Synthesis of Phenol and Benzoquinone derivatives from New Zealand
Brown Alga Perithalia capillaris
A proposal submitted to the Faculty
Of
Drexel University
By
Khalid Baig Mirza
In partial fulfillment of the requirements
for the degree of
Doctor of Philosophy
1. Introduction
A bis-prenylated benzoquinone isolated from the New Zealand brown alga Perithalia
capillaris was recently reported [1] by Perry, Sansom, Larsen, et.al. In vitro studies
indicated that this compound inhibited the superoxide production by human neutrophils
(IC50 2.1 μM). It was also highly potent at inhibiting the proliferation of HL60 cells (IC50
0.34 μM). Six other prenylated quinones and phenols along with a thaizone derivative
were isolated.
Commonly used non steroidal anti-inflammatory drugs (NSAIDS) target cyclooxygenase
and phospholipase enzymes in the cascade of reactions leading to an inflammation.
Certain diseases including gouty arthritis and non-atopic asthma are a result of
Superoxide production by neutrophils [2]. Superoxide inhibition has therefore been a
main area of research.
HL60 cell line once isolated from a patient with acute myeloid leukemia resembles
promyleocytes. These cells can be made to differentiate terminally in vitro to
granulocyte-like and monocyte / macrophage-like cells. The interesting fact about these
cells is that the c-myc proto-oncogene and c-myc mRNA levels decline rapidly once
differentiation is induced. [3]
This work intends to propose a short and viable synthesis for each of the eight natural
products reportedly isolated from Perithalia capillaris [4]. The structures of these
compounds are as listed below;
CH3
OH
CH3
CH3
OH
CH3
H3C
CH3
CH3
O
O
CH3
CH3
H3C
H3C
CH3
CH3
CH3
CH3
H3C
CH3
H3C
O
O
CH3
CH3
OH
CH3
O
O
O
S
OH
H3C
H3C
4
3
2
1
O
H2C
CH2
CH2
CH3
H3C
N
H
H3C
OH
OH
H2C
5
6
O
N
H
O
OH
7
8
2
Compound # 1
OH
OH
OH
Na, Ether Reflux
AcHN
+
2-Acetamidophenol
AcHN
Br
Prenyl Bromide
1.Aqueous NaOH
2.
Br
OH
AcHN
O
Heat Strongly
AcHN
1. H+/ H2O
2. NaNO2/ H+
3. H3PO2
OH
[5],[6],[7]
3
Compound 2
OH
Scheme 2
OH
OH
Aq. NaOH / Heat 150-180C
+
Br
+
+
FeCl 3, H or AlCl 3 , H
1:1 molar ratio
Br
OH
[8],[9]
4
H2C
Compound 3
H3C
CH3
CH3
Scheme 3
O
H2C
CH3
CH3
H2C
CH3
SO 2Cl 2
+
S
OH
CH3
S
Cl
+
-
CH3
O
CH3
CH3
Step 2 NaOH /H 2O
Cl
Et 3N
H3C
CH 2Cl 2
CH3
Cl
H2N
S
H2N
+
CH3
H2C
CH3
H2C
-
CH
S
+
CH3
O
CH3
CH3
H3C
CH3
3a
+
AlCl 3 / H
O
CH3
Br
S
CH2
CH3
1. BF 3.OEt 2
2. Raney Ni
3. NaIO 4
4. Heat
OH
+
CH3
H3C
CH3
CH3
S
CH2
CH3
H2C
OH
H3C
Small amount
CH3
CH3
O
CH3
[10],[11]
Compound 3a may also be prepared by a simple condensation reaction of hydroquinone
in THF at 65-70 C with isoprene in heptane; the reaction is catalyzed by Amberlyst-15
5
resin [12]. 3a may then be subjected to Friedel Crafts alkylation using prenylbromide and
a lewis acid to obtain compound 3.
Compound # 4
O
O
Scheme 4
OH
OCH 3
OH
+
+
2. (CH 3)2SO4 , heat
Heat. [3,3] Shift
Prenyl Bromide
NO 2
1.NaOH
1. Aq. NaOH
Br
NO 2
NO 2
1.Sn / HCl
-
2. OH
3. HONO
+2
4. CuO 2 / Cu , H2O
OCH 3
O
CAN , CH3CN - H2O
OCH 3
Br
OH
Na , Ether Reflux
OH
4a
O
+
The other
isomer...maybe in
small amount due
to steric
hinderance
[13],[14],[15]
Compound 4a after removal of the nitro group can be converted to the product by a [1, 3]
sigmatropic rearrangement of the prenyl derivative catalyzed by Florisil, [16]
6
Compound 5
HO
H3C
H2C
O
Scheme 5
CH3
H2C
CH3
CH3
H2C
CH3
CH3
OH
SO 2Cl 2
AcHN
-
+
S
S
CH3
Cl
CH3
+
O
CH3
H3C
NHAc
Cl
Step 2
NaOH /H 2O
H3C
Et 3N
CH3
CH 2Cl 2
Cl
H2N
H2C
S
CH3
CH3
H2N
H2C
AcHN
-
CH
S
+
CH3
O
CH3
CH3
H3C
S
CH2
AcHN
AcHN
CH3
1. BF 3.OEt 2
O
2. NaIO 4
CH3
OH
3. Heat
CH3
+
+
AlCl 3 / H
Br
CH3
2. OH / H2O
CH3
H3C
-
2+
3a.HONO; b. Cu 2O /Cu ; H2O
S
H2N
CH3
CH2
CH3
OH
Small amount
HO
H3C
H2C
O
CH3
CH3
CH3
[17],[18],[19]
7
Compound # 6
HO
CH3
H3C
O
CH3
Scheme 6
+
H2C
OH
H2C
CH3
SO 2Cl 2
CH3
AcHN
Cl
+
S
S
CH3
NHAc
-
CH3
O
CH3
CH3
Cl
Step 2
Et 3N
H3C
NaOH /H 2O
CH 2Cl 2
CH3
Cl
H2N
S
H2N
H2C
+
CH3
AcHN
H2C
CH3
-
CH
+
S
CH3
O
CH3
AcHN
CH3
1. BF 3.OEt 2
O
CH3
2. NaIO 4
CH3
3. Heat
H3C
S
CH2
AcHN
CH3
OH
+
1.AlCl 3 / H H3C Cl
-
2. OH / H2O
+
2+
3a.HONO; b. Cu 2O /Cu ; H2O
HO
CH3
H3C
O
CH3
H2N
H3C
CH3
S
CH2
CH3
OH
Small amount
[20],[21],[22]
8
Compound # 7
O O O
S
N
H
Scheme 7
OCH 3
O
CO 2H
OCH 3
O
AlCl 3 / Chlorobenzene
MeCl 2
Cl
+
N
H
NH
NH2
120
O
N
OCH 3H
OCH 3
OCH 3
OCH 3
O
POCl 3, CuCN, DMF, NaBH 4
+
2. H /H2O
3. SOCl 2, EtOH
4. AcCl, Et 3N / CH 2Cl 2
5.CAN /CH 3CN, H 2O
O
O O O
S
HO 2S
NH 2
C2H5OH / H 2O / H
N
H
O
N
H
CO 2H
+
N
O
CO 2Et
O
+
O
H
N
S
O
O O
N
H
CO 2H
[23],[24],[25]
Compound # 8
OH
OH
Scheme 8
OH
+
Cl
OH
OH
Na , Ether Reflux
1. NaOH / Heat
2. H20 / H+
Br
Prenyl Bromide
Cl
OH
[26].
9
The compounds can be extracted from methylene chloride and water, dried over
anhydrous MgSO4 or anhydrous CaCl2, further dried in a vacuum dessicator. The
compounds can be analyzed using various NMR techniques. The results must be
compared to the published data for a confirmation of the structural identity of the
compounds.
CONCLUSION:
In conclusion, a simple synthesis has been proposed for the compounds. They can thus be
easily synthesized on large scale.
REFERENCES:
Sansom, Larsen, Perry et.al J. Nat. Prod., 70 (12);
Brent R.Copp et.al J. Nat. Prod. 2007, 70, 936-940;
3
Br J Cancer Suppl. 1988 Dec; 9:41-5.
4
Sansom, Larsen, Perry et.al J. Nat. Prod., 70 (12);
5
Name reactions and Reagents in Organic Synthesis, Bradford, et.al. 2005, 156-157
6
Mehta and Pan; Org. Lett. 2004 Vol 6, No. 5 811-813
7
Solomons, Fryhle; Organic Chemistry; 9/e 2007; John Wiley & Sons, Inc.
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Mehta and Pan; Org. Lett. 2004 Vol 6, No. 5 811-813
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Solomons, Fryhle; Organic Chemistry; 9/e 2007; John Wiley & Sons, Inc.
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Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, (7), 1525-9; 1987
11
Sato, Miyamoto, et.al; J. Org. Chem.; 1987; 52(24) pp 5495-5497;
12
Banerji, Jain and Kalena; Molecules 1997, 2, 100–105
13
Mehta and Pan; Org. Lett. 2004 Vol 6, No. 5 811-813
14
Solomons, Fryhle; Organic Chemistry; 9/e 2007; John Wiley & Sons, Inc.
15
Chung and Kim J. Am. Chem. Soc. 2001, 123, 11071-11072
16
Talams, Smith, et.al; Tett. Lett.1997, 38, 4725
17
Sato, Miyamoto, et.al; J. Org. Chem.; 1987; 52(24) pp 5495-5497;
18
Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, (7), 1525-9; 1987
19
Solomons, Fryhle; Organic Chemistry; 9/e 2007; John Wiley & Sons, Inc.
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Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, (7), 1525-9; 1987
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Sato, Miyamoto, et.al; J. Org. Chem.; 1987; 52(24) pp 5495-5497;
22
Solomons, Fryhle; Organic Chemistry; 9/e 2007; John Wiley & Sons, Inc.
23
Tzeng, Lee, Chen, Wang Tetrahedron Letters Volume 37, Issue 35, 26 August 1996, Pages 6369-6370;
24
Copp, Brent, et.al. J. Nat. Prod. 2007, 70, 936-940;
25
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