Enantiopure arene dioxides: Chemoenzymatic synthesis and application in the production of trans-3,4-dihydrodiols

Article abstract of DOI:10.1039/b006837n

Enantiopure syn- and anti-arene dioxides are synthesised from cis-dihydrodiol metabolites; anti-benzene dioxides are reduced to enantiopure trans-3,4-dihydrodiols while synbenzene dioxides racemise thermally via 1,4-dioxocins.

Full text of DOI:10.1039/b006837n

Enantiopure arene dioxides: chemoenzymatic synthesis and application in the
production of trans-3,4-dihydrodiols
Derek R. Boyd,* Narain D. Sharma, Colin R. O’Dowd and Francis Hempenstall
School of Chemistry, The Queen’s University of Belfast, Belfast, UK BT9 5AG
Received (in Cambridge, UK) 21st August 2000, Accepted 27th September 2000
First published as an Advance Article on the web
Enantiopure syn- and anti-arene dioxides are synthesised
from cis-dihydrodiol metabolites; anti-benzene dioxides are
reduced to enantiopure trans-3,4-dihydrodiols while syn-
benzene dioxides racemise thermally via 1,4-dioxocins.
threne 3,4-oxide was found to spontaneously racemise via an
undetected oxepine intermediate and only the racemic form of
anti-dioxides 13 could be obtained by DMD oxidation. The
spontaneous racemization of benzene oxides9 similarly pre-
cludes the synthesis of enantiopure anti-benzene dioxides by the
chemical oxidation route.
The metabolism of monocyclic arenes by bacteria (procaryotes)
occurs via dioxygenase-catalysed dihydroxylation to yield cis-
dihydrodiols (e.g. metabolite 3 from benzene 1, R = H).1 In
fungi or animals (eucaryotes) however, benzene ring metabo-
lism proceeds via monooxygenase-catalysed epoxidation to
yield a rapidly equilibrating arene oxide–oxepine tautomeric
mixture (e.g. metabolites 2 " 4 from benzene 1, R = H,
Scheme 1).2
Racemic samples of syn-510 (R = Br, CO2H, CHO) and anti-
benzene dioxides 611–13 (R = H) were synthesised earlier by
multistep routes; only compound 6 (R = H) was obtained in
enantiopure form.12,13 The availability of cis-dihydrodiol
enantiomers 3 (R = Cl, Br, I) from bacterial metabolism,1,2
prompted the following new approach to the synthesis of
enantiopure syn-5 and anti-benzene dioxides 6, (Scheme 2). A
mixture of syn- (14, 85%) and anti-tetraol (17, 15%) derivatives
of cis-dihydrodiols 3 (R = Cl, Br, I), obtained (80% yield) using
the osmylation procedure reported by Donohoe et al.,14 was
separated (charcoal–Celite chromatography, EtOH–H2O as
eluent). Reaction of syn-tetraols 14 (R = Cl, Br, I) with
2-acetoxyisobutyryl bromide afforded bis-bromoacetates 15 (R
= Cl, Br, I) in ca. 86% yield. Cyclization using NaOMe yielded
the 3S,4S,5S,6S-syn-benzene dioxides 5 (R = Cl, Br, I, in ca.
75% yield) with [a]D values of 259, 256, and 256 in CHCl3
respectively. Reaction of the bis-acetonide derivative of syn-
tetraol 14 (R = I) with PhMgBr, and deprotection of the
acetonide groups, yielded syn-tetraol 14 (R = Ph), which was
similarly converted to 3S,4S,5R,6R-syn-benzene dioxide 5 (R =
Ph, [a]D 242, CHCl3). Application of this method to anti-
tetraols 17 (R = Cl, Br, I) gave 3R,4R,5S,6S-anti-benzene
dioxides 6 (R = Cl, Br, I, 78 % yield) with [a]D values of 2115,
254, and 26 in CHCl3 respectively (Scheme 2). Hydro-
genolysis (H2, Pd/C, NaOAc, MeOH) of the 3,4-acetonide
derivative of anti-tetraol 17 (R = I), and deprotection, yielded
the parent compound conduritol E, 17 (R = H), [a]D 2 320,
H2O; it was converted to 1R,2R,3R,4R-anti-benzene dioxide 6
(R = H, [a]D 2319, CHCl3) using the method shown in
Scheme 2.
Scheme 1
When further oxidation of benzene oxide–oxepine, 2 " 4 (R
= H), was carried out using dimethyl dioxirane (DMD) as
oxidant epoxidation occurred exclusively on the oxepine
valence tautomer 4. The minor symmetrical oxepine epoxide 7
was isolated but the major oxepine epoxide 8 rearranged
spontaneously to Z,Z-muconaldehyde.3 Oxepine epoxide 8 and
Z,Z-muconaldehyde have been implicated in DNA adduct
formation and possibly the carcinogenicity of benzene (Scheme
1).4 Evidence that arene dioxides can be formed in eucaryotic
systems is provided by the isolation of the anti-naphthalene
dioxide 9 as a liver metabolite of naphthalene,5 and the syn-
benzene dioxide 10 as a fungal metabolite.6
The method of conversion of cis-dihydrodiols to anti-arene
dioxides (Scheme 2) was also applied to polycyclic arenes.
Thus, 1R,2R,3R,4R-anti-naphthalene dioxide 9 ([a]D + 1,
CHCl3; +14, MeOH)† was synthesised from the available cis-
1R,2S-dihydrodiol metabolite of naphthalene ([a]D + 247,
CHCl3). Similarly the cis-3S, 4R-dihydrodiol metabolite of
Following earlier studies of remote site epoxidation of arene
oxide derivatives of polycyclic arenes using DMD,7 we have
extended this method to the synthesis of anti-arene dioxides in
mono- and polycyclic arenes. Thus the stable benzene oxide
metabolite 118 was found to yield only anti-benzene dioxide 12
upon treatment with DMD. The formation of 12 from a benzene
oxide tautomer, and of oxirane 7 from an oxepine tautomer,3
indicates that epoxidation can occur on either form. The DMD
epoxidation of configurationally stable (+)-1R,2S-naphthalene
oxide ([a]D +145, CHCl3) gave only (+)-1R,2R,3R,4R-anti-
naphthalene dioxide 9 ([a]D +1, CHCl3).† Conversely phenan-
Scheme 2 Reagents: i, OsO4, CH2Cl2, TMNO; ii, AcOCMe2COBr, MeCN;
iii, NaOMe, Et2O; iv, toluene, 85 °C; v, CO, Pd(OAc)2, K2CO3, THF–
H2O.
DOI: 10.1039/b006837n
Chem. Commun., 2000, 2151–2152
This journal is © The Royal Society of Chemistry 2000
2151

phenanthrene ([a]D + 35, MeOH) was converted to an
enantiopure sample of 1R,2R,3R,4R-anti-phenanthrene dioxide
13 ([a]D + 47, MeOH).
samples of syn-5 and anti-arene dioxides 6, 9, 13 are obtained in
high yields from the corresponding cis-dihydrodiol metabolites,
(iii) anti-benzene dioxides 6 are precursors for a new route to
trans-3,4-dihydrodiols 18, (iv) racemisation of a syn-benzene
dioxide enantiomer containing four chiral centres occurs
thermally.
We thank Dr R. Agarwal for assistance with preliminary
work on the synthesis of polycyclic arene dioxides, Professor D.
B. Harper and Dr J. Hamilton for a sample of arene oxide
metabolite 11, Dr R. Schobert for helpful discussion and the
Queen’s University of Belfast for financial support (CRO’D,
FH).
Attempts to form the carbomethoxy-substituted anti-benzene
dioxide 6 (R = CO2Me) from the corresponding vinyl iodide 6
(R = I), using a reported15 palladium-catalysed carbonylation
procedure for aryl iodides (CO, Pd(OAc)2, K2CO3, THF–H2O,
rt) formed trans-3,4-dihydrodiol 18 (R = I, [a]D 2145, MeOH)
in excellent yield ( > 85%) after 0.75 h. The anti-benzene
dioxides 6 (R = Cl, Br) also yielded 1R,2R-trans-3,4-dihy-
drodiols 18 (R = Cl, [a]D 2176, MeOH) and 18 (R = Br, [a]D
2253, MeOH) in high yields; a complex mixture of products
was obtained from the corresponding syn-benzene dioxides 5 (R
= Cl, Br, I). The mechanism of conversion of anti-benzene
dioxides 6 to the corresponding trans-3,4-dihydrodiols 18 may
involve opening of one epoxide ring followed by formation of
a p-allyl palladium complex and rearrangement, via an oxetane
intermediate, with CO acting as a reducing agent.
Notes and references
† The [a]D values observed for the enantiopure anti-arene dioxides 6 (R =
H) and 9 are significantly different from those reported,12 furthermore, the
stereochemistry of (+) anti-dioxide 9 was incorrectly assigned.12
The trans-dihydrodiols 18 (R = H, Cl, Br) have been
detected as minor metabolites of the parent benzene substrates
in animal liver systems and have been converted to diol
epoxides which are implicated in DNA adduct formation and
mutagenicity.16,17 Palladium-catalysed reaction of trans-dihy-
drodiol 18 (R = I) under similar conditions (CO, Pd(OAc)2,
NaOAc, MeOH, rt), but for an extended period (18 h) resulted
in the substitution of the iodine atom with a carbomethoxy
group to give the 3R,4R-trans-dihydrodiol 18 (R = CO2Me,
[a]D 294, MeOH) in 80% yield. The trans-3,4-dihydroxy-
3,4-dihydrobenzoic acid 18 (R = CO2H), a hydrolysis product
of chorismic acid, appears to be a growth promoter.17 The four
step approach to the synthesis of single enantiomer trans-
3,4-dihydrodiols 18 (R = Cl, Br, I) from cis-2,3-dihydrodiols
(Scheme 2) represents a significant improvement over earlier
routes requiring eight9 or more16 steps. The syn-benzene
dioxides 5 (R = Cl, Br, I, Ph), in common with other syn-
benzene dioxides 5 (R = H, CO2H, CHO),8 were found to
undergo a retro-Diels–Alder cycloaddition reaction to yield the
corresponding 1,4-dioxocins 16 at relatively low ( ~ 85 °C)
temperature. Since an enantiopure sample of a syn-benzene
dioxide was available, a thermal racemization study on the
(2)-syn-dioxide of iodobenzene 5 (R = I) was carried out
(toluene, 85 °C). Total racemization occurred over 2 h (HPLC
by Chiralcel OB, a 1.32, iPrOH+hexane, 1:5). NMR analysis
showed that the equilibrium mixture contained both the residual
syn-benzene dioxide 5 (R = I), as a minor component (12%),
and the corresponding 1,4-dioxocin isomer 16 (R = I) as a
major component (88%). Chromatographic separation of com-
pounds 16 and 5 (R = I) followed by heating either component
as before yielded the same equilibrium mixture. This unusual
example of a concerted racemisation of four chiral centres in
one enantiomer was not observed for the anti-benzene dioxide
6 (R = I).
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