Synthetic approach towards cuparene-type sesquiterpenes via highly regioselective epoxide opening under acid catalysis

Article abstract of DOI:10.1007/s00706-018-2199-6

Abstract: Obtaining cuparene-type sesquiterpenes is a significant synthetic challenge mainly because of the construction of the sterically hindered quaternary centres. We report herein the successful construction of such quaternary moiety by a highly regi

Full text of DOI:10.1007/s00706-018-2199-6

Monatshefte für Chemie - Chemical Monthly (2018) 149:1899–1904
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ORIGINAL PAPER
Synthetic approach towards cuparene-type sesquiterpenes via highly
regioselective epoxide opening under acid catalysis
Camila B. Nascimento1 • Leandro A. Avelar1 • Danilo C. Arantes1 • No eˆ mia K. Ishikawa2 • Fernando Macedo Jr.1
Received: 24 January 2018 / Accepted: 3 April 2018 / Published online: 13 August 2018
Ó Springer-Verlag GmbH Austria, part of Springer Nature 2018
Abstract
Obtaining cuparene-type sesquiterpenes is a significant synthetic challenge mainly because of the construction of the
sterically hindered quaternary centres. We report herein the successful construction of such quaternary moiety by a highly
regioselective opening of (?/-)-2,5-dimethoxy-4-methyl-a-methylstyrene oxide by the acetone silyl enol ether catalysed
by Lewis acid. Additionally, an efficient epoxidation of the highly activated 2,5-dimethoxy-4-methyl-a-styrene was
accomplished by modifications on the dioxirane-promoted epoxidation protocol. Intensive optimisations for both key steps
allowed the synthesis of the desired branched homo-aldol adduct, proposed as a key intermediate for a short synthetic
alternative towards enokipodins.
Graphical abstract
Keywords Epoxidations Á Lewis acids Á Natural products Á Total synthesis
Introduction
Bacillus subtilis and Staphylococcus aureus [5, 6]. Simi-
larly, enokipodins I and J presented antimicrobial activities
for B. subtilis, and enokipodins F, I, and G presented
antifungal activities for Aspergillus fumigatus. Antioxidant
properties have been attributed to enokipodin J [7, 8].
Because of the broad spectrum of biological activities
related to this class of natural products, several total syn-
theses of cuparene-type sesquiterpenes have been reported
[9]. In each case, the construction of the benzylic hindered
quaternary centre has been considered a specially chal-
lenging process to which a diversity of methods [10–13]
has been used, including well-succeeded enantioselective
protocols [14–18].
Enokipodins [1–4] are optically active cuparene-type
sesquiterpenes presenting sterically hindered quaternary
centres. These natural products (Fig. 1) show a diverse
spectrum of biological activities. Enokipodins A–D have
shown a good antifungal activity against Cladosporium
herbarum and antimicrobial properties against Gram-pos-
itive bacteria of known pathogenicity for humans, such as
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s00706-018-2199-6) contains supplementary
material, which is available to authorized users.
In the first enantioselective total synthesis of enokipo-
dins A–D (Scheme 1), Kuwahara and Saito [14, 15] used
Meyers’ alkylation protocol for the construction of b-
formylketone 2. Subsequently, this synthetic intermediate
was converted into the cuparenone moiety 1 by an
intramolecular condensation of 2.
&
Fernando Macedo Jr.
macedofc@uel.br
1
2
Departamento de Qu ´ı mica, Universidade Estadual de
Londrina, Londrina, Brazil
Instituto Nacional de Pesquisas da Amaz oˆ nia (INPA),
Manaus, AM, Brazil
123

1900
C. B. Nascimento et al.
O
O
O
R
OH
O
OH
O
R
HO
O
R
R = -H enokipodin A
R = -OH enokipodin C
R = - H enokipodin B
R = -OH enokipodin D
R = -OH enokipodin E
R = -H enokipodin F
R = =O enokipodin I
O
O
O
O
HO
HO
OH
OH
O
NH2
enokipodin G
Fig. 1 Chemical structures of enokipodins
enokipodin H
enokipodin J
Noteworthy, in another study, the all-carbon quaternary
of the cuparenone moiety has built up by the addition of a
tetrasubstituted allylsilane to the less hindered carbon of
regioselectivities favouring the branched homo-aldol
adduct as expected for an electronically controlled epoxide
opening.
epichlorohydrin under TiCl catalysis [19].
4
In this context, we envisaged the regioselective syn-
thesis of homo-aldol adduct 5 (Scheme 2) as a key step of a
short model synthetic alternative towards the enokipodin
quaternary moiety.
Conversely, the regioselective opening of gem-disub-
stituted epoxides such as 4 by carbon nucleophiles under
electronic control seems to be a conceptually comple-
mentary strategy for the construction of quaternary struc-
tures (Scheme 2).
We report herein the optimising studies and results for
the opening of highly activated benzylic epoxide 4 by the
acetone silyl enol ether catalysed by titanium
tetrachloride.
In fact, Lali c´ et al. reported the regiochemistry outcome
of the addition of the silyl enol ethers to mono- and vic-
disubstituted epoxides using TiCl4 as catalyst [20–22].
Under these conditions, the authors verified modest
Scheme 1
Scheme 2
1
23

Synthetic approach towards cuparene-type sesquiterpenes via highly regioselective epoxide…
1901
Results and discussion
bearing the 1,4-dioxygenated aromatic ring using a phe-
nylpyridine-N-oxide/Mn/NaOCl catalyst system (19%).
In the same study, dioxirane generated in situ from the
corresponding ketone in the presence of potassium
monopersulfate (oxone) furnished the desired epoxide at
significantly improved yield but yet fairly unsatisfactory
(43%). Noteworthy, we obtained strictly the same per-
centage of epoxide when olefin 3 was submitted to the
standard conditions for epoxidation by the acetone dioxi-
rane [24] (Table 1, entry 1).
Epoxidation
The proposed synthetic route requires an efficient
methodology for the epoxidation [23, 24] of the a-
methylstyrene moiety. Moreover, its success depends on
the suitable regiochemical outcome of the ring opening of
the epoxide 4 towards the homo-aldol adduct bearing the
benzylic quaternary centre 5.
The a-methylstyrene 3 (Scheme 3) was readily synthe-
sised in good global yield from acylation of 2,5-
dimethoxytoluene (6) followed by Wittig olefination of
aryl ketone 7 [25–27]. The characterisation parameters
obtained in this work for compounds 7 and 3 are fully
An increase of acetone concentration (entry 2) corre-
sponding to 3.0 equivalents of the olefin resulted in an
increased yield of the desired epoxidation product. The
optimised conditions were obtained by concomitant three
times increase of co-oxidant and acetone equivalents
which, after purification by recrystallisation from cold
petroleum ether, gave epoxide 4 in 72% yield (entry 3).
Efforts to reduce the amounts of oxone via increasing the
reaction temperature resulted in the decrease of the epoxide
yields probably because of decomposition. In all cases,
1
13
consistent to the data available in the literature: H and
C
NMR signals for 3 [28] and the mass spectra [26] and
melting point [29] for compound 7.
Conversely, either classical m-CPBA methodologies or
modified protocols specifically developed [30, 31] to cir-
cumvent drawbacks related to very reactive and unsta-
ble epoxides failed to furnish satisfactory yields of 4 from
styrene 3. In all cases, the major compounds obtained by us
were those resulting from the opening by m-chlorobenzoate
rigorous simultaneous slow addition of aqueous KHSO
and K CO solutions showed to be critical for obtaining the
5
2
3
epoxide adduct at detectable amounts.
(8 and 9) and from Meinwald rearrangement [32] (10;
Scheme 4).
Epoxide opening
Indeed, Lecornu e´ et al. [31] reported low yields for the
asymmetric epoxidation of a similar a-methylstyrene
The starting protocol for performing the regioselective
opening of epoxide 4 by the acetone silyl enol ether under
Scheme 3
Scheme 4
123

1902
C. B. Nascimento et al.
Table 1 Conditions for dioxirane promoted epoxidation of 3
entry 4) furnished a variable proportion of the homo-aldol
and high-molecular-weight by-products but, in this case,
followed by significant amounts of intact 4.
O
OMe
OMe
The effect of temperature was evaluated by a series of
experiments (Table 2, entries 5–8). Performing the reaction
at 0 °C throughout all reaction period furnished small
proportions of the desired homo-aldol (Table 2, entry 7).
Gratifyingly, the desired homo-aldol 5 was obtained as
the major component in the crude mixture when the reac-
tion was left to reach ice-bath temperature after being
stirred for 2 h at - 78 °C (Table 2, entry 6). Unlike all
precedent tests, GC–MS analysis suggested the presence of
traces of two isomers with m/z = 306 consistent with the
structures of aldol adducts resulting from the reaction of 5
with a second equivalent of silyl enol ether.
KHSO , acetone
5
MeO
TBAHS, CH CN MeO
3
4
3
Entry
T/°C
Eq. acetone
Eq. KHSO
5
Epoxide yield/%
1
2
3
4
0
1
3
3
3
1.4
1.4
4.5
1.4
43
54
72
38
0
0
r.t.
TiCl catalysis is based on the studies by Lali c´ et al.
4
Further improvements using either a wider temperature
range (Table 2, entry 5) or an increased concentration of
silyl enol ether (Table 2, entry 8) gave small proportions of
the desired product.
[
20–22]. It corresponds to entry 1 (Table 2), in which
excess epoxide is used.
Nevertheless, analysis by GC–MS of the crude product
obtained from treatment of the acetone silyl enol ether with
epoxide 4 at these conditions revealed the presence of the
starting material and the complete absence of homo-aldol
adducts. In addition, GC–MS revealed the presence of
multiple components presenting molecular weight twice
the starting epoxide.
The NMR spectra of the product purified by column
chromatography showed the isolation of the desired homo-
aldol regioisomer in the form of its corresponding
1
hemiketal. HSQC showed the JCH correlation of the
carbinolic methylene. Additionally, the coupling constant
values for the carbinolic methylene protons were 8.5 Hz
2
Entries 2–4 represent our efforts to suppress the by-
products yet favour the kinetics of the desired epoxide
opening by means of the concomitant decrease of the
(
J). Another pair of doublets observed at d = 2.24 and
H
2
.49 ppm ( J = 13.6 Hz), whose attached carbon resonates
2
at d = 52.17 ppm, was assigned to the remaining dia-
C
number of equivalents of TiCl and increase of the pro-
4
stereotopic methylene hydrogen. Moreover, the all-carbon
quaternary centre was confirmed by the presence of an
NMR signal at 46.53 ppm, which is absent in HSQC. The
peak of the hemiketal C0 carbon was identified at
portion of the silyl enol ether.
Although the formation of homo-aldol was verified when
either 2.0 or 1.5 equivalents of TiCl relative to 4 were used,
4
1
3
the GC–MS analysis indicated the dimerisation as the main
1
05.3 ppm in the one-dimensional C NMR spectra. The
process. Similarly, the use of stoichiometric TiCl (Table 2,
4
signal of the methyl attached to the benzylic position was
Table 2 Conditions for the epoxide opening reactions
a
a
Entry
Epoxide
Silyl enol ether
TiCl
4
T/°C
Product yield/%
Starting epoxide/%
1
2
3
4
5
6
7
8
a
2.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
3.0
3.0
2.0
1.5
1.0
1.5
1.5
1.5
1.5
- 78
–
17
8
- 78
6
- 78
21
15
–
9
- 78
11
10
8
- 78 to r.t.
- 78 to 0
0
74
9
11
4
- 78 to - 20
15
Values estimated by the peak area of the chromatogram (GC–MS)
1
23

Synthetic approach towards cuparene-type sesquiterpenes via highly regioselective epoxide…
1903
observed at d = 1.41 ppm and d = 27.6 ppm. Finally,
resulting solution was cooled in ice bath and, simultane-
H
13
C
1
3
ously, 120 cm of a solution of oxone (1.95 mol dm ) in
-3
the H and C NMR spectral parameters for the reso-
nances assigned to both the methyl bound to the hemiketal
moiety (d = 1.62 ppm, s, 3H; d = 28.6 ppm) and the
-
3
3
and 120 cm of a
aqueous Na
(EDTA) 0.05 mol dm
2
solution of potassium carbonate in distilled water
H
C
-
(0.845 mol dm ) were slowly added throughout 2 h using
3
aromatic methyl (d = 2.22 ppm, s, 3H; d = 15.9 ppm)
H
C
0
Ò
were consistent with the structure 5 . Similarly, the two
methoxyl groups as well as the two aromatic hydrogen
molecules showed chemical shifts and integration as
a digital two channels peristaltic pump with a Teflon tube
for each solution. The reaction was monitored by GC–MS
and thin layer chromatography and quenched by adding
3
100 cm distilled cold water. Immediately, the organic
0
expected to 5 .
3
phase was extracted with hexane (4 9 40 cm ), washed
3
with saturated NaHCO (1 9 40 cm ) and concentrated
3
Conclusion
under reduced pressure giving 72% of the epoxide 4. MS:
m/z (%) = 208 (48), 179 (100), 164 (68), 149 (28), 134 (9)
1
117 (15), 103 (12), 91 (53), 77 (40), 65 (18), 53 (24); H
The results obtained for the dioxirane-promoted epoxida-
tion showed that the highly activated 2,5-dimethoxy-4-
methyl-a-methylstyrene can be efficiently converted into
the corresponding oxide if performed under optimised
experimental conditions.
NMR (CDCl
(3H, s, CH Ar), 2.75 (1H, d, J = 5.4 Hz, CH
J = 5.4 Hz, CH ), 3.81 (3H, s, OCH ), 3.82 (3H, s, OCH
6.70 (1H, s, H–Ar), 6.89 (1H, s, H–Ar) ppm; C NMR
(CDCl , 100.13 MHz): d = 16.2 (CH Ar), 23.0 (CH ), 55.5
(CH ), 55.9 (OCH ), 56.0 (OCH ), 56.7 (C0–benzylic), 109.6
(CH), 113.8 (CH), 126.4 (C ), 127.8 (C ), 150.3 (C ), 151.5
(C ) ppm.
, 400.13 MHz): d = 1.63 (3H, s, CH
), 2.94 (1H, d,
),
), 2.22
3
3
3
2
2
3
3
1
3
Moreover, this study confirmed a high electronic control
on the opening of the a-methylstyrene oxide derivative 4
by the acetone silyl enol ether under the Mukaiyama con-
ditions [33]. In fact, the corresponding branched (?/-)-
homo-aldol 5 presenting the quaternary moiety was
obtained as a single regioisomer in a competitive, four-step
synthetic route towards the enokipodins.
3
3
3
2
3
3
0
0
0
0
4
-(2,5-Dimethoxy-4-methylphenyl)-2,4-dimethyltetrahydro-
0
furan-2-ol (5 , C H O ) In a round-bottom flask and
1
5 22 4
under argon atmosphere, 1.0 g of the epoxide 4 (4.8 mmol)
3
was dissolved in 4.8 cm dry dichloromethane. The solu-
tion was left under stirring and inert atmosphere while
3
.8 cm 2-(trimethylsiloxy)propene (4.8 mmol) was added
Experimental
0
slowly. Subsequently, the mixture was cooled at - 78 °C
and, after 5 min, 7.2 cm of a solution of titanium tetra-
All required chemicals were purchased from Merck, Fluka,
Anidrol, Sigma or Acros chemical companies. Infrared (IR)
3
-
3
chloride (1 mol dm , 7.2 mmol) was added dropwise.
-
1
spectra (4000–400 cm ) were obtained on KBr pastilles
on a Shimadzu IR Prestige-21 FT-IR equipment. The mass
spectra were obtained in the gas chromatograph coupled to
a mass spectrometer detector (GC–MS) Shimadzu model
GCMS-QP5000, 99604. NMR spectra were recorded in a
Bruker spectrometer Model Ascend 400 operating at
3
After 2 h, the system was warmed up to 0 °C and 10 cm
distilled water were added. The organic phase was sepa-
rated, and the aqueous phase was extracted with dichlor-
omethane, dried with sodium sulfate, and concentrated
under reduced pressure. Purification of the crude product
by column chromatography eluted with hexane/ethyl
1
13
4
00.13 MHz for H and 100.13 MHz to C and equipped
0
acetate (4:1) gave 84% of 5 as a light brownish liquid. FT-
IR (film): m = 3420, 2977, 2934, 1502, 1462, 1391, 1211,
with a multinuclear 5 mm probe. Chemical shifts were
reported as d values relative to tetramethylsilane. The
splitting of proton resonances in H NMR spectra are
-
043 cm ; MS: m/z (%) = 248 (23), 233 (100), 218 (10),
1
1
1
2
05 (8), 191 (7) 175 (15), 117 (18), 91 (25), 77 (25), 65
1
reported according to the following convention: singlet (s),
doublet (d), triplet (t), quartet (q) and complex pattern (m).
Coupling constants (J) are reported in Hz.
(18), 51 (13); H NMR (CDCl , 400.13 MHz): d = 1.41
3
(
3H, s, CH ), 1.62 (3H, s, CH ), 2.22 (3H, s, CH Ar), 2.24
3
3
3
(
1H, d, J = 13.6 Hz, CH ), 2.49 (1H, d, J = 13.6 Hz, CH ),
2
2
2
-(2,5-Dimethoxyphenyl-4-methyl)-2-methyloxirane
3.77 (3H, s, OCH
3
), 3.79 (3H, s, OCH
3
), 3.99 (1H, d,
(
propenyl-2,5-dimethoxytoluene (3, 5.2 mmol) was added
4, C H O ) In a round bottomed flask, 1.0 g 1-iso-
J = 8.5 Hz, CH
(1H, s, H–Ar), 6.71 (1H, s, H–Ar) ppm; C NMR (CDCl ,
3
2
O), 4.25 (1H, d, J = 8.5 Hz, CH O), 6.63
2
12 16 3
1
3
3
under stirring to 176 cm of an aqueous solution containing
100.13 MHz): d = 15.9 (CH
46.5 (Cbenzylic), 52.2 (CH ), 55.8 (OCH
3
Ar), 27.6 (CH
), 28.6 (CH
),
),
3
3
3
3
3
.36 g sodium borate (8.8 mmol) and Na (EDTA)
2
2
), 56.2 (OCH
-
.05 mol dm . Then, a solution of 0.22 g tetrabutylam-
3
0
76.6 (CH
2
O), 105.3 (C
Ar), 132.2 (C
0
), 110.6 (CHAr), 114.7 (CHAr),
Ar), 150.8 (C Ar), 151.6 (C Ar)
3
monium hydrogen sulfate (0.66 mmol) and 1.3 cm ace-
125.5 (C
ppm.
0
0
0
0
3
tone (15.6 mmol) in 260 cm acetonitrile was added. The
123

1
904
C. B. Nascimento et al.
16. Yoshida M, Shoji Y, Shishido K (2009) Org Lett 11:1441
´
17. Luj a´ n-Montelongo JA, Avila-Z a´ rraga JG (2010) Tetrahedron Lett
51:2232
Acknowledgements C. B. N. are recipients of scholarships from
CAPES. We thank ‘Laborat o´ rio Multiusu a´ rio de Espectroscopia’
(
SPEC)-UEL for acquisition of the NMR spectra.
1
1
8. Leboeuf D, Wright CM, Frontier AJ (2013) Chem Eur J 19:4835
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