The ideal synthetic method aimed at the leads for an α2-blocker, an inhibitor of blood platelet aggregation, and an anti-osteoporosis agent

Article abstract of DOI:10.3987/COM-06-10771

According to the definition of the ideal synthetic method, an example aimed at the leads for an α₂ blocker, an inhibitor of platelet aggregation, and an anti-osteoporosis agent is established starting from tryptamine. The originality rate, the intellectual property, and the application potential factors of the method are 71, 54, and 100, respectively. The method employs only conventional reagents and reaction conditions without using any protecting groups.{A figure is presented}.

Full text of DOI:10.3987/COM-06-10771

HETEROCYCLES, Vol. 68, No. 8, 2006
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HETEROCYCLES, Vol. 68, No. 8, 2006, pp. 1565 – 1569. © The Japan Institute of Heterocyclic Chemistry
Received, 24th April, 2006, Accepted, 20th June, 2006, Published online, 23rd June, 2006. COM-06-10771
THE IDEAL SYNTHETIC METHOD AIMED AT THE LEADS FOR AN
α2-BLOCKER,
AN
INHIBITOR
OF
BLOOD
PLATELET
AGGREGATION, AND AN ANTI-OSTEOPOROSIS AGENT1
Masanori Somei,a* Takako Iwaki,a Fumio Yamada,a Yoshio Tanaka,b Koki
Shigenobu,b Katsuo Koike,b Nobuo Suzuki,c and Atsuhiko Hattorid
a: Division of Pharmaceutical Sciences, Graduate School of Natural Science and
Technology, Kanazawa University, Kakuma, Kanazawa, Ishikawa 920-1192,
Japan. b: Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Chiba
274-8510, Japan. c: Noto Marine Laboratory, Institute of Nature and
Environmental Technology, Kanazawa University, Noto-cho, Ishikawa 927-0553,
Japan. d: Department of Biology, College of Liberal Arts and Sciences, Tokyo
Medical and Dental University, Ichikawa, Chiba 272-0827, Japan.
Corresponding author: e-mail address: somei@p.kanazawa-u.ac.jp.
Abstract – According to the definition of the ideal synthetic method, an example
aimed at the leads for an α2-blocker, an inhibitor of platelet aggregation, and an
anti-osteoporosis agent is established starting from tryptamine. The originality
rate, the intellectual property, and the application potential factors of the method
are 71, 54, and 100, respectively. The method employs only conventional
reagents and reaction conditions without using any protecting groups.
We have thus far proposed our synthetic philosophy for evaluating the effectiveness of organic synthesis
that consists of three measures such as the originality rate (OR),2a the intellectual property factor (IPF),2b
and the application potential factor (APF).2b The formulas for calculating OR, IPF, and APF are shown in
the reference 3. As evidenced by definition,2,3 the OR shows a proportion of the number of originally
developed steps to that of synthetic steps.2,3a The IPF is a total rate of one’s own intellectual properties
involved in every reaction and every compound in the synthesis.2,3b The APF is the sum of application
potential of starting material, target compound, and all synthetic intermediates.2,3c On the basis of these
factors, we have defined a synthetic method having the highest OR, IPF, and APF values as the “ideal
synthetic method”,4 in which every synthetic intermediate, including starting material and target

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HETEROCYCLES, Vol. 68, No. 8, 2006
compound, has either a biological activity or useful functionality. The ultimate is the one-step synthesis
out of the ideal synthetic methods.
a) R1 = COOMe; b) R1 = Ac; c) R1 = an appropriate
alkyl and acyl group.
Scheme 1
SST-VED-I
NH2
NHR1
NHR1
NHR1
Et3SiH
CF3COOH
Na2WO4·2H2O
30% H2O2
MeOH-H2O
Et3N, ClCO2Me
or Ac2O
N
N
H
N
N
H
H
OH
3
4
6
2
1
BF3, MeOH
BF3, MeOH
SST-VED-II
NHAc
NH2
NHCOOMe
NHAc
Br
MeO
Br
MeO
MeO
MeO
Ac2O
NaOH
N
H
Br
N
H
N
H
N
H
Br2, NaOAc
AcOH
8
5
7
Consecutive
Operation
Ac2O
RX
TsCl
1) 20% NaOH, reflux; 2) Ac2O, pyridine. Overall yield, 92%.
NHAc
NHAc
NHAc
N
N
N
N
Br
Br
Br
MeO
Br
MeO
Br
MeO
Br
N
R
Br
N
R
Br
N
Br
O
O2S
9
10
N
H
O
SST-VED-III
a) R = Ac; b) R = an appropriate
alkyl and acyl group.
SSH-BM-I
a) R = allyl; b) R = benzyl;
c) R = propargyl.
SSH-BM-II
11
Me
24
Figure 1
H
N
H
N
H
N
H
N
(CH2)5Me
(CH2)7Me
(CH2)3Me
O
O
O
O
N
N
R
N
R
N
R
R
13
12
a) R = OH: 15.7 ± 6.8%
b) R = H: 21.4%
14
15
a) R = OH: 25.6 ± 6.0%
b) R = H: 26.9 ± 11.4%
a) R = OH: 66.2 ± 13.9%
b) R = H: 70.0 ± 6.9%
a) R = OH: 79.0 ± 13%
b) R = H: 80.7 ± 2.5%
O
H
H
N
H
N
H
N
N
O
O
N
N
N
H
N
R
R
R
16
17
a) R = OH: 87.7 ± 8.53%
b) R = H: 58.6 ± 10.6%
18
a) R = OH: 17.8%
b) R = H: 60.6 ± 20.7%
19
a) R = OH: 100.0 ± 0.00%
b) R = H: 64.2 ± 8.70%
91.5 ± 1.3%
5
6.7 ± 6.7%
NHAc
NHAc
NHAc
Br
Br
N
MeO
MeO
Br
MeO
N
H
H
H
8
85.6 ± 12.0%
N
H
N
H
Br
N
Br
H
MeOOC
H
OH
20
9a
97.6 ± 2.4%
21
20.3 ± 4.6%
22
64.0 ± 4.1%
23
73.5 ± 15.3%
yohimbine: 100%

HETEROCYCLES, Vol. 68, No. 8, 2006
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To
make
our
philosophy
clearer,
we
reported
a
synthesis
of
6-cyano-5-methoxy-12-methylindolo[2,3-a]carbazole as the first concrete example of a six-step
near-ideal synthetic method in a previous paper.2b As the second example, we have now established more
sophisticated six-step near-ideal synthetic method (Scheme 1) with the OR, IPF, and APF values of 71,
54, and 100, respectively, targeting our own intellectual properties for α2-blockers,5 inhibitors of
platelet aggregation,6 and anti-osteoporosis agents,7 starting from biologically active tryptamine (1).
The first step is a conventional acylation of 1 with methyl chloroformate or acetic anhydride to give
Nb-methoxycarbonyl- (2a) and Nb-acetyltryptamines (2b) in quantitative yields, respectively. Our
1-hydroxyindole synthetic method8 is employed in the second and the third steps. Reduction was
achieved successfully with Et3SiH in trifluoroacetic acid to provide 2,3-dihydrotryptamines (3a,b).
Subsequent oxidation of 3a,b with Na2WO4·2H2O and 30% H2O2 in MeOH–H2O afforded
1-hydroxycompounds (4a,b) in 63 and 62% overall yields, respectively.
The fourth step is the unprecedented nucleophilic substitution reaction in indole chemistry.8 Treatment of
4b with BF3 in MeOH underwent regioselective methoxylation at the 5-position providing melatonin (5)
in 85% yield.9 Similar treatment of 4a produced 6 in 85% yield. Alkaline hydrolysis of 6 followed by
acetylation of the resultant 7 with Ac2O produced 5 as an alternative synthetic route. These two steps
were performed by consecutive operation in 92% overall yield.
Bromination of 5 with Br2–NaOAc (3 mol eq.) is the fifth step giving a 94% yield of
2,4,6-tribromomelatonin9 (8) that was led to 1-acetyl-2,4,6-tribromomelatonin (9) with Ac2O in a
quantitative yield. The sixth step is the treatment of 8 with allyl, benzyl, or propargyl bromides, and tosyl
chloride in the presence of K2CO3 producing 10a, 10b, 10c, and 11 in 95, 83, 97, and 75% yields,
respectively.
We have discovered that 2a and 2b are medium, whereas both 8 and 9 are potent leads for α2-blockers.
We named them SST-VED-I, -II, and -III type compounds, respectively. In order to study the
structure-activity relationship of SST-VED-I compounds, we prepared various Nb-substituted
tryptamines (2c, 12—15) and analogs (16—19) as shown in Figure 1. Yohimbine (20) is a folk medicine
widely used among people as an α2-blocker to treat erectile dysfunction (ED). When the activity of
yohimbine is made a standard for 100, those of 8, 9a, 15, 16, 17a, and 19a are found to be almost equal.5
In a series of compounds (12—15), the activity increases depending on the length of Nb-acyl side chain.5
In addition, differences in activities are small between N(1)—OH and N(1)—H compounds. Interestingly,
the adamantyl group has a remarkable enhancing effect as demonstrated in typical compounds (16—19).
As regards brominated melatonins, SST-VED-II compounds (21—23, 9a), the activity becomes stronger
as the number of bromine atom increases. Compounds (9b) are expected to be potent α2-blockers as well.

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HETEROCYCLES, Vol. 68, No. 8, 2006
On the other hand, we had discovered that 1-hydroxytryptamines were fundamentally inhibitors of
platelet aggregation.6 1-Hydroxy-Nb-methoxycarbonyltryptamine (4a: IC50 0.32 µM) is one of the best
leads and ten times more potent than cilostazole (24: IC50 3.10 µM) and 4b (IC50 3.10 µM) in the
inhibition test on arachidonic acid induced platelet aggregation in rabbit PRP.6
We have discovered that 1-alkenyl- (10a—c) and 1-tosyl-2,4,6-tribromomelatonins (11) stimulate
osteoblast activity and suppress osteoclast activity in the cultured scales10 of goldfish in 10-8 mol/L.7 Thus,
we have succeeded in creating potent and promising leads for anti-osteoporosis agents and named them
SSH–BM-I and -II type compounds, respectively.
In the above six-step synthesis, every compound has either a biological activity or a useful functionality.
The APF value of this synthesis is therefore 100 (100 x 7/7). The IPF value of the synthesis is 54 (100 x
7/13) because 4, 8, 9, 10a—c, and 11 are our compounds, and three reactions (a set of the second and the
third,8 the fourth,9 and the fifth9 steps) are our own reactions or findings. The originality rate2 of the
synthesis is 71 (100 x 5/7). The detailed results of biological evaluations will be reported in due course.
ACKNOWLEDGMENTS
The authors express their cordial gratitude to Dr. K. Kurashina (Kissei Pharmaceutical Ind.) for the
evaluations of inhibitory activity of platelet aggregation.
REFERENCES AND NOTES
1. a) This report is Part 128 of a series entitled “The Chemistry of Indoles”. b) This is presented at the
126th Annual Meeting of Pharmaceutical Society of Japan: M. Somei, F. Yamada, T. Iwaki, A.
Hattori, N. Suzuki, K. Shigenobu, and Y. Tanaka, Abstract Papers (4), Sendai, March 2006, p. 184.
c) Part 127: K. Yamada, T. Izumi, F. Yamada, and M. Somei, Heterocycles, 2005, 66, 583.
2. a) Definition of OR: M. Somei, Y. Fukui, M. Hasegawa, N. Oshikiri, and T. Hayashi, Heterocycles,
2000, 53, 1725; M. Somei, Yakugaku Zasshi, 1988, 108, 361; M. Somei, J. Synth. Org. Chem., 1982,
40, 387. b) Definitions of IPF and APF: M. Somei, F. Yamada, Y. Suzuki, S. Ohmoto, and H.
Hayashi, Heterocycles, 2004, 64, 483.
3. a) The OR is calculated by the following formula.
The Number of Newly Developed Steps + 1
OR = 100 x
Total Number of Synthetic Steps + 1
b) The IPF is figured by the following formula.
The Number of Compound
Having Intellectual Property
The Number of Synthetic Process
Having Intellectual Property
+
IPF = 100 x
2 x (The Number of Synthetic Process) + 1

HETEROCYCLES, Vol. 68, No. 8, 2006
1569
c) The APF is obtained by the following formula.
The Number of Compound Having either Biological
Activity or Other Useful Functionality
APF = 100 x
The Number of Synthetic Process + 1
4. M. Somei, Abstract Papers, 111th Meeting of Hokuriku Branch, Pharmaceutical Society of Japan,
Kanazawa, Dec., 2004, p. 1.
5. M. Somei, K. Shigenobu, and Y. Tanaka, JP Patent 2004-280104, applied Sept. 2004.
6. M. Somei, K. Yamada, M. Hasegawa, M. Tabata, Y. Nagahama, H. Morikawa, and F. Yamada,
Heterocycles, 1996, 43, 1855; M. Somei, JP Patent 1996-157475 [Chem. Abstr., 1996, 125,
195426y]; M. Somei, JP Patent 1991-31257 [Chem. Abstr., 1991, 114, 247138a].
7. M. Somei, A. Hattori, and N. Suzuki, JP Patent 2004-64408, applied March 2004; M. Somei, A.
Hattori, and N. Suzuki, JP Patent 2005-209753, applied July 2005.
8. a) M. Somei, J. Synth. Org. Chem., 1991, 49, 205. b) M. Somei, Heterocycles, 1999, 50, 1157. c) M.
Somei, Advances in Heterocyclic Chemistry, Vol. 82, ed. by A. R. Katritzky, Elsevier Science, USA,
2002, pp. 101—155.
9. M. Somei, Y. Fukui, M. Hasegawa, N. Oshikiri, and T. Hayashi, Heterocycles, 2000, 53, 1725.
Bromination of the corresponding Nb-methoxycarbonyl compound affords complex mixture.
10. a) N. Suzuki and A. Hattori, J Pineal Res., 2002, 33, 253; b) N. Suzuki and A. Hattori, Life Sciences,
2003, 73, 2237.