Total synthesis of antioxidant alkaloid carazostatin via electrocyclic ring closure of 3-butadienyl-2-methoxyindole

Article abstract of DOI:10.3987/COM-00-8940

Total synthesis of the naturally occurring antioxidant carazostatin was accomplished by an efficient method, Wittig reaction of 2-methoxyindol-3-one followed by electrocyclic reaction of 3-(1,3-butadienyl)indole.

Full text of DOI:10.3987/COM-00-8940

HETEROCYCLES, Vol. 53, No. 8, 2000, pp. 1681 - 1684, Received, 8th May, 2000
TOTAL SYNTHESIS OF ANTIOXIDANT ALKALOID
CARAZOSTATIN
VIA
ELECTROCYCLIC
RING
CLOSURE OF 3-BUTADIENYL-2-METHOXYINDOLE
Yoshinori Nonaka,*1 Tomomi Kawasaki,2 and Masanori Sakamoto*2
1
Kissei Pharmaceutical Co., LTD., 4365-1 Kashiwabara, Hotaka,
Minamiazumi, Nagano 399-8304, Japan
2 Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-
8588, Japan
Abstract – Total synthesis of the naturally occurring antioxidant
carazostatin was accomplished by an efficient method, Wittig reaction
of 2-methoxyindol-3-one followed by electrocyclic reaction of 3-(1,3-
butadienyl)indole.
Antioxidants are served as possible protective agents against a variety of diseases induced by
oxygen-derived free radicals, like myocardial and cerebral ischemia, arteriosclerosis,
1
inflammation, rheumatism, senility, autoimmune diseases, and cancer.
Recently, as a novel
class of antioxidant active compounds, several poly-substituted 3-hydroxycarbazole alkaloids
were isolated from Streptomyces. 2 Because of their potent antioxidative activities and unique
structures, the interest of many synthetic chemists was attracted in developing novel synthetic
methodologies for these alkaloids and their related compounds.3 The representative 3-
hydroxycarbazole, carazostatin (1) exhibits an antioxidant activity more effective than α-
tocopherol.2a
methodologies using the Diels-Alder reaction,4a iron-mediated oxidative cyclization,4b unique
The total syntheses of carazostatin (1) were accomplished by some
OH
Me
C H
OTMS
O
O
Ph P
+
3
Me
Me
OMe
N
N
N
C H
7
H
7
15
15
C H
7
Ac
Ac
15
OMe
Carazostatin 1
2
3
Scheme 1

aromatic annulation,4c and electrocyclization of the allene intermediate.4d We earlier reported a
synthetic method for poly-substituted 3-methoxycarbazole alkaloids, hyellazole and 4-
deoxycarbazomycin B.5 In this communication, we describe a novel synthesis of carazostatin
(1) utilizing the thermal electrocyclic ring closure of 1-(2-methoxyindol-3-yl)-2-oxybutadiene
as shown in Scheme 1.
The starting material 2-methoxyindol-3-one (2) was readily available by our previously
described method.6 The phosphonium ylide (3) was prepared as follows: Wittig reaction of
octyl aldehyde (4) with the ylide (5) gave (E)-α,β-unsaturated ester (6) in quantitative yield with
high stereoselectivity. After hydrolysis of the α,β-unsaturated ester (6) with LiOH, the
carboxylic acid (7) was converted to α,β-unsaturated acid chloride (8) by treatment with thionyl
chloride. The resulting acid chloride (8) was allowed to react with 2 equiv.of methylidene
phosphorane (9) at 0 °C affording the desired ylide (3) in good yield.
O
Ph3P=C(Me)CO 2Et
O
O
LiOH
(5)
HO
C7H15
EtO
C7H15
H
C7H15
H2O-MeOH
reflux
toluene
Me
Me
quant.
86%
4
6
7
O
O
Ph3P=CH2 (9 )
SOCl 2
Ph3P
C7H15
rt
Cl
C7H15
THF, 0 °C
83%
Me
70%
Me
8
3
Scheme 2
The reaction of 2-methoxyindol-3-one (2) with the ylide (3) in refluxing toluene took place
smoothly with Wittig reaction followed by isomerization to afford the 3-substituted indole (10)
in 72% yield. The resulting indole (10) was treated with trimethylsilyl iodide (TMSI) in the
presence of 1,1,1,3,3,3-hexamethyldisilazane (HMDS) to give stereoselectively (Z)-enolate (11)
in 75% yield. The stereochemistry of TMS-enolate (11) was confirmed by nuclear Overhauser
effect (NOE) experiments; irradiation of methyl proton enhanced the signals of the olefinic and
methylene protons as shown in Scheme 3. When the enolate (11) was heated in boiling decalin,
isomerization, cyclization, and elimination of methanol occurred to give the desired 3-
siloxycarbazole (12) in moderate yield. The desilylation of 12 was performed by treatment
with tetrabutylammonium fluoride (TBAF) to afford 3-hydroxycarbazole (13) in 49% yield.
The deacetylation of 3-hydroxycarbazole (13) by the usual hydrolysis method was unsuccessful,
however, the reductive deacetylation of 13 with lithium aluminum hydride at 0 °C provided

O
Me
Me
Ph P
C H
7
C H
7 15
3
15
O
C H
7
15
Me
(3)
O
O
OMe
N
OMe
OMe
toluene, reflux
N
N
Ac
Ac
Ac
72%
2
10
NOE
Me
H
CH -C H
6 13
OTMS
Me
OTMS
Me
C H
2
TMS-I, HMDS
CH Cl
decalin
OTMS
OMe
2
2
reflux
27%
N
Ac
N
-20 °C ~ rt
N
C H
7
7
15
15
Ac
OMe
OMe
Ac
75%
11
OTMS
Me
OH
OH
Me
C H
LiAlH
TBAF
4
Me
C H
THF, 0 °C
N
N
THF, 0 °C
N
C H
7
15
7
15
49%
H
7
15
Ac
Ac
57%
12
13
Carazostatin (1)
Scheme 3
carazostatine (1) in 57% yield. The spectroscopic data of the synthetic material were virtually
identical with those reported for the natural2a and synthetic product.4, 7
In conclusion, we accomplished the total synthesis of the naturally occurring antioxidant
carazostatin (1) using an efficient method which was based on Wittig olefination of 2-methoxy-
indol-3-one (2) followed by the electrocyclic reaction of 3-(2-trimethylsiloxybutadieny)indole
(11) .
ACKNOWLEDGMENT
1
We wish to thank Professor Satoshi Hibino (Fukuyama University, Japan) for providing the H-
NMR spectrum of synthetic carazostatin.
REFERENCES AND NOTES
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7. Carazostatin (1): mp 157.5-159 °C (from ether-hexane), (lit., mp 149-152 °C2a; 159-160 °C4d).
1H-NMR (400 MHz, CDCl3) δ: 0.89 (3H, t, J = 7 Hz), 1.20-1.50 (8H, m), 1.60-1.70 (2H, m),
2.37 (3H, s), 2.88 (2H, t, J = 8 Hz), 4.58 (1H, br s), 7.16 (1H, t, J = 8 Hz), 7.32-7.46 (3H, m),
7.75 (1H, br s), 7.93 (1H, d, J = 8 Hz). 13C-NMR (100 MHz, CDCl3) δ: 12.2, 14.4, 22.9, 29.1,
29.6, 29.8, 30.3, 32.2, 103.2, 110.9, 119.2, 120.3, 121.1, 121.6, 123.9, 124.4, 125.5, 134.2,
140.0, 148.4.