Synthesis of 3,5-disubstituted-1,2-dioxolanes: access to analogues of mycangimycin and some rearrangement products

Article abstract of DOI:10.1016/j.tetlet.2016.10.051

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-dioxolanes 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 cyclopropanol with Co(acac)₂to 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.

Full text of DOI:10.1016/j.tetlet.2016.10.051

Tetrahedron Letters 57 (2016) 5286–5289
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
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
⇑
⇑
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
⇑
Corresponding authors.
http://dx.doi.org/10.1016/j.tetlet.2016.10.051
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

T. L. Nguyen et al. / Tetrahedron Letters 57 (2016) 5286–5289
5287
O
O
Me
O
Me
R
NH2
R =
OH
O
H
O
NH
H
Plakinic acid A, 4a
Plakinic acid C, 4c
Ph
Ph
O
H
O
O
H
O
H
O
O
2
O
H
Ph
Plakinic acid D, 4d
Plakinic acid E, 4e
Plakinic acid F, 4f
Artemisinine 1
arterolane 2
Ph
Et
O
8
O
O
OH
Ph
Plakinic acid G, 4g
Z
Z
Z
8
E
E
E
Mycangimycin 3
Figure 1. Structure of artemisinin, arterolane, plakinic acids A–G, and mycangimycin.
R2-O
this method to some peroxy-acetal derivatives was unsuccessful
probably due to a lower reactivity of these species compared to
some reported peroxy-ketal derivatives, as the stabilization into
peroxonium species is partly dependent on the substitution. Some
radical pathways under oxygen were also investigated, but again,
due to the absence of substitutions compared to the original meth-
ods, expected compounds could not be obtained, considering that
radicals needed stabilization.9 Incorporation of hydroperoxy group
via a SN2 process on a secondary position proved to be particularly
difficult, in contrast to some reported methods, where the addition
of hydrogen peroxide to secondary or tertiary carbon was possible
through a SN1 fashion pathway and a stabilization of an intermedi-
ate carbocation.10
C6H11MgCl
R1-Cl
R1-O
5a, R1 =TIPS
HO
ClTi(OiPr)
3
THF, rt
imidazole
DMF
dr >20:1
OR1
5b , R1 =TBDPS
OH
OH
quantitative
7a, R1 = TIPS, R2 = TBDPS, 62%
7b , R1 = TBDPS, R2 = TIPS, 66%
7c, R1 = R2 = TBDPS, 63%
Co(acac)2
EtOH, O2
R2-O
O
O
R2-Cl
R2-O
OH
O
O
OMe
OMe
imidazole
DMF
6a, R2 = TIPS, 88%
6b, R2 = TBDPS, 80%
dr = 1:1
O-R1
8a, R1 = TIPS, R2 = TBDPS, 83%
8b , R1 = TBDPS, R2 = TIPS, 78%
8c, R1 = R2 = TBDPS, 75%
After many disappointed attempts, our most promising strategy
was to use a cyclopropanol intermediate in order to perform an
oxidative ring opening of the cyclopropyl ring affording the
expected 1,2-dioxolane ring.11
Scheme 1. Synthesis of peroxy-hemiketal rings through a Kulinkovich coupling.
Cyclopropanols were easily prepared from a Kulinkovich cou-
pling reaction between appropriate terminal olefins 5a–b and
esters 6a–b in the presence of chlorotitanium triisopropoxide
and cyclohexylmagnesium chloride.12 Thus, three different cyclo-
OTBDPS
OTBDPS
O OH
O
O
O
Et3SiH, TfOH
CH2Cl2, -78 °C
propanols 7a–c were prepared in
a 62–66% yield range
57%
8c
OTBDPS
9c
OTBDPS
(dr = 20 > 1) with a combination of different silyl protecting groups
for the hydroxyl at terminal position. Oxidative ring opening of the
cyclopropanol moiety was performed in the presence of air and a
catalytic amount (5 mol %) of Co(acac)2,13 which gave us the best
conversion rates. Thus, expected 3-hydroxy-1,2-dioxolanes 8a–c
were obtained in 75–83% yield and as a 1:1 mixture of diastere-
omers (Scheme 1).
The next step was the reduction of the hydroxyl group under
acid conditions, by using triethylsilane with triflic acid at À78 °C
in dichloromethane.14 When this reaction was performed on com-
pound 8c, expected compound 9c was obtained in 57% yield and as
a single cis diastereomer.
Interestingly, some surprising results were obtained with com-
pounds 8a and 8b. Indeed, under the same reaction conditions,
ketoester 10 was obtained from compound 8a in 52% yield.
Whereas, when 8b was treated under these reaction conditions,
new compound 11 was obtained in 54% yield (Scheme 2).
It appears that absolutely no reduction was performed in these
two last reactions, even in the presence of a silane, but rather a
rearrangement of the 1,2-dioxolane ring, which was the conse-
quence of a deprotection of the TIPS group with TfOH, yet consid-
single diastereomer
OTBDPS
OTIPS
O
O
OH
O
O
Et3SiH, TfOH
CH2Cl2, -78 °C
O
OTBDPS
52%
8a
OTIPS
10
O
Et3SiH, TfOH
CH2Cl2, -78 °C
O OH
O
TBDPSO
O
54%
8b
OTBDPS
11
Scheme 2. Reduction of peroxy-hemiketal ring 8c and unexpected rearrangement
products 10 and 11.
ered robust under acidic condition. A mechanism for the formation
of compounds 10 and 11 is proposed in Scheme 3. In the presence
of an acid, the TIPS cleavage and peroxyketal metathesis takes
place for compound 8a to produce bicyclic intermediate 12. Under

5288
T. L. Nguyen et al. / Tetrahedron Letters 57 (2016) 5286–5289
OTBDPS
OH
+
OH
H
H
O
O
O
O
O
O
TBAF
H
OR
O
OR
O
OR
O
O
O
O
O OH
H
THF, 0 °C-rt
Dess-Martin
Periodinane
NaHCO3,
9c
OTBDPS
16
OH
17
, 35%
OTBDPS
, 25%
O
8a
OTIPS
TBDPSCl,
imidazole
90%
O
TIPS
H2O
12
CH2Cl2
O
O
OR
75%
DMF
O
H
O
O
OH
10
O
Ph3Pallyl
R = TBDPS
19
18
OTBDPS
Ph3P
nBuLi THF -50 °C
OTIPS
H2O
RO
OTBDPS
O
O
OH
H
O
E:Z > 5:95
60%
H
H
O
-H2O
trans :cis ratio = 2:1
O
OTIPS
-H
OLi
O
OLi
O
O
H
O
O
OR
8b
13
Ph3P
OR
14
H
H
then H2O
OTIPS
21
OTBDPS
20
OTBDPS
O
H
O
HO
RO
OTIPS
Scheme 4. Tentative of functionalization of 1,2-dioxolane 9c.
-TIPS
-H2O
RO
O
15
11
use of less basic ylides led to similar observations, meaning this
side reaction is faster than the olefination. In front of this failure,
it was decided to functionalize as little as possible the 1,2-diox-
olane ring by forming a CAC bond, but rather introducing the
desired carbon chain at the stage of the Kulinkovich reaction.
Therefore, it was planned to synthesize as a first example of
mycangimycin analogue, a completely saturated version, contain-
ing the C-20 carbon skeleton. Kulinkovich reaction between olefin
5b and methyl palmitate 22 under optimized conditions, by using
cyclopentylmagnesium chloride instead of cyclohexyl-magnesium
chloride, afforded cyclopropanol 23 (dr >95:5) in an excellent 91%
yield. Optimization of the cobalt catalyzed oxidative ring opening
of the cyclopropanol by using pure oxygen afforded compound
24 with also an improved yield of 90%. Acid catalyzed silane reduc-
tion of peroxy-hemiketal 24 afforded expected 1,2-dioxololane
ring in 66% yield (drcis:trans = 83:17). Deprotection of the primary
hydroxyl group was performed by the use of buffered TBAF to
afford cleanly the desired alcohol 26 in 81% yield. However, pro-
longed exposure time of 1,2-dioxolane 25 to a slight excess of TBAF
led to fragmentation of the 1,2-dioxolane ring into a b-hydroxyke-
tone, known as the Kornblum-DeLaMare rearrangement.15 Further
oxidation with RuCl3 hydrate and periodic acid in a 2:3:2 CCl4/
water/MeCN mixture was performed to give carboxylic acid 27 in
88% yield. Further derivatization of the acid into methyl ester 28
(81%) was performed (Scheme 5).
Scheme 3. Plausible mechanisms for the formation of compounds 10 and 11.
acid catalysis a fragmentation of the 1,2-dioxolane ring 12 occurs
with cleavage of a CAC bond, leading to ketoester 10. This mecha-
nism appears to share some similarities with the Hock cleavage,
although some differences remains such as the presence of a
hydroperoxide or the alkyl migration15 but also with some base
mediated fragmentation of ozonides.16 Concerning the formation
of compound 11, it is important to note that some 2,3-dihydro-
4H-pyran-4-ones were previously prepared using a similar strat-
egy, through a Kulinkovich reaction-oxidative cyclopropane ring
opening sequence. However, reductive cleavage of the intermedi-
ate 1,2-dioxolane and presence of a masked ketone were neces-
sary.17 From compound 8b, the cyclization from the TIPS
protected hydroxyl group is not possible, as it would make a 4-
member ring. However, it appears that the formation of compound
11 could proceed through the opening of the hemi peroxy-ketal
ring under acid catalysis, followed by formation of the enol form
of the ketone (intermediate 13), which then attacks the peroxide
to produce epoxy-ketone intermediate 14 (this is a classical and
known decomposition product of compounds 8a–c under basic
condition). Acid catalysis Meinwald rearrangement of epoxide 14
affords enol 15,18 which leads finally to product 11 after ketal
metathesis with the hydroxyl group bearing the TIPS protection
(TIPS group could be removed from any of the intermediates or
starting material 13, 14, 15).
Nevertheless, further functionalization around the 1,2-diox-
olane ring could be performed by using compound 8c. Indeed,
mono-deprotection of the TBDPS group was possible with TBAF
in THF, by controlling the stoichiometry of the reagent, furnishing
a mixture of diol 16 and mono-protected compound 17 in 25 and
35% yield, respectively along with 15% recovered starting material
9c. Some diol 16 was also recycled by treatment with TBDPS chlo-
ride and imidazole in DMF affording product 17 in 75% yield. The
free hydroxyl-group of compound 17 was then further oxidized
into aldehyde 18 with Dess–Martin periodinane (90% yield), and
in a second step, aldehyde 18 was subjected to Wittig olefination.
Indeed, the olefination took place, but not exactly as expected since
no 1,2-dioxolane ring was detected after reaction and mainly com-
pound 19 was isolated in 60% yield (Scheme 4). It appears that the
formation of epoxy-aldehyde 21 took place first, through the pro-
duction of enolate 20, which attacks the electrophilic peroxide, in
a similar fashion than intermediate 13 in Scheme 3. Other olefina-
tion such as Wittig Horner or Julia-Kosciensky olefination and the
TiCl(OiPr)3
C5H9MgCl
OH
14
O
O
Co(acac)2
O2
OH
O
EtOH, rt
90%
THF0 °C
91%
14
OR
5b
O
+
OR
14
OR
24
dr = 1:1
22
23
dr >95:5
Et3SiH, TfOH
DCM, -78 °C
66%
O
R=TBDPS
H5IO6
RuCl3.H2O
TBAF,
CH3COOH
O
O
O
O
O
14 CCl4:H2O:
CH3CN, rt
88%
14
THF, rt
81%
14
HO
27
26
25
dr = 83:17
O
OH
OR
TMSCHN2
MeOH, rt
81%
O
O
14
MeO
28
O
Scheme 5. Synthesis of saturated analogues of mycangimycin 27, 28.

T. L. Nguyen et al. / Tetrahedron Letters 57 (2016) 5286–5289
5289
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We thank Vietnamese Government for a fellowship to T.L.
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Supplementary data
Supplementary data (experimental data and copies of the 1H,
13C NMR spectra) associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tetlet.2016.10.051.
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