A novel synthesis of tocopheryl amines and amides

Article abstract of DOI:10.1016/j.tetlet.2008.10.056

We report the synthesis of tocopheryl amines and amides from commercially available tocopherols. This synthesis improves the yield and diastereomeric purity of these biologically important compounds. The tocopheryl amines were prepared from the correspond

Full text of DOI:10.1016/j.tetlet.2008.10.056

Tetrahedron Letters 50 (2009) 19–21
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel synthesis of tocopheryl amines and amides
Elahe Mahdavian, Smink Sangsura, Geoffrey Landry, John Eytina, Brian A. Salvatore *
Department of Chemistry, Louisiana State University, Shreveport, LA 71115, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
We report the synthesis of tocopheryl amines and amides from commercially available tocopherols. This
synthesis improves the yield and diastereomeric purity of these biologically important compounds. The
tocopheryl amines were prepared from the corresponding a- and d-tocopherols using two distinct syn-
thetic routes. The introduction of the C(6)-amino group can be achieved by aryl nitration/reduction or
by Pd-catalyzed substitution of an aryl triflate, depending on the structure of the starting material. We
also prepared the succinamide and maleamide derivatives of each amine. Tocopheryl amides are more
Received 8 September 2008
Revised 13 October 2008
Accepted 13 October 2008
Available online 17 October 2008
Keywords:
Vitamin E
Tocopherol
Tocopheryl
Amine
potent pro-apoptotic anti-cancer agents than the corresponding
act selectively within the mitochondria of cancer cells.
a-tocopheryl esters. These compounds
Ó 2008 Elsevier Ltd. All rights reserved.
Amide
Nitration
Amination
Succinamide
Maleamide
We and others have been studying synthetic derivatives of vita-
min E (VE) with anti-cancer activity, among which -tocopheryl
succinate (1 in Fig. 1) is the most well known. A remarkable charac-
teristic of this compound is its direct action in the mitochondria,
selectively triggering apoptosis in cancer cells. This compound
2
a
1
has been shown to induce apoptosis in human breast, prostate, co-
lon, lung, cervical, and endometrial tumor cell cultures, yet it dis-
plays virtually no toxicity toward normal non-cancerous cells.3
Other recentstudies have demonstrated similar pro-apoptotic activ-
4
5
ity toward human neuroblastoma and mesothelioma cells. Con-
sidering the low toxicity of -tocopheryl succinate toward normal
a
cells, its remarkable anti-cancer attributes make it an attractive lead
compound for the development of new mitochondrially targeted
anti-cancer chemotherapeutic and chemopreventative agents.6
Although there have been extensive in vitro studies on the anti-
tumor activity of VE derivatives, few in vivo studies exist. One
obstacle to oral administration is that most tocopheryl esters,
including
a-tocopheryl succinate, are hydrolytically unstable.
These phenolic esters are susceptible to enzymatic cleavage by
esterases throughout the body, but mainly within the digestive
7
tract and liver. Thus, tocopherol esters readily undergo hydrolysis
in vivo, yielding the free acid and the parent tocopherol. Since
tocopherol does not induce apoptosis in cancer cells, the hydrolysis
of -tocopheryl esters in vivo poses a limitation to the clinical
a-
a
application of these compounds as anti-cancer agents. The devel-
opment of VE analogs into more effective chemotherapeutic agents
requires that hydrolysis of the drug be minimized, possibly
through delivery routes that circumvent intestinal hydrolysis. For
example, intravenous administration of tocopheryl esters with
Figure 1.
a-Tocopheryl succinate and two representative VE succinamides.
*
Corresponding author. Tel.: +1 318 797 5224; fax: +1 318 797 5090.
E-mail address: bsalvato@lsus.edu (B. A. Salvatore).
8
new delivery vehicles may enhance clinical efficacy.
0
040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.056

2
0
E. Mahdavian et al. / Tetrahedron Letters 50 (2009) 19–21
Scheme 1. Synthesis of a-tocopheryl amine from a-tocopherol, using aromatic nitration.
Another approach involves the synthesis of VE analogs that are
This approach overcomes the problem of diastereomeric product
mixtures, and it substantially improves the overall yields. Herein,
we demonstrate the syntheses of two VE amines and their amide
more resistant to hydrolysis. Some investigators have explored the
biological activity of VE ether analogs.8 The ethers display sub-
stantially greater metabolic stability than the esters, since they
are not susceptible to esterase-catalyzed hydrolysis. By contrast,
we have explored tocopheryl amide analogs, which we reasoned
would be more resistant to enzymatic hydrolysis than the parent
a,9
derivatives, specifically the
and the - and d-tocopheryl maleamides.
The synthesis of -tocopheryl amine is shown in Scheme 1. It
begins with the conversion of -tocopherol (4) to its triflate ester
a- and d-tocopheryl succinamides,
a
a
a
esters. The structures of the
2a and 3a) are shown in Fig. 1. The amides are more potent
anti-cancer agents in vitro than their ester and ether counterparts,
with -tocopheryl maleamide being the most potent agent
tested. We hypothesized that the amide analogs are more rigid
than the corresponding ester and ether analogs. Moreover, we
expect the amides to have longer in vivo half-lives than the corre-
sponding esters, since peptidase enzymes are far more substrate-
specific than esterases. Like tocopheryl esters and ethers, the
apoptogenic activity of the VE amides is completely abrogated by
esterification of the free carboxyl group.11
a
- and d-tocopheryl succinamides
with trifluoromethanesulfonic (triflic) anhydride in pyridine (5).
This ester was converted to 6 by catalytic hydrogenation with
palladium on carbon in the presence of a tertiary amine, which
neutralizes the triflic acid generated during this reaction. During
(
a
1
0
2 2
the subsequent nitration reaction (fuming nitric acid in CH Cl ,
À40 to À20 °C), only a single site on the aromatic ring [C(6)
on the benzopyran ring] is open to electrophilic attack by the
nitronium ion, providing 7. However, we also see a small amount
of aldehyde formation at one of the aromatic methyl groups
1
3
(presumably via a Nef reaction ). Conversion of 7 to
a-tocophe-
ryl amine (8) was accomplished in good yield with catalytic
hydrogenation. Similarly, the reduction of the nitro group in 7
with iron (III) chloride has also been performed with favorable
results.
To date, the only reported method for making amine and amide
derivatives of vitamin E is through total synthesis, by combining
two smaller molecules [an amino phenol and a large alcohol (phy-
1
2
tol)]. By today’s standards, that synthesis is inefficient, since the
overall yield was only 3%, and it produced an inseparable mixture
of two diastereomers, epimeric at C(2) of the benzopyran ring.
We report a new synthesis of tocopheryl amines and amides.
This represents the first new synthesis of tocopheryl amines in
over 65 years. We synthesized these amines from commercially
available natural tocopherols, rather than through total synthesis.
Although the synthetic route shown in Scheme 1 works quite
well and represents an advance in the synthesis of
amine, it is less suitable for the preparation of the three other toc-
opheryl amines (b, , and d) because multiple aromatic sites are
a-tocopheryl
c
open to nitration in those substrates. Furthermore, this protocol
was unsuitable for the synthesis of the tocotrienyl amines series
(a, b, c, and d), which contain alkenes in their side chains.
Scheme 2. Synthesis of d-tocopheryl amine from d-tocopherol, using aryl amination methodology.

E. Mahdavian et al. / Tetrahedron Letters 50 (2009) 19–21
21
Scheme 3. Representative syntheses of tocopheryl amides from the corresponding tocopheryl amines.
To offer wider applicability to the entire series of VE com-
Supplementary data
pounds, we developed another synthetic route for the conversion
of the other members of the VE family to their corresponding
C(6) amines. This route employs Buchwald’s palladium-catalyzed
N-aryl amination chemistry for substituting tocopheryl triflate
esters with nitrogen. Scheme 2 illustrates the synthesis of d-toc-
opheryl amine (12) from d-tocopherol (9). As before, the tocoph-
erol was first converted to the corresponding triflate ester (10).
However, in this route, the triflate is treated with benzophenone
imine and cesium carbonate in the presence of a catalytic amount
Representative experimental details for the synthesis and the
characterization data for key intermediates are provided. Supple-
mentary data associated with this article can be found, in the on-
line version, at doi:10.1016/j.tetlet.2008.10.056.
1
4
References and notes
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a commonly used bidentate phosphine ligand in aryl amination
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‘
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plished with hydroxylamine hydrochloride in aq THF to provide
the desired d-tocopheryl amine (12). This synthesis provides dia-
stereomerically pure products.16
In principle, the chemistry in Scheme 2 can furnish all of the VE
amines, but in practice, we found that the synthetic route de-
3.
4.
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scribed in Scheme 1 was still better suited for preparing
opheryl amine, due to the steric hindrance from the two methyl
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a-toc-
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17
their reactivity to the parent phenols. Since the tocopheryl
amines (8 and 12), are unstable in the presence of oxygen, we
promptly converted these compounds into the corresponding
amides (Scheme 3). The amide formation reactions for each amine
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Modern aryl amination methodology has never been applied
before to members of the VE family. We believe that this research
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itate research in areas beyond our own applications.
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Acknowledgments
1
6. All new compounds with the exception of 8 and 12, which proved to be
unstable, were characterized by 1H and C NMR, as well as by HRMS with
electrospray ionization [HRMS (ESI)].
13
We thank the NIH-Louisiana Biomedical Research Network
(
LBRN) and the Louisiana Board of Regents Support Fund-Research
17. Rosenau, T. Encyclopedia of Vitamin E. In Cabi; Preedy, V. E., Watson, R. R., Eds.;
Competitive Subprogram (BORSF-RCS) for financial support.
Wallingford: UK, 2007; pp 69–95.