Abstract
The thesis entitled “Studies Directed Towards the Synthesis of Acremodiol
and Acremonol; Synthesis of Styryl lactones [(+)-Crassalactone B, C, (+)-Howiionol
A, (+)-Tricinnamate, (+)-Goniofufurone, (+)-Dicinnamoyl Goniofufurone] and
Synthesis of Carbo β2-Peptides” is divided into three chapters.
Chapter I: Studies directed towards the synthesis of acremodiol and acremonol
This chapter is dealt with the studies directed towards the synthesis of
acremodiol, acremonol and epi-clonostachydiol by Yamaguchi esterification and macrolactonisation
Acremodiol (1) and acremonol (2), two 14-membered bis-macrolides, were
isolated by Berge et al.1 from a soil sample of the Bermuda Islands Acromonium-like
anamorphic fungus. Compound 1 has four stereocenters (5R, 6R, 11R, 14R) with a 5,6-vic
diol and an α, β-unsaturated ester moiety. Similarly, 2 has three asymmetric centers (6R,
two units of α, β-unsaturated esters.
11R, 14R) with a carbonyl group at C-5 and
Structurally, these compounds are closely related to clonostachydiol,2,3 and colletodiol.4,5
O
HO
O
O
14
5
6
O
O
O
11
O
R
1
R
O
14
O
6
O
HO
11
OH
O
14
5
6
O
11
OH
O
Acremodiol (1) R1 = OH, R = H
(5R, 6R, 11R, 14R)
1
Acremodiol (1a) R = H, R = OH
Acremonol (2)
(6R, 11R, 14R)
Epi clonostachydiol (3)
(5R, 6R, 11R, 14R)
(5R, 6R, 11S, 14R)
Figure 1
Macrolides 1 and 2, unlike colletodiol have shown activity against a series of
Gram positive bacteria and fungi. This chapter reports our attempts on the first synthesis6
of 1a and 2, to determine the absolute stereochemistry.
1
Abstract
Synthesis of acremonol 2
The retrosynthetic analysis of 2 is shown in Scheme 1. Macrolide 2 could be
realized by macrolactonization from the seco-acid 4, which inturn could be made from
acid 5 and alcohol 6. The acid was envisioned from D-mannitol derivative 7, while,
alcohol 6 was planned from chiral propylene oxide 8.
Scheme 1
O
5
R
6
O
O2
OH
HO
O
OH
O
OH
OPMB
O
PMBO
9
OTBS
O
O
O 14
R
10 R 11
OH
2
O
O
1
4
O
+
O
OBn
5
OBn
6
SO2Tol
O
8
OH
O
OH O
7
Synthesis of C-8 to O-1 segment
The known epoxide 87(Scheme 2) on reaction with allyl magnesium chloride in
ether and subsequent silylation of the secondary alcohol 9 (TBSCl, imidazole) in CH2Cl2
gave 9a in 70% yield. Ozonolysis of 9a and Wittig olefination of resulting aldehyde
afforded 10 (72%), which on reduction with DIBAL-H furnished allylic alcohol 11 in
77% yield. Sharpless epoxidation8 of 11 with (-)-DIPT in CH2Cl2 gave 12 (75%), which
2
Abstract
Scheme 2
OR
O
8
OTBS
b
a
O
9 R = OH
9a R = OTBS
10
OTBS
c
OH
O
11
OTBS
OTBS
d, e
f
R
O
35
OTBS
g
13
OH
14 OBn
12 R = OH
12a R = Cl
OTBS
O
OH
O
15
SO2Tol
h
O
i
O
SO2Tol
OBn 6
OBn
Reagents and conditions: a) i) allyl chloride, Mg, dry ether, -78 oC, 2 h; ii) TBSCl, Imidazole, CH2Cl2 , RT, 4
h; b) i) O3, CH2Cl2, -78 oC, 30 min; ii) Ph3P=CHCOOEt, CH2Cl2, RT, 4 h; c) DIBAL-H, CH2Cl2, -78 oC, 2
h; d) (-)-DIPT, 4, cumene hydroperoxide, Ti(OiPr)4, CH2Cl2, -20 oC, 3 h; e) Ph3P, NaHCO3, CCl4, reflux,
30 min; f) Na, Ether, RT, 12 h; g) Ag2O, BnBr, CH2Cl2, reflux, 12 h; h) i) O3, CH2Cl2 -78oC, 30 min; ii)
Ph3P=CHCOOC2H4SO2Tol, CH2Cl2, RT, 4 h; i) TMSCl, H2O, CH3CN, RT, 1 h.
on treatment with Ph3P and NaHCO3 in CCl4 followed by further reaction of 12a with
Na in dry ether afforded 13 (73%). Alkylation of 13 with BnBr and Ag2O in CH2Cl2 gave
14 (78%), which on ozonolysis in CH2Cl2 followed by Wittig olefination9 afforded 15
(71%). Finally, desilylation of 15 with TMSCl (cat.) and H2O in CH3CN gave alcohol 6
in 88% yield.
Synthesis of C-2 to O-7 segment
Commercially available known diol 7 on reaction with BzCl and Et3N in CH2Cl2
gave 16 in 78% yield (Scheme 3). Benzoate 16 on selective acetonide deprotection and
concomitant oxidative cleavage with H5IO6 in ether10 gave aldehyde 16a, which on
subsequent reduction with LAH afforded 17 (42%, three steps).
3
Abstract
Scheme 3
OH
O
a
O
O
O
18
17
d
O
H
HO
O
e
OH
OH
16a
HO
O
HO
O
O
OBz O
OBz O
16
O
c
b(ii)
H
O
O
O
7
O
OBz
O
b(i)
O
O
OH
OBz
O
OR
O
f
OPMB
19 R= H
20 R = Ts
HO
OH
g
OH
HO
OPMB
OPMB
22
21
OCH3
i
C2H5O
23
OTBS
O
OH
O
h
C2H5O
OPMB
O
j
OTBS
HO
24
OPMB
5 OPMB
Reagent and conditions:
a) BzCl, CH2Cl2, Et3N, 0 oC -RT, 12 h; b) i) H5IO6, Ether, RT, 6 h; ii) LAH, THF, 0 °C-RT, 12 h; c) anisaldehyde
dimethyl acetal, PPTS, CH2Cl2, RT, 2 h; d) DIBAL-H, CH2Cl2, 0 oC-RT, 2 h; e) TsCl, Et3N, CH2Cl2, RT, 14 h; f)
DMSO, NaBH4, 160 oC, 10 min; g) 60% aq. AcOH, RT, 12 h; h) i) NaIO4, MeOH:H2O (5:1), 0 oC -RT, 3 h; ii)
Ph3P=CHCOOEt, CH2Cl2, 0 oC-RT, 4 h; i) TBSCl, imidazole, CH2Cl2, RT, 4 h; j) 0.5N NaOH, MeOH, RT, 24 h.
Reaction of triol 17 with anisaldehyde dimethyl acetal and PPTS in CH2Cl2 gave
acetal 18 in 71% yield (dr 3:2). Reductive opening of the PMB acetal in 18 from the less
hindered side with DIBAL-H in CH2Cl2 gave the diol 19 (75%), which on selective
tosylation gave 20 (71%). Reduction of tosylate 20 with NaBH4 in DMSO11at 160 °C
furnished 21 (92%), which on acetonide deprotection with 60% aq. AcOH afforded triol
22 (88%). Oxidative cleavage of 22 and Wittig olefination gave the unsaturated ester 23
in 72% yield. Treatment of 23 with TBSCl gave 24 (90%), which finally on base
hydrolysis with 0.5N NaOH in MeOH gave acid 5 in 94% yield.
Acid 5 was subjected to esterification with alcohol 6 under Yamaguchi reaction
conditions12 to give 25 in 77% yield (Scheme 4). Desilylation of 25 with TMSCl (cat.)
and H2O in CH3CN furnished 26 (87%), which on selective hydrolysis of sulphonyl ester
with DBN in dry benzene9 afforded 4 in 78% yield. Macrolactonization of the resulting
4
Abstract
seco-acid 4 was then realized under the Yamaguchi protocol6,12 with 2,4,6tirchlorobenzoyl chloride, under high dilution conditions in toluene to afford 27 in 52%
Scheme 4
OTBS
O
O
O
O
O
OH
OPMB
PMBO
a
c
PMBO
OH
O
5
RO
+
OH
OBn
O
O
O
SO2Tol
O
b
OBn 6
4 OH
25 R = TBS
26 R = H
O
SO2Tol
O
O
O
d
O
O
f
PMBO
g
O
O
O
O
O
OBn
OH
OBn
O
e
OBn
O
29
O
2
27 R = PMB
28 R = H
Reagents and conditions: a) i) 2,4,6-trichlorobenzoyl chloride, 5, Et3N, dryTHF, RT, 2 h, ii) 6, DMAP, toluene, RT,
1 h; b) cat.TMSCl, H 2 O, CH 3 CN, RT, 1 h; c) DBN, dry benzene, RT, 12 h; d) 2,4,6-trichlorobenzoyl chloride, Et 3 N,
dry THF, RT, 2 h; ii) DMAP, toluene, 90 °C, 10 h; e) DDQ, CH 2 Cl 2 :H 2 O (19:1), RT, 3 h; f) Dess-Martin
periodinane, dry CH2Cl2, RT, 12 h; g) TiCl4, dry CH2Cl2, RT, 2 h.
yield. The oxidative deprotection of 27 with DDQ in aq. CH2Cl2 gave 28 in 68% yield.
Oxidation of secondary alcohol 28 with Dess-Martin periodinane13 in CH2Cl2 afforded 29
in 80% yield. Finally, 29 on debenzylation with TiCl4 in CH2Cl2 at room temperature for
2 h gave 2 in 79% yield.
However, the spectral data14and optical rotation value14 [α]D -55.3 (c 0.22,
MeOH); Lit.1 [α]D +40 (c 0.3, MeOH) obtained for synthetic 2 and the data reported in
the literature1 were not corresponding to each other. Thus, it is evident from the synthesis
of 2 that the structure proposed in literature for natural 2 is incorrect.
5
Abstract
Synthesis of epi-clonostachydiol
Bis-lactone 27 (Scheme 5) was treated with TiCl4 in CH2Cl2 at room temperature
for 2 h to afford epi-clonostachydiol 3 in 78% yield as white solid, m. p.165-168 °C; [α]
D, -15.7
(c 0.23, CHCl3); Lit.7 [α]D -31 (c 1.0, MeOH).
Scheme 5
O
O
O
O
a
PMBO
O
O
OBn
O
HO
OH
O
27
3
Reagents and conditions: a) TiCl4, dry CH2Cl2, RT, 2 h.
Synthesis of macrolide 1a
The stereocenters at 5, 6, 11 and 14 positions of acremodiol 1 were assigned as
5R, 6R, 11R and 14R by Berge et al. who isolated the molecule from fungi. But the
synthetic (5R, 6R, 11R, 14R) acremodiol (synthesized by our group), whose spectral data
and optical rotation values were not matching with the natural one1. The synthetic
acremonol (6R, 11R, 14R) 2, synthesized by lactonization route also did not match with
the natural 2.
From the literature data on the macrodiolide class of natural products 1 and 2 and
synthetic studies on acremonol 2, it was proposed to synthesize the (5R, 6R, 11S, 14R)
diastereomer of the originally proposed structure of acremodiol 1, to determine the
absolute stereochemistry of 1, later 2. So, we planned to synthesize acremodiol with C-11
as ‘S’ and keeping the other stereocenters as same. The retro synthetic analysis of
acremodiol 1a is shown in Scheme 6.
6
Abstract
Scheme 6
Yamaguchi esterification
O
HO
5
R
R
O 8
6
O
1
O
O 14
R
S
PMBO
11
O 1a
OH
HO
OH
OBn
O
Sharpless epoxidation
30
Yamaguchi Macrolactonisation
OTBS
OH
O
+
OH
OPMB
O
O
OBn
O
SO2Tol
O
8
32
31
OH
O
O
OH O
7
Accordingly, allylic alcohol 11 (Scheme 7) on reaction with (+)-DIPT and
Ti(Oipr)4 in CH2Cl2 gave the epoxy alcohol 33 (72%), which on reaction with Ph3P and
NaHCO3 (cat.) in CCl4 at reflex gave the epoxy chloride 33a in 66% yield.
Scheme 7
OTBS
OH
OTBS
OTBS
a
R
11
33 R = OH
33a R = Cl
OTBS
d
O
SO2Tol e
O
35
OBn
36
34 OH
O
OTBS
c
b
OH
O
O
OBn
32
SO2Tol
OBn
Reagents and conditions: a) (+)-DIPT, 4, cumene hydroperoxide, Ti(OiPr)4, CH2Cl2, -20 oC, 3 h; b) i) Ph3P,
NaHCO3, CCl4, reflux, 30 min; ii) Na, Ether, RT, 12 h; c) Na, Ether, RT, 12 h; d) Ag2O, BnBr, CH2Cl2, reflux,
12 h; d) i) O3, CH2Cl2, -78 o C, 30 min; ii) Ph3P=CHCOOC2H4SO2Tol, CH2Cl2, RT, 4 h; e) i) TMSCl, H2O,
CH3CN, RT, 1 h.
7
Abstract
Fragmentation of 33a with Na in dry ether afforded olefin 34 (75%), which on
reaction with BnBr and Ag2O in CH2Cl2 at reflux furnished ether 35 (70%). Ozonolysis
of 35 in CH2Cl2 gave aldehyde, which on subsequent Wittig olefination15 gave 36 in 70%
yield. Desilylation of 36 with TMSCl (cat.) and H2O in CH3CN afforded 32 in 85% yield.
Catalytic hydrogenation of the ester 24 (Scheme 8) with PtO2 in EtOAc afforded
37 (94%), which on hydrolysis with 0.5N NaOH in MeOH gave acid 31 (90%).
Scheme 8
OTBS
O
OTBS
a
O
O
OTBS
b
O
OH
O
OPMB 24
OPMB 31
OPMB 37
Reagents and conditions: a) PtO2, H2, EtOAc, RT, 4 h; b) 0.5N NaOH, MeOH, RT, 24 h.
Condensation of acid 31 with alcohol 32 through its mixed anhydride gave the
ester 38 in 72% yield (Scheme 9). Desilylation of 38 with HF-pyridine complex in THF
afforded 39 (73%), which on hydrolysis with DBN gave the seco-acid 30 (68%).
Scheme 9
OTBS
O
O
O
O
O
OH
OPMB
OH
TBSO
+
O
HO
OBn
O
39
O
SO2Tol
SO2Tol
32
O
O
O
O
c
PMBO
OBn
O
38 O
SO2Tol
O
OBn
b
PMBO
a
31
PMBO
O
O
d
e
HO
PMBO
OH
O
O
O
OBn
OBn
O
OH 30
40
OH
O
1a
Reagents and conditions: a) i) 2,4,6-trichlorobenzoyl chloride, 31, Et3N, dry THF, RT, 2 h; ii) 32, DMAP,
toluene, RT, 1 h; b) HF-Pyridine complex, dry THF, RT, 6 h; c) DBN, dry benzene, RT, 12 h; d)
2,4,6-trichlorobenzoyl chloride, Et3N, dry THF, RT, 2 h; ii) DMAP, toluene, 90 °C, 10 h; e) TiCl4, dry
CH2Cl2, RT, 2 h.
8
Abstract
Macro lactonization of 30 under Yamaguchi reaction conditions afforded 40 in 58%
yield. Finally, bis-lactone 40 was treated with TiCl4 in CH2Cl2 to give 1a in 80% yield.
The spectroscopic data and optical rotation values [α]
D
-52.7 (c 0.23, MeOH);
Lit.1 [α]D +98 (c 0.33, MeOH) of 1a did not match that of acremodiol1 and hence the
structure of the natural product is still unresolved.
Thus, the data of the synthetic bis-macrolides 1a and 2 resulted, while attempting
the first synthesis of acremonol and acremodiol, did not match with the spectral (1H, 13C,
ESI-MS and IR) analysis, besides the optical rotation values reported for the natural
products. Thus, the efforts in the direction of the first synthesis of acremodiol and
acremonol met with failure15 to result in the synthesis of natural products. However, this
work reports a successful synthesis of epi-clonostachydiol 3.
Chapter 2: Synthesis of Styryl-lactones [(+)-Crassalactone B, C, (+)-Howiionol A,
(+)-Tricinnamate, (+)-Goniofufurone, (+)-dicinnamoyl Goniofufurone]
This chapter is dealt with the first total synthesis of (+)-crassalactone B, (+)tricinnamate and synthesis of (+)-crassalactone C, (+)-howiionol A, (+)-goniofufurone,
(+)-dicinnamoyl goniofufurone by using Mitsunobu inversion, Meldrum’s acid,
Yamaguchi esterification and ring closing metatheses.
Styryl-lactones
(+)-crassalactone
B
(1),
(+)-crassalactone
C
(2),
(+)-
goniofufurone (4), (+)-howiionol A (5) are natural heterocyclic compounds from
Annonaceae family.16 (+)-Tricinnamate17 (6), and (+)-dicinnamoyl goniofufurone (3) are
non-natural styryl-lactones. The new styryl-lactones (+)-crassalactone B (1), (+)crassalactone C (2) were isolated17 from a cytotoxic ethyl acetate soluble extract from the
leaves and twigs
goniofufurone18 (4)
of
Polyalthia crassa along with known styryl-lactones (+)-
and (+)-howiionol A19 (5). The isolated (+)-goniofufurone (4)
reported earlier18a from the stem bark of Goniothalalamus giganteus and whose absolute
stereochemistry was determined previously through synthetic work18b-d. (+)-Howiionol A
9
Abstract
5 was reported previously by Chen et al.19b and it’s stereochemistry19a was confirmed17 by
single-crystal X-ray diffraction analysis.
O
O
OH
O
8
O
3
4
7
O
O
2
O6
5
O
O
O
1
HO
O
O
O
O
O
(+)-Crassalactone B (1)
(+)-dicinnamoyl
Goniofufurone (3)
(+)-Crassalactone C (2)
O
OH
4
O
5
O
OH
O
3
O
O
O
2
O
1
6
O
O
7
HO
O
O
O
8
O
OH
O
O
(+)-Goniofufurone (4)
(+)-Howiionol A (5)
O (+)-Tricinnamate (6)
Figure 2
The biological evaluation17,20 of new isolates 1 and 2 including synthetic (+)tricinnamate (6) revealed that they possess excellent antitumoral properties as well as
antibiotic potential with less toxicity like (+)-goniofufurone (4) and (+)-howiionol A
(5)22.
Having a general interest in the total synthesis of natural products23, this chapter
describes the first stereoselective total synthesis of 1 and 6. In addition, the synthesis of
(+)-howiionol A (5), (+)-crassalactone C (2) (+)-goniofufurone (4) and (+)-dicinnamoyl
goniofufurone (3) has also been achieved.
Synthesis of (+)-crassalactone B (1), (+)-goniofufurone (4) and (+)-tricinnamate (6)
Initially, we envisaged that the absolute configuration at C(2), C(3) and C(4) of
diacetone D-glucose (DAG) could be correlated to C(4), C(5) and C(6) of 1. Thus, the
10
Abstract
retrosynthetic analysis, depicted in Scheme 1 envisions that 1 could be obtained from 7
by Yamaguchi esterification and deprotection of benzyl group. Compound 7 in turn could
be made from 8 by the addition of Meldrum’s acid, which would result in a concomitant
lactonisation. Lactol 8 in turn would be realized from carbinol 9. Compound 9 could be
prepared from DAG 11 by Mitsunobu inversion and simple chemical transformations.
Retro synthesis
Scheme 1
OH
OBn
O 4
8
O
3
7
RO
OBn
O
6 5
O
2
OH
O
1
HO 7
O
O
RO
OH
8
R = allyl
R = cinnamoyl,
crassolactone B (1)
R = H, goniofufurone (3)
O
1
OR
7
3
8
6
OH
OH
O
O
O
4
5
OR
O
OH
2
O
OR
R = cinnamoyl,
tricinnamate (6)
RO
10
RO
OH
9
O
R = allyl
R = allyl
O 6
O1
5
O
4
O
2
HO 3 11 O
DAG
Similarly, 6 could be realized from 10 by PDC oxidation, esterification and ring
closing metathesis (RCM), which in turn could be obtained from the intermediate 9.
Thus, the three compounds 1, 3 and 6 could be very efficiently synthesized from
the common intermediate 9 that could be realized from the abundantly available Dglucose derivative DAG (11).
11
Abstract
Synthesis of (+)-crassalactone B (1)
Accordingly, commercially available D(+)-glucose derivative 11 was treated with
NaH and allyl bromide (Scheme 2) in THF to afford 12 in 95% yield. Selective
deprotection of 5, 6-O-isopropylidene group in 12 with 60% aq. acetic acid at room
temperature gave diol 13 (90%), which on oxidative cleavage (NaIO4) in aq. MeOH at
room temperature afforded aldehyde 14 (92%).
Scheme 2
O
O
O
a
O
O
HO
O
HO 11 O
O
O
O
O
O
HO
b
O
O
12
c
O
13
e
O
OR1
OH
O
O
H
O
O
d
O 14 O
+
RO 15 O
R = allyl
RO
OBn
O
OBn
O
O
h
O
i
OH
RO 16 O
RO
8 OH
R = allyl
R = allyl
HO
7
O
RO
O
l
k
O
O
OH
O
O
j
RO 17 O
R = allyl
OBn
OBn
O
15a R1= cinnamoyl; R = allyl
9 R1 = H, R = allyl
f
OBn
g
O
O
O
O
O
18
R = cinnamoyl
O
O
O 1
Reagents and conditions: a) allyl bromide, NaH, THF, 0 °C-RT, 4 h; b) 60% aq. AcOH, RT, 12 h; c)
NaIO4, MeOH:H2O (5:1), RT, 3 h; d) PhMgBr (1.1eq), THF, 0 °C-RT, 2 h; e) cinnamic acid, PPh3, DIAD,
dry THF, 0 °C-RT, 5 h; f) K2CO, MeOH, RT, 2 h; g) BnBr, NaH, THF, 0 °C-RT, 6h; h) 30% aq. AcOH,
reflux, 12 h; i) Meldrum's acid, Et3N, DMF, 40 °C, 16 h; j) 10% Pd/C, H2O, PTSA, MeOH, 80 °C, 12 h; k)
2,4,6-trichlorobenzoyl chloride, Et3N, THF, cinnamic acid, DMAP, toluene, RT, 3 h; l) TiCl4, CH2Cl2, 0
°C-RT, 2 h.
12
Abstract
Grignard reaction of 14 on treatment with PhMgBr in THF afforded two
chromatographically separable diastereomers 15 (L-ido-) and 9 (D-gluco-) in 4:1 ratio24
in 74% overall yield. Carbinol 15 was subjected to Mitsunobu inversion25 by treating
with cinnamic acid, PPh3 and DIAD in dry THF to give cinnamate 15a (72%), which on
subsequent hydrolysis with excess K2CO3 in MeOH afforded 9 in 81% yield. The spectral
data of the hydrolysis product showed matching spectral data with the minor isomer 9
obtained during Grignard reaction.
The hydroxy group in 9 was protected as benzyl ether with benzyl bromide and
NaH in THF to afford 16 in 85% yield. Compound 16 on reaction with 30% aq. AcOH at
80 °C underwent hydrolysis to give lactol 8 (74%), which on treatment with Meldrum’s
acid21,26 and Et3N in DMF gave 17 in 84% yield. The allyl group in 17 was deprotected
with Pd/C, H2O and PTSA in MeOH to afford the alcohol 7 (81%). Yamaguchi
esterification12 of 7 with cinnamic acid gave 18 in 78% yield, which on final
debenzylation on treatment with TiCl4 in CH2Cl2 at room temperature afforded 1 in 80%
yield, [α] D +31.6 (c 0.7, CHCl3); Lit.17 [α]D +8.0 (c 0.5, EtOH).
Synthesis of (+)-goniofufurone (4)
Treatment of lactone 7 with TiCl4 in CH2Cl2 at 0 °C to room temperature afforded
4 in 86% yield, [α]D +34.2 (c 0.18, CHCl3); Lit.18e[]D +39.5 (c 1.0, CHCl3).
Scheme 3
OBn
OH
O
HO
O
7
O
a
HO
O
4
O
O
Reagents and conditions: a) TiCl4, CH2Cl2, 0 °C-RT, 2 h.
Synthesis of (+)-tricinnamate (6)
Compound 9 (Scheme 4) on reaction with 30% aq. AcOH at 80 °C gave hydroxy
lactol 19 (65%), which on treatment with (ethoxycarbonylmethylene)triphenyl
phosphorane in toluene afforded a mixture of products 10 (58%) and 20 (13%).
13
Abstract
Scheme 4
O
RO 9
O
OH
OH
OH
OH
O
O
a
OH
O
RO
R = allyl
O
b
RO
19 OH
10 OH
O
+
RO 20 O
R = allyl
R = allyl
OH
O
R = allyl
O
OR
O
OH
OH
O
O
OR
OH O
c
d
OR
RO
10 OH
OR
22
R = cinnamoyl
OH OH
21
R = allyl
O
e
OR
OR
6
R = cinnamoyl
Reagents and conditions a) 30% aq. acetic acid, reflux, 12 h; b) Ph3P=CHCOOCH3, toluene, reflux, 2 h; c) Grubbs-II,
toluene, reflux, 24 h; d) cinnamic acid, DCC, DMAP, CH2Cl2, RT, 12 h; e) PDC, NaOAc, CH2Cl2, reflux, 12 h.
A highly diluted solution of diene 10 in dry toluene was heated at reflux in the
presence of Grubbs' catalyst ІI (20 mol%) to afford cyclic triol 21 (61%), which was
subjected to esterification (DCC, DMAP) with cinnamic acid in CH2Cl2 to afford 22 in
64% yield. Finally, allylic oxidation of 22 with PDC in CH2Cl2 at reflux gave 6 in 85%
yield, [α] D +180.0 (c 0.22, CHCl3); Lit.17 []D +175.8 (c 0.2, CHCl3).
Further, compound 20 (Scheme 5) was treated with Pd/C and PTSA in aq. MeOH
to afford 4 in 77% yield, [α] D +43.9 (c 0.11, CHCl3); Lit.18e [α]D +39.5 (c 1.0, CHCl3).
Scheme 5
OH
OH
O
O
a
RO 20 O
O
HO
R = allyl
O
O
4
Reagents and conditions: a) 10% Pd/C, H2O, PTSA, MeOH, 80 °C, 8 h;
Synthesis of (+)-howiionol A (5), (+)-tricinnamate (6), (+)-crassalactone C (2)
From the retrosynthetic analysis of 5 and 6 as is shown Scheme 6, these could be
obtained from ester 23 by RCM reaction, which in turn could be realized from 24 by the
reaction with (ethoxycarbonylmethylene)triphenyl phosphorane. Similarly, compound 2
14
Abstract
could also be envisioned from 24 by the addition of Meldrum’s acid which would result
in concomitant lactone formation. The crucial intermediate 24 in turn could be obtained
from 15a by a simple acid hydrolysis.
Scheme 6
OR
OR
OR
O
O
O
6 OR
HO
O
O
R=
cinnamoyl
R = cinnamoyl
OH
OR
O
2
O
RO
OR
OH
OC2H5
O
O
OH
5
OH
R = cinnamoyl
23
O
OH
R1O
24
OH
R = cinnamoyl
R1 = allyl
R = cinnamoyl
OR
O
O
O
O
HO
O
O
O
R1O
15a
O
11
R = cinnamoyl
R1= allyl
Synthesis of (+)-howiionol A (5)
Accordingly, carbinol 15 (Scheme 7) was subjected to Mitsunobu inversion25 on
treatment with cinnamic acid, PPh3 and DIAD in dry THF to give cinnamate 15a in 72%
yield. Similarly, the minor product 9, obtained by Grignard reaction, on esterification
with cinnamoyl chloride and Et3N in CH2Cl2 afforded 15a in 86% yield.
15
Abstract
Scheme 7
OH
O
O
O
9
O
b
OR
OR
OH
a
O
O
15
O
O
O
O
OH
c
O
O
O
15a
R = cinnamoyl
O
OR
OR
OH
O
OC2H5
OH
OH
R = cinnamoyl
O
RO
24
d
e
f
23
25
R = cinnamoyl
O
O
26
OH OH
O
O
R = cinnamoyl
R = cinnamoyl
O
O
OR
O
27
OR
O
g
h
O
R = cinnamoyl
5
O
OH OH
R = cinnamoyl
Reagents and conditions: a) cinnamic acid, PPh3, DIAD, dry THF, 0 °C-RT, 5 h; b) cinnamoyl chloride, Et3N,
CH2Cl2, 0 °C-RT, 12 h; c) 30% aq. acetic acid, reflux, 14 h; d) Ph3P=CHCOOEt, Toluene, reflux, 2 h; e)
Grubbs-II, Toluene, reflux, 12 h; f) 2,2 DMP, PTSA, CH2Cl2, RT, 3 h; g) PDC, NaOAc, CH2Cl2, reflux, 12 h;
h) CF3COOH, CH2Cl2, 0 °C-RT, 24 h.
Acid hydrolysis of 15a (30% aq. AcOH) at 80 °C gave diol 24 (70%), which on
further Wittig reaction with (ethoxycarbonylethylene)triphenyl phosphorane in toluene
afforded ester 23 in 72% yield (No cyclised product was observed in this reaction). A
highly diluted solution of diene 23 in dry toluene was heated at reflux under nitrogen
atmosphere in the presence of Grubbs' catalyst ІI (20 mol%) to afford olefin 25 in 70%
yield. The diol in 25 was treated with 2,2-DMP and PPTS in CH2Cl2 to afford 26 (82%),
which on oxidation with PDC in CH2Cl2 at reflux gave the lactone 27 in 69% yield.
Finally, treatment of 27 with CF3COOH in CH2Cl2 resulted in the removal of acetonide
16
Abstract
protecting group and afforded 5 in 74% yield, []D +104.8 (c 0.22, CHCl3); Lit.17 [α]D
+122 (c 0.1, CHCl3).
Synthesis of (+)-tricinnamate (6)
The diol 25 was subjected to esterification (Scheme 8) with cinnamic acid in the
presence of DCC and DMAP in CH2Cl2 to afford 22 in 73% yield. Olefin 22 on allylic
oxidation with PDC in CH2Cl2 at reflux gave lactone 6 in 85% yield, [α] D +176.2 (c 0.2,
CHCl3); Lit.17 []D +175.8 (c 0.2, CHCl3).
Scheme 8
O
OR
O
OR
a
O
OR
b
OR OR
OH OH
OR OR
22
25
6
R = cinnamoyl
R = cinnamoyl
O
R = cinnamoyl
Reagents and conditions: a) cinnamic acid, DCC, DMAP, CH2Cl2, 0 °C-RT, 12 h; b) PDC, NaOAc,
CH2Cl2, reflux,12 h.
Synthesis of (+)-crassalactone C (2)
Similarly, the diol 24 (Scheme 9) was treated with Meldrum’s acid and Et3N in
DMF to afford 28 in 85% yield. The deprotection of allyl group in 28 with Pd/C, H2O,
PTSA in MeOH afforded 2 in 81% yield, [α] D +108 (c 0.37, CHCl3); Lit.21[α]D +108.6 (c
0.5, EtOH).
Scheme 9
O
OR
OR
O
OH
R1O
OH
24
R = cinnamoyl
R1 = allyl
O
a
b
R1O
28 O
R = cinnamoyl
R1 = allyl
O
O
O
HO
2
O
Reagents and conditions: a) Meldrum's acid, Et3N, DMF, 40 °C, 16 h; b) 10% Pd/C, PTSA
MeOH, 80 °C, 12 h.
17
O
Abstract
Synthesis of (+)-Dicinnamoyl Goniofufurone (3)
Aldehyde 14 (Scheme 10) was treated with 3 eq of PhMgBr in THF to afford
phenyl group addition followed by concomittant deallylation resulting in 30 (L-ido-) and
29 (D-gluco-) as chromatographically separable diastereomers in 4:1 ratio, in 74% overall
yield.
Scheme 10
OH
O
O
H
O
O
OH
O
a
O
O
OH
HO 30 O
OR
O
O
O
HO 29 O
O
HO 29 O
14
OH
O
+
+
O
a
HO 30 O
c
OR
OH
RO
b
O
O
HO 31 O
R = cinnamoyl
RO 32 O
R = cinnamoyl
OR
O
d
OR
O
O
e
O
33 OH
RO
3 O
O
Reagents and conditions: a) PhMgBr (3eq), THF, 0 °C-RT, 10 h; b) cinnamic acid, PPh3, DIAD, dry THF, 0 °C-RT,
5 h; c) cinnamoyl chloride(1eq), Et3N, CH2Cl2, RT, 12 h; d) cinnamoylchloride (2eq), Et3N, CH2Cl2, RT, 12 h; e)
30% aq. acetic acid, THF, cat. HCl , reflux, 12 h; f) Meldrum's acid, Et3N, DMF, 40 °C, 36 h.
The major diol 30 was subjected to Mitsunobu inversion21 on treatment with
cinnamic acid, PPh3 and DIAD in dry THF to furnish ester 31 (62%), which on further
esterification with cinnamoyl chloride and Et3N in CH2Cl2 gave diester 32 in 79% yield.
The minor diol 29, obtained in Grignard reaction, on reaction with cinnamoyl chloride
and Et3N in CH2Cl2 gave 32 in 71% yield. Treatment of ester 32 with 30% aq. AcOH,
and cat.HCl in THF at reflux gave lactol 33 (69%), which on treatment with Meldrum’s
acid and Et3N in DMF afforded 3 in 83% yield, [α]D -102.7 (c 0.24, CHCl3).
18
Abstract
Thus, in conclusion, the work encompassed reports the synthesis of six styryl
lactones 1-6, while reporting the first synthesis of (+)-crassalactone B (1) and (+)tricinnamate (5). All the six lactones were synthesized from a common intermediate
derived from D-glucose and simple synthetic methods.
Chapter 3: Synthesis of C-linked carbo-β2-hydroxy β2-amino acids and their peptides
This chapter is dealt with the synthesis of novel C-linked carbo-β2-hydroxy β2amino acids and their peptides with different designs
The β-amino acids27 are part structures of several natural products and very
important components. Seebach et al.28 and Gellman et al.29 designed β-peptides with 14, 12-, 12/10-, 10- and 8-helical structures by using different β-amino acids.
Majority of the natural proteins contain (oligo)-saccharide side chains.30,31 Thus,
the incorporation of C-glycosyl amino acids in glycopeptides may serve in preparing
chemically and metabolically resistant analogues that display inhibitor activity towards
O- or N-glycosidases.32
From the general interest on the peptide synthesis, our group has started synthesis
of C-linked carbo-β-amino acids (β-Caas) and peptides33 with a variety of carbohydrate
side chains and reported different conformations in them34-35.
In continuation of our studies on the peptides, a new design of C-linked carbo-β
amino acids, having a hydroxy group and carbohydrate side chain, at the β2-positon was
proposed, mainly to observe the role of -OH group in the helix formation and stability.
NHBoc
H3CO
OH
O
O
H3CO
NHBoc
H3CO
O
OH
O
O
H3CO
O
Boc-(R)- β2-, β2-Caa-OCH3 (1)
O
Boc-(S)- β2-, β2-Caa-OCH3 (2)
Figure 3
19
O
Abstract
Synthesis of C-linked carbo β2-hydroxy β2-amino acids
According to the synthetic strategy, diacetone glucose 3 (Scheme 1) on alkylation
with MeI and KOH in dioxane at reflux gave 3a (90%). Hydrolysis (aq. AcOH) of 3a at
room temperature afforded the diol 4 (90%), which on selective protection (TrCl, Et3N)
in CH2Cl2 furnished the trityl ether 5 in 77% yield. Swern oxidation of carbinol 5 using
(COCl)2, DMSO and Et3N in CH2Cl2 gave ketone 6 (98%), which on Wittig olefination
furnished the olefin 7 (53%). Acid (CF3COOH) catalysed detritylation of 7 gave the
allylic alcohol 8 in 70% yield. Oxidation of alcohol 8 with IBX followed by (NaClO2H2O2) and further treatment with CH2N2 afforded the epoxy esters 9 and 10 in 53% yield,
as a chromatographically separable diastereomeric mixture (1.2:8.8 ratio). Epoxide ring
opening of major diastereomer 10 with NaN3 furnished azide 11 (78%), which on
reduction with Pd-C and subsequent treatment with (Boc)2O afforded 1 in 81% yield.
Scheme 1
O
HO
O
O
O
HO
a, b
O
HO 3
TrO
O
O
H3CO
O
c
4 O
H3CO
TrO
TrO
O
O
H3CO
6 O
H3CO
O
e
7
f
O
H3CO
8
O
H3CO
O
O
O
H3CO
O
O
j
O
+ O
O
9 O
H3CO 10
H3CO
minor
major
(1.2 : 8.8 ratio)
H3CO
NHBoc
OH
O
O
H3CO
g, h, i
O
N3
O
d
5 O
O
HO
O
O
O
HO
11
O
O
H3CO
k
OH
O
O
H3CO
O
O
1
Reagents and condition: a) CH3I, KOH, 1,4-dioxane, reflux, 12 h; b) 60% aq. CH3COOH, RT, 12 h; c)
Et3N, CH2Cl2, TrCl, 0 oC-RT, 8 h; d) (COCl)2, dry DMSO, Et3N, CH2Cl2, -78 oC, 3 h; e) Ph3P+CH3I,
t-BuOK, dry THF, 0 oC, 12 h; f) TFA, CH2Cl2, 0 oC-RT, 2 h; g) IBX, DMSO, RT, 2 h; h) NaClO2, 30%
H2O2, t-BuOH:H2O (7:3), 0 oC-RT, 10 h; i) NMU, 50% NaOH, ether, RT, 1 h; j) NaN3, NH4Cl,
MeOH:H2O (8:1), 80 oC, 8 h; k) Pd-C, MeOH, Et3N, RT, 2 h; ii) MeOH, (Boc)2O, 0 oC-RT, 6 h.
20
Abstract
Similarly, epoxide ring opening of minor diastereomer 9 (Scheme 2) with NaN3
furnished azide 18 (75%), which on reduction with Pd-C and subsequent treatment with
(Boc)2O afforded 2 in 79%.
Scheme 2
NHBoc
N3
O
H3CO
O
O
H3CO 9
O
H3CO
OH
O
a
O
O
b
O
H3CO
O
O
H3CO 12
O
OH
H3CO
O
O
2
Reagents and condition: a) NaN3, NH4Cl, MeOH:H2O (8:1), 80 oC, 8 h; b) i) Pd/C, MeOH, Et3N, RT, 2
h; ii) MeOH, (Boc)2O, 0 oC-RT, 6 h.
Determination of stereocentre at spiro carbon
To ascertain the absolute stereochemistry of major stereoisomer at C-5 in 10, it
was prepared using Sharpless asymmetric epoxidation8 conditions on allylic alcohol 8.
Scheme 3
O
HO
H3CO
O
O
8
HO
a
O O
O
H
b
O
O
O
O
O
H3CO 14
H3CO 13 O
c
RO
O
O
O
O
O
H3CO
15 R = H
d
10 R = CH3
Reagents and condition: a) (-)-DIPT, 4Ao MS, cumene hyroperoxide, Ti(OiPr)4, CH2Cl2, -20 oC, 3 h; b) (COCl)2,
dry DMSO, Et3N, CH2Cl2, -78 oC, 3 h; c) NaClO2, 30% H2O2, t-BuOH:H2O (7:3), 0 oC-RT, 10 h; d) NMU, 50%
NaOH, ether, RT, 1 h.
Accordingly, treatment of 8 (Scheme 3) with (-)-DIPT in CH2Cl2 gave epoxy
alcohol 12 in 75% yield. Oxidation of 12 under Swern reaction conditions afforded the
aldehyde 13, which on subsequent oxidation with NaClO2-H2O2 furnished the acid 14
(62%). Acid 14 was subjected to esterification with CH2N2 to afford the epoxy ester 10 in
83% yield. The spectral analysis of ester 10 prepared by Sharpless approach has matching
21
Abstract
data with the major diostereomer 10 that was made by earlier synthetic method as
described in Scheme 1.
A similar synthetic strategy was adopted to achieve the synthesis of minor isomer
9. Thus, treatment of 8 (Scheme 4) with (+)-DIPT in CH2Cl2 afforded epoxy alcohol 16
(73%), which on oxidation under Swern reaction conditions furnished the aldehyde 17 in
quantitative yield. Subsequently, oxidation of 17 with NaClO2-H2O2 ( 62%) followed by
reaction of the acid 18 with NMU afforded the epoxy ester 9 in 77% yield The spectral
data of minor isomer 9 (Scheme 1) and 9 preparing by (+)-DIPT (Scheme 4) are
comparable with each other, thus conforming the stereo chemistry of the epoxide unit.
Scheme 4
O
HO
H3CO
O
O O
HO
a
O
H3CO
8
O
H
O
O
b
O
H3CO
O
16
O
c
RO
O
O
O
O
O
H3CO 17
O
17
d
18 R = H
9 R = CH3
Reagents and condition: a) (+)-DIPT, 4Ao MS, cumene hyroperoxide, Ti(OiPr)4, CH2Cl2, -20 oC, 3 h; b)
(COCl)2, dry DMSO, Et3N, CH2Cl2, -78 oC, 3 h; c) NaClO2, 30% H2O2, t-BuOH:H2O (7:3), 0 oC-RT, 10 h; d)
NMU, 50% NaOH,
ether, RT, 1 h.
Synthesis of peptides
The monomers 1 (major) and 2 (minor) thus prepared were utilized and converted
into different peptides 19 to 24. In the first design, the monomer 1 was utilized in
alternating fashion with β-hGly to give 19-21, while, the second design utilized the
monomer 1 in sequential fashion (peptides 22 to 24). Peptides were prepared by using
standard peptide coupling36 conditions in the presence of water soluble 1-hydroxy-1Hbenzotriazole (HOBt), 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride
(EDCI) and DIPEA as a base in dry CH2Cl2. Dipeptides were prepared by condensation
of two monomers. Tetrapeptides were prepared by coupling of two dipeptides.
Hexapeptides were synthesized by condensing tetrapeptide acid with dipeptide amine.
22
Abstract
Accordingly, dipeptide 19 was prepared from acid generated from 1 and amine of
β-hGly, while, the tetrapeptide 20 was obtained by peptide coupling of acid and amine
prepared from dipeptide 19. Similarly, the hexa peptide 21 was prepared from the tetra
peptide acid and dipeptide amine (Figure 4).
O
O
HO
O
N
H
O
N
H
O
MeO
O
HO
O
N
H
N
H
O
MeO
O
O
O
OCH3
19 n = 0
20 n = 1
21 n = 2
O
n
Figure 4
In 1H NMR spectrum in CDCl3 and CD spectrum in MeOH of tetraeptide 20 and
hexapeptide 21, characteristic information for a well-defined secondary structure was
observed.
Figure 5: CD spectra of peptides 19, 20 and 21 in CH3OH solution at concentration of 0.2 mM
In second design, on the synthesis of homo-oligomers from 1, dipeptide 22 was
made from acid and amine prepared from 1. The thus made 22 was hydrolysed with base
and Boc deprotected with CF3COOH to give the corresponding dipeptide acid and amine,
23
Abstract
which on condensation gave the tetrapeptide 23. Finally, the hexapeptide 24 was prepared
from acid of 23 and amine of 22 (Figure 6).
O
O
HO
O
N
H
HO
O
N
H
O
O
O
N
H
O
MeO
MeO
HO
O
O
N
H
O
MeO
O
HO
OCH3
O
MeO
O
O
O
O
22 n = 0
23 n = 1
24 n = 2
O
n
Figure 6
In 1H NMR spectrum in CDCl3 and CD spectrum in MeOH of tetraeptide 23 and
hexapeptide 24, characteristic information for a well-defined secondary structure was
observed.
Figure 7: CD spectra of peptides 22, 23 and 24 in CH3OH solution at concentration of 0.2 mM
Thus, the work reports the synthesis of new amino acids and their conversions
into peptides 20, 21, 23 and 24 with secondary structures as was observed from the NMR
and CD spectra.
24
Abstract
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