Efficient synthetic method of Psammaplin A

Article abstract of DOI:10.1016/j.tetlet.2012.05.149

A new concise and efficient synthetic method of Psammaplin A was developed. Psammaplin A was obtained with 50% overall yield in nine steps from p-hydroxybenzaldehyde and ethyl acetoacetate via Knoevenagel condensation and direct nitrosation as key steps.

Full text of DOI:10.1016/j.tetlet.2012.05.149

Tetrahedron Letters 53 (2012) 4209–4211
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient synthetic method of Psammaplin A
Suckchang Hong a, Myungmo Lee a, Myunggi Jung a, Yohan Park b, Mi-hyun Kim a, Hyeung-geun Park a,
⇑
a Research Institute of Pharmaceutical Science and College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea
b College of Pharmacy, Inje University, 607 Obang-dong, Gimhae, Gyeongnam 621-749, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A new concise and efficient synthetic method of Psammaplin A was developed. Psammaplin A was
obtained with 50% overall yield in nine steps from p-hydroxybenzaldehyde and ethyl acetoacetate via
Knoevenagel condensation and direct nitrosation as key steps. This method might be very efficient to
construct a quite diverse library of Psammaplin A type analogs.
Received 4 May 2012
Revised 25 May 2012
Accepted 30 May 2012
Available online 7 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Total synthesis
Psammaplin A
Psammaplin A was originally isolated independently by three
different research groups from the Psammaplysilla sponge or
unidentified sponges in 1987.1–3 Psammaplin A has a unique
symmetrical structure of bromotyrosine-derived disulfide dimer.
Biological activity studies revealed that Psammaplin A has various
bioactivities such as antimicrobial activity,4 cytotoxicity against
the leukemia cell-line P388,1,5 and inhibition of DNA topoisomer-
ase,6 histone deacetylase,7 DNA gyrase,4 farnesyl protein transfer-
ase,8 and leucine aminopeptidase.8 In addition, Psammaplin A
analog showed 10 times higher cytoxicity than that of Psammaplin
A itself.10 As one of our research programs for the development of
new therapeutics for the treatment of cancer, we needed to develop
very concise and efficient synthetic methods of Psammaplin A and
its analogs. In this Letter, we present a new efficient and concise
synthetic method of Psammaplin A.
Nicolaou group reported a very efficient combinatorial syn-
thetic method of Psammaplin A and its analogs for systematic
SAR study as antibacterial agents against methicillin-resistant
Staphylococcus aureus (MRSA) by modification of Hoshino’s11 syn-
thesis.12,13 They employed amino acid 2 as the starting material
activates PPARc and induces apoptosis in human breast tumor
cells.9
which was converted into
thesis of Psammaplin A was completed by the
of 5 using tetrahydropyranoxyamine, followed by the symmetric
a
-keto acid 5 via oxazolone 4. The syn-
a-oxime formation
OH
OH
OH
Br
Br
amide coupling of the resulting
(Scheme 1).
a-oxime acid 6 with cystamine
O
O
S
S
Although their synthetic method is very efficient with 6–8 steps,
the synthesis starts from or via amino acids that are somewhat
limited in diversity because of the limitation of their commercial
availability. In addition, the amino group of 3 was removed during
N
H
N
H
N
N
HO
1 Psammaplin A
the conversion into a-keto acid 5 and then, a-nitrogen moiety of 6
was reintroduced by the formation of oxime, which might be less
efficient in respect to atom economics. To improve such
shortcomings, we need to find an efficient synthetic method which
does not involve amino acids as intermediates, but starts with a
more diverse and commercially available resource. As shown in
Recently, Shin group, one of our research collaborators, also iso-
lated Psammaplin A from an unidentified sponge collected from the
south region of Korea, and confirmed significant cytotoxicity
against the leukemia cell-line as reported in previous studies. Their
structure–activity relationship (SAR) study with the semi-synthetic
derivatives from Psammaplin A revealed that the tetramethoxy
Scheme 2, we planned to introduce the
by -nitrosation, followed by rearrangement.
First, we needed to prepare 10 as the substrate of nitrosation
a-oxime moiety directly
a
(Scheme 3). Since the mono-alkylation of active methylene dicar-
bonyl compounds with alkyl halides usually accompany dialkylat-
ed compounds, the purification process of mono-alkylated
⇑
Corresponding author. Tel.: +82 2 880 7871; fax: +82 2 872 9129.
E-mail address: hgpk@snu.ac.kr (H.-g. Park).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.149

4210
S. Hong et al. / Tetrahedron Letters 53 (2012) 4209–4211
CO2H
NH2
However 3-bromo moiety was partially removed during the reduc-
Br
CO2H
NH2
KBrO3, KBr
tion of the unsaturated double bond by catalytic hydrogenation.
Therefore we changed our synthetic route via introducing the 3-
bromo group after the reduction step. Knovenagel condensation
of ethyl acetoacetate with 4-hydroxybenzaldehyde (7) using piper-
0.5 N-HCl, MeOH
HO
HO
L-tyrosine
3
2
idine in acetic acid successfully gave a,b-unsaturated ester 8 (95%).
OH
O
Compound 8 was selectively reduced to 9 by the catalytic
hydrogenation using Pd/C and H2 in methanol (99%). Selective bro-
mination could be accomplished by treatment of 9 with KBrO3 and
KBr under 0.5 M-HCl in methanol to provide 10 (92%). Next, a di-
rect nitrosation of 10 was performed by modification of Barry’s
conditions.14,15 The treatment of n-butylnitrite to 10 in the pres-
ence of sodium ethoxide base under EtOH solvent at 0 °C afforded
Br
aq.TFA
Br
HO
TFAA
reflux
O
OH
N
reflux
O
HO
CF3
4
5
OH
Br
THPONH2
1
the corresponding
ate. After -nitrosation, immediately, the release of ethyl acetate
via fragmentation induced by addition of ethoxide anion to the
a-NO substituted analog of 10 as an intermedi-
a
CO2H
N
acetyl group, followed by the double bond conjugation of
a-NO
THPO
group via rearrangement afforded the key intermediate (E)-
a-oxi-
6
mino ester 11 in a high chemical yield (84%).16 The protection of
the oxime hydroxyl group of 11 using dihydropyran (DHP) in the
presence of catalytic amount of p-toluenesulfonic acid (PTSA)
was performed. Interestingly, we could get only oxime hydroxyl
group protected product 12, instead of both phenolic hydroxyl
and oxime hydroxyl groups protected one. The thin layer chro-
matographic monitoring revealed that both protected compounds
were initially formed, but gradually returned to mono-protected
product 12 (99%), which might be due to the bulky bromide group
adjacent to the phenolic hydroxyl group. The removal of THP of
phenolic hydroxyl group could be clearly completed by addition
of a drop of methanol. The ethyl ester of 12 was hydrolyzed to
the corresponding acid 6 with 1 M-KOH in ethanol (99%). Activa-
tion of 6 by coupling with N-hydroxysuccinimide using EDC in
CH2Cl2, followed by addition of cystamine afforded 14 (85% from
12). Finally, the deprotection of THP of 14 under methanolic hydro-
chloride solution afforded Psammaplin A (82%). Spectral data of the
synthetic product were identical with those reported in the litera-
ture.1–3
Scheme 1. Nicolaou group’s synthetic method of Psammaplin A (1).
O
O
O
Br
Br
nitrosation
OH
OH
N
HO
HO
O
rearrangement
Br
OH
OH
N
HO
Scheme 2. Synthetic strategy for the key intermediate of a-oxime acid.
compounds from dialkylated ones is sometimes very hard, depend-
ing on the alkyl halides. After several trials, we finally chose Knoe-
venagel condensation, followed by reduction to get the substrate of
nitrosation. Initially, Knoevenagel condensation of ethyl acetoace-
tate with 3-bromo-4-hydroxybenzaldehyde using piperidine in
acetic acid successfully gave a 3-bromo-substituted analog of 8.
In conclusion, a concise and efficient synthetic method of
Psammaplin A was developed from ethyl acetoacetate via Knove-
nagel condensation and direct nitrosation as key steps (50% yield
O
O
O
O
CHO
Pd/C, H2
MeOH
KBrO3, KBr
CH3
OEt
OEt
CH3
OEt
CH3
piperidine, AcOH
95%
0.5 N-HCl, MeOH
HO
HO
O
HO
O
99%
92%
7
8
9
OH
OH
Br
Br
O
n-BuONO, - AcOEt
NaOEt, EtOH, 0oC
84%
DHP, PTSA
1 N-KOH
EtOH
Br
OEt
CH3
O
O
CH2Cl2
99%
HO
O
10
OEt
OEt
99%
N
N
HO
11
THPO
12
OH
OH
OH
OH
Br
OH
N
NH2
NH2
Br
O
Br
Br
S
S
O
O
O
O
O
N
Et3N, MeOH
1,4-dioxane
EDC
1,4-dioxane
CO2H
S S
N
O
N
H
H
N
N
N
N
THPO
THPO
RO
OR
O
85%
6
13
14
1
R = THP
R = H
1 N HCl/Et2O
CH2Cl2:MeOH (20:1)
82%
Scheme 3. Total synthesis of Psammaplin A.

S. Hong et al. / Tetrahedron Letters 53 (2012) 4209–4211
4211
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acetoacetate and various commercially available aldehydes or alkyl
halides as starting materials, it might be a very efficient method to
construct a more diverse library of Psammaplin A type analogs. The
preparation of Psammaplin A analogs by our new synthetic meth-
od and the systematic structure–activity relationship studies on
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ˇ
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Acknowledgments
This work was supported by the National Research Foundation
of Korea Grant funded by the Korean Government (MEST) (NRF-
C1ABA001-2010-0020428) and a Grant of the Korea Healthcare
technology R&D Project, Ministry for Health, Welfare & Family
Affairs, Republic of Korea (A092006).
16. The regiochemical configuration of oxime (11) could be assigned as E-form by
NOE spectroscopic analysis.
References and notes
ˇ
1. Quinoà, K.; Phillip Crews, P. Tetrahedron Lett. 1987, 28, 3229.