Design and synthesis of a new class of nonmacrocyclic alkali metal host compounds

Article abstract of DOI:10.1021/ol006468o

A new class of nonmacrocyclic metal ion hosts has been examined that features a polyspirocyclic framework that offers a 1,3,5-triaxial presentation of ligating centers. These compounds are easily synthesized and exploit stereoelectronic influences to preorganize the metal ion binding site. While compounds bearing oxygen substituents (X = OH, OMe) failed to show appreciable binding of alkali metals, the aminated host (X = NHBn) exhibitied strong binding with association constants (K_a) greater than 10⁷-10⁸ as measured by picrate extraction analysis.

Full text of DOI:10.1021/ol006468o

ORGANIC
LETTERS
2000
Vol. 2, No. 22
3453-3456
Design and Synthesis of a New Class of
Nonmacrocyclic Alkali Metal Host
Compounds
Glenn J. McGarvey,* Marshall W. Stepanian, Andrew R. Bressette, and
Michal Sabat†
Department of Chemistry, UniVersity of Virginia, CharlottesVille, Virginia 22901
gjm@Virginia.edu
Received August 16, 2000
ABSTRACT
A new class of nonmacrocyclic metal ion hosts has been examined that features a polyspirocyclic framework that offers a 1,3,5-triaxial
presentation of ligating centers. These compounds are easily synthesized and exploit stereoelectronic influences to preorganize the metal ion
binding site. While compounds bearing oxygen substituents (X ) OH, OMe) failed to show appreciable binding of alkali metals, the aminated
host (X ) NHBn) exhibitied strong binding with association constants (Ka) greater than 107−108 as measured by picrate extraction analysis.
The rational creation of new metal ion hosts continues to be
an alluring endeavor.1 In the search for nonmacrocyclic
alternatives to the coronand and cryptand hosts, the critical
importance of preorganization of the ligating centers for
effective coordination has been recognized.2 This feature is
especially noteworthy in natural3 and synthetic acyclic
podands.4 Another novel class of nonmacrocyclic host
molecules has emerged that is based upon a 1,3,5-triaxially
substituted cyclohexane template. In particular, Angyal has
examined the metal-binding characteristics of carbohydrates
and inositols (1, Figure 1),5 while Hegtschweiler has studied
† To whom queries regarding crystallographic data should be addressed.
(1) For reviews, see: (a) Atwood, J. L., Davies, J. E. D., MacNicol, D.
D., Vogtle, F., Gokel, G. W., Eds. ComprehensiVe Supramolecular
Chemistry, Vol. 1; Pergamon: Oxford, 1996. (b) Izatt, R. M.; Pawluk, G.
W.; Bradshaw, J. S.; Bruening, R. L. Chem. ReV. 1995, 95, 2529. (c) Gokel,
G., Crown Ethers and Cryptands; The Royal Society of Chemistry:
Cambridge, UK, 1991.
(2) For a recent review, see: Hoffmann, R. W. Angew. Chem., Int. Ed.
2000, 39, 2055, and relevant references therein.
Figure 1. Nonmacrocyclic hosts based upon cyclohexane tem-
plates.
(3) Westley, J. W., Polyether Antibiotics: Naturally Occurring Acid
Ionophores, Vols. 1 and 2; Marcel Dekker: New York, 1983.
(4) For particularly pertinent examples, see: (a) Li, G.; Still, W. C.
Tetrahedron Lett. 1993, 34, 919. (b) Erickson, S. D.; Still, W. C.
Tetrahedron Lett. 1990, 31, 4253. (c) Iimori, T.; Still, W. C.; Rheingold,
A. L.; Staley, D. L. J. Am. Chem. Soc. 1989, 111, 3439.
the coordinating properties of various triamino cyclo-
hexanetriols (2).6 The polyspirocyclic tetrahydrofurans (3)
recently reported by Paquette and co-workers exhibit impres-
sive metal binding characteristics and serve to illustrate the
importance of prior organization of the ligating sites.7
Toward an objective of developing new asymmetric metal
ion host molecules, we have examined trans-15-substituted-
(5) Angyal, S. J. AdV. C arbohydr. Chem. Biochem. 1989, 47, 1.
(6) Hegetschweiler, K. Chem. Soc. ReV. 1999, 28, 239.
(7) (a) Negri, J. T.; Rogers, R. D.; Paquette, L. A. J. Am. Chem. Soc.
1991, 113, 5073. (b) Paquette, L. A.; Tae, J.; Hinkey, E. R.; Rogers, R. D.
Angew. Chem., Int. Ed. 1999, 38, 1409. (c) Tae, J.; Rogers, R. D.; Paquette,
L. A. Org. Lett. 2000, 2, 138. (d) Paquette, L. A.; Tae, J.; Gallucci, J. C.
Org. Lett. 2000, 2, 143. (NOTE: Compound 3 is depicted in its most stable,
uncomplexed conformation.)
10.1021/ol006468o CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/07/2000

1,7,9-trioxadispiro[5.1.5.3]hexadecanes of the type 4 as
attractive candidates by several criteria (Figure 2).8 As
precursor 7. This introduces two possible cis-spiroketals
(anti- and syn-isomers) of which the syn-cis isomer is desired
(syn-cis-8). It could be anticipated that stereoelectronic effects
would strongly influence the steric course of this spiro-
cyclization reaction. Previous studies in these laboratories
examined the spiroketalization of the parent diketo diol 7
(X ) H) to find that a 68:32 mixture of trans:cis bis-
spiroketals was obtained.8b This result was interpreted to be
the consequence of dipole repulsion favoring the anti
disposition of the spirocyclic oxygens that was augmented
by a twist-boat conformation of the central ring that
accommodates a geometry enabling four imperfect stabilizing
anomeric effects.
The spirocyclization of a C15*-substituted precursor, 7,
was examined in order to gain access to triaxial structures
suitable for metal binding. As shown in Scheme 1, epi-
Figure 2. Metal ion binding with substituted polyspiroketals.
Scheme 1. Thermodyamically Driven Polyspiroketal Synthesis
indicated, two possible modes of metal binding can be
envisioned, through either triaxial (5) or equatorial/diaxial
(6) coordination with a metal ion. Assuming a chair
conformation for the central ring, three staggered conforma-
tions of the outer two rings may be considered (I, II, III).
While all three conformations present converging lone pairs
to allow binding of type 5, only conformation I would allow
for the alternative binding mode 6. Consideration of stereo-
electronic effects suggests that conformation I may be the
least favorable form as it offers the fewest potential anomeric,
or gauche, effects.9 Consequently, it was anticipated that the
desired mode of binding (5) would be favored through
stereoelectronic preorganization of the ligating centers.
Adding to the appeal of this type of binding array is its
synthetic availability through thermodynamically driven
spiroketalization of readily available diketo diol precursors
(such as 7, Figure 3). As indicated, spiroketalization may
bromohydrin was treated with the vinylcuprate10 derived from
dihydropyran to assemble the intact bis-spiroketal precursor
9 in good yield. Acid-catalyzed hydration of vinyl ethers
affords 7 (X ) OH) which may be subsequently dehydra-
tively spirocyclized to a 59:7:34 mixture of 10t:syn-10c:anti-
10c in 83% yield. It is noteworthy that the C15 hydroxyl
group exerts a noticeable directing effect in favor of the
desired cis-spiro isomer, improving the trans:cis ratio relative
to the unsubstituted example (59:41 versus 68:32). While
experiments to determine the origin of this directing effect
have yet to be carried out, it may be the result of destabiliza-
tion of the twist-boat conformation of the central ring that
favors the trans-isomer in the parent compound.
Of practical value in the present study, anti-10c may be
conveniently isolated by simple flash chromatography while
the remaining inseparable mixture of 10t and syn-10c can
be quantitatively recycled through acid-catalyzed isomer-
(8) (a) McGarvey, G. J.; Stepanian, M. W. Tetrahedron Lett. 1996, 31,
5461. (b) McGarvey, G. J.; Stepanian, M. W.; Bressette, A. R.; Ellena, J.
F. Tetrahedron Lett. 1996, 37, 5465.
(9) (a) Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry;
Pergamon: Oxford, 1983. (b) The Anomeric Effect and Associated
Stereoelectronic Effects; Thatcher, G. R., Ed.; ACS Symp. Series 539;
American Chemical Society: Washington, DC, 1993.
(10) Lithiation of dihydropyran: Amouroux, R. Heterocycl. 1984, 22,
1489. Cuprate formation: Kozlowski, J. A.; Lipshutz, B. H.; Wilhelm, R.
S. Tetrahedron 1984, 24, 5005.
Figure 3. Stereochemical issues in polyspiroketalization.
proceed to afford either trans or cis relationships about the
spirocyclic centers (trans- and cis-8). To access triaxial arrays
of type 5, a pro-C15 substituent (15*) may be installed in
3454
Org. Lett., Vol. 2, No. 22, 2000

ization to the original diastereomeric mixture to allow
isolation of additional cis-spiroketal, anti-10c (Scheme 1).
In this fashion, multigram quantities of anti-10c can be
efficiently isolated.11
The installation of other C15 heteroatoms was also
explored. With ketone 11 in hand, reductive amination was
carried out as depicted in Scheme 3. When direct amination
To obtain the desired all-syn arrangement of the ligating
centers, correction of the C15 stereocenter was necessary.
This could be accomplished through reduction of ketone 11,
which is readily prepared by Dess-Martin periodinane
oxidation of purified anti-10c (Scheme 2).12 While many
Scheme 3. Reductive Amination of Ketone 11
Scheme 2. Selective Manipulation of C15
using alkylamines proved unsuccessful, the oxime intermedi-
ate 13 was exploited. Exhaustive reduction through the
agency of nickel boride16 afforded the corresponding amine
which was directly benzylated under conditions of reductive
alkylation to yield the desired product 14 in good overall
yield.17 It bears noting that the reduction of the oxime (13)
was significantly more selective and efficient than the corre-
sponding ketone (11), resulting in isolation of the final amine
without contamination by any of the undesirable epimer.
With several potential hosts in hand, attention was turned
to the examination of their metal binding properties. The
association constants (Ka) for Li+, Na+, and K+ were
measured using Cram’s picrate extraction method (Table 1).18
reducing agents, including NaBH4,13 were found to lead to
isomerization of the spiroketal linkages, LiAlH4 reduction
proceeded in almost quantitative yield to favor the desired
syn-product (syn-10c, R ) H) as a 77:22 mixture of separable
alcohol epimers. Catalytic hydrogenation proved even more
stereoselective, favoring the desired isomer as a 97:3 mixture,
but in significantly diminished yield.
Table 1. Association Constants (Ka) Determined by Picrate
Extraction from CHCl3
In an effort to obtain other potential metal binding hosts,
derivatization of the C15 substituent was examined. Treat-
ment of each C15 alcohol isomer with MeI and Ag2O14 led
to formation of the corresponding methyl ethers. The
availability of these ethers proved important not only for
subsequent metal binding studies but also for structural
assignments. The anti-isomer (anti-12) crystallized to allow
its structure to be established by X-ray crystallography (see
Scheme 2), thus establishing the stereochemical relationships
in compounds 10, 11, and 12.15 In addition, it was gratifying
to observe that all the rings in this polycyclic array existed
in chair forms with the spirocyclic oxygens axially oriented,
presumably accommodating the maximum of four stabilizing
anomeric effects.
(11) The spirocyclization reaction has been routinely carried out on more
than 10 g of precursor 9 to afford approximately 5 g of anti-10c after a
single recycle.
(12) A modified procedure was used: Danishefsky, S. J.; Jeroncic, L.
O.; Linde, R. G. J. Org. Chem. 1991, 56, 2534.
(13) Reduction using NaBH4 gave a 23:39:38 mixture of 10t:syn-10c:
anti-10c.
(14) Crabbe, P.; Drian, C. L.; Greene, A. E. J. Am. Chem. Soc. 1980,
102, 7583.
(15) The hydrogens have been omitted for clarity.
(16) Ipaktschi, J. Chem. Ber. 1984, 117, 856.
(17) Cowen, K. A.; Leuck, D. J.; Mattson, R. J.; Pham, K. M. J. Org.
Chem. 1990, 55, 2552.
Org. Lett., Vol. 2, No. 22, 2000
3455

To calibrate our binding measurements, the association
constants for dicyclohexano-18-crown-6 were obtained for
comparison with previous studies (entry 1).19 Examination
of the parent cis-spiroketal (cis-8, entry 3) allowed direct
assessment of the contribution of diaxial/equatorial binding
of type 5 (Figure 2). No appreciable binding of this type is
observed as evidenced by the low association constants
observed. Entries 4 and 5, however, offer the possibility of
triaxial metal binding with the inclusion of a syn-C15 oxygen
substituent. Poor metal ion association was also observed
for these compounds, comparable to that found in the
unsubstituted parent compound. While intramolecular hy-
drogen bonding could be expected to compete with metal
binding in alcohol syn-10c (entry 4), it was surprising that
methyl ether syn-12 (entry 5) was equally ineffective as a
host.20
more tightly while associating with the potassium ion only
slightly less tightly despite bearing only three centers for
coordination. Another useful comparison may be made with
Paquette’s spirocyclic host (3, entry 2) which exhibits binding
constants 1, 2, and 3 orders of magnitude less than 14 for
potassium, sodium, and lithium, respectively.
The impressive metal binding of 14 validates the supposi-
tion that small nonmacrocyclic arrays may be effective hosts
if appropriate preorganization of the ligating centers is
imposed. It is noteworthy that the preorganization in the
present host does not come at a high synthetic cost as
thermodynamic controlling features, including stereoelec-
tronic effects, are exploited to enforce the desirable geometry.
It is anticipated that this bis-spiroketal motif may be
profitably exploited to create useful chiral environments
about select metal ions for subsequent utilization in asym-
metric recognition and in the mediation of asymmetric
transformations.
In contrast, replacement of the oxygen substituent with
benzylamine (14, entry 6) resulted in remarkably strong
binding with all the metal ions investigated. A revealing
comparison is found with crown ether which bears six
ligating centers (entry 1). Host 14 respectively binds sodium
and lithium ions greater than 2 and 3 orders of magnitude
Acknowledgment. Support for this research from the
University of Virginia is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures for Schemes 1, 2, and 3, full characterization for
compounds 9, 10t, syn-10c, anti-10c 11, syn-12, anti-12, 11,
13, and 14 and X-ray crystallographic data for anti-12. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(18) Cram, D. J.; Kaneda, T.; Koenig, K. E.; Lein, G. M.; Stuckler, LP.
J. Am. Chem. Soc. 1979, 101, 3553.
(19) The association constants obtained were in good agreement with
those reported in other studies. See refs 4c and 18.
(20) It is noteworthy that Paquette and co-workers observed similarly
poor host characteristics with a triaxial 1,3,5-trimethoxycyclohexane
derivative. See ref 4c.
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