2
Tetrahedron
Adduct 5 was readily prepared by the MBH reaction
between commercially available α,β-unsaturated lactone 612-15
equally destabilized due to the steric hindrance related to the
spatial orientation of the methyl group at C2.
Scheme 3. Transition-state model for Johnson-Claisen
rearrangement of MBH adduct (5).
O
O
OH
Me
O
LiSePh, MeCHO
+
O
O
THF, -10 oC, 2 h
Me
The selective hydrolysis of methyl ester (E)-3b was
accomplished under basic (LiOH, THF/H2O, 120 °C, 18 h)2 and
acidic (HCl, H2O, 120 °C, 18 h) conditions,21 affording
carboxylic acid (E)-8 in 95% and 98% yield, respectively
(Scheme 4). Compound (E)-8 is one of the chemical constituents
of pressed olive juice22 and our synthetic approach afforded its
synthesis. Despite the communication of (E/Z)-8 as an
intermediate in the total synthesis of (±)-oleocanthal, the authors
utilised (E/Z)-8 in a telescoping strategy and did not report its
spectrometric data.2
99 % yield
6
7
5
O
OH
Me
OEt
O
Hg(OAc)2
O
O
Me
X
110 oC, 36 h
CHO
5
3a
Me
O
O
MeC(OMe)3
I2/SiO2
5
O
Me
O
+
120 oC, 36 h
CO2Me
CO2Me
E/Z = 1:1
HClaq, 120 oC, 18 h
98 % Yield
or
O
O
EtOC(O)Cl, THF
(E)-3b
(Z)-3b
25 % isolated yield
0 oC, 1 h
25 % isolated yield
Ref 2
(E)-3b
O
Me
O
Me
OH
then
CO2H
NaBH4, H2O
0 oC, 1 h
LiOH, THF/H2O
120 oC, 18 h
95 % Yield
(E)-8
2
57 % yield
(+)-Floribundane B
chemical constituent of
the pressed olive juice
formal synthesis of
the (±)-oleocanthal
Scheme 4. Synthesis of (E)-2-(3-ethylidene-2-oxotetrahydro-2H-
pyran-4-yl)acetic acid ((E)-8), and the total synthesis of (±)-
floribundane B (4).
and acetaldehyde (7) in almost quantitative yield, based on the
17
selenide-catalysed protocol reported by Jauch.16,
attempt to obtain intermediate 3a via
Our first
a
Claisen-like
rearrangement was based on our expertise in the tandem
transvinylation/Claisen rearrangement mediated by Hg(OAc)2.18
Despite the good results observed when MBH adducts prepared
from alkyl acrylates and aldehydes are used,18 no reaction
occured when this procedure was attempted in order to convert
adduct 5 into the desired aldehyde 3a (Scheme 2).
The total synthesis of (±)-floribundane B was concluded by in
situ NaBH4 reduction of the mixed anhydride prepared by the
reaction between (E)-8 and ethyl chloroformate.23 This step
afforded 2 in 57% yield as the only geometric isomer and in 14%
global yield from lactone 5. The analytical data for synthesized 2
matched those reported for the natural product, confirming the
chemical structure proposed by de Mendonça and co-workers.1
Scheme 2. Johnson-Claisen rearrangement of MBH adduct 5 for the
formal synthesis of (±)-oleocanthal (4).
3. CONCLUSION
To circumvent this issue, the Johnson-Claisen rearrangement
protocol described by Das and co-workers was tested (Scheme
2).19 The catalytic system for this transformation is based on
iodine supported on silica gel and afforded the desired methyl
ester 3b in 25% isolated yield of both geometric isomers after
chromatographic separation. Although the crude mixture was
sufficiently pure to be used in the next steps, chromatographic
separation was performed to obtain analytically pure samples
which were used to assign the stereochemistry of the isomers by
comparing their 1H NMR data with those previously reported for
2-alkenyl δ-valerolactones.18 This result allowed the formal
synthesis of (±)-oleocanthal (4). The combination of our
synthetic route to produce 3b and the chemical steps reported by
English and Williams2 to convert 3b to (±)-oleocanthal (4) can be
envisioned as the shortest synthetic approach to this anti-
inflammatory secoiridoid.
The first total synthesis of (±)-floribundane B (2) was
accomplished in just four linear steps from α,β-unsaturated
lactone 6 and acetaldehyde (7). Our synthetic approach took
advantage of a Johnson-Claisen rearrangement of MBH adduct 5
to prepare the key intermediate lactone (E)-3b. The formal
synthesis of (±)-oleocanthal (4) was also accomplished since
lactone (E)-3b is an intermediate in the total synthesis of this
anti-inflammatory secoiridoid. The hydrolysis of lactone (E)-3b
afforded carboxylic acid (E)-8, a chemical constituent of olive
press juice.
Acknowledgments
This work was supported by Coordenação de
Aperfeiçoamento de Pessoal de Nível Superior – Brasil
(CAPES), Conselho Nacional de Desenvolvimento Científico e
Tecnológico – Brasil (CNPq) - 477418/2013-9, Fundação de
Apoio à Pesquisa do Distrito Federal – Brasil (FAPDF)
193.000.236/2014, 193.001.049/2015 and 0193.001.560/2017,
Decanato de Pesquisa e Pós-graduação (DPG-UnB). We also
acknowledge Prof. Dr. Peter Bakuzis and Profª Drª Maria Marcia
Murta for their helpful discussions, the Central Analítica of the
IQ – UnB and Departamento de Polícia Federal (SEPLAB-INC-
DPF).
The absence of stereoselectivity for the Johnson-Claisen step
could be understood based on Basavaiah’s transition-state (TS)
model (Scheme 3).20 Assuming a chemical equilibrium involving
the chair like TS’s, TS-ax versus TS-eq, both appear to be
O
OH
Me
5
O
MeC(OMe)3
I2/SiO2
References and notes
O
O
H
Me
2
1.
2.
Borges, C. M. P.; Diakanawma, C.; de Mendonça, D. I. M. D. J. J.
Braz. Chem. Soc. 2010, 26, 1121-1125.
English, B. J.; Williams, R. M. Tetrahedron Lett. 2009, 50, 2713-
2715.
O
O
Me
2
3
3
Me
H
O
O
O
O1
1O
4
4
OMe
5
5
6
6
OMe
MeO
9
TS-ax
TS-eq
[3,3] sigmatropic
step
7.08 ppm
6.24 ppm
O
H
Me
O
O
Me
H
O
(
)-3b
E
( )-3b
Z
CO2Me
MeO2C
Souza, Diana Meneses
