A synthesis of α-tocopherol featuring benzyne trapping by an alcohol

Article abstract of DOI:10.1016/j.tetlet.2009.03.022

A formal total synthesis of α-tocopherol, the main component of Vitamin E, has been achieved in which a central step is the intramolecular trapping of a highly substituted benzyne by an alcohol group to establish the pyran ring.

Full text of DOI:10.1016/j.tetlet.2009.03.022

Tetrahedron Letters 50 (2009) 3534–3537
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A synthesis of
a
-tocopherol featuring benzyne trapping by an alcohol
*
David W. Knight , Xu Qing
School of Chemistry, Cardiff University, Main College, Park Place, Cardiff, CF10 3AT, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A formal total synthesis of a-tocopherol, the main component of Vitamin E, has been achieved in which a
central step is the intramolecular trapping of a highly substituted benzyne by an alcohol group to estab-
lish the pyran ring.
Received 6 January 2009
Revised 26 February 2009
Accepted 5 March 2009
Available online 11 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
This Letter is dedicated to the memory of
Professor Charles W. Rees of Imperial
College, London
a
-Tocopherol 1 is the major component of the naturally occur-
of which are based on an early synthesis by Cohen et al.5 The es-
sence of this strategy (Scheme 2) is disconnection of the phytyl
chain to give the alcohol 4, which is prepared by reduction of the
ketone function in the acetal 5, derived from the quinone 6. The
variations in many such syntheses are then in exactly how the qui-
none 6 or a similar intermediate is prepared.
ring ‘Vitamin E’ mixture, which is generally composed of a mixture
of less methylated tocopherols along with the four tocotrienols
having alkenes in the side-chain but the same methylation pattern
around the aryl ring.1
In order to introduce asymmetry into this method, more recent
applications have included precursor synthesis using Sharpless
asymmetric epoxidation,6 asymmetric dihydroxylation7 and various
asymmetric palladium-catalysed C–O bond formations (asymmetric
allylic alkylation and relatives).8 A neat application of Grubbs olefin
cross-metathesis has also contributed to methodology in the area,9
while a highly diastereoselective biomimetic approach indicates
how the chroman ring might be synthesised in Nature.10
HO
O
1
a
-Tocopherol acetate is produced on a multi-ton industrial
scale as a complete racemate by an acid-catalysed coupling be-
tween trimethylhydroquinone and phytol or isophytol followed
by acetylation,2,3 and is added to a wide variety of foods, pharma-
ceuticals and cosmetics where it functions as an anti-oxidant, often
by the mechanism summarised in Scheme 1, wherein a phenoxide
radical 2 is initially generated, which then undergoes ring opening
and trapping by water to give a quinone 3.4
In our exploration of new ways to prepare substituted benzy-
nes, we have defined new metallation strategies that are highly
suited to the elaboration of the amino-benzotriazole benzyne
RO
O
1
The industrial syntheses contrast somewhat with various smal-
ler-scale approaches that have been reported in recent times, many
O
O
O
OH
4
5
O
O
OH
R
OH
OH
O
R
O
O
3
2
O
Scheme 1.
6
* Corresponding author.
E-mail addresses: knightdw@cardiff.ac.uk, knightdw@cf.ac.uk (D.W. Knight).
Scheme 2.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.022

D. W. Knight, X. Qing / Tetrahedron Letters 50 (2009) 3534–3537
3535
studies had established that benzynes generated in this way are
not trapped by d-hydroxy groups, which would give rise to se-
ven-membered rings. Therefore, it was anticipated that the al-
kyne-diol 13 probably would not require any protection (i.e.,
R = H), as trapping would be highly favoured towards six-mem-
bered chroman formation, even though the reacting alcohol group
would be tertiary.14 We reasoned that both such precursors should
be reasonably readily available, and that the alkyne-diol 13 should
be obtainable in optically pure form.
Our synthesis began with known literature methods (Scheme
5). Nitration15 of commercially available 2,6-dimethylanisole 15
gave a reasonable return of the expected crystalline p-nitro deriv-
ative, in a reaction which could be carried out on a large scale.16
Transfer hydrogenation17 of the nitro group using cyclohexene as
the source of hydrogen then gave a sensitive aniline which was
immediately acetylated to give a good overall yield of the acetan-
ilide 16. This activated intermediate was then mono-iodinated
using N-iodosuccinimide in hot glacial acetic acid18 and the final
substituent, a second nitro group, introduced by a relatively slow
nitration using concentrated nitric acid in warm acetic acid, to give
the fully substituted aryl intermediate 17.
The other component of the projected Sonogashira coupling, the
alkyne-diol 20, which we anticipated from previous work,19 could
be readily obtained in a highly enantiomerically enriched form
from the cheap acetylide-acetone adduct 18 by sequential dehy-
dration20 and asymmetric dihydroxylation (AD)21 (Scheme 6). This
proved to be an erroneous assumption: while chemical yields were
acceptable, the final diol 20 was obtained in almost racemic form,
according to GC analysis of the corresponding mono-benzoate. It
appears that our previous optimism19 with regard to the levels of
enantiomeric enrichment of this compound was based on a some-
what over-enthusiastic interpretation of its HPLC analysis. How-
ever, having secured decent amounts of the racemic alkyne-diol
20, we chose to continue with the projected synthesis, in order
to establish suitable conditions for basic bond formation. The prob-
lem of obtaining the chiral, non-racemic alkyne diol was left until
later.
After a number of trials, we established that the pivotal Sono-
gashira coupling was, as anticipated, relatively difficult but that
good yields of the aryl alkyne 21 could be obtained by carrying
out the reaction in refluxing tetrahydrofuran for 24 h. Steric hin-
drance no doubt played a part in this and the subsequent one-
pot reductions of both the nitro and alkyne groups. Again after a
number of trials, we found that prolonged exposure to an atmo-
sphere of hydrogen and 20% palladium hydroxide on carbon (Pearl-
man’s catalyst) in methanol at ambient temperature secured an
R
R
R
NIS
-2N2
OH
OH
O
NNH2
N
I
N
7
8
9
Scheme 3.
precursors 7 (Scheme 3). As the subsequent benzyne generation
can be carried out under neutral conditions using, for example,
N-iodosuccinimide to carry out the necessary amine oxidation,
the resulting benzynes 8 are trapped by the pendant neutral alco-
hol groups to give excellent yields of the related chromans 9. A bo-
nus is the incorporation of an additional iodine atom, which offers
many opportunities for further elaboration of the initial prod-
ucts.11 Similarly, phenols can be used as traps to provide access
to xanthenes,12 all of which is in direct contrast to the more com-
monly encountered highly basic methods for benzyne generation
wherein any free hydroxy groups are inevitably present as the cor-
responding alkoxides. These latter ‘hard’ species are evidently
incompatible with the much softer benzynes, in terms of efficient
reactivity.13
Although this methodology makes some contribution to the
synthesis of substituted benzynes, it still fails to provide access
to very highly substituted examples. Therefore, we were interested
to test the general idea of using highly substituted benzynes, gen-
erated from 1-aminobenzotriazoles, in target synthesis in order to
demonstrate the potential of this method in general. For this,
a
-tocopherol appeared to be a highly suitable target; herein, we
report in preliminary form, the successful outcome of this idea,
together with some of the pitfalls encountered along the way.
We initially aimed to extend our metallation methodology11 to
this target, but were thwarted by a lack of regioselectivity in such
reactions involving the necessary highly substituted intermediates.
We therefore turned to more conventional methods to prepare the
required precursors; the basic strategy is outlined in Scheme 4. In
common with many previous syntheses, we reduced the problem
to one of preparing the chroman-2-methanol 4 (Scheme 2) and
therefore anticipated the iodide 10 as being the initial benzyne
product. This naturally led back to the benzotriazoles 11, and
thence to the amino-nitrobenzenes 12 or a regioisomer thereof.
Retention of the nitro group should then be useful in facilitating
a Sonogashira coupling between the alkyne-1,2-diol 13 and the
worryingly crowded, fully substituted iodobenzene 14. Previous
OR
OH
MeO
MeO
MeO
MeO
MeO
I
i - iii
iv, v
NHAc
4
O
NH
N
NHAc
N
I
OR
NO2
15
16
17
10
11
Scheme 5. Reagents and conditions: (i) concd HNO3, HOAc, 0–65 °C (ꢀ65%); (ii)
10% Pd–C, EtOH, cyclohexene, 80 °C (91%); (iii) AcCl, Et3N, THF, 0–20 °C, 16 h (89%);
(iv) NIS, HOAc, reflux, 1.5 h (70%); (v) concd HNO3, HOAc, 65 °C, 5 h (52%).
OR
OH
OR
OH
MeO
I
MeO
OH
OH
13
i
ii
NHCOR
NH2
OH
18
NO2
NO2
19
20
14
12
Scheme 6. Reagents and conditions: (i) Distill from p-toluenesulfonic acid (ꢀ35%);
(ii) AD mix b, MeSO2NH2, 1:1 tBuOH–H2O, 24 h, 20 °C (67%; ee ꢀ5%).
Scheme 4.

3536
D. W. Knight, X. Qing / Tetrahedron Letters 50 (2009) 3534–3537
late the desired amino-diol, a highly polar material, from a polar
(DMF as solvent) and highly contaminated reaction mixture, fol-
lowing an aqueous work-up.
OH
OH
OH
ii
OH
17
+
MeO
MeO
i
We therefore examined alternatives and were delighted to find
that the oxaziridine 26,23 established by Vidal and Collet as a gen-
erally useful source of electrophilic nitrogen capable of effecting
N-aminations, delivered an NHBoc moiety to the benzotriazole
24 under the simplest of conditions in essentially quantitative
yield (Scheme 8). Unexpectedly, the product 27 was isolated as
essentially a single regioisomer, of still unknown structure. In view
of the similar levels of steric hindrance which would be experi-
enced by the new NHBoc group, we speculate that the product is
indeed compound 27, due to hydrogen bonding between the
incoming reagent 26 and the diol functionality of the substrate 24.
In any event, this was irrelevant to the final benzyne generation,
for which we employed our previously reported tactic12 of depro-
tection of the N-Boc derivative 27 using trifluoroacetic acid, fol-
lowed by basification and exposure to N-iodosuccinimide
(Scheme 9). After careful chromatography, it was possible to sepa-
rate the desired iodochroman 28a in excess of 50% yield. No other
cyclised products were detected.
NHAc
NHAc
20
NO2
NH2
21
22
iii
OH
OH
OH
OH
MeO
MeO
iv
Ac
NH
N
N
N
N
N
24
23
Scheme 7. Reagents and conditions: (i) Pd(PPh3)4 (20 mol %), Et3N, 17 (1 equiv), 20
(2 equiv), THF, degas, add CuI (20 mol %), reflux, 24 h (77%); (ii) 20% Pd(OH)2–C,
MeOH, H2 (1 atm), 48 h, 20 °C (99%); (iii) 22 in MeOH, 20 °C; add aq NaNO2
(3 equiv) then add the solution to 5 M HCl at 0 °C, 0.5 h (73%); (iv) K2CO3, aq MeOH,
20 °C, 4 h (99%).
Finally, a modified Stille-type coupling reaction24 employing
copper(I) iodide as an additional catalyst with tetramethyltin as
the methyl source delivered the target
a-tocopherol precursor
excellent yield of the desired alkylated aryl diol 22 (Scheme 7).
Analysis of the intermediates during these hydrogenations clearly
showed that alkyne reduction was the slow step; the nitro group
was rapidly reduced under most conditions examined.
28b, but only after very careful chromatography, required to sepa-
rate this from both starting material 28a and deiodinated material
28c. Comparisons of spectroscopic and analytical data with those
previously reported confirmed the structural assignment.7 Mix-
tures of both products 28b and 28c could also be obtained by
low-temperature halogen-lithium exchange in tetrahydrofuran to
give a presumed dianionic intermediate, followed by treatment
with iodomethane; overall conversions were, however, poorer
than those obtained from the coupling method.
To complete an asymmetric synthesis of compound 28b, we re-
turned to the problem of obtaining an optically enriched source of
the alkyne diol 20, following our failure to use a direct AD reaction
for this purpose (Scheme 6). Of a number of options examined, a
successful method turned out to be a less direct but known version
of the same reaction: asymmetric dihydroxylation of the Weinreb
amide 29 derived from methacrylic acid is known to give the
dihydroxy amide 30 with an ee value of 93%.25 In our hands, this
Diazotisation then delivered the acetylated benzotriazole 23,
which was readily hydrolysed to give the ‘free’ benzotriazole 24
in excellent yield and as a mixture of tautomers (only one shown).
While these were irrelevant to the later benzyne formation, their
existence did rather complicate spectroscopic analysis of these
and the following intermediates. It was found important to use
an excess of sodium nitrite during the diazotisation reaction, in or-
der to lessen competitive formation of the benzimidazole 25 (and
its tautomer), which proved to be the major reason for loss of
material at this stage. Presumably, higher concentrations of nitrous
acid accelerated the diazotisation reaction at the expense of the
undesired ring closure. Not surprisingly, in view of this relatively
facile cyclisation, formation of compound 25 and the correspond-
ing alkyne was also the reason why more forcing conditions (e.g.,
heat, use of acidic conditions) could not be employed in the forego-
ing hydrogenation steps (Scheme 7). Attempts to hydrolyse the
rather stable benzimidazole were unsuccessful, as were attempts
to alter the order of reaction, that is, hydrolyse the acetanilide 22
before diazotisation of the resulting diamine.
Cl3C
OH
OH
OH
OH
MeO
MeO
O NBoc
26
NHBoc
CH2Cl2, 20 oC
16 h, 94%
NH
N
N
OH
N
N
N
MeO
24
27
OH
Scheme 8.
NH
N
OH
OH
25
MeO
MeO
i, ii
a) R = I
b) R = Me
c) R = H
NHBoc
It was now necessary to introduce an N-amino function into the
advanced intermediate 24, for which purpose we required a re-
agent capable of electrophilic amination. In our previous stud-
ies,11,12 we had optimised the use of hydroxylamine-O-sulfonic
acid22 for the preparation of the parent 1-aminobenzotriazole from
benzotriazole. However, while suitable for large-scale runs on sim-
ple substrates, we were doubtful that it would be possible to iso-
O
N
N
N
R
OH
27
28
Scheme 9. Reagents and conditions: (i) 20% TFA–CH2Cl2, 20 °C, 0.75 h; high
vacuum; K2CO3, CH2Cl2, filter, add NIS (2.5 equiv), 20 °C, 1 h (54%; R = I); (ii) Me4Sn,
(dba)3Pd2ÁCHCl3, PPh3, CuI, Et2NH, NMP, 100 °C, 24 h (67%).

D. W. Knight, X. Qing / Tetrahedron Letters 50 (2009) 3534–3537
3537
O
O
References and notes
ref 25
OMe
OMe
N
HO
N
1. Machlin, L. J. Vitamin E: A Comprehensive Treatise; Marcel Decker: New York,
1980; Kamal-Eldin, A.; Åppelqvist, L.-A. Lipids 1996, 31, 671.
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Chem. Lett. 2007, 570.
HO
30 (ee 91%)
29
i
O
O
OMe
iii
ii
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TBSO
TBSO
TBSO
N
HO
TBSO
(S)-20
32
31
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Scheme 10. Reagents and conditions: (i) TBSCl (2.2 equiv), imidazole (3.3 equiv),
DMF, 35 °C, 16 h (94%); (ii) LiAlH4, Et2O, À78 °C, 40 min, then aq 2 M NaOH (88%);
(iii) (a) PPh3, CBr4, CH2Cl2, 20 °C, 4 h (74%), (b) BuLi, THF, À30 °C, then warm to 0 °C,
1 h (59%), (c) 1 M TBAF, THF, 20 °C, 2 h (82%).
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16. WARNING: It is essential that, during the final heating stage of this nitration,
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can occur above this temperature.
reaction gave the reported excellent yields of the dihydroxy amide
30, with 91% ee, according to GC analysis (Scheme 10).26
Subsequent manipulation through to the desired alkyne diol
followed a relatively standard pathway (Scheme 10): bis-silylation
worked well to give the expected derivative 31, which we found
was best reduced to the aldehyde 32 using lithium aluminium hy-
dride at low temperature, rather than the more usual DIBAL, which
also gave substantial quantities of the corresponding alcohol and
mono-desilylated aldehyde. Corey-Fuchs homologation and desily-
lation finally gave the desired (S)-alkyne-diol, (S)-20, in acceptable
yield. As this compound would be expected to react in exactly the
same manner as the racemate 20, we had therefore formally com-
pleted an asymmetric synthesis of the target a-tocopherol precur-
17. Entwistle, I. D.; Johnstone, R. A. W.; Povall, T. J. J. Chem. Soc., Perkin Trans. 1
1975, 1300.
18. Tanemura, K.; Suzuki, T.; Nishida, Y. Chem. Lett. 2003, 932.
19. Little, P. B. PhD thesis, Cardiff University, 2001.; Knight, D. W.; Little, P. B.
Tetrahedron Lett. 1998, 39, 5105.
20. Carothers, W. H.; Coffman, D. D. J. Am. Chem. Soc. 1932, 54, 4071.
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sor 4.
Hence, overall, this synthesis clearly demonstrates that highly
substituted benzynes can indeed be generated from 1-amin-
obenzotriazoles and trapped efficiently by alcohols. The length of
this present route is not especially attractive, however, and our
current efforts are directed towards developing new chemistry
which will hopefully result in much shorter preparations of such
benzyne precursors in general.
Acknowledgements
We are grateful to Dr Paul B. Little and Mr Brian Rees for con-
ducting some preliminary experiments, to Dr Robert Jenkins for
invaluable technical assistance and to the ORS Scheme for partial
financial support (to X.Q.).
26. CDX-b column; temperatures: oven 100 °C; detector 300 °C; injection port
200 °C; helium flow at column head pressure of 20 psi; retention time of (R)-
isomer: 29 min. Ees determined against a racemic sample.