Synthesis of 1,8-di(1-adamantyl)naphthalenes as single enantiomers stable at ambient temperatures

Article abstract of DOI:10.1039/c0cc03025b

Single enantiomers of 1,8-di(1-adamantyl)naphthalenes were synthesized by the [4+2]cycloaddition reaction of 6-adamantylbenzyne and 2-adamantylfuran. The enantiomers were resolved by conversion into diastereomeric ketopinic acid esters. The absolute confi

Full text of DOI:10.1039/c0cc03025b

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Synthesis of 1,8-di(1-adamantyl)naphthalenes as single enantiomers
stable at ambient temperaturesw
Haruo Aikawa,ab Yusuke Takahiraa and Masahiko Yamaguchi*ac
Received 4th August 2010, Accepted 27th October 2010
DOI: 10.1039/c0cc03025b
Single enantiomers of 1,8-di(1-adamantyl)naphthalenes were
synthesized by the [4+2]cycloaddition reaction of 6-adamantyl-
benzyne and 2-adamantylfuran. The enantiomers were resolved
by conversion into diastereomeric ketopinic acid esters. The
absolute configuration was determined by X-ray analysis.
Kinetic studies by CD revealed an enantiomerization barrier of
29 kcal molꢀ1 for 1,8-(1-adamantyl)naphthalenes.
The construction of distorted aromatic nuclei has been a
challenge in chemistry.1 A notable feature of such aromatics is
their chirality, which imparts a three-dimensional structure to
planar aromatic rings and produces closely related isomeric
compounds. Helicenes are aromatic compounds having such
distorted chiral structures because of steric repulsions between
the terminal substituents, and an optically active [6]helicene was
reported in the 1950s,2 which is stable to heat. As the number
of benzene rings decreases, its thermal stability decreases,
and [5]helicene, [4]helicene and [3]helicene racemize at room
temperature. Introduction of appropriate alkyl substituents
retards isomerization, and substituted helicenes such as
Scheme 1
The chiral naphthalene skeleton was constructed by an
improved benzyne method (Scheme 1).9 The Diels–Alder adduct
4 was obtained by the reaction of 6-adamantylbenzyne11
generated from o-iodophenyl trifluoromethanesulfonate 3 with
10 eq. of 2-(1-adamantyl)furan. The major product 4 having
1,8-di(1-adamantyl) groups was obtained in 67% yield, and the
1,5-di(1-adamantyl) isomer in 12% yield. Then, 4 was converted
to the methyl ether 5, and acid-mediated ring opening using
2-bromopropionic acid produced the racemic naphthalene rac-1
in 66% yield. The effect of acid was crucial, and strong acids such
as aqueous HCl and TFA produced no 1. Then, rac-1 was
converted to an isomeric mixture of the (1S)-ketopinic esters
(P,S)-6 and (M,S)-6; the former was isolated by recrystallization
from dichloromethane in 45% yield (>99% de). The other
diastereomer (M,S)-6 was obtained by recrystallization of the
residue from dichloromethane/hexane in 40% yield (>99% de).
The stereochemistry of (P,S)-6 was determined by X-ray analysis.13
Interestingly, (P,S)-6 and (M,S)-6 were conformationally
stable at room temperature for one month, and heating
(P,S)-6 at 80 1C for 6 h in toluene (0.025 M) resulted only in
a weak epimerization (95% de).
10-methyldibenzo[c,g]phenanthrene,3
1,12-dimethylbenzo[c]-
phenanthrene,4 and 4-(tert-butyl)-5-methylphenanthrene3,5 were
isolated as single enantiomers. However, no naphthalenes,
[2]helicene, that are stable at ambient temperature as single
enantiomers have been reported yet.6 Among 1,8-disubstituted
naphthalenes7,8 possessing chiral distorted structures, the 1,8-
di(tert-butyl)naphthalene derivative9 2 was reported to racemize
at room temperature with an enantiomerization energy of
22.5 kcal molꢀ1. In this paper, we describe the synthesis and
resolution of 1,8-di(1-adamantyl)naphthalene 1,10 which is
stable at ambient temperatures as a single enantiomer.
a Department of Organic Chemistry, Graduate School of
Pharmaceutical Sciences, Tohoku University, Sendai 980-8578,
Japan. E-mail: yama@mail.pharm.tohoku.ac.jp;
The compound (P,S)-6 was reduced by DIBAL-H at room
temperature to produce optically pure naphthol (P)-1 (>99% ee)
in 99% yield. Similarly to (P,S)-6, (P)-1 was conformationally
stable at room temperature, and minimal racemization (93% ee)
occurred after heating at 80 1C for 6 h in toluene (0.025 M). The
naphthol (P)-1 could be methylated and acetylated at room
temperature without racemization. The dimethoxynaphthalene
(P)-7 was 3,6-dibrominated using benzyltrimethylammonium
tribromide (BTMA Br3)12 and formylated to give (P)-10
(99% ee), again without racemization.
Fax: +81 22 795 6811; Tel: +81 22 795 6812
b International Advanced Research and Education Organization,
Tohoku University, Sendai 980-8578, Japan
c WPI Advanced Institute for Materials Research, Tohoku University,
Sendai 980-8577, Japan
w Electronic supplementary information (ESI) available: Experimental
details for the synthesis of compounds, CD and UV-vis spectra, the
determination of rate constant k, and crystallographic data of (P,S)-6
and (P)-9. CCDC 777112 and 777113. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c0cc03025b
c
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Chem. Commun., 2011, 47, 1479–1481 1479

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Fig. 1 Stereoscopic ORTEPS of two views of the X-ray structure of (P)-9.
Table 1 Enantiomerization barriera
The structure of the dibromonaphthalene (P)-9 was
confirmed by X-ray analysis (Fig. 1).13 The adamantyl carbons
C11 and C21 were displaced above and below the naphthalene
mean plane by 0.34 A for C1 and C8, and by 1.358 A for
C11 and C21, which resulted in the right-handed helical
structure of the naphthalene system. Also noted was very high
pyramidalization values14 of ꢀ20.6 deg and +20.6 deg for C1
and C8, respectively, which generated the (R) central chirality
both at C1 and C8. This is a novel distorted naphthalene ring
system, which does not racemize at ambient temperatures.
(P,S)-6, (P)-9, and 1,3,6,8-tetra(tert-butyl)naphthalene8,9
possessed similar naphthalene structures. The results indicated
that the torsion energies of these distorted naphthalenes were
similar, and that the conformational stability of 1,8-di-
(1-adamantyl)naphthalenes arose from the higher energy in
the transition state. The CD spectra of the chiral naphthalenes
(P,S)-6, (P)-7, and (P)-9 were similar, whereas those of (P)-10
showed a 40 nm bathochromic shift (Fig. 2).
DGz/
DHz/
DSz/
k 10ꢀ5 sꢀ1
kcal molꢀ1
kcal molꢀ1
cal molꢀ1 Kꢀ1
(P,S)-6
(P)-7
(P)-8
(P)-9
(P)-10
2b
4.6
7.0
5.5
2.0
2.3
29.3
29.0
29.1
29.9
29.8
22.5 (22)
27.0
28.0
27.3
37.1
35.4
(18.5)
ꢀ6.0
ꢀ2.4
ꢀ4.8
19.0
14.9
(ꢀ8.4)
a
b
Values at 105 1C. Activation parameter at 144 1C. Calculated
values for 1,8-di(tert-butyl)naphthalene are shown in parentheses,
ref. 9.
1,8-di(tert-butyl)naphthalene, 18.5 kcal molꢀ1
, may be
ascribed to the steric repulsion in the former in the transition
state. Such a marked difference between the adamantyl and
tert-butyl groups has not been reported yet.16 The difference
was attributed to the difficulty in the cogwheel rotation of
1-adamantyl substituents in the transition state (Scheme 2).
tert-Butyl groups can be placed in the naphthalene plane
without inducing a strong steric repulsion. In contrast, the
repulsive proximity of 2-methylene and 3-methine hydrogen
atoms was substantial for the 1-adamantyl derivatives in the
planar transition state.
The stability of single enantiomers of naphthalenes was
estimated quantitatively. Time courses of the CD intensity at
330 nm (370 nm for (P)-10) were recorded for (P,S)-6, (P)-7,
(P)-8, (P)-9, and (P)-10 in the temperature range of 90–110 1C
in o-dichlorobenzene. From the rate constant k (sꢀ1), the
enantiomerization barrier DGz (kcal molꢀ1z), activation energy
Ea (kcal molꢀ1), activation enthalpy DH (kcal molꢀ1), and
As indicated by the results for (P)-9 and (P)-10, substitutions at
the 3- and 6-positions of the naphthalene ring caused ca.
1 kcal molꢀ1 increase in DGz (Table 1). The different DHz
and DSz values of these derivatives from those of (P)-7 and
(P)-8 were noted. The larger DHz values of (P)-9 and (P)-10
may be considered to be associated with the buttressing effect,
and the increase in DSz suggests a different mechanism of the
racemization, for example, the elongation of a C–C bond in
the transition state.
activation entropy DSz (cal molꢀ1
K
ꢀ1) were obtained
(Table 1).15 (P,S)-6, (P)-7, and (P)-8 possessed a considerably
larger activation barrier, DGz = 29 kcal molꢀ1, than 1,8-
di(tert-butyl)naphthalene derivative 2, DGz = 22.5 kcal molꢀ1
,
which was considered to indicate the high stability of
1-adamantyl derivatives to racemization. The larger DHz
of ca. 28 kcal molꢀ1 of (P,S)-6, (P)-7, and (P)-8 than that of
In summary, we synthesized stable single enantiomers
of 1,8-di(1-adamantyl)naphthalenes with distorted helical
structure. Our method provides a series of chiral naphthalenes
in gram quantities, whose applications are now under
investigation in our laboratory.
Fig.
2 CD spectra of chiral naphthalenes (o-dichlorobenzene,
0.1 mM, 25 1C).
Scheme 2 A plausible transition state for enantiomerization
c
1480 Chem. Commun., 2011, 47, 1479–1481
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This work was financially supported by JSPS (No. 22790003),
GCOE program, and TU-ERYS.
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Chem. Commun., 2011, 47, 1479–1481 1481