Amplification of dynamic chiral crown ether complexes during cyclic acetal formation

Article abstract of DOI:10.1002/anie.200351558

The dynamic duo: A more than tenfold increase in the yield of the chiral macropolycyclic polyether containing two 2,6-disubstituted 1,3,5,7-cis-tetraoxadecalin systems was obtained under thermodynamic conditions from a dynamic combinatorial virtual librar

Full text of DOI:10.1002/anie.200351558

Communications
Dynamic Covalent Chemistry
Amplification of Dynamic Chiral Crown Ether
Complexes During Cyclic Acetal Formation**
Benzion Fuchs, Alshakim Nelson, Alexander Star, J.
Fraser Stoddart,* and SØbastien Vidal
Dynamic covalent chemistry[1] relates to the study of chemical
reactions carried out under thermodynamic control. Labile
coordinative bonds associated with certain metal–ligand
interactions,[2] ring-opening/ring-closing metathesis reac-
tions,[3] and protocols for the formation of imines[4] and
disulfides[5] have all been exploited in the strict self-assembly
of catenanes and rotaxanes.[6] A wide range of other
functionalities[7–11] have also been explored in the creation
of dynamic combinatorial libraries (DCLs). We describe here
the efficient and selective acid-catalyzed formation of a chiral
macropolycyclic polyether constituted of multiple [24]crown-
8 frameworks, which incorporate either two d- or two l-
threitol residues as bicyclic diacetals, by using dynamic
template-directed approaches[12] to amplify the production
of the most thermodynamically preferred complex(es).
Carbohydrates command a unique status[13] in the realm of
dynamic covalent chemistry.[1] Acid-catalyzed formation[13,14]
of cyclic acetals from alditols and aldehydes or ketones
provides a well-known reaction[15] in which covalent (C O)
ꢀ
bonds are made and broken with varying degrees of ease
under thermodynamic control. The constitutions of the
configurationally isomeric erythro- and threo-1,2,3,4-butane-
tetraols result[16] in their undergoing three different kinds of
acetal ring closures with aldehydes and ketones: 1) 1,3:2,4-
diacetal formation yields “6/6” bicycles, 2) 1,2:3,4-diacetal
formation affords “5/5” bicycles, and 3) 1,4:2,3-diacetal for-
mation yields “5/7” bicycles. With aldehydes, “6/6” or 1,3,5,7-
tetraoxadecalin (TOD) formation usually predominates at
equilibrium, whereas with ketones, “5/5” bicycles are invar-
iably the major products. The TOD-forming reactions involv-
ing aldehydes (RCHO) are completely diastereospecific, that
is, erythritol gives trans-TOD and threitol affords cis-TOD.
The latter has long attracted the interest of stereochemists
because of its highly distinctive stereoelectronic properties.[17]
[*] Prof. J. F. Stoddart, A. Nelson, Dr. A. Star, Dr. S. Vidal
Department of Chemistry and Biochemistry
University of California, Los Angeles
405 Hilgard Avenue, Los Angeles, CA 90095-1569 (USA)
Fax: (+1)310-206-1843
E-mail: stoddart@chem.ucla.edu
Prof. B. Fuchs
School of Chemistry
(Raymond and Beverly Sackler Faculty of Exact Sciences)
Tel-Aviv University, Ramat-Aviv, 69978 Tel-Aviv (Israel)
[**] We thank the National Science Foundation (CHE 9910199) for
funding this research, which was also supported in part by
equipment grants (CHE 9974928 and CHE 0092036) from the
National Science Foundation.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
4220
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200351558
Angew. Chem. Int. Ed. 2003, 42, 4220 –4224

Angewandte
Chemie
It is beyond any doubt that the O-inside conforma-
tions of cis-TOD with equatorial substituents (R)
prevail at equilibrium.
In a recent quest for chiral [24]crown-8 deriv-
atives that will form either complexes (pseudo-
rotaxanes) or interlocked molecular compounds
(catenanes or rotaxanes) with secondary dialkyl-
ammonium (R02NH2 ) ions,[18] we have identified
+
(Scheme 1) the macropolycyclic polyether dd-1
containing two 2,6-disubstituted cis-TOD residues
with O-inside conformations which is derived from
d-threitol and linked in a macrocyclical manner by
linkers containing bismethylenedioxy units. Numer-
ous [24]crown-8 constitutions can be identified
within dd-1. Inspection of molecular models reveals
that all 12 of the oxygen atoms in dd-1 can orient
themselves toward the center of the relatively rigid
host, thus creating an electron-rich environment for
the complexation of electron-deficient guests, for
example, R02NH2+ ions.
Scheme 2. The dynamic combinatorial virtual library (DCVL) generated in CDCl3 solution
from the diacetal 2 and the diacetonide d-3, prior to the addition of CsPF6, after which
[dd-1ꢁCs]+ becomes amplified from a mixture which could, in principle, contain bicycles
with “6/6”, “5/5”, and “5/7” constitutions in all possible permutations. Although the use
of (DBA)PF6 as a template did amplify the formation of [2+2] macropolycycles in CD3CN, it
An initial attempt to react d-threitol[19] with the did not produce [dd-1ꢁDBA]+ as a pure [2]pseudorotaxane.
diacetal 2[20] failed because of the insolubility of the
former in organic solvents. We therefore decided to
The outcome of the reaction changed completely when
dibenzylammonium hexafluorophosphate ((DBA)PF6) was
employed as the template. When this salt (1 equiv) was added
to a solution of dry CDCl3 containing equimolar amounts (40
mm) of 2 and d-3, a dynamic process could be initiated by
addition of TfOH. Equilibrium was established after 3 days at
458C, and, while mass spectrometry revealed that the major
1
products are [2+2] macropolycycles, H NMR spectroscopy
indicated that they are also a complex mixture of isomers that
contain different bicyclic diacetals. The region in the 1H NMR
spectrum where signals for the acetal methine protons appear
(d = 4.4–5.5 ppm) shows that, among the several products
present, no more than 64% of the diacetal units[22] are “6/6”
bicycles. Nonetheless, while a mixture of bicyclic diacetals was
present in the reaction products, the MALDI-TOF mass
spectrum revealed a relatively intense peak at m/z 662.32
which corresponds to the [2]pseudorotaxane composed of a
DBA+ ion template encircled by a [2+2] macropolycycle.
Although it is possible that the various complexes are
kinetically stable under the conditions of the reaction, and
so do not equilibrate, it is more likely that [2+2] macropoly-
cycles containing “6/6” and other bicycles form close to
isoenergetic [2]pseudorotaxanes.
Scheme 1. Structural formulas of [24]crown-8 and the [2+2] TOD-con-
taining macropolycyclic polyether dd-1.
use a soluble derivative of d-threitol—namely the diacetonide
d-3, which was prepared[21] by stirring the tetraol in Me2CO in
the presence of H2SO4. In the absence of a template,
transacetalations (Scheme 2) between 2 and d-3 proceed
rapidly at room temperature in both CD3CN and CDCl3, after
addition of an acid catalyst (triflic acid, TfOH) to give a
complex mixture of products, including [2+2] TOD-contain-
ing [24]crown-8 derivatives, as indicated (Supporting Infor-
mation) by mass spectrometry and 1H NMR spectroscopy.
The transacetalations are expected to occur with both
enthalpic and entropic gains. For example, when dd-1 is a
product, the thermodynamically more stable “6/6” bicycles
(TODs) should be formed in preference to “5/5” bicycles,
such as is present in d-3. Entropy should increase during the
reaction of two molecules of 2 with two molecules of d-3 to
give dd-1 with the expulsion of four molecules of Me2CO and
eight molecules of MeOH.
Changing the template[23] to CsPF6 had a significantly
beneficial effect upon the outcome (Scheme 2) of the
dynamic transacetalations. The reaction between equimolar
proportions (40 mm) of the diacetal 2 with the diacetonide d-3
in dry CDCl3 at 458C, using Cs+ ions as the template, was
initiated by addition of TfOH as a catalyst. The equilibration
1
process was monitored (Figure 1) by H NMR spectroscopy,
primarily by focusing on the region (d = 4.4–5.5 ppm) where
the acetal methine protons resonate in the spectrum. As the
initially observed methine proton triplet at d = 4.52 ppm
arising from the starting diacetal 2 decreases over several
days, numerous new acetal methine signals begin to appear
further downfield beyond d = 4.8 ppm. Presumably, a com-
Angew. Chem. Int. Ed. 2003, 42, 4220 –4224
www.angewandte.org
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4221

Communications
Figure 3. MALDI-TOF mass spectra of the equilibrium mixtures,
obtained when the diacetal 2 and the diacetonide d-3 were equilibrated
for nine days in a) CDCl3 and b) CD3CN in the presence of CsPF6 as
template and TfOH as catalyst.
Figure 1. Stack of partial 1H NMR spectra (500 MHz, CDCl3, 298 K)
recorded with time of an equilibrating equimolar (40 mm) mixture of
the diacetal 2 and the diacetonide d-3 in which Cs+ ions are employed
as the template. The slanting scale entries display the times after addi-
tion of the catalyst (TfOH) to initiate the equilibration process, which
is complete after four days. The product is identified by solid lines and
the reactant by dashed ones. The signal centered around d=4.5 ppm
and indicated by the asterisk results from a by-product formed during
the reaction. It is removed during purification.
their relative intensities, which indicates that dd-1 is being
1
amplified in the presence of the Cs+ ion template. H NMR
spectroscopy indicates that the conversion[24] of 2 and d-3 into
dd-1 is all but quantitative after 3 days, that is, > 95% in dry
CDCl3 at 458C. The MALDI-TOF mass spectrum (Figure 3a)
of the equilibrated reaction mixture showed molecular ion
peaks for both [M+Na]+ (Na+ ions are present in the matrix)
and [M+Cs]+ arising from the [2+2] macropolycycle. Peaks
for higher polycyclic oligomers were absent to all intents and
purposes. When this dynamic reaction was scaled up (see
Experimental Section), dd-1 was isolated in a 58% (unopti-
mized) yield and fully characterized as the [2+2] TOD-
containing [24]crown-8 derivative by mass spectrometry and
2D NMR spectroscopy.[25] Interestingly, when CD3CN is used
as the reaction solvent, the Cs+ ion template is not nearly as
effective in amplifying dd-1 from the dynamic mixture. In
addition to this [2+2] macropolycyclic polyether, there is
evidence for the presence of higher polycyclic oligomers.
To establish beyond any shadow of a doubt that the
structure of the [2+2] macropolycyclic polyether corresponds
to dd-1, and to be in a position to compare the efficiency of
the dynamic approach with kinetic ones, we have synthesized
ll-1 in a conventional manner (Scheme 3). l-Threitol was
treated with the glycoaldehyde dimer[26] to give l-4 in 70%
yield. The ditosylate l-5 was obtained from l-4 in high yield
and was used to alkylate, rather inefficiently, 2-(benzyloxy)-
ethanol[27] to afford the dibenzyl ether l-6 in modest yield.
Following near quantitative catalytic hydrogenolysis to give
the diol l-7, it was tosylated to give the ditosylate l-8 in a
good yield. Macropolycyclization to form ll-1 was achieved
by means of two alternative pathways (Paths A and B) in the
presence of base, under high dilution conditions using Cs+
ions as templates to facilitate[28] the formation of ll-1.
Reaction (Path A) of the diol l-7 with the ditosylate l-5
gave ll-1 in 6.7% yield, whereas reaction (Path B) of the diol
l-4 with the ditosylate l-8 gave ll-1 in 5.8% yield.
plex mixture containing isomeric bicyclic diacetals with “5/5”,
“6/6”, and “5/7” constitutions is formed (Figure 2) under
kinetic control. Subsequently and concomitantly, the reso-
nances for these initially formed kinetic products decrease
and a single predominantly broad singlet at d = 4.86 ppm,
associated with the acetal methine protons in the “6/6”
bicycle, begins to experience an increase in its relative
intensity. Signals for the Ha and He protons (Scheme 1) in
dd-1 were also characteristically present in the spectrum as a
broadened pair of doublets, centered on d = 4.01 ppm and
4.22 ppm, respectively. Thus, it is clear (Figure 2) that, as the
resonances for the kinetic products undergo a decrease in
their relative intensities, those associated with the macro-
polycyclic polyether containing two “6/6” bicycles increase in
Figure 2. A graphical representation of the relative integrals (Rel.
Amts.) for the acetal proton signals with time illustrating the
Clearly, the isolated overall yields of dd/ll-1 starting from
d/l-threitol using the kinetic approach is considerably lower
(1.4% over five steps along Path A and 0.8% over six steps
along Path B) than for the thermodynamic approach (mini-
*
consumption of the diacetal 2 ( ), the production of two other
&
^
intermediate polyacetals ( and ) formed under kinetic control, and
the formation of the macropolycyclic polyether dd-1 from 2 and d-3,
both 40 mm in CDCl3 at 318 K.
4222
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2003, 42, 4220 –4224

Angewandte
Chemie
dd-1: A mixture of 2 (181 mg, 0.80 mmol), dd-3 (160 mg,
0.80 mmol), and CsPF6 (122 mg, 0.44 mmol) was added to dry
CHCl3 (20 mL) and TfOH (40 mL, 0.45 mmol) was introduced into
the stirred solution. The reaction mixture was maintained at 458C for
3 days and then quenched with iPr2NEt. The solvents were removed
under vacuum and the resulting oil was subjected to column
chromatography (SiO2, CH2Cl2/MeOH (9:1)) to afford dd-1 (108
mg, 58%) as a foamy solid. [a]D = ꢀ18.0 (c = 1, CHCl3). 1H NMR
(500 MHz, CDCl3): d = 3.60–3.78 (m, 20H), 3.79 (s, 4H), 3.98 (d, J =
12.8 Hz, 4H), 4.28 (d, J = 12.8 Hz, 4H), 4.86 ppm (brs, 4H); 13C NMR
(125 MHz, CDCl3): d = 69.1, 69.6, 69.9, 70.6, 98.6 ppm; MALDI-
TOF-MS m/z calcd for C20H32NaO12 [M+Na]+: 487.1786, found:
487.1786.
Received: April 2, 2003 [Z51558]
Keywords: combinatorial chemistry · macrocycles ·
.
supramolecular chemistry · template synthesis · transacetalation
[1] a) P. A. Brady, R. P. Bonar-Law, S. J. Rowan, C. J. Suckling, J. K.
M. Sanders, Chem. Commun. 1996, 319 – 320; b) P. A. Brady, J.
K. M. Sanders, Chem. Soc. Rev. 1997, 26, 327 – 336; c) J.-M.
Lehn, Chem. Eur. J. 1999, 5, 2455 – 2463; d) J. K. M. Sanders,
Pure Appl. Chem. 2000, 72, 2265 – 2274; e) G. R. L. Cousins, S.-
A. Poulsen, J. K. M. Sanders, Curr. Opin. Chem. Biol. 2000, 4,
270 – 279; f) L. M. Greig, D. Philp, Chem. Soc. Rev. 2001, 30,
287 – 302; g) I. Huc, R. Nguyen, Comb. Chem. High Throughput
Screening 2001, 4, 109 – 130; h) R. L. E. Furlan, S. Otto, J. K. M.
Sanders, Proc. Natl. Acad. Sci. USA 2002, 99, 4801 – 4804; i) S. J.
Rowan, S. J. Cantrill, G. R. L. Cousins, J. K. M. Sanders, J. F.
Stoddart, Angew. Chem. 2002, 114, 938 – 993; Angew. Chem. Int.
Ed. 2002, 41, 898 – 952.
[2] For examples of catenanes incorporating metal–ligand coordi-
nation within their macrocyclic components, see a) M. Fujita, F.
Ibukuro, H. Hagahira, K. Ogura, Nature 1994, 367, 720 – 723; for
examples of rotaxanes incorporating metal–ligand interactions
within their dumbbell-shaped components that are formed by
threading-followed-by-stoppering approaches, see b) A. J. Baer,
D. H. Macartney, Inorg. Chem. 2000, 39, 1410 – 1417; c) K.
Chichak, M. C. Walsh, N. R. Branda, Chem. Commun. 2000,
847 – 848; d) M. J. Gunter, N. Bampos, K. D. Johnstone, J. K. M.
Sanders, New J. Chem. 2001, 25, 166 – 173; for examples of
rotaxanes incorporating metal–ligand interactions within their
macrocyclic components that are formed by clipping reactions,
see e) S.-Y. Chang, J. S. Choi, K.-S. Jeong, Chem. Eur. J. 2001, 7,
2687 – 2697; f) C. A. Hunter, C. M. R. Low, M. J. Packer, S. E.
Spey, J. G. Vinter, M. O. Vysotsky, C. Zonta, Angew. Chem.
2001, 113, 2750 – 2754; Angew. Chem. Int. Ed. 2001, 40, 2678 –
2682; for recent examples of metal–ligand coordination guiding
other molecular self-assembly processes, see g) E. Stulz, Y.-F.
Ng, S. M. Scott, J. K. M. Sanders, Chem. Commun. 2002, 524 –
525; h) Y. Kubota, S. S. Sakamoto, K. Yamaguchi, M. Fujita,
Proc. Natl. Acad. Sci. USA 2002, 99, 4854 – 4856.
Scheme 3. a) Glycoaldehyde dimer, 1m HCl, 70%; b) TsCl, NaH, THF,
858C, 88%; c) 2-(benzyloxy)ethanol, NaH, DMF, 908C, 35%; d) H2,
Pd-C, EtOH, H2O, 92%; e) TsCl, Et3N, CH2Cl2, 68%; f) l-5, CsOTs,
NaH, DMF, 1008C, 6.9%; g) l-4, CsOTs, NaH, DMF, 1008C, 5.8%.
Ts =toluene-4-sulfonyl, Bn=benzyl.
mally 30% over two steps), thus proving the superiority of
dynamic covalent chemistry[1] over the more conventional
procedures (Scheme 3). These preliminary results lay the
foundations for the creation of much more intricate trans-
acetalations[29] and DCVLs, which will include many different
components in the virtual library, as well as a range of
templates, both reusable and consumable.
Experimental Section
2: HOCH2CH2OH (5 mL, 90 mmol) was added dropwise to a
suspension of NaH (95%, 6.80 g, 269 mmol) in ClCH2CH(OMe)2
(100 mL, 896 mmol) at 08C. The reaction mixture was heated (1408C)
under reflux for 24 h and the resulting brown gum was dissolved in
H2O (100 mL). The aqueous solution was concentrated under high
vacuum and then diluted again with H2O (250 mL). The aqueous
layer was extracted with CH2Cl2 (3 ” 250 mL). The organic layers
were combined, dried (Na2SO4), filtered, and concentrated under
vacuum. The resulting oil was subjected to column chromatography
(basic Al2O3, hexanes then CH2Cl2) to give 2 (19 g, 90%) as a pale
1
yellow liquid. H NMR (500 MHz, CD3OD): d = 3.37 (s, 12H), 3.50
(d, J = 5.2 Hz, 4H), 3.63 (s, 4H), 4.49 ppm (t, J = 5.2 Hz, 2H); 13C
NMR (125 MHz, CD3OD): d = 54.3, 71.8, 104.1 ppm; FABMS: m/z:
499.3 [2M+Na]+, 261.3 [M+Na]+, 207.2 [MꢀOMe]+; HRMS (FAB)
m/z calcd for C10H22NaO6 [M+Na]+: 261.1314, found: 261.1314.
General procedure for NMR experiments. Compounds 2 (9.5 mg,
40 mmol) and d-3 (8.1 mg, 40 mmol), in addition to either (DBA)PF6
(8.8 mg, 22 mmol) or CsPF6 (6.1 mg, 22 mmol) as the template, were
added to an NMR tube and dissolved in either CDCl3 or CD3CN
(1 mL). TfOH (2 mL, 0.02 mmol) was added to the mixture to initiate
the dynamic process while the solutions were maintained at 458C. The
equilibrations and amplifications of the products in the DCVLs were
[3] For an example of a [2]catenane synthesis employing ring-
opening and ring-closing metathesis (RORCM) and operating
under thermodynamic control, see a) T. J. Kidd, D. A. Leigh, A.
Wilson, J. Am. Chem. Soc. 1999, 121, 1599 – 1600; for an example
of a [2]catenane synthesis utilizing ring-closing metathesis
(RCM), see b) M. Weck, B. Mohr, J.-P. Sauvage, R. H. Grubbs,
J. Org. Chem. 1999, 64, 5463 – 5471; for examples of [2]rotaxane
syntheses using RCM, see c) J. A. Wisner, P. D. Beer, M. G. B.
Drew, M. R. Sambrook, J. Am. Chem. Soc. 2002, 124, 12469 –
12476; d) A. F. M. Kilbinger, S. J. Cantrill, A. W. Waltman, M.
W. Day, R. H. Grubbs, Angew. Chem. 2003, 115, 3403 – 3407;
Angew. Chem. Int. Ed. 2003, 42, 3281 – 3285.
1
monitored by H NMR spectroscopy and mass spectrometry.
Angew. Chem. Int. Ed. 2003, 42, 4220 –4224
www.angewandte.org
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4223

Communications
[4] For stoppering approaches to rotaxanes incorporating imine-
[13] J. F. Stoddart, Stereochemistry of Carbohydrates, Wiley-Inter-
science, New York, 1971.
containing dumbbells, see a) S. J. Cantrill, S. J. Rowan, J. F.
Stoddart, Org. Lett. 1999, 1, 1363 – 1366; b) S. J. Rowan, J. F.
Stoddart, Org. Lett. 1999, 1, 1913 – 1916; for rotaxanes incorpo-
rating an imine-containing macrocycle formed by clipping, see
c) P. T. Glink, A. I. Oliva, J. F. Stoddart, A. J. P. White, D. J.
Williams, Angew. Chem. 2001, 113, 1922 – 1927; Angew. Chem.
Int. Ed. 2001, 40, 1870 – 1875; d) M. Horn, J. Ihringer, P. T. Glink,
J. F. Stoddart, Chem. Eur. J. 2003, 17, 4046 – 4054; for a recent
example of the use of imines in other molecular self-assembly
processes, see e) M. Hochgürtel, R. Biesinger, H. Kroth, D.
Piecha, M. W. Hofmann, S. Kraus, O. Schaaf, C. Nicolau, A. V.
Eliseev, J. Med. Chem. 2003, 46, 356 – 358.
[14] a) S. A. Barker, E. J. Bourne, Adv. Carbohydr. Chem. 1952, 7,
137 – 207; b) J. A. Mills, Adv. Carbohydr. Chem. 1955, 10, 1 – 53;
c) R. U. Lemieux, J. Howard, Can. J. Chem. 1963, 41, 393 – 398.
[15] A good example is the acid-catalyzed reaction between glycerol
and isobutyraldehyde. Since the activation energy is less for the
formation of the five-membered (1,3-dioxolane) ring acetals,
they are formed faster under kinetic control than the six-
membered (1,3-dioxane) ring acetals—both the cis and the trans
isomers. However, since both reactions are reversible and the
dioxanes are more stable than the dioxolanes, the former
eventually constitute the major products of the reaction. More-
over, the acid-catalyzed equilibration of the dioxolane–dioxane
system proceeds via an oxycarbenium ion and does not
necessarily require water; see a) R. J. Abraham, H. D. Banks,
E. L. Eliel, O. Hofer, M. K. Kaloustian, J. Am. Chem. Soc. 1972,
94, 1913 – 1918; b) E. L. Eliel, S. H. Wilen, Stereochemistry of
Organic Compounds, Wiley, New York, 1994, pp. 678 – 682.
[16] I. J. Burden, J. F. Stoddart, J. Chem. Soc. Perkin Trans. 1 1975,
666 – 674 and 675 – 682.
[17] a) R. B. Jensen, O. Buchardt, S. E. Jorgensen, J. U. R. Nielsen, G.
Schroll, C. Altona, Acta Chem. Scand. Ser. B 1975, 29, 373 – 378;
b) J.-L. Gras, A. Poncet, Synth. Commun. 1992, 22, 405 – 409;
c) H. Senderowitz, A. Linden, I. Golender, S. Abramsom, B.
Fuchs, Tetrahedron 1994, 50, 9691 – 9706; d) H. Senderowitz, I.
Golender, B. Fuchs, Tetrahedron 1994, 50, 9707 – 9728; e) H.
Jatzke, K. Frische, M. Greenwald, I. Golender, B. Fuchs,
Tetrahedron 1997, 53, 4821 – 4834; f) A. Linden, H. Beckhaus,
S. P. Verevkin, C. Rückardt, B. Ganguly, B. Fuchs, J. Org. Chem.
1998, 63, 8205 – 8211; g) M. Grabarnik, N. G. Lemcoff, R. Madar,
S. Abramson, S. Weinman, B. Fuchs, J. Org. Chem. 2000, 65,
1636 – 1642; h) S. Abramson, E. Ashkenasi, K. Frische, I.
Goldberg, L. Golender, M. Greenwald, N. G. Lemcoff, R.
Madar, S. Weinman, B. Fuchs, Chem. Eur. J., in press.
[18] For a recent review, see S. J. Cantrill, A. R. Pease, J. F. Stoddart,
J. Chem. Soc. Dalton Trans. 2000, 3715 – 3734.
[5] For rotaxanes containing disulfide units in their dumbbell-
shaped components that are formed by riveting and stoppering
approaches, see a) A. G. Kolchinski, N. W. Alcock, R. A. Roes-
ner, D. H. Busch, Chem. Commun. 1998, 1437 – 1438; b) Y.
Furusho, T. Hasegawa, A. Tsuboi, N. Kihara, T. Takata, Chem.
Lett. 2000, 18 – 19; c) T. Oku, T. Furush, T. Takata, J. Polym. Sci.
Part A 2003, 41, 119 – 123; for examples of the use of disulfide
groups in other molecular self-assembly processes, see d) H.
Hioki, W. C. Still, J. Org. Chem. 1998, 63, 904 – 905; e) S.-W.
Tam-Chang, J. S. Stehouwer, J. Hao, J. Org. Chem. 1999, 64, 334 –
335; f) S. Otto, R. L. E. Furlan, J. K. M. Sanders, J. Am. Chem.
Soc. 2000, 122, 12063 – 12064; g) O. Ramström, J.-M. Lehn,
ChemBioChem 2000, 1, 41 – 48; h) S. Otto, R. L. E. Furlan, J. K.
M. Sanders, Science 2002, 297, 590 – 593; i) for the use of
disulfide groups in the amplification of a catalyst from a DCL,
see B. Brisig, J. K. M. Sanders, S. Otto, Angew. Chem. 2003, 115,
1308 – 1311; Angew. Chem. Int. Ed. 2003, 42, 1270 – 1273.
[6] a) D. B. Amabilino, J. F. Stoddart, Chem. Rev. 1995, 95, 2725 –
2828; b) Molecular Catenanes, Rotaxanes, and Knots (Eds.: J.-P.
Sauvage, C. Dietrich-Buchecker), Wiley-VCH, Weinheim, 1999.
[7] For an example of the use of acetals in the synthesis of natural
products, see A. Nadin, K. C. Nicolaou, Angew. Chem. 1996, 108,
1732 – 1766; Angew. Chem. Int. Ed. Engl. 1996, 35, 1622 – 1656.
[8] For examples of the use of esters in DCLs, see a) P. A. Brady, J.
K. M. Sanders, J. Chem. Soc. Perkin Trans. 1 1997, 3237 – 3253;
b) S. J. Rowan, J. K. M. Sanders, J. Org. Chem. 1998, 63, 1536 –
1546; c) G. Kaiser, J. K. M. Sanders, Chem. Commun. 2000,
1763 – 1764; d) P. S. Lukeman, J. K. M. Sanders, Tetrahedron
Lett. 2000, 41, 10171 – 10174.
[19] a) P. W. Feit, J. Med. Chem. 1964, 7, 14 – 17; b) M. Carmack, C. J.
Kelley, J. Org. Chem. 1968, 33, 2171 – 2173; c) J. Bourson, L.
Oliveros, Bull. Soc. Chim. Fr. 1977, 11, 1241.
[20] R. Fahrang, D. Sinou, Bull. Soc. Chim. Belg. 1989, 98, 387 – 393.
[21] A. B. Foster, A. H. Olavesen, J. M. Webber, J. Chem. Soc. 1961,
5095 – 5097.
[22] This percentage conversion is based on a comparison of the
integrals for all the acetal methine proton resonances in the
d = 4.4–5.5 ppm range.
[23] CsPF6 was obtained by adding a saturated aqueous solution of
NH4PF6 to an aqueous solution of CsCl. The resulting precipitate
was filtered off and dried under vacuum.
[24] This estimate of the extent of the conversion is based on the
integration of all the acetal methine proton signals in the 1H
NMR spectrum.
[25] The dynamic approach was equally successful in providing ll-1
starting from l-threitol. The optical rotation was approximately
equal to its enantiomer (dd-1), but of opposite sign ([a]D =
+ 19.0 (c = 1, CHCl3)).
[26] K. Frische, M. Greenwald, E. Ashkenasi, N. G. Lemcoff, S.
Abramson, L. Golender, B. Fuchs, Tetrahedron Lett. 1995, 36,
9193 – 9196.
[27] J. A. Marshall, J. D. Trometer, B. E. Blough, T. D. Crute, J. Org.
Chem. 1988, 53, 4274 – 4282.
[28] G. Dijkstra, W. H. Kruizinga, R. M. Kellogg, J. Org. Chem. 1987,
52, 4230 – 4234.
[29] Transacetalation has been used succesfully in the synthesis of
dendritic polyacetals; see N. G. Lemcoff, B. Fuchs, Org. Lett.
2002, 4, 731 – 734.
[9] For examples of the use of hydrazones in DCLs, see a) G. R. L.
Cousins, S.-A. Poulsen, J. K. M. Sanders, Chem. Commun. 1999,
1575 – 1576; b) R. L. E. Furlan, G. R. L. Cousins, J. K. M. Sand-
ers, Chem. Commun. 2000, 1761 – 1762; c) T. Bunyapaiboonsri,
O. Ramström, S. Lohmann, J.-M. Lehn, L. Peng, M. Goeldner,
ChemBioChem 2001, 2, 438 – 444; d) R. L. E. Furlan, Y.-F. Ng, S.
Otto, J. K. M. Sanders, J. Am. Chem. Soc. 2001, 123, 8876 – 8877;
e) G. R. L. Cousins, R. L. E. Furlan, Y.-F. Ng, J. E. Redman, J.
K. M. Sanders, Angew. Chem. 2001, 113, 437 – 442; Angew.
Chem. Int. Ed. 2001, 40, 423 – 428; f) R. L. E. Furlan, Y.-F. Ng,
G. R. L. Cousins, J. E. Redman, J. K. M. Sanders, Tetrahedron
2002, 58, 771 – 778; g) S. L. Roberts, R. L. E. Furlan, S. Otto, J.
K. M. Sanders, Org. Biomol. Chem. 2003, 1, 1625 – 1633.
[10] For an example of the use of anhydrides of hydroxyboraza-
aromatic compounds in DCLs, see P. J. Comina, D. Philp, B. M.
Kariuki, K. D. M. Harris, Chem. Commun. 1999, 2279 – 2280.
[11] For an example of the use of oximes in DCLs, see V. A.
Polyakov, M. I. Nelen, N. Nazarpack-Kandlousy, A. D. Ryabov,
A. V. Eliseev, J. Phys. Org. Chem. 1999, 12, 357 – 363.
[12] A number of dioxadiazadecalin–salen tautomeric macrocycles
and complexes have been shown to constitute dynamic combi-
natorial virtual libraries (DCVLs); see A. Star, I. Goldberg, B.
Fuchs, Angew. Chem. 2000, 112, 2797 – 2801; Angew. Chem. Int.
Ed. 2000, 39, 2685 – 2689.
4224
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2003, 42, 4220 –4224