Abstract
The thesis entitled “Synthetic studies on anthracyclinones, 1,4anthraquinones and benzo[d]naphtho[1,2-b]pyran-6-ones” describes i) a direct
synthetic access to 1,4-dihydroxyanthraquinones and exploratory studies towards
anthracyclinones (e.g. 1) and a synthesis of two naturally occurring 9,10anthraquinones ventinone A (2) and 4-methyl ether of erythroglaucin (also
proposed structure of ventinone B) (3), ii) total synthesis of 9,10-dimethoxy-2methyl-1,4-anthraquinone (4) and iii) model studies towards chrymutasins (5) and
gilvocarcins (8). The key reactions investigated are Hauser annulation and
carbonyl-ene reaction.
O
OH
OR1 O
O
OH
OMe O
R2
D
C
B
O
OH OH
R3
MeO
O
OR O
D
C
OH
1
1 : Idarubicinone
O
OMe O
2
3
2: Ventinone A, R = H, R = R = Me
3: 4-Methyl ethr of erythroglaucin,
R1= R2= Me, R3= H
CH3
E
Me
OH
A
4
OH
H
Me
HO
O
O
HO
A
B
A
O
B
O
O
NH2
5: Chrymutasin A, R = Fucose-- Digitalose
6: Chrymutin, R = H
R
C
OMe
OH OMe
7: Gilvocarcin V, R = CH=CH2
8: Gilvocarcin M, R = CH3
3-Phenylsulfanylphthalides (e.g. 9) readily react with p-benzoquinones (e.g.
10) in the presence of t-BuOLi in THF to furnish 1,4-dihydroxyanthraquinones
(e.g. 11) in good yields and one-pot operations. This methodology has been applied
to the total synthesis of naturally occurring anthraquinones, ventinone A (2) and 4methyl ether of erythroglaucin (3).
SPh
O
O
R1
t-BuOLi,
R2
60 oC to r.t.
R1
X
O
X
OH
R2
O
O
OH
O
30-70%
11
10
R1, R2 = alkyl, O-alkyl, -(CH2)4-, -(CH2)3CH(OH)-, -CH=CH-CH=CH-, etc.
15 examples have been worked out
9
Intramolecular carbonyl-ene reaction of 2-methallylated anthraquinone aldehyde
12, obtained in 10 steps has been effected for the synthesis of 13, core structure of
idarubicin. Modest attempts have been made to extend the carbonyl-ene reaction,
for the first time, to the synthesis of substituted naphthalene 16 and phenanthrene
17 as illustrated below.
O
OH
SnCl4 . 5H2O
dry DCM
CHO
O
OMe
OH OH
13
CHO
O
O
OH OH
1
SnCl4 . 5H2O
dry DCM
83%
83%
OMe 15
OMe 14
OH
OH
O
OH
SnCl4 . 5H2O
CHO dry DCM
O
OH
89%
12
OMe
O
16
17
The first yet short synthesis of the unusual anthraquinone 4 has been achieved in
5 steps from p-benzoquinone using Kochi-Anderson radical methylation as a key
step. During the course of the synthesis few unprecedented
cyclopropaanthraquinones like 19, 20 and 21 have been synthesized and their
chemistry studied.
OMe O
OMe O
18
AgNO3, AcOH,
(NH4)2S2O8,
CH3CN-H2O
reflux
OMe O
OMe O
4 (42%)
O
SPh
+
K2CO3, Me2SO4
O
O
19
OMe O
OH O
t-BuOLi, THF

O – 60 C
48%
acetone, reflux
65%
OH O
OMe O
21
20
9
Cyanophthalide 22 has been shown to undergo a tandem annulation with methyl
5,5-dimethoxy-2-methyl-6-oxo-5,6-dihydronaphthalene
1-carboxylate
(23),
obtained in 10 steps from 6-methoxy-1-tetralone, to fabricate a chrymutasin
chromophore 5 in one-pot operation and thus O-Methylhayumicinone (25) has
been synthesized during this investigation. Both C and E rings are formed in one
operation.
CH3
MeO2C
OMe CN
t-BuOLi
O+
O
O
23
22
OMe THF
- 60 °C
OMe
78%
O
CH3
E
A
OMe O
D
C
D
C
O
CH3
10% HCl,
OR O
MeOH-H2O
E
OMe 70%
B
OH O
O
OR O
A
B
O
OMe
O
OH
25 R = Me
24
CH3
O
O
NH2
5 R = Sugar
The tandem strategy has been applied to the regiospecific construction of the
core structure of gilvocarcin chromophore (e.g. 26) from O-benzylcyanophthalide
(27), prepared in 9 steps, and styryl sulfone 28, prepared in 6 steps. But, the total
synthesis of defucogilvocarcin M (32) has been foiled, due to the failures in
desulfonylation of 26.
O
CN
MeO2C
Me
t-BuOLi, THF
O
OBn O
27
PhO2S
OMe
- 60 oC
10-15%
OBn O 26
28
9 steps
O
6 steps
Me
O
OHC
Me
CO2Et
O
Me
Me
+ 29
30
OMe
H2N
OH
31
OH OMe
32
Me
O
OMe
SO2Ph
Key
words:
Synthesis,
anthracyclinone,
1,4-anthraquinone,
cyclopropaanthraquinone,
benzonaphthopyranone,
Hauser
annulation,
intramolecular carbonyl-ene reaction, Kochi-Anderson radical alkylation reaction,
Claisen rearrangement, Heck reaction.
3-Phenylsulfanylphthalides (e.g. 8a) readily react with p-benzoquinones in the presence of
LiOtBu in THF to furnish 1,4-dihydroxyanthraquinones in good yields and one-pot operations.
A Hauser-initiated tandem annulation has been developed for the rapid regiospecific synthesis
of benzonaphthopyranones. This strategy has been generalized with benzonaphthopyranones
26, 29, 32 & 35. It has also been employed in a short synthesis of chartarin (3) and Omethylhayumicinone (67).
The synthesis of 9,10-dimethoxy-2-methyl-1,4-anthraquinone, an unusual quinone, is
achieved in 5 steps from p-benzoquinone. A Kochi-Anderson radical methylation features as a
key step in the synthesis. The chemistry of a cyclopropa-1,4-anthracenedione is also described.