Novel tocopheryl compounds XXV: synthesis and comparison of the para-quinones of all four homologous tocopherol model compounds and their 3,4-dehydro derivatives

Article abstract of DOI:10.1016/j.tet.2007.03.114

Four tocopherol model compounds, the chroman-6-ols (1-4) having the typical substitution pattern of α-, β-, γ-, and δ-tocopherol (vitamin E), were oxidized to the corresponding para-quinones (5-8), and dehydrogenated to the 2H-chromen-6-ols (17-20) involving initial acetyl protection of the phenolic OH and deprotection as the last step. The chromenols were also converted into the para-quinones (21-24), which existed in the bicyclic hemiketal form, in contrast to the chromanol-derived, monocyclic quinones 5-8, the ketalization behavior agreeing well with computations on the DFT level.

Full text of DOI:10.1016/j.tet.2007.03.114

Tetrahedron 63 (2007) 5312–5318
Novel tocopheryl compounds XXV: synthesis and comparison of
the para-quinones of all four homologous tocopherol model
compounds and their 3,4-dehydro derivatives
Anjan Patel,a Thomas Netscher,b Lars Gille,c Kurt Mereiterd and Thomas Rosenaua,
*
aUniversity of Natural Resources and Applied Life Sciences, Department of Chemistry, Muthgasse 18, A-1190 Vienna, Austria
bResearch and Development, DSM Nutritional Products, PO Box 3255, CH-4002 Basel, Switzerland
cMolecular Pharmacology and Toxicology Unit, Department of Natural Sciences, University of Veterinary Medicine, Veterina€rpl. 1,
A-1210 Vienna, Austria
dDepartment of Chemistry, Vienna University of Technology, Getreidemarkt 9, A-1060 Vienna, Austria
Received 12 February 2007; revised 17 March 2007; accepted 19 March 2007
Available online 23 March 2007
Abstract—Four tocopherol model compounds, the chroman-6-ols (1–4) having the typical substitution pattern of a-, b-, g-, and d-tocopherol
(vitamin E), were oxidized to the corresponding para-quinones (5–8), and dehydrogenated to the 2H-chromen-6-ols (17–20) involving initial
acetyl protection of the phenolic OH and deprotection as the last step. The chromenols were also converted into the para-quinones (21–24),
which existed in the bicyclic hemiketal form, in contrast to the chromanol-derived, monocyclic quinones 5–8, the ketalization behavior
agreeing well with computations on the DFT level.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
In a current study to determine the suitability and properties
of tocopherol-derived oxidation products as substrates for
the mitochondrial bc1 complex in comparison to UQ and
a-pTQ, the synthesis of three compound classes was
required: the tocopherol-derived para-quinones, the 3,4-
dehydro-tocopherols, and the para-quinones of the latter.
For each class, all four homologues a–d were synthesized,
differing in the number and position of methyl substituents
at the aromatic ring (Scheme 1). In addition, the truncated
model compounds9 were to be used, which have a methyl
group instead of the isoprenoid side chain. This was done
to avoid analytical problems by lipophilic substrates during
enzyme assays, which render the determination of kinetic
constants difficult due to micelle formation.
a-Tocopherol (‘vitamin E’) and ubiquinone (UQ) are two
compounds occurring in mammalian cells, which exert im-
portant functions in antioxidative defense and bioenergetics,
respectively. Being closely related, bioquinones and bio-
chromanols can be readily interconverted by reductive cycli-
zation and oxidative ring opening. For the major component
of vitamin E, a-tocopherol, the chemistry between the re-
duced (chromanol) state and the oxidized (para-quinone)
state is well known.1–3 It is distributed in the lipid mem-
branes of various organs acting as a radical-scavenging anti-
oxidant, thereby forming the corresponding relatively stable
chromanoxyl radical upon one-electron oxidation. This
radical is either recycled by other antioxidants or further
oxidized to the two-electron oxidation product para-toco-
pheryl quinone (a-pTQ).4–6 Since this quinoid oxidation
product has a structure similar to UQ, it has been suggested
that the former interferes with certain mitochondrial UQ
functions.7 This was confirmed by the finding that a-pTQ
acted as a weak competitive inhibitor at the mitochondrial
complexes II and III.8
5a
R1
4
5
6
7
HO
1 R1 = R2 = R3 = Me, α-tocopherol model
2 R1 = R3 = Me, R2 = H, β-tocopherol model
3 R1 = H, R2 = R3 = Me, γ-tocopherol model
4 R1 = R2 = H, R3 = Me, δ-tocopherol model
3
4a
8a
2
R2
O
8
7a
1
8b
R3
Scheme 1. Formulae of truncated tocopherol model compounds (1–4) used
as starting material for the oxidation reactions.
From the comparatively low structural complexity of the tar-
get structures we actually expected a large number of refer-
ences dealing with the compounds, but we had to realize that
the situation was quite different. Apart from a-tocopherol
* Corresponding author. Tel.: +43 1 36006 6071; fax: +43 1 36006 6059;
e-mail: thomas.rosenau@boku.ac.at
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.114

A. Patel et al. / Tetrahedron 63 (2007) 5312–5318
5313
and its model, of which the para-quinones10,11 and the 3,4-
dehydro derivatives12 are mentioned aplenty in the literature,
there were two accounts of the 3,4-dehydro-d-tocopherol
model,13,14 one of the 3,4-dehydro-g-tocopherol model15
and one of the para-quinone model of d-tocopherol,16 listing
UV features but none of them giving NMR and MS data.
Other target compounds have apparently not been described
so far.
and decreasing it to less than 2 equiv resulted in appreciable
yield penalty. This is probably due to an increased acidity in
the former case and to extended reaction times required in
the latter case. It should be noted that under acidic and protic
conditions during workup and flash chromatography minor
amounts (less than 10%) of the corresponding 8a-hydroxy-
chromanones (5a–8a) were formed, which were difficult to
separate under those conditions as they were readily inter-
converted with the para-quinones. Working in aprotic
media, the neat para-quinones (5–8) were obtained.
In this paper, we would like to present our synthetic studies
towards the a-, b-, g-, and d-homologues of tocopherol-
derived para-quinones, 3,4-dehydro derivatives, and 3,4-de-
hydro-para-quinones, including optimization of the reaction
conditions for each class of compounds and reports of
comprehensive analytical data.
Both the 1H and 13C NMR spectra confirmed the para-quin-
oid structure, cf. NMR data and assignment in Table 1. The
presence of two keto carbons at about 187 ppm indicated the
absence of hemiketal structures, such as 8a-hydroxy-chro-
manones (5a–8a). A peculiar feature of the a-form was
that three of the four non-keto quinone ring carbons reso-
nated at nearly the same frequency of about 140 ppm. It
was interesting to note that a certain ‘pairing’ of the com-
pounds into an a/b-group and a g/d-group, which had also
been found in some other aspects of the chemistry of toco-
pherols, was reflected by the NMR data. The presence of
the 5a-methyl group can be assumed to be the decisive factor
2. Results and discussion
Oxidation of tocopherol-type model compounds with FeCl3
in aqueous medium is still the method of choice to obtain the
corresponding para-quinones in good yields, and was also
used in the present case to provide the quinones 5–8
(Scheme 2). It was imperative that the oxidation was carried
out at 0–5 ꢀC. Already at room temperature side reactions
became increasingly dominant and accounted for more
than one third of the conversion, whereas at the lower tem-
perature the conversion into the desired para-quinones was
virtually quantitative. Products of those side reactions
were elimination products of the aliphatic hydroxyl group
and dimers. The oxidant should be applied in about fivefold
excess. Both increasing this amount to more than 10 equiv
1
for this ‘pairing’ due to its special reactivity.17 In the H
spectra, the signals of H-4 were found at 2.58 ppm for the
first pair and at 2.45 ppm for the second one. The proton res-
onances of the two magnetically equivalent 2a-CH3 groups
were found at 1.28 ppm for the a- and b-forms, but shifted
about 0.1 ppm to higher field for g- and d-homologues. Sim-
ilarly, C-4 resonated at 21.5 ppm for a- and b-, but 3 ppm
more downfield for g- and d-forms. The CH resonated at
the highest field of the quinoid carbons at 132–133 ppm.
For the synthesis of 3,4-dehydro derivatives (chromenols)
starting from 1–4 the oxidant 2,3-dichloro-5,6-dicyano-
benzoquinone (DDQ) was used. Non-protected chromanols
afforded mixtures of different dimers, whereas the reaction
with appropriately O-protected chromanols proceeded
smoothly. The chromenol synthesis thus required suitable
protection of the phenolic hydroxyl before the actual
dehydrogenation step, and deprotection afterwards. Acetyl
protection was chosen due to reasons of simplicity and
near-quantitative yields of both attachment and removal
of the protecting group. Acetylation of the chromanols
1–4 with acetic anhydride in pyridine provided the
R1
R1
O
O
H+
i
1 - 4
(
)
O
R2
O
R2
OH
OH
R3
R3
5a R1 = R2 = R3 = Me
5 R1 = R2 = R3 = Me
6a R1 = R3 = Me, R2 = H 6 R1 = R3 = Me, R2 = H
7a R1 = H, R2 = R3 = Me 7 R1 = H, R2 = R3 = Me
8a R1 = R2 = H, R3 = Me 8 R1 = R2 = H, R3 = Me
i FeCl3 (5 eq.), H2O / MeOH, 0 °C, 2 - 30 min, 42 - 82%
Scheme 2. Synthesis of the para-quinones 5–8 derived from the four homo-
logous tocopherol model compounds (1–4).
Table 1. 1H and 13C NMR data and assignments of para-quinones 5–8 (all shift values in ppm, CDCl3, standard TMS)
Nucleus
a-Form, p-quinone 5
b-Form, p-quinone 6
g-Form, p-quinone 7
d-Form, p-quinone 8
H-2a
H-3
H-4
H-5a, 7a, 8b
H-5
H-7
1.28 (s, 6H)
1.54 (m, 2H)
2.58 (m, 2H)
2.01 (s, 6H), 2.04 (s, 3H)
1.30 (s, 6H)
1.52 (m, 2H)
2.58 (m, 2H)
2.03 (s, 6H)
1.21 (s, 6H)
1.57 (m, 2H)
1.22 (s, 6H)
1.56 (m, 2H)
2.46 (t, 2H)
1.99 (s, 3H)
6.46 (s, 1H)
6.49 (s, 1H)
2.05 (br s, 1H)
70.62
29.27
41.74
24.40
16.02
2.45 (m, 2H)
1.94 (s, 3H), 1.96 (s, 3H)
6.46 (t, 1H, 4J¼1.4 Hz)
6.55 (q, 1H, 4J¼1.3 Hz)
O–H
C-2
2.34 (s, 1H)
70.42
28.86
41.92
21.52
11.74, 12.08, 12.17
140.06, 140.23, 140.36,
144.23
1.75 (br s, 1H)
70.68
1.40 (br s, 1H)
70.62
29.24
41.78
24.29
12.02, 12.35
132.13 (CH), 140.63, 141.06,
149.25
187.56, 187.59
C-2aa
29.04
41.95
21.63
11.60, 15.77
133.13 (CH), 140.55, 144.86,
145.36
187.72, 187.73
C-3
C-4
C-5a, 7a, 8b
Non-keto quinoid
ring carbons
C-6, C-8a
132.37 (CH), 133.16, 145.98,
149.76
187.75, 187.91
187.06, 187.44
a
Two magnetically equivalent carbons.

5314
A. Patel et al. / Tetrahedron 63 (2007) 5312–5318
corresponding chromanyl acetates (9–12), which were dehy-
drogenated by DDQ in dry toluene to give the corresponding
chromenyl acetates (13–16), see Scheme 3. Both working in
an inert atmosphere and using carefully dried solvents were
imperative to boost the yields, which ranged about 70% after
chromatography. Deprotection afforded the target chro-
menols (17–20) in overall good yields. While for a- and b-
forms deprotection with potassium carbonate in methanol
was successful, the two remaining homologues required
NaOMe in MeOH for full conversion. It should be noted
that acidic deprotection, e.g., HCl or ion exchange resin,
was unsuitable as strong byproduct formation was observed.
appeared at higher field than the other (substituted) aromatic
carbons.
The 3,4-dehydro derivatives 17–20 were oxidized to the cor-
responding para-quinoid structures 21–24 according to the
procedure in Scheme 4, using FeCl3 as for the oxidation of
chromanols 1–4. In contrast to the chromanol oxidation,
which produced hemiketals only in acidic media to minor
extent, oxidation of the chromenols afforded the hemiketals
of the para-quinones exclusively. Yields were generally
rather low; the byproducts formed were not the open-chain
para-quinones, but rearrangement products and dimers of
which the structure is currently studied.
1
The assignment of the H and 13C resonances of the 3,4-
dehydro-chromanols 17–20 is given in Table 2, additional
R1
R1
1H NMR data of the intermediates are listed in Section 3.
The H NMR spectra showed the typical paired doublet
HO
R2
O
i
1
for the olefinic protons (H-3 and H-4) with a coupling con-
stant of 10 Hz. H-3 resonated at about 5.60 ppm for all ho-
mologues, while the resonance of H-4 was found at about
6.50 ppm for a- and b-forms and at about 6.20 ppm for g-
and d-forms—another example of the above-described
‘pairing’ of a/b versus g/d. This was also seen, albeit less
prominently, in the case of the C-4 resonances: 120 ppm
for the former pair versus 122.5 ppm for the latter. For all ho-
mologues, the 13C resonances of the aromatic CH carbons
O
O
R2
OH
R3
R3
17 R1 = R2 = R3 = Me
21 R1 = R2 = R3 = Me
18 R1 = R3 = Me, R2 = H 22 R1 = R3 = Me, R2 = H
19 R1 = H, R2 = R3 = Me 23 R1 = H, R2 = R3 = Me
20 R1 = R2 = H, R3 = Me 24 R1 = R2 = H, R3 = Me
i FeCl3 (5 eq.), H2O / MeOH, 0 °C, 2 - 30 min, 12 - 16%
Scheme 4. Synthesis of the para-quinone hemiketals 21–24 from the four
homologous 3,4-dehydro derivatives (17–20).
R4 R1
O
R4 R1
O
ii
O
O
R2
R2
R3
R3
1 R1 = R2 = R3 = Me, R4 = H
2 R1 = R3 = Me, R2 = R4 = H
3 R1 = R4 = H, R2 = R3 = Me
4 R1 = R2 = R4 = H, R3 = Me
13 R1 = R2 = R3 = Me, R4 = Ac
14 R1 = R3 = Me, R2 = H, R4 = Ac
15 R1 = H, R2 = R3 = Me, R4 = Ac
16 R1 = R2 = H, R3 = Me, R4 = Ac
iii
i
9 R1 = R2 = R3 = Me, R4 = Ac
17 R1 = R2 = R3 = Me, R4 = H
18 R1 = R3 = Me, R2 = R4 = H
19 R1 = R4 = H, R2 = R3 = Me
20 R1 = R2 = R4 = H, R3 = Me
10 R1 = R3 = Me, R2 = H, R4 = Ac
11 R1 = H, R2 = R3 = Me, R4 = Ac
12 R1 = R2 = H, R3 = Me, R4 = Ac
i = Ac2O / pyridine, r.t., 6 h, > 95%; ii = DDQ, toluene, reflux, 24 h, 70 - 76%;
iii = K2CO3 / MeOH, r.t., 3 h or MeONa / MeOH, 0 °C, 15 min, >95%
Scheme 3. Synthesis of the 3,4-dehydro derivatives (17–20) derived from the four homologous tocopherol model compounds (1–4).
Table 2. 1H and 13C NMR data and assignments of 3,4-dehydro-chromanols 17–20 (all shift values in ppm, CDCl3, standard TMS)
Nucleus
3,4-Dehydro-a-compound 17
3,4-Dehydro-b-compound 18 3,4-Dehydro-g-compound 19 3,4-Dehydro-d-compound 20
H-2a
H-3
H-4
H-5a, 7a, 8b
H-5
H-7
1.38 (s, 6H)
1.38 (s, 6H)
1.39 (s, 6H)
1.39 (s, 6H)
5.63 (d, 1H, 3J¼10.0 Hz)
5.66 (d, 1H, 3J¼10.0 Hz)
5.57 (d, 1H, 3J¼9.7 Hz)
6.19 (d, 1H, 3J¼9.7 Hz)
2.12 (s, 3H), 2.13 (s, 3H)
6.30 (s, 1H)
5.61 (d, 1H, 3J¼9.7 Hz)
6.22 (d, 1H, 3J¼9.7 Hz)
2.13 (s, 3H)
6.50 (d, 1H, 3J¼10.0 Hz)
6.51 (d, 1H, 3J¼10.0 Hz)
2.12 (s, 3H), 2.15 (s, 3H), 2.17 (s, 3H) 2.11 (s, 3H), 2.16 (s, 3H)
6.46 (s, 1H)
6.32 (d, 1H, 4J¼2.9 Hz)
6.47 (d, 1H, 4J¼2.9 Hz)
4.30 (br s, 1H)
75.55
27.60
131.68
122.45
15.47 (C-8b)
121.58, 126.68
110.18 (CH)
OH
4.24 (br s, 1H)
74.34
27.25
130.57
119.91
4.24 (s, 1H)
74.38
27.31
131.36
119.85
10.54 (C-5a), 15.82 (C-8b)
120.41, 123.63
116.78
144.90, 146.69
116.66 (CH)
4.38 (s, 1H)
75.43
27.56
130.82
122.43
11.68, 11.78 (C-7a, C-8b)
118.99, 125.49
109.77 (CH)
144.59, 147.01
123.54
C-2
C-2aa
C-3
C-4
C-5a, C-7a, C-8b 10.86, 11.59, 12.42
C-4a/C-8
C-5
C-6/C-8a
C-7
116.07, 122.48
117.88
145.35, 144.55
122.89
144.80, 148.62
116.97 (CH)
a
Two magnetically equivalent carbons.

A. Patel et al. / Tetrahedron 63 (2007) 5312–5318
5315
At present it cannot be decided whether the hemiketal prod-
ucts were formed by intramolecular ring closure from
initially produced para-quinones, or whether they were
generated directly from the starting chromenols without in-
termediate ring opening. Preference of 21–24 over the corre-
sponding open-chain para-quinones might be the result of
a certain pre-organization effect: apparently the steric condi-
tions for ring closure—or ring maintenance—were favorable
in the case of the more rigid olefinic side chain in 21–24 as
compared to the fully flexible aliphatic chains in the para-
quinones 5–8. Computational results on the B3LYP/6-
31G(d,p) level of theory agreed with the observed formation
of para-quinone hemiketals (21–24) from the chromenes
(17–20), while the chromanes (1–4) formed the open-chain
para-quinones (5–8). The difference of the ZPE-corrected
absolute energies between the open-chain para-quinones
and the corresponding hemiketal para-quinones was
10.5 kJ/mol in favor of the former for compounds 5–8, and
6.1 kJ/mol in favor of the latter for the bicycles 21–24.
The influence of the methyl substitution pattern was mar-
ginal with deviations from those values below 0.6 kJ/mol.
Figure 1. Thermal ellipsoid plot (50% ellipsoids) and crystallographic atom
labeling of hemiketal 23 (see CCDC 642188 for details).
free para-quinone structure as compounds 5–7. While the
four non-keto resonances of the quinoid ring were found
over a relatively small range between 132 and 149 ppm for
those para-quinones 5–7, the unsaturated side chain and
the hemiketal structure in 21–24 brought about a much
higher differentiation with shift values, especially noticeable
for the a-form. With regard to the parent chromenols the sig-
nals of 3-C were shifted about 10 ppm downfield, whereas
the 4-C resonances remained largely unchanged.
1
The assignment of the H and 13C resonances of the para-
From compound 23, 8a-hydroxy-2,2,7,8-tetramethyl-2H,
8aH-chromen-6-one, a crystal structure was obtained, which
confirmed the hemiketal structure. The quinone ring as-
sumes a very flat half-chair conformation, the pyran ring
a twisted chair conformation. The hemiketal hydroxy group
is placed nearly perpendicular to the quinone plain with
a C5–C4–C9–O3 dihedral angle of 100ꢀ, and forms an
intermolecular hydrogen bridge to the quinone oxygen
quinone hemiketals 21–24 is given in Table 3. In contrast
to the para-quinones (Table 1) and chromenes (Table 2),
the two CH3 groups at C-2 became magnetically non-equiv-
alent, as they can be either placed cis or trans with regard to
the hemiketal hydroxyl group. Conformational ring changes
(‘puckering’) can thus no longer average the shifts as it does
in the chromenes 17–20. The positive and negative shift dif-
ferences relative to the shift of the chromenes (1.38 ppm vs
1.30 and 1.57 ppm) can also be explained by the anisotropy
effect of the pyran ring double bond. The vicinal H-3/H-4
coupling constant was slightly larger than for the chrome-
nols 17–20. The resonance of H-3 appeared at 6.20 ppm
for all isomers and experienced a downfield shift by
about 0.6 ppm as compared to the chromenols. The shifts
of 4-H were similar to the chromanol case, with values at
6.55 ppm for the a- and b-isomers and 6.33 ppm for the g-
and d-isomers. A typical feature of the 13C spectra was the
signal of the hemiketal carbon (C-8a) at 89 ppm. This reso-
nance is also the main proof that compounds 21–24 have no
˚
with O(H)–O¼2.764 A (Fig. 1).
3. Experimental
3.1. General
All chemicals were commercially available and used without
further purification. Reagent-grade solvents were used for all
extractions and workup procedures. Distilled water was used
for all aqueous extractions and for all aqueous solutions.
Table 3. 1H and 13C NMR data and assignments of para-quinone hemiketals 21–24 (all shift values in ppm, all coupling constants in Hz, CDCl3, standard TMS)
Nucleus
a-Form, p-quinone 21
b-Form, p-quinone 22
g-Form, p-quinone 23
d-Form, p-quinone 24
H-2a
H-2b
H-3
1.29 (s, 3H)
1.58 (s, 3H)
1.30 (s, 3H)
1.57 (s, 3H)
1.31 (s, 3H)
1.59 (s, 3H)
1.31 (s, 3H)
1.57 (s, 3H)
6.20 (d, 1H, 3J¼10.4 Hz)
6.55 (d, 1H, 3J¼10.4 Hz)
6.21 (d, 1H, 3J¼10.8 Hz)
6.57 (d, 1H, 3J¼10.8 Hz)
1.91 (s, 3H), 2.11 (s, 3H)
6.21 (d, 1H, 3J¼10.1 Hz)
6.33 (d, 1H, 3J¼10.1 Hz)
1.86 (s, 3H), 2.10 (s, 3H)
6.21 (d, 1H, 3J¼10.1 Hz)
6.34 (d, 1H, 3J¼10.1 Hz)
2.13 (s, 3H)
H-4
H-5a/H-7a/H-8b 1.92 (s, 3H), 1.88 (s, 3H),
2.09 (s, 3H)
H-5
H-7
O–H
C-2
C-2a
C-2b
C-3
C-4
5.92 (s, 1H)
5.90 (m, 1H)
5.96 (m, 1H)
2.70 (s, 1H)
74.87
6.01 (q, 1H, 4J¼1.5 Hz)
2.64 (s, 1H)
74.33
29.64
30.72
141.64
118.77
9.82, 16.19
2.64 (s, 1H)
74.05
29.41
30.67
141.27
2.74 (s, 1H)
74.69
29.32
29.34
30.51
142.73
30.64
142.55
118.54
10.07, 11.31, 12.92
120.25a
10.91, 12.93
120.39a
15.83
C-5a, 7a, 8b
C-4a/C-5/C-7/C-8 140.86, 126.11, 130.36, 148.04 141.86, 126.69, 125.54 (CH), 146.91, 120.32 (CH),a 130.68, 147.83, 120.61 (CH),a 125.58 (CH),
154.95
89.30, 185.98
148.80
89.11, 185.72
155.61
88.96, 185.95
C-8a, C-6
89.01, 185.63
a
Assignment may be interchanged.

5316
A. Patel et al. / Tetrahedron 63 (2007) 5312–5318
n-Hexane, diethyl ether, ethyl acetate, and petroleum ether
used in chromatography were distilled before use.
chromatography (n-hexane/diethyl ether, v/v¼3:7). TLC:
Rf ¼0.24 (n-hexane/diethyl ether, v/v¼4:6), MS (EI,
70 eV): m/z 236.1 ([M+]). Anal. Calcd for C14H20O3: C,
71.16; H, 8.53; found: C, 70.81; H, 8.33.
All reactions involving non-aqueous conditions were con-
ducted in oven-dried (140 ꢀC, overnight) or flame-dried
glassware under an argon or nitrogen atmosphere. TLC
was performed using Merck silica gel 60 F254 pre-coated
plates. Flash chromatography was performed on Baker silica
gel (40 mm particle size). All products were purified to ho-
mogeneity by TLC/GC analysis; yields refer to isolated,
pure products with satisfying elemental analysis data. Melt-
ing points, determined on a Kofler-type micro hot stage with
Reichert-Biovar microscope, are uncorrected. 1H NMR
spectra were recorded at 300.13 MHz for 1H and at
75.47 MHz for 13C NMR in CDCl3. Chemical shifts, relative
to TMS as internal standard, are given in d values, coupling
constants in Hz. 13C peaks were assigned by means of APT,
HMQC, and HMBC spectra. The nomenclature of toco-
pherols and chromanols as recommended by IUPAC18,19
was used throughout. ‘d.i.’ denotes peaks with double inten-
sity. Elemental analyses were performed at the Microanalyt-
ical Laboratory of the Institute of Physical Chemistry at the
University of Vienna.
3.3.2. 3-(3-Hydroxy-3-methyl-butyl)-2,5-dimethyl-
[1,4]benzoquinone (6). 6-Hydroxy-2,2,5,8-tetramethyl-
chroman (2, 0.1 g, 0.48 mmol) and FeCl3 (2.4 mmol,
0.65 g) were used as the starting materials producing 6 in
65% yield (69 mg) after purification by flash chromato-
graphy (n-hexane/diethyl ether, v/v¼7:3/n-hexane only).
TLC: Rf ¼0.25 (n-hexane/diethyl ether, v/v¼3:7), MS (ESI
Q-TOF): m/z 245.1152 ([M+Na]+), calcd 245.1148
([M+Na]+). Anal. Calcd for C13H18O3: C, 70.24; H, 8.16;
found: C, 69.89; H, 8.26.
3.3.3. 5-(3-Hydroxy-3-methyl-butyl)-2,3-dimethyl-
[1,4]benzoquinone (7). 6-Hydroxy-2,2,7,8-tetramethyl-
chroman (3, 0.1 g, 0.48 mmol) and FeCl3 (2.4 mmol,
0.65 g) were used as the starting materials producing 7 in
82% yield (88 mg) after purification by flash chromato-
graphy (n-hexane/diethyl ether, v/v¼5:5/5:4). TLC:
Rf ¼0.15 (n-hexane/diethyl ether, v/v¼5:5), MS (ESI Q-
TOF): m/z 223.1293 ([M+Na]+), calcd 223.1329
([M+Na]+). Anal. Calcd for C13H18O3: C, 70.24; H, 8.16;
found: C, 69.92; H, 8.06.
3.2. Computations
Computations, as implemented through Spartan Pro 02 by
Wavefunction, Inc., Irvine, CA, USA, were carried out
on geometries pre-optimized by the semi-empirical PM3
method. For full geometry optimization the widely em-
ployed B3LYP hybrid method, which includes a mixture
of HF and DFT exchange terms and the gradient-corrected
correlation functional of Lee, Yang, and Parr20,21 parameter-
ized by Becke,22,23 was used, along with the double-zeta
split valence basis sets 6-31+G*,24,25 which includes diffuse
functions, or the higher 6-311-G(2df,2p) analogue. Vibra-
tional frequencies were calculated at the respective level of
theory to characterized local minima (equilibrium struc-
tures) or first-order saddle points (transition states) on the
potential energy surface and to determine zero-point vibra-
tional energies. All equilibrium geometries were character-
ized by real frequencies only, all transition states by one
imaginary frequency.
3.3.4. 2-(3-Hydroxy-3-methyl-butyl)-6-methyl-[1,4]-
benzoquinone (8). 6-Hydroxy-2,2,8-trimethylchroman (4,
0.1 g, 0.52 mmol) and FeCl3 (2.6 mmol, 0.70 g) were used
as the starting materials producing 8 in 42% yield (42 mg)
after purification by flash chromatography (n-hexane/diethyl
ether, v/v¼5:5/5:4). TLC: Rf ¼0.16 (n-hexane/diethyl
ether, v/v¼4:8), MS (ESI Q-TOF): m/z 209.1339
([M+Na]+), calcd 209.1172 ([M+Na]+). Anal. Calcd for
C12H16O3: C, 69.21; H, 7.74; found: C, 68.89; H, 7.78.
3.4. Synthesis of 3,4-dehydro derivatives 17–20
3.4.1. General procedure for the acetylation. Acetic anhy-
dride was added into the solution of the respective chroma-
nol (1–4) in pyridine, and the solution was stirred at rt for
6 h. The solvents were evaporated in vacuo and the residue
was purified by flash chromatography to give the acetate
as a white wax.
3.3. Synthesis of para-quinones 5–8
FeCl3 hexahydrate (5 equiv) was added at once into the so-
lution of the respective chromanol in the ternary solvent sys-
tem methanol/water/diethyl ether (40 mL, v/v/v¼19:1:20) at
4 ꢀC. The mixture was stirred at this temperature for 1.5 h. A
gradual color change to yellow indicated progressing forma-
tion of the para-quinone. Water (50 mL) was added and the
mixture was extracted with diethyl ether. The organic phase
was washed with brine and water, dried over MgSO4, and
concentrated in vacuo. The residue was purified by flash
chromatography on silica gel to give the para-quinone as
a yellow viscous oil.
Compound 1 (0.2 g, 0.92 mmol), pyridine (3.78 mL), and
Ac2O (7.03 mL) were employed to afford 6-acetoxy-
2,2,5,7,8-pentamethylchroman (9, 227 mg, 94%) after flash
chromatography (n-hexane/diethyl ether, v/v¼18:1). TLC:
Rf ¼0.54 (n-hexane/diethyl ether, v/v¼8:2). 1H NMR:
3
d 1.29 (s, 6H, CH3-2a), 1.78 (t, 2H, J¼6.8 Hz, H-3), 1.98
(s, 3H, CH3), 2.02 (s, 3H, CH3), 2.08 (s, 3H, CH3), 2.33 (s,
3H, acetyl CH3), 2.60 (t, 2H, 3J¼6.8 Hz, H-4).
Compound 2 (0.1 g, 0.48 mmol), pyridine (2.00 mL), and
Ac2O (3.72 mL) were employed to afford 6-acetoxy-
2,2,5,8-tetramethylchroman (10, 117 mg, 98%) after flash
chromatography (n-hexane/diethyl ether, v/v¼18:1). TLC:
Rf ¼0.36 (n-hexane/diethyl ether, v/v¼8:2). 1H NMR:
3.3.1. 3-(3-Hydroxy-3-methyl-butyl)-3,5,6-trimethyl-
[1,4]benzoquinone (5). 6-Hydroxy-2,2,5,7,8-pentamethyl-
chroman (1, 0.1 g, 0.46 mmol) and FeCl3 hexahydrate
(2.3 mmol, 0.62 g) were used as the starting materials pro-
ducing 5 in 63% yield (68 mg) after purification by flash
3
d 1.28 (s, 6H, CH3-2a), 1.79 (t, 2H, J¼6.8 Hz, H-3), 2.05
(s, 3H, CH3-5a), 2.09 (s, 3H, CH3-8b), 2.33 (s, 3H, acetyl
CH3), 2.61 (t, 2H, 3J¼6.8 Hz, H-4), 6.48 (s, 1H, ArH).

A. Patel et al. / Tetrahedron 63 (2007) 5312–5318
5317
Compound 3 (0.1 g, 0.48 mmol), pyridine (2.00 mL), and
Ac2O (3.72 mL) were employed to afford 6-acetoxy-
2,2,7,8-tetramethylchroman (11, 110 mg, 94%) after flash
chromatography (n-hexane/diethyl ether, v/v¼18:1). TLC:
Rf ¼0.33 (n-hexane/diethyl ether, v/v¼8:2). 1H NMR:
pentamethylchromene (16, 74 mg, 74%) after flash chroma-
tography (n-hexane/diethyl ether, v/v¼7:1). TLC: Rf ¼0.34
1
(n-hexane/diethyl ether, v/v¼8:2). H NMR: d 1.41 (s, 6H,
CH3-2a), 2.15 (s, 3H, CH3-8b), 2.25 (s, 3H, acetyl CH3),
5.61 (d, 1H, J¼9.8 Hz, H-3), 6.23 (d, 1H, J¼9.8 Hz, H-
3
3
3
4
4
d 1.30 (s, 6H, CH3-2a), 1.74 (t, 2H, J¼6.7 Hz, H-3), 2.01
4), 6.55 (d, 1H, J¼2.6 Hz, ArH), 6.68 (d, 1H, J¼2.6 Hz,
(s, 3H, CH3-7a), 2.10 (s, 3H, CH3-8b), 2.28 (s, 3H, acetyl
ArH).
CH3), 2.71 (t, 2H, 3J¼6.7 Hz, H-4), 6.57 (s, 1H, ArH).
3.4.3. 2,2,5,7,8-Pentamethyl-2H-chromen-6-ol (17). Into
the solution of 13 (59 mg, 0.23 mmol) in methanol (8 mL),
K2CO3 (94 mg, 0.68 mmol) was added and the mixture
was stirred for 3 h at rt. The solvent was evaporated and the
residue was purified by flash chromatography (n-hexane/
diethyl ether, v/v¼9:0.6) to afford chromenol 17 (27.6 mg,
55%) as a white solid. TLC: Rf ¼0.23 (n-hexane/diethyl
ether, v/v¼8:2). Anal. Calcd for C14H18O2: C, 77.03; H,
8.31; found: C, 76.92; H, 8.07.
Compound 4 (0.1 g, 0.52 mmol), pyridine (2.10 mL), and
Ac2O (4.00 mL) were employed to afford 6-acetoxy-2,2,8-
trimethylchroman (12, 110 mg, 90%) after flash chromato-
graphy (n-hexane/diethyl ether, v/v¼7:2). TLC: Rf ¼0.34
1
(n-hexane/diethyl ether, v/v¼8:2). H NMR: d 1.39 (s, 6H,
3
CH3-2a), 1.84 (t, 2H, J¼6.7 Hz, H-3), 2.21 (s, 3H, CH3-
3
8b), 2.32 (s, 3H, –COCH3), 2.81 (t, 2H, J¼6.74 Hz, H-4),
6.70 (t, 1H, ArH), 6.74 (s, 1H, ArH).
3.4.2. General procedure for the dehydrogenation of the
acetyl-protected tocopherol model compounds with
DDQ. The solution of the respective 6-acetoxychroman
(9–12) in anhydrous toluene (6 mL) was heated at 105 ꢀC
for 30 min. A solution of DDQ in dry toluene (6 mL) was
added dropwise over 3 h, and this mixture was refluxed for
24 h. The solution was cooled to rt and filtered, and the sol-
vent was evaporated in vacuo. The residue was dissolved in
diethyl ether, washed with 5% aq NaHCO3 solution and wa-
ter, dried over MgSO4, and the solution was concentrated in
vacuo. The residue was purified by flash chromatography on
silica gel to afford 6-acetoxychromene as viscous oil. TLC
showed the product nearly at the same position as the start-
ing material, but on spraying with 4% H2SO4 in methanol
and heating the starting material turned yellow and the
product brown, and became thus distinguishable.
3.4.4. 2,2,5,8-Tetramethyl-2H-chromen-6-ol (18). Into the
solution of 14 (39 mg, 0.16 mmol) in methanol (8 mL),
K2CO3 (66 mg, 0.48 mmol) was added and the mixture was
stirred for 3 h at rt. The solvent was evaporated and the resi-
due was purified by flash chromatography (n-hexane/diethyl
ether, v/v¼9:0.6) to afford chromanol 18 (21.2 mg, 65%) as
a white solid. TLC: Rf ¼0.37 (n-hexane/diethyl ether,
v/v¼6:4), MS (EI, 70 eV): 204.1 [M]+. Anal. Calcd for
C13H16O2: C, 76.44; H, 7.90; found: C, 76.26; H, 7.60.
3.4.5. 2,2,7,8-Tetramethyl-2H-chromen-6-ol (19). Sodium
methanolate (0.1 M, 5.52 mL, 0.552 mmol) was added drop-
wise into solution of 15 (68 mg, 0.28 mmol) in dry methanol
(2.8 mL) at 0 ꢀC. The mixture was stirred for 15 min at rt and
the reaction was monitored by TLC. After completion, the
mixture was diluted with methanol, cation exchange resin
(H+ form) was added until neutral. The solids were filtered
off and the filtrate was concentrated in vacuo. The residue
was purified by flash chromatography (n-hexane/diethyl
ether, v/v¼9:0.6) to provide chromanol 19 (43 mg, 76%)
as a yellowish wax. TLC: Rf ¼0.37 (n-hexane/diethyl ether,
v/v¼6:4), MS (ESI Q-TOF): m/z 205.1194 [MH]+, calcd
205.1223 [MH]+. Anal. Calcd for C13H16O2: C, 76.44; H,
7.90; found: C, 76.26; H, 8.28.
Acetoxychroman 9 (0.22 g, 0.84 mmol) and DDQ (0.40 g,
1.76 mmol) were employed to yield 6-acetoxy-2,2,5,7,
8-pentamethylchromene (13, 166 mg, 76%) after flash
chromatography (n-hexane/diethyl ether, v/v¼18:1). TLC:
Rf ¼0.54 (n-hexane/diethyl ether, v/v¼8:2). 1H NMR:
d 1.43 (s, 6H, CH3-2a), 2.02 (s, 3H, CH3), 2.04 (s, 3H,
CH3), 2.10 (s, 3H, CH3), 2.33 (s, 3H, acetyl CH3), 5.63 (d,
1H, 3J¼16.0 Hz, H-3), 6.47 (d, 1H, 3J¼16.0 Hz, H-4).
3.4.6. 2,2,8-Trimethyl-2H-chromen-6-ol (20). Sodium
methanolate (0.1 M, 2 equiv, 2.34 mL, 0.234 mmol) was
added dropwise into the solution of 16 (27 mg, 0.12 mmol)
in dry methanol (1.2 mL) at 0 ꢀC. The mixture was stirred
for 15 min at rt and the reaction was monitored by TLC.
After completion, the mixture was diluted with methanol,
cation exchange resin (H+ form) was added until neutral.
The solids were filtered off and the filtrate was concentrated
in vacuo. The residue was purified by flash chromatography
(n-hexane/diethyl ether, v/v¼7:2) to provide chromanol
20 (22 mg, 95%) as a yellowish wax. TLC: Rf ¼0.22 (n-
hexane/diethyl ether, v/v¼7:3), MS (ESI Q-TOF): m/z
191.1094 [MH]+, calcd 191.1066 [MH]+. Anal. Calcd for
C12H14O2: C, 75.76; H, 7.42; found: C, 75.70; H, 7.51.
Acetoxychroman 10 (0.1 g, 0.40 mmol) and DDQ (0.20 g,
0.88 mmol) were employed to yield 6-acetoxy-2,2,5,8-pen-
tamethylchromene (14, 75 mg, 76%) after flash chromato-
graphy (n-hexane/diethyl ether, v/v¼18:1). TLC: Rf¼0.36
1
(n-hexane/diethyl ether, v/v¼8:2). H NMR: d 1.41 (s, 6H,
CH3-2a), 2.03 (s, 6H, CH3), 2.30 (s, 3H, acetyl CH3), 5.61
(d, 1H, 3J¼15.2 Hz, H-3), 6.62 (d, 1H, 3J¼15.2 Hz, H-4).
Acetoxychroman 11 (0.1 g, 0.40 mmol) and DDQ (0.20 g,
0.88 mmol) were employed to yield 6-acetoxy-2,2,7,8-pen-
tamethylchromene (15, 75 mg, 76%) after flash chromato-
graphy (n-hexane/diethyl ether, v/v¼18:1). TLC: Rf ¼0.33
1
(n-hexane/diethyl ether, v/v¼8:2). H NMR: d 1.40 (s, 6H,
CH3-2a), 2.02 (s, 3H, CH3-7a), 2.12 (s, 3H, CH3-8b), 2.28
(s, 3H, acetyl CH3), 5.57 (d, 1H, J¼9.7 Hz, H-3), 6.22 (d,
3
3.5. Synthesis of para-quinone hemiketals 21–24
1H, 3J¼9.7 Hz, H-4), 6.51 (s, 1H, ArH).
FeCl3 (5 equiv) was added at once into the solution of
the respective chromenol in the ternary solvent system meth-
anol/water/diethyl ether (40 mL, v/v/v¼19:1:20) at 4 ꢀC.
Acetoxychroman 12 (0.10 g, 0.43 mmol) and DDQ (0.20 g,
0.88 mmol) were employed to yield 6-acetoxy-2,2,8-

5318
A. Patel et al. / Tetrahedron 63 (2007) 5312–5318
5. Kawase, T.; Kato, S.; Lieber, C. S. Hepatology 1989, 10, 815.
6. Quinn, P. J.; Fabisiak, J. P.; Kagan, V. E. Biofactors 1999,
9, 149.
7. Gille, L.; Staniek, K.; Nohl, H. Free Radic. Biol. Med. 2001,
30, 865.
The mixture was stirred at this temperature for 1.5 h. A grad-
ual color change to yellow indicated progressing formation
of the para-quinone hemiketals. Water (50 mL) was added
and the mixture was extracted with diethyl ether. The organic
phase was washed with brine and water, dried over MgSO4,
and concentrated in vacuo. The residue was purified by flash
chromatography on silica gel to give the para-quinone hemi-
ketals as waxy solids.
8. Gregor, W.; Staniek, K.; Nohl, H.; Gille, L. Biochem.
Pharmacol. 2006, 71, 1589.
9. For the synthesis, see for instance: (a) Dean, F. M.; Matkin,
D. A.; Orabi, M. O. A. J. Chem. Soc., Perkin Trans. 1 1981,
1437; (b) Ismail, F. M. D.; Hilton, M. J.; Stefinovic, M.
Tetrahedron Lett. 1992, 33, 3795; (c) Nilsson, J. L. G.;
Sievertsson, H.; Selander, H. Acta Chem. Scand. 1968, 22,
3160; (d) Mukai, K.; Kageyama, Y.; Ishida, T.; Fukuda, K.
J. Org. Chem. 1989, 54, 552.
10. (a) Smith, L. I.; Ungnade, H. E.; Irwin, W. B. J. Am. Chem. Soc.
1940, 62, 142; (b) John, W.; Rathmann, F. H. Chem. Ber. 1941,
74, 890; (c) John, W.; Dietzel, E.; Emte, W. Hoppe-Seyler’s Z.
Physiol. Chem. 1939, 257, 173; (d) Witkowski, S.; Poplawski,
J. Bull. Pol. Acad. Sci. Chem. 1989, 37, 205; (e) Ito, S.; Aihara,
K.; Matsumoto, M. Tetrahedron Lett. 1983, 24, 5249; (f) Smith,
L. I.; Wawzonek, S.; Miller, H. C. J. Org. Chem. 1941, 6, 229;
(g) Inglett, G. E.; Mattill, H. A. J. Am. Chem. Soc. 1955, 77,
6552; (h) Parker, V. D. J. Am. Chem. Soc. 1969, 91, 5380; (i)
Grams, G. W.; Inglett, G. E. Lipids 1972, 7, 442; (j) Nagata,
Y.; Nishio, T.; Matsumoto, S.; Kanazawa, H.; Mochizuki, M.;
Matsushima, Y. Bioorg. Med. Chem. Lett. 2000, 10, 2709; (k)
Lee, S. B.; Lin, C. Y.; Gill, P. M. W.; Webster, R. D. J. Org.
Chem. 2005, 70, 10466.
3.5.1. 8a-Hydroxy-2,2,5,7,8-pentamethyl-2H,8aH-chro-
men-6-one (21). 6-Hydroxy-2,2,5,7,8-pentamethyl-chro-
man (17, 19.5 mg, 0.089 mmol) and FeCl3 hexahydrate
(0.44 mmol, 72 mg) were used as the starting materials
producing 21 as a yellow wax in 16% yield (3.3 mg) after pu-
rification by flash chromatography (n-hexane/diethyl ether,
v/v¼7:3/8:2). TLC: Rf ¼0.23 (n-hexane/diethyl ether,
v/v¼6:4).
3.5.2. 8a-Hydroxy-2,2,5,8-tetramethyl-2H,8aH-chro-
men-6-one (22). 6-Hydroxy-2,2,5,8-tetramethylchroman
(18, 24.9 mg, 0.121 mmol) and FeCl3 (0.60 mmol, 98 mg)
were used as the starting materials producing 22 as a white
waxy solid in 12% yield (3.2 mg) after purification by flash
chromatography (n-hexane/diethyl ether, v/v¼6:5/7:3).
TLC: Rf ¼0.36 (n-hexane/diethyl ether, v/v¼3:7).
3.5.3. 8a-Hydroxy-2,2,7,8-tetramethyl-2H,8aH-chro-
men-6-one (23). 6-Hydroxy-2,2,7,8-tetramethylchroman
(19, 27.6 mg, 0.135 mmol) and FeCl3 (0.67 mmol, 0.109 g)
were used as the starting materials producing 23 as a yellow
wax in 16% yield (4.7 mg) after purification by flash chroma-
tography (n-hexane/diethyl ether, v/v¼5:5/6:4). TLC:
Rf ¼0.23 (n-hexane/diethyl ether, v/v¼4:6).
11. For NMR data, see: (a) Schudel, P.; Mayer, H.; Metzger, J.;
R€uegg, R.; Isler, O. Helv. Chim. Acta 1963, 46, 645; (b)
Matsumoto, S.; Matsuo, M.; Iitaka, Y. J. Chem. Res.,
Miniprint 1987, 3, 0601; (c) Matsuo, M.; Matsumoto, S.
J. Org. Chem. 1987, 52, 3514; (d) Selander, H.; Nilsson,
J. L. G. Acta Pharm. Suec. 1972, 9, 125.
12. (a) Burton, G. W.; Doba, T.; Gabe, E. J.; Hughes, L.; Lee, F. L.;
Prasad, L.; Ingold, K. U. J. Am. Chem. Soc. 1985, 107, 7053;
(b) Omura, K. J. Org. Chem. 1989, 54, 1987; (c) Svishchuk,
A. A.; Vysotskii, N. N. Sov. Prog. Chem. (Engl. Transl.)
1975, 41, 59; (d) Foti, M. C.; Johnson, E. R.; Vinqvist,
M. R.; Wright, J. S.; Barclay, L. R. C.; Ingold, K. U. J. Org.
Chem. 2002, 67, 5190.
13. Iyer, M.; Trivedi, G. K. Synth. Commun. 1990, 20, 1347.
14. Terashima, K.; Takaya, Y.; Niwa, M. Bioorg. Med. Chem. 2002,
10, 1619.
3.5.4. 8a-Hydroxy-2,2,8-trimethyl-2H,8aH-chromen-6-
one (24). 6-Hydroxy-2,2,8-trimethylchroman (20, 23.9 mg,
0.125 mmol) and FeCl3 (0.62 mmol, 0.101 g) were used as
the starting materials producing 24 as a white waxy solid
in 15% yield (3.8 mg) after purification by flash chromato-
graphy (n-hexane/diethyl ether, v/v¼5:6/5:5). TLC:
Rf ¼0.21 (n-hexane/diethyl ether, v/v¼3:7).
Acknowledgements
15. Creed, D.; Werbin, H.; Strom, E. T. J. Am. Chem. Soc. 1971,
93, 502.
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17. See for instance: (a) Rosenau, T.; Ebner, G.; Stanger, A.; Perl,
S.; Nuri, L. Chem.—Eur. J. 2005, 11, 280; (b) Rosenau, T.;
Stanger, A. Tetrahedron Lett. 2005, 46, 7845.
18. IUPAC-IUB. Eur. J. Biochem. 1982, 123, 473.
19. IUPAC-IUB Commission on Biochemical Nomenclature
(CBN). Arch. Biochim. Biophys. 1974, 165, 1.
The work was financially supported by the Austrian Fonds
€
zur Forderung der wissenschaftlichen Forschung, project
P-17428. A.P. gratefully acknowledges the reception of the
One-World-Scholarship from the Afro-Asian Institute in
Vienna, Austria. The authors are grateful to Dr. Andreas
Hofinger and Ms. Yuko Yoneda for recording the NMR
spectra and to Dr. Falk Liebner for GC–MS analysis.
References and notes
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