Synthesis and isolation of a monoamine having a thermodynamically stabilized pseudo-chirotopic nitrogen

Article abstract of DOI:10.1016/j.tetlet.2008.12.004

We have synthesized a tricyclic monoamine, (1S,4R)-(E)-7,3′-heptenylene-2,3:5,6-dibenzo-7-azabicyclo[2.2.1]heptane (1), by applying a ring-closing metathesis reaction in the key step of the synthetic route and by using preparative chiral HPLC for the sepa

Full text of DOI:10.1016/j.tetlet.2008.12.004

Tetrahedron Letters 50 (2009) 799–801
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Tetrahedron Letters
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Synthesis and isolation of a monoamine having a thermodynamically
stabilized pseudo-chirotopic nitrogen
*
Yuka Kobayashi , Kentaro Sano, Kazuhiko Saigo
Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-8656, Japan
a r t i c l e i n f o
a b s t r a c t
We have synthesized a tricyclic monoamine, (1S,4R)-(E)-7,30-heptenylene-2,3:5,6-dibenzo-7-azabicy-
clo[2.2.1]heptane (1), by applying a ring-closing metathesis reaction in the key step of the synthetic route
and by using preparative chiral HPLC for the separation. The X-ray crystallographic analysis of its salt
with (1R)-camphor-10-sulfonic acid showed that the geometry and absolute configuration are (E) and
(1S,4R), respectively. The theoretical calculations revealed that the inversion of the nitrogen atom at
the 7-position of (1S,4R)-(E)-1 thus isolated takes place through a very slow process and that the config-
uration of the N(7) is highly biased to (R), indicating that (1S,4R)-(E)-1 is a thermodynamically controlled
N-pseudo-chirotopic compound ((1S,4R,7R): (1S,4R,7S) = 99.68:0.32 at 120 °C).
Article history:
Received 31 October 2008
Revised 26 November 2008
Accepted 1 December 2008
Available online 6 December 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Amines containing a chirotopic nitrogen have a characteristic
that a ‘lone pair’ exists on their stereogenic center. Accordingly,
they are drawing much attention not only from a synthetic point
of view but also from the view point of application, for example,
as ligands in metal catalysts for asymmetric synthesis, selectors
for chirality-recognition, and so on. In order to fix the chirality of
a nitrogen atom, nitrogen inversion should be avoided. For this
purpose, a structural restriction has been imposed in molecular de-
sign; molecules having two nitrogen atoms linked with each other
by a methylene bridge are highly attractive for the fixation of
N-chirality, as is realized by sparteine and the Tröger base. In
contrast, the chirality of the nitrogen of a monoamine is relatively
difficult to be fixed, so that a more direct synthetic strategy is re-
quired to avoid nitrogen inversion; the synthesis of monoamines
with large strain around a nitrogen atom such as aziridine deriva-
tives1 or with bulky substituents on a nitrogen atom2 has been
tried. Because unique properties and functions are expected for
amines with a chirotopic nitrogen, steady researches have been
carried out.3 In this Letter, we report a novel strategy for the syn-
thesis and isolation of a monoamine, having a thermodynamically
stabilized pseudo-chirotopic nitrogen, with a simple tricyclic
structure.
invertomers is sufficiently slow, one of the invertomers would be
isolated. On the other hand, 7-azabicyclo[2.2.1]heptane (7-azanor-
bornane) derivatives are well known to show rather slow nitrogen
inversion, which was firstly called in terms of ‘bicyclic effect’ by
Lehn in 1977,4a and their stereodynamics has been investigated
up to now.4 On the basis of these consideration and fact, we
designed the tertiary amine 1, which has a 2,3:5,6-dibenzo-7-aza-
bicyclo[2.2.1]heptane skeleton, and is dissymmetrized by intro-
ducing a strap between the nitrogen atom and one of the
phenylene groups (Fig. 1). Although there are three stereogenic
centers at the C(1)-, C(4)-, and N(7)-positions of 1, only four ste-
reo-isomers are possible to exist for 1 even if the inversion of the
nitrogen atom at the 7-position takes place; the chiralities of the
two carbons at the 1- and 4-positions are unequivocally deter-
mined without any relation to the chirality of the nitrogen atom.
A ring-closing metathesis (RCM) reaction using the Grubbs’ cat-
alyst of the second generation5 was adopted for the synthesis of
the tertiary amine 1. Although we tried the RCM reactions of the
analogues of the diene 2 with shorter alkenyl chain(s) at the
7- and/or 30-position, no desired products were isolated. In con-
trast, when 2 was used as the substrate, the RCM reaction took
When a pair of nitrogen-inverted isomers (invertomers) of a
monoamine is not enantiomeric but diastereomeric, one of the
invertomers might be energetically stable more than the other. If
the difference in potential energy between the diastereomeric
invertomers is large enough and the equilibrium between the
Enantiomer
*
*
N
*
N
N
Diastereomer
*
*
*
*
*
*
(+)-1
,4 ,7
(-)-1
* Corresponding author. Tel.: +81 3 5841 7266; fax: +81 3 5802 3348.
E-mail address: saigo@chiral.t.u-tokyo.ac.jp (K. Saigo).
(1
S
R
R
)-1
(1
R
,4S,7
S
)-1
(1
S,4
R,7
S
)-1
Present address: Waseda Institute for Advanced Study (WIAS), Waseda Univer-
sity, Nishiwaseda, Shinjyuku-ku, Tokyo 169-8050, Japan.
Figure 1. Design of a N-pseudo chiral monoamine (1).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.004

800
Y. Kobayashi et al. / Tetrahedron Letters 50 (2009) 799–801
(7S)-1 is used for simplicity hereafter) molecules do not exist at
all in the salt crystal.
Bn
Br
b), c)
a)
+
N
NH
N
Ph
N
The observations, however, do not necessarily guarantee the
fixation of the chirality of the nitrogen atom in (1S,4R)-(E)-1 in a
solution. Therefore, the stereodynamics of (1S,4R)-(E)-1 in a solu-
tion was investigated; dynamic 1H NMR measurements were car-
ried out for (1S,4R)-(E)-1 at a temperature range of ꢀ95 to 120 °C
(solvent, CDCl3 at lower temperatures and DMSO-d6 at higher tem-
peratures). As a result, no coalescence of the 1H NMR signals was
observed in the temperature range. The result made us to expect
the fixation of the chirality of the nitrogen atom even at a high
temperature, because the coalescence temperature was reported
to be 1 °C for a 7-azanorbornane derivative.4c However, the possi-
bility of the fast inversion of the nitrogen atom even at a low tem-
perature would not be excluded only on the basis of the dynamic
1H NMR phenomenon. Thus, the dynamic 1H NMR was incompe-
tent for clarifying the behavior of (1S,4R)-(E)-1 in a solution.
Then, in order to know the thermodynamic property of (1S,4R)-
(E)-1, we performed theoretical calculations for the potential en-
ergy profile of (7R)-1/(7S)-1 using the GAUSSIAN 03 package.8 Geom-
etries were optimized with RHF/6-31g*, and single point energies
were evaluated with CASSCF(10,10)/6-31G*, which is recognized
to be appropriate for the accurate representation of complicated
F
Boc
Boc
d)
N
e)
f)
(CH2)3
HN+
Cl—
Br
i), j)
g), h)
N
HN
(CH2)3
2
1
Scheme 1. Synthesis of (1S,4R)-(E)-1. Reagents and conditions: (a) Mg activated
with BrCH2CH2Br, THF, reflux, 1.5 h, 76%;6 (b) NBS, 1,4-dioxane/H2O, rt, 3 days; (c)
quenching with KOH aq, 69% (overall yield for 2 steps); (d) (Boc)2O, Et3N, MeOH,
reflux, 1 h, 92%; (e) NBS, BPO, hn, CCl4, reflux, 3 h, 81%; (f) CH2@CHCH2MgCl, THF,
reflux, 2 h, 69%; (g) CH2@CH(CH2)3Br, K2CO3, CH3CN, reflux, 8 h; (h) quenching with
HCl, Et2O, 80% (overall yield for 2 steps); (i) the Grubbs’ catalyst (the second
generation), CH2Cl2, reflux, 3 days, 75%; (j) separation on a Daicel Chiralcel OD
column, 44%.
place very smoothly to give the corresponding ring-closed product
in 75% yield, as shown in Scheme 1. However, spectroscopic anal-
yses revealed that the product was a mixture of some stereo-iso-
mers. In order to isolate one isomer from the mixture,
preparative chiral high performance liquid chromatography (HPLC)
was carried out by means of a Daicel Chiralcel OD column with an
eluent of hexane/2-propanol (95:5, v/v); 1 diastereopure in a 1H
NMR level was obtained from the mixture in 44% yield as a singly
separable product. The geometry of the alkynylene of the strap and
the absolute configuration of the three stereogenic centers (C(1),
C(4), and N(7)) in 1 thus obtained were determined to be (E) and
(1S,4R,7R), respectively, by the X-ray crystallographic analysis of
its salt with (1R)-camphor-10-sulfonic acid.7 The crystal structure
of the salt is shown in Figure 2.
p
-bonding systems.9 An active space, which consists of 10 elec-
trons distributing among 10 orbitals, includes the orbital of the
nitrogen lone pair, the orbitals of the alkenylene part, a part of
the orbitals of the two phenylene parts, and the s orbitals of
p
p
C(1)–N(7)–C(4). All components in the active space were made to
be consistent through the calculations. Figure 3 shows the calcu-
lated potential energy profile of (7R)-1/(7S)-1; the activation en-
ergy (D
Hà) for the nitrogen inversion of (7R)-1 was evaluated to
be 15.1 kcal/mol.10 This value is almost equal to that of a 7-azanor-
bornane derivative (15.3 kcal/mol) calculated on the basis of its dy-
namic NMR analysis.4c This means that the
D
Hà for (7R)-1 is not
The C(1)–N(7)–C(4) angle has been often pointed out to be an
important factor for the suppression of the nitrogen inversion of
7-azanorbornane derivatives.4 However, the angle of (1S,4R,7R)-
(E)-1 (the abbreviation (7R)-1 is used for simplicity hereafter) in
the salt crystal determined by the X-ray crystallographic analysis
is 94.9°, which is the same as that reported for 7-methyl-7-azanor-
bornane,4c and all of the bond lengths and angles are in usual
ranges.
large enough to completely prevent nitrogen inversion.
Taking account of a static electron correlation effect, the elec-
tronic states of (7R)- and (7S)-1 were also estimated with CASSCF.
As a result, the energy difference (D
H0) between the invertomers
(7R)- and (7S)-1 was evaluated to be 4.3 kcal/mol, meaning that
the ratios of (7R)- and (7S)-1 are calculated to be 99.92:0.08 at
room temperature and 99.68:0.32 even at 120 °C, taking into ac-
count the Boltzmann distribution. These results indicate that
(7R)-1 is highly stable, compared with (7S)-1, from the view point
of thermodynamics; the invertomer (7S)-1 only can exist in an ex-
tremely low ratio under the dynamic NMR measurement condi-
These structural informations indicate that no structural strain
exists in (7R)-1. Moreover, the X-ray crystallographic analysis
shows that the invertomer (1S,4R,7S)-(E)-1 (the abbreviation
Figure 3. Potential energy surface of (1S,4R)-(E)-1 evaluated with CASSCF(10,10)/
Figure 2. X-ray crystal structure of (1S,4R,7R)-(E)-1ꢁ(1R)-camphor-10-sulfonic acid.
6-31G*.

Y. Kobayashi et al. / Tetrahedron Letters 50 (2009) 799–801
801
Acknowledgments
The present work was supported by the Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Science, Sports and
Culture, Japan (No. 17750033 and No. 19350064). Y.K. acknowl-
edges financial supports from Kurata Memorial, Hitachi Science
and Technology Foundation, and Sumitomo Foundation.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.12.004.
References and notes
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Figure 4. Molecular orbitals of HOMO and HOMO-2 of (1S,4R,7R)- and (1S,4R,7S)-1.
4. (a) Lehn, J.-M. Fortschr. Chem. Forsch. 1970, 15, 311–377; (b) Gribble, G. W.;
Easton, N. R., Jr.; Eaton, J. T. Tetrahedron Lett. 1970, 13, 1075–1078; (c) Nelsen, S.
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tions mentioned above, which resulted in apparently no observa-
tion of the coalescence of its 1H NMR signals.
The
D
H0 between (7R)- and (7S)-1 could be qualitatively eluci-
dated on the basis of their molecular orbitals. Figure 4 shows the
molecular orbitals of HOMO and HOMO-2 for (7R)- and (7S)-1.
The HOMO of (7R)-1 shows that there exists orbital interaction be-
tween the N(7)–C(chain) s orbital and the
p orbital of the pheny-
5. (a) Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1992, 114, 5426–5427; (b) Fu, G. C.;
Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc. 1993, 115, 9856–9857.
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lene ring, while such interaction is not observed in (7S)-1.
Moreover, the HOMO-2 of (7R)-1 indicates that the orbital of the
N(7) lone pair interacts with the
p orbital of the phenylene ring
7. The X-ray intensities were collected with a Rigaku Mercury CCD system by
to stabilize (7R)-1 whereas the corresponding orbital in (7S)-1
has a node to destabilize (7S)-1. These calculations strongly indi-
cate that (7R)-1 is obviously more stable than (7S)-1 owing to
the advantageous intramolecular orbital interactions.
In conclusion, we have succeeded in the synthesis and isolation
of a tricyclic monoamine, (1S,4R)-(E)-7,30-heptenylene-2,3:5,6-di-
benzo-7-azabicyclo[2.2.1]heptane (1), which exists as a thermody-
namically stabilized pseudo-single diastereomer even at 120 °C.
Although the inversion of the nitrogen atom at the 7-position of
(1S,4R)-(E)-1 takes place somewhat, we would be able to expect
some function of the chirality of the N(7). The functions of
(1S,4R)-(E)-1 are under investigation.
using Mo K
a radiation (l = 0.71073 Å). The crystal structure was solved by the
direct method with the SHELXL-97 program and refined by the full-matrix least-
squares procedure for all non-hydrogen atoms anisotropically. All hydrogen
atoms were generated geometrically. The absolute configuration of 1 was
determined on the basis of the known absolute configuration of (1R)-(ꢀ)-
camphor-10-sulfonic acid. CCDC 671578 contains the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
8. GAUSSIAN 03, Revision B.05; Gaussian, Inc., Pittsburgh, PA, 2003.
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10. We excluded the term of
DS in the estimation of the activation energy, because
its contribution to the activation energy is known to be generally very small in
the cases of 7-zanorbornane derivatives (see Ref. 4c).