester 8 in the presence of EDCI-HOBt in
dry dichloromethane gave dimer azide 10 (Scheme 3). The above dimer azide on
hydrolysis gave corresponding dimer azido acid 11, where as hydrogenation with PdC/10% in ethyl acetate gave the corresponding dimer amino ester 12 (Scheme 4).
O
O
O
O
HO
O
O
N3
6
O
+ MeO
H2 N
O
O
EDCI-HOBt
N3
N
H
CH2Cl2
O
O
O
8
Scheme-3
III
O
O
10
O
OMe
O
Synopsis
O
O
O
N3
11
O
R
THF-H2O(3:1)
O
12
O
O
H2, EtOAc
O
OR'
O
Pd-C/10%
O
O
N
H
OMe
N
H
O
O
O
LiOH
O
O
11 R = N3, R' = H
10
12 R = NH2, R' = Me
Scheme-4
Coupling of these two (11 and 12) gave tetramer azido ester 13 which on
reduction followed by treatment with Boc anhydride yielded tetramer 14 (Scheme 5). The
same sets of reactions were carried out for hexamer 15 and octamer 16.
O
O
R
i) EDCI-HOBt
+
11
12
O
O
N
H
O
H
N
O
O
O
OMe
N
H
O
O
O
CH2Cl2
O
O
O
O
O
13 R = N3
Pd-C/10%
H2, (Boc)2O
EtOAc
14 R = NHBoc Tetramer
Scheme-5
O
O
BocHN
O
O
O
H
N
N
H
O
O
O
O
O
O
H
N
N
H
O
O
O
O
O
O
OMe
N
H
O
O
O
O
O
O
O
15 Hexamer
O
O
BocHN
O
O
O
H
N
N
H
O
O
O
O
O
O
O
O
O
O
H
N
N
H
O
O
O
O
O
16 Octamer
IV
O
O
H
N
N
H
O
O
O
O
OMe
N
H
O
O
O
O
O
O
Synopsis
The above synthesized homooligomers from cis-fSAA were characterized by
circular dichroism (CD), NMR and molecular dynamics, which displayed well-defined
helical structures characterized by series of 14-membered hydrogen bonded rings (14Helix).
J. Am. Chem. Soc. 2004, 126, 13586.
Synthesis of hetero (or mixed) oligomers of cis--furanoid sugar amino acid and hGly.
The preceeding section described the synthesis of homo oligomers of cis-fSAA
and study shown that the cis-fSAA oligomer adopts in solution a well defined righthanded 14-Helix. Our next interest was to check for the conformational rigidity of this
sugar amino acid. Hence we proposed to synthesize mixed -peptides using cis-fSAA
and -hGly alternatingly to provide conformational freedom to the rigid cis-fSAA
peptides. -homoglycine is the only one naturally occurring -amino acid, which is
known to destabilize helices because the unsubstituted -homoglycine is highly flexible.
Accordingly, mixed  -peptides (23, 25, 26 having cis-fSAA at the N-terminus,
while 29, 32, 33 with -hGly at N-terminus) were prepared by conventional peptide
coupling procedure. The commercially available -homoGlycine (-hGly) was esterfied
in presence of acetyl chloride in methanol under reflux conditions to give -hGly ester
17. The synthesis of mixed -peptides having cis-fSAA at the N-terminus was started
with the coupling of azido acid 6 and -hGly ester 17 under standard reaction conditions
in presence of coupling agents EDCI, HOBt and DIPEA in CH2Cl2 to afford dipeptide 18
(Scheme 6).
Methanol
H2 N
COOH
CH3COCl
COOMe
ClH.H2 N
17
O
O
O
O
OH + ClH.H2 N
N3
COOMe
EDCI-HOBt
DIPEA,CH2Cl2
O
6
17
Scheme-6
V
O
N3
O
H
N
O
18
OMe
O
Synopsis
The dipeptide 18 was hydrolyzed using LiOH in 1:3 THF:H2O solution at 0 oC to
produce acid 19 without epimerization, whereas hydrogenolysis in the presence of
Palladium on charcoal afforded amine 20, which was protected with Boc anhydride to
give Boc protected dipeptide. The dipeptide 21 was hydrolyzed using LiOH in 1:3 THFwater solution at 0 oC to produce acid 22 (Scheme 7).
O
LiOH
O
O
N3
H
N
OMe
O
O
Pd-C10%, H2
O
20
EtOAc
18
O
19
THF-H2O
O
H
N
OR'
R
O
19 R=N3,
(Boc)2O
O
R'=H
20 R=NH2, R'=Me
21 R=NBoc, R'=Me
O
O
LiOH
21
THF-H2O
O
H
N
OH
BocN
O
22
Scheme-7
O
Coupling of Boc protected dipeptide acid 22 and monomer amine 8 gave trimer
23. Same sets of reactions were carried out for Boc protected hetero -tetramer 25
(Scheme 8) and hetero -hexamer amine 26.
O
22
+
O
EDCI-HOBt
8
CH2Cl2
O
H
N
O
H
N
OMe
BocHN
O
O
O
O
O
23
O
19
+
20
EDCI-HOBt
O
CH2Cl2
O
H
N
R
O
O
24 R = N3
Pd-C/10%
H2, (Boc)2O
EtOAc
25 R = NHBoc
Scheme-8
VI
O
O
H
N
O
O
O
N
H
OMe
Synopsis
O
O
O
O
H 2N
H
N
O
O
O
O
H
N
N
H
O
O
O
N
H
O
H
N
OMe
O
O
O
26
After preparation of mixed -peptides using cis-fSAA at N-terminus and -hGly
at C-terminus, another set of mixed -peptides were prepared using -hGly at N-terminus
and cis-fSAA at C-terminus. Accordingly, for the preparation of dipeptide, -hGly Nterminal was protected with Boc using 5% aqueous NaOH and di-ter-butyldicarbonate to
afford Boc-protected -hGly acid 27, which was used directly for the coupling reaction.
Boc-protected -hGly acid 27 was coupled with free amino esters 8, 20 using
EDCI-HOBt to give Boc-protected hetero dipeptide ester 28 and Boc protected hetero
tripeptide ester 29 respectively (Scheme 9).
(Boc)2O, NaOH
COOH
H2 N
COOH
BocHN
THF-H2O
27
O
O
O
O
+
27
O
O
OMe
H2 N
8
EDCI-HOBt
BocHN
CH2Cl2
O
O
27
+
O
28
O
O
O
OMe
N
H
O
H2 N
H
N
O
OMe
O
O
EDCI-HOBt
CH2Cl2
O
20
Scheme-9
BocHN
O
H
N
N
H
O
OMe
O
29
Boc-protected hetero dipeptide ester 28 was hydrolyzed with LiOH to give the
carboxylic acid 30 almost quantitatively, where as removal of the Boc-protecting group
from 28 with TFA furnished the TFA salt 31 (Scheme 10). Subsequent activation of the
carboxylic acid function in 30 with EDCI/HOBt/DIPEA and reaction with the TFA salt
VII
Synopsis
31 produced the Boc-protected -hetero tetramer 32. Same sets of reactions were carried
out for hexamer 33.
O
O
O
O
BocHN
LiOH
THF-H2O
O
OMe
N
H
O
O
30
R
O
31
TFA-CH2Cl2 (1:1)
0 oC
28
O
OR'
N
H
O
30 R = NHBoc, R' = H
31 R = NH2.TFA, R' = Me
O
30
+
EDCI-HOBt
31
O
H
N
BocHN
O
CH2Cl2
O
N
H
O
O
O
BocHN
N
H
N
H
O
O
N
H
O
O
O
O
O
O
OMe
O
O
O
O
N
H
O
32
Scheme 10
O
O
N
H
O
O
N
H
OMe
O
33
The above synthesized series of mixed peptides comprising of alternating cisfSAA and -hGly were characterized by circular dichroism (CD), NMR and molecular
dynamics. The structural data showed that the mixed peptide heterooligomers 25, 26 and
29, 32, 33 form robust right-handed 14-helical secondary structures in solution. These
results indicate that the secondary structure resulted exclusively from the cis-fSAA and
the presence of the incorporated highly flexible -hGly did not affect the secondary
structure.
J. Am. Chem. Soc. 2005, 127, 9664.
Cyclic homo and hetero oligomers of cis--furanoid sugar amino acid and -hGly:
The self-assembly of peptide motifs into nanotubular objects mediated by
hydrogen bonding has become an important area of research in supramolecular
VIII
Synopsis
chemistry. These nanotubes exhibit unique structural and functional properties and have
tremendous potential in biomedical and material sciences. Nanotubes based on cyclic
peptides were first proposed in 1972 by Hassall et al. and predicted that cyclic tetramers
of alternating - and -amino acids would assemble through backbone-backbone
hydrogen bonding to yield hollow cylindrical constructs. Sugar amino acids (SAAs) have
also been extensively studied as potential building blocks for the design of peptide
nanotubes. Several groups have synthesized cyclic homooligomers from furanoid and
pyranoid sugar amino acids but there were no reports of sugar peptide nanotubes. This
motivated us to synthesize sugar peptide nanotubes
Accordingly, cyclic homo oligomers of cis--furanoid sugar amino acid were
synthesized by the coupling of azido acid 6 and dimer amino ester 12 in the presence of
EDCI-HOBt in dry dichloromethane to give trimer azide 34 (Scheme 11).
O
O
EDCI-HOBt
6
+
12
N3
O
N
H
CH2Cl2
H
N
OMe
O
O
O
O
O
O
O
O
O
34
Scheme-11
The trimer azide 34 was hydrolyzed by using LiOH in THF-H2O, followed by
reduction of azide on Pd-C at 1 atm hydrogen pressure to give trimer amino acid, which
was cyclized by using (8 eq) EDCI-HOBt under high dilution condition to yield 12membered (C3-symmetric) homo tricyclic compound 35 (Scheme 12).
O
34
O
H
N
O
i) LiOH, THF-H2O, 0 oC
ii) Pd-C/10%, EtOAc, H2
O
O
O
HN
iii) EDCI-HOBt (8eq)
CH2Cl2, 48h
O
NH
O
O
O
35
Scheme-12
IX
O
O
Synopsis
Similarly, homo tetra amino acid 36 was prepared from tetramer azido ester 13.
The cyclization of homo tetra amino acid 36 was attempted with various coupling
reagents, however it turned out that FDPP, in acetonitrile at room temperature was best to
afford homo tetra cyclic 37 in 60% yield (Scheme 13).
O
O
i) LiOH, THF-H2O, 0
O
H2 N
oC
O
O
N
H
13
O
O
ii) Pd-C/10%, H2
EtOAc
O
O
H
N
O
O
O
O
O
OH
N
H
O
O
36
O
O
O
H2N
O
O
O
O
H
N
N
H
O
O
O
O
O
O
OH
O
O
FDPP, DIPEA
O
O
H
N
O
N
H
O
O
O
O
NH
NH
CH3CN
O
O
O
O
O
O
O
O
N
H
O
36
O
37
Scheme-13
The cyclic hetero oligomers were synthesized from the trimer 23 by hydrolysis
using LiOH in THF-H2O, followed by deprotection of the Boc to give trimer amino acid,
which was cyclized by using (8eq) EDCI-HOBt under high dilution condition yielded 12membered homo tri-cylic peptide 38 (Scheme 14).
O
O
O
O
H
N
O
H
N
OMe
BocHN
O
O
O
O
O
i) LiOH, THF-H2O, 0 oC
ii) TFA:CH2Cl2
iii) EDCI-HOBt (8eq)
CH2Cl2, 48h
O
H
N
O
O
O
HN
O
NH
O
23
38
Scheme-14
X
O
O
Synopsis
The hetero -tetramer azide 24 was hydrolyzed by using LiOH in THF-H2O to
yield -tetramer azido acid 39. This azido acid 39 was transformed into the
pentafluorophenyl ester followed by hydrogenation to give cyclic hetero -tetra peptide
40 in 75% yield (Scheme 15).
O
O
LiOH, THF
24
H2O, 0 oC
N3
O
H
N
O
O
O
N
H
OH
O
O
O
H
N
O
39
O
O
39
C6F5OH, EDCI,
CH2Cl2.
O
H
N
O
O
NH
NH
Pd/C-10%, H2
EtOAc
O
O
N
O H
O
O
40
Scheme-15
The self assembly of the above synthesized cyclic -peptides to form nanotubes
was characterized by NMR spectroscopy, FT-IR, Transmission Electron Microscopy
(TEM) and Scanning Electron Microscopy (SEM) and Differential Interference Contrast
(DIC) microscopy. Among the four synthesized cyclic -peptides, two cyclic peptides
(35, 40) showed nanotube formation.
XI
Synopsis
CHAPTER II: Synthesis of protected (2R,3R,4S) 4,7-diamino 2,3-dihydroxy
heptanoic acid, a constituent of Callipeltins A and D.
Callipeltin A, a cyclic depsidecapeptide isolated from the marine Lithisda sponges
Callipelta sp. and Latruncula sp., was shown to possess antifungal, anti-HIV activity and
cytotoxicity against selected human carcinoma cell lines, as well as powerful inhibition
of the Na/Ca exchanger in guinea pig left atria. The structure of callipeltin A 1 was
determined by Minale and co-workers; it contains a number of novel amino acids and a
novel fatty acid. Comparison of the bioactivity of 1 with the related compound callipeltin
B indicates that the side chain attached to the macrocycle, recently isolated as callipeltin
D is essential for anti-HIV activity. The key residue of the side chain is the novel amino
acid, (2R,3R,4S)-4-amido-7-guanidino-2,3-dihydroxy heptanoicacid (AGDHE, 2).
In continuation of our ongoing research towards the synthesis of biologically
active compounds, we planned to construct the AGDHE fragment of callipeltin A and D
and in this chapter we report an efficient synthesis of AGDHE fragment starting from
readily available L-ascorbic acid.
2R,3R,4S AGDHE
NH
H2 N
N
H
O
NH2
OH O
N
NH OH H
O
O
OH
O
H
N
N
H HN
O
O
O
OH
MeN
MeO
O
O
O
O
O
NH
N
H
NH
NMe
N
H
CONH2
NH2
NH
HN
NH2
OH
COOH
NH2 OH
2
AGDHE
OH
Callipeltin A
1
The retrosynthetic analysis of AGDHE fragment revealed that the C2-hydroxy
protected aldehyde (Scheme 1) was the key intermediate, which inturn would easily be
obtained from L-ascorbic acid.
XII
Synopsis
Retrosynthetic Analysis of AGDHE fragment of Callipeltin A:
NH
CALLIPELTIN A (1)
H2 N
N
H
HO
NHPG3
MeOOC
NH2 OH
NHPG2
NHPG3
OPG1
OPG1
O
OH
OH
NHPG2
OH
OH O
OH
HO
O
O
O
OPG1
OH
O
O
CHO
OPG1
HO
OH
L-Ascorbic acid
Scheme 1
Our synthetic approach to AGDHE fragment 2 involves chiron approach via
cheap and commercially available L-ascorbic acid as the starting material. The 5,6-diol of
L-ascorbic acid was easily protected as acetonide. The acetonide was purified through
crystallization method to get 80-85% of yield. The enone moiety in acetonide was
cleaved using H2O2, K2CO3 to afford potassium salt, which on treatment with ethyl
bromide in acetonitrile at reflex conditions afforded (2R,3S)-hydroxy ester 3 in good
yield. Inversion of configuration at C-2 in 3 by the Mitsunobu reaction provided ethyl
(2S,3S)-hydroxy ester 4 in 65% yield for two steps (Scheme-2).
OH
O
HO
HO
O 2 steps
OH
O
O
(a) chloro acetic acid,
O
O
COOEt
b) DIAD, TPP,
THF, 0 oC
Et3N, EtOH
OH
3
COOEt
OH
4
Scheme 2
Benzoylation of 4 with benzyl bromide, silveroxide in boiling acetonitrile in the
presence of catalytic amount of Bu4NI, O-Benzyl ester 5 was isolated in 80% yield after
12 h. Since a direct reduction of these esters to the corresponding aldehyde gave
XIII
Synopsis
mixtures, the two-step procedure was applied. The reduction of 5 with LiAlH4 in THF
furnished the alcohol 6 (Scheme 3).
O
O
COOEt
OH
b) Ag2O, BnBr,
O
O
COOEt
CH3CN
(c) LiAlH4,
CH2 OH
THF, 0 oC
OBn
4
O
O
OBn
6
5
Scheme 3
Oxidation of the primary alcohol 6 using IBX provided the corresponding
aldehyde 7 in good yield. The aldehyde 7 was treated with allyl bromide and Zn powder
in THF at 0 oC using saturated aqueous NH4Cl as catalyst resulted in the formation of
anti-homoallylic alcohol as major isomer in 85% combined yield, as an inseperable
syn:anti (1:5) diastereomeric mixture. The relative stereochemistry of the new
stereogenic center in the major isomer was determined by a short deprotection-protection
protocol.
After confirming the stereochemistry of the major isomer in the homoallylic
alcohols 8 (a/b), they were esterified with methane sulphonyl chloride to give the
mesylates in 92% yield. At this stage, the two diastereomers resulting from the
preceeding allyl zinc addition were easily separable by column chromatography to afford
mesylate 10 as a major single diastereomer (Scheme 4).
O
O
CH2 OH
OBn
6
O
d) IBX
O
CHO
O
OBn
8 (a/b) syn : anti (1:5)
OMs
O
O
+
cat DMAP 0 oC
OBn
8 (a/b)
OH
O
OBn
7
e) MsCl, Et3N,
OBn
allylbromide
Zn, THF, 0 oC
THF, 0 oC
OH
O
O
O
9 (minor)
OMs
O
OBn
10 (major)
Scheme 4
The mesylate 10 was converted into its azide 11 using NaN3/DMF. Azide thus
obtained was reduced to amine using LAH/THF/0 oC and protected as its tert-butyl
carbamate derivative (Boc) by treatment with 1N NaOH/(Boc)2O to give 12 (Scheme 5).
XIV
Synopsis
10
f) NaN3,
DMF, 80
O
N3
oC
O
g) LiAlH4,THF
O
(Boc)2O, 0 oC
OBn
NHBoc
O
OBn
11
12
Scheme 5
Hydroboration of 12 with BH3.Me2S followed by H2O2 furnished primary alcohol
13, which was subsequently converted to azide 14, followed by reduction on Pd-CaCO3
under 1 atm hydrogen pressure and treatment with chlorobenzylformamate gave diamino
protected compound 15 in 85% yield. After obtaining the protected diamine functionality,
1,2-isopropylidene was selectively cleaved with 0.8% H2SO4 in MeOH at ambient
temperature to result the diol 16. The diol primary alcohol was selectively oxidized by
using TEMPO/NCS and NaClO2,, NaH2PO4 to yield the acid, which was protected as its
methyl ester 17 using ethereal diazomethane (Scheme 6).
O
NHBoc
O
OBn
O
h) BH3.DMS
NHBoc
O
OH
NaOH, H2O2
Cbz-Cl CH2Cl2
DIPEA
O
OBn
14
NHBoc
O
NHCbz
k) 0.8% H2SO4
MeOH
OBn
OH
NHBoc
HO
NHCbz
OBn
16
OH
l) TEMPO-TBACl
NHBoc
N3
13
15
Na2CO3, NaHCO3
CH2Cl2 m) NaClO2,
NaHPO4, H2O2
O
O
ii) NaN3, DMF
80 oC
OBn
12
j) H2, Pd-CaCO3
EtOAc
i) TsCl, Et3N, 0 oC
CH2Cl2, DMAP
NHBoc
NHCbz
MeOOC
OBn
17
n) CH2N2, Ether
Scheme 6
In conclusion, we have developed an efficient strategy for the synthesis of
protected unusual amino acid (2R,3R,4S)-4,7-diamino-2,3-dihydroxyheptanoic acid 17
from cheaply available L-ascorbic acid. This synthetic strategy could be useful in making
reasonable quantities of the key residue 17, which can be used for the total synthesis of
callipeltins A and D.
XV
Synopsis
CHAPTER III: Introduction to antidepressants and the synthesis of antidepressant
‘Glaziovine-Sertraline hybrid’
Depression is a major mental disorder and one of the most frequent chronic illness
that effects people of all ages. There are very few drugs available for the treatment of
depression. Use of lithium salt as drugs for this disease has shown some positive effect.
Drug development activities resulted in introduction of first-generation tricyclic
antidepressants (imipramine, amitriptyline), which were found to induce severe side
effects such as anti cholinergic and cardiovascular effects. They were replaced in 1980s
by the selective serotonin reuptake inhibitors SSRIs.
The synthesis of hybrid molecules made up of two different molecular units, has
recently gained importance because many of them exhibit promising physical, chemical
and biological properties as well as being novel architectures. In this work, we designed
and synthesized a new hybrid antidepressant 1, having Sertraline 2, one of the clinical
compound that acts on CNS as SSRI and the key building block of antidepressant
glaziovine 3, one of the important alkaloid of lauraceae family.
NH-CH3
MeO
MeO
MeO
Cl
N-Boc
N
NH-Me
HO
Cl
O
Cl
Cl
1
2
O
3
Our synthetic strategy for the key building block of glaziovine was started from
vanillin 4. Methylation and bromination of vanillin using methyl iodide and K2CO3 in
acetone, molecular bromine in methanol at less than 40 oC gave the bromoaldehyde 5.
Nitroaldol reaction of bromoaldehyde 5 with nitro methane gave unsaturated
nitrocompound 6. Double bond was reduced in compound 6 using sodium borohydride to
give saturated nitrocompound 7 (Scheme 1). Saturated nitro compound 7 was reduced to
amine using LAH/THF/0oC and protected as its tert-butyl carbamate derivative (Boc) by
treatment with 1N NaOH/(Boc)2O to afford 8. This amine product was subjected to heck
reaction with ethyl acrylate using triethyl amine and palladium diacetate in polyethylene
glycol at 80 oC to give the unsaturated ester 9 (Scheme 2).
XVI
Synopsis
CHO
MeO
HO
ii) Br2,MeOH
<40 0C
MeO
acetone,reflux
4
CHO
MeO
i) MeI,K2CO3
MeO
CHO
MeO
Br
5
iii) CH3COONH4,
MeO
AcOH,CH3NO2
100 0C
MeO
NO2
Br
6
iv) NaBH4,
MeO
MeOH 0 oC
MeO
Br
NO2
7
Scheme-1
Azamichael reaction was carried out by using TFA:CH2Cl2 1:1, then basified with
Na2CO3 to give cyclic ester 10. This ester was hydrolyzed with LiOH to achieve acid 11.
The acid 11 was directly coupled with commercially available Sertraline 2 to give hybrid
product 1 (Scheme 2).
MeO
MeO
Br
NO2
NaOH,0 0C, (Boc)2O
MeO
MeO
NH-Boc
NH-Boc
Pd(OAc)2,Ph3P
PEG-400,1000C
MeO
vii) TFA:CH2Cl2 (1:1)
Na2CO3,(Boc)2O
9
Br
8
7
MeO
vi) CH2CHCOOEt,
MeO
v) LiAlH4, THF
LiOH, THF
N-Boc
MeO
COOEt
H2O-MeOH
OEt
10
O
NH-Me
MeO
EDCI-HOBt
N-Boc +
MeO
CH2Cl2
OH
MeO
N-Boc
MeO
O
MeN
Cl
11
O
Cl
2
Cl
Scheme-2
1
Cl
In conclusion, we synthesized a new hybrid antidepressant from key building
block of glaziovine and highly potent antidepressant sertraline. This hybrid compound
has shown a significant antidepressant activity in the biological tests.
XVII