Synthesis and chiroptical properties of two new planar-chiral macrocycles

Article abstract of DOI:10.1016/j.tetlet.2004.02.063

Could simple intraannular-arm macrocyclic systems exist in enantiopure stable forms? The effective synthesis of two representative compounds of such a class, their resolution into enantiomers, and experiments justifying their stability toward racemization

Full text of DOI:10.1016/j.tetlet.2004.02.063

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3309–3311
Synthesis and chiroptical properties of two new planar-chiral
macrocyclesq
Piotr Piatek,a Jarosław Kalisiakb and Janusz Jurczaka,b,
*
z
aDepartment of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland
bInstitute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
Received 22 December 2003; revised 3 February2004; accepted 13 February2004
Abstract—Could simple intraannular-arm macrocyclic systems exist in enantiopure stable forms? The effective synthesis of two
representative compounds of such a class, their resolution into enantiomers, and experiments justifying their stability toward
racemization are presented.
Ó 2004 Elsevier Ltd. All rights reserved.
Structural studies of molecules possessing an element of
planar chiralitystarted in the 1940s with the synthesis
and resolution of 1,12-dioxa[12]paracyclophane (the
first chiral ÔansaÕ compound).1 Up to now, there have
been manyexamples of planar-chiral compounds
including cyclophanes,2 metallocenes,3 bridged annu-
lenes,4 trans-cycloalkenes,5 and miscellaneous struc-
tures.6 Interest in the synthesis of planar-chiral
compounds is rapidlygrowing since theyare used as
ligands for transition metal complexes. Ligands of this
type are usually based on ferrocene or [2,2]paracyclo-
phane backbones. Complexes consisting of such planar-
chiral ligands and transition metals such as rhodium,7
iridium,8 and palladium9 have been developed as cata-
lysts for various asymmetric reactions.10
A structure under consideration should consist of a
macro-ring containing an intraannular group. There are
two indispensable requirements for such systems to exist
in chiral form. The first is related to preventing an
intraannular group from threading through the macro-
ring plane; thus a relativelysmall macro-ring and an
appropriatelylarge intraannular substituent are needed.
The second condition requires prochiral differentiation
of the macrocyclic unit.
For the preparation of compounds 8 and 9, as well as
their analogs, we planned to applythe double-amidation
13
reaction, developed recentlyin our laboratory.
In this
reaction, dimethyl, a,x-dicarboxylates react with pri-
mary, a,x-diamines in the presence of MeOÀ under
ambient conditions (methanol as solvent, room tem-
perature, several hours, and a reagent concentration of
0.1 mol dmÀ3) to afford macrocyclic diamides in good to
excellent yields. Thus, the initial stage of the synthesis is
the preparation of appropriate dimethyl dicarboxylates
and a,x-diamines (Scheme 1 and Supplementarymate-
rial). Starting from 2-nitroresorcinol 1, after catalytic
reduction of the nitro group and acylation of the
resulting amino group, we obtained compound 2,14 that
in turn was elongated with methyl bromoacetate to give
the corresponding dimethyl dicarboxylate 3. Compound
3 was then examined in a model reaction with unsub-
stituted diaminoether 4,15 to afford macrocyclic com-
pound 7 in 23% isolated yield. Examination of the
molecular model of 7 shows that the macrocyclic ring
and intraannular group are located on different faces of
the aromatic plane, because the cavityof the macro-ring
is not large enough to accommodate the intraannular
In this communication we present the synthesis and
structure elucidation of compounds 8 and 9, the planar
chiralityof which originates from a suitablysubstituted
macrocyclic amide. Designed planar-chiral systems of
this type are similar to metacyclophanes,11 however,
macrocyclic amides could interact with cations via
ethereal oxygen atoms or with anions through amide
groups.12
Keywords: Macrocycles; Planar chirality; Chiroptical properties; Syn-
thesis.
q Supplementarydata associated with this article can be found in the
online version, at doi:10.1016/j.tetlet.2004.02.063
* Corresponding author. Tel.: +48-22-632-05-78; fax: +48-22-632-66-
81; e-mail: jurczak@icho.edu.pl
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.063

3310
P. Piatek et al. / Tetrahedron Letters 45 (2004) 3309–3311
z
HO
HO
O
20
10
0
HO
9 (-)
i, ii
O2N
HN
8 (-)
9 (+)
HO
1
2
iii
O
8 (+)
-10
-20
OMe
NH2
NH2
O
O
O
O
O
210
240
λ/nm
270
300
+
HN
R
OMe
Figure 2. CD spectra of the enantiomers 8 and 9 in acetonitrile.
4 R = H
O
3
5 R = Br
iv
Even at 373 K, the benzamide group cannot pass
through the macro-ring plane. In order to introduce an
element of planar chirality, we carried out an analogous
reaction of dimethyl dicarboxylate 3 with substituted
diaminoethers 5 and 6, which led to the desired com-
pounds 8 and 9, respectively, in satisfactory yields
(Scheme 1).
6 R = COOMe
O
Ha
Hb
N
O
O
H
O
O
HN
R
H
N
O
Racemic compounds 8 and 9 were successfullyresolved
into enantiomers employing analytical chiral HPLC
(Chiralcel OD-Hâ). The separation factors a were found
to be 1.25 and 1.38, respectively, and were high enough
to allow a semi-preparative resolution. The pure
enantiomers of compounds 8 and 9 obtained were sub-
jected to CD experiments (Fig. 2).
O
7 R = H
8 R = Br
9 R = COOMe
Scheme 1. Reagents and conditions: (i) H2, Pd/C, MeOH; (ii) benzoyl
chloride, MeOH, 65%; (iii) methyl bromoacetate, K2CO3, 2-butanone,
90%; (iv) Na, MeOH, rt: 23% 7, 19% 8, 10% 9.
It is noteworthythat acetonitrile solutions of ( ))8, (+)8
and ())9, (+)9 retained their enantiopurityfor at least
two months at room temperature and even extended
boiling of solutions in acetonitrile did not lead to any
racemization.
group. A veryimportant feature of this type of chirality
is that the energybarrier of rotation must be high en-
ough to permit resolution into enantiomers. To justify
our assumption we carried out a temperature-dependent
1H NMR experiment, which showed AB-type splitting
for the isolated methylene group (Fig. 1).
In summary, we have shown that N-benzoyl substituted
macrocyclic diamides can be readily synthesized and
resolved into enantiomers, which are stable toward
racemization. Such compounds, showing planar chiral-
itycould serve as chiral ligands for inclusion complexes
with neutral as well as cationic and anionic guests.
Acknowledgements
Financial support from the State Committee for Scien-
tific Research (Project T09A 087 21) is gratefully
acknowledged.
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