Synthesis and transport studies of a new class of cage-annulated chiral macrocycles

Article abstract of DOI:10.1016/S0957-4166(03)00272-6

The synthesis of a new class of chiral pentacycloundecane cage annulated macrocycles is reported. The ability of the chiral hosts to transport racemic phenylglycine methyl ester enantioselectively through a chloroform membrane in a U-tube was compared to

Full text of DOI:10.1016/S0957-4166(03)00272-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1553–1557
Synthesis and transport studies of a new class of cage-annulated
chiral macrocycles
Thavendran Govender,a Humcha K. Hariprakasha,b Hendrik G. Krugera,* and Alan P. Marchandb
aSchool of Pure and Applied Chemistry, University of Natal, Durban, South Africa
bDepartment of Chemistry, University of North Texas, Denton, TX 76203-5070, USA
Received 18 February 2003; accepted 19 March 2003
Abstract—The synthesis of a new class of chiral pentacycloundecane cage annulated macrocycles is reported. The ability of the
chiral hosts to transport racemic phenylglycine methyl ester enantioselectively through a chloroform membrane in a U-tube was
compared to that of related pyridine macrocycles. The cage annulated macrocycles showed weak to moderate enantioselectivity
and very high rates of transport compared to previous systems reported using the same counter ion (PF6−). The rate of transport
was slowed by changing to a relatively harder counter ion (Cl−). © 2003 Elsevier Science Ltd. All rights reserved.
−
1. Introduction
port rate (0.6% h−1 with PF6 as counter-ion). A closely
related, cage annulated crown ether 2 shows a very high
−
Optically active crown ethers have been used success-
fully in transport studies of chiral ammonium ions1–3
and in related studies.4 Chiral host–guest studies are of
interest to workers in areas such as catalysis,5,6 enzyme
mimics,7,8 and enantiomeric separation of racemic mix-
tures.9,10 Cram’s bis-binol-derived crown ether, 1, trans-
ports a-methylbenzylammonium ion with good
enantioselectivity (ca. 78% ee) and at a moderate trans-
rate of transport (approx. 3% h−1 with PF6 as the
counter ion) and exhibits good enantioselectivity (ca.
79% ee) with the same guest and counter ion.3
Bradshaw4b synthesized a series of host–guest systems
that display moderate to good chiral recognition. How-
ever, due to their low lipophilicity, it is unlikely that
these systems would function effectively as transport
* Corresponding author. E-mail: kruger@nu.ac.za
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00272-6

1554
T. Go6ender et al. / Tetrahedron: Asymmetry 14 (2003) 1553–1557
agents. It has been reported both with chiral guests3 as
well as with metal ion transport experiments9,10 that the
cage annulation enhances the lipophilicity and conse-
quent transport ability of host systems. The purpose of
this study was to combine cage-annulation with Brad-
shaw’s macrocycle, 3,11 in order to investigate enan-
tioselectivity and transport ability of the resulting host
system. We therefore decided to use a similar route to
that described by Bradshaw11 in order to synthesize
macrocycle 3 and the novel macrocycles 4, 5 and 6.
ion, although thionyl chloride11 was used to form the
pyridine diacyl chloride 12. Diamines 13 and 14 were
synthesized by using established procedures.11,13 The
coupling reactions were performed at relatively high
dilution (2 mmol diamine per dm3 of solvent) and
produced the desired products in yields of 25–43% (see
Scheme 2).
2.1. Transport studies
U-tube transport studies using observed optical
rotation2 is a rapid, time-dependent method that can be
used to determine the enantioselectivity of a host–guest
system. When promising enantioselectivity is observed,
it then would be appropriate to pursue more accurate
methods, e.g. W-tube experiments,2 to determine a
more accurate % ee. In order to permit direct compari-
son of the complexation properties of the new macrocy-
cles with those already published, phenylglycine methyl
ester hydrochloride was employed as the guest
molecule. Complexation and transport of a-methylben-
zylamine hydrochloride was also studied; however, this
hydrochloride salt proved to be readily soluble in chlo-
roform. In a control run, as much as 30% dissolved into
the organic phase within 4 h.
2. Results and discussion
The reaction of pentacyclo[5.4.0.02,6.03,10.05,9]undecane-
8,11-dione 7 with excess allylmagnesium bromide
afforded the corresponding endo-8-endo-11-diol 8 (91%
yield).12 Subsequent dehydration of the diol 8 produced
the corresponding hexacyclic ether, 9.12
Ozonolysis of 9 followed by oxidative work-up afforded
the corresponding diacid, 10 (76% yield). Subsequent
reaction of 10 with oxalyl chloride produced the corre-
sponding diacyl chloride, 11, which then was coupled to
the appropriate diamine to form macrocycles 5 and 6,
respectively (see Scheme 1).
Table 1 shows the results for the transport studies of
macrocycles 5 and 6 with ( )-a-methyl-phenylglycinate
Macrocycles 3 and 4 were synthesized in similar fash-
Scheme 1. Synthesis of 11.
Scheme 2. Synthesis of macrocycles 3–6.

T. Go6ender et al. / Tetrahedron: Asymmetry 14 (2003) 1553–1557
1555
Table 1. Differential transport of enantiomers of ( )-a-methyl-phenylglycinate hydrochloride by 0.027 M hosts 5 and 6 in
−
CHCl5 and PF6 as counter ion
Run no.
Time (h)
Host
% Transported
Dominant enantiomer
% ee
1
4
5
6
7
24
1.5
2
4
8
None
3 0.5
18
24
24.5
29.7
5
5
6
6
R
R
R
R
27
20
25
22
hydrochloride with LiPF6 in the source phase (a-arm).
Hexafluorophosphate was used by Cram to promote
salting-out of the guest into the organic phase.2 The
receiving phase (b-arm) was analyzed every 30 min until
maximum optical rotation had been attained. Cage
macrocycle 5 shows a very high rate of transport (12%
h−1) and poor preference for the R-enantiomer. Macro-
cycle 6 has a lower rate of transport and only weak
selectivity for the R-enanantiomer.
candidates for transport studies. This observation indi-
cates that they are capable of forming a relatively
strong host–guest complex, but they are unable to
transport the guest into the organic phase due to their
low lipophilicity.
3. Conclusion
A new class of chiral macrocycles has been synthesized.
They exhibit the highest rate of transport (12% h−1 with
Very rapid transport by macrocycles 5 and 6 makes it
difficult to determine when the observed optical rota-
tion reaches a maximum, since at some stage the con-
−
PF6 as counter ion) reported to date, but with moder-
ate to poor enantioselectivity. It is clear that incorpora-
tion of the cage into macrocycles increases the
lipophilicity and transport ability of the host system.
Although transport rate is secondary in importance to
enantioselectivity in transport experiments, it neverthe-
less would be advantageous to develop a system that
exhibits both high enantioselectivity as well as a high
rate of guest transport. At present, efforts are underway
in our laboratory to develop a computational model
that will enable us to predict and to improve the
enantioselectivity of our macrocycles.
centration
gradient
will
work
against
enantioselectivity,2 after which time the % ee will begin
to decrease. Thus, rapid transport of the guest by the
macrocyclic host renders determination of the observed
optical rotation difficult and increases the error in
measurement of optical rotation. This was not a com-
plication in previous reports,2,3 wherein the rate of
transport was considerably slower. To overcome this
problem when macrocycles 5 and 6 were employed as
hosts, the rate of transport was slowed by replacing
PF6 as the counter ion with Cl−.
−
Table 2 shows the results obtained for the same host–
guest systems by using HCl in the source phase. The
receiving phase was analyzed every 60 min until maxi-
mum enantiomeric excess had been attained. Compari-
son of the enantioselectivities in Tables 1 and 2
confirms that a more accurate measurement of the
enantioselectivity is possible with slower rates of trans-
port as reported in Table 2. Macrocycle 6 shows mod-
4. Experimental
Melting points are uncorrected. All UV readings were
recorded by using a Varian Carey 1E UV–vis spec-
trophotometer. Optical rotations were taken on an
Optical Activity polarimeter. All mass spectrometric
analyses were carried out on a VG70-70E mass spec-
trometer. FAB mass spectra were obtained by bom-
bardment of samples with xenon atoms (1 mA at 8
keV). m-Nitrobenzyl alcohol was used as matrix. NMR
spectra were recorded on a Varian Unity Inova-300
MHz spectrometer. Elemental microanalyses were
obtained at the University of Natal. Spectroscopic
grade CHCl3 was filtered through alumina before use to
remove any traces of ethanol. All amino acids were
bought from Novabiochem.
erate
enantioselectivity
for
the
(R)-methyl
phenylglycinate (68% ee). Host 5 still shows weak
preference for the (R)-enantiomer (29% ee).
The pyridine macrocycles 3 and 4 display poor trans-
port ability with both counter ions. The presence of
host could be detected in both the source and receiving
phases after 24 h, thereby disqualifying hosts 3 and 4 as
Table 2. Differential transport of enantiomers of ( )-methyl phenylglycinate hydrochloride by 0.027 M hosts 5 and 6 in
CHCl5 and Cl− as counter ion
Run no.
Time (h)
Host
% Transported
Dominant enantiomer
% ee
1
2
3
4
5
24
12
19
12
18
None
1 0.5
16
22
6.8
13.2
5
5
6
6
R
R
R
R
29
22
48
68

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T. Go6ender et al. / Tetrahedron: Asymmetry 14 (2003) 1553–1557
4.1. 5,5-Dicarboxymethyl-4-oxahexacyclo[5.4.1.02,6.05,10
05,9.08,11]dodecane 10
.
19.86(q), 20.11(q), 29.73(d), 55.67(d), 70.30(t), 71.14(t),
72.13(t), 125.08(d), 138.67(d), 149.22(s), 163.38(s); calcd
for C21H33N3O5: C, 61.9; H, 8.16; N, 10.31; Found: C,
62.0; H, 8.2; N, 10.5.
A solution of the diene 912 (3.3 g) in dry methanol (100
mL) was cooled to −78°C via application of an external
dry ice–acetone bath and then was purged with argon
during 20 minutes. Ozone was bubbled into the mixture
until a blue-purple color persisted, thereby indicating
the presence of excess ozone and completion of reac-
tion. Excess ozone was flushed from the reaction vessel
with a stream of argon, and the reaction mixture was
concentrated in vacuo. Hydrogen peroxide (30 mL,
30%) was added dropwise to a stirred, ice bath cooled
mixture of the ozonide and formic acid (21 mL). The
resulting mixture was stirred at ambient temperature
during 1 h and then was refluxed gently during 12 h.
The reaction mixture was allowed to cool gradually to
ambient temperature and then was concentrated in
vacuo. Pure 10 (2.895 g, 76%) was thereby obtained as
a colorless microcrystalline solid: mp 175–175.5°C; IR
(KBr): wmax 3180(s), 2980(s), 1720(vs) cm−1; FAB+ MS
(m-nitrobenzyl alcohol): m/z 408 [M+H]+; 1H NMR
[DMSO, 300 MHz]: lH 1.45 (AB, JAB=10 Hz, 1H),
1.83 (AB, JAB=10 Hz, 1H), 2.36–2.80 (m, 12H), 12.15
(br s, 2H, D2O exchangeable); 13C NMR [DMSO, 50
MHz]: lC 37.94 (t), 41.27 (d), 42.81 (t), 44.04 (d), 47.91
(d), 58.55 (d), 92.56 (s) and 171.40 (s); anal. calcd for
C15H16O4 C, 65.21; H, 5.84: Found C, 65.39; H, 5.71.
4.3. General procedure for preparing macrocycles 5 and
6
A solution of 10 (4 mmol) in oxalyl chloride (10 mL)
was refluxed under argon during 12 h. The resulting
homogeneous mixture was concentrated in vacuo to
yield 11 as a pale brown oil. Mixtures of the diamine
13/14 (4 mmol) and NEt3 (1.5 mL) in toluene (750 mL)
and the diacyl choride 11 (4 mmol) in toluene (750 mL)
were added simultaneously, dropwise with stirring, to
toluene (250 mL) during 10 h at 0°C under argon. The
resulting mixture was stirred at ambient temperature
during 1 day and then was concentrated in vacuo. The
product was purified via column chromatography on
silica gel by eluting with ethyl acetate/dichoromethane
followed by fractional recrystallization of the eluate
thereby obtained from toluene.
4.3.1. Macrocycle 5. Macrocycle 5 was prepared as
described above. The crude product was purified by
chromatography on silica gel by eluting with ethyl
acetate/dichloromethane to give a clear oil from which
the pure product 5 (37%) was recrystallized from tolu-
ene to give colorless crystals: mp 94–97°C; [h]2D2 +6.8 (c
0.01, CH2Cl2); IR (KBr): wmax 3343(s), 3307(s), 2958(s),
2870(m), 1674(vs), 1517(s), and 1109(s) cm−1; FAB+
MS (m-nitrobenzyl alcohol), m/z 585 [M+H]+. 1H
NMR [CDCl3, 300 MHz]: lH 1.49 (AB, JAB=10.5 Hz,
1H), 1.82 (AB, JAB=10.6 Hz, 1H), 2.15–2.80 (m, 10H),
2.89 (AB, JAB=15.5 Hz, 1H), 2.98 (AB, JAB=14.8 Hz,
1H), 3.45–3.95 (m, 12H), 5.09–5.30 (m, 2H), 7.12–7.53
(m, 10H), 7.65 (d, J=8.1 Hz, 1H), 7.74 (d, J=8 Hz,
1H); 13C NMR [CDCl3, 75 Hz]: lC 39.55 (t), 39.58 (t),
41.00 (d), 41.35 (d), 43.15 (t), 43.68 (d), 43.98 (d), 46.22
(d), 49.76 (d), 52.80 (d), 52.85 (d), 56.36 (d), 60.06 (d),
70.22 (t), 70.89 (t), 70.94 (t), 73.91 (t), 73.94 (t), 93.98
(s), 94.05 (s), 126.62 (d), 127.01 (d), 128.04 (d), 140.25
(s), 140.32 (s), 169.14 (s); calcd for C35H41N2O6: C,
71.9; H, 6.9; N, 4.79; Found: C, 71.1; H, 7.1; N, 4.9.
4.2. General procedure for preparing macrocycles 3 and
411
A suspension of the 2,6-dimethylpyridine dicarboxylic
acid (4 mmol) was refluxed in freshly distilled thionyl
chloride (10 mL) under argon overnight. The homoge-
neous mixture was concentrated in vacuo to afforded
12 as pale brown oil. Mixtures of diamine 13/14 (4
mmol) and NEt3 (1.5 mL) in toluene (750 mL) and
diacyl choride 12 (4 mmol) in toluene (750 mL) were
added simultaneously, dropwise with stirring, to tolu-
ene (250 mL) during 10 h at 0°C under argon. The
resulting mixture was stirred at ambient temperature
during 1 day and then was concentrated in vacuo. The
product was purified via column chromatography on
silica gel by eluting varying ratios of EtOAc/CHCl3
followed by fractional recrystallization of the eluate
thereby obtained from toluene.
4.3.2. Macrocycle 6. Macrocycle 6 was prepared as
described above. The crude product was purified by
chromatography on silica gel by eluting with ethyl
acetate/hexane as eluents to give a clear oil from which
the pure product 6 (34%) was recrystallized from chlo-
roform/hexane to give white crystals: mp 103–105°C;
[h]2D2 −93.3 (c 0.0074, CHCl3); IR (KBr): 3300–3350(s),
1670(vs), 1529(s) cm−1; FAB+ MS (m-nitrobenzyl alco-
hol), m/z 518 [M+H]+. 1H NMR [CDCl3, 300 MHz]: lH
0.96 (AB, JAB=10.5 Hz, 1H), 1.01 (AB, JAB=10.6 Hz,
1H), 2.14 (septet, 2H), 3.51–3.96 (m, 12H), 8.00 (t, 1H),
8.33 (d, 2H), 8.47 (d, 2H). 13C NMR [CDCl3, 50 MHz]:
19.8(q), 20.1(q), 29.8(d), 55.6(d), 70.3(t), 71.1(t), 72.2(t),
125.1(d), 138.6 (d), 149.2 (s), 163.3 (s); calcd for
C29H44N2O6: C, 67.42; H, 8.58; N, 5.42; Found: C,
67.3; H, 8.4; N, 5.3.
4.2.1.
(4S,14S)-(−)-4,14-Diisopropyl-6,9,12-trioxa-5,
15,21 - triazabicyclo[15.5.1]henicosa - 1(20),17(21),18-
triene-2,16-dione 4. Macrocycle 4 was prepared as
described above. The crude product was purified by
chromatography on silica gel using ethyl acetate/hexane
as eluents to give a yellow oil from which the pure
product 4 (26%) was recrystallized from toluene to give
white crystals: mp 84–85°C; [h]2D2 −113.6 (c 0.02,
CHCl3); IR (KBr) 3320–3350(s), 1663(vs) cm−1; FAB+
MS (m-nitrobenzyl alcohol): m/z 408 [M+H]+; 1H
NMR [CDCl3, 300 MHz]: lH 0.90 (m, 12H), 1.53 (AB,
JAB=10.5 Hz, 1H), 1.87 (m, 3H), 2.40–2.75 (m, 10H),
2.79 (AB, JAB=15.5 Hz, 1H), 2.90 (AB, JAB=14.8 Hz,
1H), 3.45–3.85 (m, 12H), 6.97 (d, J=8.1 Hz, 1H), 7.12
(d, J=8 Hz, 1H); 13C NMR [CDCl3, 75 MHz]:

T. Go6ender et al. / Tetrahedron: Asymmetry 14 (2003) 1553–1557
1557
4.4. U-tube transport experiments
2. Newcomb, M.; Toner, J. L.; Helgeson, R. C.; Cram, D.
J. J. Am. Chem. Soc. 1979, 101, 4941.
Cation transport experiments were performed in a sim-
ple U-tube apparatus by using a previously published
procedure.2 Thus, a solution of optically active macro-
cycle (27 mmol dm−3) in CHCl3 (10 mL) was placed in
a 14 mm i.d. U-tube at 30°C. Into the source phase of
the U-tube was introduced 5.0 mL of a solution that
contained the guest ammonium salt (i.e. racemic methyl
ester, 1.0 mmol and LiPF6 (0.8 mol dm−3) in aqueous
HCl (and 0.08 mol dm−3). Into the receiving phase of
the U-tube was placed 0.10 mol dm−3 aqueous HCl (5.0
mL, 0.50 mmol). A small magnetic stirring bar was
used to mix the CHCl3 and aqueous layers at a con-
stant rate. The UV absorbance of the aqueous receiving
was measured at umax=286 nm. The optical rotation
measured using a 20 cm polarimetry cell (3 mL).
3. Marchand, A. P.; Chong, H.-S.; Ganguly, B. Tetra-
hedron: Asymmetry 1999, 10, 4695.
4. (a) Stoddart, J. F. Chem. Soc. Rev. 1979, 8, 85; (b)
Izatt, R. M.; Zhu, C. Y.; Huszthy, P.; Bradshaw, J. S.
In Crown Compounds: Towards Future Applications;
Cooper, S. R., Ed.; VCH Publishers: New York, 1992;
Chapter 12; (c) Kaneda, T. In Crown Ethers and Ana-
loguous Compounds; Hiraoka, M., Ed.; Elsevier:
Amsterdam, 1992; Chapter 6; (d) Still, W. C. Acc.
Chem. Res. 1996, 29, 155; (e) Webb, T. H.; Wilcox, C.
S. Chem. Soc. Rev. 1995, 22, 383; (f) Naemura, K.;
Tobe, Y.; Kaneda, T. Coord. Chem. Rev. 1996, 148,
199; (g) Sawada, M. J. Mass. Spectrom. Soc. Jpn. 1997,
45, 439.
5. Groves, J. T.; Viski, P. J. Org. Chem. 1990, 55, 3628.
6. O’Malley, S.; Kodadek, T. Organometallics 1992, 11,
2299.
7. Breslow, P.; Czanick, A. W.; Lauer, M.; Leppkes, R.;
Winkler, J.; Zimmerman, S. J. Am. Chem. Soc. 1986,
108, 1969.
8. Talma, A. G.; Jouin, P.; De Vries, J. G.; Troostwijk,
C. B.; Buning, G. H.; Waninge, J. K.; Visscher, J.;
Kellogg, R. M. J. Am. Chem. Soc. 1985, 107, 3981.
9. Marchand, A. P.; Kumar, K. A.; McKim, A. S.;
Mlinaric-Majerski, K.; Kragol, G. Tetrahedron 1997,
53, 3467.
10. Marchand, A. P.; Alihodzic, S.; McKim, A. S.; Kumar,
K. A.; Mlinaric-Majerski, K.; Kragol, G. Tetrahedron
Lett. 1998, 39, 1861.
The rate of transport was slowed by using 0.8 mol dm−3
HCl in the source phase.
Acknowledgements
This work was supported by grants from the National
Research Foundation (South Africa) and the University
of Natal. Dr. Louis Fourie, University of Potchef-
stroom, is acknowledged for the MS analysis and Mrs.
Anita Naidoo, University of Natal for the elemental
microanalysis. A.P.M. thanks the Robert A. Welch
Foundation (Grant B-0963), the Texas Advanced Tech-
nology Program (Grant 003659-0206-1999), and the US
Department of Energy (Grant DE-FG07-98ER14936)
for financial support of this study.
11. Huszthy, P.; Oue, M.; Bradshaw, J. S.; Zhu, C. Y.;
Wang, T.; Dalley, N. K.; Curtis, J. C.; Izatt, R. M. J.
Org. Chem. 1992, 57, 5383.
12. Marchand, A. P.; Huang, Z.; Chen, Z.; Hariprakasha,
H. K.; Namboothiri, I. N. N.; Brodbelt, J. S.; Reyzer,
M. L. J. Heterocycl. Chem. 2001, 38, 1361.
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