Synthesis of an epoxyquinol analog: Efficient methodology for the insertion of side chains into cyclohexenone cores

Article abstract of DOI:10.1016/j.tetlet.2010.10.138

A novel epoxyquinol analog was prepared by molecular simplification of monomeric and dimeric scaffolds. A feasible methodology for the insertion of side chains into cyclohexenone skeleton was developed. Insertion of the hydroxymethyl side chain was achiev

Full text of DOI:10.1016/j.tetlet.2010.10.138

Tetrahedron Letters 51 (2010) 6921–6923
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of an epoxyquinol analog: efficient methodology for the insertion
of side chains into cyclohexenone cores
⇑
Viviana Heguaburu , Valeria Schapiro, Enrique Pandolfi
Departamento de Química Orgánica, Facultad de Química, Universidad de la República, General Flores 2124, C. P. 11800, Montevideo, Uruguay
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel epoxyquinol analog was prepared by molecular simplification of monomeric and dimeric scaf-
folds. A feasible methodology for the insertion of side chains into cyclohexenone skeleton was developed.
Received 27 September 2010
Revised 22 October 2010
Accepted 26 October 2010
Available online 31 October 2010
Insertion of the hydroxymethyl side chain was achieved through
a-sulfonylcarbanion chemistry. The
alkenyl chain was inserted through palladium cross-coupling strategy.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Epoxyquinols
Molecular simplification
Analogs
a-Sulfonylcarbanions
Cross-coupling
Cyclic epoxyquinols are relatively abundant in nature and dis-
As part of our ongoing program concerning asymmetric
synthesis of natural epoxyquinols,20–22 our research group devel-
oped a new strategy for the introduction of the side chains of these
complex natural products. In this approach, molecular simplifica-
tions of the mentioned structures were designed, aiming to devel-
op an efficient methodology and to prepare simplified analogs.
Scheme 1 shows the simplifications proposed for ambuic acid
and ECH for the synthesis of deoxygenated monomers, as well as
torreyanic acid and epoxyquinol simplifications for the synthesis
of deoxygenated dimers.
play a wide range of biological activities.1 Several compounds of
this type, such as torreyanic acid, ambuic acid, and epoxyquinols
A, B, and C (Scheme 1) have been studied due to their attractive
and complex structures, and promising biological properties. In
relation to these structures it is common to find dimers along with
their corresponding monomers in the same natural source. Torrey-
anic acid, a dimeric epoxyquinone which exhibits antitumor prop-
erties, was isolated from Pestalotiopsis microspora, an endophytic
fungus associated to Torreya taxifolia.2 The related monomer,
ambuic acid, was isolated from the same fungus; it is a highly func-
tionalized epoxyquinol with antifungal activity.3 Highly oxygen-
ated heptacyclic structures, such as epoxyquinols A, B, and C, and
epoxytwinol A, exhibiting interesting antiangiogenic activities,
were isolated from an unidentified fungus along with their mono-
mer ECH, a receptor-mediated apoptosis inhibitor.4,5 Biosynthesis
of torreyanic acid and epoxyquinols is likely to occur through an
oxidative dimerization cascade pathway that involves a Diels–Al-
der dimerization between two epimeric 2H-pyrans, which are con-
structed from the natural monomers.2,6–12 Stereochemistry of
torreyanic acid and epoxyquinol A arises as a consequence of the
opposite orientation of the side chains in the endo [4+2] adduct.
Inspired by this dimerization cascade several research groups have
embraced biomimetic approaches for the synthesis of these struc-
turally attractive compounds.7,8,13–19
The proposed methodology for the insertion of a methoxy-
methyl chain is shown in Scheme 2. It is based on the acidity of
a
-sulfonyl hydrogen atoms. This strategy has been previously used
in our research group for the synthesis of prelunularin.23 For this
purpose, Michael addition of sodium p-toluensufinate followed
by basic conditions generates the
a
-sulfonylcarbanion that attacks
-halogenation followed
the appropriate electrophile.24–27 Further
a
by palladium cross-coupling reaction allows the insertion of the
alkenyl side chain.28
Introduction of a hydroxymethyl chain precursor was possible
through derivatization of the b position of the
a,bunsaturated
ketone. Michael addition of sodium p-toluensulfinate on cyclo-
hexenone in acidic conditions afforded 1 in 73% yield. Carbonyl
protection with ethyleneglycol afforded compound 2 in 99% yield.
In the presence of n-BuLi this compound acts as an excellent nucle-
ophile against choromethylmethylether and compound 3 was ob-
tained in 60% yield. Acidic treatment of this compound leads to
ketal hydrolysis and elimination of p-toluensulfinic acid.23 There-
⇑
fore, restoring the
a
,b-insaturated ketone with HF afforded 429 in
Corresponding author. Tel.: +598 2924 4066; fax: +598 2924 1906.
E-mail address: vheguab@fq.edu.uy (V. Heguaburu).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.138

6922
V. Heguaburu et al. / Tetrahedron Letters 51 (2010) 6921–6923
O
COOH
O
O
molecular
R
C5H11
simplification
O
O
OH
OH OH
OH OH
deoxygenated
analogs
ambuic acid
ECH
COOH
O
O
O
O
O
HO
OH
O
O
O
O
O
O
molecular
simplification
O
O
O
O
O
O
H
R
H
H
COOH
R
O
deoxygenated
analogs
epoxyquinol A
torreyanic acid
Scheme 1. Molecular simplification of ambuic acid, ECH and dimeric compounds.
87% yield. An addition-elimination reaction of iodine in the pres-
ence of DMAP30 permits to obtain 5 in 40% yield. Finally, Suzuki
cross-coupling reaction28 between b-iodoenone 5 and trans-1-
heptenyl boronic acid31 leads to deoxygenated monomer analog 6.
To be able to study oxidative dimerization of this type of deox-
ygenated analogs, the electrophile used to functionalize b-position
must be changed, in order to insert a substituent that can be easily
converted into a free alcohol.
O
O
O
O
O
c
b
a
Ts
PivO
Ts
OPiv
2
7
8
O
X
d
Similarly, compound 2 affords 7 in 78% yield in the presence of
chloromethylpivalate32 and n-BuLi (Scheme 3). Ketal hydrolysis
occurs with simultaneous elimination in acidic medium producing
O
O
O
OPiv
I
C5H11
9a, X=Br
9b, X=I
g
e
compound 8 in 56% yield as described above. a-Halogenation was
performed under several conditions. Only trace amounts of the ex-
pected halogenated products were obtained (compounds 9a–b).
The reaction course appeared to be sensitive to steric hindrance
of the substituted olefin. So, we decided to remove the pivalic ester
OH
OH
OH
11
10
12
f
Scheme 3. Insertion of hydroxymethyl and alkenyl chains for the synthesis of
deoxygenated analogs 10 and 12. Reagents and conditions: (a) PivOCH2Cl, n-BuLi,
THF, 0 °C to rt, 3 h, 78%; (b) HF aq, CH3CN, rt, 4 h, 56%; (c) 9a: Br2, NEt3, CH2Cl2,
reflux, 12 h, 5%, 9b: I2, DMAP, CH2Cl2, reflux, 12 h, 5%; (d) K2CO3, MeOH, rt, 5 h, 93%;
(e) I2, DMAP, CH2Cl2, reflux, 8 h, 40%; (f) K2CO3, MeOH, rt, 5 h, 55%; (g)
by reacting 8 with K2CO3 and MeOH. a-Halogenation of hydroxy-
methylenone 1033 occurs in 40% yield to afford enone 11. Attempts
to optimize the halogenation yield of 10 and 4 did not result in sig-
nificant improvements. The alkenyl side chain was inserted by the
cross-coupling protocol previously mentioned to afford deoxygen-
ated analog 12 in 51% yield. Oxidation of 12 with o-iodoxybenzoic
acid (IBX) triggers the reaction to 1334 through a electrocycliza-
tion-Diels–Alder cascade (Scheme 4). Relative stereochemistry of
this product was deduced by comparison of spectral data with tor-
reyanic acid7 and epoxyquinol A,15 displaying the two pentenyl
H
11C5CH@CHB(OH)2, Pd(PPh3)4, K2CO3, THF, H2O, reflux, 12 h, 51%
side chains opposite one another as already seen in these natural
products.
To summarize, the methodology developed for the insertion of
side chains present in epoxyquinol-type natural products, proved
to be useful for the preparation of novel deoxygenated analogs.
O
O
O
O
O
O
O
O
O
a
b
c
electrocyclization
IBX, DMF
51%
Ts
MeO
O
Ts
Ts
OH
1
2
3
H
12
O
O
I
C5H11
d
e
f
O
O
O
OMe
OMe
OMe
O
4
5
6
Diels-Alder
O
H
O
Scheme 2. Insertion of methoxymethyl and alkenyl chains over cyclohexenone for
the synthesis of deoxygenated analogs 4 and 6. Reagents and conditions: (a) p-TsNa,
AcOH, MeOH, rt, 24 h, 73%; (b) ethyleneglycol, p-TsOH, toluene, reflux, 2 h, 99%; (c)
CH3OCH2Cl, n-BuLi, THF, rt, 2 h, 60%; (d) HF aq, CH3CN, rt, 4 h, 87%; (e) I2, DMAP,
CH2Cl2, reflux, 8 h, 40%; (f) H11C5CH@CHB(OH)2, Pd(PPh3)4, K2CO3, THF, H2O, reflux,
12 h, 27%.
O
13
O
Scheme 4. Oxidative dimerization of 12.

V. Heguaburu et al. / Tetrahedron Letters 51 (2010) 6921–6923
6923
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The coupling methodology described in this work will be useful
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Acknowledgments
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The authors are grateful to PEDECIBA (PNUD/URU/06/004),
CSIC-UdelaR and ANII for financial support of this work. V.H.
thanks PEDECIBA and ANII for a doctoral fellowship. We are also
grateful to Dr. David González for helpful discussions.
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34. Spectral data for 13: 1H NMR (CDCl3) d (ppm) 6.36 (d, J = 1.2 Hz, 1H), 4.57 (s,
1H), 4.23 (dt, J1 = 0.9 Hz, J2 = 7.2 Hz, 1H), 4.06 (dd, J1 = 4.5 Hz, J2 = 9.8 Hz, 1H),
3.23 (t, J = 1.6 Hz, 1H), 2.54 (m, 9H), 2.26 (m, 2H), 2.17 (m, 2H), 2.00 (m, 4H),
1.24 (m, 12H), 0.85 (m, 6H); 13C NMR (CDCl3) d (ppm) 203.7, 190.4, 138.7,
128.0, 113.3, 100.0, 79.1, 73.2, 72.4, 53.4, 38.7, 37.5, 37.2, 36.3, 35.1, 32.7, 31.8,
31.4, 31.3, 29.7, 27.7, 26.2, 25.0, 22.7, 22.6, 22.5, 14.0; IR (KBr) 2926, 2855,
1726, 1670, 1273, 1348, 722 cmÀ1; HRMS: m/z calcd (C28H40O4Na)+: 463.2827;
exp: 463.2810.