From p-benzoquinone to useful chiral cyclohexane building blocks

Article abstract of DOI:10.1016/S0957-4166(01)00557-2

A straightforward and efficient access to 12 new cyclohexane chirons from an easily available enantiopure monoketal of p-benzoquinone is described. These chirons possess a variety of functional groups which render them useful for further synthetic elabora

Full text of DOI:10.1016/S0957-4166(01)00557-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 3077–3080
From p-benzoquinone to useful chiral cyclohexane building
blocks
Fe´lix Busque´, Pedro de March,* Marta Figueredo,* Josep Font and Sonia Rodr´ıguez
Departament de Qu´ımica, Universitat Auto`noma de Barcelona, E-08193 Bellaterra, Spain
Received 23 November 2001; accepted 11 December 2001
Abstract—A straightforward and efficient access to 12 new cyclohexane chirons from an easily available enantiopure monoketal
of p-benzoquinone is described. These chirons possess a variety of functional groups which render them useful for further
synthetic elaboration. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
pure cyclohexane building blocks. For instance,
Hudlicky1 has reported the synthesis of a large number
There are many natural products which contain a
densely functionalised, stereogenic cyclohexane unit in
their structure. In particular, there exists a variety of
polyoxygenated cyclohexanes which have interesting
anti-cancer activity. Some examples of such compounds
are bromoxone, 1, the antitumour antibiotic LL-
C10037a, 2, the manumycins, 3 and fumagillin, 4,
among others (Fig. 1). Because of the biological activity
of these substances, during the last decade many efforts
have been devoted to the development of efficient
methodologies for the preparation of enantiomerically
of enantiopure cyclohexadienediols,
5
(Fig. 2);
Ogasawara2 has described several Diels–Alder adducts
derived from p-benzoquinone, 6; the cyclohexenone 7
has been described by Sato;3 Enders4 has recently
achieved the asymmetric synthesis of several substituted
1,4-cyclohexanedione derivative, 8; and Taber has
demonstrated the utility of the cyclohexenone 9,5 by
using it as an intermediate in a synthesis of 4.6 Most of
these authors have already demonstrated the versatility
of these cyclohexane chirons as building blocks by
performing the syntheses of several natural products in
enantiopure form.
O
O
NHAc
Br
O
O
H
O
X
OH
H
OH
OH
OH
2
OH
1
OTBS
O
O
O
O
X=Cl, Br, Me, CN
H
N
7
6
5
Bu
O
O
O
H
O
O
OH
O
O
OCH3
N
3
HO
O
COOH
R
4
O
HO
O
O
O
O
3
4
O
O
O
O
O
O
H
H
H
Ph
H
Ph
H
Ph
H
O
Ph
Ph
Ph
Figure 1.
8
9
10
11
12
* Corresponding authors. Tel.: 34-935811258; fax: 34-935811265
(P.de M.); tel.: 34-935811853; fax: 34-935811265 (M.F.); e-mail:
pere.demarch@uab.es; marta.figueredo@uab.es
Figure 2.
0957-4166/01/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00557-2

3078
F. Busque´ et al. / Tetrahedron: Asymmetry 12 (2001) 3077–3080
A few years ago, we described the preparation of the
first enantiopure monoketals of p-benzoquinone
derived from C2-symmetric 1,2-diols, e.g. 10,7 and
since then we have investigated the utility of these
enantiopure substrates in several diastereoselective
transformations.8 An advantage of these ketals,9
owing to their C2-symmetry, is that both faces of the
remaining carbonyl group and both carbonꢀcarbon
double bonds are equivalent. The other important
feature is that all six carbon atoms of the cyclohex-
ane ring are functionalised. Monoketal (+)-10 can be
prepared in gram-scale from p-benzoquinone and
(R,R)-hydrobenzoin in a single step. It seems there-
fore that 10 is a very attractive precursor for the
preparation of a new set of useful and accessible
cyclohexane chirons presenting a wide variety of func-
tional groups. Thus, we have developed a new, highly
efficient synthesis of (S)-4-hydroxy-2-cyclohexen-1-
one,10 which illustrates the use of compound 10 and,
in connection with this synthesis, the conjugated
enone 11 and the allylic alcohol 12 have already been
prepared.
We have undertaken a systematic modification of the
CꢀC double bonds and the carbonyl group of 10 and
we have also studied some CꢀC coupling reactions.
As a result, we report herein the straightforward syn-
thesis of several new enantiopure polyfunctionalised
cyclohexanes
with
the
structure
of
1,4-
dioxa[4.5]decane, which may be valuable chirons for
bioactive product synthesis.
2. Results and discussion
Reaction of ketal 10 with an excess of hydrogen per-
oxide in the presence of a catalytic amount of sodium
hydroxide at room temperature afforded the cis-bise-
poxide 13 ([h]2D0=+44.1 (c 1.2, CHCl3)) as a white
solid in 95% yield (Scheme 1). The presence in the
13C NMR spectrum of eight non-aromatic signals
reveals the loss of symmetry in the molecule, and
hence shows that the epoxides have a cis-relationship.
This can also be deduced from the 1H NMR spec-
trum that presents four different signals for the oxi-
Scheme 1. (a) H2O2 excess, NaOH cat., MeOH, rt, 1 day, 95%; (b) NaBH4, MeOH, 0°C, 10 min, 81%; (c) H2, Pd/C, toluene, 15
min, 95%; (d) NaBH4, MeOH, 0°C, 15 min, 91%; (e) NaBH4, MeOH:CH2Cl2 1:1, 0°C, 30 min, 87%; (f) 1.5 equiv. Br2, CH2Cl2,
0°C, 15 min/Et3N, rt, 1 h, 73% of 19 and 24% of 20; (g) 2.5 equiv. I2, CCl4/py, rt, 3 h, 52% of 21 and 48% of 22; (h) 3 equiv.
HCHO aq., DMAP cat., THF, reflux, 7 days, 25% of 23 and 51% of 24; (i) 2 equiv. ICH2CO2Et, 1.5 equiv. In, DMF, rt, 14 h,
94%.

F. Busque´ et al. / Tetrahedron: Asymmetry 12 (2001) 3077–3080
3079
rane protons. The exclusive formation of the bisepoxides
with cis relative configuration in the oxidation of p-ben-
zoquinone ketals was already documented in the litera-
ture.11 The advantage of using a C2-symmetric chiral
auxiliary is shown here, since a unique diastereoisomer
of the cis-bisepoxide can be formed. Despite the synthetic
potential of the epoxide functionality, to the best of our
knowledge, compound 13 is the first enantiopure bisepox-
ide derived from a monoketal of p-benzoquinone.
Once the reduction and oxidation of the dienone system
of 10 had been successfully explored, our next goal was
the attachment of carbon chains to the cyclohexane
skeleton. To this end, ketal 10 was allowed to react with
an excess of aqueous formaldehyde in the presence of
4-dimethylaminopyridine (DMAP),16 delivering the
mono- and dihydroxymethyl derivatives, 23 ([h]2D0=+56.0
(c 2.0, CHCl3)) and 24 ([h]2D0=+65.2 (c 0.7, THF)), in 25
and 51% isolated yield, respectively. The 1H NMR
spectrum of 24 displays a unique olefinic proton signal
as a singlet at l 6.95, while the spectrum of 23 discloses
two deshielded protons at l 6.90–7.00 (C(6)H and
C(10)H) and a third one at l 6.26 (C(9)H). The presence
of the hydroxymethyl group is revealed by the absorptions
at l 60.2 and 57.1 in the 13C NMR spectra of 23 and 24,
respectively.
Reduction of the carbonyl group of 13 with sodium
borohydride gave the diastereoisomeric alcohols 14
([h]2D0=+20.4 (c 0.8, CHCl3)) and 15 ([h]2D0=+8.9 (c 0.9,
CHCl3)) in 54 and 27% yield, respectively, as solids. The
stereochemical assignment of the less polar and major
isomer relies on the NOE observed on two of the oxirane
protons upon irradiation of C(8)H. The same experiment
was negative for the diastereoisomer 15.
Efforts were also directed to link a carbon chain to the
ring at the carbon atom of the carbonyl group of 10.
Wittig-type reactions were originally investigated, but all
attempts to condense 10 with phosphonates derived from
ethyl acetate or acetic acid failed. However, treatment of
10 with ethyl iodoacetate in the presence of indium
powder17 led to the isolation of the new ester 25 ([h]2D0=
+11.8 (c 3.7, CHCl3)) in 94% yield as a colourless oil. The
olefinic protons resonate at l 6.1–6.3, according to the
loss of conjugation and the presence of a saturated ester
is shown by the absorption at 1731 cm−1 in the IR
spectrum.
Hydrogenation of 10 using Pd/C as catalyst and toluene
as solvent resulted in a 95% yield of 16 ([h]2D0=+38.4 (c
1.3, CHCl3)). A different preparation of 16, starting from
1,4-cyclohexanediol, was recently described by Konopel-
ski,12 in relation with the synthesis of anti-cancer
chemotherapeutic agents. Sodium borohydride reduction
of the carbonyl group of ketal 16 delivered the alcohol
17 as a solid ([h]2D0=+44.4 (c 1.2, CHCl3)) in 91% yield.
The C2-symmetry of the chiral auxiliary prevents the
formation of a new stereogenic centre at C(8) and hence
the existence of diastereoisomeric products.
In summary, we have described herein a straightforward
and efficient access to 12 new enantiopure cyclohexane
synthons, compounds 13, 14, 15 and 17–25, along with
a new synthesis of the previously known ketone 16. The
complete series displays a wide variety of functional
groups useful for further synthetic elaborations. Consid-
ering the low cost of the starting materials, p-benzo-
quinone and enantiopure hydrobenzoin, we believe that
this set of enantiopure cyclohexane compounds will
become valuable chirons for bioactive product synthe-
sis.18 Work is still in progress in our laboratories to further
increase the number of available cyclohexane chirons.
When the carbonyl group of the original ketal 10 was
subjected to NaBH4 reduction in a 1:1 mixture of
methylene chloride:methanol solution, the new bisallylic
alcohol 18 was isolated in 87% yield as a white solid
([h]2D0=+24.4 (c 2.1, CHCl3)). The absorptions at l 99.4
and 62.4 in its 13C NMR spectrum demonstrate the
presence of the ketal group and the allylic alcohol,
respectively.
Next, we explored the introduction of halogen atoms
attached to the cyclohexane moiety of ketal 10 for two
reasons. Firstly, because some bioactive compounds
present a vinylic halogen atom in their structure and,
secondly, because a vinylic halide is an appropriate
precursor for further synthetic elaborations, as the intro-
duction of side chains through well established CꢀC
coupling reactions like the Stille,13 Suzuki14 or
Sonogashira15 methodologies. Treatment of 10 with a
slight excess of bromine in methylene chloride followed
by addition of triethylamine afforded the bromo deriva-
tives19([h]2D0=+49.2(c1.0, CH2Cl2))and20([h]2D0=+36.0
(c 1.3, CH2Cl2)) as white solids in 73 and 24% yield,
respectively. The NMR spectra of 20 were very simple,
as is consistent with the high symmetry of the molecule,
while the 1H NMR spectrum of 19 showed three absorp-
tions at l 7.39, 6.97 and 6.40, corresponding to C(6)H,
C(10)H and C(9)H, respectively. The iodination reaction
was performed with an excess of iodine in carbon
tetrachloride as solvent and in the presence of pyridine.
The mono- and direction products, 21 ([h]2D0=+45.0 (c 1.7,
CHCl3)) and 22 ([h]2D0=+28.3 (c 0.6, CHCl3)), respec-
tively, were each isolated as white solids in ca 50% yield.
Acknowledgements
We gratefully acknowledge financial support of DGES
(projectPB97-0215)andCIRIT(projects1997SGR00003
and 1999SGR 00091). We also thank Universitat
Auto`noma de Barcelona for a grant to S.R. and the
Generalitat de Catalunya for a grant to F.B.
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