Toluene dioxygenase-catalyzed synthesis of cis-dihydrodiol metabolites from 2-substituted naphthalene substrates: Assignments of absolute configurations and conformations from circular dichroism and optical rotation measurements

Article abstract of DOI:10.1002/chem.200801686

cis-Dihydrodiol metabolites have been isolated from naphthalene and six 2-substituted naphthalene substrates. Their structures and absolute configurations have been determined by a combination of calculated (TDDFT) and experimentally based circular dichroism (CD) and optical rotation (OR) methods. The inverse styrene helicity rule is shown to be incorrect for the interpretation of theCD spectra of cis-dihydrodiols. A striking conclusion is that CD spectra correlate directly with the helicity of the styrene chromophore: that is, the sign of the long-wavelength Cotton effect is identical with the sign of styrene torsion angle, whereas the OR sign is dependent on the absolute configuration of the allylic carbon atom. The results demonstrate that a predictive model previously used for the determination of preferred regio- and stereoselectivity associated with TDO-catalyzed cis-dihydroxylation of substituted benzene substrates can now be successfully extended to substituted naphthalene substrates.

Full text of DOI:10.1002/chem.200801686

DOI: 10.1002/chem.200801686
Toluene Dioxygenase-Catalyzed Synthesis of cis-Dihydrodiol Metabolites
from 2-Substituted Naphthalene Substrates: Assignments of Absolute
Configurations and Conformations from Circular Dichroism and Optical
Rotation Measurements
Marcin Kwit,[a] Jacek Gawronski,*[a] Derek R. Boyd,*[b] Narain D. Sharma,[b]
Magdalena Kaik,[b] Rory A. More OꢀFerrall,[c] and Jaya S. Kudavalli[c]
Abstract: cis-Dihydrodiol metabolites
have been isolated from naphthalene
and six 2-substituted naphthalene sub-
strates. Their structures and absolute
configurations have been determined
CD spectra of cis-dihydrodiols. A strik-
ing conclusion is that CD spectra corre-
late directly with the helicity of the sty-
rene chromophore: that is, the sign of
the long-wavelength Cotton effect is
identical with the sign of styrene tor-
sion angle, whereas the OR sign is de-
pendent on the absolute configuration
of the allylic carbon atom. The results
demonstrate that a predictive model
previously used for the determination
of preferred regio- and stereoselectivity
associated with TDO-catalyzed cis-di-
hydroxylation of substituted benzene
substrates can now be successfully ex-
tended to substituted naphthalene sub-
strates.
by
a
combination of calculated
(TDDFT) and experimentally based
circular dichroism (CD) and optical ro-
tation (OR) methods. The “inverse”
styrene helicity rule is shown to be in-
correct for the interpretation of the
Keywords: absolute configuration ·
bacterial metabolites
·
circular
dichroism · diols · optical rotation
Introduction
enantiomeric excess (ee) values nor their absolute configura-
tions have been rigorously established. The TDO-catalyzed
cis-dihydroxylation of monosubstituted benzene cis-dihydro-
diols (A) was found to be very regioselective for the 2,3-
bond, giving cis-dihydrodiols of type B (Scheme 1). To date
only one example of a type C cis-dihydrodiol (X=F) has
been reported using the enzyme TDO.[13a] Although no ex-
amples of type D cis-dihydrodiols have been reported with
TDO as biocatalyst, one example has also been obtained
using benzoate dioxygenase (BZDO). Thus using whole
cells of Alcaligenes eutrophus (also described as Ralstonia
eutropha) a BDZO-catalysed oxidation of benzoic acid gave
The toluene dioxygenase-catalyzed (TDO-catalyzed) dihy-
droxylation of mono- and disubstituted benzene substrates
in bacteria has been reported to give a wide range (>200)
of cis-dihydrodiol metabolite derivatives that have mainly
been formed as single enantiomers.[1–12] Similarly, the bacte-
rial naphthalene dioxygenase-catalyzed (NDO-catalyzed) di-
hydroxylation of naphthalene and substituted naphthalenes
has recently been reported to give over 25 corresponding
cis-dihydrodiol derivatives, but in many cases neither their
[13a]
a type D cis-dihydrodiol (R=CO2H).
[a] Dr. M. Kwit, Prof. Dr. J. Gawronski
Grunwaldzka 6, 60 780 Poznan (Poland)
Fax : (+48)618291505
The NDO enzyme has not been reported to biotransform
monosubstituted benzene substrates, with the exceptions of
biphenyl A (X=Ph) and azabiphenyl analogues (X=pyri-
din-1-, -2- and -3-yl).[13] However, a marked degree of regio-
selectivity was observed in bacterial NDO-catalyzed cis-di-
hydroxylation of acceptable 2-substituted naphthalene sub-
strates (E), with preferential attack occurring at the 7,8-
bonds to give cis-dihydrodiols of type F (X=Cl, Br, Me, Et,
CO2Me, OMe, NO2) as major metabolites, (Scheme 1 and
Table 1).[14–18] The NDO enzyme present in a mutant strain
of Pseudomonas putida (9816/11) was also found to catalyse
[b] Prof. Dr. D. R. Boyd, Dr. N. D. Sharma, Dr. M. Kaik
Centre for Theory and Application of Catalysis
School of Chemistry, The Queenꢀs University of Belfast
Belfast BT9 5AG (UK)
Fax : (+44)90974687
[c] Prof. Dr. R. A. More OꢀFerrall, Dr. J. S. Kudavalli
School of Chemistry and Chemical Biology
UCD Dublin 4 (Ireland)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801686.
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Chem. Eur. J. 2008, 14, 11500 – 11511

FULL PAPER
tuted cis-dihydrodiols to
a
range of previously reported,
and new, cis-dihydrodiols ob-
tained from 2-substituted naph-
thalenes, and ii) to extend the
applicability of our predictive
model for assignment of the
most favoured type of regiose-
lectivity and stereoselectivity
during TDO-catalyzed cis-dihy-
droxylation from substituted
monocyclic arenes to their bicy-
clic counterparts, and also from
monosubstituted and disubsti-
tuted arene rings up to trisub-
stituted systems.
Scheme 1. Possible cis-dihydrodiol regioisomers (B–D, F–I) formed from dioxygenase-catalyzed cis-dihydroxy-
lation of monosubstituted benzene (A) and naphthalene (E) substrates.
Among the methods current-
ly available for stereostructure
Table 1. Relative yields [%] of cis-dihydrodiol metabolites F–H obtained
by TDO-and NDO-catalysed dihydroxylation of 2-substituted naphtha-
lene substrates E.
(absolute configuration and conformation) assignment,
methods based on the chiroptical properties of a molecule,
mainly electronic circular dichroism (ECD) and optical rota-
tion (OR), provide good alternatives to methods based on
X-ray diffraction. At present, it can be useful to compare
experimentally acquired data and quantum-chemical calcu-
lations of spectroscopic properties of molecules.[20,21] As a
result, information about both the conformation and the ab-
solute configuration of a molecule (absolute stereochemis-
try) can be obtained. Although the absolute stereochemistry
of the investigated molecule can be accurately determined
by use of just one of the chiroptical methods (i.e., ECD or
OR), concurrent use of more than one chiroptical method is
preferred for independent assignment of molecular struc-
tures, particularly in difficult cases.[22]
Many ab initio methods are now well established as indis-
pensable partners to experimental data for prediction of chi-
roptical phenomena.[23] Of these, those based on time-de-
pendent density functional theory (TD-DFT) are the most
frequently used. Among the many functionals available, the
B3LYP hybrid functional in conjunction with the basis sets
varying from the relatively small (that is, 6-31G(D)) to the
very large (that is, Aug-CC-pVXZ) appear to have the
broadest applicability.[24,25] Although the B3LYP functional
is the most frequently used for calculations of many molecu-
lar properties, including some ECD and OR calculations, it
can produce unsatisfactory results in calculations of some
properties, such as those that depend on long- and medium-
range noncovalent interactions and in the case of transition-
metal chemistry.[26,27] In recent years, the development of
new functional forms, and their validation against diverse
databases, have yielded powerful new density functionals of
broad applicability to many areas of chemistry.[28] Among
these, hybrid density functionals, including a non-local cor-
relation effect, have given promising results in cases of cal-
culations of molecular properties both in the ground and in
excited states.[29] The virtual-orbital-dependent B2PLYP
hybrid functional, recently developed by Grimme and
Schwabe, is based on a mixing of standard generalized gra-
X
F
G
H
enzyme
Br
TDO (%)
1a (33)[a,b]
1b (42)[a,b]
NDO
TDO (%)
NDO
TDO (%)
3a (27)[a,e]
3b (38)[a,f]
1a[c,d]
2a (40)[a,e]
2b (20)[a,e]
2a[c]
F
OMe
CN
Me
H
1c (17)[a,b,g] 1c (93)[c,d] 2c (52)[a,e,g] 2c (7)[g] 3c (31)[a,f,g]
1d (15)[a,b]
1e (60)[a,b,h]
1 f (100)[a,d,i]
1g (51)[a,b]
2d (57)[a,e]
2e (10)[a,e]
3d (28)[a,f]
3e (30)[a,f]
1e[d,e,g]
1 f[d]
I
2g (34)[a,e]
3g (15)[a,f]
[a] Present study. [b] Mid Rf. [c] Ref. [14]. [d] Ref. [18]. [e] Low Rf.
[f] High Rf. [g] Ref. [15–16]. [h] Ref. [17]. [i] Ref. [18].
cis-dihydroxylation at the 5,6-bonds of 2-methoxynaphtha-
lene and 2-bromonaphthalene (E, X=OMe and Br) to give
the corresponding cis-dihydrodiols G (X=OMe and Br) as
very minor metabolites (<10% relative yields).[14,15] Alter-
native Pseudomonas strains (A3 and C22) expressing a fur-
ther type of NDO were also found to catalyse cis-dihydroxy-
lation at the 1,2-bonds of the naphthalene rings in the car-
boxylic acids E (X=CO2H and CH2CO2H) to give isolable
cis-dihydrodiols I (X=CO2H and CH2CO2H) as the sole
metabolites.[19]
It is noteworthy that, to date, only the TDO enzyme has
been reported to catalyse cis-dihydroxylation at the 3,4-
bonds of 2-substituted naphthalenes E (X=Me and OMe)
to give cis-dihydrodiols H (X=Me and OMe) as minor me-
tabolites.[15,16] As a logical extension of our earlier studies of
the combined use of experimentally obtained and calculated
circular dichroism (CD) spectroscopy and optical rotation
(OR) measurements in the context of assigning absolute
configurations to cis-dihydrodiol metabolites of mono- and
disubstituted benzene substrates, this study has focused on
2-substituted naphthalene substrates E (X=H, Me, CN, F,
Br, I, OMe). The major objectives of this study were i) to
extend the validity of the calculation-based and experimen-
tally based approaches to the assignment of absolute config-
urations from CD and OR characteristics from monosubsti-
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11501

J. Gawronski, D. R. Boyd, N. D. Sharma et al.
dient approximations (GGAs), which have been used for ex-
change by Becke (B) and for correlation by Lee, Yang and
Parr (LYP) with Hartree–Fock (HF) exchange and a pertur-
bative second-order correlation part (PT2) that is obtained
from Kohn–Sham (GGA) orbitals and eingenvalues.[30] Ex-
tensive testing has recently demonstrated the outstanding
accuracy of this approach for various ground-state problems
in general chemistry applications.[31] In our computations of
chiroptical properties of naphthalene cis-dihydrodiols, we
used the B2PLYP hybrid functional in conjunction with a 6-
1e, 1 f, 2c, 3a, 3c) had been unequivocally determined earli-
er.[14–18] NMR analysis (NOE, HMBC, coupling constants)
and aromatisation and identification of the known phenolic
derivatives were used to ascertain the regiochemistries of all
of the cis-dihydrodiols isolated during the current study. The
enantiomeric excess (ee) values for all cis-dihydrodiols were
found to be >98% through the formation of chiral boronate
derivatives by methods described earlier.[32–35] The absolute
configurations were all assigned by a method of comparison
of calculated and experimentally measured CD spectra and
OR.[32–35]
311++G
ACHTUNGTRENNUNG
B3LYP/6-311++GACHTUNGTRENNUNG
Conformational analysis of cis-dihydrodiols 1a–f, 2a–e and
3a–e: In order to obtain reliable results from CD and OR
calculations, we first carried out calculations for low-energy
conformers of cis-dihydrodiols by the previously described
protocol.[32–35] The calculated structures of the low-energy
conformers were optimized by use of the B3LYP functional
Results and Discussion
TDO-catalysed cis-dihydroxylations of naphthalene 1 f and
the 2-substituted naphthalenes 1a–e and 1g: The UV4
mutant strain of Pseudomonas putida has been extensively
used as a source of TDO, and the majority of cis-dihydrodiol
metabolites from mono- and disubstituted benzene sub-
strates that have to date been isolated, identified and stereo-
chemically assigned are from this strain.[1–12] Bacterial NDO
uses naphthalene (E, X = H) as its natural substrate and it
is evident that 2-substituted naphthalene derivatives E (X =
Me, Et, CO2Me, Cl, Br, OMe, NO2) are also substrates for
this enzyme, giving mainly bioproducts of type F. Literature
reports[16,19] of the TDO-catalyzed cis-dihydroxylation of the
2-substituted naphthalene substrates E (X=Me, OMe) by
Hudlicky et al., however, suggested that this enzyme could
also produce the two other cis-dihydrodiol regioisomers of
types G and H (Table 1).
and the enhanced basis set 6-311++GACTHNUTRGNEUNG(D,P). Up to five con-
formers within the 2.0 kcalmolꢀ1 energy window were ob-
tained for each cis-dihydrodiol. These conformers belong to
two families, distinguished by their senses of helicity (M or
P) of the styrene (1,2-dihydronaphthalene) chromophore
(Scheme 2). Calculated styrene skew angles g (C2-C1-C9-
C10) of the cis-dihydrodiol metabolites (see the Supporting
Information) are all within the narrow ranges of 10.3 to
12.58 (for P) and ꢀ10.6 to ꢀ12.88 (for M).
With whole cells of P. putida UV4 (expressing TDO), bio-
transformations of naphthalene and six substituted naphtha-
lenes (E, X=H, Br, F, OMe, CN, Me, I) yielded a total of
nineteen cis-dihydrodiols of i) type F [1a (X=Br), 1b (X=
F), 1c (X=OMe), 1e (X=Me), 2d (X=CN), 1 f (X=H)
and 1g (X=I)], ii) type G [2a (X=Br), 2b (X=F), 2c (X=
OMe), 2d (X=CN), 2e (X=Me) and 2g (X=I)], and iii)
type H [3a (X=Br), 3b (X=F), 3c (X=OMe), 3d (X=
CN), 3e (X=Me), 3g (X=I)]. The majority of these cis-di-
hydrodiols had not previously been reported as metabolites.
Mixtures of the cis-dihydrodiol regioisomers were gener-
ally separated by preparative TLC. While individual samples
of compounds 1e, 2d, 3d and 3e were obtained after chro-
matography and recrystallisation, unfortunately the corre-
sponding cis-dihydrodiol isomers 1d and 2e could not be
isolated as pure compounds by these methods. A single-step
chemical substitution of the iodine atom in compound 1g
with a CN group, however, did yield a pure sample of cis-di-
hydrodiol 1d. While it was possible to estimate the relative
proportion of metabolite 2e from its NMR spectrum, nei-
ther OR nor experimental ECD data were recorded (for an-
alytical data for cis-dihydrodiols see the Supporting Infor-
mation).
Scheme 2. M and P enantiomers of the styrene chromophore in 1,2-dihy-
dronaphthalenes.
The presence of the 3,4-cis-OH systems in the cis-dihydro-
diols facilitates the preferred conformations resulting from
their rotation and hydrogen bonding. A detailed list of the
types of thermally accessible conformers for each cis-dihy-
drodiol is given in Scheme 3.
As previously noted for cis-cyclohexa-3,5-diene-1,2-
diols[32–35] all conformers feature structures stabilized by in-
tramolecular OH···O hydrogen bonds. In the M1 and P1
conformers, torsion angles a (H-C3-O-H) and b (H-C4-O-
H) are anti, whereas in the case of the M2 and P2 conform-
ers one of these torsion angles is anti and the other is syn
(Scheme 3a). Calculated values of angles a and b (see the
Supporting Information) are within the ranges of ꢁ(153 to
1658) for anti and ꢁ(50 to 918) for syn. These angles are
positive for M1 and M2 conformers and negative for P1 and
P2 conformers.
The presence of a heteroatom substituent (Br, F) or a
group bearing a heteroatom (OMe, CN) in a position vicinal
to a hydroxy group in each of 3a–d introduces an additional
The regiochemistries and absolute stereochemistries of
seven of the nineteen cis-dihydrodiol metabolites (1a, 1c,
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Naphthalene cis-Dihydrodiols
FULL PAPER
Scheme 3. Diastereomeric P and M conformers of cis-dihydrodiols: a) 1, 2; b) 1c; c) 2c; d) 3.
possibility for conformer stabilisation through an OH···he-
teroatom hydrogen bond. In each of these conformers (P3)
the pseudoaxial hydroxy group at C4 is a donor for the hy-
droxy group at C3, and this in turn is a hydrogen bond
donor to a heteroatom at C2 (Scheme 3d). In P3 conformers
both torsion angles a and b are (+)-syn.
The presence of a methoxy substituent at C2 in dihydro-
diol derivatives 1c and 2c makes the number of accessible
conformers even larger, due to rotation of this substituent
which the equatorial hydroxy group at C4 donates a hydro-
gen bond to the axial oxygen atom at C3 and the hydrogen
atom of this hydroxy group engages in the formation of a
OH···p hydrogen bond. The population of P1+P1’ conform-
ers is at least 60% (DE calculation), except in the case of
2c, for which approximately equal populations of M1+M1’
and P1+P1’ conformers were calculated. An equatorial O-
H···axial OH···p hydrogen bond pattern is apparently a sta-
bilising factor in all conformers of M1, M2, P1 and P2 type.
In the cases of dihydrodiols 3a–e, the more stable con-
formers are of M helicity, evidently reflecting stronger C3
axial OH···p bonding with the C2-substituted double bond
(M1) or the effect of stabilising dipole–dipole interaction
ꢀ
around the C2 O bond. The methyl group can be syn to
either of the hydrogen atoms at vicinal carbon atoms of the
aromatic ring (M1, M1’, P1, P1’ in Scheme 3b and c). The
effect of the vicinal hydroxy group in 3c (and to some
extent in 1c, conformer M2’) forces the methoxy group
away from the hydrogen of the hydroxy group and reduces
the number of possible conformers due to rotation of the
methoxy group.
ꢀ
ꢀ
between the vicinal O H and C X bonds (M2). Clear-cut
evidence for the effect of the nature of the C2 substituent
on the stability of M conformers is provided in dihydrodiols
3d and 3e. Whereas the M2 conformer is the most stable
for the cyano-substituted dihydrodiol 3d, it is the least
stable in the case of the methyl-substituted dihydrodiol 3e
(Scheme 3 and Table 2). This situation is reminiscent of the
conformational preferences of cis-dihydrodiol metabolites of
The calculated populations of the conformers are given in
Table 2.
In the cases of dihydrodiols 1a–f and 2a–e, the lowest-
energy conformer in each case is of the P1 (or P1’) type, in
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J. Gawronski, D. R. Boyd, N. D. Sharma et al.
Table 2. Calculated B3LYP/6-311++GACTHNUGRTNEUNG(D,P) relative energies (DE, DG)
and populations for low-energy conformers of 1a–f, 2a–e and 3a–e
(values in italics indicate the lowest energy conformation).
type B (Scheme 1), for which the M2 conformer is of the
lowest energy when X is a heteroatom substituent.[32]
Diol Conformer DE
[kcalmolꢀ1
Population
[%]
DG
Population
[%]
Absolute configurations of cis-dihydrodiols from studies of
circular dichroism and optical rotation: Dihydrodiols 1a–f,
2a–e and 3a–e each contain the styrene chromophore em-
bedded in the 1,2-dihydronaphthalene framework. Such a
structural feature is frequently encountered in other classes
of natural[36] and synthetic[37] compounds. The characteristic
electronic p–p* transition involving the orbitals of both the
benzene and the ethylene part of the styrene chromophore
is located in the electronic spectra at ca. 260-270 nm; for
1,2-dihydronaphthalene in hexane solution this transition
appears at 258 nm (e=9070).[38] Almost forty years ago,
Crabbꢂ postulated an empirical helicity rule for the styrene
chromophore, which correlates the sign of the 260–270 nm
transition Cotton effect with the helicity: that is, the sign of
the torsion angle g (Scheme 2). According to this rule, an M
helical styrene chromophore (g<0) is characterized by a
positive Cotton effect, and conversely, a negative Cotton
effect is associated with P helicity (g>0) of the styrene
chromophore.[39] However, only a limited number of styrene
chromophore-containing compounds were used in these em-
pirical correlations, so the general applicability of the rule
remains unknown. In this study we used the calculated
structures of low-energy conformers of cis-dihydrodiols
(Table 2) to calculate their CD spectra by the TDDFT
]
[kcalmolꢀ1
]
1a
M1
M2
P1
0.94
16
4
80
13
–
83
4
6
0.62
1.15
0.00
0.93
1.51
0.00
0.76
0.92
0.94
1.43
0.00
0.30
1.99
2.30
0.00
2.15
0.84
0.00
0.33
0.83
0.00
0.43
0.83
0.00
0.25
0.64
0.00
1.01
0.15
0.00
0.42
0.13
0.97
1.39
0.00
0.79
1.42
0.32
0.00
0.01
0.00
1.04
1.11
0.00
0.16
0.99
1.23
0.00
0.21
1.49
0.30
0.27
0.00
1.11
1.37
0.94
0.00
1.64
0.32
0.75
27
10
63
13
5
65
17
10
9
1.70
0.00
1.19
2.06
0.00
1.57
1.32
1.34
2.22
0.00
0.40
0.90
1.42
0.00
1.31
0.66
0.00
0.60
1.51
0.00
0.70
1.55
0.00
0.47
1.34
0.00
1.62
0.26
0.12
0.25
0.00
1.22
1.95
0.00
1.29
0.41
1.32
0.00
0.00
0.26
1.22
1.32
0.00
0.48
1.17
1.42
0.00
0.43
1.68
0.34
0.01
0.00
1.08
1.59
1.01
0.00
2.26
0.54
1.54
1b
M1
M2
P1
P2
1c
1d
M1
M1’
M2’
P1
P1’
M1
M2
P1
P2
M1
P1
M1
M2
P1
M1
M2
P1
6
–
4
59
29
15
7
71
7
24
76
25
5
70
22
5
73
28
6
62
4
21
26
21
32
10
2
48
29
3
–
97
–
1e
1 f
19
81
31
14
55
28
14
58
30
16
46
8
25
33
16
26
12
6
65
17
5
35
60
43
43
7
2a
2b
M1
M2
P1
P2
method at the B2PLYP/6-311++GACTHUNTGRNEUNG(2D,2P) level. The com-
2c
2d
M1
M1’
P1
P1’
M1
M2
P1
puted energies (lmax), oscillator strengths (f) and rotatory
strengths (R) for the styrene long-wavelength p–p* transi-
tion are collected in Table 3.
The effect of a substituent X on the calculated lmax value
of the 260–270 nm transition is distinctive. Relative to the
unsubstituted dihydrodiol 1 f, significant red shifts of lmax
are observed for cyano-substituted dihydrodiols 1d, 2d and
3d. In the case of 3d, with the cyano group attached to the
ethylene group, this shift exceeds 20 nm. Substituent effects
are also seen in the increase in oscillator strength of the
transition.
In the cases of 1d and 3d there are twofold increases in f
relative to the corresponding value for 1 f, but for 2d a two-
fold decrease in f is calculated. These changes can be ac-
counted for by a change in the conjugation pattern of the p
electron system in the isomers of the cyano-substituted cis-
dihydrodiols. The corresponding experimentally determined
values e (lmax) available for cis-dihydrodiols (in acetonitrile
solution) are as follows: e= 8500 (268 nm) for unsubstituted
1 f, e=1600 for cyano-substituted 2d (293 nm), and e=
18200 (290 nm) for 3d. A similar red shift (over 20 nm), to-
gether with either a decrease in e (for 2d) or an increase in
e (for 3d) due to the CN substituent is therefore observed
experimentally, providing a good check of the reliability of
the method of calculation used in this study. A further test
of the quality of the calculations is presented in Figure 1.
Excellent agreement between the experimentally mea-
sured and calculated UV spectra of the bromine- and fluo-
rine-substituted dihydrodiols 1a/2a/3a and 1b/2b/3b was
79
9
31
6
63
54
34
7
P2
2e
3a
M1
M2
P1
M1
M2
P1
P3
5
7
3b
3c
3d
M1
M2
P1
60
26
8
48
37
9
P3
6
6
M1
M2
P1
48
23
2
27
42
42
6
3
7
68
0
27
5
42
29
4
25
30
48
7
P3
M1
M2
P1
P2
P3
M1
M2
P1
5
10
52
3
31
14
3e
P2
11504
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ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 11500 – 11511

Naphthalene cis-Dihydrodiols
FULL PAPER
Table 3. Calculated [B2PLYP/6-311++GACTHNUGTRNEUNG(2D,2P) level] excitation ener-
obtained, including a red shift of the long-wavelength lmax of
the bromine-substituted dihydrodiol 3a in relation to its iso-
mers 1a and 2a and a small effect of the fluorine substituent
on the absorption spectra of 1b, 2b and 3b.
gies (lmax), oscillator strengths (f) and rotatory strengths (R) for the
lowest-energy electronic transitions for low-energy conformers of 1a–f,
2a–e and 3a–e.
Diol
Conformer
lmax [nm]
f
R [10ꢀ40 ergesucmGaussꢀ1
]
The calculated rotatory strengths (R) of individual con-
formers of cis-dihydrodiols (Table 3) in general correlate
well with the sense of helicity of the styrene chromophore,
except for the cases in which the calculated rotatory
strengths are low. Thus, a negative (positive) rotatory
strength is associated with M (P) helicity of the styrene
chromophore, which is in contradiction to the empirical rule
postulated by Crabbꢂ. Exceptions include the M2 conform-
ers of the bromo-substituted dihydrodiols 1a or 3d, the M1
and M2 conformers of the cyano-substituted dihydrodiol 1d
and the P1 and P2 conformers of compound 3d (2d be-
haved unexceptionally). Note, however, that the cyano sub-
stituent is a special case. Previously we have shown[32] that
the signs of the long-wavelength p–p* Cotton effects of cy-
clohexa-1,3-dienes change upon introduction of a cyano sub-
stituent into the diene p electron system.
Calculated Boltzmann-averaged and experimentally mea-
sured CD spectra of cis-dihydrodiols are shown in Figure 2.
In general, good (although not perfect) agreement between
the experimentally measured spectra and those calculated
for the assumed absolute configurations shown in Scheme 1
is observed not only for the longer-wavelength styrene chro-
mophore transition Cotton effect but also for the shorter-
wavelength CD bands. Contrary to the very good agreement
of calculated and experimentally measured UV spectra
(Figure 1), less perfect fits of the corresponding CD spectra
can be expected, as the experimentally measured CD spec-
tra are highly dependent on conformational equilibrium and
the environment (solvent effects).
1a
M1
M2
P1
M1
M2
P1
267
269
266
263
264
259
262
276
270
270
274
268
273
276
271
273
264
263
260
262
259
261
263
262
258
260
261
264
267
259
275
269
271
274
263
264
259
261
263
270
269
270
266
259
259
262
260
265
264
271
264
283
285
279
281
280
261
263
264
267
0.244
0.250
0.313
0.116
0.117
0.182
0.204
0.150
0.161
0.157
0.222
0.281
0.372
0.375
0.373
0.378
0.192
0.258
0.171
0.175
0.199
0.138
0.146
0.128
0.196
0.202
0.173
0.184
0.138
0.112
0.120
0.086
0.074
0.080
0.099
0.113
0.159
0.166
0.161
0.314
0.322
0.304
0.325
0.167
0.176
0.134
0.113
0.223
0.229
0.176
0.199
0.389
0.399
0.409
0.405
0.442
0.245
0.252
0.208
0.220
ꢀ0.830
1.151
7.312
ꢀ15.506
ꢀ17.285
31.505
1b
1c
P2
31.231
M1
M1’
M2’
P1
P1’
M1
M2
P1
P2
M1
P1
M1
M2
P1
M1
M2
P1
ꢀ7.364
ꢀ0.176
ꢀ0.855
40.680
14.762
5.010
9.306
2.488
3.170
1d
1e
1 f
ꢀ1.479
19.519
ꢀ15.426
ꢀ15.896
27.172
ꢀ21.695
ꢀ21.091
20.891
ꢀ16.570
ꢀ15.985
15.203
2a
2b
M1
M2
P1
P2
17.896
2c
2d
M1
M1’
P1
P1’
M1
M2
P1
ꢀ19.104
ꢀ17.447
14.270
11.434
ꢀ18.251
ꢀ20.378
44.058
As no pure sample of metabolite 2e was isolated, no ex-
perimentally measured CD spectrum was available for com-
parison with the calculated CD spectrum.
P2
43.597
2e
3a
M1
M2
P1
M1
M2
P1
ꢀ20.249
ꢀ20.345
19.031
ꢀ12.965
ꢀ17.756
19.722
We also note that the shapes of the experimentally mea-
sured CD spectra of the iodine-substituted dihydrodiols 1g,
2g and 3g (see the Supporting Information) are similar to
those of the bromine-substituted analogues 1a, 2a and 3a
(except for the long-wavelength part of the spectrum of 1g).
This establishes the absolute configurations of the iodine-
substituted dihydrodiols 1g (7S,8R), 2g (5R,6S) and 3g
(3R,4S). Chemical substitution of the iodine atom in com-
pound 1g {Bu3SnCN, [PdACHTNUGTRENUNG(PPh3)4], Et3N in THF} to yield a
pure sample of cis-dihydrodiol 1d provides further confir-
mation of the (7S,8R) configuration.
Further strong evidence of the assigned absolute configu-
rations for dihydrodiols 1a–f, 2a–e and 3a–e was obtained
from the calculation of their optical rotations. The calcula-
tions were carried out for each low-energy conformer and
for the Boltzmann-averaged (DE) mixtures of conformers at
P3
10.940
3b
3c
3d
M1
M2
P1
ꢀ37.052
ꢀ38.441
23.507
P3
11.266
M1
M2
P1
ꢀ23.830
ꢀ30.961
21.981
P3
10.898
M1
M2
P1
P2
P3
M1
M2
P1
ꢀ0.068
0.865
ꢀ4.254
ꢀ2.819
ꢀ12.409
ꢀ25.858
ꢀ27.502
31.970
3e
the B3LYP/6-311++GACTHNUGRTENUNG(2D,2P) level. In order to achieve
P2
27.959
high reliability in the calculations we computed the optical
rotation values at four different wavelengths (589, 578, 546,
436 nm) and compared the averaged data with the experi-
mental measurements in methanol (Table 4).
Chem. Eur. J. 2008, 14, 11500 – 11511
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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11505

J. Gawronski, D. R. Boyd, N. D. Sharma et al.
formers (P or M) of dihydrodiol
molecules 1 and 2, while an M
helical arrangement is found in
ꢀ
3. Whereas an axial allylic C O
bond contributes more strongly
to optical rotation than an
equatorial one, their contribu-
tions are of the same sign and
are due to a series of electronic
transitions occurring at shorter
wavelengths (below 250 nm, see
the Supporting Information) of
the naphthalene cis-dihydrodiol
molecules. On the other hand, a
long-wavelength
(above
250 nm) Cotton effect in the
CD spectra is due to a single
electronic transition that does
not involve orbitals of the
oxygen atom and therefore is
sensitive to non-planarity of the
styrene chromophore. We con-
clude that comparison of the
measured and calculated optical
Figure 1. Experimentally measured (in acetonitrile solution, left-hand panels) and Boltzmann-averaged calcu-
lated [B2PLYP/6-311++G(2D,2P) level, right-hand panels] UV spectra of cis-diols 1a, 2a, 3a, 1b, 2b and 3b.
All calculated spectra were wavelength-corrected to match experimentally measured long-wavelength lmax
AHCTUNGTRENNUNG
values.
In general, the calculated and experimentally measured
[a]l values are large, which makes the comparison highly re-
liable. We observe excellent agreement between the experi-
mentally measured and the calculated optical rotation data.
Therefore, in combination with the CD data discussed
above, the absolute configurations of the cis-dihydrodiols
are assigned unequivocally. As noted previously, no experi-
mental data are available for metabolite 2e.
A more detailed analysis of the calculated OR for individ-
ual conformers of cis-dihydrodiols (Table 4) reveals that,
unlike in the case of the CD spectra, the sign of optical rota-
tion does not correlate directly with the helicity of the sty-
rene chromophore. In the series 1a–f and 2a–e, M1 and M2
conformers display [a]D values of the same sign (positive) as
the P1 and P2 conformers. On the other hand, P conformers
of 3b and 3d have negative OR values. In the cases of the
M2 conformers of dihydrodiols 1b, 1 f, 2b, 2d and 2e and of
the P1 conformers of 3b and 3c, the calculated [a] values
are low and the optical rotation changes sign as the wave-
length changes. A striking finding is that the sign of OR can
be directly correlated with the helicity of the allylic bond
rotations is the most reliable and direct method for the as-
signment of absolute configurations of these naphthalene
cis-dihydrodiols.
Conclusions
We have developed a computational model to predict the
absolute configurations and conformations of (2-substituted)
naphthalene cis-dihydrodiol metabolites containing the sty-
rene chromophore. Contrary to predictions based on the
previous inverse empirical correlation (Crabbꢂ) between the
sign of the styrene torsion angle and the sign of its long-
wavelength Cotton effect, the present study shows that this
relationship is simple and direct: that is, a positive long-
wavelength Cotton effect is associated with a positive sign
for the styrene torsion angle. The absolute configuration at
the allylic carbon atom of a naphthalene cis-dihydrodiol can
be unequivocally deduced from the sign of the OR at the d
line (589 nm). Thus, positive ORs are associated with 7S
configurations in cis-dihydrodiols 1 and 6S configurations in
cis-dihydrodiols 2, whereas negative ORs of cis-dihydrodiols
3 are due to absolute configurations at C3 as shown in
Scheme 1 (R/S descriptors depending here on the nature of
the substituent at C2). We note that the success of the ECD
calculations is due to application of the B2PLYP functional
of Schwabe and Grimme. The absolute configurations ob-
tained were all as anticipated for cis-dihydrodiols of types F
and G: that is, benzylic R. Earlier work by Hudlicky et al.[15]
had indicated that the cis-dihydrodiol (3c) had a benzylic S
configuration, whereas no unequivocal stereochemical as-
signment was provided for compound 3e.[16] These CD stud-
ies of compounds 3a–e, have shown unequivocally that all
ꢀ
ꢀ
system, consisting of C5=C6 C7 O in 1a–f (P helicity), C8=
ꢀ
ꢀ
ꢀ
ꢀ
C7 C6 O in 2a–e (P helicity) and C1=C2 C3 O in 3a–e
(M helicity). Positive optical rotations at the d line (589 nm)
are calculated for all (M or P) styrene conformers in the
first two dihydrodiol series (1, 2), and negative [a]D values
(or weakly positive values) were obtained for the conform-
ers of the last series (3). The helicity of the allylic bond
system can be directly used for the assignment of absolute
configuration at the allylic position: that is, 7S in 1, 6S in 2,
3S in 3a–c and 3R in 3d and 3e. This can be explained in a
ꢀ
simple way. Both the equatorial and the axial allylic C O
bonds form a P helical system with the C=C bond in all con-
11506
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ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 11500 – 11511

Naphthalene cis-Dihydrodiols
FULL PAPER
Figure 2. Experimentally measured (in acetonitrile solution, solid lines) and Boltzmann-averaged calculated [B2PLYP/6-311++GACTHNUTRGNE(NUG 2D,2P) level, dashed
lines] CD spectra of cis-diols 1a–f, 2a–e and 3a–e. Rotatory strengths (R) were calculated in dipole-velocity representation. All calculated spectra were
wavelength-corrected to match experimentally determined long-wavelength UV lmax values. No experimental data are available for 2e.
metabolites of type H (including compound 3e) resulting
from TDO-catalyzed cis-dihydroxylation of the correspond-
ing 2-substituted naphthalenes E have benzylic S configura-
tions.
From these CD studies it is now possible to extend the
validity of an earlier predictive model[32–34] for the preferred
regio- and stereochemistry of TDO-catalyzed cis-dihydroxy-
lation of monosubstituted (A!B) and ortho-disubstituted
benzene substrates (E’!F’) to the bicyclic arene series. cis-
Dihydrodiols of type F and G thus have the same benzylic R
configurations as those of type F’, while those of type H
have the same benzylic S configurations as found at C-1 in
cis-dihydrodiols of type B. The cis-dihydroxylation of the
substituted ring in the bicyclic arenes of type E can also be
Chem. Eur. J. 2008, 14, 11500 – 11511
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11507

J. Gawronski, D. R. Boyd, N. D. Sharma et al.
Table 4. Specific optical rotations—both calculated at the B3LYP/6-311++GACHTNUGTRENNUNG
Diol
Conformer
589 nm
578 nm
546 nm
436 nm
589 nm
578 nm
546 nm
436 nm
1a
M1
M2
P1
+174
+93
+197
+189
+134
+10
+233
+110
+261
+250
+163
ꢀ24
+271
+125
+302
+290
+185
ꢀ35
+521
+216
+575
+552
+312
ꢀ149
+848
+1083
+809
+472
+711
+323
+611
+1229
+973
+787
+424
+678
+890
+714
+603
+903
+831
+355
ꢀ165
+998
+779
+362
+13
DE Boltzmann-averaged
1b
+240
+245
+284
+534
M1
M2
P1
+242
+315
+237
+178
+221
+119
+189
+319
+267
+239
+138
+238
+310
+215
+205
+276
+259
+149
+7
+290
+241
+141
+50
+134
+131
+136
+14
+234
+295
+196
+148
+173
+167
+254
+192
+168
+36
+192
+251
+192
+170
+39
+349
+449
+337
+227
+307
+151
+261
+476
+389
+334
+184
+312
+406
+302
+274
+385
+358
+182
ꢀ31
+410
+526
+395
+261
+358
+174
+305
+562
+457
+390
+214
+361
+469
+353
+318
+449
+417
+207
ꢀ42
P2
DE Boltzmann-averaged
1c
+236
+276
+240
+290
+279
+336
+539
+656
M1
M1’
M2’
P1
P1’
DE Boltzmann-averaged
1d
M1
M2
P1
P2
DE Boltzmann-averaged
1e
+216
+236
+228
+243
+263
+281
+496
+533
M1
P1
DE Boltzmann-averaged
1 f
M1
M2
P1
+416
+335
+178
+39
+203
+189
+167
-16
+334
+422
+270
+177
+216
+270
+374
+270
+208
+3
+296
+375
+288
+211
+14
+488
+391
+205
+40
+240
+222
+191
-25
+392
+495
+315
+201
+248
+322
+440
+315
+237
-5
+351
+442
+341
+241
+10
DE Boltzmann-averaged
2a
+235
+141
+247
+143
+287
+159
+540
+289
M1
M2
P1
+519
+459
+329
-121
DE Boltzmann-averaged
2b
M1
M2
P1
+798
+1015
+620
+324
+428
+735
+930
+631
+400
-124
+773
+952
+734
+417
-65
P2
DE Boltzmann-averaged
2c
+202
+190
+197
+213
+202
+205
+247
+234
+240
+469
+447
+488
M1
M1’
P1
P1’
DE Boltzmann-averaged
2d
M1
M2
P1
P2
DE Boltzmann-averaged
2e
M1
M2
P1
+225
+197
ꢀ126
ꢀ218
+9
+330
+274
ꢀ184
ꢀ309
+25
+388
+288
ꢀ216
ꢀ361
+33
+813
+638
ꢀ440
ꢀ727
+112
+53
DE Boltzmann-averaged
3a
M1
M2
P1
P3
+3
+12
+16
DE Boltzmann-averaged
ꢀ141
ꢀ256
ꢀ342
ꢀ37
ꢀ202
ꢀ379
ꢀ494
ꢀ15
ꢀ236
ꢀ447
ꢀ580
ꢀ11
ꢀ474
ꢀ941
ꢀ1196
+59
ꢀ156
ꢀ188
ꢀ183
ꢀ171
ꢀ191
ꢀ190
ꢀ198
ꢀ221
ꢀ217
ꢀ384
ꢀ428
ꢀ421
3b
M1
M2
P1
P3
ꢀ49
ꢀ43
ꢀ46
ꢀ40
DE Boltzmann-averaged
ꢀ248
ꢀ179
ꢀ309
ꢀ15
ꢀ360
ꢀ257
ꢀ438
+7
ꢀ423
ꢀ302
ꢀ513
+14
ꢀ872
ꢀ627
ꢀ1049
+111
ꢀ57
3c
M1
M2
P1
P3
ꢀ42
ꢀ44
ꢀ48
DE Boltzmann-averaged
ꢀ169
ꢀ236
ꢀ276
ꢀ555
11508
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ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 11500 – 11511

Naphthalene cis-Dihydrodiols
FULL PAPER
Table 4. (Continued)
Diol
Conformer
Calculated optical rotations
Measured optical rotations[a]
589 nm
578 nm
546 nm
436 nm
589 nm
578 nm
546 nm
436 nm
3d
M1
M2
P1
P2
P3
ꢀ81
ꢀ143
ꢀ134
ꢀ25
ꢀ93
ꢀ174
ꢀ212
ꢀ44
ꢀ104
ꢀ198
ꢀ252
ꢀ53
ꢀ146
ꢀ329
ꢀ557
ꢀ125
ꢀ661
ꢀ283
ꢀ800
ꢀ1052
+207
+530
ꢀ462
ꢀ158
ꢀ114
ꢀ223
ꢀ308
+5
ꢀ249
ꢀ144
ꢀ327
ꢀ439
+44
ꢀ296
ꢀ164
ꢀ384
ꢀ515
+58
DE Boltzmann-averaged
3e
ꢀ115
ꢀ192
ꢀ124
ꢀ196
ꢀ144
ꢀ227
ꢀ280
ꢀ443
M1
M2
P1
P2
+91
ꢀ146
+175
ꢀ202
+212
ꢀ235
DE Boltzmann-averaged
[a] in MeOH.
drodiol isomers is shown in Table 1 and the relative Rf values are shown
in Table A in the Supporting Information. While pure samples of cis-di-
hydrodiols 1d and 2e could not be obtained by chromatographic separa-
tion of relevant isomeric mixtures, cis-dihydrodiol 1d was synthesized by
substitution of the iodine atom in cis-dihydrodiol 1g. By a slight modifi-
cation—through the addition of triethylamine—in the procedure used
considered equivalent to that of trisubstituted monocylic
arenes E’’, so the validity of the predictive model can be fur-
ther extended (Scheme 4).
earlier[33] for the monocyclic cis-dihydrodiol series [Bu3SnCN, Pd
ACHTUNGTRENNUNG(PPh3)4
in THF], cis-dihydrodiol 1d was formed from cis-dihydrodiol 1g in 76%
yield.
The formation of the corresponding diastereoisomeric boronate esters
from (R)- and (S)-2-(1-methoxyethyl)benzeneboronic acid followed by
1H NMR analysis of the diastereoisomeric composition[32–35] indicated
that in all cases the ee values were >98%.
Computational details: All excited-state calculations in our computations
were performed on the basis of the ground-state geometries of single
molecules, with the use of a Gaussian program package.[40] Rotatory
strengths were calculated with the use of both length and velocity repre-
sentations. In this study, the differences between the lengths and veloci-
ties of calculated values of rotatory strengths were quite small, and for
this reason only length representations were taken into account. The CD
spectra were simulated by overlapping Gaussian functions for each tran-
sition by the procedure described by Diedrich and Grimme.[26]
Scheme 4. Preferred TDO-catalyzed cis-dihydroxylation products (B, F’’,
F’’) obtained from monosubstituted benzene (A) and naphthalene (E’
and E’’) substrates.
Our computational analyses were performed by a classical methodology.
This includes as the first step the conformational analysis for the cis-dihy-
drodiol, then the geometry optimisation of each low-energy conformer,
calculation of the rotatory strength and optical rotation for individual
stable conformers and, as the last step, comparison between the Boltz-
mann-averaged calculated CD spectra and optical rotation with the ex-
perimental data.
Experimental Section
General information: 1H NMR and 13C NMR spectra were recorded at
300 MHz (Bruker Avance DPX-500) and at 500 MHz (Bruker Avan-
ce DRX-500) in CDCl3 unless stated otherwise. Chemical shifts (d) are
reported in ppm relative to SiMe4, and coupling constants (J) are given
in Hz. CD and UV spectra were measured on JASCO 720 or 810 spectro-
polarimeters. Mass spectra were recorded at 70 eV on a VG Autospec
Conformational analyses and geometry calculations were performed at
the B3LYP/6-311++GACTHNUTRGNE(NUG D,P) level. The fully optimized P and M conform-
ers of 1 f, in which selected hydrogen atoms were replaced by the corre-
sponding substituents, were taken as starting points for conformational
analyses. In some cases geometry calculations were performed at the
B2PLYP/6-311++GACTHUNTGRNEUNG(D,P) level, but because of the similarity between re-
mass spectrometer with
a heated inlet system. Accurate molecular
sults obtained with the use of B2PLYP and B3LYP hybrids, only the
latter were taken into consideration (see the Supporting Information).
For optimized structures, frequency calculations were carried out at the
weights were determined by the peak matching method with perfluoro-
kerosene as standard. FT-IR spectra were taken as KBr pellets on a
Perkin–Elmer spectrometer. Chiral stationary phase HPLC was carried
out with a Shimadzu LC-6A liquid chromatograph connected to a Hew-
lett Packard diode array detector. The 2-substituted naphthalene sub-
strates were obtained commercially except for 2-iodonaphthalene, which
was synthesized by a literature procedure.
B3LYP/6-311++GACTHUNTGRNEUNG(D,P) level of theory to confirm that the conformers
were stable. For all conformers with relative energies ranging from 0.0 to
2.0 kcalmolꢀ1, percentage populations were calculated for each com-
pound on the basis of the DE and DG values, with use of Boltzmann sta-
tistics and T=298 K. Because of their similarity, only DE values were
taken into further consideration.
Shake flask biotransformations (1–8 g) were carried out with Pseudomo-
nas putida UV4 under the reported conditions.[13,33,41] The mixtures of cis-
dihydrodiol isomers (1a–g, 2a–f, 2g, 3a–e, g) formed from biotransfor-
mation of each of the 2-substituted naphthalene substrates were separat-
ed by flash chromatography on silica gel with elution either with hexane
and an increasing proportion of EtOAc or by multi-elution PLC with
To test which combination of functional/basis set performs best in the
case of calculations of the CD spectra of substituted naphthalene cis-di-
hydrodiols, the B2PLYP hybrid functionals were employed in combina-
tion with different basis sets (see the Supporting Information). The basis
sets differ from relatively small to enhanced, with or without the diffuse
hexane/ethyl acetate (80:20)!
G
functions. The best combination was B2PLYP/6-311++GACTHNGUTRENNU(G 2D,2P), and
Chem. Eur. J. 2008, 14, 11500 – 11511
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J. Gawronski, D. R. Boyd, N. D. Sharma et al.
this was used for calculating the CD spectra. Additionally, the CD spec-
tra were calculated with the use of B3LYP and mPW1PW91 hybrid func-
tionals and 6-311++GACHTUNGTRENNUNG(2D,2P) basis set and with the use of the B2PLYP/
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Acknowledgements
This work was supported by grant No. N N204056335 from the Ministry
of Science and Higher Education (Poland), an EU Marie Curie Host Fel-
lowship for Transfer of Knowledge, Novocat, Project No.29846 (to M.K.)
and a Science Foundation Ireland Grant No. 04/IN3/B581 (to N.D.S.). All
´
calculations were performed at Poznan Supercomputing Centre, Poland.
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Received: August 14, 2008
Published online: November 12, 2008
Chem. Eur. J. 2008, 14, 11500 – 11511
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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11511