Synthetic routes to linear Oligo-Troeger's bases

Article abstract of DOI:10.1021/ol047902f

(Chemical Equation Presented) Derivatives of Troeger's base (TB) have played important roles in receptor construction due to their rigid V-shape. A new class of these compounds are the oligo-TBs, which can function as cavitands. Herein, we describe both stepwise and one-step (oligomerization) methods suitable for the preparation of linear oligo-TBs.

Full text of DOI:10.1021/ol047902f

ORGANIC
LETTERS
2005
Vol. 7, No. 1
67-70
Synthetic Routes to Linear
Oligo-Troger’s Bases
1
Bohumil Dolensky´, Martin Val´ık, David Sy´kora, and Vladim´ır Kra´l*
Department of Analytical Chemistry, Institute of Chemical Technology,
Prague, Technicka´ 5, 166 28 Praha 6, Czech Republic
kralV@Vscht.cz
Received October 11, 2004
ABSTRACT
Derivatives of Tro1ger’s base (TB) have played important roles in receptor construction due to their rigid V-shape. A new class of these
compounds are the oligo-TBs, which can function as cavitands. Herein, we describe both stepwise and one-step (oligomerization) methods
suitable for the preparation of linear oligo-TBs.
In 1887, Julius Tro¨ger described1 the condensation reaction
of p-toluidine with formaldehyde leading to the formation
of a unique structure containing nitrogen. It does not invert
its tetradric arrangement of moieties and thus provides a
persistent chiral center. The compound is known today as
Tro¨ger’s base (TB). Many years later, TB derivatives found
important applications in supramolecular chemistry2 and drug
development.3 Their popularity stems from their rigid V-
shape (80-120°) and their inherent chirality. Both of these
structural features were utilized toward the construction of
receptors for achiral4 and chiral5 analytes.
New uses for TB derivatives were made possible by the
finding that more than one TB unit can be attached to a
central benzene ring. Thus, bis-TB can be prepared6,7 as a
mixture of boatlike (VV-bis-TB) and chairlike (VA-bis-TB)
diastereoisomers, which are mutually interconvertible under
acidic conditions. Recently, we have shown that a structure
with benzene substituted by three TB units can be prepared.7
Oligo-TBs with more than two TB units around a central
unit can be called calix-TB. Each of these unique oligo-TBs
can function as a pH-sensitive cavity-containing scaffold for
the construction of novel receptors.
In this article, we present a stepwise preparation of a new
group of oligo-TB derivatives, the linear oligo-TBs. They
have structural TB units that are interconnected, affording a
chain structure. Additionally, for the first time, a one-pot
preparation of linear oligo-TBs via an oligomerization reac-
tion is described.
A step-by-step synthesis of linear oligo-TBs has several
inherent limitations. The main drawback is the limited avail-
ability of suitable starting compounds. A five-step preparation
can be designed for the synthesis of tris-TBs 1 (Scheme 1).
(1) Tro¨ger, J. J. Prakt. Chem. 1887, 36, 225-245.
(2) (a) Bag, B. G. Curr. Sci. 1995, 68, 279-288. (b) Demeunynck, M.;
Tatibouet, A. Recent Development in Tro¨ger’s Base Chemistry. In Progress
in Heterocycles Chemistry; Gribble, G. W., Cilchrist, T. L., Eds.; Perga-
mon: Oxford, UK, 1999; pp 1-20.
(3) (a) Baldeyrou, B.; Tardy, C.; Bailly, C.; Colson, P.; Houssier, C.;
Charmantray, F.; Demeunynck, M. Eur. J. Med. Chem. 2002, 37, 315-
322. (b) Johnson, R. A.; Gorman, R. R.; Wnuk, R. J.; Crittenden, N. J.;
Aiken, J. W. J. Med. Chem. 1993, 36, 3202-3206. (c) Bailly, C.; Laine,
W.; Demeunynck, M.; Lhomme, J. Biochem. Biophys. Res. Commun. 2000,
273, 681-685.
(4) (a) Goswami, S.; Ghosh, K.; Dasgupta, S. J. Org. Chem. 2000, 65,
1907-1914. (b) Hansson, A. P.; Norrby, P.-O.; Warnmark, K. Tetrahedron
Lett. 1998, 39, 4565-4568. (c) Wilcox, C. S.; Greer, L. M.; Lynch, V. J.
Am. Chem. Soc. 1987, 109, 1865-1867.
(5) (a) Allen, P. R.; Reek, J. N. H.; Try, A. C.; Crossley, M. J.
Tetrahedron: Asymmetry 1997, 8, 1161-1164. (b) Webb, T. H.; Suh, H.;
Wilcox, C. S. J. Am. Chem. Soc. 1991, 113, 8554-8555. (c) Wilcox, C.
S.; Adrian, J. C.; Webb, T. H.; Zawacki, F. J. J. Am. Chem. Soc. 1992,
114, 10189-10197.
(6) (a) Pardo, C.; Sesmilo, E.; Gutierrez-Puebla, E.; Monge, A.; Elguero,
J.; Fruchier, A. J. Org. Chem. 2001, 66, 1607-1611. (b) Mas, T.; Pardo,
C.; Salort, F.; Elguero, J.; Torres, M. R. Eur. J. Org. Chem. 2004, 1097-
1104.
(7) Val´ık, M.; Dolensky´, B.; Petrˇ´ıcˇkova´, H.; Kra´l, V. Collect. Czech.
Chem. Commun. 2002, 67, 609-621.
10.1021/ol047902f CCC: $30.25
© 2005 American Chemical Society
Published on Web 12/15/2004

correlation) NMR spectrum. As shown in Scheme 1, both
regioisomers 1b and 1c have three bond distances to the
aforementioned atoms. Thus, 1b and 1c would be expected
to exhibit cross-peaks.
Scheme 1. Step-by-Step Preparation of Tris-TBs 1a
As the number of TB units in one molecule increases, there
is a need for an easy description of the relative configuration
of oligo-TB diastereoisomers that is not dependent on the
nature of substituents as in (R,S)-systems. In addition, the
chirality on nitrogen of a TB unit is controlled by the chirality
of the second nitrogen of the unit; thus, only a one-letter
assignment should be sufficient. We propose a description
consistent with traditional labeling of the TB shape as the
V-shape using letters V and A. By this notification, bis-TB
in chair (anti-) “conformation” can be assigned as VA-bis-
TB (or AV-bis-TB for the enantiomer) and the boat (syn-)
“conformation” as VV-bis-TB (or AA-bis-TB for the enan-
tiomer). The possible diastereoisomers of linear tris-TBs are
shown in Figure 1. Note that symmetrically substituted linear
tris-TBs can be found, due to symmetry, as only three
diastereoisomers.
Theoretically, in the final step, three regioisomers 1a, 1b,
and 1c can be formed (each as a mixture of four racemic
diastereoisomers in the case of 1b (VVV-, VVA-, VAA-, and
VAV-) or three in the cases of 1a and 1c, in which the VAA-
is, due to symmetry, an enantiomer of VVA-, vide infra).
We isolated two tris-TBs (1a-a and 1a-b) in an overall
preparative yield of 11%. In addition, we found that all tris-
TBs 1a can be converted into the two other respective tris-
TB diastereoisomers (LC-MS). This phenomenon is associ-
ated with the well-known racemization6a,8 of TB units. This
proves that only one of three possible regioisomers, 1a, 1b,
and 1c, was formed as a mixture of diastereoisomers 1a-a
and 1a-b. This strong selectivity in the preparation might
be surprising; however, it is consistent with current knowl-
edge in this area. It has been recently found that 1,2,3,4-
substituted benzene derivatives are formed exclusively. No
1,2,4,5-derivatives have been observed to date.6,7 The
above mentioned facts lead to the speculation that regioiso-
mer 1a is the isolated product. In addition, we studied the
diastereoisomers of 1a by NMR and assigned the structure
on the basis of a missing cross-peak between the CH carbon
atoms of the central benzene ring and the CH2 proton atoms
of TB units (see Scheme 1). In addition, there was a missing
cross-peak between the CH proton atoms of the central
benzene ring and the CH2 carbon atoms of TB units in the
gHMBC (gradient-enhanced heteronuclear multiple-bond
Figure 1. Graphic representation of Tris-TB diastereoisomers.
Thus, we have prepared, via a step-by-step method, the
symmetric tris-TB 1a-a (configuration VVV or VAV) as a
major diastereoisomer of 1a as well as the asymmetric tris-
TB 1a-b with the configuration VAA. The second symmetric
isomer 1a-c was prepared by racemization of 1a-a or 1a-b.
It was detected by LC-MS. The three diastereoisomers of
1a were also characterized by NMR.9
It is clear that the preparation of tris-TBs different from
1a, or the preparation of tetra-TBs or higher oligo-TBs,
would be tedious. A step-by-step synthesis would be time-
consuming and expensive. Moreover, our overall preparative
yield (11%) is low and makes the oligo-TB scaffolds labor-
(9) Tris-TB 1a-a, isomer VVV or VAV: 1H NMR (in CDCl3) δ 7.06
(2H, d, 8.8), 6.99 (2H, d, 8.8), 6.95 (2H, d, 8.8), 6.75 (2H, dd, 8.8, 3.0),
6.43 (2H, d, 3.0), 4.62 (2H, d, 16.7), 4.38 (2H, d, 16.8), 4.18 (2H, d, 16.7),
4.13 (2H, dd, 13.1, 2.6), 4.11 (2H, d, 17.2), 4.06 (2H, s), 3.83 (2H, d, 16.6),
3.78 (2H, dd, 16.9, 1.5), 3.71 (6H, s); overall preparative yield 7%. Tris-
TB 1a-b, isomer VVA: 1H NMR (in CDCl3) δ 7.04 (1H, d, 8.5), 7.02 (1H,
d, 8.8), 6.99 (1H, d, 8.8), 6.96 (1H, d, 8.8), 6.86 (2H, s), 6.74 (1H, dd, 8.7,
2.9), 6.70 (1H, dd, 8.7, 2.9), 6.42 (1H, d, 2.5), 6.41 (1H, d, 2.5), 4.64 (1H,
d, 16.8), 4.60 (1H, d, 16.8), 4.35 (1H, d, 17.1), 4.33 (1H, d, 17.1, 1H), 4.27
(2H, d, 17.3), 4.02-4.26 (8H, m), 3.81 (1H, d, 16.8), 3.79 (1H, d, 17.1),
3.78 (2H, d, 16.8), 3.70 (3H, s), 3.68 (3H, s); overall preparative yield 4%.
Tris-TB 1a-c, isomer VVV or VAV: 1H NMR (in CDCl3; only noncovered
characteristic signals in the mixture after racemization) δ 6.65 (2H, dd,
8.8, 2.8), 6.34 (2H, d, 2.7), 3.63 (6H, s).
(8) (a) Prelog, V.; Wieland, P. HelV. Chim. Acta 1944, 27, 1127-1134.
(b) Greenberg, A.; Molinaro, N.; Lang, M. J. Org. Chem. 1984, 49, 1127-
1130.
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Org. Lett., Vol. 7, No. 1, 2005

Scheme 2. Oligomerization Reaction
intensive by the above-described multistep synthesis. Hence,
asymmetric diastereoisomer of tris-TB11 VAA-3c (1% yield)
from the reaction mixture. In addition, the MS analysis shows
the formation of tetra-TB 3d (n ) 3) and penta-TB 3e (n )
4) as trace products. We have also isolated formylated and
methylated derivatives of TB 3a and their identification is
in progress. The overall yield of Tro¨ger’s bases 3 (>11%)
is promising. The oligomerization is thus an attractive
alternative for oligo-TB preparations. We found that the
degree of oligomerization can be controlled by the ratio of
amine:diamine and by the order of reactant addition.
Optimization of the oligomerization reaction aimed at
obtaining higher oligo-TBs (n > 2), improving yields and
decreasing side-products is in progress.
a one-step preparation would be preferable even with a lower
isolated yield. This motivated us to develop an alternative
synthetic protocol for this class of compounds. We applied
the oligomerization of a diamine to forming TB units. As a
suitable candidate, we chose commercially available 1,4-
diamino-2,5-dimethylbenzene, which gives only one route
to bis-TB unit formation, thus limiting byproducts.
On the basis of molecular modeling, we predicted a
possibility of forming cyclic pentakis-TB (2, n ) 5) or
hexakis-TB (2, n ) 6). Unfortunately, we did not observe
any traces of cyclo-TBs 2 in the reaction mixture of 1,4-
diamino-2,5-dimethylbenzene with urotropine in TFA by MS
analysis. The mass spectra showed a series of peaks differing
by m/z ) 172, which was expected (Scheme 2). This suggests
the possibility of their formation via employment of an
appropriate template.
In summary, we have prepared linear tris-TBs by a step-
by-step synthesis. We have additionally prepared oligo-TBs
by one-step oligomerization and isolated linear bis- and tris-
TBs from the reaction mixture. We have proven that tetra-
TBs or higher TBs can be prepared by this synthetic protocol.
Second, we tried the oligomerization of the diamine in
the presence of p-toluidine. This led to the expected mixture
of oligo-TBs 3 (Scheme 2). To date, we have isolated
Tro¨ger’s base 3a (5% yield), both diastereoisomers of bis-
TB10 3b (3% yield of 3b-a and 7% yield of 3b-b), and an
Acknowledgment. This work was supported by grants
from the Ministry of Education, Youth and Sports of the
Czech Republic (Grant CEZ: MSM 223400008), the Grant
Agency of the Czech Republic (Grants 203/02/0933 and 203/
02/0420), the EU (Grant QLRT-2000-02360 and CIDNA)
(10) Bis-TB 3b-a: HRMS (FAB+) calcd for C28H31N4 (M + H)
1
423.2549, found 423.2558; H NMR (in CDCl3) δ 6.96 (2H, d, 8.1), 6.87
(2H, dd, 8.1, 1.6), 6.57 (2H, br s), 4.44 (2H, d, 16.6), 4.40 (2H, d, 16.7),
4.32 (2H, d, 12.5), 4.16 (2H, d, 12.5), 3.92 (2H, d, 16.6), 3.68 (2H, d,
16.7), 2.12 (6H, s), 2.02 (6H, s). Bis-TB 3b-b: HRMS (FAB+) calcd for
C28H31N4 (M + H) 423.2549, found 423.2530; 1H NMR (in CDCl3) δ 7.06
(2H, d, 7.9), 6.96 (2H, dd, 8.3, 2.0), 6.70 (2H, br s), 4.46 (2H, d, 16.8),
4.33 (2H, d, 16.2), 4.20 (2H, dd, 12.5, 1.6), 4.05 (2H, dd, 12.5, 1.6), 4.05
(2H, d, >16, covered), 3.79 (2H, d, 16.8), 2.22 (6H, s), 2.10 (6H, s).
(11) Tris-TB VVA-3c: HRMS (FAB+) calcd for C39H43N6 (M + H)
1
595.3549, found 595.3573; H NMR (in CDCl3) δ 7.05 (1H, d, 8.1), 7.03
(1H, d, 8.0), 6.99-6.93 (2H, m), 6.69 (1H, br s), 6.64 (1H, br s), 4.52 (1H,
d, 16.6), 4.51 (1H, d, 16.8), 4.48 (1H, d, 16.8), 4.41 (2H, br d, 17.0), 4.30-
4.06 (8H, m), 4.01 (1H, d, 16.7), 3.83 (1H, d, 16.8), 3.75 (1H, d, 16.8),
3.72 (2H, d, 17.0), 2.21 (3H, s), 2.20 (3H, s), 2.14 (3H, s), 2.12 (3H, s),
2.09 (3H, s), 2.04 (3H, s).
Org. Lett., Vol. 7, No. 1, 2005
69

1
to V.K., and the Grant Agency of the Czech Republic (203/
03/D049) to B.D.
13C NMR for VAA-3c, and LC-MS and H NMR for a
mixture of 1a-a, 1a-b, and 1a-c. This material is available
free of charge via the Internet at http://pubs.acs.org.
Supporting Information Available: 1H and 13C NMR
and 1H-13C gHMBC for 1a-a, 1a-b, 3b-a, and 3b-b, 1H and
OL047902F
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Org. Lett., Vol. 7, No. 1, 2005