Valuable new cyclohexadiene building blocks from cationic η5-iron-carbonyl complexes derived from a microbial arene oxidation product

Article abstract of DOI:10.1002/chem.201202411

Biooxidation of benzoic acid by Ralstonia eutropha B9 provides an unusual cyclohexadiene carboxy diol that contains a quaternary stereocentre. Tricarbonyliron derivatives of this chiron, on treatment with acid, give two isomeric η⁵-cyclohexadienyl complexes as observed by NMR spectroscopy. Both of these can be subjected to the addition of nucleophiles to provide isomeric cyclohexadiene complexes with new substituent patterns, several of which have been characterised crystallographically. De-metallation of these provides a versatile library of cyclohexadiene building blocks, the utility of which is demonstrated by formal syntheses of oseltamivir. The mechanism of product formation and its stereochemical implications are discussed, as are the procedures undertaken to establish the enantiopurity of a representative cyclohexadiene product.

Full text of DOI:10.1002/chem.201202411

FULL PAPER
DOI: 10.1002/chem.201202411
Valuable New Cyclohexadiene Building Blocks from Cationic h5-Iron–
Carbonyl Complexes Derived from a Microbial Arene Oxidation Product
Monika Ali Khan,[a] Mary F. Mahon,[b] John P. Lowe,[a] Alan J. W. Stewart,[a] and
Simon E. Lewis*[a]
Abstract: Biooxidation of benzoic acid
by Ralstonia eutropha B9 provides an
unusual cyclohexadiene carboxy diol
that contains a quaternary stereocentre.
Tricarbonyliron derivatives of this
chiron, on treatment with acid, give
two isomeric h5-cyclohexadienyl com-
plexes as observed by NMR spectro-
scopy. Both of these can be subjected
to the addition of nucleophiles to pro-
vide isomeric cyclohexadiene com-
plexes with new substituent patterns,
several of which have been character-
ised crystallographically. De-metalla-
tion of these provides a versatile li-
brary of cyclohexadiene building
blocks, the utility of which is demon-
strated by formal syntheses of oselta-
mivir. The mechanism of product for-
mation and its stereochemical implica-
tions are discussed, as are the proce-
dures undertaken to establish the enan-
Keywords: arenes · biotransforma-
tions · carbonyl ligands · cyclohexa-
dienes · iron · oxidation
tiopurity
of
a
representative
cyclohexadiene product.
Introduction
sense of enantioinduction being conserved across organisms
and substrates[12] (Scheme 1a; ortho,meta oxygenation). In
contrast, organisms that express benzoate dioxygenase[13]
(BZDO) can oxidise benzoic acids[14] in a process that exhib-
its not only different regioselectivity but also the opposite
absolute sense of enantioinduction (Scheme 1b; ipso,ortho
oxygenation). The use of cis-diols of type 4 has been compa-
ratively infrequent so far.[2a,i,l,3h–i,4b,f,14a,15]
The microbial dearomatising dihydroxylation of arenes has
been known for over 40 years and the use of the cyclohexa-
diene cis-diols produced in this fashion in further synthetic
transformations is an established field.[1] The densely
packed, differentiated functionality of these chirons is a
useful feature for applications in diverse areas, such as the
synthesis of natural products,[2] pharmaceuticals,[3] carbohy-
drates,[4] polymers[5] and dyes.[6] Derivatives of cyclohexa-
diene cis-diols have been employed as catalysts for asym-
metric cyclopropanation,[7] allylic oxidation,[7,8] meso-epox-
ide desymmetrisation,[8] aldehyde allylation[8,9] and alkene
hydrogenation.[9] Applications of cyclohexadiene cis-diols as
chiral auxiliaries[10] and in metal–organic frameworks have
also been reported.[11]
The microorganisms employed for the production of cy-
clohexadiene cis-diols are most commonly those that express
benzene dioxygenase (BDO), toluene dioxygenase (TDO),
naphthalene dioxygenase (NDO) or biphenyl dioxygenase
(BPDO). These enzymes can oxidise substituted arenes in a
predictable regio- and stereoselective manner, with the
Scheme 1. Regio- and stereoselectivity of dioxygenases.
The cyclohexadiene motif in bioproducts such as 2 and 4
lends itself well to use as a ligand in tricarbonyliron(0)
chemistry. Rigid cyclohexadiene ligands in which one or
both of the sp3-hybridised carbon atoms are stereocentres
exhibit excellent stereoinduction upon their complexation
when Lewis basic substituents are present: reports on com-
plexes formed from diols of type 2 by the groups of Ste-
phenson[16] and Pearson[17] describe the formation of single
diastereomer only, in which the oxygen functionality is endo
(Scheme 2). This facial selectivity has been rationalised in
terms of the pre-coordination of a 16-valence-electron tetra-
carbonyliron fragment to one of the ligand oxygen atoms,
[a] M. Ali Khan, Dr. J. P. Lowe, Dr. A. J. W. Stewart, Dr. S. E. Lewis
Department of Chemistry, University of Bath
Claverton Down, Bath, BA2 7AY (UK)
Fax : (+44)1225386231
E-mail: S.E.Lewis@bath.ac.uk
[b] Dr. M. F. Mahon
Department of Chemical Crystallography, University of Bath
Claverton Down, Bath, BA2 7AY (UK)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202411.
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zole alkaloids[33] that demonstrate the power of dienyliron
electrophiles. They have also been used in an approach to
lycorine[34] and in the construction of functionalised medium
rings,[35] quaternary centres,[36] spirocycles[37] and indole de-
rivatives.[38]
We have recently reported on the previously unexplored
organometallic chemistry of arene diols of type 4. Specifical-
ly, the diene diol methyl ester 15 was treated with
[Fe2(CO)9] to give 16 (in which the ester is exo[39]) as the
only product (Scheme 5a).[40] Ligand 15 differs from 2 and 6
Scheme 2. Facial selectivity in iron complexation.
which serves to direct the metal to the same diene face
(Scheme 3).
Scheme 3. Rationale for facial selectivity.
TricarbonylACHTUNGTRENNUNG(diene)iron(0) complexes have a rich chemis-
Scheme 5. Organometallic chemistry of dienes of type 4.
try which has been the focus of much research over the
years.[18] In the case of cyclohexadiene cis-diol complexes
such as 5, the function of the iron is twofold. Not only does
it serve as a protecting group for an otherwise fragile struc-
tural motif,[19] it also allows access to new reaction manifolds
by means of [h5]+ cyclohexadienyl cations. Indeed, an itera-
tive [h4]![h5]+![h4]![h5]+![h4] strategy[18m,20] allows for
sequential substitution of each of the two oxygen functiona-
lities;[16f] a generalised example is shown in Scheme 4. This
strategy has been employed in approaches to hippeastrine.[21]
More generally,[22] [h4]![h5]+![h4]![h5]+![h4] sequences
from non-arene diol starting materials have been used in the
synthesis of maritidine,[23,24] lycoramine,[24] mesembrine,[25]
O-methyljoubertiamine,[26] stemodinone,[27] antiostatins,[28]
in that both diene faces present Lewis basic functionality
toward an incipient tetracarbonyliron fragment. As such, it
may be regarded as a “competition ligand”; only one previ-
ous report describes
a complex formed from such a
ligand.[41] The formation of 16 as the sole diastereomer
shows a diol to be a markedly more effective directing
group than a methyl ester in this context.[42] In an attempt to
access complexes in which the diol was in the exo position,
we prepared acetonide 17. As expected, the acetonide re-
duced the directing ability of the diol and complex 20 was
formed, in which the acetonide was indeed exo (Sche-
me 5b). Surprisingly, a ligand isomerisation occurred, result-
ing in the conjugation of the diene and ester groups in 20.[43]
We proposed that the formation of 20 occurs by an [h4]!
[h5]+![h4] process beginning with the formation of the ex-
pected product, complex 18. Subsequent Lewis acid mediat-
ed isomerisation via the cyclohexadienyl [h5]+ intermediate
19 and recombination of the pendent nucleophile w to the
ester would provide 20 (Scheme 5b). Comparable isomerisa-
tions have been reported for CpCo–diene complexes (Cp=
cyclopentadiene).[44,45] It should be noted that complex 20 is
oxygenated with the opposite absolute configuration to com-
plexes of type 5. This is of synthetic significance as it allows
access to the antipodal series of ortho,meta-arene diols that
are not directly accessible by biotransformation. Encouraged
by these results, we undertook further studies on [h4]![h5]+
![h4] derivatisations of 16. To diversify rapidly the ligand
clausines,[29]
oxydimurrayafoline,[30]
lavanduquinocin,[31]
streptoverticillin[32] and numerous other syntheses of carba-
Scheme 4. Sequential substitution of -OR1 groups.
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Cyclohexadiene Building Blocks from Cationic h5-Iron–Carbonyl Complexes
FULL PAPER
structure, we sought to employ the intermolecular addition
of nucleophiles rather than intramolecular addition, as per
the formation of 20. The results of these studies are reported
herein.
Results and Discussion
To form stable cyclohexadienyl [h5]+ complexes from 16 it
was necessary to derivatise the hydroxyl groups, as it has
Scheme 6. Regioisomeric cations arising from 16.
been established that tricarbonyliron(0)cyclohexadienyl
complexes that contain an unprotected 6-endo-hydroxyl
group can readily decompose by aromatisation of the cyclo-
hexadienyl ligand.[16e,g,41] Accordingly, we adopted the Pear-
son procedure, which involves the use of acetic anhydride as
the solvent.[46] This serves a dual purpose: to protect the hy-
droxyl groups as acetates, and to act as a desiccant when
aqueous acids such as HBF4(aq) or HPF6(aq) are used to pro-
mote deacetoxylation. In the case of 16, this procedure
could potentially give rise to two regioisomeric cations, 21
nating, loss of the distal acetate (and formation of 11) is fa-
voured.[16b,17] In contrast, the reaction is less regioselective if
R2 =Me.[16e] However, none of these literature examples
provide direct precedent for the reaction depicted in
Scheme 6 because in complex 16, the ester substituent is not
conjugated with the diene. Thus, at the outset, it was unclear
whether product 21 or 22 would predominate.
To observe in situ the formation of [h5]+ cyclohexadienyl
species from 16, we used real-time 1H NMR monitoring
with solvent suppression (Figure 1). The NMR spectra are
highly diagnostic because at 500 MHz no overlap of ring
methine resonances is observed and every ring proton may
be individually assigned for all three species present. Even
after 5 min, the neutral [h4] precursor 23 was seen to be the
ꢀ
and 22, depending on which C O bond is cleaved
(Scheme 6).
In the case of complexes of type 10 (Scheme 4), varying
degrees of regioselectivity have been reported for the corre-
sponding [h4]![h5]+ deacetoxylation reactions. When the
diene substituent R2 is strongly electron withdrawing or do-
Figure 1. 1H NMR spectra showing the real-time formation of 21 and 22. Spectra were acquired at 5 min intervals in Ac2O with HBF4·OEt2 (5 equiv) at
298 K, and by employing solvent suppression.
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S. E. Lewis et al.
minor component of the mixture; the methine resonances
for 23 are indicated with solid black arrows. The signals for
the diene termini in 23 are the only methine protonss ob-
served upfield of d=4.0 ppm, whereas the corresponding
ligand terminus resonances for 21 (grey double arrows) and
22 (white arrows) are shifted downfield due to the compara-
tively electron-poor nature of these complexes.
adduct (ꢂ)-28, which is racemic (Scheme 8). The reaction
sequence 16!22!28 is a homochiral [h4]!achiral [h5]+!
racemic [h4] sequence; analogous sequences for other
It can clearly be seen that after 1 h, 23 has been consumed
and only resonances for cations 21 and 22 are observed,
with 22 being the major component of the reaction mixture
(ꢁ3:1 ratio). Whereas 21 and 23 each exhibit five distinct
methine resonances, cation 22 exhibits three resonances, the
integrals of which are in a ratio of 2:2:1, clearly illustrating
that this complex possesses a plane of symmetry that bisects
the cyclohexadienyl ring. It must be stressed that whereas
the starting material 16 is homochiral, stereochemical infor-
mation is lost upon formation of the achiral cation 22.
Having established the viability of forming both 21 and
22, we next examined their reactivity towards nucleophiles.
In general, the major products of nucleophilic additions to
tricarbonyliron(0) cyclohexadienyl [h5]+ complexes are
those resulting from attack of the nucleophile to the exo
face of the ring (i.e., the opposite side of the ring to the iron
atom).[18m,47] Few examples of endo attack and cases of equi-
libration to endo/exo product mixtures by reversible addi-
tion are known.[48]
Regarding the regioselectivity of the addition reaction, in-
corporation of the nucleophile should typically occur at one
of the two dienyl termini.[49] For cation 21, two regioisomeric
products are therefore possible by addition at the position
either ipso or w to the ester.[50] Literature precedent shows a
terminal ester substituent to be strongly w-directing for the
nucleophilic addition of hydroxide,[51] alcohols,[52–54]
amines,[54] thiols,[54] malonate,[54,55] cyanide,[56] deuteride,[56]
cuprates[56] and Grignard reagents,[56] as well as for SEAr re-
actions of electron-rich arenes.[53,54] Thus, additions to cation
21 were expected to furnish products of type 24 (Scheme 7).
Scheme 8. Formation of racemic products from 22.
Fe(CO)3 cyclohexadiene complexes have also been report-
ed.[57]
We chose sodium thiophenolate as a prototypical nucleo-
phile with which to study additions to cations 21 and 22.
Complex 16 was treated with a variety of acids in Ac2O, fol-
lowed by precipitation by addition of diethyl ether and fil-
tration. The mixture of cations obtained was re-dissolved in
either THF or acetonitrile and treated with NaSPh. The re-
sults are summarised in Table 1.
Yields varied significantly with the choice of solvent and
acid. In each instance, (ꢂ)-30 was the major product, as an-
ticipated from the in situ NMR data that showed 22 to be
the major cation. However, with the exception of entries 7
Table 1. Optimisation of cation generation and nucleophile addition to
form thiophenolate adducts.[a]
Entry
Acid
Solvent
Yield of 29
[%]
Yield of (ꢂ)-30
[%]
1
2
3
TFA
TFA
TfOH
TfOH
HPF6
HPF6
HBF4
HBF4
HBF4·OEt2
HBF4·OEt2
THF
MeCN
THF
MeCN
THF
MeCN
THF
MeCN
THF
MeCN
4
3
3
6
6
0
4
5
0
0
25
20
36
38
45
23
14
13
57
34
4
5[b]
6
7
8
9
10
Scheme 7. Possible products of nucleophilic addition to 21.
[a] Acid (10.0 equiv), Ac2O, ꢀ108C, 1 h, then precipitation, filtration, sol-
vation in an alternative solvent, NaSPh (4.3 equiv), 08C, 1 h. [b] A by-
product was also obtained in 8% yield.[58] TFA=trifluoroacetic acid,
Tf=trifluoromethanesulfonyl.
For cation 22, the regiochemistry of addition is more
straightforward as the two dienyl termini are enantiotopic.
Thus, the addition of a nucleophile will necessarily give an
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Cyclohexadiene Building Blocks from Cationic h5-Iron–Carbonyl Complexes
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Table 2. Reactivities of diverse nucleophiles towards cations 21 and 22.[a]
Entry Nuꢀ
Product from 21
Product from (ꢂ)-22
(Yield [%]) (Yield [%])
and 8 (Table 1), the product ratio (+)-29/(ꢂ)-30 was always
less than the NMR cation ratio 21/22. Indeed, for entries 6,
9 and 10 (Table 1), product 29 was not isolated at all. These
results may be due to the instability of cation 21 (see
below). Crystals of (ꢂ)-30 that were suitable for X-ray struc-
ture determination were obtained from the diffusion of
G
ACHTUNGTRENNUNG
1[b]
2[c]
3[c]
4[c]
NaSPh
(6)
(4)
(45)
(31)
(34)
(25)
hexane into
(Figure 2).
a
solution of (ꢂ)-30 in dichloromethane
NaBH4
NaN3
(5)
NaOH
(10)
[a] For each entry, 16 was treated with HBF4·OEt2 (4 equiv) in Ac2O at
ꢀ108C for 1 h, then the cation was precipitated by using Et2O. [b] THF,
ꢀ788C to RT, 1 h. [c] MeCN, 08C to RT, 1 h.
Figure 2. Solid-state structure of (ꢂ)-30. Ellipsoids are represented at the
50% probability level. H atoms are shown as spheres of arbitrary radius.
Having ascertained that both cations 21 and 22 were reac-
tive electrophiles, we screened several other nucleophiles to
determine the scope of the addition reaction (Table 2). In
each instance, cations were generated by treatment with
HBF4·OEt2, on the basis of the results in Table 1. However,
for each entry in Table 2, the conditions for the subsequent
nucleophile addition were varied on the basis of (limited)
optimisation studies.
Yields for the addition of other nucleophiles were slightly
lower than for thiophenolate; the comparatively mediocre
reactivity of hydroxide in addition reactions to Fe(CO)3–cy-
clohexadienyl cations has been noted previously.[59] Crystals
of (ꢂ)-32 that were suitable for X-ray structure determina-
tion were obtained from the diffusion of hexane into a solu-
tion of (ꢂ)-32 in ethyl acetate (Figure 3).
Figure 3. Solid-state structure of (ꢂ)-32. Ellipsoids are represented at
50% probability. H atoms are shown as spheres of arbitrary radius.
The hydroxide adduct (ꢂ)-36 did not furnish crystals suit-
able for X-ray diffraction. However, basic methanolysis of
(ꢂ)-36 gave the diol (ꢂ)-37. Crystals of (ꢂ)-37 of sufficient
quality for analysis were obtained by slow evaporation of a
solution of (ꢂ)-37 in ethyl acetate (Scheme 9, Figure 4). The
structure confirmed once again the trans relationship of the
introduced nucleophile and the residual ring oxygenation.
The structure of 37 is significant because it is a protected
form of an arene trans-diol. Arene trans-diols are not availa-
ble from the direct biotransformation of arenes with arene
dioxygenase enzymes, although they may be accessed indi-
rectly by epoxidation with mono-oxygenases and subsequent
epoxide opening.[60] Multi-step chemo-enzymatic approaches
Scheme 9. Deacetylation of (ꢂ)-36.
to arene trans-diols have been reported,[61] and an approach
that involves [Fe(CO)3] complexes has been alluded to pre-
viously but is not described in any detail in the literature.[62]
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Table 3. De-metallation of complexes 28–35 with CAN.
Entry
Substrate
Product
Yield [%]
91
1[a,b]
2[a,b]
3[a,c]
4[a]
85
63
0
Figure 4. Solid-state structure of (ꢂ)-37. Ellipsoids are represented at
50% probability. H atoms are shown as spheres of arbitrary radius.
–
With a variety of complexes in hand, we sought to pro-
mote their de-metallation to recover the modified cyclohex-
adiene ligands (Table 3). Of the reported methods for
[Fe(CO)3] de-complexation, oxidation with ceric ammonium
nitrate (CAN)[63] proved superior to the use of trimethyla-
mine-N-oxide[64] for these substrates, allowing access to the
new cyclohexadienes 38–44 in good yield (Table 3). As
shown in Table 3, entry 4, the attempted de-metallation of
complex (ꢂ)-32 did not give the expected cyclohexadiene
product (ꢂ)-45. Instead, methyl benzoate 46 was recovered
(Scheme 10). We rationalise this finding as follows: 46 arises
from initial formation of the expected (ꢂ)-45, which then
undergoes an unusually facile re-aromatisation by the elimi-
nation of acetic acid. The spontaneous re-aromatisation of
(ꢂ)-45 is in contrast to that of cyclohexadienes 38–44 and
may be explained by the fact that only 45 is able to achieve
a conformation in which the C1 acetate and a C6 proton
have a dihedral angle of approximately 1808. The fact that
arene cis-diols re-aromatise at far greater rates than the cor-
responding arene trans-diols upon their exposure to acid has
previously been rationalised in this manner: a conformation
such as that depicted for 45 leads to a cyclohexadienyl E1 in-
termediate in which the pseudo-axial hydrogen atom is ide-
ally aligned for hyperconjugation with a p orbital of the car-
bocation intermediate.[65]
5[a,d]
6[a,e]
7[a,b]
63
64
53
100
8[a,f]
[a] CeACTHNUTRGENNUG(NH4)2ACHTUNGTRENN(UNG NO3)6 (3 equiv), acetone, 08C. [b] 5 min. [c] 50 min. [d] 3 h.
[e] 4 h. [f] 25 min.
We next sought to determine the enantiopurity of the ad-
ducts derived from [h5]+ cyclohexadienyl cation 21. Because
stereochemical information is not lost upon formation of the
(non-symmetric) cation 21, the resultant adducts (29, 31, 33
and 35) were expected to be isolated as single enantiomers.
However, the possibility that cation 21 might undergo race-
misation by equilibration[66] with achiral cation 22 could not
be excluded. Such an equilibration might plausibly occur by
participation of the neighbouring acetoxy functionality, al-
though this would involve the endo attack of the tethered
nucleophile (Scheme 11). Accordingly, we deemed it neces-
sary to determine the enantiomeric excess of an adduct de-
rived from cation 21.
Scheme 10. Facile rearomatisation of 45.
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Cyclohexadiene Building Blocks from Cationic h5-Iron–Carbonyl Complexes
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Scheme 11. Mechanism for the potential racemisation of 21.
Measurements of enantiomeric excess by chiral HPLC
were not possible for the new adducts 29, 31, 33 and 35 as
racemic material was not available for comparison. Similar-
ly, the corresponding de-metallated cyclohexadienes 38, 40,
41 and 43 are also previously unreported as either single
enantiomers or racemates. However, acetylation of the de-
metallated hydroxide adduct 43 gave the diacetate deriva-
tive 55, which has been reported as a racemate by Ogawa
et al.[67] (Scheme 12).
Figure 5. Chromatograms for 55. Left: Sample prepared by the chemoen-
zymatic route described herein. Right: Racemic sample prepared by the
protocol described by Ogawa et al. Conditions: ChiralCel OD-I column,
isocratic elution, hexane/iPrOH (95:5), 1.0 mLminꢀ1, l=254 nm, tR1=
10.50 min, tR2=12.40 min.
Scheme 12. The Ogawa et al. preparation of racemic (ꢂ)-55.
Scheme 13. Access to oseltamivir from the ipso,ortho-diol 4.
Preparation of a racemic standard of (ꢂ)-55 by the
Ogawa protocol allowed for assessment of the enantiomeric
excess of the chemoenzymatically produced 55 by chiral
HPLC (Figure 5), which was indeed produced in >99% ee.
Thus, the mechanism for potential racemisation shown in
Scheme 11 is negligible and, by inference, the adducts 29,
31, 33 and 35, derived from cation 21, may be assumed to be
enantiopure.
transposition, which can be brought about by a [h4]![h5]+!
[h4] sequence. It also requires the use of a different iron
complex as the starting material because of the different
substituents: 16 contains a methyl ester, whereas 56 contains
an ethyl ester. Accordingly, the carboxylate alkylation of 4
was undertaken with ethyl iodide and caesium fluoride as an
additive,[69] followed by treatment with nonacarbonyldiiron
to provide complex 58 as a single isomer (Scheme 14).
We next sought to expand the method described above to
an [h4]![h5]+![h4]![h5]+![h4] sequence, that is, to pro-
mote the sequential substitution of both of the enzyme-de-
rived hydroxy groups. To demonstrate the utility of such a
sequence, we undertook a concise formal synthesis of the
anti-influenza agent oseltamivir 56 (Scheme 13). Oseltamivir
has been the target of numerous syntheses,[68] and ap-
proaches initiated by microbial arene dihydroxylation have
With the ethyl complex 58 in hand, the formation of the
corresponding cations and their reaction with sodium boro-
hydride proceeded as in the case of the methyl complex 16.
been reported by the groups of Hudlicky,[3a–d] Banwell[3e] and
´
Fang.[3f] Furthermore, a route employing tricarbonyliron
complexes has been reported by Kann et al.[52] To access
oseltamivir from ipso,ortho-diol 4 requires double-bond
Scheme 14. Preparation of the ethyl ester complex 58.
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S. E. Lewis et al.
Complex (ꢂ)-60 was treated with acid for a second time to
remove the second acetoxy group and provide cation (ꢂ)-
61. Treatment of (ꢂ)-61 with potassium phthalimide then
gave complex (ꢂ)-62. The regioselectivity of this addition
agrees with precedent (Scheme 7). Finally, de-metallation
with basic hydrogen peroxide[70] gave (ꢂ)-63 (Scheme 15), a
reported intermediate in the route to oseltamivir described
by Trost et al.[71] Access to the [h5]+ complex (ꢂ)-61 also
Experimental Section
General synthetic procedures and instrumentation: Reactions were car-
ried out under an atmosphere of nitrogen. Solvents were dried and de-
gassed by passing through anhydrous alumina columns using an Innova-
tive Technology Inc. PS-400–7 solvent-purification system. Acetic anhy-
dride and acetone were laboratory-reagent-grade solvents and were not
specially dried prior to use. Petrol refers to petroleum ether, b.p. 40–
608C. TLCs were performed by using aluminium-backed plates precoated
with Alugram SIL G/UV and visualized by UV light (254 nm) and/or
KMnO4 followed by gentle warming. Flash column chromatography was
carried out by using 60 ꢁ silica gel (particle size 35–70 mm) purchased
from Fisher Scientific Ltd. All reagents were purchased from the Sigma–
Aldrich Chemical Co. or Fisher Scientific Ltd. and were used without fur-
ther purification. Nonacarbonyldiiron was dispensed in a glovebox. IR
spectra were recorded on a Perkin–Elmer Spectrum 100 FTIR spectrom-
eter with a universal ATR sampling accessory; absorbances are quoted as
n˜ in cmꢀ1. NMR analysis was done on Brꢂker Avance 250, 300, 400 or
500 MHz instruments at 298 K, unless otherwise specified. Mass spectra
were recorded with a micrOTOF electrospray time-of-flight (ESI-TOF)
mass spectrometer (Brꢂker Daltonics). Specific rotations were recorded
on an Optical Activity AA-10 Automatic polarimeter with a path length
of 1 dm. Concentrations (c) are quoted in g per 100 mL.
CCDC-865581 ((ꢂ)-30), CCDC-865582 ((ꢂ)-32) and CCDC-865583 ((ꢂ)-
37) contain the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystallograph-
ic Data Centre via www.ccdc.cam.ac.uk/data_request/cif
Formation of cations 21 and 22: Tetrafluoroboric acid diethyl etherate
(521 mg, 438 mL, 3.22 mmol, 10.0 equiv) was added to a stirred solution
of [h4] complex 16 (100 mg, 0.322 mmol, 1.00 equiv) in acetic anhydride
(3.2 mL) at ꢀ108C and stirred at this temperature for 1 h. Pre-cooled
Et2O (60 mL) was added dropwise to the reaction mixture, forming a
light-yellow precipitate. This was filtered by using suction and washed
with cold Et2O (3ꢃ5 mL). Concentration of the mother liquor and re-
crystallisation from tBuOMe gave a small quantity of additional product;
the crude cation mixture was used immediately in the next step.
Scheme 15. Formal synthesis of oseltamivir. Phth=phthaloyl.
allows for the realisation of another formal synthesis: addi-
tion of a different nitrogen nucleophile (tert-butyl carba-
mate[72]) gave complex (ꢂ)-64, which is a reported inter-
mediate in the Kann route to oseltamivir[52] (Scheme 16).
General procedure for the formation of adducts 29 to 36: The relevant
nucleophile (5.00 equiv with respect to starting complex 16) was added to
a solution of the crude cation mixture (of 21 and 22, as prepared above)
in THF or MeCN (5 mL) at the specified temperature. The reaction mix-
ture was stirred for 1 h, then quenched by addition of H2O. The product
was extracted with EtOAc or Et2O (3ꢃ20 mL). The organic layers were
combined, dried over MgSO4 and filtered. The filtrate was concentrated
under reduced pressure. The residue was purified by column chromatog-
raphy (SiO2, hexane/ethyl acetate) to give the final products 29–36.
Sodium thiophenolate as a nucleophile: formation of 29 and (ꢂ)-30: In
accordance with the general procedure, the use of THF at ꢀ788C to RT
with 16 (82 mg) gave 29 as a yellow oil (7.3 mg, 6%) and (ꢂ)-30 as a
Scheme 16. Alternative formal synthesis of oseltamivir. Boc=tert-butoxy-
carbonyl.
beige solid (52.4 mg, 45%). 29: Rf =0.15 (10:90 EtOAc/hexane); [a]D25
=
+20 (c=0.05 in CH2Cl2); 1H NMR (250 MHz, CDCl3): d=7.44–7.42
(2H, m; o-Ar-H), 7.32–7.29 (3H, m; p-Ar-H and m-Ar-H), 5.91 (1H, d,
J=4.0 Hz; H-6), 5.41 (1H, t, J=5.0 Hz; H-5), 5.24 (1H, s; H-2), 3.65
(3H, s; -COOCH3), 3.30 (1H, s; H-4), 3.26 (1H, brs; H-3), 2.05 ppm
(3H, s; -OC(O)CH3); 13C NMR (75.4 MHz, CDCl3): d=208.9
([Fe(CO)3]), 171.0, 169.3, 134.3, 129.7, 129.0, 128.4, 90.5, 83.0, 72.8, 64.8,
60.8, 55.2, 52.0, 21.0 ppm; FTIR (neat): n˜max =2061, 1991, 1749, 1717,
1438, 1370, 1272, 1229, 1097, 1026, 693, 143 cmꢀ1; HRMS (ESI): m/z
calcd for C19H16FeO7S: 466.9864 [M+Na]+; found: 466.9861; elemental
analysis calcd (%) for C19H16FeO7S: C 51.37, H 3.63; found: C 51.3, H
3.64. (ꢂ)-30: Rf =0.28 (10:90 EtOAc/hexane). M.p. 117–1188C; 1H NMR
(250 MHz, CDCl3): d=7.39–7.35 (2H, m; o-Ar-H), 7.33–7.27 (3H, m; p-
Ar-H and m-Ar-H), 5.64 (1H, ddd, J=6.0, 4.0, 1.5 Hz; H-5), 5.39 (1H,
td, J=5.5, 1.0 Hz; H-4), 3.77 (1H, d, J=6.5 Hz; H-6), 3.66 (3H, s;
-COOCH3), 3.64 (1H, d, J=4.0 Hz; H-2), 3.29 (1H, ddt, J=5.0, 3.5,
1.5 Hz; H-3), 2.18 (3H, s; -OC(O)CH3); 13C NMR (75.4 MHz, CDCl3):
d=210.0 ([Fe(CO)3]), 170.2, 168.9, 136.2, 131.0, 129.1, 127.2, 87.3, 86.6,
83.9, 61.1, 58.9, 57.6, 52.7, 21.5 ppm; FTIR (neat): n˜max =3067, 2951, 2052,
1967, 1739, 1582, 1481, 1438, 1367, 1276, 1243, 1219, 1138, 1086, 1061,
Conclusion
We have achieved the synthesis of a diverse library of new
cyclohexadiene building blocks. This was accomplished by
the rapid diversification of a single bio-derived iron–carbon-
yl complex by means of nucleophile addition to cationic
[h5]+ complexes. The extension of this approach to a second
diversification step has also been demonstrated. The enan-
tiopurity of a representative building block was established
by comparison with a known racemic material, which was
synthesised independently. We anticipate that the building
blocks reported herein will find multiple applications in syn-
thesis.
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Cyclohexadiene Building Blocks from Cationic h5-Iron–Carbonyl Complexes
FULL PAPER
1049, 1025, 987, 948, 909, 866, 809, 732, 691 cmꢀ1; HRMS (ESI): m/z
calcd for C19H16FeO7S: 466.9864 [M+Na]+; found: 466.9850.
(3H, s; -COOCH3), 3.20 (1H, d, J=6.5 Hz; H-6), 3.13 (1H, ddd, J=5.0,
3.5, 1.5 Hz; H-3), 2.71 (1H, d, J=7.0 Hz; -OH), 2.15 ppm (3H, s;
-OC(O)CH3); 13C NMR (100.6 MHz, CDCl3): d=209.9 ([Fe(CO)3]),
170.6, 169.8, 85.2, 85.1, 84.0, 77.6, 61.1, 55.7, 53.0, 21.2 ppm; FTIR (neat):
n˜max =3421, 2956, 2923, 2853, 2050, 1966, 1739, 1714, 1432, 1367, 1333,
1270, 1236, 1205, 1136, 1101, 1069, 1049, 1025, 992, 964, 929, 909, 872,
814, 763, 734, 705, 674 cmꢀ1; HRMS (ESI): m/z calcd for C13H12O8Fe:
374.9782 [M+Na]+; found: 374.9779; elemental analysis calcd (%) for
C13H12FeO8: C 44.35, H 3.44; found: C 44.7, H 3.56.
Sodium borohydride as a nucleophile: formation of 31 and (ꢂ)-32: In ac-
cordance with the general procedure, the use of MeCN at 08C to RT
with 16 (200 mg) gave 31 as a yellow solid (9.5 mg, 4%) and (ꢂ)-32 as a
yellow solid (68.8 mg, 31%). 31: Rf =0.30 (20:80 EtOAc/hexane); m.p.
67–698C; [a]2D5 = +280 (c=0.1 in CH2Cl2); 1H NMR (300 MHz, CDCl3):
d=5.94 (1H, d, J=3.0 Hz; H-6), 5.52 (1H, t, J=5.0 Hz; H-5), 5.03 (1H,
d, J=6.5 Hz; H-2), 3.68 (3H, s; -COOCH3), 3.20 (1H, brs; H-4), 2.09
(1H, dd, J=16.0, 6.5 Hz; H-3), 2.07 (3H, s; -OC(O)CH3), 1.58 ppm (1H,
dd, J=16.0, 3.5 Hz; H-3); 13C NMR (75.4 MHz, CDCl3): d=209.4
([Fe(CO)3]), 171.7, 170.2, 90.3, 84.5, 77.4, 68.1, 58.7, 51.9, 34.3, 21.2 ppm;
Methanolysis of (ꢂ)-36 to give (ꢂ)-37: Solid sodium methoxide (118 mg,
3.68 mmol, 20.0 equiv) was added to a solution of (ꢂ)-36 (64.8 mg,
0.184 mmol, 1.00 equiv) in MeOH (8 mL) and stirred for 24 h at room
temperature. The resulting reaction mixture was diluted with EtOAc
(15 mL), then washed with H2O (15 mL). The organic phase was dried
over MgSO4 and filtered. The filtrate was concentrated under reduced
pressure and purified by column chromatography to afford (ꢂ)-37 as a
yellow foam (20 mg, 35%). Rf =0.35 (50:50 EtOAc/petrol); 1H NMR
(300 MHz, CDCl3): d=5.55 (1H, t, J=4.5 Hz), 5.40 (1H, t, J=4.5 Hz),
4.07 (1H, br s), 3.77 (3H, s), 3.71 (1H, s), 3.07 (1H, br s), 2.74 (1H, d,
J=6.0 Hz), 1.86 ppm (1H, br s); 13C NMR (75.4 MHz, CDCl3): d=210.0
([Fe(CO)3]), 173.7, 84.8, 84.5, 81.5, 62.0, 59.1, 53.5 ppm; FTIR (neat):
n˜max =3426, 3361, 2059, 1983, 1708, 1274, 1122, 1014 cmꢀ1; HRMS (ESI):
m/z calcd for C11H10O7Fe: 332.9673 [M+Na]+; found: 332.9673.
˜
FTIR (neat): nmax =2952, 2850, 2055, 1972, 1737, 1713, 1583, 1435, 1368,
1343, 1270, 1235, 1132, 1097, 1042, 1029, 991, 969, 894, 865, 802, 775, 715,
685 cmꢀ1; HRMS (ESI): m/z calcd for C13H12FeO7: 358.9830 [M+Na]+;
found: 358.9834; elemental analysis calcd (%) for C13H12FeO7: C 46.46,
H 3.60; found: C 46.6, H 3.71. (ꢂ)-32: Rf =0.45 (20:80 EtOAc/hexane);
m.p. 89–918C; 1H NMR (300 MHz, CDCl3): d=5.46 (1H, t, J=5.5 Hz;
H-4), 5.35 (1H, ddd, J=6.0, 4.0, 1.0 Hz; H-5), 3.65 (3H, s; -COOCH3),
3.16 (1H, dd, J=4.0, 2.0 Hz; H-3), 3.05 (1H, d, J=6.5 Hz; H-6), 2.71
(1H, dd, J=16.0, 1.0 Hz; H-2), 2.07 (3H, s; -OC(O)CH3), 1.91 ppm (1H,
dd, J=16.5, 3.5 Hz; H-2); 13C NMR (75.4 MHz, CDCl3): d=210.5
([Fe(CO)3]), 171.8, 170.1, 87.1, 82.3, 81.4, 61.5, 60.4, 52.9, 39.9, 21.0 ppm;
FTIR (neat): n˜max =2957, 2048, 1961, 1735, 1436, 1371, 1330, 1273, 1248,
1200, 1125, 1056, 1014, 969, 947, 899, 865, 843, 810, 762, 674 cmꢀ1; HRMS
(ESI): m/z calcd for C13H12FeO7: 358.9830 [M+Na]+; found: 358.9825.
General procedure for de-metallation to give free dienes 38 to 44: A sol-
ution of ceric ammonium nitrate (3.00 equiv) in acetone (1 mL) was
added dropwise over 5 mins to a solution of the relevant iron complex in
wet acetone (2 mL) at 08C. The reaction mixture was allowed to warm to
room temperature and was stirred for an additional time period. Water
was added (5 mL) and the solution was extracted with Et2O (2ꢃ20 mL).
The combined organic layers were dried over MgSO4 and filtered. The
filtrate was concentrated under reduced pressure and purified by column
chromatography.
Sodium azide as a nucleophile: formation of 33 and (ꢂ)-34: In accord-
ance with the general procedure, the use of THF at 08C to RT with 16
(195 mg) gave 33 as a light-yellow oil (12.4 mg, 5%) and (ꢂ)-34 as a
yellow solid (81.4 mg, 34%). 33: Rf =0.43 (20:80 EtOAc/hexane); [a]D25
=
+430 (c=0.1 in CH2Cl2); 1H NMR (250 MHz, CDCl3): d=6.09 (1H, dd,
J=4.5, 1.0 Hz; H-6), 5.67 (1H, t, J=5.0 Hz; H-5), 4.95 (1H, s; H-2), 3.68
(3H, s; -COOCH3), 3.58 (1H, d, J=4.5 Hz; H-3), 3.14 (1H, td, J=5.5,
1.0 Hz; H-4), 2.11 ppm (3H, s; -OC(O)CH3); 13C NMR (75.4 MHz,
CDCl3): d=208.4 ([Fe(CO)3]), 170.9, 169.6, 91.7, 82.9, 73.0, 66.9, 63.6,
55.8, 52.2, 21.0 ppm; FTIR (neat): n˜max =2955, 2059, 1982, 1746, 1713,
1456, 1435, 1369, 1323, 1275, 1225, 1151, 1099, 1032, 971, 926, 872, 814,
Formation of 38: In accordance with the general procedure, the reaction
of 29 (3.4 mg) for 5 min gave a white solid (2.1 mg, 91%). Rf =0.35
(20:80 EtOAc/hexane); [a]2D5 = +40 (c=0.1 in CH2Cl2); 1H NMR
(500 MHz, CDCl3): d=7.53–7.50 (2H, m; Ar-H), 7.31–7.30 (3H, m; Ar-
H), 7.13 (1H, d, J=5.5 Hz; H-6), 6.28 (1H, dd, J=9.0, 5.5 Hz; H-4), 6.24
(1H, dd, J=9.0, 5.5 Hz; H-5), 6.08 (1H, s; H-3), 4.08 (1H, d, J=5.5 Hz;
H-2), 3.77 (3H, s; -COOCH3), 1.98 ppm (3H, s; -OC(O)CH3); 13C NMR
(125.8 MHz, CDCl3): d=170.3, 166.2, 135.7, 133.9, 132.2, 129.0, 128.5,
123.8, 123.7, 67.7, 52.2, 46.4, 21.2 ppm; FTIR (neat): n˜max =2924, 2854,
1743, 1715, 1580, 1439, 1369, 1286, 1228, 1078, 1025, 991, 951, 749,
694 cmꢀ1; HRMS (ESI): m/z calcd for C16H16SO4: 327.0667 [M+Na]+;
found: 327.0663.
775, 745 cmꢀ1
; HRMS (ESI): m/z calcd for C13H11FeN3O7: 399.9844
[M+Na]+; found: 399.9846; elemental analysis calcd (%) for
C13H11FeN3O7: C 44.41, H 2.94, N 11.14; found: C 41.6; H 3.00, N 10.7.
(ꢂ)-34: Rf =0.56 (20:80 EtOAc/hexane); m.p. 124–1268C; 1H NMR
(250 MHz, CDCl3): d=5.69 (1H, t, J=4.5 Hz; H-5), 5.59 (1H, t, J=
5.0 Hz; H-4), 3.90 (1H, d, J=3.5 Hz; H-2), 3.72 (3H, s; -COOCH3), 3.54
(1H, d, J=6.0 Hz; H-6), 3.05 (1H, t, J=4.5 Hz; H-3), 2.15 ppm (1H, s;
-OC(O)CH3); 13C NMR (75.4 MHz, CDCl3): d=209.4 ([Fe(CO)3]), 170.0,
Formation of (ꢂ)-39: In accordance with the general procedure, the reac-
tion of (ꢂ)-30 (63.8 mg) for 5 min gave a brown oil (37.1 mg, 85%). Rf =
0.42 (20:80 EtOAc/hexane); 1H NMR (500 MHz, CDCl3): d=7.49–7.47
(2H, m; Ar-H), 7.28–7.25 (3H, m; Ar-H), 6.36 (1H, d, J=9.5 Hz; H-6),
5.99–5.91 (3H, m; H-3,4,5), 4.04 (1H, d, J=4.5 Hz; H-2), 3.65 (3H, s;
-COOCH3), 1.99 ppm (3H, s; -OC(O)CH3); 13C NMR (125.8 MHz,
CDCl3): d=169.6, 169.5, 134.8, 131.3, 128.3, 127.0, 125.1, 123.2, 122.9,
79.6, 52.4, 48.6, 20.7 ppm; FTIR (neat): n˜max =2951, 1742, 1581, 1473,
1438, 1368, 1268, 1229, 1131, 1074, 1012, 986, 951, 909, 752, 717, 691,
651 cmꢀ1; HRMS (ESI): m/z calcd for C16H16SO4: 327.0667 [M+Na]+;
found: 327.0687.
168.1, 86.9, 85.1, 84.2, 68.0, 57.1, 55.2, 53.0, 21.3 ppm; FTIR (neat): n˜max
=
2956, 2054, 1971, 1740, 1450, 1435, 1369, 1331, 1222, 1138, 1063, 1041,
1012, 993, 946, 915, 869, 812, 766, 733, 716, 672, 649 cmꢀ1; HRMS (ESI):
m/z calcd for C13H11FeN3O7: 399.9844 [M+Na]+; found: 399.9829; ele-
mental analysis calcd (%) for C13H11FeN3O7: C 44.41, H 2.94, N 11.14;
found: C 41.5, H 2.97, N 10.7.
Sodium hydroxide as a nucleophile: formation of 35 and (ꢂ)-36: In ac-
cordance with the general procedure, the use of MeCN at 08C to RT
with 16 (233 mg) and an aqueous solution of NaOH (0.1m) as the nucleo-
phile gave 35 as a yellow oil (27.6 mg, 10%) and (ꢂ)-36 was isolated as a
light-yellow foam (64.8 mg, 25%). 35: Rf =0.26 (40:60 EtOAc/petrol);
[a]2D5 = +190 (c=0.1 in CH2Cl2); 1H NMR (250 MHz, CDCl3): d=6.07
(1H, dd, J=4.5, 1.0 Hz; H-6), 5.61 (1H, t, J=5.5 Hz; H-5), 4.66 (1H, s;
H-2), 3.87 (1H, brs; H-3), 3.68 (3H, s; -COOCH3), 3.12 (1H, t, J=
5.5 Hz; H-4), 2.70 (1H, d, J=3.0 Hz; -OH), 2.12 ppm (3H, s;
-OC(O)CH3); 13C NMR (75.4 MHz, CDCl3): d=171.42, 171.39, 91.3, 83.9,
76.9, 76.6, 61.7, 59.2, 52.1, 21.1 ppm; FTIR (neat): n˜max =3412, 2059, 1984,
1750, 1713, 1436, 1374, 1271, 1237, 1100, 1034, 969, 919, 873, 775,
685 cmꢀ1; HRMS (ESI): m/z calcd for C13H12O8Fe: 374.9782 [M+Na]+;
found 374.9774; elemental analysis calcd (%) for C13H12FeO8: C 44.35, H
3.44; found: C 43.9, H 3.64. (ꢂ)-36: Rf =0.36 (40:60 EtOAc/petrol);
1H NMR (400 MHz, CDCl3): d=5.61 (1H, ddd, J=6.0, 4.0, 1.5 Hz; H-5),
5.47 (1H, t, J=5.5 Hz; H-4), 4.17 (1H, dd, J=7.0, 3.5 Hz; H-2), 3.70
Formation of 40: In accordance with the general procedure, the reaction
of 31 (8.4 mg) for 50 min gave a white solid (3.1 mg, 63%). Rf =0.35
(20:80 EtOAc/hexane); [a]2D5 = +20 (c=0.1 in CH2Cl2); 1H NMR
(500 MHz, CDCl3): d=7.35 (1H, d, J=6.0 Hz; H-6), 6.28–6.22 (2H, m;
H-4,5), 5.91 (1H, d, J=7.0 Hz; H-2), 3.78 (3H, s; -COOCH3), 2.78 (1H,
dd, J=20.0, 3.0 Hz; H-3), 2.58 (1H, dd, J=20.0, 7.0 Hz; H-3), 1.99 ppm
(3H, s; -OC(O)CH3); 13C NMR (125.8 MHz, CDCl3): d=170.4, 166.6,
137.2, 133.0, 123.8, 122.7, 62.7, 51.9, 30.7, 21.3 ppm; FTIR (neat): n˜max
=
2961, 2923, 2859, 1716, 1658, 1467, 1378, 1261, 1079, 1030, 799 cmꢀ1
;
HRMS (ESI): m/z calcd for C10H12O4: 219.0633 [M+Na]+; found:
219.0615.
Formation of 41: In accordance with the general procedure, the reaction
of 33 (26.4 mg) for 3 h gave a colourless oil (10.5 mg, 63%). Rf =0.27
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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S. E. Lewis et al.
(20:80 EtOAc/hexane); [a]2D5 = +840 (c=0.1 in CH2Cl2); 1H NMR
(500 MHz, CDCl3): d=7.30 (1H, dd, J=6.0, 0.5 Hz; H-6), 6.52 (1H, dd,
J=9.5, 6.0 Hz; H-5), 6.21 (1H, dd, J=9.5, 5.5 Hz; H-4), 5.93 (1H, dd, J=
2.0, 1.0 Hz; H-2), 4.00 (1H, dd, J=5.5, 1.5 Hz; H-3), 3.80 (3H, s;
-COOCH3), 2.04 ppm (3H, s; -OC(O)CH3); 13C NMR (125.8 MHz,
CDCl3): d=170.0, 165.7, 135.4, 127.6, 126.5, 125.4, 66.1, 56.4, 52.3,
21.1 ppm; FTIR (neat): n˜max =2917, 2850, 1744, 1718, 1438, 1371, 1289,
and filtered. The filtrate was concentrated under reduced pressure, then
purified by chromatography (50:50 EtOAc/hexane) to give 57 as a col-
ourless oil (846 mg, 69%). Rf =0.37 (50:50 EtOAc/petrol); [a]2D5 =ꢀ140
(c=0.1 in CH2Cl2); 1H NMR (500 MHz, CDCl3): d=6.12 (1H, dd, J=
9.5, 5.5 Hz; H-5), 5.93 (1H, dddd, J=9.5, 5.5, 3.0, 1.0 Hz; H-4), 5.80 (1H,
ddt, J=9.5, 2.5, 1.0 Hz; H-3), 5.74 (1H, dd, J=9.5, 1.0 Hz; H-6), 4.83
(1H, d, J=5.0 Hz; H-2), 4.31 (2H, q, J=7.0 Hz; -CH2CH3), 3.67 (1H, s;
C1-OH), 2.84 (1H, d, J=9.5 Hz; C2-OH), 1.32 ppm (3H, t, J=7.0 Hz;
-CH2CH3); 13C NMR (125.8 MHz, CDCl3): d=175.3, 132.1, 126.7, 124.9,
122.8, 73.9, 71.0, 63.0, 14.3 ppm; FTIR (neat): n˜max =3448, 3049, 2983,
1727, 1446, 1408, 1369, 1246, 1169, 1078, 1039, 1019, 914, 858, 829, 754,
1259, 1226, 1082, 1022, 757 cmꢀ1
; HRMS (ESI): m/z calcd for
C10H11O4N3: 260.0642 [M+Na]+; found: 260.0621.
Formation of (ꢂ)-42: In accordance with the general procedure, the reac-
tion of (ꢂ)-34 (77.3 mg) for 4 h gave a white solid (34.9 mg, 64%). Rf =
0.27 (10:90 EtOAc/hexane); 1H NMR (300 MHz, CDCl3): d=6.49 (1H,
d, J=9.5 Hz; H-6), 6.37 (1H, dd, J=9.5, 5.5 Hz; H-4), 6.20 (1H, dd, J=
9.5, 5.5 Hz; H-5), 5.90 (1H, dd, J=9.0, 5.0 Hz; H-3), 3.86–3.83 (1H, m;
H-2), 3.83 (3H, s; -COOCH3), 2.02 ppm (3H, s; -OC(O)CH3); 13C NMR
(75.4 MHz, CDCl3): d=169.6, 169.4, 126.8, 126.6, 124.7, 120.1, 77.3, 57.7,
53.3, 20.7 ppm; FTIR (neat): n˜max =2957, 1744, 1438, 1371, 1272, 1235,
724, 693, 646 cmꢀ1
; HRMS (ESI): m/z calcd for C9H12O4: 207.0628
[M+Na]+; found: 207.0748; m/z calcd for C9H12O4: 391.1364 [2M+Na]+;
found: 391.1374.
Complexation to form 58: Nonacarbonyldiiron (3.05 g, 8.28 mmol,
1.5 equiv) was added to ester 57 (1.79 g, 5.52 mmol, 1.0 equiv). THF
(200 mL) was added and the reaction mixture was stirred at room tem-
perature for 5 days. The reaction mixture was concentrated under re-
duced pressure (caution! toxic pentacarbonyliron distilled over) and the
crude product was purified by chromatography (30:70 EtOAc/petrol) to
give 58 as a yellow foam (1.09 g, 61%). Rf =0.60 (30:70 EtOAc/petrol);
[a]2D5 =ꢀ180 (c=0.1 in CH2Cl2); 1H NMR (300 MHz, CDCl3): d=5.38–
5.33 (2H, m; H-4,5), 4.22–4.15 (2H, m; -CH2CH3), 3.94 (1H, s; C1-OH),
3.88 (1H, d, J=5.0 Hz; H-2), 3.26 (1H, d, J=6.5 Hz; C2-OH), 3.21 (1H,
dt, J=6.0, 2.0 Hz; H-3), 2.82 (1H, dd, J=6.0, 1.5 Hz; H-6), 1.27 ppm
(3H, t, J=7.0 Hz; -CH2CH3); 13C NMR (75.4 MHz, CDCl3): d=210.2
([Fe(CO)3]), 174.4, 84.5, 84.2, 77.2, 72.0, 67.6, 64.6, 62.7, 14.0 ppm; FTIR
(neat): n˜max =3401.5, 2991, 2905, 2051, 1960, 1720, 1574, 1446, 1377, 1297,
1233, 1175, 1133, 1063, 1026, 936, 866, 831, 737 cmꢀ1; HRMS (ESI): m/z
calcd for C12H12FeO7: 346.9825 [M+Na]+; found: 346.9926; m/z calcd for
C12H12FeO7: 670.9758 [2M+Na]+; found: 670.9853.
1075, 1021, 937, 852, 808, 746 cmꢀ1
; HRMS (ESI): m/z calcd for
C10H11O4N3: 260.0642 [M+Na]+; found: 260.0625.
Formation of 43: In accordance with the general procedure, the reaction
of 35 (14.7 mg) for 5 min gave a white solid (4.7 mg, 53%). Rf =0.19
(35:65 EtOAc/hexane); [a]2D5 = +400 (c=0.1 in CH2Cl2); 1H NMR
(500 MHz, CDCl3): d=7.26–7.25 (1H, m; H-6), 6.29–6.28 (2H, m; H-
4,5), 5.89 (1H, d, J=2.5 Hz; H-2), 4.34 (1H, brs; H-3), 3.78 (3H, s;
-COOCH3), 2.34 (1H, d, J=6.0 Hz; -OH), 2.07 ppm (3H, s;
-OC(O)CH3); 13C NMR (125.8 MHz, CDCl3): d=171.0, 166.2, 135.2,
133.0, 125.2, 124.2, 70.7, 67.7, 52.2, 21.2 ppm; FTIR (neat): n˜max =3444,
2955, 2922, 2853, 1741, 1714, 1651, 1587, 1438, 1407, 1371, 1230, 1121,
1082, 1020, 992, 960, 917, 876, 815, 743, 682 cmꢀ1; HRMS (ESI): m/z
calcd for C10H12O5: 235.0577 [M+Na]+; found: 235.0616; m/z calcd for
C10H12O5: 447.1262 [2M+Na]+; found: 447.1278.
Formation of adducts 59 and (ꢂ)-60: Tetrafluoroboric acid diethyl ether-
ate (319 mL, 2.33 mmol 4.00 equiv) was added to a stirred solution of the
[h4] complex 58 (189 mg, 0.583 mmol, 1.00 equiv) in acetic anhydride
(5.8 mL) at ꢀ108C and stirred at this temperature for 1 h. Pre-cooled
Et2O (60 mL) was added dropwise to the reaction mixture, giving a light-
yellow precipitate. This was filtered by using suction and washed with
cold Et2O (3ꢃ5 mL). The crude cation mixture was redissolved in MeCN
at 08C, and NaBH4 (111 mg, 2.91 mmol, 5.00 equiv) was added in one
portion. The reaction mixture was allowed to warm to room temperature
and was stirred for 18 h, then quenched by addition of H2O. The product
was extracted with CH2Cl2 (3ꢃ20 mL). The organic layers were com-
bined, dried over Na2SO4 and filtered. The filtrate was concentrated
under reduced pressure and the crude product was purified by chroma-
tography (10:90 EtOAc/hexane) to give 59 (10.9 mg, 5%) and (ꢂ)-60
(80.3 mg, 39%) as yellow foams. 59: Rf =0.14 (10:90 EtOAc/hexane);
[a]2D5 = +120 (c=0.1 in CH2Cl2); 1H NMR (250 MHz, CDCl3): d=5.95
(1H, dd, J=4.5, 1.5 Hz; H-6), 5.52 (1H, t, J=5.5 Hz; H-5), 5.04 (1H, d,
J=6.5 Hz; H-2), 4.24–4.02 (2H, m; -CH2CH3), 3.22–3.17 (1H, m; H-4),
2.10–2.00 (1H, m; H-3), 2.06 (3H, s; -OC(O)CH3), 1.57 (1H, ddd, J=
16.0, 4.5, 1.0 Hz; H-3), 1.24 ppm (3H, t, J=7.0 Hz; -CH2CH3); 13C NMR
(75.4 MHz, CDCl3): d=209.5 ([Fe(CO)3]), 171.2, 170.1, 90.4, 84.4, 68.5,
68.2, 61.0, 58.6, 34.3, 21.2, 14.1 ppm; FTIR (neat): n˜max =2925, 2057, 1981,
1739, 1710, 1505, 1448, 1368, 1240, 1207, 1098, 1043, 871, 752, 715,
612 cmꢀ1; HRMS (ESI): m/z calcd for C14H14FeO7 =372.9974 [M+Na]+;
found: 372.9986. (ꢂ)-60: Rf 0.25 (10:90 EtOAc/hexane); 1H NMR
(500 MHz, CDCl3): d=5.47 (1H, t, J=5.5 Hz; H-4), 5.36 (1H, t, J=
5.5 Hz; H-5), 4.18–4.07 (2H, m; -CH2CH3), 3.20–3.17 (1H, m; H-3), 3.08
(1H, d, J=6.5 Hz; H-6), 2.73 (1H, d, J=16.0 Hz; H-2), 2.09 (3H, s;
-OC(O)CH3), 1.92 (1H, dd, J=16.0, 3.5 Hz; H-2); 1.22 ppm (3H, t, J=
7.0 Hz; -CH2CH3); 13C NMR (125.8 MHz, CDCl3): d=210.6 ([Fe(CO)3]),
171.3, 170.1, 87.1, 82.3, 81.5, 61.8, 61.6, 60.5, 39.9, 21.0, 14.6 ppm; FTIR
(neat): n˜max =2985, 2051, 1969, 1740, 1427, 1370, 1251, 1196, 1097, 1054,
1014, 954, 869 cmꢀ1; HRMS (ESI): m/z calcd for C14H14FeO7: 372.9986
[M+Na]+; found: 372.9996.
Formation of (ꢂ)-44: In accordance with the general procedure, the reac-
tion of (ꢂ)-36 (13.8 mg) for 25 min gave a beige solid (8.8 mg, 100%).
Rf =0.48 (50:50 EtOAc/petrol); 1H NMR (400 MHz, CDCl3): d=6.33
(1H, d, J=9.5 Hz; H-6), 6.17 (1H, dd, J=9.5, 5.0 Hz; H-5), 6.09 (1H, dd,
J=9.5, 5.0 Hz; H-4), 6.01 (1H, dd, J=9.5, 5.0 Hz; H-3), 4.36 (1H, dd, J=
8.5, 4.5 Hz; H-2), 3.80 (3H, s; -COOCH3), 2.05 (3H, s; -OC(O)CH3),
1.94 ppm (1H, d, J=9.0 Hz; OH); 13C NMR (100.6 MHz, CDCl3): d=
170.0, 169.9, 126.6, 126.5, 124.4, 124.3, 79.6, 68.6, 52.9, 20.9 ppm; FTIR
(neat): n˜max =3452, 2955, 1985, 1732, 1436, 1412, 1370, 1273, 1232, 1136,
1078, 1047, 1019, 1000, 953, 920, 879, 812, 729, 796, 694 cmꢀ1; HRMS
(ESI): m/z calcd for C10H12O5: 235.0577 [M+Na]+; found: 235.0616; m/z
calcd for C10H12O5: 447.1262 [2M+Na]+; found: 447.1255.
Acetylation of 43 to give 55: Ac2O (3.8 mL, 0.040 mmol, 2.0 equiv) was
added portionwise to a solution of compound 43 (4 mg, 0.018 mmol,
1.00 equiv) in CH2Cl2 (2 mL) at 08C, and then Et3N (8.4 mL, 0.060 mmol,
3.2 equiv) was added. The reaction mixture was stirred at room tempera-
ture for 24 h. The reaction mixture was transferred into a separating
funnel and extracted with EtOAc (4ꢃ10 mL) and water (10 mL), and the
combined organic phases were then dried over Na2SO4 and filtered. The
filtrate was concentrated under reduced pressure and purified by flash
column chromatography (30:70 EtOAc/hexane) to give 55 as a white
solid (3 mg, 63%). Rf =0.35 (30:70 EtOAc/hexane); [a]2D5 = +440 (c=0.1
in CH2Cl2); 1H NMR (500 MHz, CDCl3): d=7.28 (1H, d, J=6.0 Hz; H-
6), 6.37 (1H, dd, J=9.5, 6.0 Hz; H-5), 6.29 (1H, dd, J=9.5, 6.0 Hz; H-4),
5.94 (1H, d, J=2.0 Hz; H-2), 5.29 (1H, dd, J=5.0, 2.0 Hz; H-3), 3.79
(3H, s; -COOCH3), 2.05 ppm (6H, s; 2ꢃ-OC(O)CH3); 13C NMR
(125.8 MHz, CDCl3): d=169.59, 169.55, 165.8, 135.1, 129.1, 126.0, 125.4,
67.7, 65.9, 52.1, 20.9, 20.8 ppm; FTIR (neat): n˜max =2955, 1742, 1717,
1594, 1437, 1370, 1295, 1221, 1084, 1022, 967, 749 cmꢀ1; HRMS (ESI): m/
z calcd for C12H14O6: 277.0683 [M+Na]+; found: 277.0773; m/z calcd for
C12H14O6: 531.1473 [2M+Na]+; found: 531.1581.
Esterification to form 57: A mixture of diol acid 4 (1.03 g, 6.63 mmol,
1.00 equiv) and caesium fluoride (1.51 g, 9.94 mmol, 1.50 equiv) in DMF
(15 mL) was stirred at room temperature for 2 min, then ethyl iodide
(0.799 mL, 9.94 mmol, 1.50 equiv) was added. The reaction mixture was
stirred for 23 h, then diluted with aqueous NaHCO3 (15 mL) and extract-
ed with EtOAc (3ꢃ15 mL). The organic layer was dried over Na2SO4
Deacetoxylation to give cation (ꢂ)-61: Iron complex (ꢂ)-60 (51.5 mg,
0.147 mmol, 1.00 equiv) was dissolved in CH2Cl2 (3 mL) at ꢀ128C and
HBF4–etherate (30.2 mL, 0.220 mmol, 1.50 equiv) was added portionwise.
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
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Cyclohexadiene Building Blocks from Cationic h5-Iron–Carbonyl Complexes
FULL PAPER
The reaction mixture was stirred at this temperature for 1 h, then added
to cold Et2O (50 mL) to give a precipitate that was isolated by filtration,
washed with Et2O and dried under vacuum to give (ꢂ)-61 as a pale-
Acknowledgements
We thank Prosidion Limited, the EPSRC and CIKTN for a CASE stu-
dentship (to M.A.K.). We are grateful to Dr C. Liana Allen and Dr
Hannah Maytum for assistance with chiral HPLC. We also thank Prof.
Andrew G. Myers for a gift of R. eutropha B9 cells.
yellow powder (55.5 mg, 100%). 1H NMR (300 MHz, CD3CN): d=7.38
(1H, t, J=5.0 Hz), 6.57 (1H, d, J=5.5 Hz), 5.91 (1H, t, J=5.5 Hz), 4.70
(1H, t, J=6.5 Hz), 4.26 (1H, q, J=7.0 Hz), 3.27 (1H, dd, J=15.5,
6.5 Hz), 1.96–1.86 (1H, m), 1.28 ppm (1H, t, J=7.0 Hz); 13C NMR
(75.4 MHz, CD3CN): d=167.6, 105.1, 103.0, 91.3, 71.8, 63.9, 56.0, 24.2,
14.1; HRMS (ESI): m/z calcd for C12H11FeO5: 290.9951 [M]+; found:
290.9925.
´
[1] For reviews, see: a) T. Hudlicky, Pure Appl. Chem. 2010, 82, 1785–
Potassium phthalimide as a nucleophile: formation of (ꢂ)-62: A suspen-
sion of the [h5]+ complex (ꢂ)-61 (78.2 mg, 0.223 mmol, 1.00 equiv) and
potassium phthalimide (124 mg, 0.699 mmol, 3.00 equiv) in CH2Cl2
(4.4 mL) was cooled to 08C. Diisopropylethyl amine (42.7 mL,
0.246 mmol, 1.10 equiv) was added dropwise and the reaction mixture
was stirred at 08C for 30 min before being allowed to warm to room tem-
perature. The reaction mixture was stirred at this temperature for 23 h,
then quenched by the addition of water, transferred to a separating
funnel and extracted with CH2Cl2 (3ꢃ30 mL). The combined organic
phases were dried over MgSO4 and filtered. The filtrate was concentrated
under reduced pressure, then purified by column chromatography (15:85
EtOAc/petrol) to give (ꢂ)-62 as a yellow solid (70.8 mg, 73%). Rf =0.73
(15:85 EtOAc/petrol); m.p. 124–1258C; 1H NMR (400 MHz, CDCl3): d=
7.79 (2H, dd, J=5.5, 3.0 Hz; Ar-H), 7.69 (2H, dd, J=5.5, 3.0 Hz; Ar-H),
6.33 (1H, d, J=4.5 Hz; H-6), 5.59 (1H, t, J=5.5 Hz; H-5), 4.90 (1H, dt,
J=11.5, 3.5 Hz; H-3), 4.24–4.08 (2H, m; -CH2CH3), 2.91 (1H, dd, J=5.0,
3.5 Hz; H-4), 2.78 (1H, dd, J=15.0, 11.5 Hz; H-2), 1.84 (1H, dd, J=15.0,
4.0 Hz; H-2), 1.26 ppm (3H, t, J=7.0 Hz; -CH2CH3); 13C NMR
(100.6 MHz, CDCl3): d=171.6, 167.7, 134.0, 131.7, 123.2, 89.5, 85.7, 60.8,
60.0, 58.2, 48.3, 26.3, 14.1 ppm; FTIR (neat): n˜max =2982, 2057, 1982,
1774, 1708, 1468, 1382, 1354, 1327, 1270, 1249, 1117, 1083, 1042, 881, 716,
649 cmꢀ1; HRMS (ESI): m/z calcd for C20H15FeNO7: 460.0091 [M+Na]+;
found: 460.0104.
´
1796; b) T. Hudlicky, J. W. Reed, Synlett 2009, 685–703; c) K. A. B.
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Lewis, Chem. Eur. J. 2012, 18, 4766–4774; b) D. R. Boyd, N. D.
Sharma, M. Kaik, P. B. A. McIntyre, P. J. Stevenson, C. C. R. Allen,
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Endoma-Arias, T. Hudlicky, Tetrahedron Lett. 2011, 52, 6632–6634;
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Duchek, T. G. Piercy, J. Gilmet, T. Hudlicky, Can. J. Chem. 2011, 89,
De-metallation to form (ꢂ)-63: Aqueous hydrogen peroxide (30%,
6.0 mL) was added to a solution of complex (ꢂ)-62 (38 mg, 0.0869 mmol,
1.00 equiv) in EtOH (17 mL) at 08C, followed by the dropwise addition
of aqueous NaOH (1.0m, 5.2 mL). The reaction mixture was stirred for
5 min, then diluted with brine (saturated, 50 mL) and the product was ex-
tracted with CH2Cl2 (3ꢃ50 mL). The combined organic phases were
dried over MgSO4 and filtered. The filtrate was concentrated under re-
duced pressure to give (ꢂ)-63 as a light yellow foam (19.8 mg, 77%).
1H NMR (400 MHz, CDCl3): d=7.84 (2H, dd, J=5.5, 3.0 Hz), 7.74 (2H,
dd, J=5.5, 3.0 Hz), 7.09–7.08 (1H, m), 6.23 (1H, ddd, J=9.5, 5.5,
3.0 Hz), 6.00 (1H, dd, J=9.5, 3.0 Hz), 5.23 (1H, ddt, J=14.5, 10.5,
3.0 Hz), 4.22 (2H, q, J=7.0 Hz), 2.93 (1H, ddd, J=17.5, 15.0, 2.5 Hz),
2.81 (1H, dd, J=17.0, 10.0 Hz), 1.30 ppm (3H, t, J=7.0 Hz). Data are in
agreement with those reported previously.[71]
709–728; k) M. G. Banwell, A. L. Lehmann, R. S. Menon, A. C.
Willis, Pure Appl. Chem. 2011, 83, 411–423; l) D. R. Adams, C. Ai-
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chinger, J. Collins, U. Rinner, T. Hudlicky, Synlett 2011, 725–729;
m) M. Labora, V. Schapiro, E. Pandolfi, Tetrahedron: Asymmetry
2011, 22, 1705–1707; n) M. G. Banwell, X. Ma, O. P. Karunaratne,
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M. T. Jones, M. G. Banwell, I. A. Cade, Org. Lett. 2010, 12, 5210–
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D. M. Pinkerton, A. C. Willis, M. G. Banwell, Eur. J. Org. Chem.
´
2010, 4365–4367; r) J. Collins, U. Rinner, M. Moser, T. Hudlicky, I.
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1044–1047.
tert-Butyl carbamate as a nucleophile: formation of (ꢂ)-64: Diisopropyl-
ethyl amine (38.5 mL, 0.221 mmol, 1.50 equiv) was added dropwise to a
suspension of the [h5]+ complex (ꢂ)-61 (51.5 mg, 0.1471 mmol,
1.00 equiv) and tert-butyl carbamate (34.5 mg, 0.294 mmol, 2.00 equiv) in
CH2Cl2 (3 mL) at 08C. The reaction mixture was stirred for 30 min
before being allowed to warm to room temperature. The reaction mix-
ture was stirred at this temperature for 23 h then quenched by the addi-
tion of water, transferred to a separating funnel and extracted with
CH2Cl2 (3ꢃ30 mL). The combined organic phases were dried over
MgSO4 and filtered. The filtrate was concentrated under reduced pres-
sure and purified by column chromatography (20:80 EtOAc/petrol) to
give (ꢂ)-64 as a yellow oil (48.2 mg, 82%). Rf =0.59 (20:80 EtOAc/
hexane); 1H NMR (400 MHz, CDCl3): d=6.20 (1H, d, J=4.0 Hz), 5.39
(1H, dd, J=6.0, 4.5 Hz), 4.40–4.17 (2H, m), 4.21–4.03 (2H, m), 3.27 (1H,
br s), 2.84 (1H, dd, J=15.0, 11.0 Hz), 1.41 (9H, s), 1.25 (3H, t, J=
7.0 Hz), 1.16 ppm (1H, dd, J=15.0, 3.0 Hz). Data are in agreement with
those reported previously.[52]
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M. Moser, D. R. Adams, T. Hudlicky, J. Org. Chem. 2011, 76,
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10050–10067; b) L. Werner, A. Machara, T. Hudlicky, Adv. Synth.
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Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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the case of entry 6 (Table 1), byproduct 65 was also obtained in low
yield. We tentatively ascribe the
formation of 65 to the deacetoxy-
lation of product (ꢂ)-29 by traces
of residual acid followed by fur-
ther nucleophilic attack to incor-
porate a second equivalent of thi-
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Received: July 6, 2012
Published online: && &&, 0000
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www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Cyclohexadiene Building Blocks from Cationic h5-Iron–Carbonyl Complexes
FULL PAPER
Synthesis Behind the Iron Curtain:
Biooxidation of benzoic acid by Ral-
stonia eutropha B9 gives an unusual
cyclohexadiene diol with a quaternary
stereocentre. New iron complexes of
this chiron, formed on treatment with
acid, provide a versatile library of
cyclohexadiene building blocks (see
scheme), which have been used in the
formal syntheses of oseltamivir.
Microbial Arene Oxidation
M. Ali Khan, M. F. Mahon, J. P. Lowe,
A. J. W. Stewart,
S. E. Lewis* ................... &&&& — &&&&
Valuable New Cyclohexadiene
Building Blocks from Cationic h5-
Iron–Carbonyl Complexes Derived
from a Microbial Arene Oxidation
Product
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
15
&
ÞÞ
These are not the final page numbers!