Total synthesis of gymnorrhizol, an unprecedented 15-membered macrocyclic polydisulfide from the Chinese mangrove bruguiera gymnorrhiza

Article abstract of DOI:10.1021/ol0703783

The total synthesis of gymnorrhizol, a naturally occurring macrocyclic polydisulfide with a new skeleton and a potent proteintyrosinephosphatase 1B inhibitor, was prepared in three steps, starting from (R)-1-bromo-3- chloroisopropanol and 1,3-dichloropropan-2-ol.

Full text of DOI:10.1021/ol0703783

ORGANIC
LETTERS
2007
Vol. 9, No. 9
1715-1716
Total Synthesis of Gymnorrhizol, an
Unprecedented 15-Membered
Macrocyclic Polydisulfide from
the Chinese Mangrove
Bruguiera gymnorrhiza
Jing-Xu Gong,† Xu Shen,*,† Li-Gong Yao,† Hualiang Jiang,*,† Karsten Krohn,‡ and
Yue-Wei Guo*,†
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, Shanghai 201203, People’s Republic of China, and
Department of Chemistry, UniVersity of Paderborn, Warburger Strasse 100,
D-33098 Paderborn, Germany
ywguo@mail.shcnc.ac.cn; xshen@mail.shcnc.ac.cn; hljiang@mail.shcnc.ac.cn
Received February 14, 2007
ABSTRACT
The total synthesis of gymnorrhizol, a naturally occurring macrocyclic polydisulfide with a new skeleton and a potent proteintyrosinephosphatase
1B inhibitor, was prepared in three steps, starting from (R)-1-bromo-3-chloroisopropanol and 1,3-dichloropropan-2-ol.
Cyclic polysulfides are relatively uncommon in nature, and
many of them show various interesting biological activities
ranging from antifungal,1 antibacterial,1c,d and cytotoxic
effects1a,c,2 to inhibition of protein kinase C.3 Gymnorrhizol
(1) is a macrocyclic polysulfide isolated by Sun and Guo
from the Chinese mangrove Bruguiera gymnorrhiza.4 Its
unprecedented new skeleton was established by a combina-
tion of spectroscopic and X-ray crystallographic analysis.5
The structure of gymnorrhizol (1) is characterized by a 15-
membered macrocyclic polydisulfide with three symmetri-
cally substituted hydroxyl groups. The achiral molecule has
a plane of symmetry; two of the hydroxyl groups are syn,
and the other one has an anti orientation.
Protein tyrosine phosphatase 1B (PTP1B) is a potential
drug target for the treatment of Type II diabetes and obesity.6
A large number of PTP1B inhibitors have been developed
over the past decade in an effort to design potent and
selective compounds as drug candidates. Unfortunately, most
of them have been hampered owing to their poor cell
† Shanghai Institute of Materia Medica.
‡ Universita¨t Paderborn.
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10.1021/ol0703783 CCC: $37.00
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Published on Web 04/05/2007

permeability and oral bioavailability. In our screening
program to search for PTP1B inhibitors from the Chinese
medicinal plants, a MeOH extract of stems and leaves of
mangrove B. gymnorrhiza exhibited PTP1B inhibitory activ-
ity, which led us to investigate the PTP1B inhibitory
compounds from this plant. Of the compounds, gymnorrhizol
(1) exhibited the strongest inhibitory activity with an IC50
value of 14.9 µM (unpublished data). The PTP1B inhibitory
activity for this unique type of macrocyclic polydisulfide
warrants further investigation and optimization. However,
the scarcity of available sample from natural sources is a
major problem for additional study of structure-activity
relationship (SAR) and structural derivatization/modification.
In addition, the new polydisulfide skeleton of gymnorrhizol
represents a synthetic challenge. All of these facts inspired
us to synthesize gymnorrhizol. In the following we report
on the total synthesis of this compound.
Scheme 1. Retrosynthetic Analysis of Gymnorrhizol
water, followed by oxidation with 30% H2O2 to give the
disulfide 4 in 74% yields. The intermediate Bunte salt 2 was
then produced by reaction of 4 with sodium thiosulfate in
aqueous ethanol. The dithiol 7 as the second building block
was prepared in 65% yield by the condensation of 1,3-
dichloro-2-propanol (6) with sodium trithiocarbonate in
The key to the synthesis of the gymnorrhizol skeleton was
the construction of the sulfur-sulfur bonds. Many methods
for the formation of disulfides have been reported, such as
oxidative coupling of thiols or Bunte salts;7 reductive
formation from sulfenyl, sulfinyl, sulfonyl or thiocyanate
derivatives;8 or the reaction of an alkyl halide with sodium
disulfide.9 A general method for the synthesis of unsym-
metrical disulfides is the reaction of an alkyl sulfenyl
thiocarbonate or sulfenyl thiocyanate with another thiol.10
Bunte salts, prepared from alkyl halides, are available not
only for synthesis of symmetrical disulfides but also for
unsymmetrical disulfides.11 The formation of unsymmetrical
disulfides using Bunte and thiol salts is mild and convenient.
Therefore, we used the Bunte salts in the synthesis of
gymnorrhizol (1). According to the retrosynthesis analysis
(Scheme 1), condensation of the dithiolate anion 3 with the
Bunte salt 2 may directly lead to gymnorrhizol (1). Inter-
mediate 2 can be obtained from dichloride 4, which in turn
may be produced using (R)-1-bromo-3-chloroisopropanol (5)
as the starting material.
Scheme 2. Synthesis of Gymnorrhizol
refluxing methanol, followed by acidification with 1 N H2-
SO4.13 The dithiol 7 was then converted into its bispotassium
salt 3 by treatment with KOH solution. Subsequent conden-
sation of this salt with the Bunte salt 2 in aqueous THF at
ambient temperature gave the target compound gymnorrhizol
(1) in 34% yield. The spectral and analytical data of the
synthetic material are in total agreement with the data
reported for the natural product.4
In summary, the first total synthesis of gymnorrhizol (1)
has been achieved in only three steps in 25% overall yield
from 5. The synthesis is amenable to large scale, and a similar
strategy will allow the synthesis of related macrocyclic
polydisulfides and analogs of 1 for further SAR study.
The synthetic routine started from (R)-1-bromo-3-chlor-
oisopropanol (5) as shown in Scheme 2. (R)-1-Bromo-3-
chloroisopropanol12 was reacted with sodium thiosulfate in
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Acknowledgment. The research work was financially
supported by the National Marine “863” Project (nos.
2006AA09Z447 and 2006AA09Z412) and SCTSM Project
(no. 054307062).
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Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0703783
(13) Petrun’kin, V. E.; Lysenko, N. M. Zh. Obshch. Khim. 1959, 29,
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