Square pegs in round holes. Preparation and intramolecular complexation of cubyl substituted β-cyclodextrins and of an adamantane analogue

Article abstract of DOI:10.1039/a905390e

The reaction of either 1-methoxycarbonyl-4-(4-nitrophenoxycarbonyl)cubane or its dimethyl analogue, 2,3-dimethyl-1-methoxycarbonyl-4-(4-nitrophenoxycarbonyl)cubane, with the primary amine of 6^A-(6-amino-hexyl)amino-6^A-deoxy-β-cyclode

Full text of DOI:10.1039/a905390e

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Square pegs in round holes. Preparation and intramolecular
complexation of cubyl substituted ꢀ-cyclodextrins† and of an
adamantane analogue
1
Bruce L. May,a Philip Clements,a John Tsanaktsidis,b Christopher J. Eastonc and
Stephen F. Lincoln*a
a Department of Chemistry, University of Adelaide, Adelaide, SA 5005, Australia
b CSIRO Molecular Science, Private Bag 10, Clayton South MDC, Clayton,
Vic 3169, Australia
c Research School of Chemistry, Australian National University, Canberra, ACT 0200,
Australia. E-mail: Stephen.Lincoln@adelaide.edu.au
Received (in Cambridge, UK) 5th July 1999, Accepted 8th November 1999
The reaction of either 1-methoxycarbonyl-4-(4-nitrophenoxycarbonyl)cubane or its dimethyl analogue,
2,3-dimethyl-1-methoxycarbonyl-4-(4-nitrophenoxycarbonyl)cubane, with the primary amine of 6A-(6-amino-
hexyl)amino-6A-deoxy-β-cyclodextrin produces the first cubyl substituted β-cyclodextrins, 6A-deoxy-6A-
{6-[N-(4-methoxycarbonylcuban-1-ylcarbonyl)amino]hexylamino}-β-cyclodextrin and its dimethyl analogue,
respectively, and 4-nitrophenolate. The reaction of 1,4-bis(4-nitrophenoxycarbonyl)cubane with 6A-(6-amino-
hexyl)amino-6A-deoxy-β-cyclodextrin produces the dimer 1,4-bis{6-[N-(6A-deoxy-β-cyclodextrin-6A-yl)amino]-
hexylaminocarbonyl}cubane. 1H NMR ROESY studies are consistent with the cubyl moiety of each of the
above three cubyl-substituted β-cyclodextrins complexing in the β-cyclodextrin annuli in D2O. The reaction
of 1-(4-nitrophenoxycarbonyl)adamantane with β-cyclodextrin produces 6A-{6-[N-(1-adamantylcarbonyl)amino]-
hexylamino}-6A-deoxy-β-cyclodextrin which shows a strong intramolecular complexation of its adamantyl moiety.
Adamantane-1-carboxylate forms intermolecular complexes with the above three cubyl-substituted β-cyclodextrins
in D2O solution and excludes the cubyl moiety from the β-cyclodextrin annulus. However, this does not occur for
6A-{6-[N-(1-adamantylcarbonyl)amino]hexylamino}-6A-deoxy-β-cyclodextrin where intramolecular complexation
appears to be sufficiently strong to prevent intermolecular complexation of adamantane-1-carboxylate.
amino]hexylamino}-β-cyclodextrin (2), 6A-deoxy-6A-{6-[N-
Introduction
(2,3-dimethyl-4-methoxycarbonylcuban-1-ylcarbonyl)amino]-
hexylamino}-β-cyclodextrin (3), dimeric 1,4-bis{6-[N-(6A-
deoxy-β-cyclodextrin-6A-yl)amino]hexylaminocarbonyl}-
cubane (4) and 6A-{6-[N-(1-adamantylcarbonyl)amino]hexyl-
amino}-6A-deoxy-β-cyclodextrin (5) (Fig. 1), which appear to be
the first reported modified βCDs with substituents incorporat-
ing cubyl and adamantyl moieties. In D2O 2–5 adopt structures
2Ј–5Ј where the substituent intramolecularly complexes inside
the βCD annulus to a significant extent as shown in Schemes
1–3.
We recently reported the intramolecular complexation of the
(6-aminohexyl)amino substituent in the β-cyclodextrin (βCD)
annulus of 6A-(6-aminohexyl)amino-6A-deoxy-β-cyclodextrin
(1) shown in Fig. 1.1 Similar intramolecular complexation of
aromatic substituents of modified βCDs is well established,
particularly in the case of those incorporating the dansyl
(dansyl = 5-dimethylaminonaphthalene-1-sulfonyl) moiety.2–6
In principle, such complexation offers the opportunity to
generate unusual molecular architectures in modified βCDs, an
aspect which is explored in this study. The driving force for
intramolecular complexation is probably similar to that for the
intermolecular complexation of guest species by CDs and
appears to arise from the summation of weak secondary forces
to give complexes of moderate stability.6–8 Commonly, intra-
molecular complexing substituents and intermolecular guests
possess hydrophobic character, a feature which is present in the
substituents of the new modified βCDs discussed here. We
selected cubyl and adamantyl substituents because they are
strongly hydrophobic and models show that their three dimen-
sional polycyclic structures fit into the βCD annulus. The cubyl
substituents appear to be of a size which permits their passage
through the primary and the secondary faces of βCD while
there is the possibility of some mechanical constraint applying
to the passage of the larger adamantyl substituent through the
primary face. Substitution at the primary amine of 1 produces
6A-deoxy-6A-{6-[N-(4-methoxycarbonylcuban-1-ylcarbonyl)-
Results and discussion
The major products arising from the deacylation of 4-nitro-
phenyl acetate by 6A-(6-aminohexylamino)-6A-deoxy-β-cyclo-
dextrin (1) are 6A-deoxy-6A-{6-[N-(methoxycarbonyl)amino]-
hexylamino}-β-cyclodextrin and 4-nitrophenolate.9 We have
adapted this reaction to produce the C6 substituted CDs, 2, 3, 4
and 5 (Fig. 1) which in principle may either exist with the sub-
stituent outside the βCD annulus or intramolecularly com-
plexed in it as shown for 2Ј, 3Ј, 4Ј and 5Ј in Schemes 1–3. (The
truncated cones represent the βCD annuli where the secondary
faces are delineated by 14 secondary hydroxy groups and the
primary faces are delineated by 6 primary hydroxy groups and a
secondary amine group.) Also shown in Fig. 1 is adamantane-1-
carboxylate (6) which competes with the cubyl substituents for
complexation in the βCD annulus as is discussed below. The
preparations of the modified CDs in Fig. 1 and their complex-
ing characteristics are now considered in more detail.
† β-Cyclodextrin = cycloheptamaltose.
J. Chem. Soc., Perkin Trans. 1, 2000, 463–469
This journal is © The Royal Society of Chemistry 2000
463

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Fig. 2 600 MHz 1H NMR ROESY spectrum of 3/3Ј in D2O at
pD ≥ 11.
Fig. 1 Structures of C6 substituted βCDs, 1/1Ј–5/5Ј where the sub-
stituent is intramolecularly complexed in the primed species and
adamantane-1-carboxylate (6) showing the atom labelling scheme. The
prefixes, hexyl, cubyl and adamantyl are used as appropriate in refer-
ring to 1H and 13C resonances in the NMR spectra.
6A-Deoxy-6A-{6-[N-(4-methoxycarbonylcuban-1-ylcarbonyl)-
amino]hexylamino}-ꢀ-cyclodextrin (2) and 6A-deoxy-6A-{6-[N-(4-
methoxycarbonyl-2,3-dimethylcuban-1-ylcarbonyl)amino]hexyl-
amino}-ꢀ-cyclodextrin (3)
The reaction of 1 with either 1-methoxycarbonyl-4-(4-nitro-
phenoxycarbonyl)cubane (7) or racemic 1-methoxycarbonyl-
2,3-dimethyl-4-(4-nitrophenoxycarbonyl)cubane (8) produces
2 and 3, respectively, and 4-nitrophenolate (9) as shown in
1
Scheme 1. The H ROESY NMR spectrum of 3 shows signifi-
cant cross-peaks arising from NOE interactions between the
cubyl methine and methyl protons and the H3 and H5 protons
which line the βCD annulus (Fig. 2 and Table 1). This is con-
sistent with the complexation of the cubyl substituent in the
annulus of 3Ј as shown in Scheme 1. (Usually, the H3 and H5
resonances occur at δ ~3.8 and ~3.5 ppm, respectively, but in
Fig. 2 they cannot be separately distinguished from the H6
resonances.) On addition of 6, these interactions and cross-
peaks are replaced by those arising from the NOE interactions
of the adamantyl protons H1–H4 with the H3 and H5 annular
protons of the intermolecular complex, 11, consistent with
the displacement of the cubyl moiety from the annulus by 6
(Fig. 3, Scheme 1 and Table 1). The orientation of 6 in 11
with the carboxylate function of 6 towards the secondary
face of the βCD annulus, shown in Scheme 1, is consistent
with modelling studies of intermolecular complexes formed
by 6 with βCD and 1.9,10 Because of the homochirality of 1
its reaction with racemic 8 produces diastereomeric 3 and 3Ј.
In the latter case it is expected that the homochiral βCD
Fig. 3 600 MHz 1H NMR ROESY spectrum of 3/3Ј and 6 in D2O at
pD ≥ 11.
1
annulus could induce different H NMR chemical shifts for
the two enantiomers of the 2,3-dimethylcubyl moiety but this
was not discerned.
The 1H ROESY NMR spectrum of 2 shows cross-peaks con-
sistent with NOE interactions occurring between the cubyl
methine protons and the annular protons H3 and H5 (Table 1)
consistent with the complexation of the cubyl moiety in the
annulus of 2Ј as shown in Scheme 1. On addition of 6, these
interactions and cross-peaks are replaced by those arising from
the NOE interaction of the adamantyl protons H1–H4 with the
H3 and H5 annular protons of the intermolecular complex, 10,
consistent with the displacement of the cubyl moiety from the
annulus by 6 (Table 1 and Scheme 1).
464
J. Chem. Soc., Perkin Trans. 1, 2000, 463–469

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Table 1 600 Mz 1H NOE cross-peaks observed in ROESY NMR spectra of solutions of cubyl and adamantyl substituted βCDsa
Cubyl protons
Methine
Adamantyl protons
Annular
protons
Solution/Species
Methyl
H2
H3
H4
H4Ј
Solution A 2/2Ј
H3
H5
H3
H5
H3
H5
H3
H5
H3
H5
H3
H5
H3
H5
ϩ
ϩ
Solution B 2/2Ј ϩ 6
Solution C 3/3Ј
ϩϩ
ϩ
ϩϩ
ϩ
ϩϩ
ϩ
ϩϩ
ϩ
ϩϩ
ϩϩ
Solution D 3/3Ј ϩ 6
Solution E 4/4Ј
ϩϩ
ϩ
ϩϩ
ϩ
ϩϩ
ϩ
ϩ
ϩ
ϩ
Solution F 4/4Ј ϩ 6
Solution G 5/5Ј
ϩϩ
ϩϩ
ϩϩ
ϩ
ϩϩ
ϩ
ϩϩϩ
ϩϩ
ϩϩϩ
ϩϩ
ϩ
ϩ
a The spectra were run in D2O at pD ≥ 11 at 298.2 K. The concentrations of the solutions of 2, 2 ϩ 6, 3, 3 ϩ 6, 4 and 5 were 0.06 mol dmϪ3 in each
species, and in the solution of 4 ϩ 6 the species concentrations were 0.06 and 0.12 mol dmϪ3, respectively. The intensity of the cross peaks increases
from ϩ to ϩϩϩ.
Fig. 4 600 MHz 1H NMR ROESY spectrum of 4/4Ј in D2O at
pD ≥ 11.
adamantyl protons H1–H4 with the H3 and H5 annular pro-
tons of the intermolecular complex 13 consistent with the dis-
Scheme 1
placement of the cubyl moiety from the βCD annulus of 4Ј (Fig.
5, Table 1 and Scheme 2). Simultaneously, the 1D H NMR
1
1,4-Bis{6-[N-(6A-deoxy-ꢀ-cyclodextrin-6A-yl)amino]hexylamino-
carbonyl}cubane (4)
spectrum (Fig. 5) simplifies to give a single resonance for the
cubyl protons consistent with both the βCD moieties becoming
equivalent and complexed by 6 in 13.
The reaction of 2 moles of 1 with 1,4-bis(4-nitrophenoxycarb-
onyl)cubane (12) produces the dimer 1,4-bis{6-[N-(6A-deoxy-β-
cyclodextrin-6A-yl)amino]hexylaminocarbonyl}cubane
(4)
6A-{6-[N-(Adamant-1-ylcarbonyl)amino]hexylamino}-6A-deoxy-
ꢀ-cyclodextrin (5)
1
together with two moles of 9 (Scheme 2). The 1D H NMR
spectrum shows at least three resonances for the non-equivalent
cubyl protons and the H ROESY NMR spectrum of 4 shows
significant cross-peaks arising from NOE interactions between
the cubyl methine protons and the H3 and H5 annular protons
(Fig. 4 and Table 1). This is consistent with the intramolecular
complexation of the cubyl moiety in one of the annuli of 4Ј
(Scheme 2). On addition of two moles of 6 these cross-peaks
are replaced by those arising from the NOE interaction of the
1
Our earlier studies showed that 1 exists predominantly in the
intramolecular complexed form 1Ј in D2O (Scheme 3).1 In prin-
ciple 1-(4-nitrophenoxycarbonyl)adamantane (14) may react
with either 1 or 1Ј to give 5 and 5Ј (and 9) which may exist in a
dynamic equilibrium if the adamantyl moiety passes through
the primary face of the βCD annulus. The NOE cross-peaks
between the annular H3 and H5 protons and the adamantyl
J. Chem. Soc., Perkin Trans. 1, 2000, 463–469
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Fig. 5 600 MHz 1H NMR ROESY spectrum of 4/4Ј and 6 in D2O at
pD ≥ 11.
Fig. 6 600 MHz 1H NMR ROESY spectrum of 5/5Ј in D2O at
pD ≥; 11.
Scheme 2
methine protons in the 1H ROESY NMR spectrum of 5 (Table
1 and Fig. 6) are consistent with the adamantyl moiety residing
in the annulus of the intramolecular complex 5Ј to a significant
extent. No change in the cross-peaks occurs on addition of two
equivalents of 6, although distinctive resonances of 6 appear
Scheme 3
ally constrained molecular slip-knot. Irrespective of whether
the entropic or the mechanical constraint rationale is correct, it
is apparent that 5Ј has an unusually low capacity to form inter-
molecular complexes.
1
in the 1D H NMR spectrum. It appears that 6 is unable to
compete with the intramolecularly complexed adamantyl sub-
stituent of 5Ј to form an intermolecular complex. This may be
because either the adamantyl substituent of 5Ј has an entropic
advantage in competing with 6, or because substitution of 1Ј by
14 through the secondary face of the βCD annulus produces 5Ј
where the adamantyl moiety is too large to pass through the
primary face. In the latter case 5Ј would constitute a mechanic-
Conclusions
The intramolecular complexation of the cubyl moiety in the
annuli of modified βCDs in preference to the hexyl chain,
which links it to the amine group at C6, is consistent with the
more spatially restricted fit of cubane producing a greater
466
J. Chem. Soc., Perkin Trans. 1, 2000, 463–469

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thermodynamic stability in the intramolecular complex than
that of the alternative complex where the flexible hexyl moiety
intramolecularly complexes and excludes the cubyl moiety.
However, despite the entropic advantage that the cubyl sub-
stituent might be expected to have in competition for occu-
pancy of the βCD annulus in the formation of intramolecular
complexes, it is excluded by 6 which forms intermolecular com-
plexes. This is consistent with the closer fit of the adamantyl
moiety in combination with its hydrophobicity stabilising its
intermolecular complex by comparison with the intramolecular
cubyl complex. This interpretation is also in accord with adam-
antan-1-ol, adamantan-2-ol and adamantane-1-carboxylic acid
forming significantly more stable intermolecular complexes
with Nα-dansyl--lysine-β-cyclodextrin than the smaller cage
species (Ϫ)-borneol, (ϩ)- and (Ϫ)-camphor and (ϩ)- and
(Ϫ)-fenchone.5
The intramolecular complexation of the reactive substituents
of modified βCDs, exemplified by the aminohexyl substituent
of 6A-(6-aminohexylamino)-6A-deoxy-β-cyclodextrin (1), offers
the opportunity for a substituent bound at C6 to form an
intramolecular complex (1Ј) and subsequently react at the
secondary face with a reactive molecule which is too large to
pass through the βCD annulus and form a mechanically con-
strained molecular slip-knot. Similarly, a substituent bound at
either C2 or C3 might react at the primary face to form a
molecular slip-knot. We are studying these possibilities.
led to the recovery of 5.97 g (8.4%) of dimethyl 2,3-dimethyl-
cubane-1,4-dicarboxylate. The aqueous solution was then
acidified with conc. HCl to pH 3 and extracted with carbon
tetrachloride (3 × 150 cm3). These extracts upon desiccation
(MgSO4) and concentration furnished 2 as a colourless solid
(38.9 g, 82.5%). Accurate mass 234.090 [M]ϩ. Calculated for
C13H14O4 [M]ϩ 234.089. δH (CDCl3) 1.24 (s, 3H), 1.28 (s, 3H),
3.70 (s, 3H), 3.81–3.91 (m, 3H), 4.06–4.17 (m, 3H); δC (CDCl3)
12.18, 44.56, 44.67, 47.88, 47.95, 51.40, 55.11, 55.31, 56.70,
56.86, 171.47, 177.22.
1-Methoxycarbonyl-4-(4-nitrophenoxycarbonyl)cubane (7)
A mixture of 4-nitrophenol (0.139 g, 1 × 10Ϫ3 mol), 1-methoxy-
carbonylcubane-4-carboxylic acid (0.207 g, 1 × 10Ϫ3 mol) and
dicyclohexylcarbodiimide (0.216 g, 1.02 × 10Ϫ3 mol) in dry
CH2Cl2 (5 cm3) was stirred at room temperature for 20 h. The
reaction mixture was filtered through a pad of Celite which was
washed with CH2Cl2 (3 × 5 cm3) and the combined filtrate was
washed successively with 5% sodium bicarbonate solution
(3 × 25 cm3) and brine (25 cm3) and dried over sodium sulfate.
The filtered solution was evaporated under reduced pressure
and the residue was dissolved in CH2Cl2 (2 cm3) and subjected
to flash chromatography (column 1.5 cm id, eluted with dichloro-
methane).17 Fractions containing the product were combined
and evaporated under reduced pressure to give the diester as
colourless needles (0.163 g, 50%). This material was used in
later steps without further purification. A small portion of
this material was recrystallised from dichloromethane–hexane,
mp 150–151 ЊC. Accurate mass 327.075 [M]ϩ. Calculated for
C17H13NO6 [M]ϩ 327.074. δH (CDCl3; 300 MHz) 8.27 (d, J = 6.8
Hz, 2H, ArH), 7.33 (d, J = 6.8 Hz, 2H, ArH), 4.4 (m, 6H, cubyl
H), 3.75 (s, 3H, MeO); δC (CDCl3) 171.6, 168.7, 155.3, 145.2,
125.1, 122.3, 55.7, 55.4, 51.5, 47.1, 47.0; IR (CDCl3) 3114 (w),
3083 (w), 3019 (w), 2996 (m), 2948 (w), 1735 (s), 1722 (s), 1589
(m), 1521 (m), 1490 (s), 1430 (s), 1342 (s), 1305 (s), 1222 (m),
Experimental
Physical methods
1
The H NMR (300 MHz) and 13C NMR (74.57 MHz) spectra
were run on a Varian Gemini 300 spectrometer, except for the
1
spectra of solutions A–G where H ROESY NMR (600 MHz)
spectra (mixing time of 0.35 s)11 were run on a Varian Inova
600 spectrometer. The spectral assignments below are listed
according to the atom labelling in Fig. 1. Thin layer chromato-
graphy (TLC) was carried out using Merck Kieselgel 60 F254
silica on aluminium sheets. Samples were eluted using a mixture
of isopropanol–ethyl acetate–water–ammonium hydroxide
(7:7:5:4). Compounds containing amino groups were detected
by dipping the developed plate into a solution of 1% ninhydrin
in ethanol and heating the plate. CDs were detected by dipping
the developed plate into a solution of 1.5% H2SO4 in ethanol
and heating the plate. Values of Rf are reported as Rc (retention
relative to βCD).
1199 (s), 1052 (s), 863 (m), 844 (m), 736 (m) cmϪ1
.
1-Methoxycarbonyl-4-(4-nitrophenoxycarbonyl)-2,3-dimethyl-
cubane (8)
A mixture of 4-nitrophenol (0.142 g, 1.02 × 10Ϫ3 mol), 1-meth-
oxycarbonyl-2,3-dimethylcubane-4-carboxylic acid (0.245 g,
1.05 × 10Ϫ3 mol) and dicyclohexylcarbodiimide (0.220 g,
1.07 × 10Ϫ3 mol) in dry CH2Cl2 (5 cm3) was stirred at room
temperature for 20 h. The reaction mixture was filtered through
a pad of Celite which was washed with CH2Cl2 (3 × 5 cm3) and
the combined filtrate was evaporated under reduced pressure.
The residue was dissolved in chloroform (2 cm3) and subjected
to flash chromatography (column 1.5 cm id, eluted with chloro-
form).17 Fractions containing the product were combined and
evaporated under reduced pressure to give a viscous oil (0.417
g) which solidified on standing. This material was used in later
steps without further purification. A small portion of this
material was recrystallised from dichloromethane–hexane, mp
79–80 ЊC. Accurate mass 355.104 [M]ϩ. Calculated for C19H17-
NO6 [M]ϩ 355.106. δH (CDCl3; 300 MHz) 8.29 (d, J = 6.7 Hz,
2H, ArH), 7.31 (d, J = 6.7 Hz, 2H, ArH), 4.25 (m, 2H, cubyl
H), 4.17 (m, 2H, cubyl H), 3.73 (s, 3H, MeO), 1.32 (s, 3H, Me),
1.31 (s, 3H, Me); δC (CDCl3) 171.0, 168.3, 155.4, 145.3, 125.1,
122.4, 57.4, 56.8, 55.9, 55.3, 55.1, 51.25, 48.2, 44.9, 12.2, 12.0.
IR (film) 3116 (w), 3085 (w), 2996 (m), 2915 (m), 2856 (m), 1745
(s), 1722 (s), 1614 (m), 1592 (m), 1525 (s), 1490 (m), 1436 (m),
1348 (s), 1324 (s), 1203 (s), 1160 (s), 1110 (s), 1091 (s), 1002 (m),
Preparation of cubyl and adamantyl substituted ꢀ-cyclodextrins
Literature methods were used to prepare 6A-(6-aminohexyl-
amino)-6A-deoxy-β-cyclodextrin,12 1-methoxycarbonylcubane-
4-carboxylic acid, cubane-1,4-dicarboxylic acid and dimethyl
2,3-dimethylcubane-1,4-dicarboxylate.13–16 Either standard pro-
cedures were employed in the preparation of the other com-
pounds used in the preparations described below, or they were
of good commercial grade. CAUTION: While no instability was
noted in the cubyl-substituted βCDs prepared in this study, it
should be noted that cubanes are high energy materials and
should be handled accordingly.
1-Methoxycarbonyl-2,3-dimethylcubane-4-carboxylic acid
A 2 dm3 molϪ1 solution of sodium hydroxide in methanol (100
cm3, 200 mmol) was added dropwise over 15 min, with stirring,
to a solution of dimethyl 2,3-dimethylcubane-1,4-dicarboxylate
(50 g, 201.4 mmol) in tetrahydrofuran (400 cm3) at ~0 ЊC, under
nitrogen. The cooling bath was then removed and the reaction
mixture stirred for 16 h before being concentrated to dryness
under reduced pressure. The resulting solid was partitioned
between water (400 cm3) and dichloromethane (250 cm3).
Desiccation (MgSO4) and concentration of the CH2Cl2 extracts
862 (m), 756 (m) cmϪ1
.
1,4-Bis(4-nitrophenoxycarbonyl)cubane (12)
A mixture of 4-nitrophenol (0.282 g, 2.00 × 10Ϫ3 mol), cubane-
1,4-dicarboxylic acid (0.193 g, 1.00 × 10Ϫ3 mol) and dicyclo-
hexylcarbodiimide (0.411 g, 2.0 × 10Ϫ3 mol) in CH2Cl2 (10 cm3)
J. Chem. Soc., Perkin Trans. 1, 2000, 463–469
467

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was stirred at room temperature for 20 h. The reaction mixture
was filtered through a pad of Celite and the pad was washed
with CH2Cl2 (30 cm3). The combined filtrates were washed with
5% sodium bicarbonate (3 × 20 cm3), water (20 cm3) and brine
(20 cm3) and dried over sodium sulfate. The filtered solution
was evaporated to about 20 cm3 and loaded onto a squat
column (30 g, 4.5 cm id) which was eluted with CH2Cl2.18,19
Fractions containing the product were combined and evapor-
ated under reduced pressure to give the diester as a white
powder (0.263 g, 60%). A small portion of this material was
recrystallised from dichloromethane–hexane, mp 215–217 ЊC.
Accurate mass 434.074 [M]ϩ. Calculated for C22H14N2O8 [M]ϩ
434.075. δH (CDCl3; 300 MHz) 8.30 (d, J = 9.2 Hz, 4H, ArH2),
7.33 (d, J = 9.2 Hz, 4H, ArH3), 4.53 (s, 6H, cubyl H);
δH(CDCl3) 168.5, 155.3, 145.5, 125.3, 122.4, 47.4. IR (Nujol)
1741 (s), 1612 (m), 1589 (m), 1521 (s), 1488 (m), 1339 (s), 1199
was filtered off and the filtrate was acidified with dilute hydro-
chloric acid and washed with CH2Cl2 (3 × 20 cm3). The aque-
ous layer was treated with AG 4-X4 weak anion exchanger (5 g)
for 1 h and the resin was removed by vacuum filtration. The
colourless filtrate was freeze-dried to give the product as a white
powder (0.092 g, 63%), Rc = 1.11; Electrospray-MS m/z 1449
(Mϩ) (Found: C, 46.94; H, 6.68; N, 1.79%. Calculated for
3ؒHClؒ4H2O (C61H105ClN2O41) C, 47.03; H, 6.79; N, 1.80%);
δC (D O) 175.8, 175.5 (C᎐O), 105.1 (C1), 86.7 (C4A), 84.2
᎐
2
(C4), 76.0, 74.8, 72.3 (C2, C3, C5), 62.8 (C6), 60.9, 59.9, 59.7,
59.1, 57.5, 57.4, 54.5, 51.5, 49.6, 46.9, 46.1, 45.6, 41.7 (C6A,
cubyl C, hexyl C1, hexyl C6, MeO), 28.5–31.4 (broad band,
hexyl C2–C5), 15.4, 14.5, 14.2 (cubyl Me).
1,4-Bis{6-[N-(6A-deoxy-ꢀ-cyclodextrin-6A-yl)amino]hexylamino-
carbonyl}cubane (4)
(s), 1049 (s) cmϪ1
.
A solution of 1 (0.128 g, 1.0 × 10Ϫ4 mol) and 12 (0.020 g,
4.61 × 10Ϫ5 mol) in dry DMF (2 cm3) was stirred at room tem-
perature for 20 h. The reaction mixture was diluted with ether
(40 cm3) and the resultant precipitate was collected by vacuum
filtration and washed with ether (3 × 10 cm3). The crude prod-
uct was dissolved in water (20 cm3) and the solution was acid-
ified with dilute hydrochloric acid and extracted with CH2Cl2
(3 × 15 cm3). The aqueous layer was treated with AG 4-X4
weak anion exchanger (5 g) for 1 h and the resin was removed
by filtration and the colourless filtrate was diluted with acetic
acid (1 cm3) to increase solubility, and was freeze-dried to give
the product as a white powder (0.046 g, 38%), Rc = 0.71;
Electrospray-MS m/z 2622 (Mϩ) (Found: C, 45.33; H, 6.75; N,
2.21%. Calculated for 4ؒ2AcOHؒ9H2O (C110H198N4O83) C,
1-(4-Nitrophenyloxycarbonyl)adamantane (14)
mixture of 4-nitrophenol (0.139 g, 1.0 × 10Ϫ3 mol),
A
adamantane-1-carboxylic acid (0.182 g, 1.0 × 10Ϫ3 mol) and
dicyclohexylcarbodiimide (0.218 g, 1.1 × 10Ϫ3 mol) in CH2Cl2
(5 cm3) was stirred at room temperature for 20 h. The reaction
mixture was filtered through a pad of Celite and the pad was
washed with CH2Cl2 (10 cm3). The filtrate was loaded onto a
squat column (30 g, 4.5 cm id)18,19 and eluted with CH2Cl2 (100
cm3). Fractions containing the ester were combined and evap-
orated under reduced pressure to give an off-white powder
(0.270 g, 90%). This material was used in later steps without
further purification. A small portion of this material was
recrystallised from dichloromethane–hexane, mp 130–132 ЊC.
Accurate mass 302.139 [M ϩ H]ϩ. Calculated for C17H20NO4
[M ϩ H]ϩ 302.139. δH (CDCl3; 300 MHz) 8.21 (d, J = 9.0 Hz,
2H, ArH), 7.22 (d, J = 9.0 Hz, 2H, ArH), 2.04 (br s, 10H), 1.91
(br s, 2H), 1.70 (br s, 3H); δC (CDCl3) 175.1, 156.0, 145.1, 124.9,
122.3, 41.0, 38.4, 38.1, 27.5. IR (Nujol) 1747 (s), 1614 (m), 1589
45.48; H, 6.87; N, 1.93%); δ (D O) 175.9, 175.6 (C᎐O), 105.1,
᎐
C
2
104.6, 104.1 (C1), 87.8, 86.9, 85.8, 84.4, 84.3, 84.0, 83.8, 83.3,
83.1 (C4), 75.8, 75.6, 75.3, 75.2, 74.9, 74.7, 74.5, 72.3, 72.2, 72.1,
70.4, 69.6 (C2, C3, C5), 63.2, 63.0, 60.5, 60.1 (C6), 51.5, 51.0,
50.8, 49.4, 49.1, 49.0, 48.8, 42.0, 41.9, 39.7 (C6A, cubyl C, hexyl
C1, hexyl C6), 34.7, 34.0, 31.8, 31.4, 31.1, 30.8, 29.6, 29.5,
29.2, 28.6, 28.3, 28.2, 27.9, 27.5, 25.6, 25.0 (broad band, hexyl
C2–C5).
(m), 1519 (s), 1488 (m), 1342 (s), 1199 (s), 1049 (s) cmϪ1
.
6A-Deoxy-6A-{6-[N-(4-methoxycarbonylcuban-1-ylcarbonyl)-
amino]hexylamino}-ꢀ-cyclodextrin (2)
6A-Deoxy-6A-{6-[N-(1-adamantylcarbonyl)amino]hexylamino}-
ꢀ-cyclodextrin (5)
A solution of 1 (0.128 g, 1.0 × 10Ϫ4 mol) and 7 (0.036 g,
1.1 × 10Ϫ4 mol) in dry DMF (2 cm3) was stirred at room tem-
perature for 20 h. The resultant yellow solution was added
dropwise with stirring to 1:1 ether–ethanol (50 cm3) cooled to
0 ЊC and the resultant fine yellow precipitate was collected by
vacuum filtration on a Celite pad. The product was dissolved
in water (5 cm3) and the Celite was removed by filtration. The
filtrate was acidified with dilute hydrochloric acid and washed
with CH2Cl2 (3 × 20 cm3). The aqueous layer was treated with
AG 4-X4 weak anion exchanger (5 g, Bio Rad Laboratories,
100–200 Mesh, free base form) for 1 h. The resin was removed
by filtration and the filtrate was freeze-dried to give a colourless
powder (0.072 g, 51%), Rc = 1.11; Electrospray-MS m/z 1421
(Mϩ) (Found: C, 45.71; H, 6.79; N, 1.75%. Calculated for
2ؒHClؒ5H2O (C59H103ClN2O42) C, 45.77; H, 6.70; N, 1.80%);
A solution of 1 (0.130 g, 1.05 × 10Ϫ4 mol) and 14 (0.037 g,
1.22 × 10Ϫ4 mol) in dry DMF (4 cm3) was stirred at room tem-
perature for 20 h. TLC showed two new spots at Rc 1.2 and 1.0.
The reaction mixture was diluted with ether (40 cm3) and the
resultant precipitate was collected by vacuum filtration and
washed with ether (3 × 10 cm3). The crude product was dis-
solved in water (20 cm3) and the solution was acidified with
dilute hydrochloric acid and extracted with CH2Cl2 (3 × 15
cm3). The aqueous layer was treated with AG 4-X4 weak anion
exchanger (5 g) for 1 h and the resin was removed by filtration
and the colourless filtrate was freeze-dried to give the product
as a white powder (0.103 g, 70%). Rc = 1.2, 1.0; Electrospray-
MS m/z 1395 (Mϩ) (Found: C, 45.98; H, 7.07; N, 1.86%. Calcu-
lated for 5ؒHClؒ7H2O (C59H111ClN2O41) C, 46.02; H, 7.27; N,
1.82%); δC (D O) 182.4 (177.1) (C᎐O), 105.2, 105.0, 104.8,
δ (D O) 176.5, 175.6 (C᎐O), 105.0 (C1), 87.3 (C4A), 83.9 (C4),
᎐
᎐
C
2
2
76.0, 74.9, 72.4, 70.6 (C2, C3, C5), 63.0 (C6), 60.6, 58.7, 55.3,
52.3, 51.6, 49.5, 49.1, 40.3 (C6A, cubyl C, hexyl C1, hexyl C6,
MeO), 25–31 (broad band, hexyl C2–5).
102.3 (C1), 87.85, 86.7, 86.0, 84.5, 84.3, 84.2, 84.1, 83.8 (C4),
79.5, 76.0, 75.9, 75.8, 75.5, 75.2, 75.1, 75.0, 74.8, 74.7, 74.6,
74.5, 73.9, 72.3, 72.2, 72.1, 70.2, 69.6 (C2, C3, C5), 63.2, 63.0,
62.8, 62.7 (C6), 57.1, 51.1, 50.6, 48.8, 45.5, 43.3, 43.2, 42.0, 41.5,
39.4, 39.2, 38.6 (C6A, hexyl C1, hexyl C6, adamantyl C1–C3),
34.9, 33.9, 31.8, 31.3, 30.7, 30.3, 30.0, 29.4, 28.5, 28.0, 27.8,
27.4, 26.0, 25.0 (hexyl C2–C5, adamantyl C4).
6A-Deoxy-6A-{6-[N-(4-methoxycarbonyl-2,3-dimethylcuban-1-
ylcarbonyl)amino]hexylamino}-ꢀ-cyclodextrin (3)
A solution of 1 (0.123 g, 1.0 × 10Ϫ4 mol) and 8 (0.058 g,
1.6 × 10Ϫ4 mol) in dry DMF (2 cm3) was stirred at room tem-
perature for 20 h. This solution was diluted with ether (50 cm3)
and the resultant precipitate was collected on a pad of Celite.
The pad was washed with ether (3 × 10 cm3) and then sus-
pended in water (25 cm3) to dissolve cyclodextrins. The Celite
600 MHz 1D 1H and 1H ROESY NMR spectra of D2O solutions
A–G
1
Solution A containing 2/2Ј. 1D H NMR data: δH 4.76 (br s,
7H, H1), 4.30 (m, 3H, cubyl H), 4.16 (m, 3H, cubyl HЈ), 3.4–4.0
468
J. Chem. Soc., Perkin Trans. 1, 2000, 463–469

View Article Online
(m, 42H, βCD H, MeO), 3.33 (m, 2H, C4A, hexyl H6), 3.06 (m,
2H, H6A, hexyl H6Ј), 2.8 (m, 1H, C6AЈ), 2.55 (m, 1H, hexyl H1),
2.40 (m, 1H, hexyl H1Ј), 1.1–1.5 (m, 8H, hexyl H2–5); 1H
ROESY NMR data: δH 3.4–4.0 (βCD H) shows cross-peaks
with 4.16 (cubyl HЈ), 4.30 (cubyl H), 4.16 shows cross-peaks
with 3.4–4.0 (βCD H), 4.30 (cubyl H) shows cross-peaks with
3.4–4.0 (βCD H).
peaks with 1.67 (adamantyl H4Ј), 1.74 (adamantyl H4), 1.84
(adamantyl H2), 2.04 (adamantyl H3).
1
Solution G containing 5/5Ј. 1D H NMR data: δH 5.1 (br s,
7H, H1), 3.5–4.0 (m, 39H, βCD H), 3.32 (t, J = 9.0 Hz, 1H,
H4A), 3.25 (m, 1H, hexyl H6), 3.0 (m, 2H, hexyl H6Ј, H6A), 2.79
(dd, J = 9.0, 12.0 Hz, 1H, H6A), 2.56 (m, 1H, hexyl H1), 2.28
(m, 4H, hexyl H1Ј, adamantyl H3), 1.94 (d, J = 12.6 Hz, 3H,
adamantyl 4), 1.84 (s, 6H, adamantyl H2), 1.79 (d, J = 12.6 Hz,
3H, adamantyl H4Ј), 1.0–1.8 (m, 8H, hexyl H2–H5); 1H
ROESY NMR data: δH 1.79 (adamantyl H4Ј) shows cross-
peaks with 3.7–4.0 (βCD H), 1.84 (adamantyl H2) shows
cross-peaks with 3.5–4.0 (βCD H), 2.28 (adamantyl H3) shows
cross-peaks with 3.7–4.0 (βCD H).
1
Solution B containing 2/2Ј and 6. 1D H NMR data: δH 5.04
(br s, 7H, H1), 4.20 (m, 2H, cubyl H), 4.12 (m, 4H, cubyl HЈ),
3.5–4.0 (m, 42H, βCD H, MeO), 3.37 (t, J = 9.6 Hz, 1H, H4A),
3.17 (m, 3H, H6A, hexyl H6), 2.87 (m, 1H, H6AЈ), 2.67 (m, 1H,
hexyl H1), 2.47 (m, 1H, hexyl H1Ј), 2.04 (br s, 3H, adamantyl
H3), 1.86 (br s, 6H, adamantyl H2), 1.75 (d, J = 12.0 Hz, 3H,
adamantyl H4), 1.64 (d, J = 12.0 Hz, 3H, adamantyl H4Ј), 1.2–
1
1
Solution H containing 5/5Ј and 6. 1D H NMR data: δH 5.1
1.5 (m, 8H, hexyl H2–H5); H ROESY NMR data: δH 1.64
(br s, 7H, H1), 3.5–4.0 (m, 39H, βCD H), 3.37 (t, J = 9.0 Hz,
1H, H4A), 3.23 (m, 1H, hexyl H6), 3.16 (m, 1H, hexyl H6Ј), 3.07
(d, J = 12.0 Hz, 1H, H6A), 2.80 (dd, J = 9.0, 12.0 Hz, 1H, H6A),
2.57 (m, 1H, hexyl H1), 2.29 (m, 1H, hexyl H1Ј), 2.17 (br s, 3H,
adamantyl H3), 1.95 (br s, 6H, adamantyl H3 of 6), 1.84 (m,
9H, adamantyl H4, adamantyl H2), 1.79 (m, 15H, adamantyl
H2 of 6, adamantyl H4Ј), 1.67 (br s, 6H, adamantyl H4 of 6),
(adamantyl H4Ј) shows cross-peaks with 3.5–4.0 (βCD H), 1.75
(adamantyl H4) shows cross-peaks with 3.5–4.0 (βCD H),
1.86 (adamantyl H2) shows cross-peaks with 3.5–4.0 (βCD
H), 2.04 (adamantyl H3) shows cross-peaks with 3.5–4.0 (βCD
H), 3.54 (βCD H) shows cross-peaks with 1.64 (adam-
antyl H4Ј), 1.75 (adamantyl H4), 1.86 (adamantyl H2), 2.04
(adamantyl H3).
1
1.0–1.8 (m, 8H, hexyl H2–5); H ROESY NMR data: δH 1.67
1
(adamantyl H4 of 6) shows cross-peaks with 3.8–4.0 (βCD H),
1.8 (adamantyl H4Ј) shows cross-peaks with 3.8–4.0 (βCD
H), 1.84 (adamantyl H2) shows cross-peaks with 3.5–4.0
(βCD H), 2.17 (adamantyl H3) shows cross-peaks with 3.8–4.0
(βCD H).
Solution C containing 3/3Ј. 1D H NMR data: δH 5.04 (br s,
7H, H1), 3.5–4.4 (m, 46H, cubyl H, βCD H, MeO), 3.42 (t,
J = 9.0 Hz, 1H, H4A), 3.19 (m, 3H, H6A, hexyl H6), 2.92 (m,
1H, H6AЈ), 2.64 (m, 2H, hexyl H1), 1.1–1.5 (m, 14H, hexyl
H2–H5, Me); 1H ROESY NMR data: δH 1.3 (Me) shows
cross-peaks with 3.5–4.0 (βCD H), 4.0–4.2 (cubyl H), 3.5–4.0
(βCD H) shows cross-peaks with 1.3 (Me), 4.0–4.2 (cubyl H),
4.0–4.2 (cubyl H) shows cross-peaks with 1.3 (Me), 3.5–4.0
(βCD H).
Acknowledgements
We are grateful to the Australian Research Council and the
University of Adelaide for supporting this research. We thank
Nihon Shokuhin Kako Co. for a gift of βCD.
1
Solution D containing 3/3Ј and 6. 1D H NMR data: δH 5.05
(br s, 7H, H1), 3.5–4.2 (m, 46H, cubyl H, βCD H, MeO), 3.36
(t, J = 9.0 Hz, 1H, H4A), 3.10 (m, 3H, H6A, hexyl H6), 2.81 (dd,
J = 7.2, 14.3 Hz, 1H, H6AЈ), 2.59 (m, 1H, hexyl H1), 2.42 (m,
1H, hexyl H1Ј), 2.05 (br s, 3H, adamantyl H3), 1.87 (br s, 6H,
adamantyl H2), 1.76 (d, J = 12 Hz, 3H, adamantyl H4), 1.61 (d,
J = 12 Hz, 3H, adamantyl H4Ј), 1.1–1.4 (m, 14H, hexyl H2–H5,
References
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Me); H ROESY NMR data: δH 1.61 (adamantyl H4Ј) shows
cross-peaks with 3.8 (H3), 1.76 (adamantyl H4) shows cross-
peaks with 3.8 (H3), 1.87 (adamantyl H2) shows cross-peaks
with 3.8 (H3), 2.05 (adamantyl H3) shows cross-peaks with 3.8
(H3), 3.8 (H3) shows cross-peaks with 1.61 (adamantyl H4Ј),
1.76 (adamantyl H4), 1.87 (adamantyl H2), 2.05 (adamantyl
H3).
6 C. J. Easton and S. F. Lincoln, Modified Cyclodextrins, Scaffolds and
Templates for Supramolecular Chemistry, Imperial College Press,
London, UK, 1999.
Solution E containing 4/4Ј. 1D 1H NMR data: δH (D2O) 5.00
(br s, 14H, H1), 2.5–4.4 (m, 142H, cubyl H, βCD H, hexyl
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H1, hexyl H6), 1.1–1.8 (m, 16H, hexyl H2–H5); H ROESY
NMR data: δH 4.1–4.4 (cubyl H) shows cross-peaks with 3.5–
4.0 (βCD H) and vice versa.
Solution F containing 4/4Ј and 6. 1D 1H NMR data: δH 5.06
(s, 14H, H1), 4.16 (s, 6H, cubyl H), 4.01 (t, J = 9.2 Hz, 2H,
H5A), 3.9–3.5 (m, 76H, H2–H6), 3.40 (t, J = 9.2 Hz, 2H, H4A),
3.30 (d, J = 13.2 Hz, 2H, H6A), 3.18 (m, 4H, hexyl H6), 3.01
(m, 2H, H6AЈ), 2.80 (m, 2H, hexyl H1), 2.68 (m, 2H, hexyl
H1Ј), 2.04 (s, 6H, adamantyl H3), 1.84 (s, 12H, adamantyl H2),
1.74 (d, J = 11 Hz, 6H, adamantyl H4), 1.67 (d, J = 11 Hz, 6H,
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1
adamantyl H4Ј), 1.2–1.6 (m, 16H, hexyl H2–H5); H ROESY
NMR data: δH 1.2–1.6 (hexyl H2–H5) shows cross-peaks with
3.18 (hexyl H6), 1.67 (adamantyl H4Ј) shows cross-peaks with
3.6–3.9 (H3, H5), 1.74 (adamantyl H4) shows cross-peaks
with 3.6–3.9 (H3, H5), 1.84 (adamantyl H2) shows cross-
peaks with 3.6–3.9 (H3, H5), 2.04 (adamantyl H3) shows cross-
peaks with 3.6–3.9 (H3, H5), 3.18 (hexyl H6) shows cross-peaks
with 1.2–1.6 (hexyl H2–H5), 3.6–3.9 (H3, H5) shows cross-
Paper a905390e
J. Chem. Soc., Perkin Trans. 1, 2000, 463–469
469