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
Natural products of medicinal importance
HO
• Natural products have long
been used for medicinal
purposes. They include
compounds like morphine,
strychnine, Atropine,
Colchicine, etc.
• Few other compounds include
• Warfarin (a coumarin analog) --- A blood thinner
• Taxol, Irinotecan ---- Anti
cancer agents
• Salicylates ---- Anti
inflammatory, Anti pyretics
OH
H3C
N
O
N
CH3
O
O
H
HO
Atropine
Morphine
O
O
OH
CH3
Warfarin
O
O
O
O
NH
O
OH
O
O
H
O
OH
OH
Taxol
O
O
O
O
Phenols,
Benzoquinone and
benzopyrans
containing drugs
OH
OH
HO
HO
NH2
Metaraminol
Phenylephrine
Treatment of hypotension
Decongestant
OH
O
OH
NH
OH
O
HO
O
OH
O
HN
OH
O
O
OH
OH
O
O
O
H2 N
Doxorubicin
Anti-cancer
CH3
OH
OH
Warfarin
Blood thinner
Fenoterol
Treatment of asthma
Compounds isolated from New Zealand brown alga
Perithalia capillaris
• Eight compounds
were isolated from
a brown alga
through a
bioactivity-directed
isolation process.
• Compound 4
inhibits superoxide
production by
human neutrophils
(IC50 2.1uM)
CH3
OH
CH3
CH3
OH
CH3
OH
O
CH3
CH3
H3C
CH3
H3C
OH
CH3
H3C
CH2
CH3
1
H3C
CH3
CH3
H3C
O
O
4
3
2
H3C
O
H2C
CH3
O
O
O
O
S
H3C
• It also is highly
potent at inhibiting
the proliferation of
HL60 cells (IC50
0.3uM)
CH3
CH3
CH3
CH3
H3C
N
H
H3C
OH
H2C
OH
N
H
O
CH2
5
6
7
8
CO 2H
•
•
•
•
•
Need for a new way to target an inflammation
Superoxide production by neutrophils are the main
cause of an inflammation in certain conditions like gouty
arthritis and non-atopic asthma, etc.
Body produces Superoxide Dismutase (SOD) to mop-up
the superoxide.
Following an inflammation in the above conditions, there
is a downregulation of SOD and also there is an
increased superoxide production.
Commonly used NSAIDS target Cyclooxygenase and
Phospholipase enzymes in the cascade of reactions
leading to an inflammation..
Therefore there is a specific need for compounds that
inhibit superoxide production in conditions associated
with acute inflammation, rheumatoid arthritis,
inflammatory bowel disease, some heart diseases,
neuropathic and cancer pain and also opiate intolerance.
Potential Anti Cancer agent
• The bis-prenylated quinone 4 also showed high potency at
inhibiting leukemia cells from HL60 cell line.
• HL60 cell line once isolated from a patient with acute
myeloid leukemia resembles promyelocytes. These cells can
differentiate terminally in vitro to granulocyte-like and
monocyte / macrophage-like cells
• Since the compounds isolated from the brown alga, inhibit
the proliferation of the HL60 cell, they could be used in
treating leukemia and related cancers
The Proposal
• Describes possible routes directed towards syntheses of
these eight compounds isolated from Perithalia capillaris.
• Compounds 1, 2, 3, 4, 5 and 6 contain a five carbon
chain (an isoprene unit) attached to them. A
regioselective synthesis involving modest number of
steps has been proposed to synthesize each compound.
• Most reactions presented in the proposal are well
established achieving quantitative yields. However a few
reactions may result in some undesired side products,
although in small percentages.
Compound 1
OH
OH
Na, Ether Reflux
AcHN
AcHN
Br
+
Prenyl Bromide
2-Acetamidophenol
9
1.Aqueous NaOH
2. Br
OH
AcHN
O
Heat Strongly
AcHN
11
10
1. H+/ H2O
2. NaNO2/ H+
3. H3PO2
CH3
OH
CH3
H3 C
CH3
1
Compound 2
OH
OH
Na, Ether Reflux
AcHN
+
2-Acetamidophenol
AcHN
Br
Prenyl Bromide
+
AlCl 3/ H
Br
OH
1. H+/ H2O
OH
+
AcHN
2.NaNO 2 / H
H 2C
CH3
3. H3PO2
CH3
2
12
Compound 3
OH
OH
Na , Ether Reflux
+
NHAc
13
Br
+
OH
1.H /H2O
2.HONO
3. Cu 2O/Cu
2+
, H2O
NHAc
OH
14
3
Compound 4
OH
H3 CO
OH
+
2. (CH 3)2SO4 , heat
Heat. [3,3] Shift
Prenyl Bromide
NHAc
1.NaOH
1. Aq. NaOH
Br
NHAc
NHAc
15
16
+
1.H / H20
2. HONO
+2
3. CuO 2 / Cu , H2O
H3 CO
O
CAN , CH3CN - H2O
Br
OH
O
4
H3 CO
18
Na , Ether Reflux
OH
17
Compound 5
CH3
H2C
H2C
CH3
H2C
OH
S
+
SO 2Cl 2
CH3
CH3
Et 3N
S
+
Cl
-
O
CH3
-
CH
CH3
S
CH3
19
+
CH3
O
CH3
22
Step 2 NaOH /H 2O
Cl
H3C
CH 2Cl 2
CH3
Cl
H2N
S
H2N
+
CH3
H2C
20
21
CH3
H3C
S
CH2
1. BF 3.OEt 2
CH3
O
CH3
3. Heat
AlCl 3 / H
OH
4. Raney Ni
25
+
CH3
2. NaIO 4
Br
CH3
23
H3C
+
CH3
S
CH3
CH3
OH
H2C
24
Small amount
H3C
CH3
CH3
O
5
CH3
CH2
Compound 6
O
OH
+
HO
1.Aq. NaOH
O
Amberlyst-15
2. Prenyl Bromide
Benzene Solv.
3.Heat [3,3] Shift
OH
OH
OH
27
26
25
6
Proposed mechanism for the formation of 27
-
SO 3 -Resin
O
+
H
HO
i. enolization
ii.[1-5] -H shift
O
H
OH
O
O
C
HO
H
HO
H
HO
H
28
27
Compound 7
O
OH
Amberlyst-15
+
O
CH3 Cl / H 3 PO4
Benzene Solv.
HO
H3 C
OH
OH
25
26
27
OH
7
Compound 8
O
O
O
S
N
H
O
N
H
CO 2H
8
Retrosynthesis
H3CO
O O O
S
N
H
O
O
O
N
H
H3CO
Cl
H3CO
30
CO 2H
O
8
+
HO 2S
29
N
H
37
NH 2
CO 2Et
H3CO
N
O
CO 2CH 3
27
NH O
H3CO
+
NH2
H3CO
31
H3CO
b
a
Cl
+
OH
H3CO
O
NH
NH2
OH
H3CO
H3CO
30
31
N
H
O
O
28
32
c,d
H3CO
H3CO
H3CO
g
N
H3CO
CN
CO 2CH 3
N
H3CO
e
OEt
N
H3CO
CO 2CH 3
34
35
h
N
H3CO
CO 2CH 3
O
CO 2CH 3
33
27
O O O
S
O
j,k
36
OH
i
H3CO
H3CO
H3CO
f
N
H
HO 2S
N
H
CO 2H
O
CO 2Et
NH 2
C2H5OH / H 2O / H
+
N
H
O
N
H
+
37
H
N
8
O
S
O
CO 2H
O O
N
H
CO 2H
a. Methylene Chloride, reflux; b. AlCl3 / Chlorobenzene, 120oC; c. NaOH/(CH3)2SO4; d. nBuLi, NCCO2CH3,
THF -78 oC; e. NaBH4, EtOH, 0oC; f. EtOH/ HCl, pH 3-4; g. Me3SiCN, ZnCl2, CH2Cl2, -78oC r.t.; h.
NaHCO3, H2O; i. HCl / H2O; j. SOCl2/EtOH ; k. CAN, MeCN/ H2O.
Conclusions
• The synthetic scheme for compounds 1-8 provides a simple and
effective way for their preparation. Compound 1 may be synthesized
from 2-acetamidophenol and prenyl bromide.
• Different conditions used during alkylation provides different
alkylation pattern.
• Similarly compound 2 maybe synthesized from 2-acetamidophenol
and prenyl bromide, however here a Friedel crafts alkylation is used
to obtain a branched chain –para alkylation.
• Further in-vitro and in-vivo studies have to be performed on animal
models in order to confirm there safety and effectiveness.
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Thank You
•
•
•
•
•
•
•
•
•
•
Dr. Robert Hutchins -- Chair
Dr. Jean-Claude Bradley – Research Advisor
Dr. Aleister Saunders
Dr. Kevin Owens
Dr. Louis Scerbo
Dr. Daniel King
Dr. Jun Xi
Dr. Anthony Addison
All the Graduate Students
Special Thanks to Dr. Anthony Wambsgans.
Questions
??