Effect of conformational preorganization of a three-armed host on anion binding and selectivity.

Article abstract of DOI:10.1002/1521-3765(20021104)8:21<4946::AID-CHEM4946>3.0.CO;2-V

A set of three-armed urea-containing anion receptors was prepared. The receptors all have the same binding topology but differ in the level of conformational preorganization with respect to the arrangement of the side-arms relative to the platform and within the side arms themselves. This is mirrored in a specific increase (x 2.5) in the binding constant for chloride and in a 12-fold increase in the chloride/nitrate-selectivity.

Full text of DOI:10.1002/1521-3765(20021104)8:21<4946::AID-CHEM4946>3.0.CO;2-V

FULL PAPER
Effect of Conformational Preorganization of a Three-Armed Host on Anion
Binding and Selectivity
Frank Hettche, Philipp Rei˚, and Reinhard W. Hoffmann*[a]
Abstract: A set of three-armed urea-containing anion receptors was prepared. The
receptors all have the same binding topology but differ in the level of conformational
Keywords: anion binding ¥ anions ¥
preorganisation with respect to the arrangement of the side-arms relative to the
conformation analysis ¥ host guest
platform and within the side arms themselves. This is mirrored in a specific increase
systems ¥ molecular recognition
(Â2.5) in the binding constant for chloride and in a 12-fold increase in the chloride/
nitrate-selectivity.
preorganisation, led us to design a series of hosts that have
identical binding topology and binding groups, but different
degrees of conformational preorganisation. Thus, the idea is
to have a tripodal host 1 consisting of a platform and three
side arms with urea moieties as sticky groups,[5, 6] see
Scheme 1. These were chosen in order to complex spherically
symmetrical anions,[6] which do not require a specific coordi-
nation geometry.
Introduction
Molecular recognition describes the association between two
molecules to form a noncovalently bonded complex.[1] The
partners are frequently dubbed as host and guest. Specificity
in molecular recognition derives from differences in the free
binding energies with respect to the complexation of different
guests. Binding enthalpies depend on the kind of interaction
(hydrogen bridges, dipolar attractions, Coulomb attractions),
binding topology, and desolvation effects. These last factors
are reflected in the binding entropies, which also comprise
solvation changes and losses of internal motions on complex-
ation. Especially with regard to the latter one tends to use
rigid hosts, which suffer less from losses of internal motions on
complexation.
Molecular recognition is the key element in nature×s
binding of effectors to receptors in biology. It is quite evident
that nature uses rigid effectors (such as steroids) or rigid
receptors only in a few instances, and indeed flexible
molecules prevail. However, many biologically active mole-
cules, particularly those of polyketide biogenetic origin show
high levels of conformational preorganisation,[2] which may
directly augment the binding free energy to the respective
host. Conformational preorganisation has thus been recog-
nised as a feature in molecular recognition,[3] since the
pioneering studies of Cram.[4] The magnitude of these effects,
however, is not easily assessed, because on comparing guests
(or hosts) of different conformational preorganisation other
structure parameters are likewise changed. This situation, in
line with our interest in the benefits of conformational
Cl
FG
FG
FG
FG
FG
Cl
1
FG
Scheme 1. Schematic representation of the tripodal host 1 and the complex
formation with the spherically symmetrical chloride anion guest. FG ˆ
urea.
The distance between the platform and the urea groups is
kept constant. The only feature to be changed is the
conformational preorganisation of the side arms relative to
the platform and within the side arms themselves. We hoped
that with a system such as 1 it would be possible to clearly
delineate the effects of conformational preorganisation on
binding energies and selectivities. Some of the results have
been communicated in preliminary form.[7] Here, we detail the
whole study.
Design of the receptors: As a central platform we chose a
triazine-trione unit,[8, 9] because the arrangement of the bond
dipoles should facilitate the positioning of a negatively
charged anion on top of the ring. Moreover, triazine-triones
are synthetically quite versatile. We envisioned the use of
four-carbon chains as side arms; these allow enough con-
formational diversity, but can in turn be easily conformation-
[a] Prof. Dr. R. W. Hoffmann, Dr. F. Hettche, Dr. P. Rei˚
Fachbereich Chemie der Philipps Universit‰t Marburg
Hans Meerwein Strasse, 35032 Marburg (Germany)
Fax : (‡49) 6421-282-5677
E-mail: rwho@chemie.uni-marburg.de
4946
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Chem. Eur. J. 2002, 8, No. 21

4946 4956
ally controlled,[10] see Scheme 2. Thus, the most flexible host
would be compound 2, in which the side-arms may explore the
full conformational space available.
Synthesis of the receptors: The three-fold symmetry of the
receptor invited a divergent synthesis from a central triazine-
trione unit, as exemplified in the synthesis of the receptors 2
and 5, cf. Schemes 4 6. To this end, cyanuric acid ( 10) was
alkylated[8] to give the tris-chloro compound 11.
FG
FG
FG
O
N
O
N
O
N
2
2
2
3
1 N
O
3
N
N
N
1
N
N
3
1
O
N
OH
NaH,
FG
FG
FG
Cl
Cl
O
O
O
O
O
BrC4H8Cl
NaN3
DMF
N
N
N
N
O
O
HO
N
OH
NaI, DMSO
FG
FG
FG
2
3
4
10
FG
Cl
11 (53%)
FG
O
O
N
O
N
O
N
2
O
2
2
3
N
N
1
3
1
N
N
1
N
N
3
N3
1) Pd(OH)2/C,
H2, MeOH
N3
FG
N
N
N
N
FG
FG
O
N
O
O
O
O
O
FG
O
O
O
N
O
2) ArNCO, THF
FG
5
FG
6
7
N3
FG
2 (9%)
12 (91%)
NPhth
FG
Scheme 4. Synthesis of host 2. FG ˆ NH-CO-NH-pC6H4-nC4H9.
8
Scheme 2. Different hosts discuused in this paper. FG ˆ NH-CO-NH-
pC6H4-nC4H9.
Nucleophilic displacement of the chloride by azide fur-
nished the tris-azide 12, which was reduced by hydrogenation
and converted into the tris-urea 2. The last reaction was not
optimised, once the poor solubility of 2 in CDCl3 had become
apparent.
Instead, we focussed on the methyl-branched compound 5.
The methyl branches constitute stereogenic centres in each
chain. To have a constitutionally homogenous receptor, which
is necessary for the binding studies by NMR titration, the side
chains in 5 have to be homochiral. Therefore, an enantiomeri-
cally pure alkylating agent 18 was required to convert 10 into
19, see Scheme 6.
The first restriction we wanted to introduce is illustrated in
host 3. Here, the methyl branches at C-1 cause a folding such
that the lateral chains arrange themselves orthogonal to the
platform to avoid A1,3-strain.[11] This system can explore the
conformations illustrated as 9a and 9b, see Scheme 3, with the
former being statistically favoured by 3:1.
FG
The synthesis of the alkylating agent 18 emanated from a
Myers alkylation of the chiral propionamide 13 to give 14
(Scheme 5).[12] Reductive cleavage of the chiral auxiliary
furnished the alcohol 15. At this stage the azido group was
introduced by a Mitsunobu reaction.[13] Finally, removal of the
silyl protecting group in 16 gave the alcohol 17, which was then
converted to the alkylating agent 18 by iodination.
FG
FG
FG
FG
9a
9b
FG
Scheme 3. Different conformations to avoid A1,3 strain. FG ˆ urea.
As the next stage of conformational preorganisation we
envisioned the receptor 4, in which the side chains should now
each adopt an extended conformation as a result of the
additional methyl group at C-3.[10] This set of three com-
pounds should therefore have an identical binding topology
towards anions such as chloride, but with various degrees of
conformational preorganisation. In the realisation of this
plan, it turned out that the solubility of host 2 in CDCl3, as the
medium of choice for the binding studies, was very low.
Because of this, host 2 was replaced by host 5; these are
equivalent in terms of conformational preorganisation.
The design of the receptors implied that all three arms
would simultaneously be involved in the binding of the anion.
To verify this premise, a two-armed (6) and a mono-armed (7)
™receptor∫ were included in the study. Since compound 7 was
accessible only in small quantities (see below) we chose the
simple phthaloyl derivative 8 as a substitute.
O
O
1) LDA, LiCl
LDA, H3B·NH3
Ph
TBDMSO
N
Xc
THF
2) TBDMSO-C2H4-I
THF
OH
14 (92%)
13
N3
OH
Ph3P, DIAD,
DPPA
HF
TBDMSO
TBDMSO
THF
MeCN
15 (75%)
16 (80%)
N3
N3
Ph3P,
imidazole, I2
I
HO
Et2O/MeCN
17 (92%)
18 (96%)
Scheme 5. Synthesis of alkylating agent 18.
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Chem. Eur. J. 2002, 8, No. 21
4947

R. W. Hoffmann et al.
FULL PAPER
Alkylation of 10 by iodide 18 provided tris-azide 19, see
Scheme 6. Instead of hydrogenation, which had been prob-
lematic with the tris-azide 12, we reduced the azide 19 through
a Staudinger procedure[14] using trimethylphosphine. This
resulted in 63% of the tris-urea 5.
O
O
O
NaHMDMS,
MeI
NaN3
THF
O
N
Cl
Xc
N3
THF
21 (80%)
20
1) NEt3, DPPA
pentane
LiOH, aq.
H2O2
O
O
HO
N3
2) ∆, pentane
Xc
N3
aq. THF
N3
23 (92%)
N3
OH
22 (77%, ds 13:1)
O
N
N
NaH, 18
N
N
N3
HO
N
OH
DMSO
O
N
O
N
O
19 (60%)
KOtBu
OCN
10
N
N
N3
THF
N3
N3
O
O
24
FG
N3
25 (66%)
FG
O
1) PMe3
2) H2O
N
N
O
1) PMe3
FG
2) H2O
3) ArNCO
O
N
O
5 (63%)
N
N
3) ArNCO
THF
FG
THF
O
N
O
FG
Scheme 6. Synthesis of host 5. Arˆ nC4H9-pC6H4-; FG ˆ NH-CO-NH-
pC6H4-nC4H9.
FG
ent-3 (22%)
Scheme 7. Synthesis of host ent-3. Arˆ nC4H9-pC6H4-; FG ˆ NH-CO-NH-
pC6H4-nC4H9.
The anion receptors 3 and 4 have stereogenic centres at C-1
of the side chain, that is the attachment point to the platform.
One way to create such structures would be by Mitsunobu
inversion using cyanuric acid (10) as the nucleophile. We had
doubts whether substantial yields could be attained in such a
three-fold alkylation reaction. For this reason we envisioned a
convergent route to compounds 3 and 4 by relying on the
cyclotrimerisation of isocyanates,[15] such as 24, see Scheme 7.
The isocyanate 24 was prepared by using an Evans alkyla-
tion[16] starting from the chloroacyl-oxazolidinone 20. First,
the azido function was introduced to give 21. Methylation of
21 could be attained with a 13:1 diastereoselectivity to furnish
22, from which the chiral auxiliary was removed by a standard
method.[16] The resulting acid 23 was then subjected to a
Curtius degradation to give the isocyanate 24, which was
immediately subjected to a KOtBu-catalysed cyclotrimerisa-
tion.[17]
1) BH3 SMe2,
Et2O
O
O
N3
O
NaOH
HO
OMe
OMe
NCO
aq. MeOH
2) DAAD, DPPA,
THF
26
27 (71%)
1) NEt3, DPPA
pentane
N3
O
N3
OH
2) ∆, pentane
29
28 (91%)
Scheme 8. Synthesis of enantiomerically pure isocyanate 29.
enantiomeric purity of the resulting half-ester was then
upgraded to 98% by recrystallisation of the R-(‡)-phenyl-
ethylammonium salts.[20]
This afforded the tris-azide 25 in 66% yield. The latter was
then converted to the receptor ent-3 as before, albeit in only
moderate yield.
Since the cyclotrimerisation of the isocyanate 24 to 25 was
readily achieved, we chose the same route for the preparation
of the receptor 4. The required isocyanate 29 was obtained
from 26 as summarized in Scheme 8.
Thus, borane reduction of the half-ester 26 gave a d-
hydroxyester, which was immediately converted to the azido-
ester 27 to prevent lactonisation. The ester 27 was saponified
to afford the acid 28. Curtius degradation of the latter
furnished the desired isocyanate 29.
During the optimisation of the synthesis of receptor 4 with
racemic starting material, we discovered information, that we
could not have gained on cyclotrimerisation of the enantio-
merically pure isocyanate 29: We obtained first experimental
indications of the conformational preorganisation within our
tailor-made side arms of the receptors of type 4. The
cyclotrimerisation of rac-29 generates a statistical 3:1 mixture
of the asymmetric (rac-30) and the C3-symmetric (rac-31)
trimer, see Scheme 9.
The presence of a 3:1 product mixture can be deduced from
the 13C NMR spectrum (Figure 1), in which several of the
signals appear to be split into ™triplets∫.
The enantiomerically pure half-ester 26 itself was obtained
in a two-step sequence. First, the corresponding meso-diester
was transformed into enantio-enriched 26[18] by a chymotryp-
sin-catalysed hydrolysis.[19] The reaction was performed for six
weeks at room temperature to reach an ee of 70%. The
The ™triplet multiplicity∫ of the individual signals can be
rationalised as a combination of a single signal for the
homochiral trimer rac-31 and two signals for the heterochiral
trimer rac-30, because in rac-30 the side chains are diaste-
reotopic to one another. The stereochemically distinct side-
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Chem. Eur. J. 2002, 8, No. 21

Three-Armed Hosts
4946 4956
N3
1) KOH,
aq. MeOH
N3
O
O
side arms heterochiral
O
side arms homochiral
O
NaN3
DMF
EtO
Cl
EtO
EtO
N3
2) ∆, xylene
EtO
O
N3
O
N3
N3
N
N
N
N
32
NCO
33 (91%)
KOt Bu
O
N
O
O
N
O
THF
1) NEt3, DPPA,
pentane
O
3 : 1
OCN
rac-29
N3
HO
N3
2) ∆, pentane
rac-31
rac-30 (78%)
N3
35
N3
34 (70%)
Scheme 9. Cyclotrimerization of rac-29.
N3
N3
O
O
KOtBu
N
N
THF
N
N
N3
N3
O
N
O
O
N
O
N3
N3
rac-19
rac-36 (59%)
Scheme 10. Synthesis of rac-36 and rac-19.
To conclude the synthesis of 4, enantiomerically pure tris-
azide 31 obtained from enantiomerically pure half-ester 26
was converted to the tris-urea 4 as before, see Scheme 11.
Figure 1. 13C NMR spectrum of the mixture of rac-30 and rac-31.
N3
FG
1) PMe3
O
N
O
N
2) H2O
N3
chains in rac-30 are present in a 2:1 ratio. Thus, a 1:2:1
intensity ratio within each ™triplet∫ will arise when the
isomers rac-30 and rac-31 are present in approximately 3:1
ratio. As the homochiral trimer 31 is available from the
cyclotrimerisation of the enantiomerically pure isocyanate 29,
the signals of the former could readily be identified.
The point to be made about the observed splitting in the
13C NMR spectrum of rac-30 and rac-31 in regards to
conformational preorganisation is the following: common
experience does not suggest that symmetry-related methyl
groups at stereogenic centres separated by four or eight
intervening bonds should have detectable differences in
chemical shift. Hence, if this is the case, a special situation
must prevail in which these stereogenic centres are so close to
one another in space that they ™talk∫ to one another. The
observed splitting of the 13C NMR signals within the side
chains of rac-30 and the differences between the signal
positions of rac-30 and rac-31 indicate that a particular folding
of these molecules prevails as anticipated in the generalised
structure 9.
The key to the conformational preorganisation within the
compounds rac-30 and rac-31 are the methyl groups at C-1 of
the side chains. There are no such methyl groups in the tris-
azide 19. Just as a control, we synthesised rac-19 admixed with
its epimer 36 by a cyclotrimerisation of the isocyanate rac-35,
see Scheme 10.
The 13C NMR spectrum of the resulting mixture has only a
single set of lines, in contrast to the rac-30/rac-31 mixture. This
indicates that the splitting observed with the rac-30/rac-31
mixture is genuinely a consequence of the conformational
preorganisation prevalent in that system.
3) ArNCO
N
N
N
N
FG
THF
O
O
O
O
N3
FG
4 (61%)
31
Scheme 11. Assembly of the side chains. Ar ˆ nC4H9-pC6H4-; FG ˆ NH-
CO-NH-pC6H4-nC4H9.
The synthesis of the dipodal receptor 6 and the monopodal
™receptor∫ 8 (cf. Scheme 2) both originated from isocyanate
29, see Scheme 12. Co-trimerisation of 29 with 10 equivalents
of tert-butyl isocyanate furnished the bis-azide 37 and mono-
azide 38 in a 13:1 ratio. Compound 37 then was converted into
the two-armed receptor 6.
Since only a very small quantitty of the mono-armed azide
38 was obtained, we turned our attention to the phthaloyl-
derivative 8 as a model for the mono-armed system. The
precursor compound, azide 40, was obtained by phthaloyla-
tion of the trimethylsilylethyl carbamate 39 derived from 29 in
60% yield. The azide 40 was in this case reduced with
polymethylhydrosiloxane in the presence of the p-butylphe-
nylisocyanate to give the receptor ent-8 in 74% yield.
Conformational analysis of the side chains in the host
molecules: The 1,3-dimethylbutyl chains in the azides 31
and 37 40 are derivatives of 2,4-di-substituted pentanes and
hence have just two low energy conformations, namely 41a
and 41b as shown in Scheme 13. Such a system can readily be
analysed on the basis of 3J(H,H) coupling constants.[21]
Chem. Eur. J. 2002, 8, No. 21
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4949

R. W. Hoffmann et al.
FULL PAPER
their different disposition relative to the phthalimido group as
prevails in conformation 41a, whereas in conformation 41b
they should be symmetrically disposed.
N3
N3
O
N
O
N
N3
KOt Bu
N3
NCO
N
N
N
N
For the tris-urea 4, solid evidence for the prevalence of
conformation 41a again comes from determination of the
3J(C,H) coupling constants. For conformational analysis we
10 equiv
tBuNCO, THF
O
O
O
O
29
38 (4%)
1
had to rely on the latter exclusively, because the H NMR
37 (51%)
signals of 4 are too broad to determine 3J(H,H) coupling
constants. The following 3J(C,H) coupling constants were
HO
31 (23%)
SiMe3
toluene
6 (63 %)
obtained:
J(H2a,Me1) ˆ 2.8 Æ 0.2 Hz;
J(H2a,Me3) ˆ 6.1 Æ
0.1 Hz, J(H2b,Me3) ˆ 4.6 Æ 0.2 Hz; J(H2b,Me1) ˆ 2.0 Æ 0.1 Hz.
As before, the observation of a large and a small coupling to
Me3 indicates the prevalence of conformation 41a in com-
pound 4. In line with this, H2b should show two small 3J(C,H)
coupling constants in conformation 41a of 4. However, one of
the values (4.6 Hz) is intermediate magnitude.[23] This indi-
cates that the conformational homogeneity of the tris-urea 4 is
not as high as in the azido compounds studied before. This
could be caused by intra- and intermolecular interactions
between the urea end-groups which can be seen in the crystal
structure of 4 (cf. Figure 2).
SiMe3
N3
N3
H
PhthO
N
O
NPhth
Ac2O, AcOH
O
40 (60%)
39 (90%)
polymethylhydro-
siloxane, Pd/C,
EtOH
O
Ar
NPhth
N
N
H
H
ArNCO
ent-8 (74%)
Scheme 12. Side chain modifications. Arˆ nC4H9-pC6H4-.
Me3
C4
H3
H2b
C4
N3
N3
Me3
H1
H3
H2b
H2a
H1
H2a
Me1
Me1
O
N
O
O
N
O
41b
41a
Scheme 13. Conformational equilibrium of 41.
If one of the conformers is favoured in the conformer
equilibrium a large alternation in the magnitude of the
coupling constants J(H2a,H1), J(H2a,H3), and J(H2b,H1),
J(H2b,H3) should result. The data compiled in Table 1 show
that this is indeed the case.[22]
Figure 2. Crystal structure of 4, butyl groups omitted for clarity.
For compound 31 the 3J(C,H) coupling constants (H2a,Me1:
2.6 Æ 0.2; H2a,Me3: 6.8 Æ 0.1; H2b,Me3: 3.6 Æ 0.2 Hz) reveal[23]
that conformation 41a is the major conformer populated. The
observation of a large and a small coupling to Me3 is uniquely
consistent with the prevalence of conformation 41a in
compound 31.
For the other azido compounds 37, 38 and 40 we only have
soft arguments to support the notion that conformer 41a is the
favoured one: the ™slim∫ imido moieties should prefer the
position lateral to the chain, rather than the more bulky C-4
methylene group, in line with previous studies.[10] The large
(1 ppm) difference in chemical shift between the two diaste-
reotopic protons H2a and H2b (see Table 1) is a telltale sign of
This X-ray crystal structure confirms our above consider-
ations, as it illustrates nicely the predicted details about the
spatial arrangement of the side-chains (in the solid state):
thus, they are arranged orthogonal to the platform, and at
least one pair of side-chains is so close in space that they may
™talk∫ to one another, as seen in the NMR-spectra of rac-30
and rac-31. The X-ray structure further shows that each of the
side chains adopts an extended conformation.
Complexation studies: The complexation of three represen-
tative anions (ClÀ, BrÀ and NO3À as tetrabutylammonium salts
in CDCl3) by the receptors was followed by NMR titration.
The complexation was monitored by following the changes in
the chemical shifts of the NH protons. In some instances
changes in the chemical shifts of the ortho-protons on the
phenylene units were also used. The resulting curves were
simulated with SigmaPlot 2000.[24] The prevalence of 1:1
complexes was secured in all cases by Job plots, again fitted
with SigmaPlot 2000. Self-association is quite common for
urea containing compounds.[25] (cf. also Figure 2) We there-
fore determined the self-association constants for some of the
Table 1. Characteristic coupling constants [Hz, Æ 0.1 Hz] for the confor-
mation of the 1,3-dimethylbutyl side chains.
Signal
3J(H,H)
40
38
37
31
H2a: d ˆ ꢀ2.35 ppm
(H2a,H1)
(H2a,H3)
(H2b,H3)
(H2b,H1)
10.9
4.3
10.1
4.3
9.9
4.0
9.3
5.2
10.1
3.9
9.3
10.3
3.7
9.6
H2b: d ˆꢀ 1.35 ppm
5.0
4.9
4950
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Chem. Eur. J. 2002, 8, No. 21

Three-Armed Hosts
4946 4956
receptors by dilution experiments, and we fitted the data with
HOSTEST.[26] In this way, the following self-association
constants were determined: 4: 16 Æ 4mÀ1; 5: 17 Æ 6mÀ1; 6:
22 Æ 4mÀ1. As the complexation constants for the anions (see
Table 3) are at least one order of magnitude larger, self-
association of the receptors is not a matter of concern.
The receptor design relied on the notion, that each of the
tripodal ligands 3 (binding studies were in fact carried out
with ent-3), 4 and 5 uses all three arms cooperatively when
complexing an anion, while in principle, each arm could
interact with the guest independently. To rule out the latter
possibility, we compared the complexing ability of the mono-
armed 8, the bis-armed receptor 6 and the tris-armed receptor
4. The data are compiled in Table 2.
arrangement of the side chains relative to the platform.
However, an additional conformational preorganisation with-
in the side chains, that is going from receptor 3 to receptor 4, is
without a pronounced effect on chloride binding. This is not
the case for the binding of bromide or nitrate; the latter
change results in a significant decrease of the binding
constant. It appears that chloride fits quite well into the
detailed binding pocket provided by receptor 4, whereas
accommodation of the larger anions (bromide or nitrate),
requires some conformational adjustments in the side-arms.
These are readily possible in the unorganised receptor 5, to
some extent in 3, but are opposed by the conformational
preferences of the side arms in the most evolved receptor 4.
Thus, conformational preorganisation may lead to an
increase in binding constants (e.g. for chloride), no changes
(bromide), or to a decrease (on binding nitrate). Obviously
then, the most pronounced effect of conformational preorga-
nisation is on binding selectivities: the chloride/nitrate
selectivity increases from two in the case of receptor 5 to 16
for receptor 3 and on to 24 for receptor 4, which has the
strongest conformational preorganisation.[28] One referee
raised a question regarding the influence of adventitious
amounts of water on binding selectivities. While we did not
study this in depth, the chloride/bromide selectivity for host 4
was found to be 5.1 in water-saturated deuterochloroform,
compared with 8.6 (cf. Table 3) in commercial deuterochloro-
form. For host 5 the corresponding values are 2.3 versus 3.7.
This indicates that binding selectivities were not over-
sensitive to changes in the water content even when binding
constants were lower in the more aqueous solvent system.
Table 2. Complexation constants [mÀ1] for tetrabutylammonium salts in
CDCl3 at 300 K.[a]
Guest/Host
ent-8
6
4
‡
Bu4N ClÀ
621 Æ 40
79 Æ 5
2610 Æ 50
646 Æ 5
19500 Æ 2100
2260 Æ 100
800 Æ 10
‡
Bu4N BrÀ
‡
À
Bu4N NO3
103 Æ 5
528 Æ 7
[a] The error limits given are standard deviations from nonlinear regression
analysis.
If the side arms were functioning completely independently
of one another, one would expect an increase in the binding
constants in a sequence 1:2:3. The data in Table 2 show that
the increase surpasses these values and is, in addition, not
uniform for all anions. This indicates a substantial coopera-
tivity of the side arms in forming 1:1 complexes (Job plots)
with those anions.
After establishing that the three-armed receptors employ
their binding groups in a cooperative manner, we can now
identify the effects of conformational preorganisation on the
binding constants and selectivities for different anions. These
results are compiled in Table 3.
Conclusion
In summary, we have synthesised a set of receptors with the
same bond connectivity and the same backbone. They just
differ in the level of conformational preorganisation. Detailed
binding studies of simple anions revealed a cooperative
binding mode and demonstrated that conformational preor-
ganisation leads to strong changes in binding selectivities
despite only moderate changes in binding strength. The
principles outlined in this study should be applicable to the
rational design of a broad range of advanced, conformation-
ally flexible receptor molecules.
Table 3. Effects of conformational preorganisation on the binding energies
[kcalmolÀ1] and binding constants [mÀ1] for tetrabutylammonium salts in
CDCl3 at 300 K.[a]
Guest/Host
5
ent-3
4
‡
Bu4N ClÀ
À 5.27 Æ 0.02
À 5.80 Æ 0.07
À 5.84 Æ 0.06
7400 Æ 280
À 4.56 Æ 0.02
1990 Æ 50
À 4.45 Æ 0.02
1840 Æ 40
18300 Æ 2270
À 4.76 Æ 0.03
3100 Æ 160
À 4.17 Æ 0.02
1150 Æ 13
19500 Æ 2100
À 4.57 Æ 0.03
2260 Æ 100
À 3.95 Æ 0.02
800 Æ 10
‡
Bu4N BrÀ
‡
À
Experimental Section
Bu4N NO3
General remarks: All temperatures quoted are uncorrected. 1H NMR,
13C NMR: Bruker ARX-200, AC-300, WH-400, AMX-500. Boiling range of
petroleum ether: 40 60 8C. Flash chromatography: Silica gel SI 60, E.
Merck KGaA, Darmstadt, 40 63 mm. pH 7 buffer was prepared dissolving
: NaH2PO4 Â 2H2O (56.2 g) and Na2HPO4 Â 4H2O (213.6 g) in water to a
final volume of 1 L.
[a] The error limits given are standard deviations from nonlinear regression
analysis.
The data in Table 3 show that the binding energies increase
in going from bromide to chloride, a feature commonly seen
for the binding of different halide ions to urea receptors.[6, 27]
The binding constants react in a diverse manner to the
changes in the conformational preorganisation of the hosts.
Chloride binding increases by a factor of 2.5 on going from the
non-preorganised receptor 5 to the host 3 with a controlled
1,3,5-Tris(4-chlorobutyl)-1,3,5-triazine-2,4,6-trione (11): A suspension of
sodium hydride in white oil (80%, 1.33 g, 44.3 mmol) was washed with
pentane (4 Â 50 mL) and
a solution of cyanuric acid (10) (1.52 g,
11.8 mmol) in DMSO (115 mL) was added at 08C. After stirring for
30 min at 08C, 1-bromo-4-chlorobutane (5.11 mL, 44.4 mmol) and sodium
iodide (340 mg, 2.27 mmol) were added. After stirring for 1 d at room
temperature, saturated aqueous NaHCO3 solution (40 mL) and water
Chem. Eur. J. 2002, 8, No. 21
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R. W. Hoffmann et al.
FULL PAPER
(60 mL) were added dropwise. The resulting solution was extracted with
ethyl acetate (450 mL). The combined organic layers were washed with
water (4 Â 50 mL), brine (10 mL), dried (MgSO4) and concentrated. Flash
chromatography of the residue with pentane/tert-butyl methyl ether 3:1 !
1:1 furnished compound 11 (2.76 g, 58%) as a slightly yellowish oil.
1H NMR (300 MHz, CDCl3): d ˆ 1.74 1.88 (m, 12H), 3.50 3.60 (m, 6H),
3.84 3.94 (m, 6H); 13C NMR (75 MHz, CDCl3): d ˆ 25.3 (3C), 29.6 (3C),
42.2 (3C), 44.2 (3C), 148.8 (3C); HRMS (EI): calcd for C15H24Cl3N3O3:
399.0883; found: 399.0884.
pentane/ether 30:1 followed by bulb-to-bulb distillation (10À1 Torr,
ꢁ508C) furnished compound 16 (4.03 g, 80%) as a colourless oil. [a]D20
ˆ
‡2.72 (c ˆ 1.47, Et2O); 1H NMR (200 MHz, CDCl3): d ˆ 0.04 (s, 6H), 0.88
(s, 9H), 0.96 (d, J ˆ 6.8 Hz, 3H), 1.28 1.46 (m, 1H), 1.52 1.73 (m, 1H),
1.80 2.00 (m, 1H), 3.12 (dd, J ˆ 11.9, 6.9 Hz, 1H), 3.26 (dd, J ˆ 11.9, 5.6 Hz,
1H), 3.55 3.75 (m, 2H); 13C NMR (50 MHz, CDCl3): d ˆ À5.5 (2C), 17.6,
18.2, 25.9 (3C), 30.5, 36.9, 57.8, 60.7; elemental analysis calcd (%) for
C11H25N3OSi (243.4): C 54.28, H 10.35, N 17.26; found: C 54.06, H 10.45, N
17.10.
(3S)-4-Azido-3-methyl-1-butanol (17): A solution of hydrofluoric acid (5%
in acetonitrile, 30 mL) was added to the TBDMS-ether 16 (3.86 g,
15.9 mmol) and the resulting emulsion was stirred for 2.5 h. Solid NaHCO3
was added slowly to saturation, followed by addition of saturated aqueous
NaHCO3 (20 mL) and diethyl ether (50 mL). The layers were separated
and the aqueous layer was extracted with ether (5 Â 50 mL). The combined
organic layers were washed with brine (20 mL), dried (MgSO4) and
concentrated. Flash chromatography of the residue with pentane/diethyl
1,3,5-Tris(4-azidobutyl)-1,3,5-triazine-2,4,6-trione (12): Sodium azide
(4.31 g, 66.3 mmol) was added into a solution of the tris-chloride 11
(1.30 g, 3.24 mmol) in DMF (60 mL). After stirring for 4 d at 658C,
saturated aqueous NaHCO3 solution (100 mL), water (100 mL) and tert-
butyl methyl ether (100 mL) were added. The layers were separated and
the aqueous layer was extracted with tert-butyl methyl ether (5 Â 50 mL)
The combined organic layers were washed with brine (100 mL), dried
(MgSO4), and concentrated. Flash chromatography of the residue with
pentane/tert-butyl methyl ether 1.5:1 ! 1:1 furnished compound 12 (1.25 g,
91%) as a slightly yellowish oil. 1H NMR (300 MHz, CDCl3): d ˆ 1.52 1.80
(m, 12H), 3.30 (t, J ˆ 6.5 Hz, 6H), 3.88 (t, J ˆ 6.5 Hz, 6H); 13C NMR
(75 MHz, CDCl3): d ˆ 25.1 (3C), 26.0 (3C), 42.3 (3C), 50.8 (3C), 148.8
(3C); elemental analysis calcd (%) for C15H24N12O3 (420.4): C 42.85, H
5.75, N 39.98; found: C 43.10, H 6.03, N 40.00.
ether 1:1 furnished compound 17 (1.88 g, 92%) as a colourless oil. [a]D20
ˆ
1
‡11.03 (c ˆ 1.36, diethyl ether); H NMR (200 MHz, CDCl3): d ˆ 0.98 (d,
J ˆ 6.6 Hz, 3H), 1.32 1.55 (m, 2H), 1.57 1.76 (m, 1H), 1.78 1.98 (m, 1H),
3.18 (dd, J ˆ 12.0, 6.3 Hz, 1H), 3.26 (dd, J ˆ 12.0, 6.2 Hz, 1H), 3.60 3.80
(m, 2H); 13C NMR (50 MHz, CDCl3):d ˆ 17.7, 30.5, 36.9, 57.8, 60.5;
elemental analysis calcd (%) for C5H11N3O (129.2): C 46.50, H 8.58, N
32.53; found: C 46.28, H 8.30, N 32.50.
1,3,5-Tris{4-[3-(4-butylphenyl)ureido]-butyl}-1,3,5-triazine-2,4,6-trione (2):
Palladium hydroxide (20% on carbon, 39 mg, 56 mmol) was added to a
solution of the tris-azide 12 (67 mg, 0.16 mmol) in methanol (11 mL). The
suspension was stirred for 3 h under an atmosphere of hydrogen. The
catalyst was removed by filtration through a cellulose acetate membrane
(Fa. Sartorius), and the filtrate was concentrated. The residue was taken up
in THF (4 mL), p-(n-butyl)-phenylisocyanate (166 mg, 946 mmol) was
added and the mixture was stirred for 7 d. Methanol (82 mL) was added to
the suspension and stirring was continued for 4 d. The solution was
concentrated in vacuo and subsequent flash chromatography of the residue
with tert-butyl methyl ether/ethyl acetate 2:1 furnished compound 2
(13 mg, 9%) as a slightly yellowish solid. M.p. 94 95 8C; 1H NMR
(500 MHz, [D6]DMSO): d ˆ 0.86 (t, J ˆ 7.5 Hz, 9H), 1.25 (sex, J ˆ 7.5 Hz,
6H), 1.40 (quin, J ˆ 7.5 Hz, 6H), 1.47 (t, J ˆ 7.5 Hz, 6H), 1.50 1.59 (m, 6H),
2.45 (t, J ˆ 7.6 Hz, 6H), 3.05 (quin, J ˆ 6.1 Hz, 6H), 3.73 (t, J ˆ 7.2 Hz, 6H),
6.04 (t, J ˆ 5.7 Hz, 3H), 6.99 (d, J ˆ 8.4Hz, 6H), 7.23 (d, J ˆ 8.4 Hz, 6H),
8.26 (s, 3H); 13C NMR (125 MHz, [D6]DMSO): d ˆ 13.8 (3C), 21.7 (3C),
24.8 (3C), 27.2 (3C), 33.3 (3C), 34.1 (3C), 38.7 (3C), 42.1 (3C), 117.7 (6C),
128.3 (6C), 134.8 (3C), 138.1 (3C), 149.0 (3C), 155.3 (3C); HRMS (ESI):
calcd for C48H69N9O6‡H: 868.5449; found: 868.5451.
1,3,5-Tris[(3S)-4-azido-3-methylbutyl]-1,3,5-triazine-2,4,6-trione (19): Imi-
dazole (2.49 g, 36.6 mmol) and iodine (5.18 g, 20.4 mmol) were added at
08C into a solution of triphenylphosphane (4.77 g, 18.2 mmol) in an ether/
acetonitrile solvent mixture (3:1, 90 mL). A solution of the alcohol 17
(1.81 g, 14.0 mmol) in the same solvent mixture (4 mL) was added followed
by flask rinsings (3 Â 8 mL). After stirring for 2 h at room temperature, the
solution was concentrated. Flash chromatography of the residue with
pentane/diethyl ether 40:1 was followed by bulb-to-bulb distillation
(10À1 Torr, ꢁ408C) to furnish compound 18 (3.21 g, 96%) as a colourless
oil, which was stored over copper turnings. 1H NMR (300 MHz, CDCl3):
d ˆ 0.96 (d, J ˆ 6.8 Hz, 3H), 1.59 1.76 (m, 1H), 1.78 2.04 (m, 2H), 3.08
3.31 (m, 4H); 13C NMR (75 MHz, CDCl3): d ˆ 4.2, 17.2, 34.8, 38.1, 57.2.
A suspension of sodium hydride in white oil (60%, containing 217 mg,
9.05 mmol NaH) was washed with pentane (4 Â 5 mL) and diluted with
DMSO (15 mL). A solution of cyanuric acid (10) (323 mg, 2.50 mmol) in
DMSO (5 mL) was added at 08C. After stirring for 40 min at room
temperature, iodide 18 (2.20 g, 9.18 mmol) was added. After stirring for 3 d
at room temperature, saturated aqueous NaHCO3 (15 mL) was added
dropwise at 08C. The resulting solution was extracted with diethyl ether
(250 mL). The combined organic layers were washed with water (3 Â
10 mL), brine (10 mL), dried (Na2SO4) and concentrated. Flash chroma-
tography of the residue with pentane/tert-butyl methyl ether 20:1 ! 3:1
furnished compound 19 (846 mg, 60%) as a colourless oil. [a]2D0 ˆ À10.1
(c ˆ 1.29, CHCl3); 1H NMR (500 MHz, CDCl3): d ˆ 1.03 (d, J ˆ 6.4 Hz,
9H), 1.44 1.55 (m, 3H), 1.67 1.80 (m, 6H), 3.18 (dd, J ˆ 12.1, 6.2 Hz, 3H),
3.26 (dd, J ˆ 12.1, 5.5 Hz, 3H), 3.84 3.97 (m, 6H); 13C NMR (125 MHz,
CDCl3): d ˆ 17.5 (3C), 31.5 (3C), 32.1 (3C), 41.0 (3C), 57.3 (3C), 148.8
(3C); elemental analysis calcd (%) for C18H30N12O3 (462.5): C 46.74, H
6.54, N 36.34; found: C 46.80, H 6.63, N 36.25.
(3S)-4-Azido-1-tert-butyldimethylsilyloxy-3-methylbutane (16): A solution
of n-butyllithium (1.66m in hexane, 66.7 mL, 111 mmol) was added
dropwise at À708C to a solution of diisopropylamine (16.8 mL, 119 mmol)
in THF (140 mL). After stirring for 10 min at 08C the mixture was cooled to
À708C and H3B ¥ NH3 (90% by weight, 4.29 g, 125 mmol) was added. The
mixture was stirred for 20 min at 08C, 20 min at room temperature and then
cooled to À108C.
A solution of (2S)-4-tert-butyldimethylsilyloxy-N-
[(1R,2R)-2-hydroxy-1-methyl-phenylethyl]-N,2-dimethylbutanoic amide[12]
(14) (10.8 g, 28.4 mmol) in THF (150 mL) was added dropwise. After
stirring for 75 min at room temperature. The reaction was quenched at 08C
by the addition of saturated aqueous NH4Cl (150 mL). After stirring for
20 min the layers were separated. The aqueous layer was extracted with
diethyl ether (5 Â 20 mL). The combined organic layers were washed with
saturated aqueous NH4Cl (2 Â 40 mL), brine (2 Â 20 mL), dried (MgSO4)
and concentrated. Flash chromatography of the residue with pentane/tert-
butyl methyl ether 5:1 furnished compound 15 (4.67 g, 75%) as a colourless
oil. [a]2D0 ˆ À7.19 (c ˆ 1.39, Et2O); 1H NMR (500 MHz, CDCl3): d ˆ 0.05 (s,
6H), 0.88 (s, 9H), 0.89 (d, J ˆ 6.9 Hz, 3H), 1.47 1.58 (m, 2H), 1.72 1.82
(m, 1H), 3.05 (brs, 1H), 3.39 (dd, J ˆ 10.9, 6.9 Hz, 1H), 3.47 (dd, J ˆ 10.9,
4.8 Hz, 1H), 3.63 (ddd, J ˆ 10.5, 7.5, 4.9 Hz, 1H), 3.70 3.76 (m, 1H);
13C NMR (50 MHz, CDCl3): d ˆ À5.5 (2C), 17.3, 18.2, 25.8 (3C), 34.3, 37.4,
61.7, 68.1. The NMR data correspond to those given in ref. [29].
1,3,5-Tris{(3S)-4-[3-(4-butylphenyl)-ureido]-3-methylbutyl}-1,3,5-triazine-
2,4,6-trione (5): A solution of trimethylphosphine (1.0m in THF,1.34 mL,
1.34 mmol) was added at 08C into a solution of the tris-azide 19 (173 mg,
374 mmol) in THF (4 mL). After stirring for 2.5 h, water (38 mL, 2.1 mmol)
was added and stirring was continued for 12 h at 458C. p-(n-Butyl)-
phenylisocyanate (520 mg, 2.97 mmol) was added and the mixture was
heated to 808C for 6 h. Ethanol (300 mL) was added dropwise and stirring
was continued for 14 h at room temp. Pentane (3 mL) was added and the
solution was added to a column with silica gel (Æ5 cm, height 13 cm) and
eluted with tert-butyl methyl ether/ethyl acetate 5:1 ! tert-butyl methyl
ether/chloroform 2:1 ! chloroform. The crude product was re-chromato-
graphed to give the tris-urea 5 (215 mg, 63%) as a colourless solid. M.p.
92 93 8C; [a]2D0 ˆ À37 (c ˆ 0.19, CHCl3); 1H NMR (500 MHz, CDCl3): d ˆ
0.85 (d, J ˆ 6.6 Hz, 9H), 0.90 (t, J ˆ 7.4 Hz, 9H), 1.08 1.19 (m, 3H), 1.32
(sex, J ˆ 7.4 Hz, 6H), 1.33 1.43 (m, 3H), 1.53 (quin, J ˆ 7.6 Hz, 6H), 1.71
1.81 (m, 3H), 2.52 (t, J ˆ 7.6 Hz, 6H), 2.84 (dd, J ˆ 13.3, 9.1 Hz, 3H), 2.98
(dd, J ˆ 13.3, 4.7 Hz, 3H), 3.81 3.96 (m, 6H), 5.62 (brs, 3H), 7.05 (d, J ˆ
8.2 Hz, 6H), 7.89 (d, J ˆ 8.4 Hz, 6H), 7.47 (brs, 3H); 13C NMR (125 MHz,
Diisopropyl azodicarboxylate (DIAD, 5.40 g, 26.7 mmol) was added at 08C
into a solution of triphenylphosphane (7.09 g, 27.0 mmol) in THF (160 mL).
After stirring for 15 min a solution of the alcohol 15 (4.52 g, 20.7 mmol) in
THF (10 mL) and diphenoxyphosphoryl azide (DPPA, 6.83 g, 24.8 mmol)
were added. Stirring was continued for 1 d at room temperature and the
solution was concentrated. Flash chromatography of the residue with
4952
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Chem. Eur. J. 2002, 8, No. 21

Three-Armed Hosts
4946 4956
CDCl3): d ˆ 13.9 (3C), 17.4 (3C), 22.3 (3C), 31.9 (3C), 32.0 (3C), 33.7 (3C),
35.0 (3C), 40.8 (3C), 46.0 (3C), 120.7 (6C), 128.9 (6C), 136.4 (3C), 137.9
(3C), 148.9 (3C), 156.8 (3C); HRMS (FAB): calcd for C51H75N9O6‡H:
910.5919; found: 910.5892.
1H); 13C NMR (125 MHz, CDCl3) d ˆ 16.9, 26.7, 30.7, 38.7, 51.4, 179.6.
Compare the data given in ref. [31].
1,3,5-Tris[(1S)-4-azido-1-methylbutyl]-1,3,5-triazine-2,4,6-trione (25): Tri-
ethylamine (552 mL, 3.98 mmol) and diphenoxyphosphoryl azide (DPPA,
933 mL, 4.32 mmol) were added at 08C to a solution of the acid 23 (580 mg,
3.69 mmol) in pentane (20 mL). The mixture was stirred for 30 min at 08C
and for 15 h at 408C. The supernatant liquid was removed with a cannula
and the residue was extracted with pentane (5 Â 5 mL). The combined
extracts were concentrated in vacuo and the residue was bulb-to-bulb
distilled (10À1 Torr, ꢁ458C). The obtained oily isocyanate 24 (410 mg,
2.66 mmol) was taken up immediately in THF (2 mL) and potassium tert-
butoxide (16.0 mg, 143 mmol) was added. After stirring for 12 h the
suspension was concentrated. Flash chromatography of the residue with
pentane/tert-butyl methyl ether 7.5:1 ! 4:1 furnished compound 25
(374 mg, 66%) as a colourless oil. [a]2D0 ˆ ‡16.7 (c ˆ 1.20, CHCl3); 1H NMR
(500 MHz, CDCl3): d ˆ 1.44 (d, J ˆ 7.02 Hz, 9H), 1.39 1.50 (m, 3H), 1.51
1.61 (m, 3H), 1.74 1.85 (m, 3H), 2.04 2.17 (m, 3H), 3.22 3.34 (m, 6H),
4.78 4.88 (m, 3H); 13C NMR (125 MHz, CDCl3): d ˆ 18.0 (3C), 25.6 (3C),
30.4 (3C), 51.0 (3C), 51.6 (3C), 148.8 (3C); elemental analysis calcd (%)
for C18H30N12O3 (462.5): C 46.74, H 6.54, N 36.34; found: C 46.72, H 6.69, N
36.53.
(4S)-3-(5-Chloropentanoyl)-4-isopropyl-oxazolidin-2-one (20): A solution
of n-butyllithium (1.47m in hexane, 55.0 mL, 80.9 mmol) was added
dropwise at À788C into a solution of the (4S)-4-isopropyl-oxazolidinone[30]
(9.65 g, 75.3 mmol) in THF (300 mL). After stirring for 1 h a solution of
5-chloro-pentanoyl chloride (12.8 g, 82.9 mmol) in THF (100 mL) was
added dropwise. Stirring was continued for 30 min at À788C and 3 h at
room temperature. Saturated aqueous NaHCO3 (500 mL) and tert-butyl
methyl ether (100 mL) were added, the layers were separated and the
aqueous layer was extracted with tert-butyl methyl ether (4 Â 150 mL). The
combined organic layers were washed with brine (100 mL), dried (Na2SO4),
and concentrated. Flash chromatography of the residue with pentane/tert-
butyl methyl ether 3:1 furnished compound 20 (14.2 g, 76%) as a colourless
1
oil. [a]2D0 ˆ ‡59.4 (c ˆ 4.31, CHCl3); H NMR (300 MHz, CDCl3): d ˆ 0.85
(d, J ˆ 6.8 Hz, 3H), 0.89 (d, J ˆ 7.1 Hz, 3H), 1.72 1.90 (m, 4H), 2.26 2.44
(m, 1H), 2.80 3.08 (m, 2H), 3.54 (t, J ˆ 5.9 Hz, 2H), 4.15 4.32 (m, 2H),
4.36 4.47 (m, 1H); 13C NMR (500 MHz, CDCl3): d ˆ 14.6, 17.9, 21.7, 28.4,
31.8, 34.7, 44.5, 58.4, 63.4, 154.1, 172.7; elemental analysis calcd (%) for
C11H18ClNO3 (247.7): C 53.33, H 7.32, N 5.65; found: C 53.25, H 7.37, N 5.46.
1,3,5-Tris{(1S)-4-[3-(4-butylphenyl)-ureido]-1-methylbutyl}-1,3,5-triazine-
2,4,6-trione (ent-3): Tris-azide 25 (300 mg, 649 mmol) was converted into
tris-urea ent-3 as described for the preapration of 5. Flash chromatography
of the crude product with pentane/tert-butyl methyl ether 1:4 ! tert-butyl
methyl ether/chloroform 3:1 furnished compound ent-3 (130 mg, 22%) as a
colourless solid. M.p. 90 92 8C; [a]2D0 ˆ ‡9.1 (c ˆ 1.1, CHCl3); 1H NMR
(500 MHz, CDCl3): d ˆ 0.89 (t, J ˆ 7.4 Hz, 9H), 1.19 1.29 (m, 3H), 1.31
(sex, J ˆ 7.4 Hz, 6H), 1.34 1.48 (m, 6H), 1.42 (d, J ˆ 6.9 Hz, 9H), 1.51
(quin, J ˆ 7.6 Hz, 6H), 2.11 2.23 (m, 3H), 2.49 (t, J ˆ 7.6 Hz, 6H), 2.95
3.06 (m, 3H), 3.18 3.28 (m, 3H), 4.78 4.92 (m, 3H), 5.82 (brs, 3H), 7.00
(d, J ˆ 8.3 Hz, 6H), 7.14 (d, J ˆ 8.3 Hz, 6H), 7.54 (brs, 3H); 13C NMR
(125 MHz, CDCl3): d ˆ 13.9 (3C), 18.5 (3C), 22.3 (3C), 27.7 (3C), 30.3
(3C), 33.7 (3C), 34.9 (3C), 39.8 (3C), 51.3 (3C), 120.6 (6C), 128.9 (6C),
136.4 (3C), 137.8 (3C), 148.9 (3C), 156.8 (3C); HRMS (ESI): calcd for
C51H75N9O6‡H: 910.5919; found: 910.5890.
(4S)-3-(5-Azido-pentanoyl)-4-isopropyl-oxazolidin-2-one (21): Chloro-
compound 20 (14.9 g, 57.3 mmol) was converted into azido-compound 21
as described for the preparation of 11. Flash chromatography of the residue
with pentane/tert-butyl methyl ether 2:1 furnished compound 21 (11.6 g,
80%) as a slightly yellowish oil. [a]2D0 ˆ ‡74.5 (c ˆ 1.06, CHCl3); 1H NMR
(200 MHz, CDCl3): d ˆ 0.85 (d, J ˆ 7.0 Hz, 3H), 0.89 (d, J ˆ 7.0 Hz, 3H),
1.52 1.84 (m, 4H), 2.20 2.48 (m, 1H), 2.77 3.09 (m, 2H), 3.29 (t, J ˆ
5.9 Hz, 2H), 4.13 4.31 (m, 2H), 4.35 4.47 (m, 1H); 13C NMR (50 MHz,
CDCl3): d ˆ 14.6, 17.9, 21.5, 28.2, 28.3, 34.9, 51.1, 58.3, 63.4, 154.0, 172.5;
elemental analysis calcd (%) for C11H18N4O3 (254.3): C 51.96, H 7.13, N
22.03; found: C 51.85, H 6.91, N 21.87.
(4S)-3-[(2S)-5-Azido-2-methylpentanoyl)-4-isopropyl-oxazolidin-2-one
(22): A solution of sodium hexamethyldisilazide (2.0m in THF, 20.5 mL,
41.0 mmol) was added dropwise at À788C into a solution of the azido-
compound 21 (8.71 g, 34.2 mmol) in THF (250 mL). After stirring for
30 min at À788C, methyl iodide (6.60 mL, 106 mmol) was added dropwise.
After stirring was continued for 1 h at À788C, saturated aqueous NH4Cl
(40 mL) was added. After reaching room temperature further saturated
aqueous NH4Cl (40 mL), tert-butyl methyl ether (100 mL), and water
(100 mL) were added. The layers were separated and the aqueous layer was
extracted with tert-butyl methyl ether (6 Â 50 mL). The combined organic
layers were washed with brine (50 mL), dried (Na2SO4), and concentrated.
Flash chromatography of the residue with pentane/tert-butyl methyl ether
5:1 furnished compound 22 (7.08 g, 77%) as a 13:1 diastereomer mixture.
Repeated flash chromatography furnished eventually pure 22 (2.93 g,
32%) as a colourless oil. [a]2D0 ˆ ‡94.8 (c ˆ 1.91, CHCl3); 1H NMR
(500 MHz, CDCl3): d ˆ 0.86 (d, J ˆ 6.9 Hz, 3H), 0.90 (d, J ˆ 7.0 Hz, 3H),
1.22 (d, J ˆ 6.9 Hz, 3H), 1.41 1.50 (m, 1H), 1.53 1.63 (m, 2H), 1.75 1.85
(m, 1H), 2.28 2.29 (m, 1H), 3.20 3.37 (m, 2H), 3.75 ( ysex, J ˆ 6.9 Hz,
1H), 4.19 (dd, J ˆ 9.1, 3.0 Hz, 1H), 4.24 4.29 (m, 1H), 4.42 4.48 (m, 1H);
13C NMR (125 MHz, CDCl3): d ˆ 14.6, 17.8, 17.9, 26.6, 28.4, 30.0, 37.4, 51.3,
58.3, 63.2, 153.6, 176.5; elemental analysis calcd (%) for C12H20N4O3
(268.3): C 53.72, H 7.51, N 20.88; found: C 53.47, H 7.56, N 20.99.
Methyl
(2R,4S)-5-azido-2,4-dimethylpentanoate
(27):
BH3 ¥ SMe2
(1.60 mL, 16.6 mmol) was added at 08C to a solution of the 1-methyl-5-
hydrogen (2R,4S)-2,4-dimethyl-pentanedioate 26 (2.04 g, 11.7 mmol) in
diethyl ether (15 mL). The mixture was stirred for 20 min at 08C and 1 h at
room temperature. NaHCO3 (ca. 10 mg) was added at 08C followed by a
glycerol/water mixture (3:1, 8 mL). NaCl was added to saturate the
aqueous layer. After stirring for 15 min, the layers were separated and the
aqueous layer was extracted with diethyl ether (4 Â 10 mL). The combined
extracts were washed with brine (10 mL), dried (MgSO4), and concen-
trated. The residue was taken up in THF (5 mL). This solution was added at
08C to
a freshly prepared mixture of triphenylphosphane (3.80 g,
14.5 mmol), diisopropyl azodicaboxylate (DIAD, 2.80 mL, 14.4 mmol) in
THF (80 mL). Finally, diphenoxyphosphoryl azide (3.03 mL, 14.1 mmol)
was added and the mixture was stirred for 1 d at room temperature. The
mixture was concentrated. Two-fold flash chromatography of the residue
with pentane/tert-butyl methyl ether 5:1 and pentane/tert-butyl methyl
ether 20:1 followed by bulb-to-bulb distillation (10À1 Torr, ꢁ408C)
furnished the azido-ester 27 (1.53 g, 71%) as a colourless oil. [a]D20
ˆ
À26.7 (c ˆ 3.64, CHCl3); 1H NMR (300 MHz, CDCl3): d ˆ 0.96 (d, J ˆ
6.6 Hz, 3H), 1.15 1.25 (m, 1H), 1.16 (d, J ˆ 6.9 Hz, 3H), 1.62 1.79 (m,
2H), 2.49 2.58 (m, 1H), 3.11 (dd, J ˆ 12.0, 6.4 Hz, 1H), 3.18 (dd, J ˆ 12.0,
5.7 Hz, 1H), 3.67 (s, 3H); 13C NMR (75 MHz, CDCl3): d ˆ 17.5, 18.1, 31.7,
37.1, 38.4, 51.6, 57.8, 176.8; elemental analysis calcd (%) for C8H15N3O2
(185.2): C 51.88, H 8.16, N 22.69; found: C 51.74, H 7.95, N 22.90.
(2S)-5-Azido-2-methylpentanoic acid (23): Aqueous hydrogen peroxide
(30%, 5.80 mL, 51.2 mmol) and lithium hydroxide monohydrate (621 mg,
14.8 mmol) were added at 08C to a solution of the oxazolidinone 22 (2.08 g,
7.75 mmol) in a THF/water mixture (3:1, 200 mL). After stirring for 1 h at
08C, a solution of Na2SO3 (6.92 g, 54.9 mmol) in water (44 mL) was added
dropwise. The pH of the solution was adjusted to 10 by addition of Na2CO3
(2 g). The volume of the solution was reduced in vacuo in order to remove
most of the THF. The solution was extracted with dichloromethane (4 Â
50 mL). The aqueous layer was acidified with hydrochloric acid to pH 2 and
was extracted with ethyl acetate (5 Â 50 mL). The combined extracts were
dried (Na2SO4), and concentrated. Bulb-to-bulb distillation of the residue
(10À1 Torr, ꢁ858C) furnished compound 23 (1.12 g, 92%) as a colourless
(2R,4S)-5-Azido-2,4-dimethylpentanoic acid (28): Aqueous NaOH (1n,
25.8 mL, 25.8 mmol) was added to a solution of the ester 27 (3.77 g,
20.4 mmol) in methanol (25 mL). After stirring for 41 h, the mixture was
concentrated and the residue was washed with tert-butyl methyl ether (2 Â
10 mL). Hydrochloric acid (2n) was added to the residue until the pH
reached 2. The solution was extracted with diethyl ether (6 Â 10 mL). The
combined extracts were washed with brine (10 mL), dried (MgSO4), and
concentrated. Bulb-to bulb-distillation at (10À1 Torr, ꢁ1008C) furnished
the acid 28 (3.19 g, 91%) as a colourless oil. [a]2D0 ˆ À25.4 (c ˆ 3.62,
CHCl3); 1H NMR (300 MHz, CDCl3): d ˆ 0.98 (d, J ˆ 6.7 Hz, 3H), 1.17
1.27 (m, 1H), 1.15 (d, J ˆ 7.0 Hz, 3H), 1.73 1.85 (m, 2H), 2.49 2.59 (m,
1
oil. [a]2D0 ˆ ‡18.1 (c ˆ 1.93, CHCl3); H NMR (500 MHz, CDCl3): d ˆ 1.23
(d, J ˆ 7.0 Hz, 3H), 1.52 1.61 (m, 1H), 1.66 (quin, J ˆ 7.0 Hz, 2H), 1.73
1.82 (m, 1H), 2.55 (sex, J ˆ 6.9 Hz, 1H), 3.29 (t, J ˆ 6.8 Hz, 2H), 9.40 (brs,
Chem. Eur. J. 2002, 8, No. 21
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4953

R. W. Hoffmann et al.
FULL PAPER
1H), 3.12 (dd, J ˆ 12.0, 6.3 Hz, 1H), 3.20 (dd, J ˆ 12.0, 5.7 Hz, 1H), 11.18
(br s, 1H); 13C NMR (75 MHz, CDCl3): d ˆ 17.4, 17.9, 31.5, 37.1, 38.1, 57.7,
183.0; elemental analysis calcd (%) for C7H13N3O2 (171.1): C 49.11, H 7.65,
N 24.54; found: C 49.39, H 7.64, N 24.73.
with pentane/tert-butyl methyl etherˆ 10:1 ! 1:4 furnished compound
1
rac-33 (2.48 g, 91%) as a colourless oil. H NMR (300 MHz, CDCl3): d ˆ
0.96 (d, J ˆ 6.4 Hz, 3H), 1.19 1.29 (m, 6H), 1.65 1.81 (m, 2H), 1.94 2.08
(m, 1H), 3.16 (dd, J ˆ 12.1, 6.0 Hz, 1H), 3.22 (dd, J ˆ 12.1, 5.6 Hz, 1H), 3.41
(dd, J ˆ 8.5, 6.3 Hz, 1H), 4.12 4.24 (m, 4H); 13C NMR (75 MHz, CDCl3):
d ˆ 14.0 (2C), 17.3, 31.6, 32.9, 49.8, 57.3, 61.4 (2C), 169.1, 169.3; elemental
analysis calcd (%) for C11H19N3O4 (257.3): C 51.35, H 7.44, N 16.33; found:
C 51.10, H 7.48, N 16.16.
1,3,5-Tris[(1R,3S)-4-azido-1,3-dimethylbutyl]-1,3,5-triazine-2,4,6-trione
(31): The carboxylic acid 28 (782 mg, 4.57 mmol) was converted into the
isocyanate and then the triazine-trione as described for the preparation of
25. Flash chromatography of the residue with pentane/tert-butyl methyl
ether 10:1 ! 4:1 furnished compound 31 (601 mg, 78%) as a colourless oil.
5-Azido-4-methylpentanoic acid (rac-34): Aqueous KOH (5n, 4.20 mL,
21.0 mmol) was added to a solution of the malonate rac-33 (1.95 g,
7.56 mmol) in ethanol (4.2 mL). The solution was heated for 18 h to 758C.
After evaporation to dryness the residue was taken up in water (30 mL).
The resulting solution was washed with ether (2 Â 20 mL). The aqueous
layer was acidified with hydrochloric acid to pH 2, saturated with NaCl and
extracted with diethyl ether (7 Â 20 mL). The combined extracts were dried
(Na2SO4) and concentrated. The residue was taken up in o-xylene (10 mL)
and heated for 30 min to 1308C and 60 min to 1508C. After evaporation of
the solvent flash chromatography with pentane/tert-butyl methyl ether 5:1
! 2:1 furnished acid rac-34 (833 mg, 70%) as a slightly yellowish oil.
1H NMR (300 MHz, CDCl3): d ˆ 0.96 (d, J ˆ 6.6 Hz, 3H), 1.43 1.61 (m,
1H), 1.67 1.87 (m, 2H), 2.29 2.51 (m, 2H), 3.16 (dd, J ˆ 12.1, 6.1 Hz, 1H),
3.21 (dd, J ˆ 12.1, 5.9 Hz, 1H), 11.19 (brs, 1H); 13C NMR (75 MHz, CDCl3):
d ˆ 17.3, 28.8, 31.4, 32.9, 57.4, 179.4; elemental analysis calcd (%) for
C6H11N3O2 (157.2): C 45.85, H 7.05, N 26.74; found: C 45.69, H 6.80, N 26.65.
1
[a]2D0 ˆ ‡22.9 (c ˆ 4.28, CHCl3); H NMR (500 MHz, CDCl3): d ˆ 0.96 (d,
J ˆ 6.6 Hz, 9H), 1.35 (ddd, J ˆ 13.8, 9.6, 4.9 Hz, 3H), 1.39 1.49 (m, 3H),
1.43 (d, J ˆ 6.9 Hz, 9H), 2.35 (ddd, J ˆ 13.8, 10.3, 3.7 Hz, 3H), 3.12 (dd, J ˆ
14.3, 6.3 Hz, 3H), 3.14 (dd, J ˆ 14.3, 6.3 Hz, 3H), 4.90 4.99 (m, 3H);
13C NMR (125 MHz, CDCl3): d ˆ 17.4 (3C), 18.6 (3C), 31.4 (3C), 37.6 (3C),
49.6 (3C), 57.7 (3C), 148.7 (3C); elemental analysis calcd (%) for
C21H36N12O3 (504.6): C 49.99, H 7.19, N 33.31; found: C 49.87, H 7.05, N
33.37.
1,3,5-Tris{(1R,3S)-4-[3-(4-butylphenyl)-ureido]-1,3-dimethylbutyl}-1,3,5-
triazine-2,4,6-trione (4): Tris-azide 31 (219 mg, 430 mmol) was converted
into the tris-urea as described for the preparation of 5. Flash chromatog-
raphy of the crude product with pentane/tert-butyl methyl ether 1:1 ! 1:3
furnished compound 4 (250 mg, 61%) as a colourless solid. M.p. 99
1
1008C; [a]2D0 ˆ ‡16.9 (c ˆ 1.36, CHCl3); H NMR (500 MHz, CDCl3): d ˆ
0.79 (d, J ˆ 6.3 Hz, 9H), 0.89 (t, J ˆ 7.3 Hz, 9H), 1.06 1.14 (m, 3H), 1.14
1.22 (m, 3H), 1.30 (sex, J ˆ 7.5 Hz, 6H), 1.39 (d, J ˆ 6.9 Hz, 9H), 1.50 (quin,
J ˆ 7.6 Hz, 6H), 2.02 2.14 (m, 3H), 2.48 (t, J ˆ 7.9 Hz, 6H), 2.68 2.77 (m,
3H), 3.06 3.15 (m, 3H), 4.88 4.99 (m, 3H), 6.08 (brs, 3H), 6.98 (d, J ˆ
8.2 Hz, 6H), 7.14 (d, J ˆ 8.2 Hz, 6H), 7.66 (brs, 3H); 13C NMR (125 MHz,
CDCl3): d ˆ 13.9 (3C), 17.9 (3C), 18.4 (3C), 22.3 (3C), 32.3 (3C), 33.7 (3C),
34.9 (3C), 38.0 (3C), 46.4 (3C), 49.6 (3C), 120.2 (6C), 128.6 (6C), 136.7
(3C), 137.2 (3C), 148.5 (3C), 157.1 (3C); HRMS (FAB): calcd for
C54H81N9O6‡Na: 974.6207; found: 974.6207.
1,3-Bis[(3R*)-4-azido-3-methylbutyl]-5-[(3S*)-4-azido-3-methylbutyl]-
1,3,5-triazine-2,4,6-trione (rac-36) and 1,3,5-tris[(3R*)-4-azido-3-methyl-
butyl]-1,3,5-triazine-2,4,6-trione (rac-19): Acid rac-34 (1.97 g, 12.5 mmol)
was converted to the isocyanate 35 and to the triazinetrione as described for
the preparation of compound 25. Flash chromatography of the crude
product with pentane/tert-butyl methyl ether 4:1 furnished the compounds
rac-36 and rac-19 (1.14 g, 59%) as a colourless oil, which showed NMR
spectra identical to those recorded for 19.
Crystallographic data, see also ref. [7] (excluding structure factors) have
been deposited with the Cambridge Crystallographic Data Centre as no.
CCDC-178240. Copies of the data can be obtained free of charge via
www.cdcc.cam.ac.uk/conts/retrieving.html or on application to CCDC, 12
Union Road, Cambridge CB21EZ, UK (fax:(‡44)1233-336033 or e-mail :
deposit@ccdc.cam.ac.uk).
1,3-Bis[(1R,3S)-4-azido-1,3-dimethylbutyl]-5-(tert-butyl)-1,3,5-triazine-
2,4,6-trione (37): Potassium tert-butoxide (74 mg; 655 mmol) was added into
a
solution of the isocyanate 29 (233 mg, 1.39 mmol) and tert-butyl
isocyanate (1.303 g, 13.10 mmol) in THF (10 mL). After stirring for 16 h
the mixture was concentrated. Flash chromatography of the residue with
pentane/tert-butyl methyl ether 20:1 ! 5:1 furnished the bis-azide 37
(153 mg, 51%) as a colourless solid, the tris-azide 31 (53 mg, 23%) as
colourless oil, and the mono-azide 38 (22 mg, 4%) as a colourless resin. Bis-
azide 37: m.p. 66 67 8C; [a]2D0 ˆ ‡7.59 (c ˆ 1.58, CHCl3); 1H NMR
(500 MHz, CDCl3): d ˆ 0.97 (d, J ˆ 6.7 Hz, 6H), 1.34 (ddd, J ˆ 14.1, 9.3,
5.0 Hz, 2H), 1.40 (d, J ˆ 6.9 Hz, 6H), 1.43 1.52 (m, 2H), 1.62 (s, 9H), 2.32
(ddd, J ˆ 14.1, 10.1, 3.9 Hz, 2H), 3.13 (dd, J ˆ 13.7, 6.3 Hz, 2H), 3.15 (dd,
J ˆ 13.7, 6.3 Hz, 2H), 4.88 (dqd, J ˆ 10.1, 6.9, 5.0 Hz, 2H); 13C NMR
(125 MHz, CDCl3): d ˆ 17.5 (2C), 18.7 (2C), 29.4 (3C), 31.4 (2C), 37.8
(2C), 49.5 (2C), 57.8 (2C), 62.7, 149.1 (3C); elemental analysis calcd (%)
for C19H33N9O3 (435.5): C 52.40, H 7.64, N 28.94; found: C 52.33, H 7.67, N
28.64.
1,3-Bis[(1R*,3S*)-4-azido-1,3-dimethylbutyl]-5-[(1S*,3R*)-4-azido-1,3-
dimethylbutyl]-1,3,5-triazine-2,4,6-trione
(rac-30)
and
1,3,5-
tris[(1R*,3S*)-4-azido-1,3-dimethylbutyl]-1,3,5-triazine-2,4,6-trione (rac-
31): The racemic acid rac-28 (820 mg, 4.79 mmol) was converted into the
isocyanate and the triazine-trione as described for the preparation of
enantiomerically pure material under 31. Flash chromatography of the
crude product with pentane/tert-butyl methyl ether 10:1 furnished a 3:1
mixture of the compounds rac-30 and rac-31 (586 mg, 73%) as a colourless
oil. This allowed us to record the following spectral data of rac-30: 1H NMR
(500 MHz, CDCl3): d ˆ 0.95 (d, J ˆ 6.5 Hz, 3H), 0.95 (d, J ˆ 6.5 Hz, 6H),
1.31 1.39 (m, 3H), 1.39 1.49 (m, 3H), 1.42 (d, J ˆ 6.8 Hz, 3H), 1.42 (d, J ˆ
6.9 Hz, 6H), 2.35 (yddd, J ˆ 13.6, 10.4, 3.5 Hz, 3H), 3.11 3.15 (m, 6H),
4.90 4.99 (m, 3H); 13C NMR (125 MHz, CDCl3): d ˆ 17.3, 17.4 (2C), 18.5,
18.6 (2C), 31.3, 31.3 (2C), 37.6 (3C), 49.6 (3C), 57.6, 57.6 (2C), 148.7 (3C).
Mono-azide 38: [a]2D0 ˆ ‡8.91 (c ˆ 2.02, CHCl3); 1H NMR (500 MHz,
CDCl3): d ˆ 0.96 (d, J ˆ 6.6 Hz, 3H), 1.35 (ddd, J ˆ 14.2, 9.3, 5.2 Hz, 1H),
1.38 (d, J ˆ 6.9 Hz, 3H), 1.44 1.54 (m, 1H), 1.60 (s, 18H), 2.28 (ddd, J ˆ
14.2, 9.9, 4.0 Hz, 1H), 3.11 (dd, J ˆ 11.9, 6.6 Hz, 1H), 3.17 (dd, J ˆ 11.9,
6.1 Hz, 1H), 4.88 (m, 1H); 13C NMR (125 MHz, CDCl3): d ˆ 17.5, 18.8, 29.4
(6C), 31.4, 38.0, 49.0, 57.9, 62.1 (2C), 149.0, 150.6 (2C); elemental analysis
calcd (%) for C17H30N6O3 (366.5): C 55.72, H 8.25, N 22.93; found: C 55.95,
H 8.55, N 22.72.
Diethyl 2-(3-chloro-2-methylpropyl)-malonate (rac-32): Diethyl malonate
(11.4 mL, 75.0 mmol) was added slowly to a suspension of sodium hydride
(60% in white oil, 3.11 g, 77.8 mmol) in THF (220 mL) followed by the
addition of 1-bromo-3-chloro-2-methyl-propane (9.24 mL, 79.0 mmol).
After stirring for 18 h at 808C, saturated aqueous NaHCO3 (100 mL),
water (100 mL) and tert-butyl methyl ether (300 mL) were added. The
layers were separated and the aqueous layer was extracted with tert-butyl
methyl ether (4 Â 50 mL). The combined organic layers were washed with
brine (100 mL), dried (MgSO4), and concentrated. Distillation of the
residue (10À1 Torr, 69 73 8C) furnished compound rac-32 (10.0 g, 53%) as
1,3-Bis{(1R,3S)-4-[3-(4-butylphenyl)-ureido]-1,3-dimethylbutyl}-5-(tert-
butyl)-1,3,5-triazine-2,4,6-trione (6): Bis-azide 37 (109 mg, 250 mmol) was
converted in to the bis-urea 6 as described for the preparation of compound
5. Flash chromatography of the crude product with pentane/tert-butyl
methyl ether 1:1 ! 1:4 furnished compound 6 (115 mg, 63%) as a
colourless solid. M.p. 160 161 8C; [a]2D0 ˆ ‡32.1 (c ˆ 1.34, CHCl3);
1H NMR (500 MHz, CDCl3): d ˆ 0.85 0.95 (m, 12H), 1.10 1.21 (m,
2H), 1.22 1.32 (m, 2H), 1.31 (t, J ˆ 7.4 Hz, 4H), 1.42 (d, J ˆ 6.9 Hz, 6H),
1.52 (quin, J ˆ 7.7 Hz, 4H), 1.58 (s, 9H), 2.24 2.38 (m, 2H), 2.50 (t, J ˆ
7.7 Hz, 4H), 2.86 (brs, 2H), 3.15 (brs, 2H), 4.86 4.97 (m, 2H), 5.81 (brs,
2H), 7.02 (d, J ˆ 8.2 Hz, 4H), 7.14 (d, J ˆ 8.2 Hz, 4H), 7.22 (brs, 2H);
13C NMR (125 MHz, CDCl3): d ˆ 13.9 (2C), 17.6 (2C), 18.8 (2C), 22.3 (2C),
29.5 (3C), 32.0 (2C), 33.7 (2C), 35.0 (2C), 38.1 (2C), 46.4 (2C), 49.4 (2C),
1
a colourless oil. H NMR (300 MHz, CDCl3): d ˆ 1.02 (d, J ˆ 6.4 Hz, 3H),
1.24 (d, J ˆ 7.4 Hz, 6H), 1.73 1.94 (m, 3H), 2.04 2.15 (m, 1H), 3.37 3.52
(m, 2H), 4.13 4.27 (m, 4H); 13C NMR (75 MHz, CDCl3): d ˆ 14.0 (2C),
17.4, 32.8, 33.3, 49.8, 50.3, 61.4 (2C), 169.1, 169.3; elemental analysis calcd
(%) for C11H19ClO4 (250.7): C 52.70, H 7.64; found: C 52.69, H 7.58.
Diethyl 2-(3-azido-2-methylpropyl)-malonate (rac-33): Chloro-compound
rac-32 (2.66 g, 10.6 mmol) was converted into the azide as described for the
preparation of compound 11. Flash chromatography of the crude product
4954
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/02/0821-4954 $ 20.00+.50/0
Chem. Eur. J. 2002, 8, No. 21

Three-Armed Hosts
4946 4956
62.8, 120.6 (4C), 128.9 (4C), 136.4 (2C), 137.9 (2C), 149.1 (3C), 156.7 (2C);
HRMS (ESI): calcd for C41H63N7O5‡Na: 756.4788; found 756.4819.
[1] a) J.-M. Lehn, in Frontiers in Supramolecular Organic Chemistry and
Photochemistry (Eds.: H.-J. D¸rr, H. Schneider), VCH, Weinheim,
1991, p. 2; b) J.-M. Lehn, in Supramolecular Chemistry, VCH,
Weinheim, 1995, pp. 11 13.
[2] R. W. Hoffmann, Angew. Chem. 1992, 104, 1147 1157; Angew. Chem.
Int. Ed. Engl. 1992, 31, 1124 1134.
N-[(1R,3S)-4-Azido-1,3-dimethylbutyl]-O-[2-trimethylsilylethyl] carba-
mate (39): Triethylamine (845 mg, 0.835 mmol) and diphenoxyphosphoryl
azide (DPPA, 2.30 g, 0.835 mmol) were added to a solution of the acid 28
(1.43 g, 0.835 mmol) in toluene (6 mL). After heating for 2 h to 808C,
2-trimethylsilylethanol (1.98 g, 1.67 mmol) was added dropwise. After
stirring at 808C for 6 h, the mixture was concentrated. Flash chromatog-
raphy of the residue with pentane/diethyl ether 7:1 furnished the
carbamate 39 (2.03 g, 90%) as a colourless liquid. [a]2D0 ˆ ‡0.54 (c ˆ 7.4,
CHCl3); 1H NMR (200 MHz, CDCl3): d ˆ 0.02 (s, 9H), 0.92 1.02 (m, 2H),
0.99 (d, J ˆ 6.6 Hz, 3H), 1.17 (d, J ˆ 6.6 Hz, 3H), 1.17 1.26 (m, 1H), 1.44
1.55 (m, 1H), 1.78 1.90 (m, 1H), 3.17 (d, J ˆ 6.4 Hz, 2H), 3.47 (brs, 1H),
4.12 (brd, J ˆ 7.0 Hz, 2H), 4.37 (brd, J ˆ 6.5 Hz, 1H); 13C NMR (50 MHz,
CDCl3): d ˆ À1.5 (3C), 17.5, 17.7, 22.5, 30.7, 42.0, 44.6, 58.0, 62.8, 156.3;
elemental analysis calcd (%) for C12H26N4O2Si (286.5): C 50.32, H 9.15, N
19.56; found: C 50.25, H 9.10, N 19.82.
[3] a) P. W. Smith, W. C. Still, J. Am. Chem. Soc. 1988, 110, 7917 7919;
b) M. Wilstermann, J. Balogh, G. Magnusson, J. Org. Chem. 1997, 62,
¬
3659 3665; c) D. R. Bundle, R. Alibe s, S. Nilar, A. Otter, M. Warwas,
¬
P. Zhang, J. Am. Chem. Soc. 1998, 120, 5317 5318; d) J. L. Jime nez -
¬
Blanco, J. M. Benito, C. Ortiz Mellet, J. M. Garcia Fernandez, Org.
Lett. 1999, 1, 1217 1220; e) K. S. Jeong, J. W. Lee, T.-Y. Park, S.-Y.
Chang, Chem. Commun. 1999, 2069 2070 and references therein.
[4] D. J. Cram, Angew. Chem. 1986, 98, 1041 1060; Angew. Chem. Int.
Ed. Engl. 1986, 25, 1039 1057.
[5] a) R. Jairam, P. G. Potvin, J. Org. Chem. 1992, 57, 4136 4142; b) E.
Fan, S. A. Van Arman, S. Kincaid, A. D. Hamilton, J. Am. Chem. Soc.
1993, 115, 369 370; c) C. Raposo, M. Almaraz, M. Martin, V.
N-[(1R,3S)-4-Azido-1,3-dimethylbutyl]-phthalimide (40): Phthalic anhy-
dride (148 mg, 1.00 mmol), the carbamate 39 (286 mg, 1.00 mmol), acetic
acid (3 mL), and acetic anhydride (1 mL) were heated for 12 h to reflux.
After cooling saturated aqueous Na2CO3 was carefully added until the pH
of the solution was 9. The mixture was extracted with dichloromethane
(3 Â 15 mL). The combined organic layers were washed with brine (10 mL),
dried (MgSO4), and concentrated. Flash chromatography of the residue
with pentane/diethyl ether 3:1 furnished compound 40 (163 mg, 60%) as a
¬
¬
¬
Weinrich, M. L. Mussons, V. Alkazar, M. C. Caballero, J. R. Moran,
Chem. Lett. 1995, 759 760; d) F. Werner, H. J. Schneider, Helv. Chim.
Acta 2000, 83, 465 478; e) H.-J. Choi, Y. S. Park, S. H. Yun, H.-S.
Kim, C. S. Cho, K. Ko, K. H. Anh, Org. Lett. 2002, 4, 795 798; f) S. R.
Waldvogel, A. R. Wartini, P. H. Ramussen, J. Rebek jr., Tetrahedron
Lett. 1999, 40, 3515 3518; g) S. R. Waldvogel, R. Froelich, C. A.
Schalley, Angew. Chem. 2000, 112, 2580 2583; Angew. Chem. Int. Ed.
Engl. 2000, 39, 2472 2475.
1
colourless oil. [a]2D0 ˆ À6.3 (c ˆ 1.1, CHCl3); H NMR (500 MHz, CDCl3):
[6] H.-J. Schneider, J. F. J. Engbersen, D. N. Reinhoudt, Recl.Trav. Chim.
Pays-Bas 1996, 115, 307 320.
[7] R. W. Hoffmann, F. Hettche, K. Harms, Chem. Commun. 2002, 782 783.
[8] M. Ghosh, M. J. Miller, J. Org. Chem. 1994, 59, 1020 1026 .
[9] H. Sugimoto, Y. Yamane, S. Inoue, Tetrahedron: Asymmetry 2000, 11,
2067 2075.
d ˆ 0.98 (d, J ˆ 6.6 Hz, 3H), 1.40 (ddd, J ˆ 14.0, 10.1, 4.3 Hz, 1H), 1.47 (d,
J ˆ 6.9 Hz, 3H), 1.53 (m, 1H), 2.38 (ddd, J ˆ 14.0, 10.9, 4.3 Hz, 1H), 3.11
(dd, J ˆ 12.0, 6.6 Hz, 1H), 3.17 (dd, J ˆ 12.0, 5.9 Hz, 1H), 4.45 4.50 (m,
1H), 7.69 7.73 (m, 2H), 7.80 7.84 (m, 2H); 13C NMR (125 MHz, CDCl3):
d ˆ 17.0, 19.3, 31.0, 37.8, 44.7, 57.9, 123.1 (2C), 131.8 (2C), 133.9 (2C), 168.4
(2C); elemental analysis calcd (%) for C14H16N4O2 (272.3): C 61.75, H 5.92,
N 20.58; found: C 61.77, H 5.96, N 19.66.
[10] R. W. Hoffmann, D. Stenkamp, T. Trieselmann, R. Gˆttlich, Eur. J.
Org. Chem. 1999, 2915 2927.
N-[(1R,3S)-4-Phthalimido-1,3-dimethylbutyl]-N'-(4-butyl-phenyl)urea (8):
Palladium on carbon (5%, 20 mg), 4-butylphenylisocyanate (634 mg,
3.67 mmol), and poly(methylhydrosiloxane) (87 mg, 1.5 mmol) were added
sequentially to a solution of the azide 40 (200 mg, 0.734 mmol) in ethanol
(2 mL). The mixture was stirred for 12 h and was then filtered through a
membrane filter. The filter was washed with methanol (25 mL) and the
combined filtrates were concentrated. Flash chromatography of the residue
with pentane/diethyl ether 1:1 ! 0:1 furnished compound 8 (224 mg, 74%)
[11] a) F. Johnson, Chem. Rev. 1968, 68, 375 413; b) R. W. Hoffmann,
Chem. Rev. 1989, 89, 1841 1860.
[12] A. G. Myers, L. McKinstry, J. Org. Chem. 1996, 61, 2428 2440.
[13] a) B. Lal, B. M. Pramanik, M. S. Manhas, A. K. Bose, Tetrahedron
Lett. 1977, 18, 1977 1980; b) H. H. Wasserman, S. L. Henke, E.
Nakanishi, G. Schulte, J. Org. Chem. 1992, 57, 2641 2645.
¬
[14] N. Knouzi, M. Vaultier, R. Carrie, Bull. Soc. Chim. Fr. 1985, 815 819.
[15] a) H. Ulrich in Cycloadditions of Heterocumulenes, Academic Press,
New York, 1967, p. 128; for leading references see: b) J. Tang, T.
Mohan, J. C. Verkade, J. Org. Chem. 1994, 59, 4931 4938.
[16] H.-E. Hˆgberg in Houben-Weyl, Methods of Organic Synthesis,
Vol. E21a (Eds.: G. Helmchen, R. W. Hoffmann, J. Mulzer, E.
Schaumann), Thieme, Stuttgart, 1995, pp. 883 899.
[17] Z. Bukac, A. Nechaiev, J. Sebenda, Collect. Czech. Chem. Commun.
1982, 47, 2219 2226.
[18] P. Mohr, N. Waespe-Sarcevic, C. Tamm, Helv. Chim. Acta 1983, 66,
2501 2511.
[19] C. Schregenberger, D. Seebach, Liebigs Ann. Chem. 1986, 2081 2103;
the stereodescriptors used differ from those in the other references.
[20] P. J. Kocienski, R. C. D. Brown, A. Pommier, M. Procter, B. Schmidt,
J. Chem. Soc. Perkin Trans. 1 1998, 9 39.
[21] R. Gˆttlich, B. C. Kahrs, J. Kr¸ger, R. W. Hoffmann, Chem. Commun.
1997, 247 251.
[22] Inspection of Table 1 further reveals that the conformational prefer-
ence of the side chains (i.e., the alternation of the coupling constants)
increases in a monotonous series from 38 to 37 to 31; the arms on the
three-armed derivative 31 have the highest conformational preorga-
nisation. The phthaloyl-derivative 40 stands out from this series. The
azido-compound 40 already has a slightly higher preference for
adopting conformation 41a, than the other azido compounds, a
preference which is increased further in going to the urea compound 8
(3J(H,H) ˆ 11.3 and 2.7 Hz). Clearly, in compound 8 the folding of the
side-chain cannot be influenced by the formation of intramolecular
hydrogen bridges between urea groups as in 4.
as a colourless oil, which solidified on standing. M.p. 85 87 8C; [a]D20
ˆ
‡31.6 (c ˆ 0.73, CHCl3); 1H NMR (500 MHz, CDCl3): d ˆ 0.90 0.94 (m,
7H), 1.29 1.37 (m, 2H), 1.45 (d, J ˆ 6.5 Hz, 3H), 1.44 1.50 (m, 1H), 1.52
1.59 (m, 2H), 2.43 (ddd, J ˆ 13.8, 11.3, 2.7 Hz, 1H), 2.57 (t, J ˆ 7.9 Hz, 2H),
3.00 3.07 (m, 1H), 3.10 3.16 (m, 1H), 4.47 4.51 (m, 1H), 4.64 (s, 1H;
NH), 6.03 (s, 1H; NH), 7.12 (d, J ˆ 6.6 Hz, 2H), 7.16 (d, J ˆ 6.7 Hz, 2H),
7.66 7.68 (m, 2H), 7.76 7.78 (m, 2H); 13C NMR (50 MHz, CDCl3): d ˆ
13.9, 17.4, 22.3, 22.6, 30.0, 33.6, 34.9, 41.8, 43.5, 44.2, 121.2 (2C), 123.2 (2C),
128.8 (2C), 131.9 (2C), 133.9 (2C), 136.5, 137.7, 155.9, 168.7 (2C);
elemental analysis calcd (%) for C25H31N3O3 (421.5): C 71.23, H 7.41, N
9.97; found: C 71.11, H 7.12, N 9.95.
Complexation studies: 15 Incremental amounts of the solution of the
tetrabutylammonium salt (26 mm in CDCl3, 100 mL in total) were added
with syringe to a solution of the host (1 mm, in CDCl3 Aldrich, 99.6% D,
600 mL). 1H NMR spectra were recorded at 500 MHz. The signals of the
host did not sharpen upon addition of the guest, but instead broadened
further (nitrate > bromide  chloride).
Acknowledgement
We would like to thank the European Community (TMR Network
ERBFMRXCT 960011 and the Fond der Chemischen Industrie for
supporting this study. We thank Dr. K. Harms for providing the crystal
structure of 4. We are grateful to Professor T. Schrader, Marburg, for many
helpful suggestions.
[23] P. E. Hansen, Progr. NMR Spectrosc. 1981, 14, 175 296.
[24] SPSS Inc., 2000, we thank Prof. A. P. Davis (Bristol) and Prof. H.-J.
Schneider (Saarbr¸cken) for special routines to analyse 1:1 com-
plexes.
Chem. Eur. J. 2002, 8, No. 21
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FULL PAPER
[25] E. Fan, J. Yang, S. J. Geib, T. C. Stoner, M. D. Hopkins, A. D.
Hamilton, J. Chem. Soc. Chem. Commun. 1995, 1251 1252.
[26] C. Wilcox, HOSTEST ed. 5.6, University of Pittsburgh, 1997.
W. J. Belcher, M. G. Boutelle, P. J. Cragg, J. Dhaliwal, M. Fabre, J. W.
Steed, D. R. Turner, K. J. Wallace, Chem. Commun. 2002, 358 359.
[29] J. Yan, J. W. Herndon, J. Org. Chem. 1998, 63, 2325 2331.
[30] D. A. Evans, M. D. Ennis, D. J. Mathre, J. Am. Chem. Soc. 1982, 104,
1737 1739.
¬
[27] A. J. Ayling, M. N. Perez-Payan, A. P. Davis, J. Am. Chem. Soc. 2001,
123, 12716 12717.
¬
[28] The selectivities are thus higher than those reported recently for
another tripodal receptor of similar topology: L. O. Abouderbala,
[31] N. Khoukhi, M. Vaultier, R. Carrie, Tetrahedron 1987, 43, 1811 1822.
Received: June 3, 2002 [F4149]
4956
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Chem. Eur. J. 2002, 8, No. 21