A straightforward hetero-diels-alder approach to (2-ambo,4′R, 8′R)-α/β/γ/δ-4-thiatocopherol

Article abstract of DOI:10.1002/ejoc.200901493

A simple and original inverse electron demand hetero-Diels-Alder reaction has been successfully applied to the synthesis of (2-ambo,4′R,8′R)- α/β/γ/δ-4-thiatocopherol. Commercially available methyl hydroquinones and. (2E,7R,11R)-(+)-phytol were exploited for the preparation of the ortho-thioquinones, acting as electron-poor dienes, and of the proper 1,3-diene used as dienophile, respectively. The benzoxathiine cycloadducts, with the required tocopherol-like skeleton, were obtained with complete control, of regio and chemoselectivity. The antioxidant activity of 4-thiatocopherols was measured and rationalized in comparison with that of the corresponding natural components of Vitamin E.

Full text of DOI:10.1002/ejoc.200901493

FULL PAPER
DOI: 10.1002/ejoc.200901493
A Straightforward Hetero-Diels–Alder Approach to
(2-ambo,4ЈR,8ЈR)-α/β/γ/δ-4-Thiatocopherol
Stefano Menichetti,*[a] Riccardo Amorati,[b] Maria Grazia Bartolozzi,[a]
Gian Franco Pedulli,[b] Antonella Salvini,[a] and Caterina Viglianisi[a]
Keywords: Vitamins / Tocopherols / Sulfur heterocycles / Antioxidant / Cycloaddition
A simple and original inverse electron demand hetero-Diels–
Alder reaction has been successfully applied to the synthesis
of (2-ambo,4ЈR,8ЈR)-α/β/γ/δ-4-thiatocopherol. Commercially
available methyl hydroquinones and (2E,7R,11R)-(+)-phytol
were exploited for the preparation of the ortho-thioquinones,
acting as electron-poor dienes, and of the proper 1,3-diene
used as dienophile, respectively. The benzoxathiine cycload-
ducts, with the required tocopherol-like skeleton, were ob-
tained with complete control of regio and chemoselectivity.
The antioxidant activity of 4-thiatocopherols was measured
and rationalized in comparison with that of the correspond-
ing natural components of Vitamin E.
Introduction
Vitamin E (Vit. E) is a mixture of eight compounds,
namely α-, β-, γ- and δ-tocopherol 1a–d and tocotrienol 2a–
d (Figure 1), with α-tocopherol (α-TOH, 1a) being the main
and more bio-available component. Actually, after more
than 80 years from the discovery that this dietary sup-
plement is indispensable for reproduction in rats,[1] the
mechanism of action of Vit. E remains unclear.[2] Neverthe-
less, the major part of investigations indicate that the bio-
logical importance of Vit. E is connected to its antioxidant
activity.[2b] Actually, α-TOH has been demonstrated, above
all by the huge work done by K. U. Ingold and co-workers,
to be the more efficient natural lipophilic chain breaking
antioxidant.[3]
Figure 1. Vitamin E components.
While the study of the antioxidant activity of natural
compounds, including polyphenols, represents a wide field
of research, the preparation of synthetic antioxidants, with
optimized activity, solubility, bioavailability and lack of tox-
icity, is much less developed. For example, to the best of
our knowledge, only three examples of compounds with the
α-TOH structure but different hetero atoms in the chro-
mane skeleton have been reported in the literature.
ambo,4ЈR,8ЈR)-pyridinol[6] was synthesized to exploit the
high radical scavenging activity and good stability achieved
by introducing nitrogen atoms both in the saturated and in
the aromatic ring[7] (Figure 2). However, the procedures to
prepare derivatives 3a, 3b and 4 are complex, require many
steps and lead to low overall yields, and thus have not been
tested for the synthesis of β-, γ- and δ-analogues.
In this paper we report an original approach for the syn-
thesis of (2-ambo,4ЈR,8ЈR)-α/β/γ/δ-4-thiatocopherols 5a–d
(Figure 2) based on an inverse electron demand hetero-
Diels–Alder reaction (HDAR) of electron-poor ortho-
thioquinones (o-TQs), used as dienes, with a 1,3-diene act-
ing as dienophile. As a validation of the synthetic method-
ology, the antioxidant profile of derivatives 5a–d, obtained
by determining the Bond Dissociation Enthalpies (BDE) of
the phenolic OH bond and the rate constants (kinh) for the
reaction with peroxyl radicals, is also reported and rational-
ized in comparison with the activities of the natural ana-
logues.
In particular, all-rac-α-thiotocopherol[4] (3a) and α-sel-
enotocopherol[5] (3b) have been prepared in order to check
the effect of different chalcogen atoms. Derivative 4 (2-
[a] Dipartimento di Chimica “U. Schiff” Polo Scientifico e Tecnol-
ogico Università di Firenze,
Via della Lastruccia 13, 50019 Sesto Fiorentino, Italy
Fax: +39-055-4573531
E-mail: stefano.menichetti@unifi.it
[b] Dipartimento di Chimica Organica “A. Mangini” Università di
Bologna,
Via S. Giacomo 11, 40126 Bologna, Italy
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901493.
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A Straightforward Hetero-Diels–Alder Approach to Thiatocopherols
= phthaloyl), as reported in Scheme 1.[9,12,13] During the
study of o-TQs cycloaddition reactions, we discovered that
they can react as electron-poor dienes with 1,3-dienes that
behave as electron-rich dienophiles. This distinctive Diels–
Alder process occurs in any case with cyclic dienes and un-
der thermodynamic control with acyclic derivatives.[14] In
all the examples studied we observed a complete control of
regio- and chemoselectivity, thus, for example, the cycload-
dition of o-TQs with 2-methylpenta-1,3-diene affords a sin-
gle benzoxathiine product, deriving from the exclusive par-
ticipation of the 1,3-diene terminal double bond as dien-
ophile, and bearing the oxygen atom in the allylic position
(Scheme 1).[12,14]
This result prompted us to prepare the α-, β-, γ- and
δ-4-thiatocopherols with a common strategy following the
disconnection reported in Scheme 2.
Figure 2. Literature-available hetero analogues 3a, 3b, 4 of α-to-
copherol, and 4-thiatocopherols 5a–d reported in this paper.
Results and Discussion
In recent years the HDAR of o-TQs with properly substi-
tuted styrenes, used as dienophiles, allowed us to prepare
several hydroxy and methoxy substituted 2-aryl benzoxathi-
ines (Scheme 1).
Scheme 2. Disconnection for the HDAR-based synthesis of 4-thia-
tocopherols.
Methylhydroquinones were envisaged as starting materi-
als for the dienic o-TQs, while (2E,7R,11R)-phytol (7) was
chosen as a suitable precursor of the 1,3-diene 8 required
as dienophile (Scheme 2).
Indeed, the ortho-hydroxy-N-thiophthalimides 9a–d, i.e.
the precursors of the proper o-TQs, were prepared as re-
ported in Scheme 3 from commercially available 2,3,5-tri-
methyl-, 2,3-dimethyl- and 2-methylhydroquinone, while
2,5-dimethylhydroquinone was easily obtained by reduction
Scheme 1. Generation and reactivity of o-TQ as electron-poor
dienes. Reagents and conditions: a) PhtNSCl (6), CHCl3, room
temp.; b) Et3N, CHCl3, 65 °C.
We have shown that these heterocycles, for their ability to of the corresponding commercial quinone. The more hin-
act as radical scavengers, metal chelators and hydroperoxide dered phenolic OH of trimethylhydroquinone was protected
quenchers, can be considered multi-defense antioxidants, as the TBDMS ether by a known method[12] while the other
resembling flavonoids, such as catechin, and tocopherols, hydroquinones were directly monoprotected using
the two more important families of natural polyphenolic TBDMSCl and imidazole (IMI) in dry DMF. In this way,
antioxidants.[8–12]
the subsequent sulfenylations with 6 occurred regiospecif-
o-TQs were generated in situ by base-mediated elimi- ically ortho to the free OH group affording the expected N-
nation of phthalimide from ortho-hydroxy-N-thiophthal- thiophthalimides 9a–d as single, pure crystalline, indefi-
imides which, in turn, are the products of the SEAr of phen- nitely stable derivatives (Scheme 3, see Exp. Sect. and Sup-
ols with the phthalimidesulfenyl chloride 6, PhtNSCl (Pht porting Information).
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S. Menichetti et al.
FULL PAPER
tions. The best result, in terms of yield and purity of diene
8, i.e. with the lower amount of internal isomers, is reported
in Scheme 4.
Another simple transformation of phytone (10) into
diene 8 we considered was the oxidation of 10, using o-
iodoxybenzoic acid (IBX) as described by Nicolaou et al.,
to the corresponding α,β-unsaturated ketone, followed by a
Wittig olefination to introduce the required extra carbon
and the 1,3-diene function (Scheme 5).
Scheme 3. Synthesis of the o-TQ precursors 9a–d. Reagents and
condition: a) PivCl, Py, DCM, room temp.; b) TBDMSCl, IMI,
DMF, room temp.; c) KOH, MeOH/DMF, room temp.; d) 6,
CHCl3, room temp. (–10 °C for 9a).
The preparation of (6R,10R)-2,6,10,14-tetramethylpenta-
deca-1,3-diene (8) using enantiopure phytol 7 as starting
material was more synthetically demanding.
Our initial strategy, foresaw the transformation of 7 into
(6R,10R)-6,10,14-trimethylpentadeca-2-one (10), known as
phytone,[15] followed by the one-pot conversion of the latter
into diene 8 as recently reported in the literature.[16] The
synthesis of enantiopure ketone 10 was easily achieved, in
two steps and very good yield, by OsO4/NMO mediated
dihydroxylation followed by
a
Pb(OAc)4 oxidation
(Scheme 4).[17]
Scheme 5. IBX (failed) and POP paths for the synthesis of 1,3-
diene 8. Reagents and conditions: a) Ph3PCH3Br, (Me3Si)2NLi,
THF, –78 °C, 1 h, 92 %; b) TsOH (0.3 equiv.), toluene, 90 °C, 23 h,
91%; c) m-CPBA (2 equiv.), DCM, room temp., 40 min, 98%; d)
Ph3PO/Tf2O (POP, 2 equiv.), TEA (5 equiv.), K2CO3 (5 equiv.),
DCE, 90 °C, 2 h, 40 %.
Regrettably, we failed in the α,β-oxidation of 10, either
using the commercial available IBX or a freshly prepared
sample obtained with both the oxone[18] and the KBrO3
preparative methodologies.[19] We tried without success the
oxidation of 10 with IBX under the original reaction condi-
tions[20] as well as using many of the successive reported
adjustments[21] (Scheme 5).
Despite these disappointing initial results, we were able
to prepare diene 8 in satisfactory yields using phytone 10 as
starting material as depicted in Scheme 5. An initial Wittig
olefination allowed us to prepare the terminal alkene 11
which was converted into the thermodynamic internal iso-
Scheme 4. Transformation of (2E,7R,11R)-(+)-phytol (7) in
(6R,10R)-phytone (10) and one-pot synthesis of 1,3-diene 8. Rea-
gents and conditions: a) OsO4 (0.2 mol-%), NMO (2 equiv.),
tBuOH/THF/H2O, room temp., 48 h; 98%; b) Pb(OAc)4, (3 equiv.),
toluene, room temp., 2 h; 98%; c) Me2SO2, tBuOK, DMAC, 90 °C.
Then, the one-pot transformation of ketone 10 into diene mer 12 with 0.3 equiv. of TsOH in toluene at 90 C°. The
8 using dimethyl sulfone and tBuOK in dimethylacetamide alkene 12 was oxidized with m-CPBA to the corresponding
was carefully investigated.[16]
epoxide 13. These three steps occurred with very good
Unfortunately, we were unable to obtain reasonable yield yields and can be carried out without purification of the
of 8 and, more disappointingly, even stopping the reaction intermediates. Eventually, epoxide 13 reacted with freshly
far from the complete consumption of the starting ketone, prepared Hendrickson reagent (or POP)[22] to give the ex-
the target 1,3-diene was always isolated together with vari- pected 1,3-diene 8 isolated in 40% yield (Scheme 5). This
able amounts of the corresponding internal isomers, that methodology required more steps than those initially envis-
became the unique products under harsher reaction condi- aged and the yield of the last step was not brilliant. How-
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A Straightforward Hetero-Diels–Alder Approach to Thiatocopherols
ever, its simplicity and reproducibility allowed the prepara-
Kinetic measurements with peroxyl radicals were per-
tion of diene 8, isolated as single regio- and stereoisomer, formed by studying the inhibited autoxidation of styrene at
in practical amount for the following steps of the sequence 303 K in chlorobenzene, initiated by azobisisobutyronitrile
leading to the four target thiatocopherols.
(AIBN), in the presence of 5a–d, using 2,2,5,7,8-penta-
Having in hand the N-thiophthalimide precursors of the methyl-6-chromanol (PMHC) as reference antioxi-
dienic o-TQs required for the formation of α-, β-, γ- and δ- dant.[3a,27] The autoxidations were followed by monitoring
4-thiachromane aromatic ring, and the proper dienophile the oxygen consumption in an oxygen uptake apparatus
for the introduction of the phythyl aliphatic tail, we per- based on a differential pressure transducer, which has been
formed the cycloaddition reactions to produce the bicyclic described previously.[28] The observed kinetics are in agree-
skeleton. N-thiophthalimides 9a–d were treated with TEA ment with Equations (1), (2), (3), (4), (5) and (6).[27]
in CHCl3 at 65 °C to generate o-TQs 14a–d in the presence
of 1,3-diene 8 as reported in Scheme 6. To our satisfaction,
the benzoxathiines 15a–d, possessing the expected to-
copherol-like skeleton, were isolated as single regioisomers
in reasonable to good yields (Scheme 6).
(1)
(2)
(3)
(4)
(5)
(6)
With the exception of 5d, the investigated compounds
show a neat inhibition period in styrene (see Figure 3), the
length (τ) of which provides the stoichiometric coefficient,
i.e., the number of peroxyl radicals trapped by one molecule
of antioxidant: n = Ri τ/[AH], where Ri is the initiation rate,
measured in a preliminary set of experiments, and [AH] is
the concentration of antioxidants. The coefficients n for 5a–
c are in the range 1.9Ϯ0.2, typical of phenolic antioxidants
acting via reactions 5 and 6.[3a]
Scheme 6. HDAR based synthesis of α-, β-, γ- and δ-4-thiatoco-
pherol 5a–d. Reagents and conditions: a) TEA (1 equiv.), 8
(1.2 equiv.), CHCl3, 65 °C; 16 h, 64–72%; b) H2 (10 atm), Pd/C
10%, toluene, 60 °C; c) TBAF·3H2O (1 equiv.), THF, room temp.,
3 h, 56–70% over two steps.
The reduction of the C1Ј–C2Ј double bond by catalytic
hydrogenation with Pd/C, followed[23] by desilylation of
phenolic TBDMS ethers with TBAF hydrate in dry THF,
afforded the target α-, β-, γ- and δ-4-thiatocopherol 5a–d as
described in Scheme 6. The formation, during cycload-
dition, of the new stereogenic center on C2, occurred with-
out control of the absolute stereochemistry. In fact, benz-
oxathiines 15a–d, and, 4-thiatocopherols 5a–d, were ob-
tained and isolated as near 1:1 mixtures of diastereoisomers
(i.e. 2-ambo,4ЈR,8ЈR). Diastereoisomeric ratios were ob-
1
tained by H NMR spectra that showed two almost coinci-
dent and equivalent signals for the AB systems correspond-
ing to the S-CH2 groups (see experimental).[24] All the
attempts of separation, at every step of the synthetic se-
quence, were, disappointingly but not surprisingly, unsuc-
cessful.
Figure 3. Oxygen consumption recorded during the AIBN (0.05 )
initiated styrene (4.3 ) autoxidation in chlorobenzene at 303 K in
the presence of the investigated thiatocopherols and PMHC used
as a reference antioxidant (all 6.3ϫ10–6 ).
The antioxidant activity of 4-thiatocopherols 5a–d was
evaluated by measuring the rate constant (kinh) for their re-
The rates of reaction with peroxyl radicals kinh, reported
action with peroxyl radicals and the dissociation enthalpy in Table 1, were obtained by using Equation (7),[3a] where kp
of the phenolic O–H bond (BDE).
is the rate constant of propagation of styrene (41 –1 s–1).[29]
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S. Menichetti et al.
FULL PAPER
Table 1. BDE(O–H) and kinh of 4-thiatocopherols 5a–d, natural
tocopherols1a–d, BHT and BHA.
The BDE values reported in Table 1 were calculated from
the known BDE(O–H) value of the reference species ArЈOH
by means of Equation (9) with the assumption that the en-
tropic term can be neglected.[30] In this study, the reference
phenol was BHT, the revised BDE(O–H) of which is
79.9 kcalmol–1.[30,31]
[b]
[b]
BDE[a]
kinh
BDE[a] kinh
5a
78.8
80.6
80.7
1.3ϫ106
1a
1b
1c
1d
77.1[c] 3.2ϫ106 [d]
[e]
5b
7.6ϫ105
–
–
–
1.3ϫ106 [d]
1.4ϫ106 [d]
4.4ϫ105 [d]
[e]
[e]
5c
5d
BHA
BHT
5.8ϫ105
3.0ϫ105
81.8
77.2[c]
1.1ϫ105 [d]
BDE(ArO–H) = BDE(ArЈO–H) – RT lnK8
(9)
79.9[c]
1.4ϫ104 [d]
To check the reliability of the results, log(kinh) values for
5a–d were plotted against their BDE(O–H), in comparison
to reference phenols characterized by different substituents
in ortho position to the phenolic OH (Figure 5). The loga-
rithms of the rate constants for H-atom abstraction are
known to be inversely proportional to the BDE(O–H)s. The
slope and the y-intercept of these plots are dependent on
the nature of the abstracting radicals and on the steric
crowding around the phenolic OH group, respec-
tively.[30,32,33] In Figure 5 it is shown that 5b–d are on the
same line of unhindered phenols, this being consistent with
the presence, in ortho position to the OH group, of only
one methyl group in 5b,c and with the absence of any sub-
stituent in 5d. Compound 5a is near to the line of 2,6-di-
methylphenols, as expected from its structure.
[a] Solvent benzene, kcalmol–1, error Ϯ0.3 kcalmol–1. [b] Solvent
styrene/chlorobenzene, –1 s–1, error Ϯ10%. [c] From refs.[30,31] [d]
From ref.[27] [e] Not available.
–1
–∆[O2]t = kp [styrene] kinh ln(1 – t/τ)
(7)
In Table 1, the kinh values for natural tocopherols 1a–d,
and for two synthetic antioxidants, 2,6-di-tert-butyl-4-meth-
ylphenol (or butyl hydroxy toluene, BHT) and 2,6-di-tert-
butyl-4-methoxyphenol (or butyl hydroxy anisole, BHA),
are also reported.[3a,27]
The O–H bond-dissociation enthalpies (BDE) in phenols
5a–d were determined by measuring, by means of EPR
spectroscopy, the equilibrium constant, K8, for the hydro-
gen-atom transfer reaction between the investigated mole-
cule (ArOH), a reference phenol (ArЈOH) and the corre-
sponding phenoxyl radicals generated under continuous
photolysis; see Equation (8) and Figure 4.[30]
(8)
Figure 5. Plot of BDE(O–H) and logkinh values for the investigated
compounds (black dots) and for some reference phenols: (o) 2,6-
tBu-4-XPhOH; (∆) 2,6-Me-4-XPhOH; (ᮀ) 4-XPhOH.[33]
Similarly to natural derivatives, the antioxidant activity
of 4-thiatocopherols increases with the number of methyl
groups on the aromatic ring. α-4-Thiatocopherol 5a has the
lowest BDE(O–H) and is the most active antioxidant (high-
est kinh) of the compounds prepared (Table 1). The kinh
value of this compound indicate that it is a much better
inhibitor of the autoxidation reaction than, for example,
BHT and BHA, two synthetic antioxidants commonly used
as stabilizers and preservatives (Figure 6).
In agreement with our previous studies on the antioxi-
dant activity of benzoxathiines,[12] 4-thiatocopherols are
slightly poorer radical scavengers than the corresponding
tocopherols (Table 1), because the volume of the sulfur
atom and the length of the carbon–sulfur bonds induce
conformational modifications in the saturated fused ring
which decrease the stability of 4-thiatocopheroxyl radi-
cals.[12] X-ray analyses of structurally related benzoxathiines
showed that in these compounds C3 lays almost on the
Figure 4. Experimental (a, c) and simulated (b, d) EPR spectra ob-
tained irradiating a benzene solution of 5a (a, b) and a mixture of
5a and BHT (c, d) in concentration ratio 1:1.7.
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A Straightforward Hetero-Diels–Alder Approach to Thiatocopherols
was added 4-methylmorpholine N-oxide (NMO) (3.17 g,
27.00 mmol) and OsO4 (2.5% in tButOH, 220 µL, 0.017 mmol).
The solution was stirred at room temperature and checked by TLC.
After 24 h additional NMO (1.10 g, 9.40 mmol) and OsO4 (220 µL,
0.017 mmol) were added and stirring continued for further 24 h,
then saturated aqueous Na2SO3 solution was added and the mix-
ture stirred for 30 min, diluted with AcOEt, washed with aqueous
HCl (7%), water and brine, dried with anhydrous Na2SO4 and con-
centrated in vacuo to give the desired triol that was used without
further purification (4.92 g, 14.90 mmol, 98% yield). 1H NMR
(400 MHz, CDCl3): δ = 0.82–0.86 (m, 12 H), 0.97–1.56 (m, 24 H),
3.47–3.50 (m, 1 H), 3.62–3.73 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = (21 signals for 40 nonequivalent C) 19.6, 19.7, 21.0,
22.1, 22.6, 22.7, 24.5, 24.7, 27.9, 31.1, 32.76, 32.81, 37.2, 37.4, 37.5,
37.6, 39.3, 39.5, 63.2, 74.5, 75.8 ppm.
Figure 6. Schematic reaction of tocopherols with peroxyl radicals
and conformational effects on the stability of α-tocopheroxyl and
4-thia-α-tocopheroxyl radicals.
plane containing the aromatic ring, O1 and S4.[34] This
pushes C2 out of this plane more than in natural to-
copherols (Figure 6).[27,35] As a consequence, the lone pair
orbital on O1, responsible for the stabilization of 4-thia-α-
TO·, is more twisted and, hence, less conjugated with the
aromatic π-system than in tocopheroxyl radical α-TO· (Fig-
ure 3).
(6R,10R)-6,10,14-Trimethylpentadecan-2-one (10): To a solution of
the triol (4.92 g, 14.90 mmol) in toluene (170 mL) Pb(OAc)4 95%
(19.85 g, 42.56 mmol) was added at room temperature and the solu-
tion stirred for 2 h. After this time, the mixture was diluted with
Et2O and washed with a NaHCO3 saturated aqueous solution,
water and brine, dried with anhydrous Na2SO4 and concentrated
in vacuo to give ketone 10 as a colourless oil (3.94 g, 14.60 mmol,
98% yield). Spectroscopic data were in agreement with those avail-
able in literature.[15] 1H NMR (400 MHz, CDCl3): δ = 0.81–0.85
(m, 12 H), 0.96–1.64 (m, 19 H), 2.10 (s, 3 H), 2.37 (t, J = 7.6 Hz,
2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 19.5, 19.7, 21.4, 22.5,
22.6, 24.4, 24.7, 27.9, 29.7, 32.6, 32.7, 36.4, 37.17, 37.23, 37.3, 39.3,
44.1, 209.2 ppm.
Conclusions
We have shown a practical HDAR approach for the syn-
thesis of (2-ambo,4ЈR,8ЈR)-α/β/γ/δ-4-thiatocopherol. This
novel access to the tocopherol skeleton exploits the ability
of o-TQs to react with 1,3-dienes with complete control of
the regio and chemoselectivity. The activity of these very
efficient multi-defence antioxidants has been measured and
rationalized using natural tocopherols as model com-
pounds.
(6R,10R)-2,6,10,14-Tetramethylpentadec-1-ene (11): A solution of
LiHMDS 1.0  in THF (48 mL, 48.00 mmol) was added to a sus-
pension of CH3PPh3Br (17.15 g, 48.00 mmol) in dry THF (120 mL)
The possibility of application of such HDAR for the kept at –20 °C under nitrogen. The resulting mixture was warmed
to room temperature and the orange solution was stirred for 1 h,
then cooled to –78 °C and phytone (10) (1.61 g, 6.00 mmol) in dry
THF (15 mL) was added. The mixture was warmed to room tem-
perature and stirred for additional 1 h. The reaction was quenched
at –78 °C with a saturated aqueous solution of NH4Cl and ex-
tracted with DCM. The combined organic phases were washed
with water and brine, dried with anhydrous Na2SO4 and concen-
trated in vacuo. The residue was filtered through a short pad of
silica gel using petroleum ether as eluent to give 11 as a colourless
oil (1.47 g, 5.52 mmol, 92% yield). [α]2D3 = +1.87 (c = 0.2). 1H NMR
(400 MHz, CDCl3): δ = 0.84–0.88 (m, 12 H), 1.02–1.58 (m, 19 H),
1.72 (s, 3 H), 1.99 (t, J = 7.2 Hz, 2 H), 4.67–4.69 (m, 2 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 19.74, 19.75, 22.4, 22.6, 22.7,
24.5, 24.8, 25.1, 28.0, 32.7, 32.8, 36.7, 37.3, 37.40, 37.44, 38.1, 39.4,
109.5, 146.3 ppm.
preparation of other hetero-modified tocopherols is under
investigation in this laboratory.
Experimental Section
General: Unless noted otherwise, materials were purchased from
commercial suppliers and used without further purification. THF,
DMF, CHCl3, DCM and Et3N, were dried following standard pro-
cedures. Progress of reaction was monitored by thin-layer
chromatography (TLC) on commercially available precoated plates
(silica gel 60 F254) and the products were visualized with acid vanil-
lin solution. Purification of the products was performed by flash
column chromatography using silica gel 60 (230–400 mesh). Melt-
ing points were determined in a capillary tube using a Büchi 510
melting point apparatus and are uncorrected. 1H and 13C NMR
spectra were recoded at 400 or 200 and 100 or 50 MHz, respec-
tively. Chemical shifts (δ) are expressed in ppm using residual non-
deuterated solvent as an internal standard. Coupling constants (J)
are given in Hertz (Hz). Mass spectra were obtained with a Shim-
adzu QP5050. Optical rotations were measured in CHCl3. Phthal-
imidesulfenyl chloride (6) was prepared from the corresponding
commercially available disulfide (purchased from Chemper s.n.c.)
as reported elsewhere.[12] Protection as TBDMS ethers and sulf-
enylation of methyl hydroquinones have been carried out as pre-
viously reported.[12] Preparation and isolation of N-thiophthal-
imides 9a–d as well as spectroscopic details of cycloadducts 15a–d
are available as Supporting Information.
(6R,10R)-2,6,10,14-Tetramethylpentadec-2-ene (12): To a solution
of alkene 11 (651 mg, 2.45 mmol) in toluene (25 mL) p-toluenesul-
fonic acid (270 mg, 1.40 mmol) was added and the mixture was
heating at 90 °C for 23 h. The solution was cooled to room tem-
perature, diluted with hexane and washed with saturated aqueous
solution of NaHCO3, water and brine, dried with Na2SO4 anhy-
drous and concentrated in vacuo to give 12 as a coulorless oil used
without further purification (less than 4% of residual terminal iso-
mer 11 was detected) (590 mg, 2.22 mmol, 91% yield). [α]2D3 = +1.68
1
(c = 0.2). H NMR (400 MHz, CDCl3): δ = 0.84–0.88 (m, 12 H),
1.02–1.58 (m, 17 H), 1.61 (s, 3 H), 1.69 (s, 3 H), 1.88–2.06 (m, 2
H), 5.11 (t, J = 7.2 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 17.6, 19.6, 19.7, 22.6, 22.7, 24.4, 24.8, 25.6, 25.7, 28.0, 32.4,
32.8, 37.1, 37.30, 37.32, 37.4, 39.4, 125.1, 130.9 ppm.
(7R,11R)-3,7,11,15-Tetramethyl-1,2,3-hexadecanetriol: To a solu-
tion of (2E,7R,11R)-phytol (7) (purchased from Molecular Bio-
sciences, 4.50 g, 15.20 mmol) in tBuOH/THF/H2O (10:6:1 84 mL)
2,2-Dimethyl-3-[(3R,7R)-3,7,11-trimethyldodecyl]oxirane (13): To a
solution of 12 (1.23 g, 4.76 mmol) in DCM (40 mL) at 0 °C, m-
Eur. J. Org. Chem. 2010, 2218–2225
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2223

S. Menichetti et al.
FULL PAPER
CPBA (2.34 g, 9.52 mmol) was added. The reaction mixture was
stirred at room temperature for 40 min, then a 10% aqueous solu-
tion of Na2SO3 was added and stirred for additional 30 min. The
mixture was extracted with DCM, the organic phase was washed
with 6% aqueous solution of NaHCO3 and water, dried with anhy-
drous Na2SO4 and concentrated in vacuo to give 13 as a colorless
oil used without furter purification (1.32 g, 4.68 mmol, 98% yield).
1H NMR (400 MHz, CDCl3): δ = 0.83–0.88 (m, 12 H), 1.01–1.62
(m, 25 H), 2.69 (t, J = 6.2 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = (29 signals for 38 nonequivalent C) 18.6, 18.7, 19.57,
19.62, 19.7, 22.6, 22.7, 24.3, 24.4, 24.8, 24.9, 26.4, 26.5, 27.9, 32.6,
32.7, 32.8, 33.47, 33.51, 37.1, 37.26, 37.27, 37.33, 37.4, 39.3, 58.2,
58.3, 64.7, 64.8 ppm.
gel using DCM as eluent afforded 4-thiatocopherols 5a–d isolated
as pale yellow oils.
(2-ambo,4ЈR,8ЈR)-α-4-Thiatocopherol (5a): 56% Yield over two
steps. 1H NMR (400 MHz, CDCl3): δ = 0.83–0.87 (m, 12 H), 1.00–
1.75 (m, 21 H), 1.36 (s, 3 H), 2.11 (s, 3 H), 2.14 (s, 3 H), 2.17 (s, 3
H), 2.86 (two almost coincident AB systems, J = 12.8 Hz, 2 H,
CH2-S), 4.26 (s, 1 H, OH) ppm. 13C NMR (100 MHz, CDCl3): δ
= (32 signals for 56 nonequivalent C) 12.0, 12.2, 19.6, 19.66, 19.73,
21.0, 21.1, 22.6, 22.7, 23.9, 24.4, 24.8, 28.0, 32.63, 32.64, 32.8,
34.70, 34.75, 37.28, 37.33, 37.37, 37.44, 39.4, 39.8, 39.9, 72.8, 114.5,
116.5, 119.5, 124.6, 142.2, 145.2 ppm. MS: m/z (%) = 448 (35)
[M+·], 195 (23), 184 (100), 57 (40). C28H48O2S (448.75): calcd. C
74.94, H 10.78; found C 74.88, H 10.53.
(6R,10R)-2,6,10,14-Tetramethylpentadeca-1,3-diene (8): Under a ni-
trogen atmosphere, to a stirred solution of triphenylphosphane ox-
ide (661 mg, 2.33 mmol) kept at 0 °C in dry 1,2-dichloroethane
(3.4 mL), a 0.5  solution of triflic anhydride (1.73 mmol) in
dichloroethane was added dropwise and stirred at 0 °C for 10 min,
while a white precipitate of POP is formed. To this suspension dry
K2CO3 (812 mg, 5.88 mmol) was added, followed by a solution of
epoxide 13 (391 mg, 1.13 mmol) in 1,2-dichloroethane (1 mL) and
Et3N (800 µL, 5.78 mmol). The precipitate of POP dissolves
quickly. The solution was heated to reflux and stirred for 2 h. After
this time the solution was diluted with H2O and extracted with
DCM, the organic phase was dried with anhydrous Na2SO4 and
concentrated in vacuo. Purification of the residue by column flash
chromatography on silica gel using hexane/DCM, 10:1 as eluent
allowed the isolation of diene 8 as a colorless oil (118 mg, 40%
(2-ambo,4ЈR,8ЈR)-β-4-Thiatocopherol (5b): 61% Yield over two
steps. 1H NMR (400 MHz, CDCl3): δ = 0.83–0.87 (m, 12 H), 1.00–
1.74 (m, 21 H), 1.35 (s, 3 H), 2.11 (s, 3 H), 2.13 (s, 3 H), 2.87 (two
almost coincident AB systems, J = 12.8 Hz, 2 H, CH2-S), 4.28 (br.
s, 1 H, OH), 6.39 (s, 1 H, H7) ppm. 13C NMR (100 MHz, CDCl3):
δ = (31 signals for 54 nonequivalent C) 11.8, 16.1, 19.61, 19.65,
19.7, 21.00, 21.02, 22.6, 22.7, 23.9, 24.4, 24.8, 28.0, 32.6, 32.8,
34.50, 34.54, 37.28, 37.30, 37.38, 37.43, 39.4, 39.76, 39.81, 72.4,
113.8, 117.3, 117.7, 125.8, 142.6, 146.2 ppm. MS: m/z (%) = 434
(37) [M+·], 181 (34), 170 (100), 57 (48), 43 (78). C27H46O2S (434.72):
calcd. C 74.60, H 10.67; found C 74.41, H 10.76.
(2-ambo,4ЈR,8ЈR)-γ-4-Thiatocopherol (5c): 70% Yield over two
steps. 1H NMR (400 MHz, CDCl3): δ = 0.84–0.88 (m, 12 H), 1.01–
1.76 (m, 21 H), 1.37 (s, 3 H), 2.11 (s, 3 H), 2.12 (s, 3 H), 2.85 (two
almost coincident AB systems, J = 12.8 Hz, 2 H, CH2-S), 4.34 (s,
1 H, OH), 6.39 (s, 1 H, H5) ppm. 13C NMR (100 MHz, CDCl3): δ
= (32 signals for 54 nonequivalent C) 11.9, 12.1, 19.61, 19.64, 19.7,
20.99, 21.03, 22.6, 22.7, 24.1, 24.4, 24.8, 28.0, 32.60, 32.62, 32.8,
34.4, 34.5, 37.27, 37.31, 37.37, 37.43, 39.4, 39.8, 39.9, 73.4, 109.7,
113.7, 120.6, 127.9, 142.3, 147.0 ppm. MS: m/z (%) = 434 (18)
[M+·], 181 (14), 170 (75), 167 (21), 57 (44), 43 (100). C27H46O2S
(434.72): calcd. C 74.60, H 10.67; found C 75.01, H 11.03.
yield). [α]2D3 = +0.68 (c = 0.2). H NMR (400 MHz, CDCl3): δ =
1
0.83–0.88 (m, 12 H), 1.02–1.56 (m, 15 H), 1.84 (br. s, 3 H), 1.87–
1.97 (m, 1 H), 2.07–2.16 (m, 1 H), 4.86 (s, 2 H), 5.64 (dt, J = 15.2
and 7.6 Hz, 1 H), 6.12 (d, J = 15.2 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 18.7, 19.7, 22.6, 22.7, 24.5, 24.8, 28.0, 29.7,
31.9, 32.7, 37.0, 37.2, 37.3, 39.4, 40.4, 114.0, 129.7, 133.8, 142,
2 ppm. MS: m/z (%) = 264 (8) [M+·], 149 (8), 109 (36), 57 (100).
C19H36 (264.49): calcd. C 86.28, H 13.72; found C 86.58, H 13.32.
(2-ambo,4ЈR,8ЈR)-δ-4-Thiatocopherol (5d): 64% Yield over two
steps. 1H NMR (400 MHz, CDCl3): δ = 0.83–0.87 (m, 12 H), 1.01–
1.75 (m, 21 H), 1.36 (s, 3 H), 2.12 (s, 3 H), 2.85 (two almost coinci-
dent AB system, J = 12.8 Hz, 2 H), 4.32 (s, 1 H, OH), 6.40 (two
almost coincident AB systems, J = 3.2 Hz, 2 H, H5, H7) ppm. 13C
NMR (100 MHz, CDCl3): δ = (29 signals for 52 nonequivalent C)
16.3, 19.61, 19.63, 19.7, 20.9, 22.6, 22.7, 24.1, 24.4, 24.8, 28.0, 32.6,
32.8, 34.48, 34.51, 37.27, 37.32, 37.37, 37.43, 39.4, 39.8, 39.8, 73.3,
110.2, 114.6, 117.1, 129.3, 142.6, 148.3 ppm. MS: m/z (%) = 420
(26) [M+·], 167 (21), 156 (86), 57 (53), 43 (100). C26H44O2S (420.69):
calcd. C 74.23, H 10.54; found C 74.49, H 10.73.
Cycloaddition Reactions. General Procedure: The cycloaddition re-
actions were carried out heating the o-hydroxy-N-thiophthalimide
derivatives 9a–d with 1 equiv. of Et3N and 1.2 equiv. of diene 8 in
dry chloroform (0.05 ) at 65 °C. After 16 h, a complete consump-
tion of the thiophthalimides was monitored by TLC, evaporation
of the solvent and flash chromatography on silica gel allowed the
isolation of the cycloadducts 15a–d, spectroscopic details are avail-
able as Supporting Information
Hydrogenation Reactions. General Procedure: In a glass vial placed
in a stainless-steel autoclave, a solution of compounds 15a–d in
toluene (0.04 ) and 5% Pd/C (10mol-%) were introduced. The
autoclave was then pressurized at room temperature with 10 atm
H2, placed in a thermostatic oil bath at 60 °C (Ϯ 1 °C) and rocked
overnigth. At the end of the reaction, the autoclave was cooled to
room temperature and the gaseous contents were vented off. Fil-
tration through a Celite pad and evaporation of the solvent gave
the reduced cycloadducts as yellow oils, used without further puri-
fication in the next step.
Kinetic Experiments: The rate constants for the reaction with per-
oxyl radicals, kinh, were measured by following the oxygen con-
sumption during the autoxidation of styrene (4.3 ) in chloroben-
zene at 30 °C using AIBN (0.05 ) as radical initiator, in the pres-
ence of compounds 5a–5d and in concentrations ranging from 3 to
9ϫ10–6 . The reaction was performed in an oxygen uptake appa-
ratus built in our laboratory[28] using a procedure previously de-
scribed.[12] The rate of initiation Ri was determined in preliminary
experiments using PMHC as reference antioxidant, whose n = 2.[3a]
Desilylation Reactions. General Procedure:
A
solution of
TBAF·3H2O (1 equiv.) in dry THF (0.05 ) was added dropwise to
a solution of TBDMS ethers, in dry THF (0.05 ) kept at room
temperature. The reactions were monitored by TLC untill the dis-
appearance of silylated starting product (roughly 3 h). The solu-
tions were diluted with DCM, washed with saturated aqueous
NH4Cl solution and H2O, dried with anhydrous Na2SO4 and con-
centrated in vacuo. Purification by flash chromatography on silica
Thermochemical Measurements: The BDE(O-H) values were deter-
mined by using the EPR equilibration technique, which consists in
photolyzing concentrated (0.05 ) benzene solutions of the investi-
gated compound and a reference phenol (BHT) in the presence of
di-tert-butyl peroxide (5% v/v).[30] As the consumption of the re-
acting phenols is negligible, the equilibrium constant can be calcu-
2224
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2218–2225

A Straightforward Hetero-Diels–Alder Approach to Thiatocopherols
[16]
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[18]
[19]
[20]
Supporting Information (see also the footnote on the first page of
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Acknowledgments
Financial support from Ministero dell’Università e della Ricerca
(MIUR) (research projects “Radicals and Radical Ions: Basic As-
pects and Role in Chemistry, Biology, and Material and Environ-
mental Sciences”, contract 2006033539 and “Stereoselection in Or-
ganic Synthesis: Methodology and Application”, contract
2007FJC4SF) is gratefully acknowledged. Ente Cassa di Risparmio
di Firenze and Consorzio Interuniversitario Nazionale, Metodolo-
gie e Processi Innovativi di Sintesi (CINMPIS) are acknowledged
for grants to C. V. and M. G. B., respectively.
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Received: December 22, 2009
Published Online: March 2, 2010
Eur. J. Org. Chem. 2010, 2218–2225
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2225