Study of the synthesis of poecillanosine

Article abstract of DOI:10.1016/j.tetlet.2006.12.059

The synthesis of poecillanosine, a natural N-hydroxy-N-nitroso-alkylamine compound, was studied. Poecillanosine was shown to be unstable under acidic nitrosation conditions. Only degradation compounds of poecillanosine were obtained under such conditions, however, the O-methyl derivative of poecillanosine was synthesised and confirmed.

Full text of DOI:10.1016/j.tetlet.2006.12.059

Tetrahedron Letters 48 (2007) 1209–1212
Study of the synthesis of poecillanosine
Ming Xian* and Brian J. Shuhler
Department of Chemistry, Washington State University, Pullman, WA 99164, USA
Received 21 October 2006; revised 3 December 2006; accepted 12 December 2006
Abstract—The synthesis of poecillanosine, a natural N-hydroxy-N-nitroso-alkylamine compound, was studied. Poecillanosine was
shown to be unstable under acidic nitrosation conditions. Only degradation compounds of poecillanosine were obtained under such
conditions, however, the O-methyl derivative of poecillanosine was synthesised and confirmed.
Ó 2006 Elsevier Ltd. All rights reserved.
The chemistry of N-hydroxy-N-nitrosoamines had not
received much attention prior to the discoveries that
(1) nitric oxide (NO) can be released from these com-
pounds1,2 and (2) NO has diverse and dramatic physio-
logical effects.3–5 Recently, the chemical and biological
properties of a series of aromatic N-hydroxy-N-nitroso-
amines have been studied.6–8 The results revealed that
these compounds yield NO by undergoing a one-elec-
tron oxidation. The oxidation can be achieved through
chemical, electrochemical and enzymatic methods
(Scheme 1). The amount of NO generation is dependent
on both the oxidation potential applied and the substit-
uents on the phenyl ring. Therefore, these compounds
are considered as new types of redox-sensitive, and
redox-adjustable NO donors.
In general, N-hydroxy-N-nitroso-alkylamines are rare
natural products. So far, only four have been reported
(Scheme 2): alanosine,11 dopastin,12 nitrosofungin13
and poecillanosine.14 Poecillanosine was the most recent
one, isolated from a marine sponge in 1997 and acts as a
free radical scavenger.14 Since mass spectral and NMR
peaks of poecillanosine itself provided no useful infor-
mation (it is likely that poecillanosine decomposes under
analytic conditions),14 it was converted into a more sta-
ble methyl ether derivative which led to the structure
elucidation. Poecillanosine structurally differs from
other N-hydroxy-N-nitroso-alkylamine natural products
with the inclusion of a long lipophilic carbon chain.
In order to investigate NO-related biological properties
of poecillanosine, we carried out the synthesis of this
natural product. Here we report the synthetic study
results.
N-Hydroxy-N-nitrosoamine derivatives were also
reported to be inhibitors of some metal containing
enzymes such as tyrosinase9 and superoxide dismutase.10
The inhibition activity is likely to be derived from the N-
hydroxy-N-nitrosoamine group, which could potentially
interact with the metal ion at the enzyme active sites.
From the retrosynthetic perspective, (S)-1,2-heptade-
canediol 1 serves as the key intermediate (Scheme 3).
Obviously, sharpless asymmetric dihydroxylation (AD)
O
OH
N
NH2
O
OH
NO
OH
N
H
NO
ON
N
NO
N
NO
N
HO
N
_
HO
NO
+
.
-1e
O
O
Alanosine
Dopastin
NO
Nitrosofungin
X
X
X
OH
OAc
N
Scheme 1.
ON
Poecillanosine
*
Corresponding author. Tel.: +1 509 335 6073; fax: +1 509 335
8867; e-mail: mxian@wsu.edu
Scheme 2.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.059

1210
M. Xian, B. J. Shuhler / Tetrahedron Letters 48 (2007) 1209–1212
problem because hydrogenation of the double bond
OH
N
OAc
OH
followed. Catalytic hydrogenation of 4 followed by the
removal of the acetonide furnished chiral diol 1 in
an excellent yield. This five-step sequence allowed us
to prepare 1 in a large quantity with a high enantiomeric
excess (98% ee).
ON
Poecillanosine
HO
1
With diol 1 in hand, we turned to explore the synthesis
of the precursor of poecillanosine (compound 7). As
shown in Scheme 5, the first approach was to convert
the primary hydroxyl of 1 into a tosylate 5. Then, acet-
ylation of 5 followed by displacement of the tosylate
with hydroxylamine provided N-alkyl-N-hydroxyamine
7. This approach involved three steps, but the overall
yield (17%) was low. In the second approach, the pri-
mary hydroxyl group was selectively protected as TBS
silyl ether 8 and the secondary hydroxyl group was pro-
tected as acetate. The resulting compound 9 was then
treated with tetrabutylammonium fluoride to provide
alcohol 10. Swern oxidation20 of 10 followed by oxime
formation with hydroxylamine and NaCNBH3 reduc-
Scheme 3.
of corresponding olefin is the most efficient pathway to
prepare 1. However, similar to previous reports,15,16
AD reactions on 1-heptadecene provided desired diol 1
in 90–93% yields with 72% ee as the highest enantio-
meric excess. Therefore, another route was adopted as
described in Scheme 4. R-Glyceraldehyde (3) was pre-
pared from D-mannitol by acetonide formation and oxi-
dative cleavage of diol 2.17 Then, the alkyl chain was
enlarged under Wittig olefination.18,19 Olefin 4 was ob-
tained as the mixture of Z/E isomers (Z/E = 92/8). In
this case, the E/Z ratio of the products presented no
O
OH
OH OH
O
O
NaIO4
95%
O
HO
O
O
OH
SnCl2
93%
OH
O
OH OH
D-Mannitol
2
1. H2, Pd/C
O
H
O
(Ph)3P-CH2(CH2)12-CH3
( )12
O
2. Amberlyst-15
95%
BuLi
91%
O
3
4
OH
HO
1
Scheme 4.
OAc
OH
( )14
Ac2O
TsCl
Py
91%
TsO
approach I
1
TsO
( )14
Py
95%
5
6
OH
HN
OAc
NH2OH
20%
( )14
7
OH
( )14
OAc
Ac2O
TBSCl
Et3N, DMAP
90%
1
approach II
TBSO
TBSO
DMAP
95%
( )14
9
8
OAc
OAc
( )14
TBAF
86%
Swern [O]
96%
O
HO
( )14
H
10
11
OH
HN
OAc
1. NH2OH.HCl, Py.
2. NaCNBH3
60%
( )14
7
Scheme 5.

M. Xian, B. J. Shuhler / Tetrahedron Letters 48 (2007) 1209–1212
1211
tion furnished 7, the precursor of poecillanosine. The
second approach was three steps longer than the first ap-
proach, but the overall yield (42%) was more acceptable.
H3C
OAc
( )14
1. NH2OMe.HCl, Py.
O
OAc
( )14
O
HN
2. NaCNBH3
67%
H
11
13
Next, two nitrosation methods were applied to 7 to
complete the synthesis of poecillanosine. However, both
methods failed. The nitrosation employing alkyl nitrites
(ethyl nitrite, butyl nitrite, iso-butyl nitrite) under differ-
ent temperatures and solvents did not lead to any prod-
uct even after 24 h. Only starting materials were
recovered. In contrast, upon the treatment with
NaNO2/HCl, the starting material was consumed com-
pletely, however, two isolated products were 12a and
12b (Scheme 6), instead of the desired poecillanosine.
NaNO2
HCl
85%
H3C
ON
O
N
OAc
14
Scheme 8.
In conclusion, the synthesis of poecillanosine, a natural
N-hydroxy-N-nitroso-alkylamine compound, was stud-
ied. Poecillanosine was shown to be unstable under acidic
nitrosation conditions. Only degradation compounds of
poecillanosine were obtained under such conditions.
However, the O-methyl derivative of poecillanosine was
synthesised and confirmed. Currently we are carrying
out experiments to synthesise other stable derivatives of
poecillanosine using the procedure reported here. Their
biological activities will also be studied.
In this nitrosation step, we propose that the treatment
with NaNO2/HCl of 7 did lead to the formation of poe-
cillanosine temporarily. However, as an unstable species
(especially under acidic conditions), poecillanosine
underwent hydronium ion catalysed solvolysis to gener-
ate N2O and alcohol derivatives (Scheme 7). A similar
mechanism has been proposed for the hydrolysis of
other N-hydroxy-N-nitroso-alkylamines.21 In the case
of poecillanosine, because of the presence of a-acetate
group, two regio-isomers (12a and 12b) were formed.
Acknowledgments
Unable to obtain stable poecillanosine, we then adopted
a similar route towards the synthesis of the O-methyl
ether of poecillanosine 14 (Scheme 8). The treatment
of aldehyde 11 with O-methyl hydroxylamine followed
by sodium cyanoborohydride reduction provided alkyl
hydroxylamine derivative 13. Nitrosation of 13 with
NaNO2/HCl went smoothly to furnish the O-methyl
ether of poecillanosine 14 in a good yield.
This research was supported by the Washington State
University. We thank Professor George Wang (the Ohio
State University) for helpful discussion.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.12.059.
OH
HN
OAc
RONO
no reaction
References and notes
7
OAc
( )14
12a
+
HO
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OH
HN
OH
N
OAc
( )14
OAc
( )14
NaNO2
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95%
ON
Poecillanosine
OH
7
AcO
not isolated
( )14
12b
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/
= 3/7
Scheme 6.
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O
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H3O
O
-H2O
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( )14
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H2O
OAc
OH
( )14
HO
+
AcO
( )14
Scheme 7.

1212
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