On the dimers of β-tocopherol

Article abstract of DOI:10.1016/j.tet.2011.05.006

Upon oxidation in aprotic media, β-tocopherol (2) forms a spiro-dimer (10) as the main product. The reaction mechanism is a hetero-Diels-Alder process with inverse electron demand of two intermediate ortho-quinone methide molecules. The spiro-dimer can be

Full text of DOI:10.1016/j.tet.2011.05.006

Tetrahedron 67 (2011) 4858e4861
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
On the dimers of b-tocopherol
a
a
b
c
a,
*
€
Stefan Bohmdorfer , Anjan Patel , Thomas Netscher , Lars Gille , Thomas Rosenau
a University of Natural Resources and Life Sciences Vienna (BOKU), Department of Chemistry, Muthgasse 18, A-1190 Vienna, Austria
b DSM Nutritional Products, Research and Development, PO Box 2676, CH-4002 Basel, Switzerland
c
€
Molecular Pharmacology and Toxicology Unit, Department of Biomedical Sciences, University of Veterinary Medicine Vienna, Veterinarplatz 1, A-1210 Vienna, Austria
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 April 2011
Received in revised form 29 April 2011
Accepted 3 May 2011
Available online 10 May 2011
Upon oxidation in aprotic media, b-tocopherol (2) forms a spiro-dimer (10) as the main product. The
reaction mechanism is a hetero-DielseAlder process with inverse electron demand of two intermediate
ortho-quinone methide molecules. The spiro-dimer can be reduced to the corresponding symmetric
ethano-dimer (11). In contrast to the well-studied
not form a reversible redox pair, their interconversion is accompanied by coupling reactions at C-7 with
7a-( -tocopher-5a-yl)- -tocopherol (13) as the main byproduct besides some oligomeric material. The
full NMR assignments (1H, 13C) of the
-tocopherol oxidation products are given.
Ó 2011 Elsevier Ltd. All rights reserved.
a-tocopherol case, spiro-dimer and ethano-dimer do
b
b
b
1 R1=R2=R3=Me, α-tocopherol
2 R1=R3=Me, R2=H, β-tocopherol
3 R2=R3=Me, R1=H, γ-tocopherol
4 R3=Me, R1=R2=H, δ-tocopherol
1. Introduction
5a
R1
Vitamin E, a term often used synonymously (and incorrectly)
-tocopherol (1), is a mixture of four tocopherols and four
tocotrienols, the latter subgroup possessing an unsaturated side
chain. Among the tocopherols, the -form is the most common, it
also has the highest vitamin E activity. With the recent recogni-
tion of important non-antioxidant functions of
-tocopherol,1 the
attention for the non- -tocopherols, which offer free aromatic
positions at the aromatic core, increased as well. They thus rep-
resent desmethyl derivatives of the -congener and differ in the
number and position of aromatic methyl substituents. In contrast
4
5
6
4a
8a
for
a
HO
3
2a
1'
1
O
a
7
R2
7a
2
12'
4'
8'
8
R2
8b
a
a
RR-C16H33
a
2. Results and discussion
to a
-tocopherol, they are potent traps of electrophiles,2 such as
nitroxide-derived3 or halogen-derived species.4 The 5a-methyl
group, which is critically involved in the formation of the ortho-
quinone methide (oQM) intermediate and the resulting spiro-
The oxidation chemistry of
a
-tocopherol (1) has been well
-tocopherol (1),7 the
established for quite some time.6 When
a
main component in vitamin E, is oxidized under aprotic conditions,
it affords an ortho-quinone methide (oQM, 5). This primary in-
termediate is formed quite selectively at position C-5a while for-
mation at position C-7a is minor (97% vs 3% at rt).6 This
intermediate and the reason for its selectivity of formation have
been studied in detail, also with regard to the concept of strain
induced bond localization in benzo-anellated aromatics.8 If no
coreactants or trapping agents, for example, electron-rich dien-
ophiles, are present, oQM 5 undergoes dimerization to the so-
dimer in the case of
a-tocopherol, is missing in the g- and
d
-counterparts (3 and 4), which thus show a completely different
oxidation behavior.5
b
-Tocopherol (2), however, offers the
-tocopheroldbut lacks the 7a-methyl
-tocopherol is only a minor constituent in
natural and semisynthetic vitamin E mixtures as compared to the
dominant - and -forms, it is certainly an integral constituent of
such mixtures. In the present study, we would like to communi-
cate the dimerization behavior of -tocopherol in comparison to
its well-studied -counterpart and for the first time report the full
5a-methyl groupdas does
substituent. Although
a
b
a
g
b
called spiro-dimer of a-tocopherol (6), an interesting compound
a
for which a structure of two rapidly interconverting diastereomers
was demonstrated and a full NMR assignment was performed9 (see
Scheme 1, path A). This dimer is one of the major tocopherol
oxidation products both in vitro and in vivo. Reduction of the spiro-
NMR assignment of its spiro-dimer and ethano-dimer and the
side products in this oxidation system.
dimer forms the so-called ‘ethano-dimer of
a-tocopherol’, an 1,2-
* Corresponding author. Tel.: þ43 1 36006 6071; fax: þ43 1 36006 6059; e-mail
address: thomas.rosenau@boku.ac.at (T. Rosenau).
bis( -tocopher-5-yl)ethane (7). This compound is quantitatively
g
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.006

€
S. Bohmdorfer et al. / Tetrahedron 67 (2011) 4858e4861
4859
Ag2O (5 eq.),
CHCl3, r.t.,
quantitative
O
HO
A
O
R
O
R
5
1
R
O
O
R
immediate
spiro-
dimerization
B
O
FeCl3, MeOH/H2O,
r.t., quantitative
HO
red.
ox.
O
HO
O
O
R
O
R
6
O
R
7
8
HO
Scheme 1. Oxidation chemistry of a
-tocopherol (1). Spiro-dimer 6 and ethano-dimer 7 form a reversible redox pair.6
oxidized back into spiro-dimer 6 under aprotic conditions. This
happens almost independently of the oxidant used, and also in
two-phase systems containing the oxidant in the aqueous
phase and the tocopherol in the organic phase the reconversion
of 7 into 6 is complete. Thus, spiro-dimer and ethano-dimer of
While re-oxidation to the spiro-dimer is quantitative in the a-
tocopherol case, the oxidation of 11 back to spiro-dimer 10 was in
our hands impossible to conduct in a quantitative way. Best yields
were again achieved with an excess of freshly prepared silver oxide
(92%), but even in this optimum case oligomeric byproducts (14)
were formed. With other oxidants (DDQ, Pb(OAc)4, Cr(VI) com-
pounds) these oligomers even became dominant, yields of 10
dropping drastically below 20e30%. In protic media, oxidation of 11
afforded both oligomers 14 and the corresponding bis(para-qui-
none), but no 10 was produced.
a
-tocopherol form a largely reversible redox pair in aprotic media,
and this redox ‘cycling’ can be performed several times without
any loss of material due to side reactions. Under protic conditions,
a
-tocopherol is oxidized quantitatively to a-tocopheryl quinone (8)
(see Scheme 1, path B), and ethano-dimer 7 affords a mixture of
spiro-dimer 6 and small amounts of the corresponding bis(para-
quinone).6
Byproduct 13, formed upon aprotic oxidation of
(2), and the oligomeric products 14, which resemble 13 in having
7a-( -tocopher-5a-yl)- -tocopheryl substructures, are also worth
mentioning: compound 13 is formed by the alkylating action
of oQM 9 toward excess -tocopherol (2). It is a competitive re-
b-tocopherol
Oxidation of
water/alcohol mixtures, provides quantitative yields of
pheryl quinone (12), the analytical data of which we have recently
described.10 By oxidation of
-tocopherol (2) with excess silver
oxide in aprotic media, the spiro-dimer of -tocopherol (10) is
b-tocopherol (2) in protic media, such as water or
b
b
b-toco-
b
b
action to the dimerization of two molecules of oQM 9 to spiro-
dimer 10 (Scheme 2). Accordingly, these byproducts dominate
if little excess of oxidant is used so that formed oQM always
b
formed quantitatively via the oQM 9. When working in a two-
phase system with the tocopherol dissolved in petroleum ether
and alkaline potassium ferricyanide as the oxidant in the aqueous
phase, the yields of 10 from 2 were indeed good, between 82% and
encounters spare
b-tocopherol to react with. A large excess of
oxidant generates high concentrations of oQM, thus spiro-dimer
production is favored. MALDI analysis of 14 showed that all
components were exclusively composed of b-tocopheryl units
88%,11 but not quantitative as in the
b
a
-case. As side products,
-tocopheryl quinone (12, 10e14%) and 7a-( -tocopher-5a-yl)-
-tocopherol (13, 2e4%) were formed. This procedure, which is the
-tocopherol spiro-
-tocopherol,12 is thus inferior in the
-tocopherol
b
(M¼414.7 g molꢀ1), from trimer (M¼1246.1 g molꢀ1) to nonamer
(M¼3734.3 g molꢀ1), the pentamer (M¼2075.5 g molꢀ1) and
hexamer (M¼2490.2 g molꢀ1) being most prominent in this
oligomer mixture (Scheme 2). NMR spectra confirmed a regular
structure, the terminal C-7 protons distinctively resonating at
6.62 ppm (1H) and the methylene bridges at 24.3 ppm (13C). Due
to the structural similarity of the compounds, shift differences
b
‘classical’ protocol for the formation of the
dimer from
a
a
b
case and cannot be recommended, especially as 10 and 13 are
difficult to separate by column chromatography. Also other oxi-
dants gave a good to excellent, yet not a quantitative outcome. The
1H NMR spectrum of 10 exhibits two characteristic singlets at
6.60 ppm and 5.78 ppm representing one aromatic and one vinylic
proton, respectively. The resonances at 2.07 ppm and 1.98 ppm
originate from the two 8b-methyl groups at the aromatic and
quinoid moiety. In the 13C NMR spectrum, resonances at 202 ppm
(carbonyl carbon, C-60), 147 ppm (phenol ether carbon, C-6), and
81 ppm (spiro carbon, C-50) are indicative of the spiro-dimer
structure, as well as the two carbons of the ethylene bridge
in the central ring resonating at 18 ppm (C-5a) and 27 ppm (C-5a0).
The atom numbering (see also Experimental section) is based on
the numbering of tocopherols, denoting the spiro-moiety with
primed numbers.
between the
b-tocopheryl units in the different oligomers are
negligible in both the 1H and 13C domains.
Two-dimensional ROESYexperiments proved that 10 consisted of
a mixture of two interconverting diastereomers (Scheme 3), similar
€
to the spiro-dimer of a-tocopherol (6) examined by Schroder and
Netscher.13 A fluxional nature was thus confirmed for both spiro-
dimers, the interconversion rate of the -compounds being
slightly slower than that of the -compound as shown by
b
a
temperature-dependent NMR measurements. A rough approxima-
tion of the relative rates gave an activation energy difference of
25 kJ molꢀ1, so that at rt the interconversion of the
a-dimer would be
3.2 times faster than that of the b-counterpart.
Reduction of spiro-dimer 10 to the corresponding ethano-dimer
11 proceeds quantitatively, regardless of the reductants used (sulfite,
ascorbate, NaBH4, ferrous sulfate), a reaction behavior, which par-
Establishing the analytical data of the oxidation products of
-tocopherol will help in the analysis of the complex in vivo reaction
b
mixtures of vitamin E, since the minor constituents of these mix-
tures derived from -tocopherol and -tocopherol are rather diffi-
cult to analyze. We hope that this study will help to improve the data
situation for -tocopherol oxidation products and render it similarly
satisfying as that of the well-studied - and -constituents.
allels that of
a
-tocopherol. Though ethano-dimer 11 is very similar
b
g
to
b
-tocopherol, it can be identified in 1H NMR by the 4-methylene
protons resonating at 2.73 ppm (vs 2.62 ppm in 2) and the aromatic
proton at C-7 resonating at 6.56 ppm (vs 6.39 ppm in 2).
b
a
g

€
4860
S. Bohmdorfer et al. / Tetrahedron 67 (2011) 4858e4861
R
O
O
R
HO
O
quantitative
reduction
14
1-7
O
R
HO
O
R
HO
HO
12
2
11
FeCl3, r.t.,
MeOH/H2O,
quantitative
+
HO
R
O
ox. (Ag2O, 5 eq.,
CHCl3, -78°C)
R
R
HO
O
O
O
O
R
HO
O
oxidation
+ oligomeric
byproducts
immediate
HO
spiro-
O
HO
dimerization
O
R
O
R
O
R
10
O
R
9
13
Scheme 2. Oxidation chemistry of
b
-tocopherol (2). Under protic conditions, b-tocopheryl quinone (12) is formed. Spiro-dimer 10 is formed quantitatively only under carefully
controlled conditions. Reduction of 10 to the ethano-dimer 11 is quantitative, but re-oxidation is not, precluding full redox reversibility between 10 and 12.
colorless oil solidifying to a wax below 15 ꢂC (0.82 g, 99%). TLC:
R
R
O
Rf¼0.64 (n-hexane/ethyl acetate, v/v¼19:1). 1H NMR
d: 0.80e0.91
(24H, H-s13, H-s12a, H-s8a, H-s4a; H-s130, H-s12a0, H-s8a0, H-s4a0),
1.00e1.18,1.20e1.46 (16H, H-s3, H-s5, H-s7, H-s9; H-s30, H-s50, H-s70,
H-s90), 1.06e1.39 (8H, H-s6, H-s10; H-s60, H-s100), 1.12e1.17 (4H, H-
O
O
O
O
s11, H-s110),1.24 (3H, H-2a
2a0
*
),1.24e1.48 (4H, H-s2, H-s20),1.25 (3H, H-
*
), 1.32e1.46 (4H, H-s4, H-s8; H-s40, H-s80), 1.52 (4H, H-s1, H-s10),
O
1.52e1.55 (2H, H-s12, H-s120), 1.60e1.78 (4H, H-3, H-30), 1.92 and
2.02 (4H, 5a, 5a0), 1.98 (3H, H-8a0), 2.05 and 2.42 (2H, H-4a and H-
4a0), 2.07 (3H, H-8a), 2.32, 2.48, 2.54, 2.60 (2H, H-4b and H-4b0), 5.78
O
10
R
O
R
(1H, H-70), 6.60 (1H, H-7). 13C NMR : 16.0 (C-8b), 16.5 (C-40), 17.6 (C-
d
8b0), 18.0 (C-5a), 18.6 (C-4), 19.7, 19.8 (C-s8a, C-s4a), 20.9 (C-s2), 22.3
(C-2a), 22.6 (C-2a0), 22.6, 22.7 (C-s13, C-s12a), 24.5 (C-s6), 24.8 (C-
s10), 27.3 (C-5a0), 27.9 (C-s12), 29.9 (C-3), 30.3 (C-30), 32.6, 32.7 (C-s4,
C-s8), 37.2e37.5 (C-s3, C-s5, C-s7, C-s9), 39.1 (C-s11), 40.2, 40.25 (C-
Scheme 3. Interconversion process in spiro-dimer 10.
3. Experimental
s1), 73.4 (C-2), 74.7 (C-20), 81.4 (C-50), 115.6 (C-7), 115.9 (C-4a
), 117.7
*
3.1. General
-Tocopherol (2) was used as the starting material.14 The
(C-4a0
*
), 118.4 (C-5
), 121.3 (C-7), 125.1 (C-8), 143.1 (C-8a0), 145.6 (C-
*
8a), 147.1 (C-6), 152.4 (C-80), 202.1 (C-60). Calcd for C56H92O4: C 81.10,
H 11.18. Found: C 81.02, H 11.28.
(all-R)-
b
b
-tocopherol model compound 2a was available from previous
work.3 All other chemicals were obtained from commercial sup-
pliers (SigmaeAldrich). Thin layer chromatography (TLC) was per-
formed on silica gel 60 plates (5ꢁ10 cm, 0.25 mm) with
fluorescence detection under UV light at 254 nm. Column chro-
3.1.2.
b-Tocopherol ethano-dimer (11). b-Tocopherol spiro-dimer
(10, 0.50 g, 0.60 mmol) was dissolved in iso-propanol (20 ml) and
sodium borohydride (2 mmol) was added. The mixture was stirred
at 40 ꢂC for 2 h, neutralized by slow addition of 1 N HCl and
extracted three times with n-hexane. The combined extracts were
washed with water and dried over Na2SO4. The residue obtained
after separation of the solids and evaporation of the solvent was
purified by flash chromatography (n-hexane/ethyl acetate, v/
v¼9:1). TLC: Rf¼0.33 (n-hexane/ethyl acetate, v/v¼9:1), white wax
matography was performed on silica gel G60 (40e63 mm).
1H NMR spectra were recorded at 400.13 MHz for 1H and at
100.13 MHz for 13C NMR in CDCl3 if not otherwise stated. Chemical
shifts, relative to TMS as internal standard, are given in
d values,
coupling constants in hertz. 13C peaks were assigned by means of
APT, HMQC, and HMBC spectra, which were acquired according to
standard pulse programmes.15 Two-dimensional ROESY experi-
ments used the following parameters: 1024 t1 data points, 2048 t2
data points, zero filling, mixing time 0.5 s, resolution f1: 4 Hz (1H)
and 16 Hz (13C) and f2: 2 Hz. Resonances of the isoprenoid side
chain, denoted by the letter s followed by the numbering, are only
negligibly affected (<0.1 ppm for 13C) by modifications of the
chroman skeleton, the corresponding side chain resonances are
(0.50 g, 99%). 1H NMR
d: 0.80e0.91 (24H, H-s13, H-s12a, H-s8a,
H-s4a), 1.00e1.46 (16H, H-s3, H-s5, H-s7, H-s9), 1.06e1.39 (8H,
H-s6, H-s10), 1.10e1.19 (4H, H-s11), 1.24e1.42 (4H, H-s2), 1.26 (6H,
H-2a), 1.32e1.44 (4H, H-s4, H-s8), 1.51e1.56 (2H, H-s12), 1.52 (4H,
H-s1), 1.64e1.82 (4H, H-3), 2.12 (6H, H-8a), 2.71 (4H, s, H-5a), 2.73
(4H, t, JH,H¼7.1 Hz, H-4), 5.46 (2H, s, OH), 6.56 (2H, H-7). 13C NMR
d:
16.0 (C-8b), 19.7, 19.8 (C-s4a, C-s8a), 20.5 (C-4), 20.7 (C-s2), 22.6,
22.8 (C-s13, C-s12a), 23.8 (C-2a), 24.5 (C-s6), 24.7 (C-s10), 26.7
(C-5a), 27.9 (C-s12), 31.4 (C-3), 32.6, 32.7 (C-s4, C-s8), 37.2e37.5
(C-s3, C-s5, C-s7, C-s9), 39.1 (C-s11), 40.2 (C-s1), 74.4 (C-2), 115.8
thus very similar for all four tocopherols. An asterisk (
assignment that can be exchanged.
*
) denotes
(C-7), 118.9 (C-5), 123.3 (C-4a), 124.9 (C-8), 146.0 (C-6
*
*
), 146.1 (C-
3.1.1.
b-Tocopherol spiro-dimer (10). b-Tocopherol (2, 0.83 g,
8a ). Calcd for C56H94O4: C 80.91, H 11.40. Found: C 80.87, H 11.52.
2 mmol) was dissolved in MeCN (20 ml) and freshly precipitated and
pulverized Ag2O (10 mmol, 2.32 g) was added at once. The mixture
was stirred at rt for 10 min, solids were filtered off, and the solvent
was removed in vacuo. The oily residue was purified by flash chro-
matography (n-hexane/ethyl acetate, v/v¼19:1) to provide 10 as
3.1.3.
b-Tocopheryl quinone (12). b-Tocopherol (2, 0.83 g, 2 mmol)
was dissolved in 50 ml of methanol and a solution of FeCl3
hexahydrate (12 mmol, 3.25 g) in 100 ml of water was added. The

€
S. Bohmdorfer et al. / Tetrahedron 67 (2011) 4858e4861
4861
mixture was stirred for 10 min at rt and extracted three times with
Acknowledgements
n-hexane (50 ml each). The combined organic extracts were
washed with diluted acetic acid (1 N, 50 ml) and two times with
water (50 ml each) and dried over Na2SO4. The solids were filtered
off and the solvent was evaporated in vacuo at rt. Purification by
flash chromatography (n-hexane/diethyl ether, v/v¼9:1) afforded
a colorless oil (0.79 g, 92%). TLC: Rf¼0.39 (n-hexane/diethyl ether,
€
The financial support by the Austrian Fonds zur Forderung der
wissenschaftlichen Forschung, project P-19081 is gratefully
acknowledged.
References and notes
v/v¼9:1). 1H NMR
d: 1.29 (s, 6H, H-2a), 1.52 (m, 2H, H-3), 1.74 (br s,
ꢀ
1. (a) Azzi, A.; Stocker, A. Prog. Lipid Res. 2000, 39, 231e255; (b) Brigelius-Flohe, R.;
1H, eOH), 2.03 (s, 6H, H-5a, H-8b), 2.57 (m, 2H, H-4), 6.55 (q, 1H,
Galli, F. Mol. Nutr. Food Res., 54, 583e587, and the whole volume.
2. Christen, S.; Woodall, A. A.; Shigenaga, M. K.; Southwell-Keely, P. T.; Duncan, M.
W.; Ames, B. N. Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 3217e3222.
3. Patel, A.; Liebner, F.; Netscher, T.; Mereiter, K.; Rosenau, T. J. Org. Chem. 2007, 72,
6504e6512.
4JH,H¼1.3 Hz, H-6), numbering of tocopherols maintained, data of
isoprenoid side chain not given. 13C NMR
d: 11.6 (C-5a),15.8 (C-8b),
21.6 (C-4), 26.0 (C-2a), 41.9 (C-3), 70.7 (C-2), 133.1 (CH in quinone),
140.6, 144.9, 145.4 (C in quinone), 187.7, 187.8 (C]O in quinone),
isoprenoid side chain: 19.76 (C-4a0), 19.84 (C-8a0), 21.1 (C-20),
22.67 (C-130), 22.74 (C-12a0), 24.5 (C-60), 24.6 (C-100), 28.0 (C-120),
32.64 (C-80), 32.75 (C-40), 37.3 (C-70), 37.46 (C-50), 37.47 (C-90),
37.52 (C-30), 39.3 (C-110), 39.7 (C-10). Calcd for C28H48O3: C 77.73, H
11.18. Found: C 77.65, H 11.30.
€
4. Patel, A.; Bohmdorfer, S.; Hofinger, A.; Netscher, T.; Rosenau, T. Eur. J. Org. Chem.
2009, 4873e4881.
5. The oxidation behavior of g- and d-tocopherol is the subject of a forthcoming
study reporting the main products and byproducts of oxidation under aprotic
conditions.
6. (a) The Encyclopedia of Vitamin E; Preedy, V. R., Watson, R. R., Eds.; CABI:
Wallingford, 2007; (b) Rosenau, T.; Bohmdorfer, S. In Quinone Methides; Steven,
€
E. R., Ed.; Wiley-VCH: Weinheim, 2009; pp 163e215.
7. (a) The Encyclopedia of Vitamin E; Preedy, V. R., Watson, R. R., Eds.; CABI:
€
Wallingford, 2007; (b) Baldenius, K. U.; von dem Bussche-Hunnefeld, L.; Hil-
3.1.4. 7a-(b-Tocopher-5a-yl)-b-tocopherol (13). b-Tocopherol (2,
€
gemann, E.; Hoppe, P.; Sturmer, R. In Ullmann’s Encyclopedia of Industrial
0.83 g, 2 mmol) was dissolved in MeCN (20 ml) and freshly pre-
cipitated and pulverized Ag2O (2 mmol, 0.46 g) was added slowly
during 10 min. The mixture was stirred at rt for another 10 min,
solids were filtered off, and the solvent was removed in vacuo. The
oily residue was purified by flash chromatography (n-hexane/ethyl
acetate, v/v¼19:1) eluting first spiro-dimer 10 (see above, 36%),
followed by 13 (colorless oil, 47%) and by unchanged starting ma-
Chemistry; VCH Verlagsgesellschaft: Weinheim, 1996; Vol. A27, pp 478e488, pp
594e597; (c) Vitamin E in Health and Disease; Packer, L., Fuchs, J., Eds.; Marcel
Dekker: New York, NY, 1993; (d) Isler, O.; Brubacher, G. Vitamins I; Georg
Thieme: Stuttgart, 1982, pp 126.
8. Rosenau, T.; Ebner, G.; Stanger, A.; Perl, S.; Nuri, L. Chem.dEur. J. 2005, 11,
280e287.
9. The issue of the two diastereomers formed by attack of the phenolic OH at
either side of oQM-1 and their interconversion has been discussed including
a full NMR assignment: See Ref. 13. An earlier work proposed a fluxational
structure with the two diastereomers contributing Fales, H. M.; Lloyd, H. A.;
Ferretti, J. A.; Silverton, J. V.; Davis, D. G.; Kon, H. J. J. Chem. Soc., Perkin Trans. 2
1990, 1005e1010.
terial. TLC: Rf¼0.22 (n-hexane/ethyl acetate, v/v¼19:1). 1H NMR
d:
1.28 (s, 6H, CH3), 1.80 (m, 4H, H-30, H-3), 1.98, 2.02, 2.16 (s, 9H,
AreCH3), 2.62 (t, 1H, H-4, JH,H¼7.1 Hz), 2.70 (t, 2H, H-4, JH,H¼7.1 Hz),
10. Patel, A.; Netscher, T.; Gille, L.; Mereiter, K.; Rosenau, T. Tetrahedron 2007, 63,
5.00 (s, 1H, eOH), 6.62 (s, 1H, H-7). 13C NMR
d: 11.6 (C-5a), 15.8,15.9
5312e5318.
(C-8b, C-8b0), 21.6, 21.65 (C-4, C-40), 23.6, 23.8 (C-2a, C-2a0), 24.3 (C-
5a0), 31.4, 31.5 (C-3, C-30), 74.4, 74.5 (C-2, C-20), 116.0 (C-70), 117.3 (C-
4a), 118.9 (C-5), 119.6 (C-4a0), 121.5 (C-7), 121.8 (C-8), 124.0 (C-50),
124.4 (C-80), 144.1 (C-6), 144.9 (C-60), 145.1 (C-8a), 146.1 (C-8a0).
Calcd for C56H94O4: C 80.91, H 11.40. Found: C 81.02, H 11.42. Res-
onances of the isoprenoid side chain are identical (ꢃ0.05 ppm) to
those of ethano-dimer 11.
11. The given ranges of yield are from 12 experiments with slightly altered reaction
conditions. Varied parameters: concentration of oxidant in the aqueous phase,
temperature, reaction time.
12. Nilsson, J. L. G.; Daves, G. D., Jr.; Folkers, K. Acta Chem. Scand. 1968, 22, 207e218.
€
13. Schroder, H.; Netscher, T. Magn. Reson. Chem. 2001, 39, 701e708.
14. Possible erosion of the stereochemistry, especially at C-2, as a consequence of
the chemical manipulations was not further studied.
15. Braun, S.; Kalinowski, H.-O.; Berger, S. 150 and More Basic NMR Experiments: A
Practical Course;
Wiley-VCH: Weinheim, 1998.