Abstract
The thesis entitled “Studies directed towards the total synthesis of Dolabelides A & B,
synthesis of Ophiocerins B & D, cyclic amides and -amino acids” is divided into
three chapters.
Chapter I: Stereoselective synthesis of C1-C14 fragment and studies
towards synthesis of C15-C30 fragment of Dolabelides A and B
This chapter deals with the stereoselective synthesis of C1-C14 and studies towards the
synthesis of C15-C30 fragment of Dolabelides A and B.
The marine natural products dolabelides A and B (Figure 1) have been isolated in
1995 from the Japanese sea hare Dolabella auricularia by Ojika and Yamada.1 These 22membered macrolides exhibit cytotoxic activity against HeLa-S3 cells with IC50 values of
6.3 and 1.3 μg/mL, respectively. In 1997, the same group disclosed two closely related
24-membered congeners, dolabelides C and D2, from the same marine source. These
compounds have also been shown to exhibit cytotoxicity against HeLa-S3 cell lines with
IC50 values of 1.9 and 1.5 g/mL, respectively.
OAc OAc
OH
OAc OAc
OAc
OH
O
O
OH
OAc
OH
Dolabelide A
OH
Figure 1
OH
O
O
OH
OAc
Dolabelide B
Stereoselective Synthesis of C1-C14 of Dolabelides A-B
The retro synthetic plan is depicted in Scheme 1. Dolabelides could be realised
from two fragments I and II by coupling through Yamaguchi esterification and
macrocyclisation through the ring closing metathesis under Grubb’s reaction conditions.
1
Abstract
Scheme 1
OAc OAc
OH
4
9
OAc OAc
7
1
11
OR
14
OH
2
OH
O
O
OH
19
21
23
OR
OAc
25
27
OH
O
OH
O
OAc
30
Dolabelides A: R = OAc
Dolabelides B: R = H
OAc OAc
9
OH
4
7
2
+
3
15
1
11
OR
OH
OH
OH
19
21
23
OH
O
C1-C14
segment (I)
OAc
25
27
30
C15-C30
segment (II)
14
Retro synthetic analysis of C1-C14 segment of Dolabelide A-B
The retro synthetic plan is depicted in Scheme 2. The synthesis of target fragment
1 is planned by a C-C bond formation between C6 and C7 carbons via acetylene 3 on
addition to the aldehyde 2, while the sub segment C1-C6 (3) could be synthesized from
5. The other sub fragment 2 could be prepared from commercially available 1,4-butane
diol.
Scheme 2
PMP
O
I
OH
O
BnO
OP
11
14
9
7
1
1
OBn
3
PMP
OP
O
O
CHO
BnO
+
OBn
2
BnO
3a P = MPM
3b P = TBS
OH
4
HO
OBn
5
2
Abstract
Accordingly, the known epoxide 63, was derived from mono benzyl ether of 1,4butane diol 4 (Scheme 3). Epoxide 6 on treatment with Red-Al in dry THF gave diol 7,
which, on reaction with anisaldehyde dimethylacetal in dry CH2Cl2 gave 8. Acetal 8 on
treatment with DIBAL-H, followed by Swern4 oxidation of 9 gave the aldehyde 10,
which on further reaction with (methoxycarbonylmethylene)triphenyl phosphorane in
benzene at reflux afforded ester 11. Reduction of ester 11 with DIBAL-H gave allyl
alcohol 12. Stereoselective epoxidation of allyl alcohol 12 with (+)-DIPT furnished
epoxide 13 (de 97:3). Further, epoxide 13 on treatment with Red-Al furnished diol 14,
which on oxidative acetalization with DDQ,5 gave acetal 15. Finally, oxidation of
terminal alcohol in 14 with Dess-Martin periodinane6 furnished aldehyde 2.
Scheme 3
PMP
H
OH
O
BnO
6
a
OH
7
H
BnO
R
d
OH
b
e
BnO
9 R = CH2OH
10 R = CHO
8
PMBO
R
f
O
BnO
OPMB
OPMB
c
O
BnO
g
H
BnO
O
OH
11 R = CO2Me
12 R = CH2OH
13
H
PMP
PMBO
a
O
OH
h
BnO
O
i
BnO
2
15
14
Reagents and conditions: a) Red-Al, THF, 0 oC, 5 h, 84%; b) PMBacetal, PPTS, CH2Cl2, 0 oC-rt, 2 h, 83% ; c) DIBAL-H,
CH2Cl2, CH2Cl2, 0 oC, 1 h, 86%; d) (COCl)2, DMSO, Et3N, CH2Cl2, -78 oC, 3 h, 85%; e) Ph3P=CHCO2Me, benzene,
reflux, 5 h, 78%; f) DIBAL-H, CH2Cl2, 0 oC, 4 h, 83%; g) (+) DIPT, Ti(iOPr)4, cumene hydroperoxide, CH2Cl2, -20 oC, 6
h, 75%; h) DDQ, CH2Cl2, MS-4o, 0 oC-rt, 8h, 74%; i) Dess-Martin periodinane, NaHCO3, CH2Cl2, 0 oC- rt, 2 h, 86%.
OH
OH
Oxazolidinone 16 (Scheme 4) on treatment with chloromethyl benzyl ether7
(BOMCl) in the presence of TiCl4 and Et3N in dry CH2Cl2 and subsequent reduction with
NaBH4 in MeOH gave alcohol 178. Oxidation of alcohol 17 under Swern reaction
conditions gave 18. For the synthesis of fragment 3a (Scheme 4), the addition of (Z)enolate, generated from 16, under Evans’ syn aldol9 protocol, by use of Bu2BOTf and
iPr2EtN, to the aldehyde 18 gave 19 with excellent diastereoselectivity (de 95:5).
Reduction of 19 with LiBH4 in ether resulted in diol 20, whose newly generated
stereocentres were confirmed from the nOe studies of the acetonide 21. For further
3
Abstract
synthesis, 20 was treated with anisaldehyde dimethyl acetal and 10 mol% of PPTS to
afford 22, which on reaction with DIBAL-H gave 23. Further, oxidation of alcohol 23
under Swern oxidation conditions gave aldehyde 24, which on reaction with OhiraBestmenn diazophosphonate10 reagent resulted in acetylenic compound 3a.
Scheme 4
O
O
O
O
N
a, b
BnO
16 Bn
d
OR
O
OBn
N
O
R = 17 CH2OH
R = 18 CHO
c
OH
Bn
e
19
OH
f
OBn
HO
O
O
OBn
20
21
g
PMP
O
OPMB
O
OPMB
h
OBn
HO
OBn
22
i
j
OHC
23
3a
OBn
24
o
Reagents and conditions: a) TiCl4, Et3N, BnOCH2Cl, CH2Cl2, 0 C, 8 h, 83%; b) NaBH4, MeOH, 0 oC, 5 h, 82%; c)
(COCl)2, DMSO, Et3N, CH2Cl2, -78 oC, 3 h, 75%; d) 16, Bu2BOTf, DIPEA, CH2Cl2, -78 oC, 3 h, 80%; e) LiBH4,
ether, 0 oC, 3 h, 85%; f) 2,2-DMP, PPTS, CH2Cl2, 1 h, rt, 91%; g) PMBacetal, PPTS, CH2Cl2, 0 oC-rt, 1 h, 83%; h)
DIBAL-H, CH2Cl2, 0 oC, 2 h, 87%; i) (COCl)2, DMSO, Et3N, CH2Cl2, -78 oC, 3 h, 88%; j) dimethyl-1-diazo-2oxopropylphosphonate, K2CO3, MeOH, 7 h, 75%.
In a different study, the aldol product 19 was treated with TBSOTf and 2,6lutidine11 to give 25
(Scheme 5),
which on reduction with DIBAL-H furnished
aldehyde 26. Finally, aldehyde 26 on reaction with Ohira-Bestmann diazophosphonate9
reagent was converted in to 3b.
Scheme 5
O
19
a
O
O
OTBS
OTBS
N
Bn
b
OBn
25
c
OHC
OBn
3b
26
Reagents and conditions: a) TBSOTf, 2,6-lutidine, CH2Cl2, 0 oC, 2 h, 92%; b) DIBAL-H, CH2Cl2, -78 oC, 1 h, 75%; c) dimethyl1-diazo-2-oxopropyl phosphonate, K2CO3, MeOH, 7 h, 74% (over two steps).
4
Abstract
Attempted coupling of aldehyde 2 with 3a and 3b independently under a variety
reaction conditions met with failure to afford the expected carbinol (Scheme 6)
Scheme 6
PMP
PMP
O
O
CHO
BnO
2
O
a
+
OH
O
BnO
X
OP
OP
OBn
1
OBn
3a P = PMB
3b P = TBS
Reagents and conditions: a) n-BuLi, THF, -78 oC.
Cross-Metathesis approach:
Having met with failure by the ynone approach to achieve the synthesis of C1C14 fragment, a different synthetic strategy was planned. According to the retro synthetic
analysis (Scheme 7), the synthesis of C1-C14 fragment I could be achieved from 27,
which inturn could be realised by regioselective cross metathesis (CM)12 between
Scheme 7
Ph
O
A
O
OH
OR
9
7
3
1
BnO 14
11
OBn
27
Ph
O
O
OR
OH
BnO
OBn
+
28
BnO
4
29a R = TBS
29b R = H
HO
OH
OBn
5
5
Abstract
fragments 28 and 29. The syn 1,3-diol in 28 could be attained by oxa-Michael13 addition
reaction, which inturn could be prepared from commercially available 1,4-butane diol.
Similarly, other sub segment 29 could be achieved from oxazolidinone 16 by aldol
reaction under Crimmins protocol.14
Accordingly, ester 11 (Scheme 8), on oxidative deprotection of PMB ether with
DDQ in aq. CH2Cl2 furnished alcohol 30, which on conjugate addition of a hemiacetal
anion made in situ from benzaldehyde in the presence of a catalytic amount of potassium
tertbutoxide,13 led to ester 31. Reduction of 31 with DIBAL-H at -78 oC gave aldehyde
32 which on treatment with vinylmagnesium bromide furnished 33 as a mixture of
isomers (1:1). The mixture of alcohols 33 was subjected to oxidation with Dess-Martin
periodinane in dry CH2Cl2 to give 34, which on reduction with Coreys’ chiral
oxazaborolidine15 using [R-(CBS)] gave 28 (94% de).
Scheme 8
Ph
OR
O
O
b
BnO
OMe
a
11 R = PMB
30 R = H
R
c
Ph
O
OH
O
e
BnO
d
31 R = CO2Me
32 R = CHO
Ph
O
O
BnO
O
O
BnO
33
f
28
34
Reagents and conditions: a) DDQ, CH2Cl2:H2O, rt, 5 h, 84%; b) PhCHO, t-BuOK, THF, 0 oC, 8 h, 77%; c) DIBAL-H,
CH2Cl2, -78 oC, 1 h, 68%; d) vinyl magnesium bromide, THF, 0 oC, 2 h, 84% (over two steps); e) Dess-Martin periodinane,
NaHCO3, CH2Cl2, 0 oC, 2 h, 78%; f) (R)-CBS, catecholborane, toluene, -78 oC, 12 h, 76%.
Aldol product 19 (Scheme 9) on reductive removal of the chiral auxiliary with
DIBAL-H in CH2Cl2 at -78 oC furnished the aldehyde 35, while, the similar reaction on
25 gave 26. The aldehydes 26 and 35 were homologated with (methylene)triphenyl
phosphorane in THF at 0 °C for 8 h to afford 29a and 29b respectively
6
Abstract
Scheme 9
OTBS
OTBS
a
OHC
25
OBn
OBn
26
29a
OH
OH
b
OHC
19
OBn
a
OBn
35
29b
Reagents and conditions: a) PPh3CH3I, n-BuLi, THF, 0 oC-rt, 9 h, 85%; b) DIBAL-H, -78 oC, 1 h, 90%
In order to synthesize 27, the two fragments 28 and 29a (Scheme 10) were
subjected to cross-metathesis reaction by using Grubbs’ 2nd generation catalyst,16 which
met with failure. However, cross metathesis reaction of 28 and 29b gave the expected
product 36 along with the formation of alkene dimer of 29b. Catalytic hydrogenation of
36 by use of PtO2 in EtOAc at room temperature gave 27.
Scheme 10
Ph
O
O
OH
Ph
BnO
28
+
OTBS
a
O
O
X
OH
OH
BnO
OBn
OBn
29a
Cl
O
O
NMes
MesN
Ph
OH
Cl
Ph
BnO
28
+
OH
a
O
O
OH
H
36
OBn
OBn
H
b
29b
27
Reagents and conditions:a) Grubbs-II, CH2Cl2, 40 oC, 6 h, 65%; b) H2, PtO2, EtOAc, rt, 2 h, 85%
7
PCy3 Ph
Gr-II
OH
BnO
Ru
Abstract
After the successful completion of the synthesis of 27, the studies were next
aimed at the synthesis of C15-C30 segment. According to the retro synthetic plan
(Scheme 11), fragment 37 could be made by coupling of two sub fragments 38 and 39,
while, 38 could be made from commercially available 1, 5-pentane diol derivative 40.
Similarly, the synthesis of fragment 39 could be achieved starting from 3-butyne 1-ol 41a
through vinyl iodide 41.
Scheme 11
PMBO
15
II
BnO
19
OTBS OH
OMOM
21
27
23
nPr
37
PMBO
OTBS
OMOM
CHO
BnO
I
+
nPr
38
BnO
39
OH
I
OH
40
41
OH
41a
The known epoxide 4218 on treatment with Red-Al in dry THF gave 43 (Scheme
12). Diol 43 was treated with anisaldehyde dimethyl acetal in the presence of PPTS in dry
CH2Cl2 to furnish 44, which on reduction with DIBAL-H in CH2Cl2 gave 45. Oxidation
of 45 under Swern oxidation conditions and subsequent reaction of 46 under Evans syn
aldol protocol using Bu2BOTf and i-Pr2EtN in CH2Cl2 gave 47. To get the required
stertochemistry at C21 position, the hydroxy group at C21 in 47 was inverted by
Mitsunobu reaction using DIAD and PhCO2H in THF to furnish benzoate 48, which on
hydrolysis with K2CO3 in MeOH afforded alcohol 49. Protection of alcohol in 49 with
TBSOTf furnished 50, which finally on reduction of the amide with LiBH4 in ether gave
alcohol 51. Oxidation of alcohol 51 with Dess-Martin periodinane gave aldehyde 38.
8
Abstract
Scheme 12
OH
H
O
42
O
b
a
OH
BnO
PMP
BnO
OH
43
H
BnO
d
OH
PMBO
OR
O
h
f
BnO
Xc
47
PMBO
46
O
BnO
Xc
g
48 R = COPh
49 R = H
PMBO
OTBS O
OTBS
j
i
BnO
e
CHO
BnO
OH
45
PMBO
44
OPMB
OPMB
c
BnO
O
BnO
Xc
OH
50
38
51
o
o
Reagents and conditions: a) Red-Al, THF, -20 C to 0 C, 4 h, 91%; b) PMBacetal, PPTS, CH2Cl2, 0 oC, 2 h, 80%; c)
DIBAL-H, CH2Cl2, 0 oC, 2 h, 80%; d) (COCl)2, DMSO, Et3N, CH2Cl2, -78 oC, 3 h, 79%; e) 16, Bu2BOTf, i-Pr2NEt, CH2Cl2,
-78 oC, 4 h, 89%; f) PhCO2H, DIAD, Ph3P, THF, 0 oC, 8 h, 64%; g) K2CO3, MeOH, rt, 4 h, 68%; h) TBSOTf, 2, 6-lutidine,
CH2Cl2, 0 oC, 1 h, 94%; i) LiBH4, ether, 0 oC, 2 h, 86%; j) Dess-Martin periodinane, NaHCO3, CH2Cl2, 0 oC, 2 h, 85%.
The other sub fragment 39 was prepared starting from commercially available 3butyne-1-ol
52.
Accordingly,
52
(Scheme
13)
on
zirconocene-promoted
carboalumination17 and quenching with iodine resulted the corresponding vinyl iodide 41,
which on oxidation under Swern oxidation conditions gave 53. Grignard reaction of 53
with n-propyl magnesium iodide in THF gave 54, which on oxidation gave the ketone 55.
Scheme 13
OH
ref. 17
OH
41
52
b
a
I
OH
CHO
53
O
c
I
I
54
55
OH
d
I
e
I
56
OMOM
I
39
o
Reagents and conditions: a) (COCl)2, DMSO, Et3N, -78 C, 3 h, 81%; b) n-propyl iodide, Mg, THF, 0 oC, 4 h, 75%; c) DessMartin periodinane, NaHCO3, CH2Cl2, 0 oC, 2 h, 92%; d) (R)-CBS, catecholborane, toluene, -78 oC, 12 h, 76%; e) MOMCl,
i-Pr2NEt, CH2Cl2, 0 oC-rt, 8 h, 82%.
Selective reduction of 55 with Coreys’ chiral oxazaborolidine15 [(R)-CBS] furnished 56
with required stereochemistry. Finally, alcohol 56 was protected on reaction with
MOMCl to furnish 39.
9
Abstract
Chapter II: Stereoselective Total Synthesis of Ophiocerin-B and D
Section A: Total synthesis of Ophiocerin-D
This section deals with the stereoselective total synthesis of Ophiocerin-D from D-xylose.
The chemical investigations on fresh water aquatic fungi by Gloer et al.20 resulted
in the isolation of tetrahydropyran derivatives ophiocerins A-C and ophiocerin D (1) from
Ophioceras venezuelense (Magnaporthaceae).21 The structural analysis of ophiocerin AD was arrived at by Gloer et al. from the spectral studies, while, the absolute
stereochemistry was assigned by CD spectrometry by the use of excitation chirality
method.
The retro-synthetic analysis of 57 (Scheme 15) indicated that it could be prepared
from 58 and butynoic acid 59, while, 58 in turn could be prepared from D-xylose
derivative 60. Thus, the synthetic strategy would be: a) deoxygente C-5 to methyl group,
b) retention of C3/C4 for C5/C6 of 57 and c) introduction of C3/C4 diol of 57 by
asymmetric dihydroxylation.
Scheme 15
Yamaguchi
protocol
OH
O
Deoxygenation
OMOM
OH
HO
O
OMOM
O
O
O
O
O
57
58
O
O
60
Wittig/dihydroxylation
+
COOH
59
Accordingly, the alcohol22 61 (Scheme 16) on protection with benzyl bromide
gave 62. The benzyl ether 62 on acid (5% H2SO4, THF) catalyzed hydrolysis at room
temperature gave 63. Oxidative cleavage of 63 with H5IO6 in EtOAc at room temperature
afforded the aldehyde 64, which on concomitant Wittig olefination furnished the ester 65.
Treatment of 65 with TBDMSCl and imidazole in CH2Cl2 gave TBS ether 66.
Asymmetric dihydroxylation23 of ester with AD-mix- gave the diol 67, which on
protection with MOMCl in the presence of DIPEA afforded the MOM ether 68. Having
established all the four stereocentres with absolute stereochemistry, next it was aimed at
the cyclization and introduction of isocrotonyl side chain at C-5 OH group.
10
Abstract
Accordingly, ester 68 on reduction with LAH in THF at room temperature gave
the alcohol 69, which on further reaction with p-TsCl (Et3N, CH2Cl2) furnished tosylate
70. Tosylate 70 was exposed to TBAF at room temperature to result in desilylation and
Scheme 16
O
O
O
OH
OH
c
b
O
HO
O
O
a
BnO
O
BnO
62
63
CHO
64 OBn
OH
61
OR
TBSO
O
OR
O
f, g
d, e
TBSO
OMe
OMe
h, i
OR
OBn OR
67 R = H
68 R = MOM
OBn
65 R = H
66 R =TBS
OMOM
OBn OMOM
69 R = H
70 R = Ts
Reagents and conditions: (a) BnBr, NaH, THF, 0 oC-rt, 4 h, 87%; (b) 5% H2SO4, THF, 40 oC, 8 h, 71%; (c) H5IO6,
EtOAc:H2O, 0 oC, 5 h, 82%; (d) Ph3P=CHCO2Me, benzene, reflux, 4 h, 75%; (e) TBDMSCl, imidazole, CH2Cl2, rt, 5
h, 92%; (f) AD-mix-, BuOH, rt, 12 h, 62%; (g) MOMCl, DIPEA, CH2CL2, rt, 8 h, 91%; (h) LAH, THF, 0 oC-rt, 1
h, 89%; (i) p-TsCl, Et3N, CH2Cl2, 0 oC-rt, 3 h, 68%.
concomitant cyclization in one-pot to give the cyclized product 71 in 78% yield. TBAF24
in the present study acted as a desilylating agent, besides as a base to promote a facile
cyclization reaction (Scheme 17).
Scheme 17
OMOM
RO
OMOM
OMOM
a
O
OMOM
c
b
O
O
71 R = Bn
60 R = H
O
72
OMOM
O
OMOM
d
57
O
O
73
(j) TBAF, THF, rt, 5 h, 78%; (k) H2, Pd(OH)2, MeOH, rt, 5 h, 87%; (l) 2-butynoic acid, 2,4,6trichlorobenzoyl chloride, Et3N, THF, DMAP, toluene, rt, 10 h, 79%; (m) Lindlar catalyst, MeOH, rt, 2 h, 75
%; (n) t-BuOH, PPTS, 70 oC, 3 h, 71%.
For the introduction of the side chain, the benzyl group in 71 was removed by
hydrogenation using Pd(OH)2 in MeOH to give the alcohol 60. Further, acylation of 60
11
Abstract
with 2-butynoic acid 59 under Yamaguchi reaction25 conditions gave 72 in 79% yield,
which on selective hydrogenation in the presence of Lindlar catalyst26 afforded 73.
Finally, PPTS catalyzed deprotection of MOM groups in 73 furnished ophiocerin D 57.
The optical rotation value [α]D +38.4 of synthetic 57 was matching with that of natural
product [α]D +40.
Section B: Stereoselective total synthesis of Ophiocerin-B
This section deals with the stereoselective total synthesis of Ophiocerin-B from L-malic
acid.
The retro-synthetic analysis of 74 (Scheme 18) indicated that ophiocerin-B could
be prepared from 75, while 75 in turn could be prepared from L-malic acid. Thus, the
synthetic strategy would be: a) deoxygenation of γ-hydroxy group to methyl group b)
introduction of C3/C4 of 74 diol by Sharpless asymmetric dihydroxylation.
Scheme 18
OH
OTBS O
OH
OH
O
O
HO
OH
OMe
O
ophiocerin B
75
O
O
L-malic acid
74
Accordingly, the known alcohol 7627 (Scheme 19) derived from L-malic acid, on
oxidation under Swern reaction conditions gave aldehyde 77, which on Wittig olefination
with (ethoxycarbonylmethylene)triphenyl phosphorane in benzene reflux furnished ester
78.
Scheme 19
OTBS
L-malic acid
Ref. 27
a, b
R
OTBS
CO2Et
76 R = CH2OH
77 R = CHO
OTBS O
OH
TBSO
c
78
CO2Et
d
CO2Et
O
75
Reagents and conditions: a) (COCl)2, DMSO, Et3N, CH2Cl2 -78 oC, 3 h, 84%; b) Ph3P=CHCO2Et, benzene,
reflux, 4 h, 75%; c) AD-mix-, t-BuOH, rt, 12 h, 65%; d) 2,2-DMP, PPTS, CH2Cl2, rt, 2 h, 85%.
79
OH
Asymmetric dihydroxylation of 78 using AD-mix-β and catalytic amount of
methane sulfonamide in t-BuOH/H2O (1:1) (Scheme 19) furnished diol 79. Acetonation
12
Abstract
of vic-diol with 2,2-DMP and catalytic PPTS gave 75, which on reduction with DIBALH furnished 80. Tosylation of 80 with p-TsCl and Et3N in CH2Cl2 gave 81, which on
reaction with TBAF in dry THF gave 82. In the present study, TBAF acted as a
desilylating agent besides as a base to promote cyclisation in single step to afford 82.
Finally, deprotection of acetonide using PTSA in MeOH gave 74.
Scheme 20
O
a
75
O
O
TBSO
O
c
d
OR
74
O
80 R = H
81 R = Ts
b
82
Reagents and conditions: a) DIBAL-H, CH2Cl2, 0 oC, 2 h, 86%; b) p-TsCl, Et3N, CH2Cl2, rt, 4 h, 78%; c) TBAF,
THF, rt, 10 h, 65%; d) PTSA, MeOH, rt,4 h, 85%.
Chapter III: Synthesis of cyclic amides and -amino acids
Section A: Synthesis of cyclic amides
This section deals with the synthesis of cyclic amides from D-mannose
The cyclic amides that stack on top of one another forming nanotube-like
structures have been the subject of many investigations due to their utility in chemical,
biological and materials science.28 These cyclic oligomers, composed of carbohydrate
O
O
NH
O
HN
NH
O
O
O
NH
O
83
N
O
O
O
O
O
O
O
O
O
86
O
O
O
O
O
O
O
O
HN
O
O
O
O
NH
HN
O
Figure 2
13
N
85
O
O
NH
HN
NH
O
84
O
O
O
HN
NH
O
O
O
O
O
HN
O
O
O
HN
O
HN
O
O
O
O
O
O
O
NH
O
N
N
87
O
O
Abstract
units, have been used in the areas of drug delivery, asymmetric synthesis and also as
enzyme mimetics.29 Vancomycin, a representative of the glycopeptide class of
antibiotics,30 is being used for over four decades as a weapon of last resort to combat
bacterial disease. The cyclic peptides adopt antiproliferative activity by inhibiting the
growth of several cancer cell lines31 and cyclic peptides form tublar ion-conducting
channels in phospholipid layers.32 Kessler et al.33,34 prepared cyclic peptides using
constrained sugar amino acid and β-hGly alternatively, which showed symmetry in
acetonitrile. In the present study cyclic amides 83-87 (Figure 2) were prepared.
Accordingly, known 2, 3; 5, 6 di-O-isopropyledine D-mannose 88, (Scheme 20)
obtained from commercially available D-mannose, was treated with trimethylsulfoxinium
iodide in the presence of potassium tert. butoxide in dry DMSO at room temperature for
8 h to afford mannose methonal 89. Conventional tosylation of primary alcohol 89 with
p-TsCl, Et3N and catalytic DMAP in CH2Cl2 at room temperature for 5 h gave 90.
Tosylate 90 was further treated with NaN3 in DMF at 80 C for 8 h to afford azide 91,
which on reduction with LAH in dry THF furnished 92.
Scheme 20
O
O
O
OH
O
O
OH
b
a
D-Mannose
O
O
O
O
O
88
d
OTs
c
O
O
O
90
89
O
O
O
O
O
O
N3
O
O
O
e
O
NH2
O
91
O
92
Reagents and conditions: a) cat. H2SO4, Dry CuSO4, Acetone, rt, 12 h, 92%; b) TMSOI, t-BuOK, DMSO, rt; 3 h,
86% c) TsCl, Et3N, DMAP, CH2Cl2, rt, 3 h, 83%; d) NaN3, DMF, 80 oC, 8 h, 65%; e) LAH, THF, 0 oC, 2 h, 76%.
Condensation of amine 92 (Scheme 21) with isophthaloyl chloride 97 gave 93 as
a major product, while with pyridine 2,6-dicarbonyl dichloride 98, it furnished 94 as a
major product. The diacetonides in 93 and 94 were hydrolysed to give the respective
diols 93a and 94a which were subjected to oxidative cleavage to give aldehydes 95 and
14
Abstract
96, aldehydes 95 and 96 on further reduction with NaBH4 gave alcohols 95a and 96a,
which were treated with MsCl and Et3N in dry CH2Cl2 to furnish the corresponding
mesylates, which, on further reaction with NaN3 in DMF furnished respective azides 99
and 100. Finally, reduction of the azides 99 and 100 with Ph3P in MeOH furnished 101
and 102 respectively.
Scheme 21
O
NH
92
a
O
X
O
HN
NH
O
O
O
O
O
O
O
O
OH
O
O
93 X = CH
94 X = N
X
NH
c, d
O
O
O
O
R
HO
93a X = CH
94a X = N
HN
O
O
e, f
O
O
O
R
95 X = CH; R = CHO
95a X = CH; R = CH2OH
96 X = N; R = CHO
96a X = N; R = CH2OH
O
X
NH
HN
O
O
HO
OH
O
O
O
O
O
O
HN
O
b
O
O
X
g
O
O
R1
R1
1
99 X = CH, R = N3; 100 X = N, R1 = N3
101 X = CH, R1 = NH2; 102 X = N, R1 = NH2
Reagents and conditions:a) isophtaloyl chloride/2,6-dicorbonyl dichloride, Et3N, CH2Cl2, rt, 6 h, 85%; b) PTSA,
MeOH, rt, 1 h, 80%; c) NaIO5, CH2Cl2, rt, 6 h, 75%; d) NaBH4, MeOH, 0 oC-rt, 8 h, 84%; e) MsCl, Et3N, CH2Cl2,
0 oC, 4 h, 75%; f) NaN3, DMF, 80 oC, 4 h, 78%; g) , LAH, THF, rt, 1 h, 75%.
For the synthesis of the cyclic amides 83 and 85 the common precursor was 101.
Thus, condensation of 101 with 97 gave 83, while, with 98 it gave 85. Similarly,
condensation of 102 with 98 afforded 84.
Likewise, the other two cyclic amides 86 and 87 (Scheme 22) were prepared
from diol 95a, wherein condensation of 95a with 97 gave 86, while with 98 it furnished
87.
15
Abstract
Scheme 22
101
a
83
a
102
b
b
84
86
O
95a
b
85
87
X
Cl
O
Cl
97 X = CH
98 X = N
Reagents and conditions: a) 97, Et3N, CH2Cl2, 0 oC, rt, 6 h, 35%; b) 98, Et3N, CH2Cl2, 0 oC, rt, 7 h, 30%
The above cyclic amides 83-87 showed metal binding with Li, Na, K, Rb and Cs.
Further, Li and Na have shown strong binding with these cyclic amides. The MSMS
studies showed Li and Na binding inside the cavity of the cyclic amides while, K, Rb and
Cs were found not binding strongly, indicating only peripheral binding with the cyclic
amides.
Section B: An efficient ZrCl4 catalyzed aza-Michael addition reaction:
synthesis of C-linked carbo β3-amino acids
This section deals with the synthesis of C-linked carbo -amino acids using ZrCl4 as a
Lewis acid catalyst
The synthesis of β-amino acids,35 which are constituents of several natural
products and useful starting materials for the synthesis of bioactive compounds, has
received much attention in the recent past.36 β-Peptides,37 the non-natural oligomers of βamino acids, are targeted as potential peptidomimetics,38 since they are stable to
peptidases and conformationaly more rigid unlike peptides derived from α-amino acids.
The presence of an additional methylene group in them provides an opportunity to create
skeletal as well as stereochemical diversity. A new method was envisaged for the
efficient preparation of β- amino acids by aza-Michael addition.
Accordingly, to evaluate the validity of ZrCl4 (10 mol%) as a catalyst for azaMichael addition using the of aromatic amines and methyl acrylate as Michael acceptor
gave the dialkylated amine, while, acrylonitrile formed the mono alkylated product
16
Abstract
(Scheme 23). The method has been established with a variation of aromatic and aliphatic
amines.
Scheme 23
CO2Me
R'NH2 / ZrCl4 (10 mol%)
CO2Me
R'
N
CO2Me
RT
R ' = alkyl, aryl
R'NH2 / ZrCl4 (10 mol%)
R
CN
N
CN
R'
RT
R ' = alkyl, aryl
Scheme 24
O
O R'
BnNH2 / ZrCl4 (10 mol%)
R
H3CO
103
H3CO
RT
R''
R
104
R ' = H, R" = NHBn
R' = NHBn, R" = H
R = Sugar
TABLE 1: ZrCl4 catalysed aza-Michael addition of g-alkoxy-a, b-unsaturated esters
Entry
-unsaturated ester
O
O
R
O
1
O
H3CO
O
O
O
OCH3
H3CO
O
R1
O
O
2
104e:104f
90:10
1
O
O
O
O
O
O
103c
104c:104d
90:10
R1
R
H3CO
O
O
OCH3
104c R = H, R1= NHBn
104d R = NHBn, R1= H
(93%)
O
O
O
O
O
3
R
H3CO
103b
H3CO
1
104a R = H, R 1= NHBn
104b R = NHBn, R = H
(92%)
O
2
104a:104b
87:13
O
H3CO
103a
O
time (h)
R1
H3CO
O
H3CO
d..r
b- amino ester (Yield%)
O
104e R = H, R1= NHBn
104f R = NHBn, R1= H
(81%)
17
Abstract
Having established the ZrCl4 catalyzed solvent free conditions for aza- Michael
addition, the study was then extended to γ-alkoxy α, β-unsaturated esters 103 (Scheme
24) derived from the corresponding carbohydrate aldehydes. Accordingly, reaction of
ester 103a with BnNH2 (1 eq.) at room temperature in the presence of ZrCl4 (10 mol %),
was indeed very facile and gave a separable diastereomeric mixture of 104a and 104b
(Table 1) in 1-2 h. This is a remarkable advancement over our earlier procedure. Further,
reaction of esters 104b and 104c under ZrCl4 catalyzed conditions with BnNH2 gave
104c/104d and 104e/104f respectively as a separable mixture.
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20