Accessing the antipodal series in microbial arene oxidation: A novel diene rearrangement induced by tricarbonyliron(0) complexation

Article abstract of DOI:10.1039/c0cc01169j

A cyclohexadiene ligand prepared by microbial arene 1,2-dihydroxylation undergoes spontaneous rearrangement upon complexation to tricarbonyliron(0). Subsequent iron removal affords a novel route to formal arene 2,3-dihydroxylation products enantiomeric to

Full text of DOI:10.1039/c0cc01169j

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Accessing the antipodal series in microbial arene oxidation: a novel diene
rearrangement induced by tricarbonyliron(0) complexationwz
Monika Ali Khan,a John P. Lowe,a Andrew L. Johnson,a Alan J. W. Stewartb and
Simon E. Lewis*a
Received 28th April 2010, Accepted 23rd July 2010
DOI: 10.1039/c0cc01169j
A cyclohexadiene ligand prepared by microbial arene 1,2-dihydroxy-
lation undergoes spontaneous rearrangement upon complexation
to tricarbonyliron(0). Subsequent iron removal affords a novel
route to formal arene 2,3-dihydroxylation products enantiomeric
to those obtainable by direct microbial arene oxidation.
Since the first report in 1968,1 enzymatic dihydroxylation of
aromatic substrates to afford enantiopure building blocks for
synthesis has become an established methodology.2 In excess
of 400 arene cis-diol products have been reported. The vast
majority of these are produced by organisms expressing
Scheme 2 Lewis basic functionality directs iron coordination.
toluene dioxygenase (TDO), naphthalene dioxygenase (NDO)
and biphenyl dioxygenase (BPDO) enzymes. These metabolise
substituted arene substrates in a regio- and stereoselective fashion.
A reliable predictive model has been reported for such
transformations3 and the sense of enantioinduction is
conserved across organisms and substrates (Scheme 1a). In
contrast, organisms expressing benzoate dioxygenase (BZDO)
enzymes oxidise benzoic acids in a process that exhibits not
only different regioselectivity, but also the opposite sense of
enantioinduction. For example, R. eutrophus B9,4 P. putida
U1035 and P. putida KTSY01 (pSYM01)6 oxidise benzoic
acid to benzoate 1,2-cis-dihydrodiol 4 (Scheme 1b). Diol
4 has proved to be a versatile chiron for synthesis, having
seen several applications,7 most notably in the synthesis of
tetracycline antibiotics.8
Dienes such as 2 and 4 may be derivatised as the corresponding
tricarbonyliron(0) complexes9 and we have recently shown that
the methyl ester of 4 coordinates to iron with complete facial
selectivity.10 The sole isomer obtained is that in which the diol
is endo (6, Scheme 2a), which is noteworthy since the diene
presents Lewis basic functionality on both faces. Coordination
to iron permits stereoselective ligand modification at the
carbons adjacent to the diene, by means of cationic Z5-dienyl
intermediates.11 In this context we sought to access a complex
in which the diol was exo, by protecting the diol as an
acetonide (Scheme 2b). We reasoned that additional steric
bulk on the lower face would disfavour the precoordination of
the iron to a Lewis basic diol oxygen lone pair, which has been
proposed to rationalise the facial selectivity observed
previously.
In the event, treatment of acetonide 7 with Fe2(CO)9 in
THF gave 9, in which the acetonide was indeed exo, but an
isomerisation had occurred such that the ester was now
conjugated to the diene (Scheme 3). The structure of 9 was
determined by X-ray crystallography (Fig. 1).12
Isomerised complex 9 underwent facile oxidative demetallation
with trimethylamine N-oxide to afford uncomplexed diene
(2S,3R)-11 (Scheme 4). The enantiopurity of (2S,3R)-11
was determined to be >95% ee by means of ester reduction
and subsequent formation of Mosher’s ester derivatives.z
Attempted removal of the acetonide in (2S,3R)-11 upon
exposure to Brønsted acid proved unsuccessful due to facile
Scheme 1 Regio- and stereoselectivity of dioxygenases.
a Department of Chemistry, University of Bath, Bath, BA2 7AY, UK.
E-mail: S.E.Lewis@bath.ac.uk; Fax: +44 (0)1225 386231;
Tel: +44 (0)1225 386568
b Prosidion Limited, Windrush Court, Watlington Road, Oxford,
OX4 6LT, UK
w This article is part of the ‘Emerging Investigators’ themed issue for
ChemComm.
z Electronic supplementary information (ESI) available: Synthesis
and characterisation of Mosher’s esters. Details of NMR lineshape
analysis. Experimental procedures and spectra. Crystallographic data
for 9. CCDC 768284. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c0cc01169j
Scheme 3 Diene rearrangement upon complexation.
Chem. Commun., 2011, 47, 215–217 | 215
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Scheme
5
Isotopic labelling of substrate confirms acetonide
migration.
Fig. 1 X-Ray structure of 9. (50% Thermal ellipsoids for all non-
hydrogen atoms.)
In view of the above, a mechanism may be proposed that
invokes a cationic Z5-cyclohexadienyl intermediate,11 17. This
could plausibly arise from initial formation of the expected
1,2-isomer 8, subsequent co-ordination of an unspecified
Lewis-acidic species to an acetonide oxygen and C–O bond
scission. Attack of the tethered nucleophile (exo to iron and
o- to the electron-withdrawing group, as is precedented)16
would then generate 9 (Scheme 5). In addition to 17,
the regioisomeric Z5 cation 19 may also be formed as a
transient intermediate by means of C–O bond scission at the
other acetonide oxygen. The two cations 17 and 19 differ
appreciably in electronic structure as the ester is conjugated
to the dienyl system only in 17. Crucially, 19 is achiral;
recombination of the tethered nucleophile at either terminus
of the Z5 dienyl ligand in 19 will effect racemisation of 8.17
That (2S,3R)-11 and, by inference, 9 are not in fact racemic
is suggestive of the reaction being under kinetic control.
Specifically, formation of 17 may be kinetically favoured
over 19 due to relief of steric strain as the ester a-carbon
rehybridises such that the ester is in the plane of the dienyl
system. If formation of 17 from 16 is effectively irreversible
(due to the aforementioned preference for nucleophile
recombination o- to the ester) and k1 c k2 (Scheme 6), the
ee of 9 will not be eroded.
Scheme 4 Deprotection of 9.
dehydration/rearomatisation. However, in preliminary experi-
ments, iodine in methanol13 has been observed by NMR to
afford 12 from (2S,3R)-11, albeit with a degree of concomitant
rearomatisation.
Direct microbial oxidation of methyl benzoate to afford a
2,3-diol and subsequent acetonide formation has been
reported.14,15 However, in this instance, the opposite enantiomer,
(2R,3S)-11, was obtained. Indeed, the enantiomer reported here,
(2S,3R)-11, has not been described to date; this iron-mediated
diene rearrangement represents a new route to an arene 2,3-cis-
diol derivative antipodal to that obtained by direct biooxidation.
Thus far, the synthetic utility of arene 2,3-cis-diols has been
constrained by the comparative difficulty in accessing the
non-natural enantiomeric series. We anticipate that the
transformation reported here will be of great synthetic utility,
for example in allowing the synthesis of D-configured carbasugars
(many L-carbasugars have been synthesised from diols of type 2;
the synthesis of (2S,3R)-11 reported here constitutes
formal syntheses of carba-b-D-galactopyranose, carba-b-D-
talopyranose and carba-a-D-talopyranose).15 In addition,
elaboration of the ester will permit access to numerous
antipodal arene 2,3-cis-diols not accessible by other means.
As regards the mechanism of formation of 9, isotopic
labelling studies were undertaken to ascertain the identity
of the migrating group. Biooxidation of p-deuterobenzoic
afforded 13, which then permitted the preparation of 15
(Scheme 5). Regioisomer 14 was not formed, confirming that
9 arises through migration of the acetonide and not the
carboxymethyl group.
Variable temperature 13C{1H} NMR spectra for the carbonyl
region of complex 9 clearly show fluxional behaviour. This
fluxionality may be ascribed to turnstile rotation of the iron
Scheme 6 Possible formation of 9 via cationic Z5-dienyl intermediate.
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216 | Chem. Commun., 2011, 47, 215–217

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carbonyl ligands. The variable temperature spectra of 9
were simulatedz in order to derive the activation parameters
S. C. Taylor, J. Organomet. Chem., 1989, 370, 97;
G. R. Stephenson, P. W. Howard and S. C. Taylor,
J. Organomet. Chem., 1991, 419, C14; A. J. Pearson,
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11, 936.
for the exchange process of Ea = 46.8 ꢁ 1.7 kJ molꢂ1
,
DHz = 44.4 ꢁ 1.6 kJ molꢂl, DSz = ꢂ22.8 ꢁ 5.2 J Kꢂ1 molꢂ1
and DGz(298) = 51.2 ꢁ 3.1 kJ molꢂ1. Use of 13C{1H} VT-NMR
to probe fluxionality in tricarbonyliron(0) complexes is well
established and thermodynamic parameters have been derived
by this method for numerous other tricarbonyliron(0)diene
10 M. Ali Khan, M. F. Mahon, A. J. W. Stewart and S. E. Lewis,
Organometallics, 2010, 29, 199.
11 For reviews, see: W. A. Donaldson and S. Chaudhury, Eur. J. Org.
Chem., 2009, 3831; I. Bauer and H.-J. Knolker, in Iron Catalysis in
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Germany, 2008, pp. 1–27; R. Gree and J. P. Lellouche, in Advances
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12 Crystal data for 9: C14H14FeO7, M = 350.10, monoclinic, a =
10.1710(4) A, b = 7.2170(4) A, c = 10.6320(6) A, b = 110.426(3)1,
V = 731.36(6) A3, T = 150(2) K, space group P2(1), Z = 2,
complexes.18,19 The calculated value of DGz
for 9 is
(298)
comparable to that for the analogous tropone complex
(DGz
= 53.1 ꢁ 2.1 kJ molꢂ1).18
(298)
In summary, we have defined a rearrangement route to
arene 2,3-cis-diol derivatives of non-natural configuration.
The complex through which this rearrangement is realised
exhibits hindered ligand rotation, for which thermodynamic
data are presented. Our approach is complementary to other
strategies reported previously for achieving this ‘‘enantiomeric
switch’’. For example, substituted iodobenzenes can undergo
2,3-dihydroxylation followed by reductive iodine removal,20,22
but this can preclude the use of diol derivatives possessing
reductively labile functionality. The conceptually distinct
approach of enantiodivergent synthesis has also been
employed,21,22 requiring that two different synthetic routes
be established. In contrast, the approach we describe utilises
only oxidative conditions and will permit access to both
enantiomers of a given target by the same synthetic pathway.
Investigations to elucidate further the mechanism of formation
of 9 and to demonstrate the scope of this transformation are
underway in our laboratory and will be reported in due course.
We thank Prosidion Limited, EPSRC and CIKTN for a
CASE studentship (to MAK). We also thank Prof. Andrew G.
Myers (Harvard) for a generous gift of R. eutrophus B9 cells.
m(MoKa)
= , 6905 reflections measured, 3713
1.063 mmꢂ1
independent reflections (2y = 8.57–30.451, Rint = 0.0685) against
203 parameters gave R1 = 0.0385 and wR2 = 0.1056 [I > 2s(I)]
and R1 = 0.0404 and wR2 = 0.1107 (for all data). The goodness of
fit on F2 was 1.054. Flack parameter = ꢂ0.003(16).
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