Efficient synthesis of new macrocycles with planar chirality

Article abstract of DOI:10.1055/s-2004-829082

Two new macrocycles possessing planar chirality were efficiently synthesized and resolved into enantiomers employing HPLC. CD spectra of 11 and 12 confirm their enantiomeric relationship and chiral stability.

Full text of DOI:10.1055/s-2004-829082

1616
LETTER
Efficient Synthesis of New Macrocycles with Planar Chirality
E
fficient
S
a
ynthesis of
r
N
ew
M
o
acrocycles
w
s
ith
P
lanar
ł
Chiral
a
ity w Kalisiak,a Janusz Jurczak*a,b
a
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
Department of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland
Fax +48(22)6326681; E-mail: jurczak@icho.edu.pl
b
Received 24 March 2004
was then examined in a model reaction with diamino ether
8, affording macrocyclic compound 1013 in good (60%)
isolated yield (Scheme 1). Analogous compounds lacking
such an intraannular group were synthesized in 16%
yield.14 This clearly proved our assumption that an in-
traannular ethereal group significantly increases the yield
of macrocyclization.
Abstract: Two new macrocycles possessing planar chirality were
efficiently synthesized and resolved into enantiomers employing
HPLC. CD spectra of 11 and 12 confirm their enantiomeric relation-
ship and chiral stability.
Key words: amides, macrocycles, synthesis, supramolecular
chemistry, enantiomeric resolution
Further examination of molecular models of 11 shows that
the macro-ring and the benzyl group are located in differ-
The element of planar chirality plays an important role in
many modern ligand systems.1,2 The majority of planar
chiral ligands are based on ferrocene3 derivatives or are-
ne-transition metal complexes.4 There are, however, rela-
tively few examples in the literature on the use of planar
chiral cyclophane-based ligands in catalytic asymmetric
processes,5 despite the fact that the parent 1,12-di-
oxa[12]paracyclophane (the first chiral ‘ansa’ compound)
was first synthesized and resolved into enantiomers in the
1940s.6,7
In our communication we present the synthesis of two
macrocycles with planar chirality based on chiral systems
similar to those of metacyclophanes.8 There are some ad-
vantages of our approach compared to [2.2]metacyclo-
phanes. Macrocyclic amides can interact with cations via
ethereal oxygen atoms or with anions via amide groups.9
In our compounds, as an intraannular group, we intro-
duced an additional ethereal group which could play an
important role in the interactions with cations and in in-
creasing the preparation yield. For the preparation of com-
pounds 11 and 12, as well as their analogs, we planned to
apply the double-amidation reaction, developed recently
in our laboratory.10 In this reaction, dimethyl a,w-dicar-
boxylates react with primary a,w-diamines in the presence
of MeO– under ambient conditions (MeOH as solvent, r.t.,
several hours, reagent concentration of 0.1 mol dm–3) 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,w-diamines.11
O-Alkylation of pyrogallol 1 with BnBr or NaphCH2Cl
afforded the corresponding compounds 212 and 3 in 33%
and 20% yields, respectively. Subsequently, the benzyl
derivative 2 was reacted with NBS to give compound 4.
The 1,3-dihydroxy derivatives 2–4 were subjected to reac-
tion with methyl bromoacetate to give the corresponding
dimethyl dicarboxylates 5–7, respectively. Compound 5
Scheme
1
Reagents and conditions: i) NaH, PhCH2Br or
SYNLETT 2004, No. 9, pp 1616–1618
Advanced online publication: 29.06.2004
DOI: 10.1055/s-2004-829082; Art ID: G09104ST
2
2.
0
7.
2
0
0
4
NaphCH2Cl, DMF; ii) NBS, SiO2, CCl4; iii) methyl bromoacetate,
K2CO3, 2-butanone; iv) Na, MeOH, r.t.
© Georg Thieme Verlag Stuttgart · New York

LETTER
Efficient Synthesis of New Macrocycles with Planar Chirality
1617
ent faces of the aromatic plane because the macro-ring is Table 1 CD Data for 11 and 12
too small to accommodate the intraannular group
(Scheme 2). If we introduce an asymmetric group in such
Compounds CD spectral data (lext.
)
a macrocyclic compound, the right and left sides will be
different, and the substance will show chiral properties.
(+)11
(-)11
(+)12
(-)12
192.5 (De +3.8), 218.0 (De +4.2), 238.5 (De +5.3)
192.5 (De –4.1), 218.0 (De –3.6), 238.5 (De –4.7)
200.5 (De –1.9), 220.0 (De –6.9), 234.5 (De +10.2)
199.5 (De +1.5), 219.0 (De +6.5), 234.5 (De –9.4)
boiling of solutions in MeCN for 20 hours caused no race-
mization.
In summary, we have demonstrated that O-benzyl or O-
methylenenaphthyl substituted macrocyclic diamides can
be synthesized in excellent yields and resolved into enan-
tiomers. These products are stable towards racemization.
Such compounds, possessing planar chirality, could serve
as chiral ligands for the inclusion complexes, especially
for cationic guests.
Scheme 2 Molecular model of 11
In order to verify this assumption, we carried out a tem-
1
perature-dependent H NMR experiment of 10, which
showed AB-type splitting for the isolated methylene
group. Even at 373 K, the benzyl group cannot pass
through the macro-ring plane. In order to introduce an el-
ement of planar chirality, we carried out an analogous re-
action of dimethyl dicarboxylates 6 with diamino ether 8
which gave the desired compounds 1115 in good yield
(72%). The size of the macrocyclic cavity plays an impor-
tant role in intermolecular interactions, especially in cat-
ion binding. To synthesize a macrocyclic compound
possessing a larger macro-ring, we reacted dimethyl di-
carboxylate 7 with diamino ether 9.16 In the case of com-
pound 12, the yield was not as satisfactory as it was for
macrocyclic diamides 10 and 11. This is probably due to
the steric hindrance of the naphthyl group. Racemic com-
pounds 11 and 1217 were successfully resolved into enan-
tiomers by analytical HPLC on chiral stationary phase
(Chiralcel OD-H®).18 The separation factors a were found
to be 1.10 and 1.13, respectively, and high enough to al-
low a semi-preparative resolution. The pure enantiomers
of compounds 11 and 12 were subjected to CD
experiments19 (Figure 1 and Table 1).
Acknowledgment
Financial support from the State Committee for Scientific Research
(Project T09A 087 21) is gratefully acknowledged.
References
(1) (a) Bolm, C.; Muniz, K. Chem. Soc. Rev. 1999, 28, 51.
(b) Deng, W.-P.; You, S.-L.; Hou, X.-L.; Dai, L.-X.; Yu,
Y.-H.; Xia, W.; Sun, J. J. Am Chem. Soc. 2001, 123, 6508.
(2) For reviews, see: (a) Ferrocenes; Togni, A.; Hayashi, T.,
Eds.; VCH: Weinheim, 1995. (b) Richards, C. J.; Locke, A.
J. Tetrahedron: Asymmetry 1998, 9, 2377. (c) Togni, A.;
Bieler, N.; Burckhardt, U.; Köllner, C.; Pioda, G.; Schneider,
R.; Schnyder, A. Pure Appl. Chem. 1999, 71, 1531. (d)Dai,
L.-X.; Hou, X.-L.; Deng, W.-P.; You, S.-L.; Zhou, Y.-G.
Pure Appl. Chem. 1999, 71, 1401.
(3) (a) Tye, H.; Comina, P. J. J. Chem. Soc., Perkin Trans. 1
2001, 1729. (b) Farrell, A.; Goddard, R.; Guiry, P. J. J. Org.
Chem. 2002, 67, 4209. (c) You, S.-L.; Hou, X.-L.; Dai,
L.-X.; Yu, Y.-H.; Xia, W. J. Org. Chem. 2002, 67, 4684.
(4) Gibson, S. E.; Ibrahim, H. Chem. Commun. 2002, 21, 2465.
(5) (a) Gibson, S. E.; Knight, J. D. Org. Biomol. Chem. 2003, 1,
1256. (b) Rozenberg, V.; Kharitonov, V.; Antonov, D.;
Sergeeva, E.; Aleshkin, A.; Ikonnikov, N.; Orlova, S.;
Belokon, Y. Angew. Chem., Int. Ed. Engl. 1994, 33, 91.
(c) Pye, P. J.; Rossen, K.; Reamer, R. A.; Tsou, N. N.;
Volante, R. P.; Reider, P. J. J. Am. Chem. Soc. 1997, 119,
6207. (d) Dahmen, S.; Bräse, S. J. Am. Chem. Soc. 2002,
124, 5940. (e) Wu, X.-W.; Yuan, K.; Sun, W.; Zhang, M.-J.;
Hou, X.-L. Tetrahedron: Asymmetry 2003, 14, 107.
It is noteworthy that the MeCN solutions of (–)11, (+)11,
(–)12, and (+)12 retained their enantiomeric purity for at
least three months at room temperature and even extended
(6) (a) Lüttringhaus, A.; Gralheer, H. Justus Liebigs Ann. Chem.
1942, 550, 67. (b) Lüttringhaus, A.; Gralheer, H. Justus
Liebigs Ann. Chem. 1947, 557, 108. (c) Lüttringhaus, A.;
Gralheer, H. Justus Liebigs Ann. Chem. 1947, 557, 112.
(7) For reviews, see: (a) Vögtle, F.; Neumann, P. Top. Curr.
Chem. 1974, 48, 67. (b) Vögtle, F.; Hohner, G. Top. Curr.
Chem. 1978, 74, 1. (c) Boekelheide, V. Acc. Chem. Res.
1980, 13, 65. (d) Collet, A.; Dutasta, J.-P.; Lozach, B.;
Canceill, J. Top. Curr. Chem. 1993, 165, 103.
Figure 1 CD spectra of the enantiomers 11 and 12 in MeCN
Synlett 2004, No. 9, 1616–1618 © Thieme Stuttgart · New York

1618
J. Kalisiak, J. Jurczak
LETTER
(15) 19-Benzyloxy-18-bromo-2,8,14-trioxa-5,11-diaza-
(8) (a) Vögtle, F.; Meurer, K.; Mannschreck, A.; Stühler, G.;
Puff, H.; Roloff, A.; Sievers, R. Chem. Ber. 1983, 116,
2630. (b) Kang, G. J.; Chan, T. H. J. Org. Chem. 1985, 50,
452. (c) Meurer, K.; Luppertz, F.; Vögtle, F. Chem. Ber.
1985, 118, 4433. (d) Grimme, S.; Pischel, I.; Vögtle, F.;
Nieger, M. J. Am. Chem. Soc. 1995, 117, 157.
bicyclo[13.3.1]nonadeca-1 (18),15 (19),16-triene-4,12-
dione (11). Purified by column chromatography (silica gel,
EtOAc) to give 11 (1720 mg, 72%) as a white solid; mp
172.6–173.6 °C. 1H NMR (500 MHz, CDCl3): d = 8.59–8.53
(br d, 1 H, NHCO), 7.99–7.93 (br d, 1 H, NHCO), 7.58–7.54
(m, 2 H), 7.46–7.41 (m, 3 H), 7.37 (d, J = 9 Hz, 1 H), 6.81
(d, J = 9 Hz, 1 H), 5.06 (dAB, J = 9.5 Hz, CH2Ph, 1 H), 4.99
(dAB, J = 9.5, CH2Ph, 1 H), 4.89 (dA1B1, J = 16.5, CH2CO, 1
H), 4.82 (dA2B2, J = 16.1 Hz, CH2CO, 1 H), 4.63 (dA1B1, J =
16.5 Hz, CH2CO, 1 H), 4.52 (dA2B2, J = 16.1 Hz, CH2CO),
3.80–3.71 (m, 2 H), 3.19–3.10 (m, 3 H), 3.04–2.99 (m, 1 H),
2.96–2.88 (m, 1 H), 2.64–2.57 (m, 1 H). 13C NMR (125
MHz, CDCl3): d = 168.5, 168.1, 153.0, 151.3, 142.5, 134.9,
130.2, 129.8, 129.3, 128.8, 115.5, 109.1, 78.5, 73.8, 72.5,
69.3, 69.1, 38.9, 38.8. HR–ESI (MeOH): m/z [M + Na]+
calcd for C21H23N2O679BrNa: 501.0632; found: 501.0646.
Anal. Calcd for C21H23N2O6Br: C, 52.62; H, 4.84; N, 5.84;
Br, 16.67. Found: C, 52.49; H, 4.93; N, 5.63; Br, 16.52.
(16) Piątek, P.; Kalisiak, J.; Jurczak, J. Tetrahedron Lett. 2004,
45, 3309.
(e) Hochmuth, D. H.; König, W. A. Liebigs Ann. 1996, 947.
(f) Müller, D.; Böhme, M.; Nieger, M.; Rissanen, K.; Vögtle,
F. J. Chem. Soc., Perkin Trans. 1 1996, 2937. (g) Grimme,
S.; Harren, J.; Sobański, A.; Vögtle, F. Eur. J. Org. Chem.
1998, 1491. (h) Iwamoto, H.; Yang, Y.; Usui, S.; Fukazawa,
Y. Tetrahedron Lett. 2001, 42, 49. (i) Es, D. S.; Gret, N.;
Rijke, M.; Eis, M. J.; Kanter, F. J. J.; Wolf, W. H.;
Bickelhaupt, F.; Menzer, S.; Spek, A. L. Tetrahedron 2001,
57, 3557.
(9) (a) Schmidtchen, F. P.; Berger, M. Chem. Rev. 1997, 97,
1609. (b) Kubik, S.; Goddard, R. J. Org. Chem. 1999, 64,
9475. (c) Piątek, P.; Jurczak, J. Chem. Commun. 2002,
2450. (d) Bondy, C. R.; Loeb, S. J. Coord. Chem. Rev. 2003,
240, 77. (e) Choi, K.; Hamilton, A. D. Coord. Chem. Rev.
2003, 240, 101.
(10) (a) Gryko, D. T.; Gryko, D.; Jurczak, J. Synlett 1999, 1310.
(b) Piątek, P.; Gruza, M. M.; Jurczak, J. Tetrahedron:
Asymmetry 2001, 12, 1763.
(11) General Procedure for Synthesis of Macrocyclic
Compounds 10–12: To a mixture of appropriate ester (5
mmol) and appropriate amine (5 mmol) in anhyd MeOH (60
mL) was added solution of MeONa (12.5 mmol) in anhyd
MeOH (50 mL). The mixture was left at r.t. for several hours
(monitored by TLC). The solvent was evaporated and the
residue was purified by column chromatography.
(17) 11-Bromo-26-(1-naphthylmethoxy)-2,8,15,21-tetraoxa-
5,18-diaza-tricyclo[20.3.1.0*9,14*]hexacosa-1 (25),9
(14),10,12,22 (26),23-hexaene-4,19-dione (12). Purified by
column chromatography (silica gel, EtOAc) to give 12 (465
mg, 15%) as white solid; mp 166.5–167.8 °C. 1H NMR (500
MHz, CDCl3): d = 8.30–8.26 (m, 1 H), 7.98–7.93 (m, 2 H,
NHCO), 7.85–7.80 (m, 1 H), 7.74–7.67 (m, 2 H), 7.52–7.47
(m, 2 H), 7.35–7.30 (m, 1 H), 7.13 (t, 1 H, J = 8.4), 6.89 (dd,
1 H, J1 = 8.6 Hz, J2 = 2.2 Hz), 6.79–6.74 (m, 2 H), 6.55 (d, 1
H, J = 2.2 Hz), 6.36 (d, 1 H, J = 8.6 Hz), 5.47 (s, 2 H,
CH2Naph), 4.79 (ddAB, J1 = 8.2 Hz, J2 = 15.6 Hz, 2 H,
CH2CO), 4.58 (dAB, J = 15.6 Hz, 2 H, CH2CO), 3.90–3.80
(m, 2 H), 3.71–3.65 (m, 1 H), 3.62–3.52 (m, 3 H), 3.38–3.30
(m, 2 H). 13C NMR (125 MHz, CDCl3): d = 168.7, 168.6,
153.4, 153.3, 148.3, 146.8, 139.3, 133.5, 132.0, 131.5,
129.5, 128.9, 127.1, 126.4, 125.8, 125.7, 125.1, 123.4,
123.2, 115.4, 112.9, 112.7, 111.2, 111.0, 74.2, 70.9, 70.7,
67.3, 67.2, 38.6, 38.5. HR–ESI (MeOH): m/z [M + Na]+
calcd for C31H29N2O779BrNa: 643.1050, found: 643.1039.
Anal. Calcd for C31H29N2O7Br: C, 59.91; H, 4.70; N, 4.51;
Br, 12.86. Found: C, 60.01; H, 4.84; N, 4.38; Br, 12.74.
(18) HPLC analyses for 11 and 12. Column: Chiralcel OD-H®,
length 250 mm; i.d. 4.6 mm. For 11: i-PrOH–hexane, 3:1;
flow rate 0.7 mL/min.; l = 254 nm. For 12: i-PrOH–hexane,
1:1; flow rate 1.1 mL/min.; l = 254 nm. Enantiomeric
purities obtained: (+)11: 93% ee, [a]D26 = +61.8 (c = 0.56,
CHCl3); (–)11: 88% ee, [a]D26 –59.3 (c = 0.55, CHCl3);
(+)12: 99% ee, [a]D26 = +18.9 (c = 0.37, CHCl3); (–)12: 94%
ee, [a]D26 –17.9 (c = 0.37, CHCl3).
(12) Yu, M. J.; McCowan, J. R.; Phebus, L. A.; Towner, R. D.;
Ho, P. P. K.; Keith, P. T.; Luttman, C. A.; Saunders, R. D.;
Ruterbories, K. J.; Lindstrom, T. D.; Wikel, J. H.; Morgan,
E.; Hahn, R. A. J. Med. Chem. 1993, 36, 1262.
(13) 19-Benzyloxy-2,8,14-trioxa-5,11-diaza-
bicyclo[13.3.1]nonadeca-1 (18),15 (19),16-triene-4,12-
dione (10). Purified by column chromatography (silica gel,
EtOAc) to give 10 (60%) as a white solid; mp 183.9–184.5
°C. 1H NMR (500 MHz, DMSO-d6): d = 7.82–7.76 (m, 2 H,
NHCO), 7.60 (d, J = 7.0 Hz, 2 H), 7.48 (t, J = 7.0 Hz, 2 H),
7.43–7.39 (m, 1 H), 7.16 (dd, J1 = 1.9 Hz, J2 = 7.3 Hz, 1 H),
7.09 (d, J = 7.8 Hz, 2 H), 5.04 (s, 2 H, CH2Ph), 4.76 (dAB
J = 16.5 Hz, 2 H, CH2CO), 4.69 (dAB, J = 16.5 Hz, 2 H,
,
CH2CO), 3.52–3.43 (m, 2 H), 3.12–3.05 (m, 4 H), 2.87–2.82
(m, 2 H). 13C NMR (125 MHz, DMSO-d6): d = 167.9, 152.7,
139.4, 136.1, 128.8, 128.7, 128.6, 128.5, 125.9, 125.7,
113.4, 113.2, 76.7, 71.3, 68.4, 38.6. HR–ESI (MeOH): m/z
[M + Na]+ calcd for C21H24N2O6Na: 423.1532; found:
423.1542. Anal. Calcd for C21H24N2O6: C, 63.00; H, 6.00; N,
7.00. Found: C, 63.10; H, 6.01; N, 7.06.
(19) CD experiments were measured in MeCN in a 0.1 cm cell at
24 °C.
(14) Gryko, D. T.; Piątek, P.; Jurczak, J. Tetrahedron 1997, 53,
7957.
Synlett 2004, No. 9, 1616–1618 © Thieme Stuttgart · New York