Selective lithium ion binding involving inositol-based tris(spirotetrahydrofuranyl) ionophores: Formation of a rodlike supramolecular ionic polymer from a homoditopic dimer

Article abstract of DOI:10.1021/ja010103x

The stereoselective replacement of all three hydroxyl groups in myo-inositol orthoformate by spirotetrahydrofuran rings in that manner which projects the C-O bonds in the molecular interior has been examined. The heterocyclic components were introduced se

Full text of DOI:10.1021/ja010103x

4974
J. Am. Chem. Soc. 2001, 123, 4974-4984
Selective Lithium Ion Binding Involving Inositol-Based
Tris(spirotetrahydrofuranyl) Ionophores: Formation of a Rodlike
Supramolecular Ionic Polymer from a Homoditopic Dimer
Leo A. Paquette* and Jinsung Tae
Contribution from the EVans Chemical Laboratories, The Ohio State UniVersity, Columbus, Ohio 43210
ReceiVed January 10, 2001
Abstract: The stereoselective replacement of all three hydroxyl groups in myo-inositol orthoformate by
spirotetrahydrofuran rings in that manner which projects the C-O bonds in the molecular interior has been
examined. The heterocyclic components were introduced sequentially, a protocol that demonstrated the utility
of precomplexation to LiClO4 as a stereocontrol tactic. The capability of 3 to coordinate to alkali metal ions
was quantified. The conformationally restricted nature of this ligand conveys high selectivity for binding to
lithium ion. Beyond that, the ionophore prefers to form 2:1 complexes with Li+ and exhibits little tendency
for 1:1 stoichiometry. These properties are shared by the “dimer” 36, in which two building blocks of type 3
have been conjoined by a 1,3-butadiyne tether positioned at the ortho ester terminus. This bifacial ligand
reacts with one equivalent of LiClO4 or LiBF4 to form rodlike ionic polymers. Alternative recourse to lithium
picrate results in production of the doubly capped homoditopic complex 41. Various other aspects of the
chemistry peculiar to these systems are discussed.
Very recently, attention has been turned to the preparation
In connection with our studies of polyspiro(tetrahydrofuranyl)
compounds,7 we have sought to develop synthetic routes to
ligands that have their oxygen-centered binding sites covalently
anchored to an inositol orthoformate platform. Structure 3, which
represents a prototypical member of this new heterocyclic
family, was targeted because of its potential for serving as a
very specific ionophore for lithium ion. The need for developing
lithium-sensitive electrodes for monitoring Li+ concentrations
in the blood of manic depressive patients being administered
large daily doses of lithium carbonate8 continues to attract strong
interest.9 Beyond that, the utilization of alkali metal ions for
the preparation of ionic supramolecules is an attractive goal. In
this connection, the anticipated good selectivity of 3 for chelating
of macrocyclic systems having at least two exotopic binding
sites because of the latent potential of these systems to serve as
precursors to new types of metallosupramolecular structures.
To the present time, interest has been focused to a large extent
on 2,2′-bipyridines1 and phenanthrolines 2 of the general formula
1 to capitalize on the capability of these ligands to bind to
transition metal ions in a well-defined way.3,4 4,4′-Dipyridines
of type 2 have similarly been utilized as building blocks5
(6) (a) Yaghi, O. M.; Li, H.; Davis, C.; Richardson, D.; Troy, T. L. Acc.
Chem. Res. 1998, 31, 474. (b) Batten, S. R.; Robson, R. Angew. Chem.,
Int. Ed. 1998, 37, 1451. (c) Champness, N. R.; Schro¨der, M. Curr. Opin.
Solid State Mater. Chem. 1998, 3, 419. (d) Blake, A. J.; Champness, N. R.;
Li, W.-S.; Withersby, M. A.; Schro¨der, M. Coord. Chem. ReV. 1999, 183,
117.
(7) (a) Paquette, L. A.; Branan, B. M.; Stepanian, M. Tetrahedron Lett.
1996, 37, 1721. (b) Paquette, L. A.; Stepanian, M.; Branan, B. M.;
Edmondson, S. D.; Bauer, C. B.; Rogers, R. D. J. Am. Chem. Soc. 1996,
118, 4504. (c) Paquette, L. A.; Lowinger, T. B.; Bolin, D. G.; Branan, B.
M. J. Org. Chem. 1996, 61, 7486. (d) Paquette, L. A.; Stepanian, M.;
Mallavadhani, U. V.; Cutarelli, T. D.; Lowinger, T. B.; Klemeyer, H. J. J.
Org. Chem. 1996, 61, 7492. (e) Stepanian, M.; Trego, W. E.; Bolin, D. G.;
Paquette, L. A.; Sareth, S.; Riddell, F. G. Tetrahedron 1997, 53, 7403. (f)
Paquette, L. A.; Bolin, D. G.; Stepanian, M.; Branan, B. M.; Mallavadhani,
U. V.; Tae, J.; Eisenberg, S. W. E.; Rogers, R. D. J. Am. Chem. Soc. 1998,
120, 11603. (g) Paquette, L. A.; Tae, J.; Hickey, E.; Rogers, R. D. Angew.
Chem., Int. Ed. 1999, 38, 1409. (h) Paquette, L. A.; Tae, J.; Branan, B. M.;
Eisenberg, S. W. E.; Hofferberth, J. E. Angew. Chem., Int. Ed. 1999, 38,
1412. (i) Paquette, L. A.; Tae, J. Tetrahedron Lett. 1999, 40, 5971.
(8) Birch, N. J., Ed., Lithium: Inorganic Pharmacology and Psychiatric
Use; IRL Press: Oxford, 1988.
(9) (a) Kimura, K.; Yano, H.; Kitazawa, S.; Shono, T. J. Chem. Soc.,
Perkin Trans. 2 1986, 1945. (b) Kataky, R.; Nicholson, P. E.; Parker, D. J.
Chem. Soc., Pertin Trans. 2 1990, 321. (c) Kataky, R.; Nicholson, P. E.;
Parker, D.; Covington, A. K. Analyst 1991, 116, 135. (d) Suzuki, K.;
Yamada, H.; Sato, K.; Watanabe, K.; Hisamoto, H.; Tobe, Y.; Kohiro, K.
Anal. Chem. 1993, 65, 3404. (e) Faulkner, S.; Kataky, R.; Parker, D.;
Teasdale, A. J. Chem. Soc., Perkin Trans. 2 1995, 1761.
for the construction of rodlike metal-coordinated network
polymers.6
(1) (a) Schmittel, M.; Ganz, A. Synlett 1997, 710. (b) Schmittel, M.;
Ganz, A. Chem. Commun. 1997, 999.
(2) (a) Kelly, T. R.; Lee, Y.-J.; Mears, R. J. J. Org. Chem. 1997, 62,
2774. (b) Kaes, C.; Hosseini, M.; Rickard, C. E. F.; Skeleton, B. W.; White,
A. H. Angew Chem., Int. Ed. 1998, 37, 920. (c) Kaes, C.; Hosseini, M. W.;
De Cian, A.; Fischer, J. Tetrahedron Lett. 1997, 38, 3901. (d) Schmittel,
M.; Ammon, H. Synlett 1999, 750.
(3) Lehn, J.-M. Supramolecular Chemistry; VCH: Weinheim, 1995; p
138.
(4) (a) Philip, D.; Stoddart, J. F. Angew. Chem., Int. Ed. Engl. 1996, 35,
1154. (b) Conn, M. M. Chem. ReV. 1997, 1647.
(5) (a) Sauvage, J.-P.; Collin, J.-P.; Chambron, J.-C.; Guillerez, S.;
Coudret, C.; Balzani, V.; Barrigelletti, F.; De Cola, L.; Flamigni, L. Chem.
ReV. 1994, 94, 993. (b) Abrahams, B. F.; Hardie, M. J.; Hoskins, B. F.;
Robson, R.; Sutherland, E. E. J. Chem. Soc., Chem. Commun. 1994, 1049.
(c) Whiteford, J. A.; Lu, C. V.; Stang, P. J. J. Am. Chem. Soc. 1997, 119,
2524. (d) Carlucci, L.; Ciani, G.; Proserpio, D. M. J. Chem. Soc., Chem.
Commun. 1999, 449. (e) Champness, N. R.; Khlobystov, A. N.; Majuga,
A. G.; Schro¨der, M.; Zyk, N. V. Tetrahedron Lett. 1999, 40, 5413.
10.1021/ja010103x CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/03/2001

Ionophores with Capacity for Bifacial Complexation
J. Am. Chem. Soc., Vol. 123, No. 21, 2001 4975
Scheme 1
Li+ was believed to offer positive prospects for the generation
Results and Discussion
of the novel homopolymers typified by 4.
Elaboration of the Conformationally Fixed Ionophore 3.
In view of the ease with which inexpensive myo-inositol (5)
can be transformed into 6,11 we first explored direct conversion
of the latter into triketone 7 (Scheme 1). This obvious maneuver
would presumably set the stage for three-fold “capping”12 and
very direct conversion to 3. Unfortunately, however, the close
proximity of the hydroxyl substituents in 6 and the aldol nature
of partially oxidized intermediates served effectively to render
the conversion to 7 inoperative under a wide variety of
conditions. Recourse was therefore made to installation of the
spirotetrahydrofuran rings in a stepwise manner.
The salient feature of the addition of the Normant reagent13
to 10 is the expectation that the new C-C bond will be formed
from the equatorial direction. This trajectory guarantees that
the developing tetrahydrofuran ring will be constituted of an
axial C-O bond, provided that the initially formed diol is
cyclized under basic conditions by way of the primary mono-
In the present paper, we describe in detail our comprehensive
efforts in this area, both preparative and analytical.10 Particularly
noteworthy is the high selectivity with which 3 and a “dimer”
thereof bind Li+ relative to Na+. This property lends itself very
suitably to arrival at 4. Moreover, this polymerization can be
controlled under the proper conditions, thus enabling the
isolation of a discrete bifacial complex.
(11) Lee, H. W.; Kishi, Y. J. Org. Chem. 1985, 50, 4402.
(12) Paquette, L. A.; Negri, J. T.; Rogers, R. D. J. Org. Chem. 1992,
(10) For preliminary reports describing select aspects of this work,
consult: (a) Tae, J.; Rogers, R. D.; Paquette, L. A. Org. Lett. 2000, 2, 139.
(b) Paquette, L. A.; Tae, J.; Gallucci, J. C. Org. Lett. 2000, 2, 143.
57, 3947.
(13) Cahiez, G.; Alexakis, A.; Normant, J. F. Tetrahedron Lett. 1978,
3013.

4976 J. Am. Chem. Soc., Vol. 123, No. 21, 2001
Paquette and Tae
tosylate. Following controlled reaction of the Normant adduct
with tosyl chloride and triethylamine, however, two products
were seen by H NMR to have been formed in a 1.9:1 ratio.
Scheme 2
1
Because this pair of products proved to be difficultly separable,
the mixture was subjected to hydrogenolysis in advance of
chromatography. The conclusion that 11 and 12 were not
diastereomers was confirmed by a simple four-step chemical
interconversion that did not perturb the stereogenic centers (see
Scheme 1). Five additional pieces of evidence confirmed that
12 was the alkyl chloride. The white powdery solid 12 exhibited
the very same melting point as 11, in line with anticipated
thermal extrusion of hydrogen chloride. The HRMS (EI) spectra
of the two compounds exhibited identical fragmentation patterns,
a likely consequence of the conversion of 12 to 11 under the
conditions of the measurements. The FAB MS of 12 and its
combustion analysis were distinctive for C19H33ClO6Si. Last,
Table 1. Association Constants (Ka) Determined by Picrate
Extraction into Chloroform at 20 °C
1
select key H and 13C NMR resonances, for example, δ 3.59
for -CH2Cl and 44.9 for -CH2Cl in CDCl3 solution, conform
to anticipated chemical shifts. The existence of 12 and related
chlorides (see below) reflects the feasibility of tosylate displace-
ment by chloride ion during the functionalization process. This
phenomenon has been observed previously.14
The ketone obtained following oxidation of 11 with the
Dess-Martin periodinane15 was capped in the predescribed
manner. The virtually exclusive operation of exo attack was
readily discerned by the Cs-symmetric nature of 13. The
simplified nature of its 13C NMR spectrum was particularly
telling. As seen earlier, the generation of 13 was accompanied
by formation of the chloride 14 in near-equivalent proportions.
The general features of the 1H and 13C NMR spectra of 14 are
reconcilable with the absence of any element of symmetry.
Treatment of either 13 or 14 with tetra-n-butylammonium
fluoride in THF delivered carbinol 15.
We next addressed the introduction of the third and final
tetrahydrofuran subunit. Under entirely comparable Normant
conditions, 16 was unexpectedly converted into 17 as the major
product.7i The source of this remarkable reversal in the
stereoselectivity of the 1,2-carbonyl addition was considered
to be the coordinated complex A, the intervention of which
would be followed by nucleophilic attack from the axial surface.
To reverse this untoward course of events, a complementary
experiment was performed in which 5 equiv of LiClO4 was first
added to 16 in the hope that ligation to Li+ as in B would now
relegate attack of the nucleophilic reagent entirely to the
equatorial π-surface. This ploy proved quite successful in that
only 3 was now formed in good yield. The two trispiro products
are readily distinguished on the basis of the enhanced (C3ν)
symmetry of the intended target 3.
debenzylation, and repetition of the first step. An X-ray
crystallographic analysis of 1916 revealed the distances between
the methoxyl oxygens to be 2.9606, 2.8852, and 2.9096 Å.
Although 3 crystallized well, complications were encountered
in gaining access to a comparable solid-state analysis in this
instance. Subsequently, however, the derivative 35 was found
to lend itself to structural corroboration as discussed below.
The Ligating Properties of 3. The association constants Ka
for the complexation of 3 to lithium-, sodium-, and potassium
picrate were determined by extraction from water into chloro-
form.17 At this point, comparison with 20 is warranted.7g,h
Although this trispiro system adopts the all-equatorial conforma-
tion in the ground state, the all-axial arrangement is readily
populated and is therefore available for coordination to alkali
metal ions without difficulty. As seen in Table 1, the ability of
3 and 20 to bind Li+ is closely comparable. However, the
enhanced geometric constraints imposed on 3 manifest them-
selves when the larger Na+ is involved. The fact that 3 cannot
accommodate the sodium ion as intimately increases the Ka-
(Li+)/Ka(Na+) selectivity ratio from 32, the value exhibited by
20, to the significantly elevated value of 440. This heightened
For comparison purposes, the trimethoxy analogue 19 was
also synthesized (Scheme 2). This goal was easily reached by
sequential O-methylation of the known alcohol 18,11 2-fold
(14) For example: Reveli, G. A.; Gros, E. G. Synth. Commun. 1993,
23, 1111.
(15) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
level of discrimination on the part of 3 for binding lithium is
required of useful sensing ionophores.

Ionophores with Capacity for Bifacial Complexation
J. Am. Chem. Soc., Vol. 123, No. 21, 2001 4977
Figure 1. 13C NMR spectra (75 MHz) recorded during the titration of 3 with LiClO4 in 1:1 CH3CN/CDCl3. Equivalents of added salt: (a) 0.00;
(b) 0.25; (c) 0.50; (d) 0.75; (e) 1.00; (f) 1.50.
The contrasting behavior of 19, which shows no ability to
extract any of the picrate salts, establishes that this arrangement
of three syn-methoxy groups is not conducive to binding. The
progression from an acyclic to a cyclic ether, for example,
diethyl ether to tetrahydrofuran, has long been recognized to
enhance intrinsic basicity and foster improved hydrogen-bonding
capability.18 The steric origins of these phenomena are believed
to contribute in important ways here. A further consideration
is the need on the part of all three ligating oxygens to orient
one of their nonbonded electron pairs toward the central core
as binding is initiated. Molecular models indicate that the
associated rotational process is more easily accomplished when
tetrahydrofuran moieties are involved.
Titration experiments involving the conformationally re-
stricted host 3 were conducted in 1:1 CH3CN/CDCl3 and
This somewhat more restricted complexation stoichiometry
was construed to be ideal for the planned polymerization studies,
since molecules of type 4 owe their existence precisely to this
monitored by 13C NMR. As seen in Figure 1, 3 is smoothly
transformed into the 2:1 sandwich complex 21 upon addition
of 0.5 equiv of LiClO4. This response is essentially identical to
mode of binding. When the solution used for the NMR studies
that exhibited by 20. The striking difference between these
in Figure 1 was concentrated, triturated with CH2Cl2, and freed
related ionophores manifests itself as additional lithium salt is
of the excess LiClO4 prior to dilution with hexane, crystals of
introduced. Whereas 20 is transformed rapidly into a 1:1
21 suitable for crystallographic analysis were obtained. The six
oxygens around the lithium atom are seen to adopt a nicely
complex when a total of 1.0 equiv is present, 3 does not undergo
this chemical change to generate 22. Figure 1 reveals that only
staggered arrangement. The melting point of 21 (>254 °C) is
slight line broadening and minor chemical shift changes
reasonably elevated.
materialize.
Titration of 3 with NaClO4 in an entirely comparable manner
does not alter the 13C NMR spectrum of the ionophore. Another
(16) This analysis was performed by Prof. Robin Rogers of the University
of Alabama.
(17) Cram, D. J.; Lein, G. M. J. Am. Chem. Soc. 1985, 107, 3657
(18) For a compilation of relevant references, consult: Paquette, L. A.;
Tae, J.; Hickey, E. R.; Trego, W. E.; Rogers, R. D. J. Org. Chem. 2000,
65, 9160.
glimpse of the ion-selective binding properties of 3 was gained
in this way.
Synthesis of a Bifacial Ligand. The synthesis of structurally
intricate ionophores having the capacity to engage in bifacial

4978 J. Am. Chem. Soc., Vol. 123, No. 21, 2001
Paquette and Tae
complexation has received little attention.19 The hexaspirocy-
clohexane 23 is unable to serve in this capacity as a direct
consequence of its inability to exist in the all-axial conformer.7h
The same powerful electrostatic effects operate in 24. This
substrate, which has been produced by the acid hydrolysis and
O-methylation of 3 and therefore originates as the all-axial
conformer (Scheme 3), rapidly undergoes essentially irreversible
Scheme 3
Figure 2. ORTEP diagram of 35.
availability22 from the known (p-methoxy)phenoxyacetonitrile.23
In a crucial first step, heating 25 with myo-inositol (5) in DMF
under acid catalysis for 24 h succeeded in delivering 26 in 95%
yield at the 57% conversion level. As in the parent series, triol
26 was amenable to chemoselective silylation of its equatorial
hydroxyl and mono-O-benzylation of the symmetric resulting
1,3-diol. This pair of steps allowed for exploration of the
possibility for oxidation to ketone 29 and “capping” of its
carbonyl group to generate the monospirotetrahydrofuran 30.
As observed earlier, the chloro diol 31 was formed alongside
30 from which it proved chromatographically separable. The
spectral features that distinguish 30 from 31 were recognized
to be distinctive and diagnostic. As part of a mini-program of
yield enhancement, 31 was transformed into 30 in 67% overall
yield via a sequence of four rapidly executed steps.
The route continued uneventfully through installation of the
second (as in 32) and third heterocyclic rings (see 33). Of course,
proper attention was paid to complexation of the dispiro ketone
intermediate with LiClO4 to guarantee proper stereoselection
in the final addition of the Normant reagent. With this necessary
step in place, the yield for the conversion of 32 to 33 was 78%
overall.
Deprotection of the PMP group with ceric ammonium nitrate
in aqueous acetonitrile proceeded to completion within 10 min
at 0 °C. With alcohol 34 in hand, the time had arrived to screen
the feasibility of its oxidation to the aldehyde. The use of the
Dess-Martin periodinane or tetra-n-propylammonium perru-
thenate proved not to be utilitarian. We soon realized that the
highly polar nature of 34 and the aldehyde precluded the use
of oxidants that require significant purification during the
ensuing workup. In the final analysis, Swern oxidation worked
best, although the level of efficiency was only modest. The
attendant consequences on homologation of the aldehyde to 35
proved not to be damaging. Direct reaction with dimethyl
1-diazo-2-oxopropylphosphonate24 and K2CO3 in methanol
resulted in relatively rapid conversion to the terminal alkyne.
A notable property of this substance is its limited solubility in
CH2Cl2, which permitted the acquisition of crystals well-suited
to X-ray crystallograpic analysis (Figure 2). The O(2)- - -O(2)
distance in 35 is 2.831 Å.
chair-to-chair interconversion to the nonpolar, highly crystalline
all-equatorial counterpart. Like all-trans hexamethoxycyclohex-
ane,20 24ax exhibits no binding capability to metal ions.
This being the case, there seemed to be an opportunity to
produce structurally unique homoditopic ligands by linking two
molecules of 3 via the methine carbon of its ortho ester subunit
as in C. In principle, this synthetic transformation might be most
conveniently met by implementation of a dimerization reaction.
One such possibility is the Glaser coupling reaction,21 wherein
diacetylenes are produced by the oxidative coupling of terminal
alkynes. Accordingly, the route originally developed to access
3 was modified to accommodate a higher level of substitution
(Scheme 4).10b
Since the p-methoxyphenyl (PMP) group held the promise
of being sufficiently robust to be carried through the synthesis,
the decision was made to begin with the ortho ester 25. The
particular choice of 25 was in keeping with its anticipated ready
(19) For background information, see: (a) Paquette, L. A.; Tae, J.;
Branan, B. M.; Bolin, D. G.; Eisenberg, S. W. E. J. Org. Chem. 2000, 65,
9172. (b) Rablen, P. R.; Paquette, L. A.; Borden, W. T. J. Org. Chem.
2000, 65, 9180.
(20) (a) Anderson, J. E. J. Chem. Soc., Perkin Trans. 2 1993, 441. (b)
Anderson, J. E.; Angyal, S. T.; Graig, D. C. Carbohydr. Res. 1995, 272,
141.
(21) (a) Glaser, C. Ber. 1869, 2, 422. (b) Glaser, C. Ann. 1870, 154,
159.
(22) Voss, G.; Gerlach, H. HelV. Chim. Acta 1983, 66, 2294.
(23) (a) Johnson, R. E.; Baizman, E. R.; Becker, C.; Bohnet, E. A.; Bell,
R. H.; Birsner, N. C.; Busacca, C. A.; Carabateas, P. M.; Chadwick, C. C.
J. Med. Chem. 1993, 36, 3361. (b) Ferrand, G.; Dumas, H.; Decerprit, J.
Eur. J. Med. Chem. 1992, 27, 309.

Ionophores with Capacity for Bifacial Complexation
J. Am. Chem. Soc., Vol. 123, No. 21, 2001 4979
Scheme 4
Scheme 5
Remarkably, submission of 35 to modified Glaser condi-
tions,25 consisting of the use of CuCl in TMEDA under an
atmosphere of dry air, resulted in quantitative formation of dimer
36. This product is a highly polar substance that does not melt
below 280 °C and is freely soluble in CH2Cl2. Slow evaporation
of such solutions results in the formation of colorless feather-
shaped crystals that turn cloudy on drying.
The Complexation of 36 with Lithium Ions. The association
constants for the binding of Li+-, Na+-, and K+ picrate to 36
(Table 1) expectedly reveal that the dimeric compound closely
parallels monomer 3 in its strong preference for coordinating
to the lithium ion.
Given the previously acknowledged capability of 20 to enter
readily into formation of a 2:1 complex with Li+, and in light
of the modestly stronger binding ability of 20 (Ka(Li+) ) 7.9
× 107) relative to 3 (Ka(Li+) ) 1.1 × 107) toward this guest
ion, we envisioned the possibility that admixing of 2 equiv of
37 with 36 might well eventuate in the formation of the bifacial
complex 38 (Scheme 5). When this experiment was conducted
in a 1:1 CH3CN-CH2Cl2 solvent system in which both reactants
were soluble, the immediate precipitation of a white powdery
solid was observed. Although this substance proved minimally
soluble in the most common solvents (CH3CN, CH2Cl2, CH3-
OH, H2O), it did dissolve in DMF and DMSO. Decantation of
the reaction solvent and concentration returned half of the
original amount of 37. No free 20 was detected in any of the
isolates.
The solid was characterized by electrospray ionization mass
spectrometry.26 The major peaks recorded from dilute CH3CN
solutions of the material were found at m/z ) 674.0 (100%
intensity, 36‚Li+), 925.9 (20%, 36‚Li+‚37), and 1339.8 (5%,
36‚Li+‚36). Although the targeted bifacially capped 38 was not
observed, the 2:1 sandwich complex 39 was found as the highest
molecular ion peak. When an analogous reaction was carried
out in 1:1 DMSO-CH2Cl2, a clear solution was formed.
However, only 37 was recovered following further processing.
(24) (a) Muller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett
1996, 521. (b) Gilbert, J. C.; Weerasooriya, U. J. Org. Chem. 1982, 47,
1837. (c) Delpech, B.; Lett, R. Tetrahedron Lett. 1989, 30, 1521. (d) Parry,
R. J.; Muscate, A.; Askonas, L. J. Biochemistry 1991, 30, 9988. (e) Hauske,
J. R.; Dorff, P.; Julin, S.; Martinelli, G.; Bussolari, J. Tetrahedron Lett.
1992, 33, 3715. (f) Nerenbrg, J. B.; Hung, D. T.; Somers, P. K.; Schreiber,
S. L. J. Am. Chem. Soc. 1993, 115, 12621.
(25) (a) Hamilton, D. G.; Prodi, L.; Feeder, N.; Sanders, J. K. M. J.
Chem. Soc., Perkin Trans. 1 1999, 1057. (b) Hay, A. S. J. Org. Chem.
1962, 27, 3320.
(26) Schalley, C. A.; Castellano, R. K.; Brody, M. S.; Rudkevich, D.
M.; Siuzdak, G.; Rebek, J., Jr. J. Am. Chem. Soc. 1999, 121, 4568 and
references therein.

4980 J. Am. Chem. Soc., Vol. 123, No. 21, 2001
Paquette and Tae
Scheme 6
Quite evidently, the proper complexation equilibria are not
established in the presence of DMSO.
Overview. The conformationally fixed trispiro ether 3 derived
from myo-inositol has proven to be a lithium ion-selective host
molecule. Its Ka(Li+)/Ka(Na+) selectivity ratio of 440 constitutes
a greater than 10-fold improvement relative to the more flexible
20, and qualifies it as a neutral, liphophilic, Li+-sensing
ionophore with potential application in ion-selective electrodes
having clinical utility. NMR titration experiments have dem-
onstrated that this host molecule prefers to form a 2:1 sandwich
complex with Li+ rather than enter into 1:1 coordination.
In a companion study, a synthesis of a highly preorganized
bifacial ionophore was successfully completed. The binding
properties of 36 are comparable to those of 3. Self-assembly of
36 with LiBF4 and LiClO4 gave rise to supramolecular structures
that take advantage of the 2:1 coordination preference to deliver
alkali metal complexes that are presumably rodlike in nature.
As discussed earlier, one of the goals of our program is to
achieve enhanced capacity for the determination of Li+ activities
in biological systems. To this end, we hope to report on the
preparation of congeners of 3 and 36, and to detail their binding
characteristics soon.
Treatment of 36 in CH3CN-CH2Cl2 with 1 equiv of lithium
perchlorate resulted in the rapid precipitation of a white solid
that was insoluble in the most polar solvents including DMF.
Alternate use of lithium tetrafluoroborate delivered in quantita-
tive yield a white powder that does not melt up to 280 °C but
is soluble in DMF and in DMSO. The material is not crystalline,
1
and its H NMR spectrum in DMSO-d6 is broad. Electrospray
mass spectral analysis of these samples in the positive ion mode
gave spectra consisting of broad humps of low intensity over
the m/z 2000-6000 range. The lack of resolution of individual
peaks indicates that the substances are polymers such as 40 of
much higher mass. Consequently, oligomeric rodlike networks
of type 4 with spacers constructed of 1,3-butadiyne segments
can be readily produced (Scheme 6).27
The polymerization process that leads to 40 could be
harnessed by making recourse instead to an internally chelated
lithium salt such as lithium picrate. Such co-reactants can
effectively deliver Li+ ions to the binding sites of 36 without
disruption of the preexisting coordination. A direct consequence
of this property is the efficient formation of the bifacially capped
complex 41. Admixture of a solution of 36 in CH2Cl2 with 2
equiv of Li+Pic- dissolved in CH3CN resulted in the deposition
of yellow crystals well-suited to X-ray crystallographic analysis.
These crystals were fragile and turned cloudy as they dried in
the air due to loss of solvent of crystallization.
Experimental Section
General. THF and ether were distilled from sodium benzophenone
ketyl under nitrogen just prior to use. For CH2Cl2 and benzene, the
drying agent was calcium hydride. All reactions were performed under
a N2 atmosphere. Analytical thin-layer chromatography was performed
on E. Merck silica gel 60 F254 aluminum-backed plates. All chromato-
graphic purifications were performed on E. Merck silica gel 60 (230-
400 mesh) using the indicated solvent systems. Melting points are
uncorrected. 1H and 13C NMR spectra were recorded on Bruker
instruments at 300 and 75 MHz, respectively, except where noted.
Elemental analyses were performed at Atlantic Microlab, Inc., Norcross,
Georgia. The organic extracts were dried over anhydrous MgSO4. The
high-resolution mass spectra were recorded at The Ohio State University
Campus Chemical Instrumentation Center.
(27) A reviewer has questioned why comparison of the formation of 40
with the reactivity of diacetylenes toward heat and light28 was not made.
While the prior work in the latter field is elegant and defining, the chemistry
comprises reactions at the sp-hybridized carbon atoms. The generation of
40 involves instead the coordination of Li+ to a bifacial ligand along a
chain in repetitive fashion. The acetylenic centers play no direct part in
this process and serve only to anchor the ligands together. This is not
diacetylene polymerization.
(1r,5r,6â,7r,8â,9r)-8-(Benzyloxy)-9-(tert-butyldimethylsiloxy)-
2,4,10-trioxaadamantan-6-ol (9). To sodium hydride (80%, 1.19 g,
39.6 mmol) in DMF (20 mL) was added the diol 811 (12.4 g, 40.9
mmol) dissolved in DMF (10 mL) followed by benzyl bromide (4.28
mL, 36.0 mmol) at 0 °C. After 30 min, the mixture was warmed to
room temperature, stirred for an additional 2 h, quenched with saturated
NH4Cl solution, and extracted with CH2Cl2 (3 × 50 mL). The combined
(28) (a) Wenz, G.; Wegner, G. Makromol. Chem., Rapid Commun. 1982,
3, 231. (b) Lieser, G.; Wegner, G.; Mueller, W.; Enkelmann, V. Makromol.
Chem., Rapid Commun. 1980, 1, 621. (c) Schermann, W.; Wegner, G.;
Williams, J. O.; Thomas, J. M. J. Polym. Sci., Polym. Phys. Ed. 1975, 13,
753. (d) Wegner, G. Makromol. Chem. 1971, 145, 85. (e) Haedicke, E.;
Mez, E. C.; Krauch, C. H.; Wegner, G.; Kaiser, J. Angew. Chem., Int. Ed.
Engl. 1971, 10, 266b. (f) Wegner, G. J. Polym. Sci., Part B: Polym. Phys.
1971, 9, 133.

Ionophores with Capacity for Bifacial Complexation
J. Am. Chem. Soc., Vol. 123, No. 21, 2001 4981
organic layers were dried and concentrated to leave a residue that was
purified by chromatography on silica gel (elution with 10-25% ethyl
acetate in hexanes) to afford 11.1 g (69%) of 9 as a colorless liquid,
along with the dibenzyl ether (3.40 g) and starting material (2.96 g);
Conversion of 12 into 11. A CH2Cl2 solution (20 mL) of 12 (1.00
g, 2.63 mmol), pyridine (0.94 mL, 11.6 mmol), acetic anhydride (0.55
mL, 5.8 mmol), and DMAP (20 mg) was stirred for 5 h at room
temperature. The reaction mixture was diluted with 1 N HCl solution
and extracted with CH2Cl2 (3 × 50 mL). The combined organic phases
were dried and concentrated in vacuo. The residue was purified by
chromatography on silica gel (elution with 10-25% ethyl acetate in
hexanes) to afford the acetate. A THF (10 mL) solution of this acetate
was treated with 1 N TBAF (5.80 mL, 5.80 mmol) for 2 h. The solvent
was evaporated, and the residue was purified chromatographically on
silica gel (elution with 50% ethyl acetate in hexanes containing 10%
MeOH) to afford the alcohol.
To a CH2Cl2 solution (20 mL) of this alcohol and imidazole (791
mg, 11.6 mmol) was added tert-butyldimethylchlorosilane (875 mg,
5.80 mmol) at 0 °C. The reaction mixture was warmed to room
temperature, stirred for 15 h, diluted with saturated NH4Cl solution,
and extracted with CH2Cl2 (3 × 50 mL). The combined organic phases
were dried and concentrated in vacuo to leave a residue that was purified
by chromatography on silica gel (elution with 10-25% ethyl acetate
in hexanes) to afford the product which was treated with LiAlH4 (500
mg, 13.2 mmol) in THF (20 mL) for 1 h at room temperature. The
reaction mixture was quenched with 1 N NaOH solution, filtered, and
concentrated in vacuo. The residue was purified by chromatography
on silica gel (elution with 10-25% ethyl acetate in hexanes) to afford
0.53 g (59%) of 11, identical in all respects to the material prepared
above.
tert-Butyldimethyl[[(1′r,5′r,6′â,7′r,8′â,9′r)-tetrahydrodispiro[fu-
ran-2(3H),6′-[2,4,10]trioxaadamantane-8′,2′′(3′′H)-furan]-9′-yl]oxy]-
silane (13). To a cooled (0 °C) CH2Cl2 solution (100 mL) of 11 (3.29
g, 9.55 mmol) was added the Dess-Martin periodinane reagent (8.10
g, 19.1 mmol). After being warmed to room temperature for 15 h, the
reaction mixture was filtered through a short silica gel plug and
concentrated. The residue was purified by chromatography on silica
gel (elution with 50% ethyl acetate in hexanes) to afford 3.30 g of the
ketone as a white solid.
To a cooled (0 °C) solution of the above ketone in THF (100 mL)
was added 0.26 N Normant reagent (75 mL, 19.5 mmol). The reaction
mixture was warmed to room temperature for 2 h, quenched with
saturated NH4Cl solution, and filtered. The filtrate was concentrated,
and the residue was purified by chromatography on silica gel (elution
with 50% ethyl acetate in hexanes) to afford the diol as a colorless
liquid.
1
IR (film, cm-1) 3502, 1472, 1398, 1259, 1166; H NMR (300 MHz,
CDCl3) δ 7.45-7.25 (m, 5 H), 5.47 (s, 1 H), 4.66 (s, 2 H), 4.48-4.35
(m, 2 H), 4.30-4.20 (m, 2 H), 4.15-4.10 (m, 2 H), 3.62 (d, J ) 10.0
Hz, 1 H), 0.95 (s, 9 H), 0.15 (s, 6 H); 13C NMR (75 MHz, CDCl3) δ
136.0, 128.8, 128.7, 128.0, 102.5, 74.9, 73.1, 72.5, 68.3, 67.5, 60.9,
25.9, 18.3, -4.6, -4.7; HRMS m/z (M+ - t-Bu) calcd 337.1107, obsd
337.1103.
Anal. Calcd for C20H30O6Si: C, 60.89; H, 7.15. Found: C, 61.07;
H, 7.57.
(1r,5r,7r,8â,9r)-8-(Benzyloxy)-9-(tert-butyldimethylsiloxy)-2,4,-
10-trioxaadamantan-6-one (10). To a cooled (0 °C) CH2Cl2 solution
(150 mL) of 9 (6.68 g, 16.9 mmol) was added the Dess-Martin
periodinane reagent (10.8 g, 25.4 mmol). After 15 h at room
temperature, the stirred reaction mixture was filtered through a short
silica gel plug and concentrated. The residue was purified by chroma-
tography on silica gel (elution with 25% ethyl acetate in hexanes) to
afford 5.70 g (86%) of 10 as a white solid, mp 62-64 °C (from 5%
CH2Cl2 in hexanes); IR (film, cm-1) 1733, 1472, 1362, 1254, 1164;
1H NMR (300 MHz, CDCl3) δ 7.45-7.25 (m, 5 H), 5.64 (s, 1 H), 4.65
(d, J ) 11.9 Hz, 1 H), 4.51 (d, J ) 11.9 Hz, 1 H), 4.45-4.00 (series
of m, 5 H), 0.94 (s, 9 H), 0.14 (s, 6 H); 13C NMR (75 MHz, CDCl3)
δ 199.7, 136.5, 128.7, 128.4, 127.8, 102.9, 82.0, 76.7, 72.8, 71.8, 70.8,
66.0, 25.7, 18.2, -4.7, -4.8; HRMS m/z (M+ - t-Bu) calcd 335.0951,
obsd 335.0958.
(1′r,5′r,6′â,7′r,8′â,9′r)-9′-(tert-Butyldimethylsiloxy)dihydrospiro-
[furan-2(3H),6′-[2,4,10]trioxaadamantan]-8′-ol (11). To a cooled (0
°C) solution of 10 (2.36 g, 6.01 mmol) in THF (50 mL) was added
0.26 N Normant reagent13 (35 mL, 9.02 mmol). The reaction mixture
was warmed to room temperature for 2 h, quenched with saturated NH4-
Cl solution, and filtered. The filtrate was concentrated, and the residue
was purified by chromatography on silica gel (elution with 25% ethyl
acetate in hexanes) to afford the diol as a colorless liquid.
This diol was dissolved in CH2Cl2 (20 mL), treated with p-
toluenesulfonyl chloride (2.29 g, 12.0 mmol), triethylamine (3.35 mL,
24.1 mmol) and DMAP (50 mg), stirred at room temperature for 15 h,
and refluxed for 3 d. The reaction mixture was washed with water,
and the aqueous layer was extracted with CH2Cl2 (2 × 20 mL). The
combined organic phases were dried and concentrated in vacuo. The
residue was purified by chromatography on silica gel (elution with 10-
25% ethyl acetate in hexanes) to afford 2.34 g (90%) of the spiro ether
11 and its HCl complex 12 (ratio 1.9:1) as a colorless oil.
The above material (3.50 g, 8.05 mmol) and 10% palladium on
carbon (500 mg) in ethyl acetate (20 mL) was hydrogenolyzed under
40-50 psi of hydrogen for 8 h. The reaction mixture was filtered
through Celite and concentrated in vacuo. The residue was purified by
chromatography on silica gel (elution with 10-25% ethyl acetate in
hexanes) to furnish 1.63 g (59%) of 11 and 0.96 g (31%) of 12, both
as white solids.
This diol in CH2Cl2 (50 mL) was treated with p-toluenesulfonyl
chloride (3.67 g, 19.3 mmol), triethylamine (5.37 mL, 38.5 mmol),
and DMAP (50 mg) at room temperature for 15 h and refluxed for 3
d. The reaction mixture was washed with water, and the aqueous layer
was extracted with CH2Cl2 (2 × 50 mL). The combined organic
solutions were dried and concentrated in vacuo. The residue was purified
by chromatography on silica gel (elution with 5-25% ethyl acetate in
hexanes) to afford 3.20 g (84%) of the separable product mixture 13
and 14 (1.1:1).
For 13: mp 163-165 °C (from 5% CH2Cl2 in hexanes); IR (film,
cm-1) 1462, 1249, 1157, 1079; 1H NMR (300 MHz, CDCl3) δ 5.45 (s,
1 H), 4.30 (m, 1 H), 4.00-3.85 (m, 4 H), 3.62 (m, 2 H), 3.46 (m, 1
H), 2.45-2.30 (m, 2 H), 2.25-2.10 (m, 2 H), 1.95-1.85 (m, 4 H),
0.91 (s, 9 H), 0.11 (s, 6 H); 13C NMR (75 MHz, CDCl3) δ 103.0, 80.7,
For 11: mp 133-135 °C (from 5% CH2Cl2 in hexanes); IR (film,
1
cm-1) 3459, 1463, 1461, 1257, 1164; H NMR (300 MHz, CDCl3) δ
5.45 (s, 1 H), 4.45-4.35 (m, 1 H), 4.20 (m, 1 H), 4.10-4.00 (m, 2 H),
3.94 (t, J ) 6.7 Hz, 2 H), 3.82 (m, 1 H), 3.67 (m, 1 H), 2.29 (t, J )
7.4 Hz, 2 H), 1.96 (m, 2 H), 0.92 (s, 9 H), 0.12 (s, 6 H); 13C NMR (75
MHz, CDCl3) δ 102.5, 81.7, 76.8, 74.5, 71.7, 70.0, 68.3, 62.1, 34.7,
25.9, 24.6, 18.3, -4.70, -4.73; HRMS m/z (M+ - t-Bu) calcd
287.0951, obsd 287.0932.
77.5, 76.1, 69.6, 63.8, 34.9, 25.9, 24.4, 18.3, -4.7; HRMS m/z (M+
t-Bu) calcd 327.1264, obsd 327.1279.
-
Anal. Calcd for C19H32O6Si‚0.5CH2Cl2: C, 54.85; H, 7.79. Found:
C, 54.55; H, 7.84.
For 14: colorless oil; IR (film, cm-1) 1463, 1416, 1361, 1255, 1163;
1H NMR (300 MHz, CDCl3) δ 5.43 (s, 1 H), 4.71 (s, 1 H), 4.25 (m, 1
H), 3.97 (t, J ) 6.7 Hz, 2 H), 3.73 (m, 1 H), 3.65 (m, 1 H), 3.57(m, 1
H), 3.51 (m, 1 H), 2.45-2.25 (m, 2 H), 2.20-1.90 (m, 6 H), 0.93 (s,
9 H), 0.13 (s, 6 H); 13C NMR (75 MHz, CDCl3) δ 102.6, 81.7, 77.0,
76.3, 74.0, 71.1, 70.2, 62.9, 45.3, 34.8, 32.9, 25.9, 24.6, 18.4, -4.62,
-4.67; HRMS m/z (M+ - t-Bu‚HCl) calcd 327.1264, obsd 327.1279.
Anal. Calcd for C19H33ClO6Si: C, 54.21; H, 7.66. Found: C, 54.67;
H, 7.85.
For 12: mp 133-135 °C (from 5% CH2Cl2 in hexanes); IR (film,
1
cm-1) 3331, 1470, 1415, 1245, 1162; H NMR (300 MHz, CDCl3) δ
5.44 (s, 1 H), 4.57 (s, 1 H), 4.30 (m, 1 H), 4.15-4.05 (m, 2 H), 3.93
(m, 1 H), 3.76 (m, 1 H), 3.59 (t, J ) 6.3 Hz, 2 H), 2.25-2.05 (m, 1
H), 2.05-1.85 (m, 3 H), 0.93 (s, 9 H), 0.14 (s, 6 H); 13C NMR (75
MHz, CDCl3) δ 102.1, 77.0, 73.9, 71.8, 70.5, 67.9, 61.5, 44.9, 33.0,
25.7, 25.2, 18.2, -4.91, -4.95; HRMS m/z (M+- t-Bu•HCl) calcd
287.0951, obsd 287.0924; FAB-MS m/z (M+ + 1) calcd 381.15, obsd
381.00.
Anal. Calcd for C16H28O6Si‚HCl: C, 50.44; H, 7.41. Found: C,
50.28; H, 7.48.
(1′r,5′r,6′â,7′r,8′â,9′r)-Tetrahydrodispiro[furan-2(3H),6′-[2,4,-
10]trioxaadamantane-8′,2′′(3′′H)-furan]-9′-ol (15). A. From 13. A

4982 J. Am. Chem. Soc., Vol. 123, No. 21, 2001
Paquette and Tae
THF solution (20 mL) of 13 (1.44 g, 3.74 mmol) was treated with 1 N
TBAF (7.49 mL, 7.49 mmol) for 15 h. The solvent was concentrated,
and the residue was purified by chromatography on silica gel (elution
with 50% ethyl acetate in hexanes containing 10% MeOH) to afford
1.01 g (100%) of 15 as a white solid, mp 192-194 °C (from 5% CH2-
tography on silica gel (elution with 20-50% ethyl acetate in hexanes)
to afford 262 mg of the monotosylate as a white solid.
To a benzene (10 mL) solution of the monotosylate was added 0.5
N potassium hexamethyldisilazide (2.2 mL, 1.1 mmol) at 0 °C. After
30 min, the reaction mixture was warmed to room temperature, stirred
for 15 h, quenched with deionized H2O (10 mL), and extracted with
CH2Cl2 (3 × 20 mL). The combined organic phases were washed with
deionized H2O (10 mL) and concentrated in vacuo without drying to
give 144 mg (73% for 3 steps) of 3 as a white solid, mp >280 °C
(from 10% CH2Cl2 in hexanes); IR (film, cm-1) 1440, 1350, 1250,
1125; 1H NMR (300 MHz, CDCl3) δ 5.37 (s, 1 H), 3.95 (t, J ) 6.8
Hz, 6 H), 3.51 (s, 3 H), 2.26 (t, J ) 7.3 Hz, 6 H), 1.91-1.80 (m, 6 H);
13C NMR (75 MHz, CDCl3) δ 102.4, 80.0, 75.9, 69.4, 36.3, 23.9; HRMS
m/z (M+) calcd 310.1416, obsd 310.1427.
1
Cl2 in hexanes); IR (film, cm-1) 3550, 1455, 1246, 1140; H NMR
(300 MHz, CDCl3) δ 5.41 (s, 1 H), 4.17-4.10 (m, 1 H), 4.05-3.85
(m, 4 H), 3.73 (m, 2 H), 3.50 (m, 1 H), 3.20 (d, J ) 11.8 Hz, 1 H),
2.45-2.30 (m, 2 H), 2.25-2.10 (m, 2 H), 2.00-1.85 (m, 4 H); 13C
NMR (75 MHz, CDCl3) δ 103.1, 80.2, 77.4, 75.8, 69.6, 63.5, 34.9,
24.4; HRMS m/z (M+ + 1) calcd 271.1181, obsd 271.1180.
Anal. Calcd for C13H18O6‚0.6CH2Cl2: C, 50.85; H, 6.02. Found: C,
50.98; H, 6.22.
B. From 14. A THF solution (10 mL) of 14 (1.00 g, 2.38 mmol)
was treated with 1 N TBAF (5.20 mL, 5.20 mmol) for 2 h. The solvent
was evaporated, and the residue was purified by chromatography on
silica gel (elution with 50% ethyl acetate in hexanes containing 10%
MeOH) to afford 527 mg (82%) of 15, which proved spectroscopically
identical to the compound isolated in part A.
Anal. Calcd for C12H22O6: C, 61.92; H, 7.14. Found: C, 61.68; H,
7.06.
(1r,5r,6â,7r,8â,9â)-6,8,9-Trimethoxy-2,4,10-trioxaada-
mantane (19). Alcohol 1811 (5.26 g, 14.2 mmol) was treated with 80%
sodium hydride (852 mg, 28.4 mmol) and an excess of methyl iodide
(1.77 mL) in THF (50 mL) for 15 h at room temperature. The reaction
mixture was quenched with water and extracted with CH2Cl2 (3 × 50
mL). The combined organic layers were dried and concentrated. The
residue was purified by chromatography on silica gel (elution with 25%
ethyl acetate in hexanes) to afford the monomethyl ether.
The above unpurified product in EtOH (20 mL) was hydrogenolyzed
over 10% palladium on carbon (1.00 g) under 1 atm of hydrogen for
15 h. The reaction mixture was filtered through Celite and concentrated
in vacuo. The residue was used directly in the next step.
(1′r,5′r,6′â,7′r,8′â)-Tetrahydrodispiro[furan-2(3H),6′-[2,4,10]tri-
oxaadamantane-8′,2′′(3′′H)-furan]-9′-one (16). To a cooled (-78 °C)
CH2Cl2 solution (50 mL) of oxalyl chloride (0.86 mL, 9.86 mmol) were
added DMSO (1.11 mL, 15.6 mmol) in CH2Cl2 (5 mL) and 15 (1.01
g, 3.74 mmol) dissolved in CH2Cl2 (15 mL) within 5 min. The mixture
was stirred for 2 h at -78 °C, treated with triethylamine (2.72 mL,
19.5 mmol), and warmed to room temperature for 1 h before being
washed with water and extracted with CH2Cl2 (2 × 50 mL). The
combined organic phases were dried and concentrated in vacuo to leave
a residue that was purified by chromatography on silica gel (elution
with 50% ethyl acetate in hexanes containing 5% MeOH). There was
isolated 974 mg (97%) of 16 as a white solid, mp 244-246 °C (from
The diol was treated with 80% sodium hydride (1.70 g, 56.8 mmol)
and an excess of methyl iodide (4.0 mL) in THF (50 mL) for 2 h at
room temperature. The reaction solution was quenched with water and
extracted with CH2Cl2 (3 × 50 mL). The combined organic phases
were dried and evaporated. The residue was purified by chromatography
on silica gel (elution with 50% ethyl acetate in hexanes) to afford 2.51
g (76% over 3 steps) of 19 as a colorless crystalline solid, mp 177-
179 °C (from 5% CH2Cl2 in hexanes); IR (film, cm-1) 1452, 1224,
1
5% CH2Cl2 in hexanes); IR (film, cm-1) 1767, 1462, 1378, 1267; H
NMR (300 MHz, CDCl3) δ 5.61 (s, 1 H), 4.05-3.90 (m, 6 H), 3.70
(m, 1 H), 2.55-2.40 (m, 2 H), 2.30-2.15 (m, 2 H), 2.05-1.85 (m, 4
H); 13C NMR (75 MHz, CDCl3) δ 200.2, 102.5, 82.9, 80.1, 78.4, 70.0,
34.9, 24.3; HRMS m/z (M+) calcd 268.0947, obsd 268.0924.
1
1192, 1147; H NMR (300 MHz, CDCl3) δ 5.47 (s, 1 H), 4.45 (m, 3
(1r,5r,6r,7r,8â,9â)-Hexahydrotrispiro[2,4,10-trioxaadamantane-
6,2′(3′H);8,2′′(3′′H);9,2′′′(3′′′H)-trisfuran] (17). To a cooled (-78 °C)
solution of 16 (112 mg, 0.418 mmol) in THF (10 mL) was added 0.26
N Normant reagent (3.2 mL, 0.83 mmol). The reaction mixture was
warmed to room temperature for 2 h, quenched with saturated NH4Cl
solution, and filtered. The filtrate was concentrated, and the residue
was purified by chromatography on silica gel (elution with 25% ethyl
acetate in hexanes) to afford the diol (∼10:1) as a colorless liquid.
H), 4.03 (m, 3 H), 3.44 (s, 9 H); 13C NMR (75 MHz, CDCl3) δ 102.9,
75.0, 67.7, 58.2; HRMS m/z (M+) calcd 232.0947, obsd 232.0936.
Anal. Calcd for C10H16O6: C, 51.72; H, 6.94. Found: C, 51.97; H,
6.93.
(5r,6â,7r,12â,13r,18â)-6,12,18-Trimethoxy-1,8,14-trioxatrispiro-
[4.1.4.1. 4.1]octadecane (24). A solution of 3 (200 mg, 0.644 mmol)
in 25 mL of 1:2 HCl-MeOH was refluxed for 30 min and evaporated
to give the triol, which was treated with 80% sodium hydride (200
mg, 6.67 mmol) and an excess of methyl iodide (1.5 mL) in DMF for
1 h at room temperature. The reaction mixture was quenched with water
at 0 °C and extracted with CH2Cl2 (3 × 50 mL). The combined organic
phases were dried and concentrated in vacuo. The residue was purified
by chromatography on silica gel (elution with 20% ethyl acetate in
hexanes) to afford 195 mg (88%) of 24 as a colorless crystalline solid,
mp 130-132 °C (from 5% CH2Cl2 in hexanes); IR (film, cm-1) 1445,
1375, 1250, 1170; 1H NMR (300 MHz, CDCl3) δ 3.80 (t, J ) 6.5 Hz,
6 H), 3.54 (s, 9 H), 3.31 (s, 3 H), 2.00-1.90 (m, 6 H), 1.90-1.80 (m,
6 H); 13C NMR (75 MHz, CDCl3) δ 89.0, 88.1, 67.5, 62.0, 29.0, 24.4;
HRMS m/z (M+) calcd 342.2042, obsd 342.2047.
This diol in CH2Cl2 (10 mL) was treated with p-toluenesulfonyl
chloride (159 mg, 0.834 mmol), triethylamine (0.23 mL, 1.6 mmol),
and DMAP (10 mg) at room temperature for 15 h and refluxed for 1
d. The reaction mixture was concentrated in vacuo, and the residue
was purified by chromatography on silica gel (elution with 50% ethyl
acetate in hexanes) to afford 58 mg (45%) of 17 as a colorless oil; IR
(film, cm-1) 1434, 1372, 1280, 1157; 1H NMR (300 MHz, CDCl3) δ
5.36 (s, 1 H), 4.05-3.85 (m, 4 H), 3.75-3.60 (m, 4 H), 3.55 (m, 1 H),
2.45-2.25 (m, 2 H), 2.25-2.15 (m, 2 H), 2.10-2.00(m, 2 H), 2.00-
1.85 (m, 4 H), 1.80-1.70 (m, 2 H); 13C NMR (75 MHz, CDCl3) δ
102.1, 80.8, 76.6, 74.4, 71.0, 69.2, 63.2, 35.9, 33.3, 25.8, 23.9; HRMS
m/z (M+) calcd 310.1416, obsd 310.1430.
Anal. Calcd for C18H30O6: C, 63.14; H, 8.83. Found: C, 62.99; H,
8.75.
(1r,5r,6â7r,8â,9â)-Hexahydrotrispiro[2,4,10-trioxaadamantane-
6,2′(3′H);8,2′′(3′′H);9,2′′′(3′′′H)-trisfuran] (3). To a cooled (-78 °C)
solution of 16 (170 mg, 0.634 mmol), which was precomplexed with
LiClO4 (337 mg, 3.17 mmol) in THF (10 mL) for 2 h at room
temperature, was added 0.26 N Normant reagent (7.3 mL, 1.90 mmol).
The reaction mixture was warmed to room temperature for 15 h,
quenched with saturated NH4Cl solution, and filtered. The filtrate was
concentrated, and the residue was purified by chromatography on silica
gel (elution with 50% ethyl acetate in hexanes containing 5% MeOH)
to afford the diol.
(1r,5r,6r7r,8â,9â)-3-[(p-Methoxyphenoxy)methyl]-2,4,10-triox-
aadamantane-6,8,9-triol (26). Into an ethanol solution (22 mL, 0.38
mmol) of (p-methoxy)phenoxyacetonitrile23 (62 g, 0.38 mmol) was
bubbled dry hydrogen chloride for 1 h with mechanical stirring to give
a yellowish solid that was stored for 1 d at 0 °C. The resulting imidate
was dried in vacuo for 2 h, taken up in 500 mL of 1:1 EtOH-Et2O,
and refluxed for 2 d. The solid residue was separated by filtration, and
the filtrate was evaporated in vacuo. The residue taken up in 500 mL
of 20% EtOAc-hexanes, and the resulting solid was filtered. The filtrate
was concentrated in vacuo to give ortho ester 25, which was used
without further purification.
This diol in CH2Cl2 (10 mL) was treated with p-toluenesulfonyl
chloride (255 mg, 1.34 mmol), triethylamine (0.37 mL, 2.7 mmol),
and DMAP (10 mg) at room temperature for 15 h. The reaction mixture
was concentrated in vacuo, and the residue was purified by chroma-
The crude ortho ester 25, myo-inositol (30 g, 166.6 mmol) and
p-toluenesulfonyl chloride (3 g) in DMF (250 mL) were heated at 100

Ionophores with Capacity for Bifacial Complexation
J. Am. Chem. Soc., Vol. 123, No. 21, 2001 4983
°C for 24 h. After cooling, 3 g of NaHCO3 was added, and the unreacted
inositol (12 g) was separated by filtration. Next, the DMF was
evaporated in vacuo to give a gummy solid, which was triturated with
CH2Cl2 and filtered to give 26 as a white solid. The filtrate was
concentrated and purified by chromatography on silica gel (elution with
30% i-PrOH in hexanes) to afford additional 26 (combined 31 g, 57%,
95% based on recovered 5), mp 179-181 °C (from 50% MeOH in
CH2Cl2); IR (film, cm-1) 3210, 1495, 1430, 1215; 1H NMR (300 MHz,
DMSO-d6) δ 6.95-6.75 (m, 4 H), 5.47 (d, J ) 6.2 Hz, 2 H), 5.26 (d,
J ) 6.2 Hz, 1 H), 4.32 (s, 2 H), 4.20-4.00 (m, 4 H), 3.84 (s, 2 H),
3.68 (s, 3 H); 13C NMR (75 MHz, DMSO-d6) δ153.8, 152.5, 116.1,
114.7, 106.4, 75.3, 70.1, 69.7, 67.3, 58.2, 55.5; HRMS m/z (M+) calcd
326.1001, obsd 326.1016.
This diol in CH2Cl2 (100 mL) was treated with p-toluenesulfonyl
chloride (5.05 g, 26.5 mmol), triethylamine (7.38 mL, 52.9 mmol),
and DMAP (50 mg) at room temperature for 15 h and refluxed for 2
d. The reaction mixture was washed with water, and the aqueous layer
was extracted with CH2Cl2 (50 mL × 2). The combined organic phases
were dried and concentrated in vacuo. The residue was purified by
chromatography on silica gel (elution with 10-25% ethyl acetate in
hexanes) to afford the monospiro ether and its HCl complex product
as a colorless oil.
The above products and 10% palladium on carbon (500 mg) in ethyl
acetate (20 mL) were hydrogenolyzed under 40-50 psi of hydrogen
pressure for 15 h. The reaction mixture was filtered through Celite
and concentrated in vacuo. The residue was purified by chromatography
on silica gel (elution with 10% to 25% ethyl acetate in hexanes) to
elute 3.56 g (55%) of 30 and 31 (ratio 1.9:1) as colorless oils.
Anal. Calcd for C15H18O8: C, 55.21; H, 5.56. Found: C, 55.13; H,
5.64.
1
(1r,5r,6â,7r,8â,9r)-9-(tert-Butyldimethylsiloxy)-3-[(p-methox-
yphenoxy)methyl]-2,4,10-trioxaadamantane-6,8-diol (27). To a DMF
solution (50 mL) of 26 (17.7 g, 54.2 mmol) and imidazole (4.43 g,
65.1 mmol) was added tert-butyldimethylchlorosilane (8.18 g, 54.2
mmol) at 0 °C. The reaction mixture was warmed to room temperature,
stirred for 15 h, diluted with saturated NH4Cl solution, and extracted
with CH2Cl2 (3 × 50 mL). The combined organic phases were dried
and concentrated in vacuo. The solid product was filtered, and the oily
filtrate was purified by chromatography on silica gel (elution with 20-
50% ethyl acetate in hexanes) to afford a combined 12.3 g of 27 as a
white solid (55%, 82% based on recovered 26), the bissilylated product
(4.66 g), and 26 (5.82 g).
For 27: mp 115-117 °C (from 10% CH2Cl2 in hexanes); IR (film,
cm-1) 3420, 1495, 1425, 1215; 1H NMR (300 MHz, CDCl3) δ 6.95-
6.75 (m, 4 H), 4.55 (m, 2 H), 4.30-4.20 (m, 4 H), 3.95 (s, 2 H), 3.91
(d, J ) 7.6 Hz, 2 H), 3.75 (s, 3 H), 0.94 (s, 9 H), 0.14 (s, 6 H); 13C
NMR (75 MHz, CDCl3) δ 154.4, 152.7, 116.4, 114.5, 106.6, 75.5, 70.8,
69.1, 68.2, 59.9, 55.7, 25.8, 18.3, -4.6; HRMS m/z (M+) calcd
440.1866, obsd 440.1831.
For 30: IR (film, cm-1) 3455, 1435, 1210; H NMR (300 MHz,
CDCl3) δ 6.95-6.75 (m, 4 H), 4.44 (m, 1 H), 4.20 (s, 2 H), 4.10-3.90
(series of m, 6 H), 3.80-3.75 (m, 1 H), 3.74(s, 3 H), 2.40-2.30 (m, 2
H), 2.10-1.90 (m, 2 H), 0.94 (s, 9 H), 0.132 (s, 3 H), 0.127 (s, 3 H);
13C NMR (75 MHz, CDCl3) δ 154.2, 152.9, 116.2, 114.4, 106.8, 81.5,
77.7, 75.3, 72.2, 70.6, 70.1, 68.1, 61.4, 55.6, 34.7, 25.8, 24.6, 18.3,
-4.60, -4.63; HRMS m/z (M+) calcd 480.2215, obsd 480.2166.
Anal. Calcd for C24H36O8Si: C, 59.98; H, 7.55. Found: C, 59.87;
H, 7.55.
1
For 31: IR (film, cm-1) 3400, 1420, 1210; H NMR (300 MHz,
CDCl3) δ 6.95-6.75 (m, 4 H), 4.64 (s, 1 H), 4.29 (s, 1 H), 4.19 (m, 1
H), 4.15-3.85(seires of m, 5 H), 3.75(s, 3 H), 3.59 (t, J ) 6.3 Hz, 2
H), 2.25-1.90 (m, 4 H), 0.94 (s, 9 H), 0.13 (s, 6 H); 13C NMR (75
MHz, CDCl3) δ 154.2, 152.7, 116.3, 114.5, 106.6, 78.0, 74.9, 71.9,
71.3, 70.5, 68.0, 60.9, 55.7, 45.2, 33.2, 25.8, 25.5, 18.3, -4.59, -4.62;
HRMS m/z (M+ - HCl) calcd 480.2215, obsd 480.2167; FAB MS
m/z (M+ + 1) calcd 517.20, obsd 517.08.
Conversion of 31 into 30. A CH2Cl2 solution (40 mL) of 31 (3.21
g, 6,21 mmol), pyridine (2.22 mL, 27,4 mmol), acetic anhydride (1.30
mL, 13.7 mmol), and DMAP (20 mg) was stirred for 5 h at room
temperature. The reaction mixture was diluted with 1 N HCl solution
and extracted with CH2Cl2 (3 × 50 mL). The combined organic phases
were dried and concentrated in vacuo to leave a residue that was purified
by chromatography on silica gel (elution with 10-25% ethyl acetate
in hexanes) to afford the acetate. A THF solution (20 mL) of this acetate
was treated with 1 N TBAF (13.7 mL, 13.7 mmol) for 2 h. The solvent
was evaporated and the residue was purified chromatographically on
silica gel (elution with 50% ethyl acetate in hexanes containing 10%
MeOH) to afford the alcohol.
To a CH2Cl2 solution (40 mL) of this alcohol and imidazole (1.87
g, 27.4 mmol) was added tert-butyldimethylchlorosilane (2.07 g, 13.7
mmol) at 0 °C. The reaction mixture was warmed to room temperature,
stirred for 15 h, diluted with saturated NH4Cl solution, and extracted
with CH2Cl2 (3 × 50 mL). The combined organic phases were dried
and concentrated in vacuo. The residue was purified by chromatography
on silica gel (elution with 10-25% ethyl acetate in hexanes) to afford
the product, which was treated with LiAlH4 (1.18 g, 31.2 mmol) in
THF (40 mL) for 1 h at room temperature. The reaction mixture was
quenched with 1 N NaOH solution, filtered and concentrated in vacuo.
The residue was purified by chromatography on silica gel (elution with
10-25% ethyl acetate in hexanes) to give 30 (2.00 g, 67%).
(1′r,5′r,6′â,7′r,8′â,9′r)-Tetrahydro-3′-[(p-methoxyphenoxy)m-
ethyl] dispiro[furan-2(3H),6′-[2,4,10]trioxaadamantane-8′,2′′(3′′H)-
furan]-9′-ol (32). To a cooled (0 °C) CH2Cl2 solution (50 mL) of 30
(1.76 g, 3.66 mmol) was added the Dess-Martin periodinane reagent
(2.33 g, 5.49 mmol). After being warmed to room temperature for 2 h,
the reaction mixture was filtered on a short silica gel plug and
concentrated. The residue was purified by chromatography on silica
gel (elution with 50% ethyl acetate in hexanes) to afford the ketone as
a colorless oil.
Anal. Calcd for C21H32O8Si: C, 57.25; H, 7.32. Found: C, 57.34;
H, 7.27.
(1r,5r,7r,8â,9r)-8-(Benzyloxy)-9-(tert-butyldimethylsiloxy)-3-[(p-
methoxyphenoxy)methyl]-2,4,10-trioxaadamantan-6-one (29). To a
sodium hydride (80%, 484 mg, 16.1 mmol) in DMF (10 mL) was added
27 (6.46 g, 14.7 mmol) in DMF (10 mL) followed by benzyl bromide
(1.74 mL, 14.7 mmol) at 0 °C. After 30 min, the reaction mixture was
warmed to room temperature, stirred for additional 2 h, quenched with
saturated NH4Cl solution, and extracted with CH2Cl2 (3 × 50 mL).
The combined organic phases were dried and concentrated in vacuo.
The residue was purified by chromatography on silica gel (elution with
10-25% ethyl acetate in hexanes) to afford the monobenzyl ether 28
(4.32 g, 56%, 86% based on recovered 27) as a colorless liquid
alongside the dibenzyl ether (2.87 g) and unreacted 27 (2.30 g).
To a cooled (0 °C) CH2Cl2 solution (75 mL) of 28 (4.32 g, 8.14
mmol) was added the Dess-Martin periodinane reagent (5.18 g, 12.2
mmol). After being warmed to room temperature for 15 h, the reaction
mixture was filtered through a short silica gel plug and concentrated.
The residue was purified by chromatography on silica gel (elution with
25% ethyl acetate in hexanes) to afford 29 as colorless oil (3.74 g,
1
87%); IR (film, cm-1) 1750, 1490, 1440, 1210; H NMR (300 MHz,
CDCl3) δ 7.40-7.25 (m, 5 H), 6.95-6.75 (m, 4 H), 4.66 (d, J ) 11.9
Hz, 1 H), 4.51 (d, J ) 11.9 Hz, 1 H), 4.50-4.25 (series of m, 4 H),
4.10-3.95 (m, 1 H), 4.04 (s, 2 H), 3.75 (s, 3 H), 0.94 (s, 9 H), 0.129
(s, 3 H), 0.122 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 199.8, 154.4,
152.7, 136.5, 128.7, 128.4, 127.9, 116.3, 114.5, 107.7, 82.4, 77.5, 73.7,
71.9, 70.5, 70.2, 65.5, 55.6, 25.7, 18.1, -4.69, -4.78; HRMS m/z (M+)
calcd 528.2179, obsd 528.2191.
(1′r,5′r,6′â,7′r,8′â,9′r)-9′-(tert-Butyldimethylsiloxy)dihydro-3′-
[(p-methoxyphenoxy)methyl]spiro[furan-2(3H),6′-[2,4,10]trioxaada-
mantan]-8′-ol (30). To a cooled (0 °C) solution of 29 (7.00 g, 13.2
mmol) in THF (100 mL) was added 0.26 N Normant reagent (76 mL,
19.9 mmol). The reaction mixture was warmed to room temperature
for 2 h, quenched with saturated NH4Cl solution, and filtered. The
filtrate was concentrated, and the residue was purified by chromatog-
raphy on silica gel (elution with 25% ethyl acetate in hexanes) to afford
the diol as a colorless liquid.
To a cooled (0 °C) solution of the ketone in THF (30 mL) was added
0.26 N Normant reagent (29.0 mL, 7.54 mmol). The reaction mixture
was warmed to room temperature for 2 h, quenched with saturatd NH4-
Cl solution, and filtered. The filtrate was concentrated, and the residue
was purified by chromatography on silica gel (elution with 50% ethyl
acetate in hexanes) to afford the diol as a colorless liquid.

4984 J. Am. Chem. Soc., Vol. 123, No. 21, 2001
Paquette and Tae
This diol in CH2Cl2 (50 mL) was treated with p-toluenesulfonyl
chloride (1.40 g, 7.34 mmol), triethylamine (2.04 mL, 14.6 mmol),
and DMAP (50 mg) at room temperature for 15 h and refluxed for 2
d. The reaction mixture was washed with water, and the aqueous layer
was extracted with CH2Cl2 (2 × 50 mL). The combined organic phases
were dried and concentrated in vacuo. The residue was purified by
chromatography on silica gel (elution with 5-25% ethyl acetate in
hexanes) to afford the product as a colorless oil.
with CH2Cl2 (3 × 20 mL), and the combined organic phases were dried
over K2CO3 and concentrated in vacuo.
This residue was dissolved with K2CO3 (344 mg, 2.49 mmol) in
methanol (15 mL) and treated with dimethyl 1-diazo-2-oxypropylphos-
phonate24 (286 mg, 1.49 mmol) for 6 h at room temperature. The
reaction mixture was diluted with deionized water (20 mL) and CH2-
Cl2 (20 mL), and the separated aqueous layer was extracted with CH2-
Cl2 (3 × 20 mL). The combined organic phases were dried over K2CO3
and concentrated in vacuo. The solid residue was washed with 50%
EtOAc-hexane, and the remainder was dissolved in 10% MeOH-
CH2Cl2. The solvent was removed in vacuo to give 135 mg (33% over
two steps) of 35 as a white solid, mp >270 °C dec (from 5% MeOH
A THF solution (10 mL) of the oil was treated with 1 N TBAF
(7.32 mL, 7.32 mmol) for 2 h. The solvent was evaporated, and the
residue was purified by chromatography on silica gel (elution with 50%
ethyl acetate in hexanes containing 10% MeOH) to afford 1.25 g (79%
1
over four steps) of 32; IR (film, cm-1) 3470, 1440, 1280, 1215; H
1
in CH2Cl2); IR (film, cm-1) 3400, 2100, 1615, 1255, 1040, 960; H
NMR (300 MHz, CDCl3) δ 6.95-6.75 (m, 4 H), 4.14 (d, J ) 11.7 Hz,
1 H), 4.00-3.90 (m, 6 H), 3.84 (m, 2 H), 3.72(s, 3 H), 3.56 (s, 1 H),
3.16 (d, J ) 11.7 Hz, 1 H), 2.45-2.35 (m, 2 H), 2.25-2.10 (m, 2 H),
2.00-1.85 (m, 4 H); 13C NMR (75 MHz, CDCl3) δ 153.8, 152.2, 115.6,
113.9, 106.8, 79.6, 77.3, 76.1, 70.1, 69.2, 62.2, 55.1, 34.3, 23.8; HRMS
m/z (M+) calcd 406.1627, obsd 406.1626.
NMR (300 MHz, CDCl3) δ 3.96 (t, J ) 6.9 Hz, 6 H), 3.60 (s, 3 H),
2.53 (s, 1 H), 2.32 (t, J ) 7.6 Hz, 6 H), 1.88 (m, 6 H); 13C NMR (75
MHz, CDCl3) δ 101.4, 79.2, 77.2, 77.0, 69.8, 69.3, 36.1, 23.6; HRMS
m/z (M+) calcd 334.1416, obsd 334.1430.
3,3′′′′-(Butadiynylene)bis[(1r,5r,6â,7r,8â,9â)-hexahydrotrispiro-
[2,4,10-trioxaadamantane-6,2′(3′H);8,2′′(3′′H);9,2′′′(3′′′H)-trisfu-
ran]] (36). To a CH2Cl2 solution (15 mL) of 35 (128 mg, 0.383 mmol)
and TMEDA (0.144 mL, 0.766 mmol) was added CuCl (38 mg, 0.38
mmol) under dry air conditions with protection by means of a CaCl2
drying tube. After 4 h at room temperature, the reaction mixture was
diluted with deionized water (20 mL), extracted with CH2Cl2 (4 × 30
mL), and dried over K2CO3. The concentrated filtrate was purified by
chromatography on silica gel (elution with 5-10% MeOH in CH2Cl2)
to afford 128 mg (100%) of the 36 as a white solid, mp >280 °C (from
CH2Cl2); IR (film, cm-1) 3418, 1633, 1462, 1264; 1H NMR (300 MHz,
CDCl3) δ 3.95 (t, J ) 6.8 Hz, 12 H), 3.57 (s, 6 H), 2.25 (t, J ) 7.6 Hz,
12 H), 1.87 (m, 12 H); 13C NMR (75 MHz, CDCl3) δ 102.3, 79.7,
77.7, 73.4, 69.8, 64.9, 36.6, 24.1; HRMS m/z (M+) calcd 666.2676,
obsd 666.2707.
Attempted Complexation of 36 with 37. To a CH2Cl2 solution (1.0
mL) of 36 (10 mg, 0.015 mmol) was added 37 (11 mg, 0.030 mmol)
dissolved in CH2Cl2 (1.0 mL) dropwise. Solvent was allowed to
evaporate during 12 h and the precipitate triturated with CH2Cl2 (1.0
mL). The solvent was decanted, and the residue was dried under vacuo
to give 39 as a powdery white solid (15 mg), mp >280 °C; ESI-MS
for 36.Li+, m/z (M+ + 1) calcd 674.3, obsd 674.0 (intensity, 100%);
for 36.Li+.37, m/z (M+) calcd 925.4, obsd 925.9 (intensity, 20%); for
36.Li+.36, m/z (M+) calcd 1339.5, obsd 1339.8 (intensity, 5%).
(1r,5r,6â,7r,8â,9â)-Hexahydro-3-[(p-methoxyphenoxy)methyl]-
trispiro [2,4,10-trioxaadamantane-6,2′(3′H);8,2′′(3′′H);9,2′′′(3′′′H)-
trisfuran] (33). To a cooled (-78 °C) CH2Cl2 solution (30 mL) of
oxalyl chloride (0.67 mL, 7.68 mmol) were added DMSO (1.09 mL,
15.54 mmol) in CH2Cl2 (5 mL) and 32 (1.68 g, 3.87 mmol) in CH2Cl2
(15 mL) within 5 min. The mixture was stirred for 2 h at -78 °C and
treated with triethylamine (2.69 mL, 19.2 mmol) and then warmed to
room temperature for 1 h. The reaction mixture was washed with water,
and the aqueous layer was extracted with CH2Cl2 (2 × 50 mL). The
combined organic phases were dried and concentrated in vacuo. The
residue was purified by chromatography on silica gel (elution with 25-
50% ethyl acetate in hexanes) to afford the ketone as a colorless oil.
To a cooled (-78 °C) solution of the ketone, which was precom-
plexed with dry LiClO4 (2.06 g, 19.4 mmol) in THF (50 mL) for 2 h
at room temperature, was added 0.26 N Normant reagent (45.0 mL,
11.7 mmol). The reaction mixture was warmed to room temperature
for 15 h, quenched with saturated NH4Cl solution and filtered. The
filtrate was concentrated, and the residue was purified by chromatog-
raphy on silica gel (elution with 50% ethyl acetate in hexanes containing
5% MeOH) to afford the diol.
This diol in CH2Cl2 (100 mL) was treated with p-toluenesulfonyl
chloride (1.47 g, 7.71 mmol), triethylamine (2.16 mL, 15.5 mmol),
and DMAP (50 mg) at room temperature for 15 h and refluxed for 2
d. The reaction mixture was quenched with deionized H2O (50 mL)
and extracted with CH2Cl2 (3 × 50 mL). The combined organic phases
were concentrated in vacuo without drying, and the residue was purified
by chromatography on silica gel (gradient elution with 50% ethyl acetate
in hexanes to 5% MeOH in CH2Cl2) to afford 1.35 g (78%) of 33 as
a white solid, mp 189-191 °C (from 10% CH2Cl2 in hexanes); IR
The decanted CH2Cl2 solution from the above reaction was concen-
trated to give 6 mg of recovered 37.
Complexation of 36 to Lithium Tetrafluoroborate. To a CH2Cl2
solution (1.0 mL) of 36 (10 mg, 0.015 mmol) was added LiBF4 (1.4
mg, 0.015 mmol) dissolved in CH3CN (0.05 mL) dropwise. Solvent
was allowed to evaporate during 12 h, and the precipitate was triturated
with CH2Cl2 (1.0 mL) and CH3CN (1.0 mL). The solvent was decanted,
and the residue was dried under vacuo to give 40b as a powdery white
solid (11 mg), mp >280 °C.
Complexation of 36 to Lithium Picrate. To a CH2Cl2 solution (0.5
mL) of 36 (9.0 mg, 0.014 mmol) was added lithium picrate (6.3 mg,
0.027 mmol) dissolved in CH3CN (2.0 mL) dropwise. Yellow crystals
of 41 suitable for X-ray diffraction analysis were deposited from the
solution.
1
(film, cm-1) 1440, 1220, 1060, 1020; H NMR (300 MHz, CDCl3) δ
6.84-6.70 (m, 4 H), 3.93 (t, J ) 6.8 Hz, 6 H), 3.86 (s, 2 H), 3.69 (s,
3 H), 3.91 (s, 3 H), 2.26 (t, J ) 7.6 Hz, 6 H), 1.83 (m, 6 H); 13C NMR
(75 MHz, CDCl3) δ154.2, 152.8, 115.9, 114.4, 106.8, 80.0, 76.3, 70.3,
69.5, 55.5, 36.2, 23.9; HRMS m/z (M+) calcd 446.1940, obsd 446.1958.
Anal. Calcd for C24H30O8CH2Cl2: C, 56.50; H, 6.07. Found: C,
56.06; H, 5.82.
(1r,5r,6â,7r,8â,9â)-3-Ethynylhexahydrotrispiro[2,4,10-triox-
aadamantane-6,2′(3′H);8,2′′(3′′H);9,2′′′(3′′′H)-trisfuran] (35). To a
cold solution (0 °C) of 33 (328 mg, 0.735 mmol) in 10 mL of 4:1
CH3CN-H2O was added ceric ammonium nitrate (1.01 g, 1.84 mmol).
After 10 min, the reaction mixture was quenched with deionized water
(20 mL) and extracted with CH2Cl2 (3 × 20 mL). The combined organic
phases were dried over K2CO3, filtered, and concentrated in vacuo.
The residue was purified by chromatography on silica gel (gradient
elution with 55% ethyl acetate in hexanes to 5% MeOH in CH2Cl2) to
afford 163 mg (69%) of 34 as a white solid.
Acknowledgment. This work was supported by the National
Science Foundation. We are grateful to Professor Robin Rogers
(University of Alabama) and Dr. Judith Gallucci for the X-ray
crystallographic determinations, Dr. A. Daniel Jones (Penn State
University) for the electrospray mass spectra, and Dr. Kurt
Loening for assistance with nomenclature.
Supporting Information Available: Tables giving the
crystal data and structure refinement information, bond lengths
and bond angles, atomic and hydrogen coordinates, and isotropic
and anisotropic displacement coordinates for 35 (PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
To a cooled (-78 °C) CH2Cl2 (15 mL) solution of oxalyl chloride
(0.22 mL, 2.52 mmol) were added DMSO (0.35 mL, 4.93 mmol) in
CH2Cl2 (1 mL) and 34 (423 mg, 1.24 mmol) in CH2Cl2 (5 mL) within
5 min. The mixture was stirred for 1 h at -78 °C, treated with
triethylamine (0.87 mL, 6.21 mmol), warmed to room temperature for
1 h, and washed with deionized water. The aqueous layer was extracted
JA010103X