Asymmetric biomimetic oxidations of phenols: The mechanism of the diastereo- and enantioselective synthesis of thomasidioic acid

Article abstract of DOI:10.3390/molecules13010129

Enantiopure chiral amidic derivatives of sinapic acid were oxidised with hydrogen peroxide using horseradish peroxidase (HRP) as the catalyst to give the aryltetraline dilignol thomasidioic acid. Trans-diastereoselectivity and enantioselectivity in the fo

Full text of DOI:10.3390/molecules13010129

Molecules 2008, 13, 129-148
molecules
ISSN 1420-3049
© 2008 by MDPI
www.mdpi.org/molecules
Full Paper
Asymmetric Biomimetic Oxidations of Phenols: The Mechanism
of the Diastereo- and Enantioselective Synthesis of Thomasidioic
Acid
Luca Zoia, Maurizio Bruschi, Marco Orlandi*, Eeva-Liisa Tolppa and Bruno Rindone
Department of Environmental Sciences, University of Milan, Piazza della Scienza, 1, 20126 Milan,
Italy; E-mails: luca.zoia@unimib.it, maurizio.bruschi@unimib.it; eeva-liisa.tolppa@unimib.it;
bruno.rindone@unimib.it
* Author to whom correspondence should be addressed. E-mail: marco.orlandi@unimib.it; Tel.
(+39)0264482812; Fax (+39)0264482839.
Received: 26 November 2007; in revised form: 21 January 2008 / Accepted: 21 January 2008 /
Published: 23 January 2008
Abstract: Enantiopure chiral amidic derivatives of sinapic acid were oxidised with
hydrogen peroxide using horseradish peroxidase (HRP) as the catalyst to give the
aryltetraline dilignol thomasidioic acid. Trans-diastereoselectivity and enantioselectivity in
the formation of thomasidioic acid was observed. Computational methods show that the
enantioselectivity is controlled by the β-β oxidative coupling step, while the
diastereoselectivity is controlled by the stability of the reactive conformation of the
intermediate quinomethide.
Keywords: Diastereoselection, enantioselection, lignans, horseradish peroxidase, oxidative
phenol coupling, conformational analysis, semiempiric calculations
Introduction
Organic compounds obtained from radical coupling of phenylpropenoidic phenols have an
important biological role. In fact, they constitute organic polymers such as lignin [1], lignans [2],
suberin [3] and algal cell walls [4].

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Molecules 2008, 13
The lignans represent a structurally very diverse class of vascular plant products. They are
typically dimers and their primary physiological role in plants is in plant defense [5]. Some lignans
have found application in medicine, such as podophyllotoxin in venereal wart treatment [6], or its
semisynthetic derivatives etoposide, and teniposide in cancer therapies [7]. Stereoselective total
syntheses of lignans can involve multistep procedures [8]. In particular Charlton’s group has
synthesized important podophyllotoxin analogs with applications in medicine. [9].
A bimolecular phenoxy radical coupling could be an alternative way to perform stereoselective
syntheses of lignans, but, unlike most biological oxidations, the bimolecular phenoxy radical coupling
reaction is not under a strictly regio- and stereospecific control [10]. This is due to the fact that
phenoxy radicals are very persistent and the dimerization reaction is slow. Hence the stereogenic
carbons formed in the oxidative phenol coupling reaction in vitro are racemic [11]. Sarkanenen has
studied the radical phenol coupling since 1973 and he has demonstrated that the β-β coupling of
phenols such as (E)-isoeugenol is remarkably stereospecific and produces exclusively threo-
compounds, whereas the (Z)-isoeugenol gives threo- and erythro-coupling products in equal amounts.
He has proposed that the differences in the probabilities of coupling modes in the oxidations of (E) and
(Z)-isoeugenol must be considered to be due to the characteristics of these intermediate complexes
rather than to the differences in spin densities [12]. A similar enzymatic oxidative coupling of ferulic
acid derivatives was observed by us for the diastereoselective synthesis of benzo[b]phenylcoumarans
[13].
Scheme 1. The formation of (+) pinoresinol by directing protein mediated coupling of
coniferyl alcohol.
H3CO
OH
HO
OH
CH2OH
CH2OH
H
H
O
H
H
Ox
re si
re
si
DP
O
OCH3
OCH3
OCH3
OH
O
H3CO
HO
O
O
OCH3
DP
DP
Coniferyl alchool
DP = directing protein
(+)-pinoresinol
Recently Lewis has proposed a new biosynthetic pathway to enantiopure lignans. A protein
isolated from Forsythia species is suggested to be responsible for the formation of enantiomeric pure
pinoresinol from coniferyl alcohol [14]. In this case, the protein acts as a chiral inducer. The
mechanism of steroselective coupling of coniferyl phenoxy radical mediated by a directing protein

131
Molecules 2008, 13
proposed by Lewis is shown in Scheme 1 [15]. The role of the directing protein is supposed to be at
the level of β-β coupling of phenols. Stereocontrol in enzymatic oxidative coupling of ferulic acid
derivatives to enantioselectively give benzo[b]phenylcoumarans [16] has been recently shown by us
to be possible in the oxidative phenol coupling reaction [17] using a chiral inducer and the horseradish
peroxidase (HRP)-catalyzed oxidative coupling in presence of hydrogen peroxide as the oxidant. The
chiral inducers were aminoacid ethyl esters, camphorsultam and aryloxazolidinones[18].
On these bases we focused our attention to thomasidioic acid (1, Figure 1). This lignan in the trans
configuration was isolated for the first time from Ulmus thomasii in 1969 and shown to be cytotoxic
[19]. Recently this acid has been shown to prevent the peroxynitrite-mediated protein nitration [20].
Figure 1.
OH
OH
(E)
(R)
(E)
H3CO
HO
H3CO
HO
O
O
O
O
(S)
(R)
(S)
OCH3
OH
OCH3
OH
H3CO
OCH3
H3CO
OCH3
OH
OH
1
Several synthetic methods have been developed to prepare racemic trans thomasidioic acid: Stobbe
condensation of 3,4,5-trimethoxybenzaldehyde with dimethylsuccinate [21]; alkaline treatment of
sinapic acid 2 [22], oxidative coupling of sinapic acid 2 [23] or of sinapic acid methyl ester 3d [24]
with ferric chloride in aqueous acetone (Scheme 2). Higher yields were obtained using hydrogen
peroxide as the oxidant and horseradish peroxidase as the catalyst [25].
Scheme 2. Synthesis of amides from sinapic acid.
O
OH
O
R*
He
Hd
(E)
(E)
R*
+
H3CO
O
OCH3
H3CO
OCH3
OH
OH
3(a-d)
2
O
Ha
(S)
Ha
(S)
Hb
Hc
H3bC
C
H3gCH2fCO
R* =
O
C
N
HN
(S)
OCH3
HN
Hb
Hc
Ha
d
a
c
b

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Molecules 2008, 13
These reactions are important in food processing because sinapic acid 2 is a major constituent of
canola oil [26]. This finding stimulated the question whether thomasidioic acid 1 is really a natural
product. Charlton has demonstrated that trans thomasidioic acid can be formed also by air oxidation of
sinapic acid at pH 13. On this basis and on the basis that “natural” trans thomasidioic acid is optically
inactive, he suggested that this acid is not a real natural product of plant metabolism, but it is generated
during the extraction procedure from basic aqueous extracts of Ulmus thomasii [27]. Chiral induction
was obtained in a preliminary study showing that Me (R)-mandelyl sinapate could be dimerized
diastereoselectively to give a 1,2-trans thomasidioate diester [28].
Results and Discussion
Here we report an enantioselective biomimetic approach to synthesize thomasidioic acid (1). In
order to achieve this result we performed a preliminary oxidation of methyl-(E)-sinapate 3d catalyzed
by horseradish peroxidase (HRP, EC 1.11.1.7), using hydrogen peroxide as the reactant. The best
results of oxidative coupling were obtained in a dioxane 30%-buffer pH 4, 70% solution.
Figure 2.
O
O
Hn
Ho
Hn
Ho
(E)
H3CO
HO
H3CO
HO
(E)
R*
R*
R*
R*
Hi
(R)
Hi
(S)
(S)
(R)
Hh
Hh
OCH3
OCH3
O
Hl
O
Hl
H3CO
OCH3
H3CO
OCH3
OH
OH
4
5
The yield of racemic mixture of trans-thomasidioic acid dimethylesters 4d, 5d was 70%. In
agreement with literature data it was no amounts of cis-thomasidioic acid dimethylesther were
observed. The enantioselective oxidative phenol coupling of sinapic acid derivatives 3(a-c) having an
amide bond with (S)-phenylalanine ethyl ester, (S)-methylbenzylamine, (S)-2-phenyloxazolidinone as
chiral auxiliaries was performed using the same oxidation system. These sinapamides with the chiral
auxiliaries were obtained in high yields in a one pot reaction from sinapic acid 2 (Scheme 2). The
mixture of the two trans diastereoisomers 4, 5 (Figure 2) was obtained with the diastereoisomeric
excesses reported in Table 1.

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Molecules 2008, 13
Table 1. The enantioselective oxidative phenol coupling with chiral sinapamides.
Yields in 4 + 5
Yield in
Yield in Diastereoisomeric
Chiral auxiliary R*
(%)
60
peak 1 (%) peak 2 (%)
excess (%)
(S)-phenylalanine ethyl ester
(S)-methylbenzylamine
45
35
34
15
15
6
50
40
70
50
(S)-2-phenyloxazolidinone
40
The diastereoisomeric excess was evaluated by RP-HPLC analysis of the crude reaction mixture.
Separation by preparative RP-HPLC allowed to obtain the individual diastereoisomers which were
characterized by 1H-NMR.
The hydrolysis of the individual trans-thomasidioic acid amides 4 and 5 (Scheme 2) was performed
with LiOOH in tetrahydrofuran (Table 2).
Table 2. The hydrolysis of thomasidioic acid derivatives.
Chiral auxiliary R*
Reactant
Solvent
Time (hours) Yield of 1 (%)
(S)-Phenylalanine ethyl ester
(S)-Methylbenzylamine
LiOOH
LiOOH
LiOOH
THF
THF
THF
5
4
5
20
10
60
(S)-2-Phenyloxazolidinone
In order to account for the origin of the observed enantioselection and diasteroselection in the
formation of thomasidioic acid derivatives 4, 5, the reaction mechanism has been investigated in detail
by quantum-mechanical methods. As shown in Table 1 the chiral auxiliaries (S)-2-phenyl-
oxazolidinone gave considerably higher selectivities (e.e. 70 %) compared to the (S)-phenylalanine
ethyl ester and (S)-methylbenzylamine. Therefore, the compounds having (S)-2-phenyloxazolidinone
as the chiral auxiliary were chosen for the theoretical study.
The proposed reaction pathway involves two steps; the first step is the β-β oxidative coupling of
two quinomethide radicals 6 to give the bisquinomethide 7, and the second step is the ring closure of 7
to give the final product (see Scheme 3). For this mechanism the absolute configuration of
thomasidioic acid should be determined by the absolute configuration of the two stereogenic centers of
the bisquinomethide 7 formed in the β-β oxidative coupling, and by the trans or cis ring closure of the
bisquinomethide 7.
The relative orientation of the two quinomethide radicals 6 in the β-β oxidative coupling
determines the configuration of the stereogenic centres in 7. In fact, coupling at the re-re and si-si face
lead to the formation of R,R- and S, S-bisquinomethide 7, while coupling at the re-si face results in the
corresponding R,S/S,R mesoform. In this context, the preferred absolute configuration of 7 should be
controlled by the different stabilities of the pre-reactive van der Waals complexes of dimers of 6, and
the corresponding transition states along the reaction path to give the bisquinomethide 7.

134
Scheme 3. Radical coupling to form bisquinone methide 7 followed by aromatisation of one ring.
Molecules 2008, 13
O
O
O
(E)
(E)
C2
C3
C2
C3
H3CO
O
H3CO
O
H3CO
HO
R
R
R
R
R
R
(E)
(E)
OCH3
(E)
O
OCH3
OCH3
O
O
(E)
(E)
(E)
H3CO
OCH3
H3CO
OCH3
H3CO
OCH3
O
O
O
7
8
6
It should be noted that the computational study of the β-β oxidative coupling is complicated by the
diradical nature of the molecular system along the reaction path, which can only be modelled
accurately by using the Configuration Interaction approach (CI). For this reason the semiempirical CI-
PM3 level of theory has been adopted to investigate the β-β oxidative coupling of quinomethide
radicals 6. Due to the large size of the molecular system only the frontier orbitals were included in the
active space for the CI vector.
Initially, a conformational analysis of the quinomethide radical 6 has been performed in order to
find the most stable conformations involved in the β-β coupling. In this analysis two energy minimum
conformers has been characterized, one in which the amide bond is trans (6a) and the other one in
which the amide bond is cis (6b). The former is more stable than the latter by about 2 kcal·mol-1.
Therefore, the conformer 6a with trans amide bond was chosen for the study of the β-β oxidative
coupling.
Figure 3 shows the computed profile along the reaction pathway for the β-β coupling at the re-re,
si-si, and re-si faces. In Figure 4 the molecular geometries of the pre-reactive van der Waals
complexes and the corresponding bisquinomethide products in the first conformation after the
formation of the C-C in the radical coupling are also shown. It is interesting to note that the energy
barrier calculated for the si-si coupling is higher by more than 4 kcal·mol-1 than that calculated for the
re-re and re-si coupling. This result suggests that the formation of the R,R (from re-re coupling), and
R,S/S,R (from re-si coupling) bisquinomethide 7 is preferred with respect to the formation of the S,S
(from si-si coupling) bisquinomethide 7.
Sarkanen et al. suggested that the excess of the threo β-β coupling products over the erithreo ones,
observed for some quinomethide derivatives such as syringylresinol and 2-propenylphenol [12] is due
to the different stability of the re-re, si-si and re-si pre-reactive complexes. However, as shown in
Figure 1, the pre-reactive complexes calculated in this work are almost isoenergetic, suggesting that
for the bisquinomethide 7 the stereochemistry is not controlled by the formation of this pre-reactive
complex.
As discussed above, the second step of the reaction mechanism is the ring closure of the
bisquinomethide 7 (see Scheme 2). The cyclization step determines the observed diasteroselection to
the trans isomer. The diasteroselection should be controlled by the relative orientation of the two

135
Molecules 2008, 13
quinomethide rings which should feature a preferred conformation in order to give the “correct” ring
closure, as well as to the energy of the transition state along the reaction path to give the final product.
Figure 3. Reaction profile of the β-β oxidative coupling of two quinometide radicals
Figure 3. Reaction profile of the β-β oxidative coupling of two quinometide radicals 6 at
6 at the re-re (●-●), si-si (■-■), and re-si (♦-♦) faces.
the re-r (● ●), si-si (■-■), and re-si (♦-♦) faces.
-250
-260
-270
-280
-290
-300
2
3
4
5
C2-C3 distance (Å)
Figure 4a. Molecular geometry of the van der Waals pre-reactive complex with the
monomers at the re-re face (a), and the corresponding bisquinomethide product (b).
a
b
It should be noted that the cyclization should occur after the aromatization of one of the rings of
bisquinomethide 7 with loss of one stereogenic center (Scheme 3, compound 8). However, the carbon
backbone of the intermediate 8 is much more rigid than in bisquinomethide 7, possibly preventing

136
Molecules 2008, 13
rearrangements to conformations with the rings in a different orientation. On the basis of this
observation, the diasteroselection to the trans isomer should be controlled by the relative orientation of
the two quinomethide rings in the most stable conformations of bisquinomethide 7. The same
assumption has been used by us to show that the observed trans-diastereoselectivity in the cyclization
of ferulic acid derivatives to dihydrobenzo[b]furans [29] derives from thermodynamic control in the
formation of diastereoisomeric quinomethide intermediates. These considerations prompted us to carry
out a theoretical investigation of the potential energy surface (PES) of the quinomethide intermediate
in the R,R enantiomer and R,S mesoforms.
Figure 4b. Molecular geometry of the van der Waals pre-reactive complex with the
monomers at the si-si face (a), and the corresponding bisquinomethide product (b).
a
b
Figure 4c. Molecular geometry of the van der Waals pre-reactive complex with the
monomers at the re-si face (a), and the corresponding bisquinomethide product (b).
a
b

137
Molecules 2008, 13
Scheme 4. Schematic representation of the θ and φ dihedral angles (on the top). For the
mesoform 2R,3S positive values of the φ angle should lead to the formation of trans-
thomasidioic acid 1, while negative values the φ angle should lead to the formation of cis
isomer (on the bottom).
C1-C2-C3-C4 = θ
C2-C3-C4-R2 = φ
H
MeO
O
C1
C2
COCH3
OMe
θ
H
R1 =
R2 =
O
C3
O
H
COCH3
O
C4
OMe
OMe
φ
OMe
R1
OH
OMe
7 (R, S) φ = 90°
H
O
O
MeO
MeO
HO
COCH3
COCH3
H
H
R1
COCH3
O
O
COCH3
O
H
H
OMe
R2
OMe
7 (R, S) φ = -90°
H
O
O
MeO
MeO
HO
COCH3
COCH3
H
H
H
COCH3
O
COCH3
O
O
R2
R1
OMe
H
OMe
Because of the large number of degrees of freedom in the bisquinomethide 7 with the two chiral
auxiliaries, we preliminarly performed an analysis of the PES for the bisquinomethide in which the
chiral auxiliaries are replaced by -OCH3 groups 7d, and for which, diasteroselection to the trans
isomer is also observed. The PES of the quinomethide 7d has been calculated as a function of the φ
and θ dihedral angles as shown in Scheme 4.
An inspection of the molecular structure of the quinomethide 7 shows that for the R,S mesoform,
conformations with positive dihedral angle φ are expected to lead to the formation of thomasidioic acid
1 in the trans configuration, while conformations with negative dihedral angle φ should lead to the

138
Molecules 2008, 13
formation of compound 1 in the cis configuration. The contrary holds true for the R,R enantiomer, in
which negative and positive values of the dihedral angle φ lead to the formation of trans- and cis-
compound 1, respectively (see Table 3).
In addition, the two carbon atoms involved in the ring closure approach to each other for values of
the θ angle around 0°, while they are at the maximum distance for a value of θ angle equal to about
180°. The PES computed at the semiempirical PM3 level of theory for the quinomethide 7 R,S
mesoform and R,R enantiomer are shown in Figures 5a and 5b, respectively. In Table 3 the values of
the heat of formation corresponding to the local minima identified on the PES are reported.
Table 3. Energy minima on the PES of the quinomethides 7 calculated as a function of
the θ and φ dihedral angles (see Scheme 3) at the semiempirical PM3 level of theory.
Heat of
Thomasidioic acid
Quinomethide 7
θ (Degrees) φ (Degrees)
formation
(kcal·mol-1)
-286.6
(1) (predicted)
R,S
R,S
R,S
R,S
R,S
R,S
R,R
R,R
R,R
R,R
180
60
120
120
120
-60
-90
-90
1R,2S/1S,2R trans
1R,2S/1S,2R trans
1R,2S/1S,2R trans
1R,2R/1S,2S cis
1R,2R/1S,2S cis
1R,2R/1S,2S cis
1R,2S trans
-284.8
-60
180
60
-284.3
-286.1
-279.9
-279.4
-285.3
-286.0
-284.6
-282.1
-60
180
60
-90
-120
-120
30
1R,2R trans
-60
60
1R,2S trans
1R,2R cis
In the case of the R,S mesoform a total of six local minima have been located on the PES; three,
with positive values, and three with negative values of φ. Two almost isoenergetic minima are
characterized by a value of θ of about 180° and values of φ of about 120° (-286.5 kcal·mol-1) and -60°
(-286.1 kcal·mol-1). However, as noted above, in these conformations the two carbon atoms involved
in the ring closure are at their maximum distance. The other local minima are located along the
reaction coordinate corresponding to the rotation of the θ angle from 180° to 0°, for which the two
carbon atoms are close to each other. It is interesting to note that the two minima characterized by a
positive value of φ (θ = 60°, φ = 120° ΔΗ = -284.8; θ = −60°, φ = 120° ΔΗ = -284.3) are lower in
energy by about 5 kcal·mol-1 with respect to those characterized by negative values of
φ (θ = 60°, φ = −90° ΔΗ = -279.9; θ = −60°, φ = −90° ΔΗ = -279.4). This clearly indicates that the
most stable conformation in the region of the PES where the two carbon atoms are close enough to
give rise ring closure predicts for the formation of trans-(1S,2R, or 1R,2S) thomasidioic acid 1.
In the case of the R,R enantiomer only four local minima have been located on the PES; three with
negative values, and one with a positive value of φ. The lowest energy minimum is characterized by a
value of θ of about 60° and a value of φ of about -120° (-286.0 kcal·mol-1). This minimum is located
along the reaction coordinate which leads to the ring closure with the formation of trans-thomasidioic

139
Molecules 2008, 13
acid 1. The only local energy minimum which should lead to the formation of cis-thomasidioic acid (1)
θ = 60°, φ = 30° ΔΗ = -282.1) is about 4 kcal·mol-1 higher in energy. Again, the most stable
conformation in the region of the PES where the two carbon atoms are close enough to give rise to ring
closure predicts for the formation of trans-(1S,2R, or 1R,2S) thomasidioic acid (1).
Figure 5. Potential energy surface as a function of the θ and φ angles of quinomethide 7
with the R,R (a) and R,S (b) absolute configurations.
-1
Energy [kcal mol ]
-260
-270
-280
-290
150
100
50
-150
-100
0
θ angle
-50
-50
-100
-150
0
50
100
φ angle
150
(a)
-1
Energy [kcal mol ]
-260
-270
-280
-290
150
100
50
-150
-100
0
θ angle
-50
-50
-100
-150
0
50
100
φ angle
150
(b)
The same conformational analysis is than performed in order to predict the enantioselectivity in the
formation of trans-thomasidioic acid 1 from quinomethides having a (S)-2-phenyloxazolidinone chiral

140
Molecules 2008, 13
auxiliary group. Table 1 shows the enantioselectivity obtained experimentally. Three diastereoisomers
are possible for this intermediate; a) R,R, SS; b) S,S, SS; c) S,R, SS/R,S, SS (mesoform). As for the case
of the compound free of auxiliary groups, the conformational analysis was performed at the PM3 level
by rotating the θ and φ angles (see Scheme 3). Conformations corresponding to energy minima on the
PES was then fully optimized. For the three isomers the energies of the most stable conformations, and
the corresponding θ and φ angles are reported in Table 4.
The relative stabilities of the different conformations allows to predict the amount of each
quinomethide 7 isomer at the equilibrium. In this respect, we note that all energy minimum
conformations calculated for the 2S,3S, SS isomer are significantly less stable than that calculated for
the R,R, SS and R,S, SS isomers (see Table 4). The low stability observed for the S,S, SS isomer is due
to a larger steric hindrance between the two phenyl groups in the chiral auxiliary group. On the other
hand, the energies of the R,R, SS and R,S, SS isomers are very similar, both for the conformation with
the θ angle near to 180° (in which the two carbon atoms involved in the ring closure are at the
maximum distance), and for the conformation with the θ angle near to 0° (in which the two carbon
atoms involved in the ring closure are at the minimum distance). As discussed for the compounds free
of auxiliary groups, in the case of the R,R, SS isomer conformations with positive dihedral angle φ are
expected to lead to the formation of thomasidioic acid 1 in the cis configuration, while conformations
with negative dihedral angle φ should lead to the formation of compound 1 in the trans configuration
(see Table 4).
Table 4. Energy minima on the PES of the quinomethides 7 calculated as a function of
the θ and φ dihedral angles (see Scheme 3) at the semiempirical PM3 level of theory.
Heat of
Quinomethide
7
Thomasidioic acid (1)
(predicted)
θ
φ
R*
formation
(Degrees) (Degrees)
(kcal·mol-1)
67
50
-117
66
-294.6
-290.1
-286.4
-295.5
-294.1
-287.6
-293.2
-288.2
-291.5
-286.3
-281.9
-276.2
1S, 2R trans
1R, 2R cis
R,R
(S)-2-
(isomer 1)
phenyloxazolidinone
180
-175
47
91
---
-95
73
---
1R, 2S / 1S, 2R trans
-61
-84
-178
-80
-59
161
172
-88
-113
94
1R, 2S / 1S, 2R cis
R,S/S,R
(S)-2-
(mesoform)
phenyloxazolidinone
---
---
-118
128
117
-94
1R, 2S trans
1S, 2S cis
---
S,S
(S)-2-
(isomer 2)
phenyloxazolidinone
---

141
Molecules 2008, 13
Notably, the conformation with a negative value of φ is about 4 kcal·mol-1 more stable than that
with a positive value of φ, indicating that the ring closure to give the trans 1S,2R absolute
configuration thomasidioic acid 1 should be preferred to the ring closure to the cis 1R,2R absolute
configuration. In the case of the R,S mesoform, the ring closure to give the trans configuration is still
significantly preferred with respect to that which give the cis configuration. However, in this case the
reaction of the two non equivalent prochiral carbon atoms present at the quinomethide double bonds
with the two ortho carbons of the phenyl ring can give both the trans 1S,2R and, trans 1R,2S absolute
configurations.
In Table 5 are also reported the stabilities of conformers of the aromatic intermediate 8 for two
different values of the φ angle (see Scheme 3). The conformations have been obtained by the geometry
optimization of stable conformers of bisquinomethide 7 in which the two rings approach to each other.
As discussed above, the conformational analysis of 8 is simpler than that of 7, due to the loss of one
stereogenic centre and to the rigidity of the carbon backbone. For both the R, SS and S, SS isomers the
two conformers are characterized by a negative and positive value of φ, respectively. Interestingly the
trend discussed above for the bisquinomethide 7 is fully confirmed. In fact, for the R, SS isomer, the
conformer with a negative φ angle is more than 10 kcal·mol-1 stable than the conformer with a positive
φ angle, while the opposite is true in the case of the S, SS isomer. The ring closure starting from the
most stable conformations of the R, SS and S, SS isomers leads in both cases to the thomasidioic acid 1
in the trans configuration, with the 1S, 2R and 1R, 2S absolute configuration, respectively.
Table 5. Heat of formation of conformers of the aromatic intermediate 8, obtained for two
different values of φ angle (see Scheme 3), and of the corresponding Thomasidioic acid
amide obtained after the ring closure computed at the semiempirical PM3 level of theory.
Aromatic
φ
(Degrees)
-121
Heat of formation
(kcal·mol-1)
-300.2
Thomasidioic acid Heat of formation
intermediate 8
amide
(kcal·mol-1)
→
R
R
S
1S, 2R trans
1R, 2R cis
1R, 2S trans
1S, 2S cis
-326.6
→
→
→
16
-287.3
-321.2
130
-299.3
-320.8
S
-106
-291.3
-329.4
The results reported above, show that the diasteroselection to the trans thomasidioic acid 1 begin at
the level of bisquinomethide 7 where the conformers that leads to the ‘correct’ ring closure are more
stable with respect to the conformers that leads to the cis isomer. The difference in stability is even
larger after the aromatization of 7 to give the intermediate 8. Finally, it should be noted that trans-
thomasidioic acid amides 4, 5 are more stable than the corresponding cis isomers by about 5 kcal·mol-1
(see Table 5). If the assumption is made that the energy of activation for the ring closure of 8 is
correlated to the stability of the products, we can predict that the energy barrier of the cyclization to
the trans thomasidioic acid is also lower than the energy barrier to the cis isomer. The larger stabilities
of 7 and 8 conformers which can give ring closure to the trans isomer, and the lower energies of the
corresponding transition states along the cyclization pathway clearly explain the total
diasteroselectivity to the trans thomasidioic acid 1.

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Molecules 2008, 13
Conclusions
In summary, our computational investigation of the β-β oxidative coupling of quinomethide radical
6 shows that the R,R, S,S and R,S, S,S isomers of bisquinomethide 7 should be formed in larger
amounts with respect to the S,S, S,S isomer. The former, after aromatization preserves only one R
centre that gives ring closure to the trans 1S,2R absolute configuration, while the latter after
aromatization can preserve both an R or S centre, giving ring closure to both the trans 1S,2R, and
1R,2S absolute configurations. Hence, the still unknown configuration of thomasidioic acid (1) from
the enantioselective synthesis here reported is predicted to be 1S,2R. Work is in progress towards the
determination of the crystal structure of the synthetic material.
Acknowledgments
We thank University of Milan-Bicocca FAR 2006 for the financial support. We thank also our
students: A. Bianchia and F. Gironi.
Experimental
General
All chemicals were from Sigma-Aldrich. IR spectra were recorded with a FT-IR Jasco
spectrophotometer in KBr pellets. Mass spectra were determined by the direct injection system mode
with positive electron impact using a VG 7070 EQ instrument. 1H-NMR spectra were recorded at 300
MHz with a Bruker AMX 300 instrument (in CDCl3 solutions). Chemical shifts are given as ppm from
tetramethylsilane and J values are given in Hz. HPLC analyses were performed using a Waters 600 E
instrument equipped with a HP 1040 Diode Array Detector and a column Agilent XDB-C18 (5 µm,
4.6 x 250 mm) was used. Water-acetonitrile (1:1) was used as a mobile phase. The total flow was 1
mL/min and the injection volume was 20 µL.
Preparation of compound 3a
To a solution of (S)-phenylalanine ethyl ester hydrochloride (1.00 g, 4.35 mmol) in anhydrous
tetrahydrofuran (100 mL), triethylamine (0.6 mL, 4.35 mmol) were added dropwise. After
solubilisation of the salt, sinapic acid 2 (0.97 g, 4.35 mmol) and dicyclohexylcarbodiimide (DCC, 0.90
g, 4.35 mmol) were added under stirring and the mixture was stirred for further 4 h at room
temperature. A few drops of acetic acid were then added, the urea was filtered off and the resulting
solution was evaporated under reduced pressure to give a residue which was dissolved in ethyl acetate
(50 mL), washed with water saturated with NaCl (60 mL) and dried over Na2SO4. The solvent was
evaporated under reduced pressure, and the residue was purified by silica gel flash chromatography
(eluent ethyl acetate-petroleum ether 7:3). Compound 3a was obtained in 50% yield. Anal. calc. for
C22H25NO6 (399.44): C 66.15%, H 6.31%, N 3.51%, O 24.03%; found: C 66.17%, H 6.29%, N 3.49%;
1
MS: 399.4 (M+); H-NMR: δH 1.12 (3 H, t, J=8.0, Hg), 2.95 (1 H, dd, J=15.0-8.0, Hb), 3.20 (1 H, dd,

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Molecules 2008, 13
J=15.0-4.0, Hc), 3.60 (2 H, q, J=8.0, Hf), 3.75 (6 H, s, OCH3), 4.55 (1 H, ddd, J=12.0-8.0-4.0, Ha), 5.62
(1 H, s, O-H), 5.78 (1 H, d, J=12.0 N-H) 6.55 (1 H, d, J=15.0, He), 7.20 (2 H, s, Ar-H), 7.30 (1 H, d,
J=15.0, Hd), 7.35-7.50 (5 H, m, Ar-H); FT-IR (KBr, νmax, cm-1): 3347 (N-H), 3161 (O-H), 1661 (C=O),
1603 (C=C), 1109 (O-CH3).
Preparation of compound 3b
To a solution of sinapic acid (2, 1.00 g, 4.46 mmol) in anhydrous dichloromethane (100 mL), N-
methylmorpholine (0.50 mL, 4.46 mmol) and isobutylchloroformate (0.80 mL, 4.46 mmol) were
added. The mixture was stirred at 0° C for 1 h, then N-methylmorpholine (0.50 mL) and (S)-methyl-
benzylamine (0.60 mL) were added. The mixture was stirred at room temperature for 2 h. The
resulting solution was washed with a pH 4 solution of aqueous HCl (60 mL), with a 10% aqueous
NaHCO3 solution (60 mL), with saturated brine (60 mL) and finally dried over Na2SO4. The solvent
was evaporated under reduced pressure, and the residue was purified by silica gel flash
chromatography, (eluent ethyl acetate and petroleum ether 7:3). The yield was 40% to give 3b. Anal.
calc. for C19H21NO4 (327.34): C 69.71%, H 6.47%, N 4.28%, O 19.55%; found: C 69.65%, H 6.50%,
1
N 4.31%; MS: 327.3 (M+); H-NMR: δH 1.50 (3 H, d, J=6.8, Hb), 3.75 (6 H, s, OCH3), 5.20 (1 H, m,
J=6.8-12.0, Ha), 5.62 (1 H, s, O-H), 5.78 (1 H, d, J=12.0, N-H), 6.55 (1 H, d, J=15.5, He), 6.80 (2 H, s,
Ar-H), 7.30 (1 H, d, J=15.5, Hd), 7.20-7.40 (5 H, m, Ar-H); FT-IR (KBr, νmax, cm-1): 3345 (N-H), 3155
(O-H), 1665 (C=O), 1602 (C=C), 1111 (O-CH3).
Preparation of compound 3c
Sinapic acid 2 (1 g, 4.46 mmol), 2-chloro-1-methylpyridine iodide (0.52 g, 4.46 mmol) and (S)-2-
phenyloxazolidinone (0.35 g, 4.46 mmol) was dissolved in 20 ml of dry CH2Cl2 under nitrogen
atmosphere. A solution of triethylamine (0.7 mL, 5.6 mmol), dissolved in dry CH2Cl2 (4 mL) was
added dropwise for 15 min. The mixture was stirred at room temperature for 120 hours, then a
saturated aqueous NaCl solution (20 mL) was added. The organic phase was separated, then washed
with a pH 4 solution of aqueous HCl (20 mL), with a 10% aqueous NaHCO3 solution (20 mL), with
water saturated with NaCl (20 mL) and finally dried over Na2SO4. The solvent was evaporated under
reduced pressure, and the residue was purified by silica gel flash chromatography, (eluent CH2Cl2-
acetone 7:3). Compound 3c was obtained in 40% yield. Anal. calc. for C20H19NO6 (369.37): C 65.03%,
1
H 5.18%, N 3.79%, O 25.99%; found: C 65.10%, H 5.15%, N 3.80%; MS: 369.4 (M+); H-NMR: δH
3.75 (6 H, s, OCH3), 4.20 (1 H, dd, J=9.0-9.0, Ha), 4.73 (1 H, dd, J=9.0-9.0 Hb), 4.97 (1 H, dd, J=9.0-
9.0, Hc), 5.62 (1 H, s, O-H), 6.55 (1 H, d, J=15.0, He), 7.20 (2 H, s, Ar-H), 7.30 (1 H, d, J=15.0, Hd),
7.20-7.40 (5 H, m, Ar-H); FT-IR (KBr, νmax, cm-1): 3155 (O-H), 1750 (C=O), 1659 (C=O), 1605
(C=C), 1110 (O-CH3).
Horseradish Peroxidase (HRP)-catalyzed oxidative phenol coupling methyl synapate 3d
A solution of 3d (1.0 mmol) in dioxane (14 mL) and 0.02 M phosphate/citric acid buffer pH 3.5
(4.0 mL) was added of a 0.86 M aqueous hydrogen peroxide solution (0.60 mL, 0.5 mmol) and

144
Molecules 2008, 13
aqueous HRP (0.93 mL, 837 U) at 0 °C in small portions over 15 minutes. The mixture was then
stirred at 0 °C. After 4 hours a saturated aqueous NaCl solution (20 mL) was added. The organic phase
was then evaporated under reduced pressure and the resulting solution was extracted with ethyl acetate
(4 x 20 mL). The combined organic extracts were washed with 10% aqueous NaHCO3 (25 mL), then
with water saturated with NaCl (25 mL), and dried over Na2SO4. The solvent was evaporated under
reduced pressure, and the residue was chromatographed on a silica gel flash column with hexane-ethyl
acetate (gradient mode, from 4:1 to 1:1) yielding a racemic mixture of trans thomasidioic metyl ester
1
(4-5d), yield = 70%. Racemic mixture of 4-5d had: m.p. 203 °C; H-NMR: δH 3.69 (6 H, s, OCH3),
3,70 (3 H, s, OCH3) , 3.75 (6 H, s, OCH3), 3.90 (3 H, s, OCH3), 3,99 (1 H, s, Hi) 4.99 (1 H, s, Hh),
5.00 (1 H, s, OH), 5.40 (1 H, s, OH), 6.21 (2 H, s, Hl), 6.58 (1 H, s, Hn), 7.60 (1 H, s, Ho); MS: 474
(M+); FT-IR (KBr, νmax, cm-1): 3300 (O-H), 1730 (C=O), 1700 (C=O), 1110 (O-CH3)
Horseradish Peroxidase (HRP)-catalyzed oxidative phenol coupling with compounds 3(a-c)
A solution of 3(a-c) (1.0 mmol) in dioxane (14 mL) and 0.02 M phosphate/citric acid buffer pH 3.5
(4.0 mL) was added of a 0.86 M aqueous hydrogen peroxide solution (0.60 mL, 0.5 mmol) and
aqueous HRP (0.93 mL, 837 U) at 0 °C in small portions over 15 minutes. The mixture was then
stirred at 0 °C. After 4 hours a saturated aqueous NaCl solution (20 mL) was added. The organic phase
was then evaporated under reduced pressure, and the resulting solution was extracted with ethyl
acetate (4 x 20 mL). The combined organic extracts were washed with 10% aqueous NaHCO3 (25
mL), then with water saturated with NaCl (25 mL), and dried over Na2SO4. The solvent was
evaporated under reduced pressure, and the residue was purified with preparative RP-HPLC to obtain
the individual diastereoisomers, named peak1 and peak 2 in eluative order. The diastereoisomeric
excess was calculated by HPLC (Table 1). Compounds 4a, 5a had: Peak 1: Anal. calc. for
C44H48N2O12 (796.86): C 66.32%, H 6.07%, N 3.52%, O 24.09%; found: C 66.30%, H 6.05%, N
3.55%; MS: 796.9 (M+); FT-IR (KBr, νmax, cm-1): 3155 (O-H), 1750 (C=O), 1659 (C=O), 1605 (C=C),
1110 (O-CH3); [α]D25 = -160.27°; 1H-NMR: δH 1.12 (3 H, t, J=8.0, Hg), 1.30 (3 H, t, J=8.0, Hg), 3.08 (2
H, d-d, J=6.0-15.0, Hb), 3.15 (2 H, d-d, J=8.0-15.0 Hc), 3.69 (3 H, s, OCH3), 3,70 (1 H, s, Hi) , 3.75 (6
H, s, OCH3), 3.90 (3 H, s, OCH3), 4.05 (2 H, q, J=8.0, Hf), 4.20 (2 H, q, J=8.0, Hf), 4.69 (1 H, d-d,
J=6.0-8.0 , Ha), 4.87 (1 H, d-d, J=6.0-8.0, Ha), 4.99 (1 H, s, Hh), 5.00 (1 H, s, OH), 5.40 (1 H, s, OH),
6.21 (2 H, s, Hl), 6.58 (1 H, s, Hn), 6.75 (1 H, d, J=8.0 Hz, N-H), 7.00-7.20 (10 H, m, Ar-H), 7.60 (1 H,
d, J=8.0 Hz, N-H), Ho is in the aromatic zone. Peak 2: Anal. calc. for C44H48N2O12 (796.86): C
66.32%, H 6.07%, N 3.52%, O 24.09%; found: C 66.30%, H 6.05%, N 3.55%; MS: 796.9 (M+); FT-IR
25
(KBr, νmax, cm-1): 3155 (O-H), 1750 (C=O), 1659 (C=O), 1605 (C=C), 1110 (O-CH3); [α]D
=
1
+127.88°; H-NMR: δH 1.15 (3 H, t, J=8.0, Hg), 1.20 (3 H, t, J=8.0, Hg), 3.08 (2 H, d-d, J=6.0-15.0,
Hb), 3.15 (2 H, d-d, J=8.0-15.0 Hc), 3.69 (3 H, s, OCH3), 3,70 (1 H, s, Hi) , 3.75 (6 H, s, OCH3), 3.90
(3 H, s, OCH3), 4.10 (2 H, q, J=8.0, Hf), 4.15 (2 H, q, J=8.0, Hf), 4.70 (1 H, d-d, J=6.0-8.0 , Ha), 4.80
(1 H, d-d, J=6.0-8.0, Ha), 5.02 (1 H, s, Hh), 5.00 (1 H, s, OH), 5.40 (1 H, s, OH), 6.21 (2 H, s, Hl), 6.58
(1 H, s, Hn), 6.75 (1 H, d, J=8.0 Hz, N-H), 7.00-7.20 (10 H, m, Ar-H), 7.60 (1 H, d, J=8.0 Hz, N-H),
Ho is in the aromatic zone. Compounds 4b, 5b had: Peak 1: Anal. calc. for C38H40N2O8 (652.73): C
69.92%, H 6.18%, N 4.29%, O 19.61%; found: C 69.88%, H 6.21%, N 4.34%; MS: 652.7 (M+); FT-IR
(KBr, νmax, cm-1): 3155 (O-H), 1750 (C=O), 1659 (C=O), 1110 (O-CH3); [a]D25 = -80.21°; 1H-NMR: δH

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Molecules 2008, 13
1.15 (3 H, d, J=5.0 Hz, Hb), 1.40 (3 H, d, J=5.0 Hz, Hb), 3.45 (6 H, s, OCH3), 3,65 (1 H, s, Hi), 3.67 (3
H, s, OCH3), 3.90 (3 H, s, OCH3), 4.72 (1 H, m, J=5.0 Hz, Ha), 4.92 (1 H, s, Hh), 5.15 (1 H, m, J=5.0
Hz,Ha), 5.30 (1 H, s, OH), 5.73 (1 H, s, OH), 6.21 (2 H, s, Hl), 6.52 (1 H, d, J=8.0 Hz, N-H), 6.58 (1 H,
s, Hn), 7.02-7.20 (10 H, m, Ar-H), 7.55 (1 H, d, J=8.0 Hz, N-H), Ho is in the aromatic zone. Peak 2:
Anal. calc. for C38H40N2O8 (652.73): C 69.92%, H 6.18%, N 4.29%, O 19.61%; found: C 69.88%, H
6.21%, N 4.34%; MS: 652.7 (M+); FT-IR (KBr, νmax, cm-1): 3155 (O-H), 1750 (C=O), 1659 (C=O),
1605 (C=C), 1110 (O-CH3); [α]D25 = +51.63°; H-NMR: δH 1.35 (3 H, d, J=5.0 Hz, Hb), 1.45 (3 H, d,
1
J=5.0 Hz, Hb), 3.65 (6 H, s, OCH3), 3.72 (1 H, s, Hi), 3.75 (3 H, s, OCH3), 3.81 (3 H, s, OCH3), 4.88
(1 H, m, J=5.0 Hz, Ha), 4.92 (1 H, s, Hh), 5.08 (1 H, m, J=5.0 Hz, Ha), 5.30 (1 H, s, OH), 5.73 (1 H, s,
OH), 6.21 (2 H, s, Hl), 6.52 (1 H, d, J=8.0 Hz, N-H), 6.58 (1 H, s, Hn), 7.02-7.20 (10 H, m, Ar-H), 7.55
(1 H, d, J=8.0 Hz, N-H), Ho is in the aromatic zone. Compounds 4c, 5c had: Peak 1: Anal. calc. for
C40H36N2O12 (736.72): C 65.21%, H 4.93%, N 3.80%, O 26.06%; found: C 65.25%, H 4.90%, N
3.77%; MS: 736.7 (M+); FT-IR (KBr, νmax, cm-1): 3155 (O-H), 1750 (C=O), 1659 (C=O), 1605 (C=C),
1
1110 (O-CH3); H-NMR: 3.65 (3 H, s, OCH3), 3,69 (1 H, s, Hi) , 3.75 (6 H, s, OCH3), 3.90 (3 H, s,
OCH3), 4.10 (1 H, dd, J=9.0-9.0, Ha), 4.20 (1 H, dd, J=9.0-9.0, Ha), 4.61 (1 H, dd, J=9.0-9.0 Hb), 4.73
(1 H, dd, J=9.0-9.0 Hb), 4.85 (1 H, dd, J=9.0-9.0, Hc), 4.97 (1 H, dd, J=9.0-9.0, Hc), 4.99 (1 H, s, Hh),
5.00 (1 H, s, O-H), 5.40 (1 H, s, O-H), 6.21 (2 H, s, Hl), 6.58 (1 H, s, Hn), 7.00-7.20 (10 H, m, Ar-H),
Ho is in the aromatic zone. Peak 2: Anal. calc. for C40H36N2O12 (736.72): C 65.21%, H 4.93%, N
3.80%, O 26.06%; found: C 65.25%, H 4.90%, N 3.77%; MS: 736.7 (M+); FT-IR (KBr, νmax, cm-1):
1
3155 (O-H), 1750 (C=O), 1659 (C=O), 1605 (C=C), 1110 (O-CH3); H-NMR: 3.65 (3 H, s, OCH3),
3,69 (1 H, s, Hi) , 3.75 (6 H, s, OCH3), 3.90 (3 H, s, OCH3), 4.10 (1 H, dd, J=9.0-9.0, Ha), 4.20 (1 H,
dd, J=9.0-9.0, Ha), 4.61 (1 H, dd, J=9.0-9.0 Hb), 4.73 (1 H, dd, J=9.0-9.0 Hb), 4.85 (1 H, dd, J=9.0-9.0,
Hc), 4.97 (1 H, dd, J=9.0-9.0, Hc), 4.99 (1 H, s, Hh), 5.00 (1 H, s, O-H), 5.40 (1 H, s, O-H), 6.21 (2 H,
s, Hl), 6.58 (1 H, s, Hn), 7.00-7.20 (10 H, m, Ar-H), Ho is in the aromatic zone.
LiOOH hydrolysis of aryltetralines
To a solution of aryltetralin 4 peak 1 (0.171 mmol) in tetrahydrofuran (20 mL) containing 30%
hydrogen peroxide (1 mL), LiOH (69 mg, 2.87 mmol) dissolved in water (3 mL) was added and the
solution was stirred at room temperature for 18 h. The resulting suspension was then cooled at 0 °C
and a saturated solution of sodium bisulphite was added until peroxides were completely reduced, then
concentrated under reduced pressure, acidified with a HCl solution pH 5 and extracted with ethyl
acetate. The organic phase was dried over anhydrous sodium sulphate, then evaporated at reduced
pressure to give thomasidioic acid 1. Anal. calc. for C22H22O10 (446.40): C 59.19%, H 4.97%, O
35.84%; found: C 59.22%, H 5.00%; MS: 446.4 (M+); FT-IR (KBr, νmax, cm-1): 3155 (O-H), 1750
1
(C=O), 1659 (C=O), 1605 (C=C), 1110 (O-CH3); H-NMR: δH 3.65 (6 H, s, OCH3), 3.70 (3 H, s,
OCH3), 3.81 (3 H, s, OCH3), 4.03 (1 H, s, Hi), 4.95 (1 H, s, Hh), 5.30 (1 H, s, O-H), 5.75 (1 H, s, O-H),
6.20 (2 H, s, Hl), 6.62 (1 H, s, Hn), 7.57 (1 H, s, Ho); [α]D25 = -90.27°

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Molecules 2008, 13
Computational details
All calculations have been performed at the semiempirical PM3 level [30] of theory using
Gaussian 03 [31] and Mopac2000 [32] suite of programs.
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