Synthesis of, and structural assignments to the stereoisomers of bis (2,2′)- and tris (2,2′,2″)-tetrahydrofurans: Conformational features and ionic binding capacities of these gateway polycyclic networks

Article abstract of DOI:10.1021/jo0708238

(Chemical Equation Presented) Construction of the polytetrahydrofuranyl building blocks 6-10 from the common bissiloxyacetone precursor 11 is detailed. The approach is concise and, for the bis-(THF) pair, capitalizes on the full retention of configuration

Full text of DOI:10.1021/jo0708238

Synthesis of, and Structural Assignments to the Stereoisomers of Bis
2,2′)- and Tris (2,2′,2′′)-Tetrahydrofurans: Conformational
(
Features and Ionic Binding Capacities of These Gateway Polycyclic
Networks
†
‡
§
†
†
Emel Adaligil, Barry D. Davis, David G. Hilmey, Young Shen, Jason M. Spruell,
‡
†
,§
Jennifer S. Brodbelt, K. N. Houk, and Leo A. Paquette*
Department of Chemistry and Biochemistry, UniVersity of California, Los Angeles, 405 Hilgard AVenue,
Los Angeles, California 90095-1569, Department of Chemistry and Biochemistry, UniVersity of Texas
at Austin, Austin, Texas 78712, and Department of Chemistry, The Ohio State UniVersity,
1
00 West 18th AVenue, Columbus, Ohio 43210
paquette.1@osu.edu
ReceiVed April 24, 2007
Construction of the polytetrahydrofuranyl building blocks 6-10 from the common bissiloxyacetone
precursor 11 is detailed. The approach is concise and, for the bis-(THF) pair, capitalizes on the full
retention of configuration observed during the rhodium-promoted decarbonylation of aldehydes 18 and
1
9. The capability of the title compounds to associate with alkali metal ions in solution and the gas
+
+
+
phase has demonstrated a preference for Li over Na and K in all cases, with 6 and 7 exhibiting
somewhat higher binding selectivities than 8-10. The relative energy orderings of attainable conformations
with the bis-THF and tris-THF series were explored computationally. The various envelope arrangements
present in the individual THF units are shown to play a significant role alongside prevailing gauche
interactions. The “gauche effect” is shown computationally not to be an accurate predictor of the lowest
energy conformer.
In more advanced studies of conformational analysis, a key
point of investigation involves molecules in which unshared
electron pairs and/or polar bonds are linked to adjacent
CN, OCH3, F) share in the unusual consequences of their vicinal
arrangement, the greatest level of attention has been accorded
to ethers because of their unique ligating features and chemical
6
1-5
carbons. Although several small, electronegative groups (e.g.,
(
4) (a) Phillips, L.; Wray, V. J. Chem. Soc. Chem. Commun. 1973, 90.
b) Juaristi, E.; Antunez, S. Tetrahedron 1992, 48, 5941.
5) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic
(
*
To whom correspondence should be addressed. Tel: 1 614 292 2520. Fax:
(
1
614 292 1685.
†
Compounds; John Wiley: New York, 1994; pp 606-615.
UCLA.
The University of Texas.
The Ohio State University.
‡
(6) (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) V o¨ gtle, F. Supramolecular Chemistry; John 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.
§
(
1) (a) Zefirov, N. S. Tetrahedron 1977, 33, 3193. (b) Zefirov, N. S.;
Samoshin, V. V.; Subbotin, O. A.; Baranenkov, V. I.; Wolfe, S. Tetrahedron
978, 34, 2953.
1
(
2) Van-Catledge, F. A. J. Am. Chem. Soc. 1974, 96, 5693.
(3) (a) Wolfe, S.; Rauk, A.; Tel, L. M.; Csizmadia, I. G. J. Chem. Soc.
B 1971, 136. (b) Wolfe, S.; Tel, L. M.; Haines, W. J.; Robb, M. A.;
Csizmadia, I. G. J. Am. Chem. Soc. 1973, 95, 4863. (c) Wolfe, S. Acc.
Chem. Res. 1972, 5, 102.
1
0.1021/jo0708238 CCC: $37.00 © 2007 American Chemical Society
Published on Web 07/13/2007
J. Org. Chem. 2007, 72, 6215-6223
6215

Adaligil et al.
7
relevance. Thus, 1,2-dimethoxyethane (1) is well recognized
to adopt a gauche rather than a perfectly staggered spatial
8
arrangement. Polyoxyethylene, (OCH2CH2)n, exhibits the same
energetic bias and, as a consequence, assumes an overall helical
9
conformation. Such compounds provide a logical starting point
for the development of a class of open-chain molecules having
defined spatial arrangements.
yet been fully documented. This fact is in large part attributable
to the absence until recently of a synthetic route amenable to
unambiguously distinguishing the two diastereomers from each
The progression from an acyclic ether to one cyclic in nature
e.g., diethyl ether to tetrahydrofuran) has profound conse-
1
9
(
other. An enantioselective synthesis of 7 was disclosed in
2
0
quences. For example, miscibility with water and intrinsic
basicity differ strikingly, with the ring compound exhibiting
2004. Because the 6/7 isomer pair as well as the three tris-
(THF) homologues 8, 9, and 10 constitute an important subset
of reference compounds, we have pursued the development of
10
greater hydrogen-bonding capability and enhanced gas-phase
1
1
proton affinity. Faster rates of proton attachment in solution
also fit this pattern.12 Such factors are recognized to offer
contrasting properties, although this need not necessarily be the
case. Two illustrative examples follow. Whereas 2 is an
impressively selective ligand for lithium ions, 3 is not at all
1
3
conducive to binding to any alkali metal ion in solution. On
14
the other hand, both the hexamethyl ether of scyllo-inositol (4)
and all-trans-hexaspiro(THF)cyclohexane (5)15,16 display a
strong inherent preference for adoption of the all-equatorial
oxido conformer. This overwhelming predilection for equatorial
O-alkyl occupancy interesting for theoretical reasons and has
been examined computationally.1
7,18
a scheme capable of delivering in unequivocal fashion, pure
samples of each member in preparative amounts.21 This full
complement of short-chain polytetrahydrofuranyl networks has
come to be regarded as gateway molecules central to our fuller
appreciation of the prospects anticipated for longer-chain
polyether entities. All segments can partake of conformational
flexibility. Rotation about the interconnective C-C bonds is,
of course, an energetically inexpensive way to relieve intramo-
lecular conformational effects.
In light of these developments, it is striking that the properties
of threo-(6) and erythro-bis(2,2′)-tetrahydrofuran (7) have not
(
7) (a) Koert, U.; Stein, M.; Harms, K. Angew. Chem., Int. Ed. Eng.
st
1
994, 33, 1180. (b) Paquette, L. A. In Chemistry for the 21 Century;
Keinan, I., Schechter, I., Eds.; Wiley-VCH: Weinheim, 2001; 37-53.
8) Matsuura, H.; Miyauchi, N.; Murata, H.; Sakakibara, M. Bull. Soc.
Chem. Jpn. 1979, 52, 344.
9) (a) Ohsaku, M.; Imamura, A. Macromolecules 1978, 11, 970. (b)
(
(
Abe, A.; Mark, J. E. J. Am. Chem. Soc. 1976, 98, 6468. (c) Eliel, E. L.
Acc. Chem. Res. 1970, 3, 1.
The Synthetic Route. Our comprehensive synthetic pathway
was founded on the initial assembly of a pair of perhydrogenated
(
10) (a) Berthelot, M.; Besseau, F.; Laurence, C. Eur. J. Org. Chem.
1
998, 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.
(19) (a) Reichstein, T. A.; Gr u¨ ssner, H.; Zschokke, H. HelV. Chim. Acta
1932, 15, 1066. (b) Kondo, H.; Suzuki, H.; Takeda, K. J. Pharm Soc. Jpn.
1935, 55, 142. (c) Fieser, L. F.; Fry, E. M.; Jones, R. N. J. Am. Chem. Soc.
1939, 61, 1849. (d) Shima, K.; Tsutsumi, S. Bull. Chem. Soc. Jpn. 1963,
36, 121. (e) Micovic, V. M.; Stojcic, S.; Mladenovic, S.; Stefanovic, M.
Tetrahedron Lett. 1965, 21, 1559. (f) Van Tamelen, E. E.; Schwartz, J.;
Brauman, J. I. J. Am. Chem. Soc. 1970, 92, 5798. (g) Sakakibara, T.;
Haraguchi, K. Bull. Chem. Soc. Jpn 1980, 53, 279. (h) Yanagida, S.; Azuma,
T.; Kawakani, H.; Kizumoto, H.; Sakura ¨ı , H. J. Chem. Soc., Chem. Commun.
1984, 1, 21. (i) Yanagida, S.; Azuma, T.; Midori, Y.; Pac, C.; Sakurai, H.
J. Chem. Soc., Perkin Trans. 2 1985, 1487. (j) Kharrat, A.; Gardrat, C.;
Maillard, B. Can. J. Chem. 1984, 62, 2385. (k) Bourgeois, M. J.; Maillard,
B.; Montaudon, E. Tetrahedron 1986, 42, 5309. (l) Zeug, N.; B u¨ cheler, J.;
Kisch, H. J. Am. Chem. Soc. 1985, 107, 1459. (m) Shine, H. J.; Soroka, M.
Tetrahedron 1986, 42, 6111. (n) Crabtree, H.; Brown, S. H. J. Am. Chem.
Soc. 1989, 111, 2946. (o) Gevorgyan, V.; Gavars, M.; Liepins, E.; Priede,
E.; Lukevics, E. J. Organomet. Chem. 1990, 393, 333. (p) Jung, J. C.; Choi,
H. C.; Kim, Y. H. Tetrahedron Lett. 1993, 34, 3581. (q) Murai, A.; Fujiwara,
K.; Hayashi, N. Tetrahedron 1997, 53, 12425. (r) Negele, S.; Wieser, K.;
Severin, T. J. Org. Chem. 1998, 63, 1138. (s) Kelly, D. R.; Nally, J.
Tetrahedron Lett. 1999, 40, 2209.
1
989, 30, 2571. (d) Laurence, C.; Nicolet, P.; Helbert, M. J. Chem. Soc.,
Perkin Trans. 2 1986, 1081.
11) Bordeje, M. C.; Mo, O.; Yanez, M.; Herreros, M.; Abboud, J. L.
M. J. Am. Chem. Soc. 1993, 115, 7389.
12) (a) Pines, E.; Fleming, G. R. Isr. J. Chem. 1993, 33, 179. (b)
(
(
Krygowski, T. M.; Radomski, J. P.; Rzeszowiak, A.; Wrona, P. K.;
Reichardt, C. Tetrahedron 1981, 37, 119. (c) Westera, G.; Blomberg, C.;
Bickelhaupt, F. 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.
(13) (a) Paquette, L. A.; Tae, J.; Hickey, E. R.; Trego, W. E.; Rogers,
R. D. J. Org. Chem. 2000, 65, 9160. (b) See also: Paquette, L. A.; Ra, C.
S.; Gallucci, J. C.; Kang, H.-J.; Ohmori, N.; Arrington, M. P.; David, W.;
Brodbelt, J. S. J. Org. Chem. 2001, 66, 8629.
(
14) Anderson, J. E.; Angyal, S. J.; Craig, D. C. Carbohydr. Res. 1995,
72, 141.
15) Paquette, L. A.; Tae, J.; Branan, B. M.; Bolin, D. G.; Eisenberg, S.
W. E. J. Org. Chem. 2000, 65, 9172.
16) See also: Paquette, L. A.; Stepanian, M.; Branan, B. M.; Edmond-
son, S. D.; Bauer, C. B.; Rogers, R. D. J. Am. Chem. Soc. 1996, 118, 4504.
2
(
(
(
17) Anderson, J. E. J. Chem. Soc. Perkin Trans. 2 1993, 441.
(20) Alexakis, A.; Tomassini, A.; Leconte, S. Tetrahedron 2004, 60,
9479.
(18) (a) Rablen, P. R.; Paquette, L. A.; Borden, W. T. J. Org. Chem.
2
000, 65, 9180. (b) Hay, B. P.; Oliferenko, A. A.; Uddin, J.; Zhang, C.;
(21) Paquette, L. A.; Hilmey, D. G.; Gallucci, J. C. Org. Lett. 2006, 8,
2635.
Firman, T. K. J. Am. Chem. Soc. 2005, 127, 17043.
6216 J. Org. Chem., Vol. 72, No. 16, 2007

Bis (2,2′)- and Tris (2,2′,2′′)-Tetrahydrofurans
SCHEME 1
(
2,2′)bifuranyls monofunctionalized in a manner that would
derivative 13, it proved most expedient to proceed via the two-
step sequence involving treatment with excess TBAF in THF,
followed by monosilylation. Clean conversion of 13 to the
aldehyde by way of the Swern protocol laid the foundation for
second-stage annulation. The absence of stereoselectivity,
revealed in the 1:1 distribution of 14 and 15, parallels the
response customarily observed for the 1,2-addition of Grignard
reagents to highly substituted aldehydes and offered no surprises.
In fact, the absence of discernible chelation control was counted
on to provide us with the maximum level of both products for
more advanced synthetic applications. Of equivalent significance
was the finding that 14 could be readily separated from 15 by
chromatography on silica gel. The independent desilylation of
14 and 15 gave isomerically pure samples of alcohols 16 and
17. From this point, the aldehydes 18 and 19 were made
available by Swern oxidation. These carbonyl-functionalized
intermediates were to play several important synthetic roles.
Prior to this, it was mandatory that their relative configurations
be unequivocally established. This objective was realized by
the derivatization of 18 as its 2,4-dinitrophenylhydrazone 20
and X-ray crystallographic analysis of the latter. In this way,
the detailed structures of both 18 and 19 were made known.
allow simultaneously for the chromatographic separation of
diastereomers and for crystallographic analysis to establish their
relative configuration. Further, the reaction channel should be
amenable to bifurcation, with one option leading simply and
individually to 6 and 7, and the other functioning as advanced
scaffolding for the ultimate production of 8-10. The level of
functionality resident in the bissiloxyacetone 11, in combina-
tion with the Normant reagent,23 proved adequate to address
these issues concisely and efficiently.
22
Admixing of approximately equimolar amounts of these
reactants in THF at -78 °C gave the expected 1,4-diol, thereby
setting the stage for cyclization to 12 via the monotosylate
2
4
(Scheme 1). The symmetry inherent in 12 guarantees that it is
the sole product of this reaction. To arrive at the monohydroxy
(
(
22) Calter, M. A.; Zhu, C.; Lachicotte, R. J. Org. Lett. 2002, 4, 209.
23) Cahiez, G.; Alexakis, A.; Normant, J. F. Tetrahedron Lett. 1978,
3
013.
(24) (a) Negri, J. T.; Rogers, R. D.; Paquette, L. A. J. Am. Chem. Soc.
1
991, 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.
1
996, 61, 7492.
25) For example: Paquette, L. A.; Wiedeman, P. E.; Bulman-Page, P.
C. J. Org. Chem. 1988, 53, 1441.
The elucidation of these details provided us with the insight
needed to undertake the decarbonylation of these aldehydes.
(
J. Org. Chem, Vol. 72, No. 16, 2007 6217

Adaligil et al.
SCHEME 2
TABLE 1. Association Constants (Ka) Determined by Picrate
Walborsky and Allen reported in 1971 that optically active
aldehydes bearing an adjacent stereogenic center are decarbo-
Extraction from CHCl3
ligand
Li+
Na+
K+
nylated with retention of configuration in the presence of
Wilkinson’s catalyst.26 This stereochemical outcome was real-
15-crown-5a
syn/anti 8
syn/anti 9
syn/anti 10
9.4 × 104
6.3 × 106
1.1 × 106
4
4
4
2.9 × 10
1.6 × 10
1.3 × 10
ized irrespective of the particular hybridization of the carbon
atom to which the carbonyl group is bonded. In the case of 18,
heating with (Ph3P)3RhCl in xylene at 160 °C for 6 h gave rise
to 6 in 52% yield. The analogous treatment of 19 provided 7 as
4
4
4
4.3 × 10
2.7 × 10
1.7 × 10
4
4
4
2.7 × 10
1.9 × 10
1.2 × 10
a
For calibration purposes; see Paquette, L. A.; Tae, J.; Hickey, E. R.;
Rogers, R. D. Angew. Chem. Int. Ed. 1999, 38, 1409.
1
the exclusive product (61% isolated). Although the H NMR
spectra of 6 and 7 hold many similarities, their 13C NMR spectra
are sufficiently distinctive to allow stereochemical assignment
on this basis.
The processing of 18 through a third-stage annulation afforded
two tris(THF) stereoisomers, which proved readily amenable
to chromatographic separation on silica gel. The structural
assignments to these products awaited the comparable chemical
modification of 19 (Scheme 2). Once this was accomplished, it
was made clear that the minor product (1.4:1) of the first reaction
sequence was chemically identical to the minor product (1:1.5)
of the second. Since the only common isomer can be 9, the
stereochemical features of all three isomers are made unequivo-
cally apparent.27
FIGURE 1. Positive ion mode MS spectrum of a solution containing
ligand 8 (10 µM) and LiCl, NaCl, and KCl (100 µM each).
Solution-Phase Complexation Studies. The three tris-
(2,2′,2′′)-tetrahydrofuran isomers were subjected to picrate
extraction involving water/chloroform mixtures according to the
procedure laid out by Cram and co-workers.28 The objective
was to determine to what degree alkali metal binding would
occur through the coordination of picrate salts by these
basis, high levels of binding were not anticipated. As seen in
Table 1, alkali metal ions are in fact not particularly well
accommodated. As expected, a general trend can be noted
wherein higher Ka values are seen for all isomers with the
lithium cation. The lowest values are associated with the larger
potassium ion. While the data for the two symmetric tris-(THF)
isomers are closely comparable, the asymmetric 9 exhibits 1.5
times the Ka value for all three metal ions.
13
potentially specific host molecules. C NMR titrations involving
the syn/syn isomer 8 and its anti/anti counterpart 10 with lithium
29
perchlorate in 1:1 CH3CN:CDCl3 proved inconclusive. On this
(
26) Walborsky, H. M.; Allen, L. E. J. Am. Chem. Soc. 1971, 93, 5465.
Electrospray Ionization-Mass Spectrometry Measure-
ments. Electrospray ionization mass spectrometry (ESI-MS)
was used to evaluate the alkali metal ion selectivities of the
(27) The title compounds have been universally depicted with a zigzag
conformation of their backbone carbon chains. The resulting conformational
representations are not intended to imply that the all-anti arrangements are
thermodynamically more stable (see the sequel). All of the polycyclics are
either meso or racemic in nature. Despite the indicated standardization,
visualization remains less than obvious in certain cases. The pair of formulas
presented below illustrates the problem, which is reminiscent of that
associated with the use of Fisher projections.
30
ligands. A typical mass spectrum obtained upon electrospray
ionization of one of the ligands in methanol in the presence of
excess alkali metals is shown in Figure 1. A summary of the
metal selectivities, in terms of the distribution of lithium,
sodium, and potassium complexes obtained from the abundances
of complexes in the ESI-mass spectra for each ligand, is shown
in Table 2. For all of the ligands, the lithium-cationized
complexes had the greatest abundances, and the abundances of
(
28) Koenig, K. E.; Lein, G. M.; Stuckler, P.; Kaneda, T.; Cram, D. J.
J. Am. Chem. Soc. 1979, 101, 3553.
29) Hilmey, D. G. Ph.D. Dissertation, The Ohio State University, 2006.
(30) Blair, S.; Kempen, E.; Brodbelt, J. S. J. Am. Soc. Mass Spectrom.
1998, 9, 1049.
(
6218 J. Org. Chem., Vol. 72, No. 16, 2007

Bis (2,2′)- and Tris (2,2′,2′′)-Tetrahydrofurans
TABLE 2. ESI-MS Metal Ion Selectivities of Bis- and Tris-(THF)
TABLE 5. Relative RHF/6-31G(d) Energies of Lowest Energy
Conformers of bis-THF
a
Ligands
ligand
Li (%)
Na (%)
K (%)
E+ZPE
E+ZPE
Meso conformer
(kcal/mol)
Rac conformer
(kcal/mol)
6
7
8
9
94
96
81
87
77
6
4
16
11
20
<1
<1
3
2
3
A
0
C
0
0.2
0.5
2.1
0.2
0.3
1.5
1.6
1.7
2.4
10
B
D
E
2
2
2
.1
.5
.5
a
Percentage of Li, Na, and K complexes obtained from the ESI-mass
spectrum of solutions containing one ligand and a mixture of all three alkali
metals in methanol.
2
2
.4
.4
TABLE 3. Meso Conformers and Calculated Energies
RHF/6-31G(d)
B3LYP/6-31G*
B3LYP/6-31+G**
0-0.5
0.00
0.00
2.1-2.5 kcal/mol
0.9 kcal/mol
1.5 kcal/mol
FIGURE 2. B3LYP/6-31+G** optimized structures of lowest energy
conformers of A and B.
TABLE 4. Rac Conformers and Calculated Energies
RHF/6-31G(d)
B3LYP/6-31G*
B3LYP/6-31+G**
0-0.3
0.00
0.00
1.5-1.7
2.0
1.5
2.4 kcal/mol
2.6 kcal/mol
2.5 kcal/mol
the potassium complexes were very low. The differences in
lithium versus sodium selectivity within each series of bicyclic
or tricyclic ligands were not deemed significant based on the
precision of the measurements. The ESI-MS method affords a
rapid way to screen the metal selectivities of these ligands and
reveals that all favor complexation with lithium over the larger
alkali metals, thus mirroring the trend obtained from the picrate
extraction results.
Conformational Analysis of the Bis-Tetrahydrofurans.
Conformers of the meso and rac diastereomers of 2,2′-bis-
tetrahydrofurans (-THF’s) were first explored by a Monte Carlo
conformational search using the MMFF94 force field in
Macromodel.
FIGURE 3. B3LYP/6-31+G** optimized structures of lowest energy
conformers of C, D, and E.
interactions, is the lowest in energy and differs within the family
only by the specific envelope conformations of the THF rings.
The second family of conformers, B, containing a gauche
OCCO, a gauche CCCC, a gauche OCCC, and an anti OCCC
interaction, is higher in energy by each type of calculation. The
lowest energy conformers of A and B are shown in Figure 2.
For the rac diastereomer, there are three families of low
energy conformers. The lowest energy family, C, contains a
gauche OCCO, an anti CCCC, and two gauche OCCC interac-
tions; the intermediate energy family, D, contains an anti OCCO,
a gauche CCCC, and two gauche OCCC interactions; and the
highest energy family, E, contains a gauche OCCO and gauche
CCCC interactions. Again, each energy family differs in the
conformations about the THF cycles. Each basis set and method
applied give the same relative trend in energies. The lowest
energy conformers of C, D, and E are shown in Figure 3.
Given the energetic preference for electronegative atoms to
be gauche rather than anti, generally known as the gauche
The resulting 16 lowest energy conformers were then
reoptimized by RHF/6-31G(d) calculations, which maintain the
same relative energy order but reduce the energy differences.
The lowest energy conformers of the meso and rac diastereomers
were also reoptimized by B3LYP/6-31G* and B3LYP/6-
31+G**. Their designations and relative conformational prefer-
ences are given in Tables 3 and 4, and their energies are listed
in Table 5.
3
1
For the meso diastereomer, there are two families of unique
low energy conformers. The family of conformers, A, containing
an anti OCCO, an anti CCCC, and two gauche OCCC
effect, the anti OCCO conformations are expected to be
(31) Wolfe, S. Accounts Chem. Res. 1972, 5, 102.
J. Org. Chem, Vol. 72, No. 16, 2007 6219

Adaligil et al.
relatively less stable than the gauche. However, the anti OCCO
conformer is the minimum in the meso and of intermediate
energy in the rac diastereomer, respectively.
the COCC moiety in nearly an eclipsing conformation, whereas
the standard values are appropriate for staggered conformations.
Consequently, energies of the (C)OCCO(C) conformers when
the CCO(C) is eclipsed were studied. The torsional angles about
the COCC, OCCO, and CCOC bonds from the optimized
structures of the 2,2′-bis-THF’s were determined; subsequently,
1,2-dimethoxyethane with its dihedrals locked in the same angles
was optimized with B3LYP/6-31G*. The same analysis was
performed on n-hexane to determine how conformational
constraint to a geometry appropriate for 2,2′-bis-THF’s better
influences the standard values. These results are summarized
We explored whether additive effects of conformational
preferences in acyclic molecules could explain the relative
conformational preference of these polar acyclic molecules,
32
similar to the additivity used in the conformational analysis
of hydrocarbon acyclic systems. The three types of gauche
interactions that can occur between vicinal groups, involving
OCCO, OCCC, and CCCC dihedral angles, were analyzed to
determine if the relative preferences of these would explain the
conformational preference of each diastereomer. The simple
component, 1,2-dimethoxyethane, was chosen as a model system
to establish the OCCO preference, 1-propanol for the OCCC
preference, and n-butane for the CCCC preference.
-
+
in Table 6, where e and e refer to eclipsing counterclockwise
and eclipsing clockwise, respectively.
In the 1,2-dimethoxyethane model, both anti OCCO confor-
mations are lower in energy than the gauche OCCO conforma-
tions; however, the two anti conformers differ by 0.7 kcal/mol,
and the three gauche conformations range across 1.7 kcal/mol
in energy. This effect is even more pronounced in the case of
hexane, where the global minimum has a CCCC anti conforma-
tion, as expected, but another anti arrangement, C, is 1.4 kcal/
mol higher in energy.
These larger deviations from standard acyclic conformational
preferences arise from steric and electronic interaction of the
terminal methyls and oxygen lone pairs. These interactions are
also important in cyclic systems where vicinal groups are
constrained.
Regardless of the exact energetic differences, it is clear that
meso conformer B is higher in energy than conformer A due
mainly to the unfavorable gauche CCCC interaction across the
central linkage; the gauche OCCO conformation is also unfa-
vorable. For the rac-isomer, conformer D experiences mainly
destabilizing gauche CCCC interactions, while conformer E has
gauche CCCC and rather severe gauche OCCO repulsions since
the lone pairs are aimed at each other.
Conformational Evaluation of the Tris-Tetrahydrofurans.
Conformations of the tris-THF’s were explored in a similar
fashion. There are two diastereoisomers, having up to 21
conformers within 3 kcal/mol of the lowest energy conformation
at the RHF/6-31G(d) level. The lowest energy conformers from
RHF/6-31G(d) optimizations are shown in Figure 4 for each of
the two diastereomers (RR or SS (the center carbon is not a
stereogenic center), and RRS or SSR). The many different
conformers with slightly different energies vary in the envelope
conformations of the individual THF units.
The origin of the gauche preference in 1,2-dihydroxyethane
has been the subject of much debate in recent years. A number
of theoretical33 and experimental studies have been conducted
to elucidate the nature of the gauche effect in 1,2-dihydroxy-
ethane (ethylene glycol), some citing the possibility of intramo-
lecular H-bonding adding to the preference due to stereoelec-
tronic effects. In all studies, the three dihedral angles making
up the molecular backbone are important in determining the
conformational preference. For three single bonds, there are 27
possible conformers of which 10 are unique. The dihedral angles
34
+
-
are designated as g , t, and g , respectively, for gauche
clockwise, anti, and gauche counterclockwise torsions about
+
-
C-O, and G , T, and G for torsions about C-C. Thus, the
all anti conformer would be designated tTt. Whereas the gauche
C-C conformations of 1,2-dihydroxyethane predominate over
the anti conformations, the reverse is true of 1,2-dimethoxy-
ethane; the tTt conformer is the global minimum, 0.5 kcal/mol
lower than the tGt and tGg conformers. A 0.5 kcal/mol
preference for anti OCCO over gauche OCCO was adopted as
the reference.
-
35
The simple four atom backbone molecules, 1-propanol and
butane, were used as models for the other vicinal interactions
across the THF linkage. The gauche conformer of 1-propanol
is known36 to be preferred by 0.4 kcal/mol over the anti
conformer; therefore, a 0.4 kcal/mol preference was adopted
32
for gauche OCCC over anti OCCC. The well-known 0.9 kcal/
mol preference of anti butane over gauche butane was used.
For the meso diastereomer, the standard values described in
the previous paragraph predict a 1.8 kcal/mol difference between
the two diastereomers, whereas the full B3LYP/6-31+G**
computations predict a difference of 1.5 kcal/mol. For the rac
diastereomer, the standard values predict relative B3LYP/6-
3
1+G** energies of 0, 0.4, and 1.7 kcal/mol versus the
computed values of 0, 1.5, and 2.5 kcal/mol. Although the order
is correct, the quantitative values deviate substantially.
The conformational preference of OCCO torsions is very
3
3
sensitive to the torsions about the peripheral O-C bonds. In
the 2,2′-bis-THF diastereomers, the five-membered ring holds
(
32) Lowe, J. P. Prog. Phys. Org. Chem. 1968, 6, 1.
FIGURE 4. RHF/6-31G(d) optimized structures of lowest energy
conformers F and G.
(33) (a) Cramer, C. J.; Truhlar, D. G. J. Am. Chem. Soc. 1994, 116,
3
9
892. (b) Guvench, O.; MacKerrell, A. D. J. Phys. Chem. A 2006, 110,
934.
Summary. Synthetic protocols that allow unequivocal access
to the bis- and tris-tetrahydrofurans 6-10 have been successfully
devised. All issues surrounding the individual assignment of
configuration to this group of polycyclic ethers have been fully
clarified. The ability of 6-10 to complex to alkali metal ions
was evaluated in solution as well as in the gas phase. In
(34) (a) Petterson, K. A.; Stein, R. S.; Drake, M. D.; Roberts, J. D. Magn.
Reson. Chem. 2005, 43, 225. (b) Bak o´ , I.; Gr o´ sz, T.; Palinkas, G.; Bellissent-
Funel, M. C. J. Chem. Phys. 2003, 118, 3215.
(
35) Tsuzuki, S.; Uchimaru, T.; Tanabe, K.; Hirano, T. J. Phys. Chem.
993, 97, 1346.
36) Houk, K. N.; Eksterowicz, J. E.; Wu, Y.-D.; Fuglesang, C. D.;
Mitchell, D. B. J. Am. Chem. Soc. 1993, 115, 4170.
1
(
6220 J. Org. Chem., Vol. 72, No. 16, 2007

Bis (2,2′)- and Tris (2,2′,2′′)-Tetrahydrofurans
TABLE 6. Acyclic Conformational Analysis Based on 1,2-dimethoxyethane (red) and n-hexane (blue) Constrained Across Three Dihedral
Angles (degrees) as Determined by the Meso and Rac Conformers
[1]
Optimized dihedral angle along the periphery of the central bond. [2] Optimized dihedral angle along the central bond. [3] Energies optimized with the
shown dihedral angles restricted.
particular, ESI-MS has allowed the rapid assessment of relative
alkali metal binding selectivities involving these fascinating
structural networks. All five polycyclic tetrahydrofurans prefer
to associate with lithium ions over sodium and potassium, and
the two bis isomers exhibit slightly higher selectivities for
lithium than the three tris isomers. Conformational searches with
force field methods and optimizations with HF or B3LYP
indicate that these molecules have a large number of readily
accessible conformations, both with respect to the conformations
of individual tetrahydrofuran rings and with respect to rotation
about the CC bonds connecting these rings. Preferred geometries
are explained by a combination of steric and electronic effects.
the reaction mixture was stirred at rt for 2 days and quenched with
saturated NH Cl solution. The separated aqueous phase was
extracted with CH Cl
dried and evaporated. The residue was chromatographed on silica
gel (elution with 10% ethyl acetate in hexanes) to afford 3.0 g of
4
2
2
(3×), and the combined organic phases were
1
2 along with 3.8 g of the tosylate intermediate. The latter was
dissolved in benzene (100 mL), treated with KHMDS in toluene
18 mL of 0.5 M, 9.0 mmol) at 0 °C, stirred for 1 h, and worked
up in the predescribed manner. There was isolated an additional
(
-1
2.5 g of 12 (total yield 83%) as a colorless oil; IR (neat, cm
)
1
1
471, 1255, 1096; H NMR (300 MHz, CDCl
3
) δ 3.82 (t, J ) 6.5
Hz, 2H), 3.56 (d, J ) 10.0 Hz, 2H); 3.46 (d, J ) 10.0 Hz, 2H),
13
1.89-1.73 (m, 4H), 0.88 (s, 18H), 0.04 (s, 12H); C NMR (75
MHz, CDCl ) δ 85.5, 68.7, 65.5, 29.3, 26.1, 25.9, 18.3, -5.4; ES
HRMS m/z (M + Na) calcd 383.2414, obsd 383.2408.
-(tert-Butyldimethylsiloxymethyl)-2-(hydroxymethyl)tetrahy-
3
+
Experimental Section
2
2
,2-Bis(tert-butyldimethylsiloxymethyl)tetrahydrofuran (12).
A cold (-78 °C) solution of 11 (5.85 g, 18.4 mmol) in dry THF
100 mL) was treated dropwise with the Normant reagent (55.0
mL of 0.4 M in THF, 22 mmol), stirred at low temperature for 1
h, quenched with saturated NH Cl solution, and allowed to warm
to room temperature. After dilution with CH Cl , the aqueous phase
was separated and extracted with CH Cl
drofuran (13). A solution of 12 (5.5 g, 15 mmol) in THF (36 mL)
was cooled to 0 °C, treated with TBAF (36.0 mL of 1 M in THF,
36 mmol), and stirred for 2.5 h. After solvent evaporation, the
residue was eluted through silica gel (50% ethyl acetate in hexanes)
to deliver 1.95 g (97%) of the diol. This material (0.63 g, 4.5 mmol)
was redissolved in THF (10 mL) and added dropwise to a cooled
slurry of sodium hydride (0.19 g of 60% in oil, 4.7 mmol) in THF
(25 mL). After 30 min, the reaction mixture was allowed to warm
to rt prior to the addition of a solution of tert-butyldimethysilyl
chloride (0.71 g, 4.9 mmol) in THF (5 mL). After 3 h, saturated
(
4
2
2
2
2
(3×). The combined
organic solutions were dried and evaporated. The residue was
chromatographed on silica gel (elution with 35% ethyl acetate in
hexanes) to afford the diol as a colorless oil (6.1 g, 86%).
The above diol was taken up in CH
triethylamine (6.6 mL, 47 mmol) and DMAP (50 mg), and cooled
to 0 °C. After the addition of tosyl chloride (1.72 g, 9.0 mmol),
2
Cl
2
(250 mL), admixed with
3
NaHCO solution and ether were introduced, and the separated
aqueous phase was extracted with ether (3×). The combined organic
phases were dried and evaporated, and the residue was chromato-
J. Org. Chem, Vol. 72, No. 16, 2007 6221

Adaligil et al.
graphed on silica gel. Elution with 20% ethyl acetate in hexanes
slow addition of DMSO (0.12 mL, 1.7 mmol). After 15 min, a
furnished 0.94 g (84% over two steps) of 13 as a colorless oil; IR
2 2
solution of 16 (100 mg, 0.58 mmol) in CH Cl (2 mL) was
-1
1
(
(
(
neat, cm ) 3432, 1254, 1091; H NMR (300 MHz, CDCl
t, J ) 6.0 Hz, 2H), 3.62-3.40 (m, 4H), 2.26 (s, 1H), 1.97-1.71
m, 4H), 0.88 (s, 9H), 0.46 (s, 6H); 13C NMR (75 MHz, CDCl
) δ
3
) δ 3.83
introduced via syringe. After 1 h of stirring, triethylamine (0.49
mL, 3.5 mmol) was admixed, and the reaction mixture was warmed
to rt and diluted with water. Workup in the predescribed manner
3
-
1
8
4.8, 68.7, 66.2, 66.1, 29.9, 26.1, 25.8, 18.2, -5.5; ES HRMS m/z
furnished 98 mg (92%) of 18 as a colorless oil; IR (neat, cm ),
+
1
(M + Na) calcd 269.1549, obsd 269.1544.
1729, 1078; H NMR (300 MHz, CDCl
3
) δ 9.63 (s, 1H), 4.04 (t,
Oxidation and Spiroannulation of 13. A solution of oxalyl
J ) 7.2 Hz, 1H), 4.00-3.82 (m, 2H), 3.77-3.66 (m, 2H), 2.14-
2.05 (m, 1H), 2.00-1.65 (m, 7H); 13C NMR (75 MHz, CDCl
) δ
3
chloride (0.72 mL, 8.3 mmol) in CH
78 °C and treated slowly with a solution of DMSO (1.2 mL, 16
mmol) in the same medium (5 mL). After 15 min, 13 (1.35 g, 5.5
mmol) dissolved in CH Cl (10 mL) was introduced via syringe.
2
Cl
2
(20 mL) was cooled to
-
204.3, 90.6, 81.5, 69.7, 68.6, 29.6, 26.3, 25.9, 25.8; ES HRMS m/z
+
(M + Na) calcd 193.0841, obsd 193.0834.
2
2
The 2,4-dinitrophenylhydrazone derivative 20 consisted of yellow
Following 30 min, the reaction mixture was charged with triethyl-
amine (4.6 mL, 33 mmol), stirred for 1 h, warmed to rt, and diluted
with water. The separated aqueous phase was extracted with CH Cl
2 2
-1
1
needles, mp 163-164 °C; IR (neat, cm ) 3297, 1614, 1589; H
NMR (300 MHz, CDCl ) δ 11.0 (s, 1H), 9.12 (d, J ) 2.6 Hz, 1H),
.32 (dd, J ) 2.6, 9.5 Hz, 1H), 7.90 (d, J ) 9.5 Hz, 1H), 7.50 (s,
H), 4.08 (t, J ) 6.9 Hz, 1H), 3.95-3.78 (m, 4H), 2.48-2.38 (m,
3
8
1
1
1
6
3
(
3×), and the combined organic phases were dried and evaporated
to leave a residue that was chromatographed on silica gel. Elution
with 10% ethyl acetate in hexanes afford 1.25 g (93%) of the oily
aldehyde that was immediately taken up in THF (40 mL), cooled
to -78 °C, and treated dropwise with the Normant reagent (19.2
mL of 0.4 M in THF, 7.7 mmol). After 3 h of stirring in the cold,
13
3
H), 2.03-1.72 (series of m, 7H); C NMR (75 MHz, CDCl ) δ
52.7, 147.9, 145.1, 130.0, 129.6, 123.4, 116.5, 86.7, 83.2, 70.2,
8.9, 31.0, 27.3, 27.1, 26.0; ES HRMS m/z (M + Na) calcd
+
73.1124, obsd 373.1111.
Bicyclic Aldehyde 19. A 240 mg (1.4 mmol) sample of 17 was
saturated NH
separated aqueous phase was extracted with CH
combined organic phases were dried and evaporated to leave an
oil that was chromatographed on silica gel (elution with 10%
methanol in 50% ethyl acetate/hexanes). There was isolated 1.2 g
4
Cl solution and CH
2
Cl
2
were introduced, and the
Cl
oxidized in the manner described above to afford 229 mg (96%)
2
2
(3×). The
-1
1
of 19 as a colorless oil; (IR, neat, cm ) 1732, 1068; H NMR
300 MHz, CDCl ) δ 9.60 (s, 1H), 4.12 (t, J ) 7.0 Hz, 1H), 4.03-
.82 (m, 3H), 3.74 (q, J ) 6.0 Hz, 1H), 2.24-2.10 (m, 1H), 1.95-
(
3
3
1
7
1
13
3
.65 (m, 7H); C NMR (75 MHz, CDCl ) δ 204.4, 90.7, 81.5,
(77%) of the diol as a colorless oil that was directly taken up in
+
0.1, 68.9, 29.6, 26.2, 25.7, 25.5; ES HRMS m/z (M + Na) calcd
93.0841, obsd 193.0842.
CH Cl (130 mL), treated with triethylamine (1.7 mL, 12 mmol)
2
2
and DMAP (50 mg) prior to cooling to 0 °C and the addition of
tosyl chloride (0.90 g, 4.7 mmol). After 48 h of stirring, the reaction
Decarbonylation of 18. The bicyclic aldehyde 18 (50 mg, 0.29
mmol) was dissolved in previously distilled xylenes (1.5 mL) and
kept under N . Following the addition of Wilkinson’s catalyst (270
4
mixture was diluted with saturated NH Cl solution, the separated
2
aqueous phase was extracted with CH Cl
2
2
(3×), and the combined
mg, 0.29 mmol), the suspension was refluxed for 6 h and cooled.
The reaction mixture was directly loaded onto a silica plug and
eluted with 20% ether in hexanes. After careful evaporation of the
solvent without heat, column chromatography (elution with 15%
organic layers were dried and concentrated. Chromatography of
the residue on silica gel (elution with 10% ethyl acetate in hexanes)
afforded 0.51 g of 14 and 0.53 g of 15 (65%) over three steps.
-
1
1
For 14: IR (neat, cm ) 1463, 1255, 1083; H NMR (300 MHz,
CDCl ) δ 3.95 (t, J ) 6.5 Hz, 1H), 3.86-3.72 (m, 4H), 3.53 (d, J
10.0 Hz, 1H), 3.42 (d, J ) 10.0 Hz, 1H), 1.94-1.65, (series of
ether in CH
a colorless oil; IR (neat, cm ) 2866, 1033; H NMR (300 MHz,
CDCl ) δ 3.91-3.73 (m, 6H), 2.00-1.75 (m, 6H), 1.65-1.50 (m,
H); 13C NMR (75 MHz, CDCl
) δ 81.4, 68.4, 28.1, 25.9.
Decarbonylation of 19. The bicyclic aldehyde 19 (49 mg, 0.29
mmol) was dissolved in previously distilled xylenes (1.5 mL) and
kept under N . Following addition of Wilkinson’s catalyst (270 mg,
.29 mmol), the suspension was refluxed for 6 h and cooled. The
2 2
Cl ) provided the volatile 6 in 52% yield (21 mg) as
3
-
1
1
)
13
3
m, 8H), 0.88 (s, 9H), 0.38 (s, 6H); C NMR (75 MHz, CDCl
3
) δ
2
3
8
6.2, 81.6, 69.2, 68.3, 66.7, 29.7, 26.5, 26.3, 26.2, 25.9, 18.2, -5.5;
+
ES HRMS m/z (M + Na) calcd 309.1862, obsd 309.1870.
-1
1
For 15: colorless oil; IR (neat, cm ) 1458, 1253, 1073; H NMR
300 MHz, CDCl ) δ 3.92-3.79 (m, 4H), 3.76-3.68 (m, 1H), 3.61
d, J ) 10.0 Hz, 1H), 3.51 (d, J ) 10.0 Hz, 1H), 1.93-1.77 (m,
2
(
(
6
3
0
13
reaction mixture was directly loaded onto a silica column and
gradient elution from hexanes to 10% ether in hexanes followed
by careful solvent evaporation without heat provided the volatile 7
H), 1.71-1.60 (m, 2H), 0.88 (s, 9H), 0.04 (s, 6H); C NMR (75
MHz, CDCl
3
) δ 86.7, 81.9, 69.5, 68.2, 66.5, 28.9, 26.6, 26.2, 26.0,
+
2
3
5.9, 18.2, -5.5; ES HRMS m/z (M + Na) calcd 309.1862, obsd
-1
in 61% yield (25 mg) as a colorless oil; IR (neat, cm ) 2971, 2870,
09.1870.
1
1
1
8
067; H NMR (300 MHz, CDCl ) δ 3.90-3.70 (m, 6H), 2.06-
3
Bicyclic Alcohol 16. A solution of 14 (0.41 g, 1.4 mmol) in
13
3
.82 (m, 6H), 1.75-1.65 (m, 2H); C NMR (CDCl , 75 MHz) δ
1.0, 68.5, 28.2, 25.7.
THF (10 mL) was treated with tetrabutylammonium fluoride (2.1
mL of 1 M in THF, 2.1 mmol), stirred for 2 h, and concentrated
on a rotary evaporator. Chromatography of the residue on silica
gel (elution with 50% ethyl acetate in hexanes to 10% methanol in
Annulation of 18. Aldehyde 18 (85 mg, 0.50 mmol) was
suspended in THF (5 mL) at -78 °C, stirred in the presence of the
Normant reagent (1.9 mL of 0.4 M in THF, 2.7 mmol) for 3 h,
5
0% ethyl acetate/hexanes) afforded 240 mg (99%) of 16 as a
-
1
1
2 2
quenched with 5% HCl, and diluted with CH Cl . The separated
colorless oil; IR (neat, cm ) 3436, 1057; H NMR (300 MHz,
CDCl
) δ 3.99-3.65 (m, 5H), 3.68 (d, J ) 11.2 Hz, 1H), 3.44 (s,
aqueous phase was extracted with CH
organic solutions were dried and evaporated prior to being
2
Cl
2
(3×), and the combined
3
H), 1.90-1.70 (m, 8H); 13C NMR (75 MHz, CDCl
1
6
3
) δ 85.8, 82.2,
8.9, 68.3, 66.1, 29.2, 26.6, 26.5, 25.9; ES HRMS m/z (M + Na)+
redissolved in CH Cl (10 mL), charged sequentially at 0 °C with
2
2
calcd 195.0997, obsd 195.1005.
triethylamine (0.6 mL, 1.2 mmol), DMAP (25 mg), and tosyl
chloride (90 mg, 0.47 mmol), and stirred overnight. Another 30
mg of tosyl chloride was added, and after another 24 h, the
predescribed workup was applied. There was isolated 35 mg of 8
and 25 mg of 9 (61% over two steps) following chromatographic
separation on silica gel (elution with 10% ethyl acetate in hexanes).
Bicyclic Alcohol 17. Desilylation of 15 (0.39 g, 1.4 mmol)
dissolved in THF (10 mL) with TBAF (2.1 mL of 1 M in THF) in
the predescribed manner afforded 17 (240 mg, 99%) as a colorless
-
1
1
oil: IR (neat, cm ) 3429, 1062; H NMR (300 MHz, CDCl
3
3
) δ
.95-3.67 (series of m, 5H), 3.68 (s, 2H), 2.88 (s, 1H), 1.90-1.54
series of m, 8H); 13C NMR (75 MHz, CDCl
) δ 85.9, 82.6, 69.0,
For 8: colorless oil; IR (neat, cm-1) 2975, 1071; H NMR (300
1
(
6
3
+
8.3, 66.0, 29.4, 26.6, 26.0, 25.6; ES HRMS m/z (M + Na) calcd
95.0997, obsd 195.0992.
MHz, CDCl ) δ 3.94 (t, J ) 7.8 Hz, 2H), 3.82-3.66 (m, 6H), 1.95-
3
1.72 (m, 12H); 13C NMR (75 MHz, CDCl ) δ 87.1, 82.7, 69.5,
1
3
+
Bicyclic Aldehyde 18. A solution of oxalyl chloride (0.076 mL,
68.3, 28.9, 27.0, 26.5, 26.1; ES HRMS m/z (M + Na) calcd
0
.87 mmol) in CH
2
Cl
2
(5 mL) was cooled to -78 °C prior to the
235.1310, obsd. 235.1309.
6222 J. Org. Chem., Vol. 72, No. 16, 2007

Bis (2,2′)- and Tris (2,2′,2′′)-Tetrahydrofurans
For 9: colorless oil; IR (neat, cm- ) 2968, 1064; H NMR (300
1
1
performed with the following settings: Max#Iterations at 10000;
Mixed MCMM/Low Mode; Automatic Setup; Converge on gradi-
ent; Force field MMFF94; Energy window 50 kJ/mol. MMFF94
structures within ∼3 kcal/mol above the global minimum were
chosen for further geometry optimization and frequency calcula-
tions. Gas-phase optimized atoms were performed with Gaussian03
rev. B.05 at the RHF/6-31G(d), B3LYP/6-31G*, and B3LYP/6-
31G** levels of theory.39
MHz, CDCl
m, 11H), 1.61-1.50 (m, 1H); C NMR (75 MHz, CDCl
2.9, 82.5, 69.7, 68.1, 68.0, 28.0, 27.4, 26.8, 26.5, 26.3, 25.9; ES
3
) δ 3.96-3.70 (series of m, 8H), 2.01-1.71 (series of
13
38
3
) δ 87.9,
8
+
HRMS m/z (M + Na) calcd 235.1310, obsd 235.1309.
Annulation of 19. A 95 mg (0.56 mmol) sample of 19 was
processed in a manner analogous to that detailed above. Final
chromatographic purification on silica gel (elution with 10% ethyl
acetate in hexanes) provided 35 mg of 9 and 45 mg of 10 (67%
over two steps).
Acknowledgment. Funding from the Welch Foundation
(F1155 to J.S.B.), National Science Foundation (CHE-0315337
to J.S.B.; CHE-0548209 to K.N.H.), and the Astellas U.S.A.
Foundation (to L.A.P.) is gratefully acknowledged.
-1
1
For 10: colorless oil; IR (neat, cm ) 2974, 1072; H NMR (300
MHz, CDCl ) δ 3.99-3.91 (m, 4H), 3.85 (t, J ) 6.8 Hz, 2H), 3.75-
.69 (m, 2H), 1.93-1.75 (m, 8H), 1.70-1.64 (m, 4H); C NMR
75 MHz, CDCl ) δ 88.0, 83.2, 70.0, 68.2, 28.1, 27.1, 26.5, 25.7;
3
13
3
(
3
+
ES HRMS m/z (M + Na) calcd 235.1310, obsd 235.1302.
Electrospray Ionization-Mass Spectrometry. The metal bind-
ing selectivities were assessed by dissolving a ligand in methanol
at 10 µM and adding LiCl, NaCl, and KCl at 100 µM each. The
high concentration of metal salts was necessary to minimize the
contribution of environmental sodium. Analysis was performed on
a quadrupole ion trap mass spectrometer equipped with an elec-
trospray ionization source. The analyte solutions were directly
infused into the mass spectrometer with a flow rate of 5 µL/min.
Positive mode ionization was employed, using an ESI voltage of
1
13
Supporting Information Available: Spectroscopic ( H/ C
NMR) characterization for all new compounds as well as crystal-
lographic details for 20. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO0708238
(37) Saunders, M.; Houk, K. N.; Wu, Y. D.; Still, W. C.; Lipton, M.;
Chang, G.; Guida, W. C.; J. Am. Chem. Soc. 1990, 112, 1419.
(
(
38) Halgren, T. A. J. Comp. Chem. 1999, 20, 730.
39) RHF/6-31G(d): Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.;
+
5 kV and a heated capillary temperature of 150 °C. All other
Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.;
Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.;
Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.;
Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda,
R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai,
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parameters were optimized on a daily basis for highest signal
intensity. The selectivity of each ligand for the three alkali metals
was calculated by summing the intensities of all ions containing a
particular metal and dividing by the total intensity of all ions in
the spectrum. Ions containing more than one ligand molecule were
weighted accordingly. ESI-mass spectra were also recorded for
each ligand with a single alkali metal salt instead of a mixture of
all three alkali metals, and the abundances of the metal complexes
in the resulting ESI-mass spectra were used to estimate ESI spray
efficiencies. For these ligands, there were no significant differences
noted in spray efficiencies.
Computational Details. A Monte Carlo conformational search37
using the Schr o¨ dinger Maestro Macromodel Version 5.1.016 was
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