Synthesis of new chiral molecular tweezers with a tris-Tro?ger's base skeleton

Article abstract of DOI:10.1070/MC2004v014n06ABEH002016

For the first time, chiral molecular tweezers with a tris-Tr?ger's base skeleton have been synthesised. Three new compounds 9a, 9b and 9c differ in their stereochemistry.

Full text of DOI:10.1070/MC2004v014n06ABEH002016

, 2004, 14(6), 235–237
Synthesis of new chiral molecular tweezers with a tris-Tröger’s base skeleton
Thierry Mas,a Carmen Pardo*a and José Elguerob
a Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid,
E-28040 Madrid, Spain. Fax: +34 91 394 4103; e-mail: chpardo@quim.ucm.es
b Instituto de Química Médica, Centro de Química Orgánica ‘Manuel Lora-Tamayo’, E-28006 Madrid, Spain
DOI: 10.1070/MC2004v014n06ABEH002016
For the first time, chiral molecular tweezers with a tris-Tröger’s base skeleton have been synthesised. Three new compounds 9a,
9b and 9c differ in their stereochemistry.
Tröger’s base 11 is a concave chiral molecule, the chirality of
which results from the blocked configuration of its stereogenic
nitrogen atoms. Tröger’s base and its derivatives have been
described as ‘fascinating molecules’,2 and they provide relatively
rigid chiral frameworks for the construction of chelating and
biomimetic systems, which were essentially developed by Wilcox
and co-workers.3–7 Tröger’s bases show a perpendicular arrange-
ment of the two aromatic rings,3 as in Kagan’s ether, which was
used by Harmata and co-authors for the synthesis of molecular
tweezers.8,9 In this context, we have utlilized the Tröger’s
skeleton as a scaffold for the construction of molecular clips
2,10 311 and 412 (Figure 1). Recently, Klärner and co-workers13
have described the synthesis of another family of molecular
clips 5 with three methylene bridges. These results prompted us
to report our preliminary results in the synthesis of chiral mole-
cules with a tris-Tröger’s base skeleton.
These tris-Tröger’s bases can exist as four stereoisomers:
anti–anti, anti–syn, syn–anti and syn–syn (Figure 2), the last
being the most interesting compound with its cage structure and
expected different host properties compared to the other three
stereoisomers, which have structures more alike to the bis-
Tröger’s bases.
We have prepared the tris-Tröger’s bases starting from com-
pound 2 (Scheme 1), following a synthetic pathway similar to
Mendeleev Commun. 2004 235

, 2004, 14(6), 235–237
Table 1 Aliphatic 1H chemical shifts (d) of bases 9 in [2H6]acetone at 500 MHz.
Base H-6na H-6x H-7n H-7x H-12n H-12x H-18n H-18x H-19n H-19x H-24n H-24x H-25a H-25b H-26a H-26b H-27a H-27b
9a
9b
9c
3.80
3.96
3.88
4.20
4.34
4.29
3.82
3.94
3.95
4.27
4.30
4.31
4.28
4.21
4.11
4.72
4.63
4.63
4.21
4.02
4.14
4.51
4.34
4.46
3.99
3.81
4.01
4.31
4.30
4.32
3.99
4.05
3.89
4.47
4.55
4.46
3.93
4.12
4.04
4.02
4.16
4.08
4.01
3.97
4.03
4.01
4.03
4.03
4.24
4.09
4.16
4.24
4.09
4.16
aProtons Hn (endo) and Hx (exo) are respectively placed under and aside the methylene bridge.
that used for the synthesis of the last compound.10 Base 2
was hydrogenated over Pd (10% C) to corresponding amino
derivative 6. The reaction of amine 6 with 2-amino-5-nitro-
benzoic acid in the presence of dicyclohexylcarbodiimide (DCC)
yielded amide 7, which was reduced to amine 8 by treatment
with a borane–tetrahydrofurane complex. Finally, the reaction
N
N
N
N
N
N
Me
Me
of 8 with aqueous formaldehyde and concentrated hydrochloric
1
acid in ethanol afforded a mixture of three tris-Tröger’s bases,
which were separated by flash chromatography over silica gel.
Elution with ethyl acetate/methanol (98/2) yielded successively
11% of 9a, 7% of 9b and 8% of 9c.
R
R'
New compounds 9a, 9b and 9c were identified by a com-
2 R = Me, R' = NO2
3 R = R' = NO2
4 R = R' = Me
bination of analytical (HRMS)† and spectroscopic methods
1
(1D and 2D H and 13C NMR).14,15 Tables 1 and 2 show the
1H NMR data of these compounds.
We have previously proved in bis-Tröger’s base systems,
whose structures were established by X-ray diffraction, that in
5
Figure 1
N
N
the syn arrangement of two consecutive methylene bridges the
protons of the external aromatic rings are more shielded than
those in the anti arrangement.10,11 The NMR data shown in
Table 2 allow us to assign tentatively the stereochemistry anti–
syn to 9a, the syn–anti to 9b and the syn–syn to 9c.
In conclusion, we present in this communication a synthesis
of new chiral molecular teewzers, one of them, 9c, with a cage
structure and interesting possibilities in host–guest chemistry.
Studies towards the isolation of the fourth stereoisomer, anti–
Me
NO2
N
N
2
i
42%
N
N
Me
NH2
N
N
N
N
6
N
N
ii 45%
N
N
N
NO2
N
N
Me
N
NO2
H
N
Me
Me
Me
N
N
N
N
O
NH2
NO2
N
N
7
iii 40%
NO2
Me
anti–syn 9a
syn–anti 9b
N
N
N
Me
H
N
25
5 N N23
N
Hx
22
4
NH2
6
21
8
24
N
3
N 20
N
Hn
iv 26%
1
7
26
Me
O2N
8 N
9
19
N
N
N
N
NO2
10
15
N
16
11
N
13
N
N
N
18
N
17
12
27
9
N
syn–syn 9c
N
Scheme 1 Reagents and conditions: i, H2/Pd (10% C), EtOH, room tem-
perature; ii, 2-amino-5-nitrobenzoic acid, DCC, DMF, room temperature;
iii, BH3–THF, THF, reflux; iv, 37% aq. CH2O, 36% HCl, 95% EtOH, 90 °C.
NO2
†
9a: mp 280–285 °C, M+ 569.2549.
anti–anti 9d
9b: mp 265–267 °C, M+ 569.2531.
9c: mp 250–253 °C, M+ 569.2540.
Figure 2
236 Mendeleev Commun. 2004

, 2004, 14(6), 235–237
4
5
6
7
M. Harmata and M. Kahraman, Tetrahedron Asymmetry, 2000, 11, 2875.
J. Jensen, M. Strozyc and K. Wärnmark, Synthesis, 2002, 2761.
J. Jensen, J. Tejler and K. Wärnmark, J. Org. Chem., 2002, 67, 6008.
A. Hannson, J. Jensen, O. F. Wendt and K. Wärnmark, Eur. J. Org.
Chem., 2003, 3179.
M. Harmata and C. L. Barnes, J. Am. Chem. Soc., 1990, 112, 5655.
J. Fleischhauer, M. Harmata, M. Kahraman, A. Koslowski and C. J. Welch,
Tetrahedron Lett., 1997, 38, 8655.
Table 2 Aromatic 1H chemical shifts (d) of bases 9 in [2H6]acetone at
500 MHz.
Base H-1 H-3 H-4 H-9 H-10 H-13 H-15 H-16 H-21 H-22
9a
9b
9c
6.68 6.90 6.92 6.98 6.99 7.83 7.92 7.30 6.81 6.81
6.65 6.86 6.93 6.88 6.85 7.87 7.95 7.30 6.93 6.96
6.45 6.71 6.79 6.91 6.89 7.69 7.81 7.15 6.85 6.85
8
9
10 C. Pardo, E. Sesmillo, E. Gutierrez-Puebla, A. Monge, J. Elguero and
A. Fruchier, J. Org. Chem., 2001, 66, 1607.
11 T. Mas, C. Pardo, F. Salort, J. Elguero and M. R. Torres, Eur. J. Org.
Chem., 2004, 1097.
anti 9d, to the improvement of the synthetic methodology and
to the unequivocally assignation of their stereochemistry are
currently under investigation in this laboratory.
12 T. Mas, C. Pardo and J. Elguero, Arkivoc, 2004 (iv), 86.
13 F. G. Klärner, M. Lobert, U. Naatz, H. Bandmann and R. Boese, Chem.
Eur. J., 2003, 9, 5036.
14 J. Cudero, P. Jiménez, C. Marcos, C. Pardo, M. Ramos, J. Elguero and
A. Fruchier, Magn. Reson. Chem., 1996, 34, 328.
15 C. Pardo, M. Ramos, A. Fruchier and J. Elguero, Magn. Reson. Chem.,
1996, 34, 708.
This work was supported by the DGI-MCYT (project
no. BQU2000-0645). T. Mas acknowledges the support of the
European Community, a Marie Curie individual fellowship (the
programme ‘Improving Human Research Potential and the Socio-
economic Knowledge Base’, contract no. HMPF-CT-2001-01120).
References
1
2
J. Tröger, J. Prakt. Chem. 1877, 36, 225.
Fascinating Molecules in Organic Chemistry, ed. F. Vögtle, John
Wiley, Chichester, 1992, p. 237.
3
For a recent review, see: M. Demeunynck and A. Tatibouët, in Progress
in Heterocyclic Chemistry, eds. G. W. Gribble and T. L. Gilchrist,
Pergamon Press, Oxford, 1999, vol. 11, p. 1 and references therein.
Received: 25th August 2004; Com. 04/2341
Mendeleev Commun. 2004 237