Tetrahedron Letters
Synthesis of 3,5-disubstituted-1,2-dioxolanes: access to analogues of
mycangimycin and some rearrangement products
a,
Thuy Linh Nguyen a,b, Laurent Ferrié a, , Bruno Figadère
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a BioCIS, Univ. Paris-Sud, CNRS, Université Paris-Saclay, 92290 Châtenay-Malabry, France
b Institute of Marine Biochemistry-Vietnam Academy of Science and Technology (VAST), Cau Giay, Hanoï, Viet Nam
a r t i c l e i n f o
a b s t r a c t
Article history:
Mycangimycin is a eicosa-heptenic acid containing an unprecedented 3,5-disubstituted-1,2-dioxolane
ring with promising anti-fungal and antimalarial activity. Most reported methods to prepare 1,2-diox-
olanes are targeting 3,3,5,5-tetrasubstituted or 3,3,5-trisubstituted 1,2-dioxolanes. Thus, some methods
for synthesizing these unusual 3,5-disubstituted 1,2-dioxolanes were investigated. The most promising
approach was the use of a Kulinkovich reaction followed by an oxidative ring opening of the cyclo-
propanol with Co(acac)2 to reach the peroxy-hemiketal structure. Successive triflic acid mediated silane
reduction of the corresponding peroxy-hemiketal afforded the expected 3,5-disubstituted-1,2-dioxolane
ring. Through our studies, some unprecedented rearrangements of 1,2-dioxolane rings were observed,
which will be discussed in this Letter. Finally, two saturated analogues of mycangimycin were
synthesized.
Received 15 September 2016
Revised 7 October 2016
Accepted 14 October 2016
Available online 15 October 2016
Keywords:
Peroxide
Kulinkovich reaction
Natural product
Fatty acid
Ó 2016 Elsevier Ltd. All rights reserved.
Anti-malarial
Peroxide rings are primary targets in pharmaceutics since the
discovery of the bioactivity of artemisinin 1, one of the most potent
anti-malarial drug.1 From this discovery, many efforts were con-
ducted in the exploration of analogues and the development of
chemical methods to supply the world demand. The search of some
synthetic antimalarial peroxide compounds such as arterolane 2
(in phase III clinical trials) is still ongoing (Fig. 1).2
More recently, a new peroxide containing fatty acid, called
mycangimycin 3, was isolated from the southern pine beetle (Den-
droctonus frontalis).3 This compound is not produced by the insect
itself, but rather by a bacterial symbiont, which helps the beetle to
resist to some antagonistic fungi such as Ophistoria minus. By con-
sequence, mycangimycin 3 exhibited a potent anti-fungal activity
against a variety of fungi, with some efficiency similar to ampho-
tericin B. Additionally, mycangimycin 3 displayed some promising
anti-malarial activity, similar to 1 (EC50 = 17 ng/mL vs EC50 = 10 ng/
mL for artemisinin 1, chloroquine, pyrimethamine, or mefloquine)
(Fig. 1).
the first 1,2-dioxolane containing fatty acid to be reported. Indeed,
prostaglandin H2 is an arachidonic acid derivative and a precursor
of all other prostaglandins.4 Also, plakinic acids 4a–g were exten-
sively studied, however, their 1,2-dioxolane ring is 3,3,5,5-tetra-
substituted.5 This difference is of great importance in the
synthesis of the 1,2-dioxolane ring moiety and also could be the
origin of the difference of biological activity between mycangimy-
cin 3 and plakinic acids 4a–g (indeed, 4a–g are not reported to
exhibit an antimalarial activity). Also in a recent report, most of
1,2-dioxolane ring analogues of arterolane 2 showed no antimalar-
ial activity, while only few got a moderate one.6 The degree of sub-
stitution of the 1,2-dioxolane ring is also important in a synthetic
point of view, because only few examples of preparation of 3,5-dis-
ubstituted-1,2-dioxolane ring were reported in the literature
(Fig. 1).7
Considering the promising anti-malarial activity of mycangimy-
cin 3, probably due to the 1,2-dioxolane moiety, and also consider-
ing that mycangimycin 3 could be relatively unstable due to the
polyenic chain, we were interested to explore some chemical
routes to synthesize more simple analogues of mycangimycin 3.
Because of the absence of general methods to obtain 3,5-disubsti-
tuted-1,2-dioxolanes, many routes from the literature describing
the access to 3,3,5,5-tetrasubstituted or 3,3,5,-trisubstituted-1,2-
dioxolanes were explored in order to obtain analogues of mycangi-
mycin 3.
The chemical structure of mycangimycin 3 is particularly origi-
nal. It is an unprecedented C-20 heptenic fatty acid containing a
3,5-disubstituted-1,2-dioxolane ring between position 3 and 5
with a cis relative configuration and a 3S, 5S absolute configuration.
The double bonds are all conjugated between C-7 and C-20 with a
(Z, Z, E, E, Z, E) stereochemical pattern. It should be noted it is not
The chemistry of peroxonium ions was first investigated, from
the works of Woerpel or Dussault.8 However, the application of
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Corresponding authors.
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