Synthesis of a cryptand with tetrahedral connectivity using multiple ring-closing olefin metathesis

Article abstract of DOI:10.1016/j.tetlet.2004.09.090

By connecting six terminal olefins sequentially in one molecule under metathesis conditions, three macrocycles were formed efficiently in one pot yielding a novel cryptand with tetrahedral connectivity.

Full text of DOI:10.1016/j.tetlet.2004.09.090

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8501–8504
Synthesis of a cryptand with tetrahedral connectivity using
multiple ring-closing olefin metathesis
Shiyue Fang and Donald E. Bergstrom*
Department of Medicinal Chemistry and Molecular Pharmacology, 201 S University Street, Purdue University,
West Lafayette, IN 47907, USA
Walther Cancer Institute, Indianapolis, IN 46208, USA
Received 31 July 2004; revised 3 September 2004; accepted 13 September 2004
Available online 29 September 2004
Abstract—By connecting six terminal olefins sequentially in one molecule under metathesis conditions, three macrocycles were
formed efficiently in one pot yielding a novel cryptand with tetrahedral connectivity.
Ó 2004 Elsevier Ltd. All rights reserved.
Since its emergence in 1967,1 host–guest chemistry has
found wide applications in areas such as molecular rec-
ognition, catalysis, separation, transportation, molecu-
lar electronics, and drug delivery.2–5 Of various host
molecules developed, the ones that contain a cavity
formed by multiple macrocycles have the advantage of
more restricted conformation, richer interactions be-
tween host and guest, and thus, higher affinity between
them. However, compared to the preparation of other
host molecules that possess no or only one macrocycle,
the synthesis of such hosts is more challenging; usually,
the multiple macrocycles are formed in separate steps,
high dilution and/or slow addition techniques are re-
quired to prevent intermolecular oligomerization, and
in some cases, even under these conditions, oligomeriza-
tion products prevail. Consequently, the discovery of
methodologies for efficient preparation of such hosts is
highly desired. In recent years, olefin ring-closing
metathesis (RCM) has proved to be a reliable tool for
the construction of various macrocycles.6,7 It has not
only been used for the synthesis of numerous biologi-
cally active natural products, but also been used for
the preparation of interesting architectures such as cyclic
polymers,8 catenanes,9 rotaxanes,10 and cored dendrim-
ers.11–13 The application of this reaction in the synthesis
of macrocyclic molecules that are useful for host–guest
chemistry also has been reported. For example, using
olefin metathesis as the macrocyclization reactions,
Grubbsꢀ group prepared crown ether analogs14 and
McKerveyꢀs group constructed bridged, multifunctional
calixarenes.15 However, to the best of our knowledge,
there are no literature reports on the application of mul-
tiple RCM in the synthesis of artificial receptors that
posses a cavity formed by multiple macrocycles, which
are potentially useful for complexation of various ions
or small molecules. In this communication, we report
the results on the preparation of a bell-shaped cryptand
using such a strategy.
As shown in Scheme 1, the synthesis commenced with
saponification of the known methyl ester 211–13 with
KOH to give 3. Carboxylic acid 3 was then activated
with i-butylchloroformate and coupled to 4,16,17 and
the coupled intermediate treated with trifluoroacetic
acid to remove the Boc protecting group to give 5.
The pentaerythritol derivative 618 was oxidized with
NaIO4 and a catalytic amount of RuCl3Æ3H2O following
a reported procedure19 to give the triacid 7. Without
purification, triacid 7 was transformed to triacid chlo-
ride by treating with excess SOCl2 in CH2Cl2 at reflux.20
After removal of excess SOCl2 on a rotary evaporator
and drying under vacuum, the residue was allowed to re-
act with amine 5 in CH2Cl2 in the presence of pyridine
to give the multiple macrocyclization precursor 8. Mul-
tiple olefin RCM of 8 was simply achieved by stirring its
solution in CH2Cl2 at 40°C or room temperature at a
concentration of 0.001M catalyzed by 30mol% Grubbsꢀ
catalyst (9) under inert atmosphere for 12h (Scheme 2).
Keywords: Cryptand; Host; Macrocyclization; Receptor; Ring-closing
metathesis.
*
Corresponding author. Tel.: +1 765 494 6275; fax: +1 765 494 9193;
e-mail: bergstrom@purdue.edu
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.090

8502
S. Fang, D. E. Bergstrom / Tetrahedron Letters 45 (2004) 8501–8504
O
O
NH2
O
O
MeO
O
O
HO
O
NHBoc
H
N
O
NH2
a
4
O
O
O
b,c
O
O
2
3
5
t Bu
t Bu
Ph Si Ph
O
Ph Si Ph
O
e
d
8
O
O
O
O
O
(See Scheme 2
for structure)
O
CO2H
CO2H
CO2H
7
6
Figure 1. Partial variable temperature 1H NMR of 1.
Scheme 1. Synthesis of the olefin RCM precursor 8. Reagents and
conditions: (a) KOH (2.5equiv), THF/EtOH/H2O (1:1:1), rt, 5h, 88%;
(b) i-BuOC(O)Cl (1.1equiv), N,N-diisopropylethylamine (2.0equiv),
DMF, 0°C, 1h, then, 4 (1.1equiv), 0°C to rt, 2h, 75%; (c) TFA, rt, 2h,
93%; (d) NaIO4 (30equiv), RuCl3Æ3H2O (20mol%), H2O/MeCN/CCl4
(3:2:2), rt, 4h, 52%; (e) SOCl2 (15equiv), CH2Cl2, reflux, 4h, volatile
as complex multiplets. In an effort to find out whether
this was a result of different conformers or different ste-
reoisomers or both, variable temperature 1H NMR
spectra were obtained. As shown in Figure 1, although
the resonances of olefinic hydrogens at d 5.59–5.48
(H3) became almost symmetric at 60°C and had a ten-
dency to merge to a single peak at À30°C, the signals
of H1 remained unchanged even at 60°C (note, there
was a broad signal due to exchangeable protons moving
from d ꢀ 6.19 at 30°C to d ꢀ 6.78 at 60°C). This infor-
mation was insufficient to draw conclusions about the
number and identity of the stereoisomer(s) in the prod-
uct. In order to see if reduction of the three double
components removed on rotary evaporator, then,
pyridine (10equiv), CH2Cl2, rt, 12h, 58%.
5 (3.6equiv),
The catalyst was decomposed by bubbling air through
the solution, which was then concentrated under
reduced pressure. As revealed by TLC (silica gel,
CH2Cl2/MeOH, 19:1), there were two UV active spots
with Rf = 0.42 and 0.39, respectively, which were sepa-
rated by flash chromatography (silica gel, CH2Cl2/
MeOH, 19:1). The upper spot gave only a very small
amount of gray oily material, which was not pure as
indicated by NMR and MALDI-MS; its purification
and characterization was not further pursued. The more
UV intense lower spot, cryptand 1, was isolated as a
white foam in 66% yield irrespective of the temperature
under which the reaction was performed. In the 1H
NMR spectra (Fig. 1) at 30°C, signals of H1 (d ꢀ 6.90,
see Scheme 2 for hydrogen denotation), H2 (d ꢀ 6.49),
H3 (d 5.59–5.47), and H4 (d ꢀ 2.40, not shown) appeared
1
bonds could simplify the H NMR spectra, a solution
of 1 in ethanol was stirred under a hydrogen atmosphere
in the presence of Pd/C to give 10 (Scheme 2). The H3
resonances moved from d 5.59–5.47 to d 1.49 as a broad
singlet (not shown), while those of H1 (d ꢀ 6.90) and H2
(d ꢀ 6.49) remained complex below 0°C, but became
simpler at higher temperature. However, this did not
prove that 1 contained more than one stereoisomer
because reduction of the double bonds could change
tBu
Ph Si Ph
O
tBu
Ph Si Ph
O
O
O
O
O
O
P(Cy)3
Ru
O
O
O
Cl
Cl
O
NH
H1
O
HN
O
HN
HN
O
HN
O
b
Ph
O
O
P(Cy)3
9
HN
H4
HN
O
O
O
O
H2
a
H3
O
H3
O
3
H3
H
O
O
O
O
10
O
O
NH
NH
NH
NH
O
O
O
O
NH
NH
H1
O
O
O
O
O
O
O
O
H4
O
O
O
O
O
O
H2
8
H3
1
Scheme 2. Synthesis of the bell-shaped cryptand 1 and its hydrogenation. Reagents and conditions: (a) 9 (30mol%), CH2Cl2 (0.001M 8), 40°C or rt,
12h, 66%; (b) Pd/C (10%), H2 (1atm), EtOH, rt, 24h, 86%.

S. Fang, D. E. Bergstrom / Tetrahedron Letters 45 (2004) 8501–8504
8503
gen atoms with respect to the plane of the benzene
ring.21 The shift differences for the c and d positions
are of similar magnitude. Formation of a 22-membered
ring would either leave an unreacted terminal alkene in
the third arm (easily distinguishable by NMR) or higher
order products formed through oligomerization. Such
products if formed would have been lost in the purifica-
tion of compound 1, whose purity was established by the
presence of a single spot on thin layer chromatography.
In conclusion, using an unprecedented multiple olefin
RCM strategy, we successfully synthesized and charac-
terized a novel cryptand with tetrahedral connectivity.
Potentially, by using other molecules, instead of the
pentaerythritol derivative, as platforms, other linkers
between the platform and the olefins, and other RCM
olefin units, a novel class of host molecules may be
accessible through this approach. Because the olefin
RCM is tolerant of a broad range of functional groups,
the linkers could potentially include peptides and other
oligomers capable of presenting a rich molecular land-
scape. Research toward this end and investigation of
the ability of cryptand 1 to complex guest molecules
and ions are under investigation.
Figure 2. MALDI-MS of cryptand 1. The peaks at m/z 1588.7, 1609.7,
1625.7 correspond to [M + H]+ (calcd 1588.9), [M + Na]+ (1610.9),
[M + K]+ (1626.9), respectively.
the flexibility of the molecule. Despite its complex NMR
spectra, the structure irrespective of the geometry of the
three double bonds of cryptand 1 was clearly supported
by the MALDI-MS spectrum. As illustrated in Figure 2,
the peaks at m/z 1588.7, 1609.7, 1625.7 corresponded to
[M + H]+ (calcd 1588.9), [M + Na]+ (1610.9), [M + K]+
(1626.9), respectively. The less intense peaks at m/z
1640.0 and 1650.7 could be due to complexation of other
metal ions to 1; no other peaks with comparable inten-
sity were observed. The lack of peaks in the region m/z
3100–3400 (Supplementary material) supports the ab-
sence of products formed through dimerization of com-
pound 8. Other possible RCM cyclizations (Scheme 3)
could lead to 11- and 22-membered ring products. Only
two examples (11 and 12) are shown in the figure, but
the absence of these and other products containing 11-
Acknowledgements
Grant support from the National Institutes of Health
(GM53155) and the Showalter Trust Fund is gratefully
acknowledged. Assistance from the National Cancer
Institute Grant (P30 CA23168) awarded to Purdue
University is also gratefully acknowledged.
1
and 22-membered rings is supported by H NMR. The
formation of the 11-membered ring as shown in struc-
ture 11 has been demonstrated to be improbable.11–13
If such a product were formed, the resulting NMR spec-
trum would contain easily distinguishable features that
are not present in the NMR spectrum of compound 1.
In particular, as has been shown for an 11-membered
ring metacyclophane, the two methylene protons at the
b positions show significant chemical shift differences
(>1ppm) because of the relative placement of the hydro-
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2004.09.090. Experimental procedures for the prepara-
tion of intermediates 3, 5, 7, 8, and 14, cryptand 1 and
its hydrogenation product 10 are available as supple-
1
mentary data. The H NMR, 13C NMR, and MALDI
spectra of 1 are also included.
tBu
Ph Si Ph
O
O
O
O
O
O
O
Ph
Si
Ph
O
O
O
HN
NH
HN
O
O
O
t Bu
N
H
N
H
2
O
O
3
O
11
O
O
O
HN
O
NH
O
O
O
O
O
O
O
HN
O
O
12
Scheme 3. Conceptional examples of 11- and 22-membered ring products.

8504
S. Fang, D. E. Bergstrom / Tetrahedron Letters 45 (2004) 8501–8504
12. Zimmerman, S. C.; Zharov, I.; Wendland, M. S.; Rakow,
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