Preorganized ligand arrays based on spirotetrahydrofuranyl motifs. Synthesis of the steyeoisomeric 1,8,14-trioxatrispiro[4.1.4.1.4.1]octadecanes and the contrasting conformational features and ionic binding capacities of these belted ionophores

Article abstract of DOI:10.1021/jo001430a

The cis,trans trispiro ether 4 is accessible from several synthetic directions as a consequence of a crossover in reaction selectivity when proceeding from nucleophilic attack on the cis dispiro ketone to oxygenation of the α,β-unsaturated ester 17. Its cis,cis isomer 3 was obtained in 17 steps and 14.6% overall yield from 3,5-dimethoxybenzoic acid by making use of the alicyclic side chain in N as a "conformational lock". Although 4 shows no measurable tendency to complex with alkali metal ions, 3 binds strongly to Li⁺ and Na⁺ ions, as well as to CH₃NH₃⁺. Whereas the 3eq conformation is populated in the solid state and in solution, complex formation occurs readily. ¹³C NMR studies have defined slow exchange limits as the 2:1 sandwich complex with lithium ion is initially formed and transformed progressively into a 1:1 species upon the addition of more LiClO₄. Only the 2:1 complex with sodium ion is formed during comparable titration with NaClO₄. Association constants, molecular mechanics calculations, and X-ray crystallographic studies provide insight into the binding capacity of this belted tridentate ionophore.

Full text of DOI:10.1021/jo001430a

9160
J . Org. Chem. 2000, 65, 9160-9171
P r eor ga n ized Liga n d Ar r a ys Ba sed on Sp ir otetr a h yd r ofu r a n yl
Motifs. Syn th esis of th e Ster eoisom er ic
1,8,14-Tr ioxa tr isp ir o[4.1.4.1.4.1]octa d eca n es a n d th e Con tr a stin g
Con for m a tion a l F ea tu r es a n d Ion ic Bin d in g Ca p a cities of Th ese
Belted Ion op h or es
Leo A. Paquette,* J insung Tae, Eugene R. Hickey, William E. Trego, and Robin D. Rogers†
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210, and
Department of Chemistry, The University of Alabama, Tuscaloosa, Alabama 35487
paquette.1@osu.edu
Received October 2, 2000
The cis,trans trispiro ether 4 is accessible from several synthetic directions as a consequence of a
crossover in reaction selectivity when proceeding from nucleophilic attack on the cis dispiro ketone
to oxygenation of the R,â-unsaturated ester 17. Its cis,cis isomer 3 was obtained in 17 steps and
14.6% overall yield from 3,5-dimethoxybenzoic acid by making use of the alicyclic side chain in N
as a “conformational lock”. Although 4 shows no measurable tendency to complex with alkali metal
ions, 3 binds strongly to Li+ and Na+ ions, as well as to CH3NH3+. Whereas the 3eq conformation
is populated in the solid state and in solution, complex formation occurs readily. 13C NMR studies
have defined slow exchange limits as the 2:1 sandwich complex with lithium ion is initially formed
and transformed progressively into a 1:1 species upon the addition of more LiClO4. Only the 2:1
complex with sodium ion is formed during comparable titration with NaClO4. Association constants,
molecular mechanics calculations, and X-ray crystallographic studies provide insight into the binding
capacity of this belted tridentate ionophore.
The differing physical properties of diethyl ether (1)
and its cyclic dehydro congener tetrahydrofuran (2), while
extraordinary, are often taken for granted. For example,
conducive to the population of those conformations well
suited to metal ion binding.5 The incorporation of oxygen-
containing rings in favorable topological arrangements
is of continuing importance in the synthesis of preorga-
nized receptors of chemical and biological relevance.6-12
(4) (a) Gokel, G. Crown Ethers and Cryptands; The Royal Society
of Chemistry: Cambridge, England, 1991. (b) Cooper, S. R., Ed. Crown
Compounds: Toward Future Applications; VCH Publishers: New York,
1992. (c) Vo¨gtle, F. Supramolecular Chemistry; J ohn Wiley and Sons:
Chichester, England, 1991. (d) Inoue, Y.; Gokel, G. W. Cation Binding
by Macrocycles; Marcel Dekker: New York, 1990. (e) Westley, W. J .,
Ed. Polyether Antibiotics; Marcel Dekker: New York, 1983; Vols. I and
II. (f) Dobler, M. Ionophores and Their Structures; Wiley-Inter-
science: New York, 1981. (g) Izatt, R. M.; Christensen, J . J . Synthetic
Multidentate Macrocyclic Compounds; Academic Press: New York,
1978.
(5) (a) Kilburn, J . D.; Patel, H. K. Contemp. Org. Synth. 1994, 1,
259. (b) Izatt, R. M.; Pawlak, K.; Bradshaw, J . S.; Bruening, R. L.
Chem. Rev. 1991, 91, 1721. (c) Schneider, H.-J . Angew. Chem., Int.
Ed. Engl. 1991, 30, 1417. (d) Cram, D. J . Angew. Chem., Int. Ed. Engl.
1988, 27, 1009.
(6) (a) Li, G.; Still, W. C. J . Am. Chem. Soc. 1993, 115, 3804. (b)
Wang, X.; Erickson, S. D.; Iimori, T.; Still, W. C. J . Am. Chem. Soc.
1992, 114, 4128. (c) Li, G.; Still, W. C. J . Org. Chem. 1991, 56, 6964.
(d) Erickson, S. D.; Still, W. C. Tetrahedron Lett. 1990, 31, 4253. (e)
Iimori, T.; Still, W. C.; Rheingold, A. L.; Staley, D. L. J . Am. Chem.
Soc. 1989, 111, 3439.
(7) (a) Burke, S. D.; McDermott, T. S.; O’Donnell, C. J . J . Org. Chem.
1998, 63, 2715. (b) Burke, S. D.; Heap, C. R.; Porter, W. J .; Song, Y.
Tetrahedron Lett. 1996, 37, 343. (c) Burke, S. D.; O’Donnell, C. J .;
Porter, W. J .; Song, Y. J . Am. Chem. Soc. 1995, 117, 12649.
(8) (a) McGarvey, G. J .; Stepanian, M. W.; Bressette, A. R.; Ellena,
J . F. Tetrahedron Lett. 1996, 37, 5465. (b) McGarvey, G. J .; Stepanian,
M. W. Tetrahedron Lett. 1996, 37, 5461.
advantage is routinely taken of the complete miscibility
of THF with water and the contrasting limited aqueous
solubility of ether. It is also widely recognized that the
progression from an acyclic to a cyclic ether significantly
affects intrinsic basicity, with THF exhibiting greater
hydrogen bonding capability,1 enhanced gas-phase proton
affinity,2 and faster rate of proton attachment in solu-
tion.3 Many of the natural ionophores utilize cyclic ether
fragments as ligand arrays for ionic recognition and
transport.4 In the latter context, the inherent stereo-
chemistry of these arrays make matters particularly
† To whom inquiries regarding the X-ray crystallographic analyses
should be addressed at The University of Alabama.
(1) (a) Berthelot, M.; Besseau, F.; Laurence, C. Eur. J . Org. Chem.
1998, 925. (b) Catalan, J .; Gomez, J .; Couto, A.; Laynez, J . J . Am.
Chem. Soc. 1990, 112, 1678. (c) Abraham, M. H.; Grellier, P. L.; Prior,
D. V.; Morris, J . J .; Taylor, P. J .; Laurence, C.; Berthelot, M.
Tetrahedron Lett. 1989, 30, 2571. (d) Laurence, C.; Nicolet, P.; Helbert,
M. J . Chem. Soc., Perkin Trans. 2 1986, 1081.
(2) Bordeje, M. C.; Mo, O.; Yanez, M.; Herreros, M.; Abboud, J . L.
M. J . Am. Chem. Soc. 1993, 115, 7389.
(9) (a) Koert, U.; Stein, M.; Wagner, H. Liebigs Ann. 1995, 1415.
(b) Koert, U.; Stein, M.; Harms, K. Angew. Chem., Int. Ed. Engl. 1994,
33, 1180.
(10) Mehta, G.; Vidya, R. Tetrahedron Lett. 1997, 38, 4173, 4177.
(11) (a) Lee, W. Y.; Park, C. H. J . Org. Chem. 1993, 58, 7149. (b)
Lee, W. Y.; Park, C. H.; Kim, S. J . Am. Chem. Soc. 1993, 115, 1184.
(12) (a) Hormuth, S.; Schade, W.; Reissig, H.-U. Liebigs Ann. 1996,
2001.
(3) (a) Pines, E.; Fleming, G. R. Isr. J . Chem. 1993, 33, 179. (b)
Krygowski, T. M.; Rodomski, J . P.; Rzeszowiak, A.; Wrona, P. K.;
Reichardt, C. Tetrahedron 1981, 37, 119. (c) Westera, G.; Blomberg,
C.; Bickelhaupt, F. J . Organomet. Chem. 1978, 155, C55. (d) Arnett,
E. M.; Mitchell, E. J .; Murty, T. S. S. R. J . Am. Chem. Soc. 1974, 96,
3875. (e) Lee, D. G.; Cameron, R. Can. J . Chem. 1972, 50, 445.
10.1021/jo001430a CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/06/2000

Ligand Arrays Based on Spirotetrahydrofuranyl Motifs
J . Org. Chem., Vol. 65, No. 26, 2000 9161
In view of the central position held by substituted
tetrahydrofurans in natural ionophores and their en-
hanced capacity for chelation, we have sought to exploit
this binding efficacy by designing and synthesizing belted
spirocyclic polyether networks.13 With level of substitu-
tion, locus of the oxygen atoms, and relative stereochem-
istry as relevant principles of rational design, it was
anticipated that heightened levels of structural preorga-
nization could be achieved. This paper focuses on the
trispiro cyclohexanes 3 and 4. The cis,cis isomer 3 clearly
three-dimensional features not previously examined in
the context of crown ethers and offer scenarios having
potential application in many areas of investigation.
Syn th etic Con sid er a tion s
Rou tes Th a t Lea d to th e Tr a n s Isom er . In an
earlier paper,16b we reported that potential access routes
to 3 and 4 by way of the meso- and dl-diols 6 and 7,
respectively, are plagued with high inefficiency at several
steps. The neopentyl nature of the carbinol centers was
one of the contributory causes. The present synthetic
strategy skirts this problem by involving 3,5-dimethoxy-
benzoic acid as the triply functionalized precursor. The
sequential Birch reduction and lithium aluminum hy-
dride treatment of this inexpensive benzenoid compound
to give 8 has been detailed previously.17 Subsequent
O-benzylation of alcohol 8 in advance of exposure to
isobutyl alcohol in the presence of a catalytic quantity of
concentrated sulfuric acid produced 918 (Scheme 1). This
enjoys a level of binding-site convergence and comple-
mentarity not available to 4. As a consequence, the
cumulative noncovalent interactions capable of material-
izing in 3 when its three C-O bonds are axially disposed
were expected to qualify this isomer, but not 4, as an
effective host molecule for the smaller alkali metal ions.
The cyclohexane belt confers a defined spatial relation-
ship among the tetrahydrofuran subunits while not
instilling absolute rigidity. Thus, the spirocyclic nature
of the substituent rings was expected to facilitate rather
than inhibit the interconversion of 3a x with 3eq.14 As
Sch em e 1a
will be seen, the preferential adoption of one or the other
of these conformers is less predictable, since the confor-
mational bias is controlled by a complex interplay of
steric and electronic effects.15 However, these incremental
preferences should be overridden by favorable ligation,
at least as far as lithium and sodium ions are concerned.
Finally, we point out that while 3 is capable of coor-
dination uniquely in a monofacial sense, it represents the
logical starting point for the development of a class of
bifacial ligands typified by 5.16a Such structurally defined
compounds are of interest because they feature extended
a
Key: (a) NaH, BnBr; (b) i-BuOH, conc H2SO4; (c) ClMg(CH2)3O-
MgCl; 1 N HCl; (d) TsOH, CH2Cl2; (e) TsCl, Et3N.
5-substituted 3-alkoxycyclohexenone afforded, following
coupling to the Normant reagent19 and hydrolysis with
(13) (a) Negri, J . T.; Rogers, R. D.; Paquette, L. A. J . Am. Chem.
Soc. 1991, 113, 5073. (b) Paquette, L. A.; Negri, J . T.; Rogers, R. D. J .
Org. Chem. 1992, 57, 3947. (c) Paquette, L. A.; Stepanian, M.;
Mallavadhani, U. V.; Cutarelli, T. D.; Lowinger, T. B.; Klemeyer, H.
J . J . Org. Chem. 1996, 61, 7492.
(14) The requirement that three ether oxygens or three methylene
groups must be syn-axially oriented will result in appreciable flattening
of the cyclohexane chair. Further, the 1,3,5-placement of the spiro rings
does not introduce vicinal eclipsing during ring inversion. Both of these
factors are expected to contribute to a lowering of the barrier associated
with conformational flexing in both the forward and reverse directions.
For a discussion of associated issues, consult: Eliel, E. L.; Wilen, S.
H.; Mander, L. N. Stereochemistry of Carbon Compounds; J ohn Wiley
and Sons: New York, 1994; pp 686-720.
(15) (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, 4505. (c) 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.
(16) (a) Paquette, L. A.; Tae, J .; Branan, B. M.; Eisenberg, S. W. E.;
Hofferberth, J . E. Angew Chem. Int. Ed. 1999, 38, 1412. (b) Paquette,
L. A.; Stearns, B. A.; Mooney, P. A.; Tae, J . Heterocycles 1999, 50, 27.
(c) For a preliminary communication of the present results, consult
Paquette, L. A.; Tae, J .; Hickey, E. R.; Rogers, R. D. Angew. Chem.,
Int. Ed. Engl. 1999, 38, 1409.
(17) (a) Wilkie, J . S.; Winzenberg, K. N. Austr. J . Chem. 1989, 42,
1207. (b) Nishikawa, T.; Isobe, M. Tetrahedron 1994, 50, 5621.

9162 J . Org. Chem., Vol. 65, No. 26, 2000
Paquette et al.
Sch em e 2a
1 N HCl, an approximate 1:1 mixture of the enone and
cyclized monospiro ketones. Complete conversion to 10
and 11 was easily accomplished with p-toluenesulfonic
acid in CH2Cl2. Although 10 and 11 proved not to be
easily purified due to difficulties with â-elimination, their
more advanced capping with additional Normant reagent
gave rise to a chromatographically separable 5:3 mixture
of 12 and 13. These isomers are readily distinguished
both structurally and conformationally. Thus, the Cs
symmetry of 12 is evident on the basis of its 13-line 13C
NMR spectrum (13 is characterized by 18 peaks). Beyond
that, the cis isomer (Rf ) 0.2 in 1:1 hexanes/ethyl acetate)
is appreciably more polar than its trans counterpart (Rf
) 0.7), and exhibits an axial methine proton that is
highly deshielded (compare A and B). These data confirm
that the two oxygens in 12 are oriented axially at ambient
temperature.
In complementary studies, the mixture of spiro ketones
10 and 11 was coupled to both allylmagnesium bromide
and the allylindium reagent. As expected,20 the ether
oxygens are too remote from the electrophilic carbon
center to affect the stereochemistry of the reaction. In
fact, both organometallic reagents gave rise to the same
5:3 mixture of 14 and 15 (Scheme 2). Following their
chromatographic separation, these carbinols were indi-
vidually cyclized in a two-step sequence featuring hydro-
boration to again provide 12 and 13. In light of these
observations, it is apparent that the two diastereomeric
monospiro ketones are attacked preferably from the
equatorial direction as reflected in C and D, and to the
same degree.
a
Key: (a) BrMgCH2CHdCH2, THF (83%); (b) BrCH2CHdCH2,
ln, THF (83%); (c) BH3‚THF; H2O2, NaOH; (d) TsCl, Et3N; (e) H2,
10% Pd/C, EtOH, 40 psi; (f) o-(NO2)PhSeCN, Bu3P, THF; (g) 30%
H2O2, THF; (h) O3, MeOH/CH2Cl2; Me3S; (i) BrMgCH2CHdCH2;
(j) BH3; NaOOH.
reaction led unmistakingly to the Cs-symmetric 4. This
trispiro ether exhibits a 10-line 13C NMR spectrum and
average polarity. Discussion of the conformational rami-
fications associated with the stereochemical course of this
allylmagnesium bromide addition is deferred to a later
segment of this paper.
The second synthetic thrust relied on a deconjugation-
epoxidation sequence.22 The cis dispiro aldehyde 20 was
homologated under Wadsworth-Emmons conditions,23
giving 17 in 72% overall yield from 12 (Scheme 3). When
this ester was treated with potassium hexamethyldi-
silazide in THF-HMPA at -78 °C, little chemical change
was noted. Warming of such reaction mixtures to 0 °C
resulted in rapid decomposition. Fortunately, deconju-
gation was seen to proceed well at -15 °C without
destruction of the reactant, affording 18 in 76% isolated
yield. Epoxidation of 18 with m-chloroperbenzoic acid24
and subsequent â-elimination in the presence of DBU
afforded 19 as the only stereoisomeric product. The
relative stereochemistry of this carbinol was established
by a sequence of steps involving hydrogenation, lithium
aluminum hydride reduction, and cyclization of the
The stage was now set to proceed with an elimination
in 12. Following hydrogenolytic cleavage of the benzyl
group, dehydration was indirectly, but smoothly, imple-
mented via the o-nitrophenyl selenocyanate.21 The result-
ing exomethylene derivative 16 was subsequently ozo-
nolyzed to provide the labile cis dispiro cyclohexanone
which was treated immediately with allylmagnesium
bromide in THF at 0 °C. Under these conditions, no
evidence was uncovered for the generation of â-elimina-
tion products. In contrast, the Normant reagent chan-
neled matters completely in this undesirable direction.
Capping of the single carbinol isolated from the Grignard
(18) The free alcohol derived from 9 has been previously described:
(a) Reference 17b. (b) Grieco, P. A.; Dai, Y. J . Am. Chem. Soc. 1998,
120, 5128.
(19) Cahiez, G.; Alexakis, A.; Normant, J . F. Tetrahedron Lett. 1978,
3013.
(20) Paquette, L. A.; Lobben, P. C. J . Org. Chem. 1998, 63, 5604.
(21) Grieco, P. S.; Gilman, S.; Nishizawa, M. J . Org. Chem. 1976,
41, 1485.
(22) Ikeda, Y.; Ukai, J .; Ikeda, N.; Yamamoto, H. Tetrahedron 1987,
43, 743.
(23) Wadsworth, W. S. J . Org. React. 1977, 25, 73.
(24) Attempted oxidation of 18 with dimethyldioxirane resulted in
exclusive attack of the activated methylene group R to the carbethoxy
group.

Ligand Arrays Based on Spirotetrahydrofuranyl Motifs
J . Org. Chem., Vol. 65, No. 26, 2000 9163
Sch em e 3a
of signals showed the conformer having its hydroxyl
group projected equatorially as in F to be dominant
(57%). This assignment was made possible by spectral
comparison with 21 prepared independently from the
trans dispiro aldehyde. Especially noteworthy is the very
appreciable downfield shift of Hâ (δ 7.31) in major
conformer F . This deshielding necessarily arises as a
consequence of proximity to both axial oxygens as shown.
In contrast, the two vinylic protons in minor conforma-
tional isomer E (HR, δ 6.62; Hâ, δ 7.00) are closely similar
to those of the conformationally stable 21 (HR, δ 6.56; Hâ,
δ 7.01). While the favored status accorded to F has
interesting implications, the Keq is too small to warrant
extensive discussion.
a
Key: (a) H2, 10% Pd/C, EtOH, 40 psi; (b) Swern, CH2Cl2; (c)
(EtO)2P(dO)CH2COOEt, DBU, LiCl, CH3CN; (d) KHMDS, THF/
HMPA, -78 f -15 °C; satd NH4Cl, -78 °C; (e) m-CPBA; (f) DBU;
(g) H2, 10% Pd/C; (h) LiAlH4; (i) TsCl, Et3N.
monotosylate. The resulting colorless oil was identical in
all respects to the sample of 4 generated earlier. Conse-
quently, there must occur a clean stereochemical cross-
over during peracid attack on the double bond in 18
relative to allylation of the corresponding ketone under
Grignard conditions.
Con for m a tion a l Ch a r a cter istics of F u n ction a l-
ized Cis Disp ir o Cycloh exa n es. The cis dispirocyclo-
hexanone prepared in this investigation and its homolo-
gated R,â-unsaturated ester 17 share in common the ca-
pacity for equilibrating between two chair conformers13b,29
as G a H and I a J , respectively. The consequence of
To gain a broader perspective on this stereoselectivity
issue, 20 was condensed with 4-chlorophenylsulfinyl
acetate in the presence of piperidine.25-28 The ensuing
SPAC reaction27 proceeds by consecutive Knoevenagel
condensation, CdC double bond shift, [2,3]-sigmatropic
rearrangement, and hydrolysis to deliver the γ-hydroxy-
R,â-unsaturated ester directly. Application of this simple
procedure to 20 gave rise exclusively to 19 (Scheme 4).
As before, this substance shows one spot on TLC, but is
1
conformationally dynamic on the H and 13C NMR time
scales at room temperature. Integration of several sets
Sch em e 4a
these ring inversions is the exchange of two equatorially
disposed C-O bonds with two axial C-C bonds and vice-
versa. Since neither substance is crystalline and their
1H NMR spectra exhibit an appreciable overlapping of
signals, direct experimental analysis of the preferred
conformation in each instance has not been possible.
However, when the two structures were subjected to a
standard Monte Carlo conformational search by way of
the MacroModel software package (version 5.0)30 and the
(25) (a) Yamagiwa, S.; Sato, H.; Hoshi, N.; Kosugi, H.; Uda, H. J .
Chem. Soc., Perkin Trans. 1 1979, 570. (b) Nokami, J .; Mandai, T.;
Imakura, Y.; Nishiuchi, K.; Kawada, M.; Wakabayashi, S. Tetrahedron
Lett. 1981, 22, 4489.
(26) (a) Tanikaga, R.; Nozaki, Y.; Tanakaga, K.; Kaji, A. Chem. Lett.
1982, 1703. (b) Tanikaga, R.; Nozaki, Y.; Tamura, T.; Kaji, A. Synthesis
1983, 134.
(27) Corey, E. J .; Carpino, P. Tetrahedron Lett. 1990, 31, 7555.
(28) (a) Burgess, K.; Henderson, I. Tetrahedron Lett. 1989, 30, 3633,
4325. (b) Burgess, K.; Cassidy, J .; Henderson, I. J . Org. Chem. 1991,
56, 2050.
(29) Paquette, L. A.; Branan, B. M.; Friedrich, D.; Edmondson, S.
D.; Rogers, R. D. J . Am. Chem. Soc. 1994, 116, 506.
a
Key: (a) p-(Cl)PhS(dO)CH2COOEt, piperidine, CH3CN, reflux;
(b) H2/10% Pd/C; (c) Swern; (d) LiAlH4; (e) TsCl, Et3N.

9164 J . Org. Chem., Vol. 65, No. 26, 2000
Paquette et al.
MM3-minimized results31 were further refined using the
full matrix Newton Raphson protocol, the energy differ-
ences were found to be quite small. The relative energies
generated for gas-phase structures by this procedure
favored H over G by 1.13 kcal/mol, and I over J by only
0.54 kcal/mol. These data lead us to conclude that the
flattened nature of the cyclohexane “belt” in these
structures diminishes the level of potential conforma-
tional dominance to vanishingly small levels. In addition,
the barriers to interconversion are expected to be low as
previously indicated for multispiro systems of this type.14
Notwithstanding the above, both substrates have been
found to undergo highly stereoselective reactions, thereby
implicating the involvement of a specific conformer
during product formation. For example, Grignard addi-
tion to the ketone can be expected to proceed from the
equatorial direction as foreshadowed, inter alia, by C and
D, and with heightened levels of steric approach control.
We therefore conclude, in light of the fact that 4 is
ultimately formed, that the transition state must re-
semble K. Note that the two ethereal C-O bonds are
equatorially disposed.32
ketone involve G and proceed via equatorial attack (see
K), the stereoselectivity of this reaction class is identical
to that involving oxygenation reactions of the R,â-
unsaturated ester which involve axial delivery to I as in
L and M.
Acqu isition of th e All-Cis Isom er . Despite the fact
that the reactive conformers G and I both feature
equatorial C-O bonds, this structural characteristic is
obviously not conducive to a stereocontrolled synthesis
of 3. A superior, more reliable control feature was
therefore mandated. The more biased conformational
structure N was considered to be favorably populated
prior to closure of the second spirotetrahydrofuran ring.
The silyl-protected (3-hydroxypropyl) substituent, origi-
nally introduced via allylation (Scheme 2), is sufficiently
bulky (i.e., comparable to ethyl) to warrant its equatorial
occupancy in the lowest energy conformation.32b Further-
more, exposure of this intermediate to a Grignard reagent
should be met with rapid deprotonation and formation
of the chelate O. The two C-O bonds will now be oriented
axially with significant shielding of the top face of the
carbonyl group. As a consequence, the customary equato-
rial entry of the nucleophile should continue to operate
and fix the triad of oxygens in an all-syn relationship.
The feasibility of this strategy is demonstrated in
Scheme 5. The Normant reagent was added to the 10/11
mixture as before. Following chromatographic purifica-
tion, the major diol was regioselectively silylated to
provide 22 in 71% yield for the two steps. Following
conventional transformation of 22 into the methylenecy-
clohexane 23,35 the ketone was generated through ozo-
nolysis, and coupled to allylmagnesium bromide.
Hydroboration-oxidation of the double bond in 24 was
beset by problems associated with hydrolytic cleavage of
the TBS substituent. The tetraol so produced is not
soluble in the common organic solvents and was accord-
ingly difficult to process. For this reason, 24 was con-
verted into the dispiro alcohol 25 prior to activation of
the allylic side chain. In this instance, the hydroxy
tosylate required 15 h in refluxing CH2Cl2 to undergo
complete cyclization in the presence of DMAP. Signifi-
cantly, however, only 3 was produced, as expected if the
N f O paradigm was operative. It proved an easy matter
to effect the O-methylation of 25 as in 26 for comparative
complexation studies to be described in the sequel.
The all-cis trispiro ether 3 is a crystalline solid, mp
111-113 °C, of C3v-symmetry as revealed by the appear-
ance of only five signals in its 13C NMR spectrum. The
striking feature of the solid-state structure of 3 is the
adoption in the crystal of the all-equatorial conformation
The normal stereochemical preference of peracid ep-
oxidation for axial attack on methylenecyclohexenes,
originally discussed in terms of product development
control,32a has more recently been attributed to a com-
bination of bond torsion and rotor effects,33 with possible
lesser contributions from σ f σ* (Cieplak-type) interac-
tions.34 In the specific case of 17, equatorial orientation
of the tetrahydrofuranyl oxygens can be expected to
facilitate delivery of the oxygen atom as shown in L. This
enhanced preference to involve conformer I is likewise
encountered during the [2,3]-sigmatropic rearrangement
of the sulfoxide M.
The magnitudes of transition state steric and torsional
energy contributions to ∆∆G‡ are such as to pose an
interesting dilemma. Since nucleophilic additions to the
(30) Mohamadi, F.; Richards, N. G. J .; Guida, W. C.; Liskamp, R.;
Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J .
Comput. Chem. 1990, 11, 440.
(31) Allinger, N. L.; Yuh, Y. H.; Lii, J .-H. J . Am. Chem. Soc. 1989,
111, 8551.
(32) (a) Carlson, R. G.; Behn, N. S. J . Org. Chem. 1967, 32, 1363.
(b) Corey, E. J .; Feiner, N. F. J . Org. Chem. 1980, 45, 765.
(33) (a) Vedejs, E.; Dent, W. H., III; Kendall, J . T.; Oliver, P. A. J .
Am. Chem. Soc. 1996, 118, 3556. (b) Shi, Z.; Boyd, R. J . J . Am. Chem.
Soc. 1993, 115, 9614. (c) Wu, Y.-D., Tucker, J . A.; Houk, K. N. J . Am.
Chem. Soc. 1991 113, 5018.
(35) Two minor problems were encountered during this three-step
sequence. Hydrogenolysis of the benzyl ether in ethanol caused
wholesale cleavage of the TBS protecting group. This unwanted
reaction could be limited to the 10% level by carrying out the reduction
in ethyl acetate as solvent. When the aryl selenide was oxidized with
30% hydrogen peroxide, the TBS group was again very effectively
cleaved. Although reprotection could be readily accomplished, use of
MCPBA as the oxidant served to bypass this complication.
(34) Cieplak, A. S.; Tait, B. D.; J ohnson, C. R. J . Am. Chem. Soc.
1989, 111, 8447.

Ligand Arrays Based on Spirotetrahydrofuranyl Motifs
J . Org. Chem., Vol. 65, No. 26, 2000 9165
Sch em e 5a
The preference for axial oxygen occupancy in the gas
phase presumably arises from an interplay between the
torsional requirements of the three sets of geminal
C(quat)-O and C(quat)-CH2 bonds. Nonbonded axial-axial
CH2- - -CH2 repulsions probably disfavor 3eq and Q
despite the fact that flattening of the cyclohexane ring
diminishes these steric interactions to some degree. The
preference for adoption of 3eq in the crystal lattice sug-
gests that intermolecular stacking interactions may make
a contribution to the observed packing. The dominant
effect may be the avoidance of collinear, axially oriented
C-O-C dipoles in 3a x. Their intermolecular juxtaposi-
tioning could well promote the population of 3eq.
Com p lexa tion Stu d ies
Deter m in a tion of Associa tion Con sta n ts. The as-
sociation constants (Ka) for 3, 4, and 26 were determined
relative to Li+, Na+, and K+ picrates in a H2O-CDCl3
solvent mixture according to Cram’s extraction method.
These data, along with comparative values for 15-crown-
5, are listed in Table 1. The assumption is made that the
high relative concentrations of picrate salts used in these
measurements normalize matters to dealing with 1:1
complexes only. From the outset, the inability of 4 to
measurably extract any of the picrate salts demonstrated
how dramatically a change at a single stereocenter can
affect the strength and specificity with which oxophilic
metal ions are bound. The all-cis trispiro ether 3 has
strong chelating ability for Li+, over 2 orders of magni-
tude higher than that exhibited by 15-crown-5. This
ligand also exhibits a significant binding capacity for Na+
that is on a par with that shown by the simple crown
ether. The Ka for K+ (3.3 × 104) is much weaker, thereby
indicating that potassium ion is too large to reside
comfortably in the binding pocket.
a
Key: (a) ClMgO(CH2)3MgCl, 1 N HCl; (b) TBSCl, Et3N; (c) H2,
10% Pd/C, EtOAc; (d) (o-NO2)PhSeCN, Bu3P, THF; (e) m-CPBA,
CH2Cl2, -20 °C, (i-Pr)2NH, rt; (f) O3, MeOH-CH2Cl2, Me2S; (g)
BrMgCH2CHdCH2, THF; (h) TBAF, THF; (i) TsCl, Et3N, DMAP,
CH2Cl2; (j) BH3, THF, NaOH, 30% H2O2; (k) KHMDS, THF, Mel.
3eq (Figure 1). These findings conflict with the gas-phase
computational results realized with the MacroModel 5.0
software package. Using the energy minimization condi-
tions described earlier, we found 3eq to be 3.93 kcal/mol
less stable than 3a x. For comparison purposes, the two
conformers generated for cis,trans isomer 4 by this
procedure favored P over Q by a smaller margin (1.24
kcal/mol). Recourse to calculations at a higher dielectric
would likely result in much smaller energy differences.
The monomethoxy derivative 26 displays only a small
reduction of binding ability to Li+ relative to 3, but a
considerably lessened capacity for coordination to Na+.
This ligand exhibited a Ka for K+ (6.5 × 103), which we
F igu r e 1. Perspective plot of 3 as determined by X-ray crystallography.

9166 J . Org. Chem., Vol. 65, No. 26, 2000
Paquette et al.
Ta ble 1. Associa tion Con sta n ts (Ka ) Deter m in ed by
P icr a te Extr a ction in to Ch lor ofor m a t 20 °Ca
F igu r e 2. Perspective plot of the 2:1 sandwich complex of 3
with LiBF4 as the CH2Cl2 solvate.
a
The method developed by Koenig et al. (Koenig, K. E.; Lein,
G. M.; Struckler, P.; Kaneda, T.; Cram, D. J . Am. Chem. Soc. 1979,
101, 3553) was utilized. b Values previously reported by: Erickson,
S. D.; Still, W. C. Tetrahedron Lett. 1990, 30, 4235. See also: Inoue,
Y.; Amano, F.; Okada, N.; Inada, H.; Ouchi, M.; Tai, A.; Kakushi,
T.; Lin, Y.; Tong, L.-H. J . Chem. Soc., Perkin Trans. 2 1990, 1239.
F igu r e 3. Perspective plot of the 2:1 sandwich complex of 3
with NaBF4.
consider as too small to be significant.6e,d Increased se-
lectivity for Li+ relative to larger Na+ and K+ ions consti-
tutes a pattern often observed for branched crown ethers.
The consequence of belting as in 3 and 26 is, however,
quite special. The observed high selectivities for Li+
apparent in these tridentate examples (KaLi/KaNa ) 32 and
85, respectively) is comparable to values reported for
highly preorganized spherands36 and smaller cryptands.37
The value for 15-crown-5 is approximately 0.015.
the distance at which the metal ion resides above the 01,
02, 03 plane. For Li+, this value is 1.279 Å. The larger
Na+ is somewhat further away at 1.553 Å.
The relative ratio of [(crown)2‚M]+/[(crown)‚M]+ peaks
in FAB-MS has been used to correlate binding energies
in sandwich complexes.39 The intensity ratios for 27 and
28 were 0.1349 and 0.1571, respectively.
X-r a y Cr ysta llogr a p h y a n d F AB-MS Mea su r e-
m en ts. The readiness with which 3 forms complexes with
the smaller alkali metal ions was made apparent during
our investigation of its synthesis. If the utmost care was
not exercised to preclude the adventitious introduction
of Li+ or Na+ ions, complexes would be isolated. The
independent, purposeful preparation of the 2:1 sandwich
complexes 27 and 28 provided crystals amenable to the
acquisition of X-ray crystal structure data (Figures 2 and
3). Note that while 27 was obtained as a solvate with
CH2Cl2, 28 was not. The counterion selected for this
-
phase of the investigation was BF4 since this species
does not coordinate to cations and thus favors sandwich
formation.38 As expected, the ligand configuration is the
same in both complexes. The major difference resides in
Cocrystallization of 3 and methylamine perchlorate
from CH2Cl2 gave clear crystals of a 1:1 hydrogen bonded
complex 29 exhibiting a melting point of 94-96 °C
(Figure 4). The hydrogen bond associates the complex
into a dimer around a center of inversion. Each am-
monium component forms six hydrogen bonds, with
(36) Cram, D. J .; Lein, G. M. J . Am. Chem. Soc. 1985, 107, 3657.
(37) Lehn, J .-M.; Sauvage, J . P. J . Am. Chem. Soc. 1975, 97, 6700.
(38) Hilgenfeld, R.; Saenger, W. Top. Curr. Chem. 1982, 101, 1.
(39) Takahashi, T.; Uchiyama, A.; Yamada, K. Tetahedron Lett.
1992, 33, 3825.

Ligand Arrays Based on Spirotetrahydrofuranyl Motifs
J . Org. Chem., Vol. 65, No. 26, 2000 9167
H1-N involved with a single hydrogen bond to the anion
and H3-N with a single hydrogen bond to O2 of one
molecule of 3. Interestingly, H2-N is directed toward the
center of a second molecule of 3, thus forming a trifur-
cated hydrogen bond with O1, O2, and O3.
13C NMR Titr a tion Exp er im en ts. The conforma-
tional changes undergone by free ligands as they enter
into metal complexation is often accompanied by signifi-
cant changes in 13C NMR chemical shifts.40 The complex-
ing ability of 3 toward LiClO4 was probed by incremental
titration in 4:1 CH3CN/C6D6 at the normal operating
temperature according to the reference procedure.41 Upon
the addition of 0.25 equiv of the lithium salt, a separate
set of carbon signals attributable to the 2:1 complex
appears (Figure 5). The next experimental point (total
of 0.50 equiv) generates a spectrum which is exclusively
that of the 2:1 sandwich. When this amount of salt is
exceeded, the clearly defined signals of the 1:1 complex
replace those seen earlier.
F igu r e 4. Perspective plot of the 2:1 complex of 3 with
-
CH3NH3+ClO4
.
F igu r e 5. Incremental titration of 3 with LiClO4 in 4:1 CH3CN/C6D6 with monitoring of the level of complexation by 13C NMR
spectroscopy. The sequence of events is depicted from bottom to top.

9168 J . Org. Chem., Vol. 65, No. 26, 2000
Paquette et al.
F igu r e 6. Top views of 3 as the free ligand and its complex to Li+ showing the differing arrangement of the nonbonded electrons
on oxygen (top). Side views of the Li+, Na+ and K+ complexes to 3 showing the extent to which the metal ion protrudes above the
ring (middle and bottom).
The appearance of separate sets of carbon signals is a
direct consequence of slow exchange between the free
ligand and its 2:1 complex, as well as between the 2:1
sandwich and the 1:1 complex (Scheme 6). The strong
complexing stabilities witnessed earlier in the mass
spectral measurements are equally well reflected in
Figure 6. The changes in chemical shift suggest that a
conformational change may be occurring upon metal
complexation. Since the three ether oxygens must be
axially disposed to allow 3 to serve as a ligand, the
solution conformation of free 3 is likely the all-equatorial
arrangement as it is in the solid state. This partiality
for equatorial oxygen occupancy is not seen in the simple
monospiro example where 32a is favored over 32e by
2.1:1.43
The complexing capability of 3 toward NaClO4 is
phenomenologically different. As seen in Figure 7, con-
siderable line broadening sets in following the addition
of 0.25 equiv of sodium ion. When a second identical
increment of NaClO4 is introduced, sharp lines attribut-
able to the 2:1 complex make their appearance. This
spectrum does not change as more sodium perchlorate
is added (up to 1.5 equiv). Thus, the 2:1 complex of 3 to
Na+ is stable and not prone to conversion into the 1:1
complex under ordinary conditions, as in the case with
lithium ion.
(40) For a recent example, consult: Hoffmann, R. W.; Mu¨nster, I.
Liebigs Ann./ Recueil 1997, 1143.
(41) Fredriksen, S. B.; Dale, J . Acta Chem. Scand. 1992, 46,
1188.
(42) (a) Hay, B. P.; Rustad, J . R.; Hostetler, C. J . J . Am. Chem. Soc.
1993, 115, 11158. (b) Hay, B. P.; Rustad, J . R. J . Am. Chem. Soc. 1994,
116, 6316 and the many relevant references therein.
(43) Pederson, C. J .; Frensdorff, H. K. Angew. Chem., Int. Ed. Engl.
1972, 11, 16.

Ligand Arrays Based on Spirotetrahydrofuranyl Motifs
J . Org. Chem., Vol. 65, No. 26, 2000 9169
F igu r e 7. Incremental titration of 3 with NaClO4 in 4:1 CH3CN/C6D6 with monitoring of the level of complexation by 13C NMR
spectroscopy. Compare with Figure 5.
Sch em e 6
water were unsuccessful. Alternatively, advantage was
taken of the fact that 3 is freely soluble in ether and less
soluble in water. Heating a suspension of 31 in 1:1 ether/
water at the reflux temperature with vigorous stirring
afforded 64% of 3 in the organic phase and 25% of
recovered complex.
Molecu la r Mech a n ics Stu d y of th e Alk a li Meta l
Ion Com p lexes of 3. Several groups have found it
informative to develop molecular mechanics models for
the purpose of predicting the structures of ligands and
their metal ion complexes as a means of evaluating the
magnitude of steric strain within them. Most often, this
has been done for a series of ligands that differ in
structure but contain the same number and type of donor
atoms.42 For the present purposes, the cis,cis isomer 3
was first minimized in MODEL KS 2.96, thus obtaining
its MM2-based energy (47.54 kcal/mol) and locating the
nonbonding electron pairs residing at the three oxygen
atoms (Figure 6). Thereby revealed was the preference
of the free ligand to orient these filled orbitals ap-
proximately coplanar with the C-C bonds of the cyclo-
hexene core.
For the computations involving the 1:1 lithium, so-
dium, and potassium complexes, the Macintosh-based
CHEM-3D PLUS version 3.0 software package was found
to properly orient the lone pairs toward the metal ion
with attendant conformational modification of spirotet-
rahydrofuran conformation in all three pendant rings
(Figure 6). We have adopted the working assumption that
the force-field parameters used for arriving at the low-
Th e Decom p lexa tion P r ocess. Attempts to decom-
plex 31 by selective crystallization of 31 from 4:1 methanol/

9170 J . Org. Chem., Vol. 65, No. 26, 2000
Paquette et al.
Ta ble 2. Str a in En er gies a n d O-M Dista n ces for 3 a n d
Its Com p lexes by Mea n s of MODEL KS 2.96 a n d
CHEM-3D P a r a m eter s
considerable flexibility while defining a specific place-
ment of the three heteroatoms which is particularly
conducive to the binding of Li+ and Na+. The design,
synthesis, and complexation of new belted systems
anticipated to have application as bifacial chelators, ion
channel mimics, specific ion transport agents, and the
like are underway.
CHEM-3D
energy
(kcal/mol)
MODEL
energy
(kcal/mol)
O-M
distance
(Å)
cation
free ligand
47.54
47.54
“distorted” liganda
Li+
Na+
K+
69.89
73.28
84.70
70.05
73.45
84.88
1.839
2.145
2.636
Exp er im en ta l Section
a
(5R,7S)-13-Met h ylen e-1,8-d ioxa d isp ir o[4.1.4.3]t et r a -
d eca n e (16). A mixture of 12 (900 mg, 2.69 mmol) and 10%
palladium on charcoal (200 mg) in ethanol (30 mL) was stirred
under an atmosphere of hydrogen (40 psi) for 3 h, filtered
through a pad of Celite, and freed of solvent under reduced
pressure to deliver 580 mg (95%) of the primary alcohol as a
colorless liquid.
The reported strain energies are for the conformations adopted
in the respective complex after removal of the metal ion.
energy conformations of the complexes (see illustrations)
were ideally suited to removal of the metal cations
without disruption of the spatial orientation of the ligand.
These “distorted ligands” were then examined for their
CHEM-3D and MODEL MM2 energies without further
processing. The results are compiled in Table 2.
To a solution of this alcohol (510 mg, 2.25 mmol) and
o-nitrophenylseleno-cyanate (615 mg, 2.70 mmol) in THF (10
mL) was added tri-n-butylphosphine (0.67 mL, 2.70 mmol).
After 40 min of stirring, the solvent was removed and the
residue was chromatographed on silica gel (elution with 50%
ethyl acetate in hexanes) to afford the selenide, which was
dissolved in THF (15 mL), cooled to -20 °C, and treated with
30% hydrogen peroxide (3.0 mL). The reaction mixture was
maintained at -20 °C for 30 min, stirred at 20 °C for 16 h,
poured into saturated NaHCO3 solution (50 mL), and extracted
with ether (20 mL) and CH2Cl2 (2 × 20 mL). The combined
organic phases were dried and concentrated in advance of
chromatographic purification (silica gel, elution with 50% ethyl
acetate in hexanes). There was isolated 368 mg (79% overall)
of 16 as a colorless oil: IR (film, cm-1) 1651, 1449, 1337, 1072;
1H NMR (300 MHz, C6D6) δ 4.62 (t, J ) 1.4 Hz, 2 H), 3.73-
3.58 (m, 4 H), 2.39 (d, J ) 12.9 Hz, 1 H), 2.23-2.08 (m, 4 H),
1.78 (dt, J ) 12.9, 1.9 Hz, 1 H), 1.70-1.50 (m, 6 H), 1.35-1.25
(m, 2 H); 13C NMR (75 MHz, C6D6) ppm 145.0, 111.3, 82.7,
66.3, 49.2, 46.6, 34.8, 26.3; HRMS m/z (M+) calcd 208.1463,
obsd 208.1460.
(5r,7r,13â)-1,8,14-Tr ioxa t r isp ir o[4.1.4.1.4.1]oct a d ec-
a n e (4). A solution of 16 (119 mg, 0.57 mmol) in 1:1 methanol/
CH2Cl2 (40 mL) was ozonolyzed at -78 °C and treated with
methyl sulfide (3.0 mL). After overnight stirring, the solvent
was evaporated and the residue was chromatographed on silica
gel (elution with 25% ethyl acetate in hexanes) to afford the
ketone, which was immediately dissolved in THF (5 mL),
cooled to 0 °C, and treated with allylmagnesium bromide (2.4
mL of 1 N, 2.4 mmol). After 2 h at room temperature, the
reaction mixture was quenched with saturated NH4Cl solution
(10 mL), the separated aqueous layer was extracted with CH2-
Cl2 (2 × 10 mL), and the combined organic phases were dried
and concentrated. The residue was chromatographed on silica
gel (elution with 25% ethyl acetate in hexanes) to afford the
alcohol as a colorless oil.
As a consequence of the crystallographic data subse-
quently obtained for 27 and 28, it is apparent that the
atomic coordinates derived computationally for the O-M
bond lengths overestimate the actual distances involved
by 0.5-0.6 Å. Notwithstanding, the conformational re-
alignment experienced by the trio of tetrahydrofuran
rings, as required for proper bonding of the three oxygen
centers to the metal ion, is clearly revealed. As the size
of the central metal ion increases, 3 experiences progres-
sive distortion of its carbocyclic framework in an attempt
to accommodate proper 3-fold attachment to the metal.
For the Li+ f Na+ progression, the energy difference is
3.4 kcal/mol. In our view, the necessity for this structural
distortion is the major contributor to the ion selectivity
of this ligand, Ka(Li+)/Ka(Na+) ) 32. The even less
preferred M-O bond length for the potassium complex,
which involves an added energy increment in excess of
11 kcal/mol, reflects the size mismatch involved and the
very substantive selectivity for lithium as Ka(Li+)/Ka(K+)
) 2400. Consequently, in the present situation the size-
match selectivity theory,43 which states that a metal ion
will form the most stable complex with a ligand that
offers the best cavity size, and is frequently not adhered
to by conformationally flexible systems,44 may have
validity because of prevailing structural rigidity arising
from the spiroannulated rings.
Su m m a r y
A stereocontrolled synthesis of the belted all-cis
trispirotetrahydrofuran 3 has been accomplished in 17
steps from 3,5-dimethoxybenzoic acid in 14.6% overall
yield. Whereas its cis,trans isomer 4 does not enter into
complexation with alkali metal ions, 3 exhibits increased
Li+/Na+ selectivity relative to 15-crown-5. The conversion
of 3 into 2:1 sandwich complexes is general and leads to
shelf-stable products. Tridentate ionophore 3 populates
the 3eq conformation in the solid state and in solution.
For complexation to materialize, that conformation in
which the three oxygen atoms converge on a small
volume of space as in 3a x must be adopted. The present
data suggest that the 3eq a 3a x equilibrium is defined
by a barrier high enough to show a single conformation
on the NMR time scale, but of sufficiently low energy to
allow for facile complexation. The backbone of 3 provides
To a cold (0 °C) solution of this alcohol in THF (5 mL) was
added borane‚THF complex (2.2 mL of 1 N in THF, 2.2 mmol).
After being stirred for 1 h at this temperature, 3 N NaOH (2.2
mL) and 30% hydrogen peroxide were added. The reaction
mixture was allowed to warm to 20 °C for 2 h, quenched with
brine (10 mL) and CH2Cl2 (10 mL), and processed in the
prescribed manner to deliver the diol. The latter was dissolved
in CH2Cl2 (5 mL) and treated with tosyl chloride (185 mg, 0.97
mmol), triethylamine (0.20 mL, 1.43 mmol) and DMAP (10
mg). After 1 day, the reaction mixture was washed with water,
dried, and concentrated. Chromatography of the residue (silica
gel, elution with 25% ethyl acetate in hexanes) delivered 63
mg (44% overall) of 4 as a colorless liquid: IR (film, cm-1) 1448,
1
1349, 1177, 1047; H NMR (300 MHz, C6D6) δ 3.75-3.60 (m,
4 H), 3.60-3.48 (m, 2 H), 2.15-1.95 (m, 3H), 1.75-1.40 (series
of m, 15 H); 13C NMR (75 MHz, C6D6) ppm 82.9, 82.5, 66.7,
65.9, 48.0, 45.9, 38.9, 36.7, 26.4, 25.2; HRMS m/z (M+) calcd
252.1725, obsd 252.1730.
Anal. Calcd for C15H24O3: C, 71.39; H, 9.59. Found: C, 71.10;
H, 9.38.
(44) Reference 4d, pp 265-267.

Ligand Arrays Based on Spirotetrahydrofuranyl Motifs
J . Org. Chem., Vol. 65, No. 26, 2000 9171
(5r,7r,13r)-1,8,14-Tr ioxa t r isp ir o[4.1.4.1.4.1]oct a d ec-
a n e (3). To a cold (0 °C) solution of 25 (272 mg, 1.08 mmol) in
THF (10 mL) was added borane‚THF complex (2.2 mL of 1 N
in THF, 2.2 mmol). After 1 h at 0 °C, 3 N NaOH (2.2 mL) and
30% hydrogen peroxide (2.2 mL) were introduced, and the
reaction mixture was warmed to room temperature for 2 h and
quenched with brine (2 mL) and THF (20 mL). The separated
aqueous layer was extracted with CH2Cl2 (2 × 20 mL), and
the predescribed workup followed. Chromatography on silica
gel (elution with 50% ethyl acetate in hexanes containing 10%
methanol) afforded the diol (242 mg, 83%) as a colorless liquid.
The above material was dissolved in CH2Cl2 (20 mL) and
treated with tosyl chloride (366 mg, 1.92 mmol), triethylamine
(0.53 mL, 3.84 mmol), and DMAP (20 mg) at 20 °C for 6 h and
at the reflux temperature for 15 h. After concentration, the
residue was chromatographed on silica gel (elution with 50%
ethyl acetate in hexanes) to afford 184 mg (81%) of 3 as
colorless crystals, mp 111-113 °C (from 1:1 ether/hexanes),
and 30 mg (11%) of the (3)2‚NaBF4 complex.
1.91-1.80 (m, 9 H), 1.75-1.70 (m, 6 H), 1.52 (d, J ) 14.0 Hz,
3 H); 13C NMR (75 MHz, CDCl3) ppm 81.8, 67.7, 44.5, 40.0,
24.6; positive FAB MS m/z for 3‚Na+ calcd 275, obsd 275.16
(100%); for (3)2Na+ calcd 527, obsd 527.22 (15.7%).
Anal. Calcd for C30H48BF4NaO6: C, 58.64; H, 7.87. Found:
C, 58.82; H, 7.76.
For m ation of th e Meth ylam m on iu m P er ch lor ate Com -
p lex 29. A solution containing 50 mg (0.20 mmol) of 3 and
130 mg (0.99 mmol) of methylammonium perchlorate in CH3-
CN (3 mL) was stirred overnight at room temperature. After
solvent evaporation, CH2Cl2 (3 mL) was introduced and the
unreacted amine salt was filtered off. The filtrate was con-
centrated and the residue was triturated with dry ether. After
decantation, 20 mg of 3 was recovered. Recrystallization of the
remaining solid from CH2Cl2 afforded 40 mg (50%) of 29 as
1
colorless crystals: mp 94-96 °C; H NMR (300 MHz, CDCl3)
δ 3.83 (t, J ) 6.9 Hz, 6 H), 2.65 (q, J ) 6.2 Hz, 3 H), 1.95-
1.80 (m, 9 H), 1.75-1.60 (m, 6 H), 1.49 (d, J ) 14.0 Hz, 3 H);
13C NMR (75 MHz, CDCl3) ppm 81.5, 66.7, 44.7, 38.8, 25.6,
24.8; positive FAB MS m/z for 3‚H+ calcd 253, obsd 253.21
For 3: IR (film, cm-1) 1454, 1222, 1044; 1H NMR (300 MHz,
CDCl3) δ 3.80 (t, J ) 6.9 Hz, 6 H), 1.95-1.80 (m, 9 H), 1.70-
1.65 (m, 6 H), 1.57 (d, J ) 13.6 Hz, 3 H); 13C NMR (75 MHz,
CDCl3) ppm 81.5, 66.0, 45.5, 37.5, 25.3; HRMS m/z (M+) calcd
252.1725, obsd 252.1712.
+
(100%); for 3‚CH3NH3 calcd 284, obsd 284.21 (69.7%).
13C NMR Titr a tion Stu d ies. A solution of 3 (50 mg, 0.20
mmol) in 4:1 CH3CN/C6D6 was placed in an NMR tube. A
separate solution of LiClO4 (32 mg, 0.30 mmol) in the same
solvent system (1.2 mL) was prepared. A 13C NMR spectrum
was recorded after incremental addition of 0.20 mL (0.25 equiv)
aliquots of the perchlorate salt up to 1.5 equiv of LiClO4.
The resulting NMR solution was evaporated and the CH2-
Cl2-soluble complex was recrystallized from CH2Cl2 to furnish
65 mg (92%) of 31 as colorless crystals, mp 254-256 °C. The
latter were used for decomplexation studies described above.
Anal. Calcd for C15H24O3: C, 71.39; H, 9.59. Found: C, 71.28;
H, 9.56.
F or m a tion of th e Lith iu m Tetr a flu or obor a te Com p lex
27. A 24 mg (0.095 mmol) sample of 3 was added to a solution
of lithium tetrafluoroborate (4.5 mg, 0.048 mmol) in CH3CN
(2 mL), stirred overnight, and freed of solvent. Recrystalliza-
tion of the residue from 20% CH2Cl2 in hexanes) afforded 20
mg (70%) of 27 as colorless crystals, mp >290 °C dec; 1H NMR
(300 MHz, CDCl3) δ 3.76 (t, J ) 6.2 Hz, 6 H), 1.95-1.70 (m,
15 H), 1.55 (d, J ) 14.0 Hz, 3 H); 13C NMR (75 MHz, CDCl3)
ppm 81.6, 68.1, 45.3, 39.7, 25.0; positive FAB MS m/z for 3‚
Li+ calcd 259, obsd 259.15 (100%); for (3)2Li+ calcd 511, obsd
511.42 (13.5%).
Ack n ow led gm en t. We thank the National Science
Foundation and Hoechst Marion Roussel for partial
financial support of this research and Dr. Kurt Loening
for assistance with nomenclature.
Anal. Calcd for C30H48BF4LiO6: C, 60.21; H, 8.08. Found:
C, 60.14; H, 7.95.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectroscopic data for all compounds not described
in the printed format, details of the complexation studies, and
X-ray structure reports for 3, [3]2‚LiBF4‚CH2Cl2, [3]2‚NaBF4,
and 29. This material is available free of charge via the
Internet at http://pubs.acs.org.
F or m a tion of th e Sod iu m Tetr a flu or obor a te Com p lex
28. A solution of 3 (38 mg, 0.15 mmol) in 1:1 aqueous
acetonitrile (4 mL) containing sodium tetrafluoroborate (8.3
mg, 0.75 mmol) was stirred overnight, freed of solvent to leave
a residue that was crystallized from 20% CH2Cl2 in hexanes
to furnish 30 mg (65%) of 28 as colorless crystals: mp >295
°C dec; 1H NMR (300 MHz, CDCl3) δ 3.78 (t, J ) 6.6 Hz, 6 H),
J O001430A