Vol. 66, No. 9
Chem. Pharm. Bull. 66, 843–846 (2018)
843
Communication to the Editor
7
)
while D-α-tocopherol derivative, NP843, did not. Another DL-
tocopherol derivative, γ-VE5, exhibited an anti-tumor efficacy
in phosphatase and tensin homolog (PTEN)-negative cancer
Synthesis of 2,2-Dialkyl Chromanes by
Intramolecular Ullmann C–O Coupling
Reactions toward the Total Synthesis of
D-α-Tocopherol
8)
cells through PHLPP1-facilitated Akt inactivation. More-
over, there are many reports on bioactive natural compounds
containing chromane cores, which are the key structure of
9)
10)
tocopherols. Tetrahydrocannabinol (THC), cochlearol B,
,
a,b
a
a
Tetsu Tsubogo,* Saki Aoyama, Rika Takeda, and
11)
and strongylophorine-2 are well-known examples (Fig. 1),
and they showed biological activities such as those resulting
from anti-Alzheimer’s disease, anti-tumor, anti-inflammation,
anti-cancer, and anti-liver fibrosis. Thus, the development of
new methods for the synthesis of chromane cores is important.
The synthetic methodology of chromane cores was de-
veloped for vitamin E production. The artificial synthesis
,
a,b
Hiromi Uchiro*
a
Faculty of Pharmaceutical Sciences, Tokyo University of
Science; 2641 Yamazaki, Noda, Chiba 278–8510, Japan: and
b
Division of Fusion of Regenerative Medicine with DDS, Research
Institute for Science and Technology (RIST), Tokyo University of
Science; 2641 Yamazaki, Noda, Chiba 278–8510, Japan.
Received June 16, 2018; accepted July 2, 2018
12,13)
of all-rac-α-tocopherol was published in 1938.
Subse-
quently, researchers have focused on developing numerous
different methodologies for the synthesis of chromanes.
The complete synthesis of D-α-tocopherol was achieved
using our developed-Ullmann C–O coupling reaction as a
key reaction. The synthesis of the core structure of D-α-
tocopherol, which is a chiral chromane, has never been re-
ported using intramolecular Ullmann C–O coupling reactions
owing to the low reactivity of electron-rich iodoarenes with
tertiary alcohols. Because the developed intramolecular C–O
14–20)
However, we are currently interested in the application of
Ullmann C–O coupling reactions to synthesize natural prod-
21–23)
ucts containing cyclic ether.
This method could be used
for the reaction with sterically hindered secondary alcohols
using excess amounts of strongly coordinating monodentate
2
3)
coupling reactions prefer electron-rich iodoarenes with tertia- ligands (Chart 1). Therefore, we envisioned that our method
ry alcohols, we successfully synthesized the chiral chromane could be applied to intramolecular C–O coupling reactions
2
4,25)
core and achieved the total synthesis of D-α-tocopherol.
for tertiary alcohols with aryl iodides.
Recently, Reisman
et al. reported the synthesis of 2,2-dialkylchromane prepared
from a tertiary alcohol with bromoarene in the total synthesis
Key words Ullmann C–O coupling reaction; D-α-tocopherol;
,2-dialkyl chromane
2
2
6)
of (+)-Psiguadial B
by copper-catalyzed coupling reac-
tions, which were originally investigated by Satyanarayana
In the Satyanarayana’s catalyst system,
cal form of vitamin E, is important for the human body a bridgehead alcohol might be necessary or substitutions
It is known that vitamin in 4-positions are required to enhance the reactivity by
E is an antioxidant protecting us from free radicals in the Thorpe–Ingold effect. Furthermore, the product yields of
1,2)
27,28)
(
2R,4′R,8′R)-α-Tocopherol or D-α-tocopherol (1), a chemi- and colleagues.
2
6)
3
–6)
28)
owing to its biological activities.
2
9)
4)
metabolic process. In recent studies, the applications of reported compounds were unsatisfactory except in some cases.
the biological activities of the tocopherols were refocused. In this manner, reactions posed a challenge to prepare 2,2-di-
It was reported that an unnatural L-α-tocopherol derivative, alkylchromane containing electron-donating groups in the
ent-NP843, had inhibitory activity against L-MDM2-L-p53, benzene ring because of steric bulkiness, acidity of the ter-
Fig. 1. D-α-Tocopherol, PMC, and Chromane Derivatives
*
©
2018 The Pharmaceutical Society of Japan