Synthesis of phototrappable shape-shifting molecules for adaptive guest binding

Article abstract of DOI:10.1021/ja107314p

We have designed and synthesized oligosubstituted bullvalenes 1 and 2 as adaptive molecules that can change their shapes in order to bind tightly to a suitable guest. By incorporation of a photolabile o-nitroveratryloxycarbonate (NVOC) group into bullvalenes 1 and 2, tightly binding species can be selectively isolated from a population of hundreds of interconverting structural isomers. Spontaneous strain-assisted Cope rearrangements allow these shape-shifting molecules to exist in a dynamic equilibrium of configurationally distinct valence isomers, as revealed by dynamic NMR and HPLC studies. When NVOC bullvalenes 1 and 2 were exposed to UV light, the cleavage of the NVOC group resulted in a mixture of static isomers of the corresponding bullvalone. Binding studies of NVOC bisporphyrin bullvalene 1 demonstrated that the dynamic isomeric equilibrium shifted in the presence of C₆₀, favoring configurations with more favorable binding affinities. Irradiation of a mixture of 1 and C₆₀ with UV light and isolation of the major static isomer yielded an isomer of bisporphyrin bullvalone with a binding affinity for C ₆₀ that was ～2 times larger than that of the nonadapted isomer bisporphyrin bullvalone 41.

Full text of DOI:10.1021/ja107314p

Published on Web 10/14/2010
Synthesis of Phototrappable Shape-Shifting Molecules for
Adaptive Guest Binding
Alexander R. Lippert, Atsushi Naganawa, Vasken L. Keleshian, and
Jeffrey W. Bode*,†
Roy and Diana Vagelos Laboratories, Department of Chemistry, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104, United States
Received August 14, 2010; E-mail: bode@sas.upenn.edu
Abstract: We have designed and synthesized oligosubstituted bullvalenes 1 and 2 as adaptive molecules
that can change their shapes in order to bind tightly to a suitable guest. By incorporation of a photolabile
o-nitroveratryloxycarbonate (NVOC) group into bullvalenes 1 and 2, tightly binding species can be selectively
isolated from a population of hundreds of interconverting structural isomers. Spontaneous strain-assisted
Cope rearrangements allow these shape-shifting molecules to exist in a dynamic equilibrium of config-
urationally distinct valence isomers, as revealed by dynamic NMR and HPLC studies. When NVOC
bullvalenes 1 and 2 were exposed to UV light, the cleavage of the NVOC group resulted in a mixture of
static isomers of the corresponding bullvalone. Binding studies of NVOC bisporphyrin bullvalene 1
demonstrated that the dynamic isomeric equilibrium shifted in the presence of C60, favoring configurations
with more favorable binding affinities. Irradiation of a mixture of 1 and C60 with UV light and isolation of the
major static isomer yielded an isomer of bisporphyrin bullvalone with a binding affinity for C60 that was ∼2
times larger than that of the nonadapted isomer bisporphyrin bullvalone 41.
Introduction
modification of these conditions. Even so, typical systems often
suffer from long equilibration times and the need for additional
Chemical systems that can adapt in response to environmental
cues represent an emerging paradigm in the discovery and
implementation of new host-guest interactions.1 Dynamic
combinatorial libraries consist of sets of functional molecules
that form reversible bonds with each other to generate a virtual
library of transient species in thermodynamic equilibrium. In
response to an appropriate stimulus, usually a molecular guest,
this thermodynamic equilibrium shifts toward those species that
have the most favorable interactions with the guest molecule.
Such a system has the ability to dynamically respond to a species
or stimulus of interest, an approach that has been used to
discover novel receptors,2 sensors,3 catalysts,4 and systems
capable of self-assembly and self-replication.5
The successful design of an adaptive dynamic system requires
careful consideration of its constituent components and the
reversible reactions used to mediate the interconversion of the
transient species that make up the library. Imine-like exchange,2f
disulfide formation,2g and acyl exchange6 reactions have suc-
cessfully been utilized to generate structurally and functionally
diverse dynamic libraries. The efficacy of these transformations
results from their high reversibility under a given set of
conditions and the ability to quench this reversibility upon
reagents both to mediate the reversible reactions and to freeze
the equilibrium once adaptation has occurred. Furthermore,
many of these systems generate diversity through the formation
of cyclic and linear oligomers from a set of component
monomers. The multicomponent assembly of such structures
faces statistical and entropic challenges in forming oligomeric
macrocyclic structures from monomeric components.
In order to overcome these inherent challenges to the
expanding field of dynamic combinatorial chemistry, we have
sought to develop “self-contained dynamic combinatorial librar-
ies”, in which the adaptive structures are limited to intramo-
lecular rearrangements. This proposal requires the identification
of discrete chemical entities that can spontaneously change their
configuration or chemical properties without the need for added
chemical reagents or catalysts that might interfere with the
desired recognition events or favor selected members of the
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† Present address: Laboratorium fu¨r Organische Chemie, ETH-Zu¨rich,
Zu¨rich 8093, Switzerland.
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10.1021/ja107314p  2010 American Chemical Society

Synthesis of Phototrappable Shape-Shifting Molecules
A R T I C L E S
Scheme 1. Degenerate Strain-Assisted Cope Rearrangements of
Bullvalene and Oligosubstituted Bullvalenes Synthesized in This
Work
interconverting population. A considerable number of chemical
systems that equilibrate between two or more different structural
isomers are known, including epimerizable stereocenters,7
metastable atropisomers,8 ring-chain tautomers,9 and dynamic
foldamers.10 The majority of these, however, would not make
suitable platforms for dynamic combinatorial chemistry because
of either the very small number of structurally distinct isomers
or the presence of highly reactive chemical functionality.
Bullvalene11 is a 10-carbon bridged tris(vinyl)cyclopropane
whose unique bonding pattern endows it with the intriguing
ability to alter the bonding pattern and spatial orientation of its
atoms spontaneously through degenerate strain-assisted Cope
rearrangements (Scheme 1). The dynamic properties of bullvalene
were first conceived by Doering and Roth11a,b during their work
on strain-assisted Cope rearrangements. They hypothesized that
a structure such as bullvalene would give rise to a rapid fluxional
tautomerism of ∼1.2 million degenerate structures resulting in
1
studies of the nature of this spontaneous rearrangement.14 While
isomerization occurs rapidly at ambient temperature, this dy-
namic molecular skeleton is remarkably stable even at high
temperatures. Although the rapidity and reagentless nature of
this rearrangement could provide a powerful reaction to mediate
the interconversion of configurationally distinct isomers of an
appropriately functionalized bullvalene,1f the lack of a versatile
synthesis to provide these intricately functionalized bullvalenes
has precluded its successful application as a dynamic shape-
shifting molecule.
Herein, we report a versatile stepwise synthesis of novel
highly functionalized bullvalene derivatives, including photo-
labile o-nitroveratryloxycarbonate (NVOC) bullvalenes 1 and
2. This synthetic challenge required not only an efficient method
to access the fluxional tetracyclic bullvalene scaffold but also
methods for the installation of recognition motifs such as
porphyrin units, a means of inducing the dynamic behavior at
a late stage in the synthetic sequence, and the design and
incorporation of a mechanism to halt the dynamic isomerization
of the bullvalene core. NVOC bisporphyrin bullvalene 1 con-
stitutes a dynamic combinatorial library that rapidly equilibrates
and can be immobilized without the need for additional chemical
reagents. Using 1H NMR and UV binding studies, we were able
to demonstrate that this molecule can adapt its shape to form
favorable binding interactions with C60 (Figure 1). Furthermore,
these structural conformations could be frozen and isolated,
establishing the utility of 1 as a virtual library in which all of
the components can be accessed by a single molecule. The self-
contained nature of this system offers advantages over the more
complex multicomponent assemblies and opens up new pos-
sibilities for the development of self-contained dynamic com-
binatorial libraries.
a single H NMR resonance. Indeed, the subsequent photo-
chemical synthesis of bullvalene by Schroeder11c as well as other
syntheses of bullvalene11d,e,12 and its fundamental derivatives13
have validated this hypothesis and allowed for informative
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A R T I C L E S
Lippert et al.
Figure 1. NVOC bisporphyrin bullvalene 1 exists in a dynamic equilibrium of 840 possible isomers. After it is adaptively bound to a C60 guest, UV
irradiation cleaves the NVOC group, resulting in static isomers of bisporphyrin bullvalone with optimized binding affinities.
Scheme 2. Retrosynthetic Analysis of Bullvalone 3
Scheme 3. Intramolecular Bisdiazoketone Decomposition Route To
Form Enedione 7
formation of the tetracyclic bullvalene core consisting of a
bridged tris(vinyl)cyclopropane. Second was the requirement
that this core contain functional handles by which desired
recognition motifs could be appended in a highly convergent
manner. It was also necessary to design a mechanism by which
the exchange process between the valence isomers could be
halted, allowing for the analysis and isolation of an adapted
species. Our initial synthetic target, bisallyl bullvalone 315
(Scheme 2), satisfied these criteria, as an intramolecular cyclo-
propanation could form the tetracyclic core, allylic arms
provided handles for further elaboration, and a ketone to enol
tautomerization could serve as a base-sensitive switch for
toggling between the static bullvalone and a dynamic hydroxy-
bullvalene.
Working from a synthesis of unfunctionalized bullvalene
performed by Serratosa,12 we imagined that trisubstituted
bullvalone 3 could be attained from regioselective functional-
ization of the triketone 4 containing a desymmetrizing group
that would allow for steric differentiation of the ketones (Scheme
2). A key intramolecular cyclopropanation of diazoketone 5 or
sulfur ylide 6 derived from enedione intermediate 7 would
provide the tetracyclic skeleton. Initially, we sought to synthesize
enedione 7 through an intramolecular bisdiazoketone decom-
position of meso intermediate 8, which could be generated
through parallel functionalization of commercially available
dimethyl acetone-1,3-dicarboxylate (9).
statistical mixture of the olefinic tautomers 10 and 11 were
obtained. Hydrogenation of this mixture under high-pressure
H2 in the presence of PtO2 followed by hydrolysis of the methyl
esters provided bisacid 13 in excellent yield over the three-step
sequence from 9. In the conversion of bisacid 13 to the
corresponding bis(acid chloride), we found it necessary to
employ a stoichiometric amount of the Vilsmeier salt 1417 at
-10 °C in order to avoid cleavage of the tert-butyl ester as
well as cyclic anhydride formation, as these side products
plagued a large number of other conditions attempted for the
preparation of the bis(acid chloride). Treatment of the bis(acid
chloride) with freshly prepared diazomethane provided bisdia-
zoketone 8 in 50% overall yield from the diacid. With catalysis
by chlorocyclopentadienylbis(triphenylphosphine)ruthenium-
(II)18 (15), 8 underwent intramolecular bisdiazoketone decom-
position to produce enedione intermediate 7 in 63% yield.
Revised Route to the Enedione Intermediate. Although this
route provided access to the desired enedione 7, the modest
yield of the diazoketone formation as well as the hazards
associated with the large-scale preparation of diazomethane
prompted us to seek a more practical route to this intermediate.
We postulated that instead of the formation of a seven-
membered ring through a sequence of steps that required
multiple functional group transformations prior to the ultimate
ring-closing event, this same intermediate could be more easily
attained in a scalable fashion through the oxidative elaboration
of cycloheptanone.
Synthesis of Enedione 7 via Diazoketone Decomposition. The
synthetic endeavor began with the Wittig olefination16 of 9 with
tert-butyl triphenyl phosphorane (Scheme 3). Good yields of a
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Synthesis of Phototrappable Shape-Shifting Molecules
A R T I C L E S
Scheme 4. Revised Synthesis of Enedione 7
Scheme 5. Synthesis of Diazoketone 5 from Phosphorus Ylide 24
Scheme 6. Intramolecular Cyclopropanation To Form Tetracyclic
Cyclopropane 4
Cycloheptadienone 20 was readily prepared from cyclohep-
tanone by a known procedure19 (Scheme 4). Protection of the
ketone as an acetal was followed by bisbromination with
elemental bromine and biselimination with sodium hydroxide.
Cleavage of the acetal with dilute sulfuric acid produced 20 in
60% yield over the four-step sequence. Carbon-carbon bond
formation was accomplished with a titanium tetrachloride-
catalyzed Mukaiyama Michael addition20 using tert-butyl tri-
methylsilyl ketene acetal21 to produce enone 21 in excellent
yield. A direct tert-butyl peroxide-mediated, metal-catalyzed
allylic oxidation of enedione 21 was attempted using a range
of metal catalysts, including Pd(OH)2,22 rhodium(II) caprolac-
tam,23 [Cu(I)(CH3CN)4]PF6, and Cu(I)(OTf). The best result was
obtained using rhodium(II) carprolactam, which provided the
oxidized product 7 in a modest 45% yield. Selenium dioxide
followed by PCC oxidation24 and chromium(III) oxide and
dimethylpyrazole25 also gave only low yields of the oxidized
product. The best results were obtained in a two-step procedure
starting with an AIBN-initiated radical bromination followed
by an N-methylmorpholine-N-oxide-mediated Ganem26 reaction
to transform the secondary bromide into a ketone. This provided
oxidized enedione 7 in good yield on a multigram scale; the
only observed side product was the bisenone formed by
elimination of the bromide.
Activation of the acid with isobutyl chloroformate followed by
coupling with ethyltriphenylphosphorane produced the doubly
stabilized ylide 24 in 74% yield.28 A screening of sulfonyl
azides, including tosyl azide, mesyl azide, o-nitrophenylsulfonyl
azide, and perfluorobutylsulfonyl azide (nofyl azide)29 revealed
that nofyl azide most effectively mediated this transformation,
producing diazoketone 5 in 44% yield.
Reactions using [Cu(I)(CH3CN)4]PF6 and Rh(II)2(OAc)4 as
catalysts did not produce any of the desired cyclopropane
product in the key intramolecular cyclopropanation (Scheme
6). We suspected that the olefin was too electron-deficient for
the carbene-mediated cyclopropanation to occur. However,
studies by Aggarwal30 demonstrated that the addition of catalytic
sulfides could promote cyclopropanation of diazoketones with
electron-deficient olefins through the intermediacy of a catalyti-
cally generated sulfur ylide. Inspired by these studies, a sulfur
ylide-mediated cyclopropanation was pursued. Stoichiometric
amounts of pentamethylene sulfide and catalytic Rh(II)2(OAc)4
were used to form doubly stabilized sulfur ylide 6. Heating 6
in degassed dichloroethane at 180 °C did indeed afford triketone
4, albeit in low yield.
Intramolecular Cyclopropanation. In the initial attempts to
form the desired triketone 4 via an intramolecular cyclopropa-
nation, it was necessary to advance the tert-butyl ester func-
tionality into a stabilized diazoketone. Inspired by a report of
the transformation of phosphorus ylides into diazoketones
through the use of sulfonyl azide diazo-transfer reagents,27 we
began to study the possibility of installing the diazoketone in
this manner. Treatment of enedione 7 with a 1:1 mixture of
trifluoroacetic acid (TFA) and dichloromethane followed by
aqueous workup yielded the deprotected acid 23 (Scheme 5).
In order to circumvent the low-yielding diazoketone forma-
tion, we investigated the direct coupling of a sulfur ylide with
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Scheme 7. Ylide Coupling and Optimized Cyclopropanation
Scheme 9. Elucidation of Degradation Pathways of Bullvalones 3
and 30
Scheme 8. Synthesis of Bisallyl Bullvalone 3
phine/iodine,34 catalytic acid, phosphorus pentachloride with
various bases,35 and thionyl chloride with various bases,36
revealed that premixing of thionyl chloride and pyridine37
followed by addition of the meso diol 26 gave the best results
for the elimination of the meso diastereomer, yielding the desired
bullvalone 3 in 60% yield. When the chiral diastereomer was
subjected to the same conditions, however, tetrahydrofuran
product 28 was the major product. Further experimentation
revealed that upon treatment of the chiral diol 27 with a
premixed solution of Hu¨nig’s base and thionyl chloride followed
by addition of pyridine, the desired bullvalone 3 could be
obtained in 40% yield.
Elucidation of Degradation Pathways. Previous deuterium
incorporation studies15 revealed that ketone to enol tautomer-
ization of the carbonyl of bisallyl bullvalone 3 could be used
as a chemical switch to toggle between a static bullvalone and
a dynamic hydroxybullvalene. While these experiments dem-
onstrated that base could indeed result in configurational
isomerization via the mediation of a transient hydroxybullvalene,
incomplete deuterium incorporation suggested that degradation
pathways resulting in static constitutional isomers might be
present. Isolation of the major components after treatment with
base revealed that some of the isomers had structures that could
not be assigned to a bullvalone and were most likely ring-opened
structures such as 29 (R ) CO2Et). It was theorized that Cope
rearrangements of the hydroxybullvalene would produce some
isomers in which the hydroxyl group was positioned on the
cyclopropane ring. If in addition the ester were positioned
appropriately, then a donor-acceptor ring opening of the
cyclopropane could occur. Our initial approach to solve this
problem was to remove the acceptor aspect of the donor-acceptor
pair by converting the ester into the primary alcohol 30 using
a three-step procedure (Scheme 9). Unfortunately, deuterium
incorporation experiments suggested that a decomposition
pathway still existed. It was also found that TFA could mediate
the isomerization and ring opening. Isolation of ring-opened
products such as 29 (R ) CH2OH) indicated that a proton could
an activated carboxylate.31 We were delighted to discover that
after activation of acid 23 with isobutyl chloroformate, coupling
with the pentamethylenesulfide-derived ylide 25 produced the
desired coupled ylide 6 (Scheme 7), nicely establishing a new
carbon-carbon bond and setting up the requisite functionality
in a single step. Surprisingly, however, the sulfur ylide
synthesized in this way failed to produce any of the desired
triketone 4, even at elevated temperatures.
We postulated that residual Rh(II)2(OAc)4 from the conver-
sion of 5 into sulfur ylide 6, whose presence was evidenced by
its green coloration and mass spectral analysis, may have
catalyzed the cyclopropanation. Reasoning that the Rh(II)2-
(OAc)4 acted as a Lewis acid to promote the cyclopropanation,
we investigated the effects of other Lewis acids to facilitate the
desired transformation. We found that the ylide was smoothly
converted to the desired triketone 4 (Scheme 7) using a variety
of Lewis acids. Optimization revealed chlorobenzene to be
the best solvent, and Sc(III)(OTf)3 performed better than
Yb(III)(OTf)3, Y(III)(OTf)3, or Zn(II)Cl2, reproducibly forming
triketone 4 in 70% yield.
Synthesis of Oligosubstituted Bullvalone. Having developed
a scalable route to the advanced triketone intermediate, we
turned our efforts toward its functionalization and conversion
into an elaborately derivatized bullvalene. Selective function-
alization of the two less hindered ketones by reaction with
allylmagnesium bromide yielded a mixture of the meso dias-
tereomer 26 and the chiral diastereomer 27 (26/27 ≈ 3:2;
Scheme 8). Exploration of a variety of biselimination conditions,
including Burgess reagent,32 xanthate formation,33 triphenylphos-
(31) (a) Ratts, K. W.; Yao, A. N. J. Org. Chem. 1966, 31, 1689–1693. (b)
Ziegler, E.; Wittmann, H.; Sterk, H. Monatsh. Chem. 1987, 118, 115–
125.
(34) Alvarez-Manzaneda, E. J.; Chahboun, E.; Torres, C.; Alvarez, E.;
Alvarez-Manzaneda, R.; Haidour, A.; Ramos, J. Tetrahedron Lett.
2004, 45, 4453–4455.
(32) (a) Burgess, E. M.; Penton, H. R.; Taylor, E. A. J. Am. Chem. Soc.
1970, 92, 5224–5225. (b) Burgess, E. M.; Penton, H. R.; Taylor, E. A.
J. Org. Chem. 1973, 38, 26–31.
(35) Sauers, R. R. J. Am. Chem. Soc. 1959, 81, 4873–4876.
(36) Nicolaou, K. C.; Gray, D. L. F.; Tae, J. J. Am. Chem. Soc. 2004, 126,
613–627.
(33) Nace, H. R. Org. React. 1962, 12, 57–100.
(37) Greene, A. E.; Edgar, M. T. J. Org. Chem. 1989, 54, 1468–1470.
9
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Synthesis of Phototrappable Shape-Shifting Molecules
A R T I C L E S
Scheme 10. Synthesis of Isobutyl Carbonate Bisallyl Bullvalene 31
also act as an acceptor in the donor-acceptor ring opening of
the bullvalone cyclopropane. On the basis of these experiments,
it became clear that it would be necessary to remove the donor
capability of the hydroxyl group in order for a robust and stable
isomerization to occur.
Synthesis of Isobutyl Carbonate Bisallyl Bullvalene 31. It was
reasoned that trapping of the enolate of bisallyl bullvalone 3
might provide access to an isolable oligosubstituted bullvalene.
After treatment with LiHMDS at -78 °C, the lithium enolate
was treated with isobutyl chloroformate and allowed to warm
to room temperature (Scheme 10). Upon workup and purifica-
tion, the stable isobutyl carbonate bisallyl bullvalene 31 was
isolated and characterized.38 Variable-temperature (VT) NMR
spectroscopy demonstrated that the strain-assisted Cope rear-
rangement occurred spontaneously at room temperature with
complete coalescence of the bullvalene core protons at 120 °C
in (CD3)2SO. Additionally, two-dimensional exchange correla-
tion spectroscopy (2D-EXSY) revealed chemical exchange
among the olefin, cyclopropyl, and methine protons.38
HPLC Demonstration of Interconversion. Chromatographic
purification of functionalized bullvalenes was complicated by
the fact that the purified material appears as multiple bands by
chromatographic analysis. For example, the HPLC trace of the
purified isobutyl carbonate bisallyl bullvalene 31 displayed
multiple peaks at different retention times (Figure 2a); the
broadening and peak-shape distortion attest that significant
isomerization occurred during elution of the bullvalene through
the HPLC column. After isolating four fractions from the HPLC
column and reinjecting each of these fractions into the chro-
matograph, we observed the reappearance of the peaks from
the original bullvalene isomeric distribution (Figure 2b-e). This
attests to the identity of these compounds as interconverting
isomers. Most of the isolated bullvalene fractions resulted in
nearly perfect reproductions of the original bullvalene chro-
matogram upon reinjection, indicating rapid equilibration.
Reinjection of the fraction with a retention time of 9-10 min
(Figure 2d), however, provided a chromatogram with an altered
isomeric ratio, indicating the presence of slowly equilibrating
or static compounds.
NVOC Bisallyl Bullvalene 2. A crucial component of a
dynamic combinatorial library is the mechanism to halt the
reversibility of the equilibration reaction, allowing the isolation
and analysis of an adapted product. We had originally proposed
that the ketone of a bullvalone could serve as a chemical handle
capable of mediating between the static bullvalone and the
dynamic bullvalene. However, it was determined that the
bullvalone was not stable under the conditions necessary to
toggle between these two states. Trapping the hydroxybullvalene
as a carbonate presented a solution in that the ring-opening
pathways responsible for degradation of the bullvalone could
be suppressed while still allowing for the diversity-generating
Cope rearrangements to occur. In addition, selecting a carbonate
Figure 2. Isolation of bullvalene isomers followed by reinjection into the
HPLC column. (a) HPLC trace of purified isobutyl carbonate bisallyl
bullvalene 31. (b-e) HPLC traces after isolation and reinjection of the
fractions from (b) tr ) 7 to 8 min, (c) tr ) 8 to 9 min, (d) tr ) 9 to 10 min,
and (e) tr ) 12.5 to 13.5 min.
protecting group that could be cleaved under the desired
conditions would provide a way to halt the dynamic rearrange-
ment of the bullvalene. In order to explore this possibility, we
sought to prepare bullvalene derivatives with photolabile
carbonate substituents. To this end, NVOC bisallyl bullvalene
2 was synthesized by trapping the lithium enolate of bullvalone
3 with NVOC chloroformate (Scheme 11).
As in the case of isobutyl carbonate bisallyl bullvalene 31,
the HPLC trace of NVOC bisallyl bullvalene 2 also appeared
(38) Lippert, A. R.; Keleshian, V. L.; Bode, J. W. Org. Biomol. Chem.
2009, 7, 1529–1532.
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A R T I C L E S
Lippert et al.
Scheme 11. Synthesis and Photolysis of NVOC Bisallyl
Bullvalene 2
correct mass in 38% yield. Although initial studies utilizing
supercritical-fluid CO2 chromatography revealed that this bispor-
phyrin molecule does indeed bind C60, it was eventually found
that the TFA deprotection step caused a ketone-to-enol tau-
tomerization (as in Scheme 9) followed by a Cope rearrangement
and donor-acceptor ring opening of the resulting hydroxycy-
clopropane to yield the static isomer 38.
A successful strategy was finally found using acrylamide
porphyrin 4038 as a cross-metathesis coupling partner (Scheme
13). It is known that acrylamides are excellent substrates for
cross-metathesis with terminal olefins,45 and we were pleased
to find that cross-metathesis with 40 (formed from the known
aminoporphyrin 3946) using Grubbs second-generation catalyst
in CH2Cl2 at 40 °C yielded bisporphyrin bullvalone 4138 in 20%
yield. Furthermore, similar conditions were used to form isobutyl
bisporphyrin bullvalene 4238 in 19% yield and NVOC bispor-
phyrin bullvalene 1 in 13% yield (Scheme 14).
as multiple peaks (Figure 3). Irradiation of the purified bull-
valene 2 at 365 nm for 20 h resulted in a complete disappearance
of the peaks due to the starting material as well as the appearance
of peaks corresponding to isomers of bisallyl bullvalone 3.
Synthesis of Bisporphyrin Bullvalenes. With a versatile route
to bisallyl bullvalenes in hand, we investigated appending
suitable recognition motifs to the bullvalene core in order to
demonstrate that an appropriately functionalized bullvalene is
capable of responding to a guest molecule. The strong π-π
Dynamic Combinatorial Chemistry. NVOC bisporphyrin
bullvalene 1 contains all of the elements needed for dynamic
combinatorial chemistry: the bullvalene core provides a spon-
taneous and rapid process by which configurationally distinct
isomers can interconvert with each other, the π-π interactions
between the bisporphyrin units and C60 provide a template for
adaptation, and the photocleavable carbonate allows the system
to be frozen after it has responded to the desired stimuli. Using
1H NMR and UV studies, we previously explored the com-
plexation of isobutyl carbonate bisporphyrin bullvalene 42 and
compared its binding properties with those of bisporphyrin
bullvalone 41 as a static control.38 During the course of these
studies, we established NMR methods to measure the binding
constants of the major binding isomers of 42. Comparison of
these values with that of the static bisporphyrin bullvalone
revealed that the bullvalene could adapt its shape in the presence
of C60 to form isomers with more favorable binding properties.
Having demonstrated that a bisporphyrin bullvalene could
adapt its shape in response to C60, we next wished to ascertain
whether these constitutional isomers could be frozen and
isolated. UV irradiation of NVOC bisporphyrin bullvalene 1,
which possesses a photolabile carbonate, should produce a
mixture of static isomers of bisporphyrin bullvalone. We
performed titration experiments on 1 before and after UV
irradiation. Bullvalene 1 was loaded into NMR tubes with
increasing amounts of C60. Spectra were recorded for these
samples before and after UV irradiation (Figure 4). Before
irradiation, spectra similar to those observed for isobutyl
39
interactions between porphyrins and C60 provided an ideal
host-guest interaction to interrogate the possibility of utilizing
functionalized bullvalenes as dynamic combinatorial libraries.
A necessary prerequisite for this goal was the development of
an efficient and versatile strategy to effect the functionalization
of a dynamic bisallyl bullvalene. We envisaged that cross-
metathesis would provide a convergent and chemoselective
conjugation reaction to append complex molecular fragments
such as porphyrins to the terminal olefins of the bisallyl
bullvalene core.
Initial studies of the cross-metathesis reaction were performed
using bisallyl bullvalone 3. Attempts at metathesis with ally-
lamide porphyrin 33 (synthesized from methyl ester-function-
alized porphyrin 3140 as outlined in Scheme 12) using either
Grubbs second-generation catalyst 3441 or Hoveyda second-
generation catalyst42 (not shown) failed to produce the corre-
sponding bisporphyrin bullvalone 35 (not shown), probably as
a result of ruthenium-catalyzed isomerization of the olefin
followed by decomposition of the resulting enamide.43 A second
stepwise strategy consisting of a successful metathesis with the
known tert-butyloxycarbonyl-protected bisamine cis-olefin 3644
produced the protected bisamine bullvalone 37 (Scheme 13).
Deprotection of the amine groups and coupling to the activated
carboxylate of porphyrin 32 yielded a single product with the
(39) (a) Marois, J.-S.; Cantin, K.; Desmarais, A.; Morin, J.-F. Org. Lett.
2008, 10, 33–36. (b) Hosseini, A.; Taylor, S.; Accorsi, G.; Armaroli,
N.; Reed, C. A.; Boyd, P. D. W. J. Am. Chem. Soc. 2006, 128, 15903–
15913. (c) Haino, T.; Fugii, T.; Fukazawa, Y. J. Org. Chem. 2006,
71, 2572–2580. (d) Boyd, P. D. W.; Reed, C. A. Acc. Chem. Res.
2005, 38, 235–242. (e) Sun, D.; Tham, S. F.; Reed, C. A.; Chaker,
L.; Boyd, P. D. W. J. Am. Chem. Soc. 2002, 124, 6604–6612.
(40) Li, X.; Tanasova, M.; Vasileiou, C.; Borhan, B. J. Am. Chem. Soc.
2008, 130, 1885–1893.
(41) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953–956.
(42) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoyveda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168–8179.
(43) Alcaide, B.; Almendros, P.; Alonso, J. M. Chem.sEur. J. 2003, 9,
5793–5799.
(44) Morita, T.; Maughon, B. R.; Bielawski, C. W.; Grubbs, R. H.
Macromolecules 2000, 33, 6621–6623.
(45) Choi, T.-L.; Chatterjee, A. K.; Grubbs, R. H. Angew. Chem., Int. Ed.
2001, 40, 1277–1279.
Figure 3. HPLC traces for the photolysis of NVOC bisallyl bullvalene
2 upon exposure to UV irradiation after (green) 0, (red) 4, and (blue)
20 h.
(46) Imahori, H.; Hagiwara, K.; Aoki, M.; Akiyama, T.; Taniguchi, S.;
Okada, T.; Shirakawa, M.; Sakata, Y. J. Am. Chem. Soc. 1996, 118,
11771–11782.
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15796 J. AM. CHEM. SOC. VOL. 132, NO. 44, 2010

Synthesis of Phototrappable Shape-Shifting Molecules
A R T I C L E S
Scheme 12. Synthesis of Allylamide Porphyrin 33
Scheme 13. Synthesis of Bisporphyrin Bullvalone 41
Scheme 14. Synthesis of Bisporphyrin Bullvalenes 1 and 42
Next, these NMR tubes were irradiated with UV light for
17 h, and spectra were again recorded. The peaks that were
observed after irradiation arose from static isomers of bispor-
phyrin bullvalone 41. As expected, we found an increasing
amount of the more tightly binding isomers in the experiments
that had greater amounts of C60. Calculation of the binding
constants of these major peaks gave values of 3270 ( 670 M-1
(entry 7) and 7580 ( 1930 M-1 (entry 8) for the less-upfield
and more-upfield peaks, respectively. Finally, we isolated the
major bullvalone product from the photolysis of 1 in the
presence of C60. Analysis by MALDI mass spectrometry
(MALDI-MS) indicated this product had the mass of an isomer
of 41. Calculation of its binding affinity for C60 by spectropho-
tometric titration yielded a binding constant of 7490 ( 440 M-1
(entry 9), which is remarkably close to the value calculated for
the more tightly bound isomer in the NMR titration of NVOC
bisporphyrin bullvalene 1 after photocleavage.
Table 1 summarizes the binding constants measured for
bisporphyrin bullvalone 41 (entries 1, 2, and 10), isobutyl
carbonate bisporphyrin bullvalene 42 (entries 3, 4, and 11),
NVOC bisporphyrin bullvalene 1 before (entries 5, 6, and 12)
and after (entries 7 and 8) photocleavage, and the major
bisporphyrin bullvalone isomer isolated after photocleavage
(entry 9). Similar values were obtained from 1H NMR measure-
ments on isobutyl carbonate bisporphyrin bullvalene 42 and
NVOC bisporphyrin bullvalene 1 for both the higher binding
complex (∆δ ) 0.27) and the lower binding complex (∆δ )
0.24) at 25 ºC as well as the coalesced peak at 90 °C.
Importantly, the values of the binding constants of NVOC
bisporphyrin bullvalene 1 before and after photocleavage are
comparable, demonstrating that the relatively slow exchange
between the dynamic binding isomers introduces minimal error
into the values obtained. The close agreement between value
carbonate bisporphyrin bullvalene 42 were observed. Two peaks
appeared in the region of the porphyrin N-H resonance, each
corresponding to a binding isomer in fast exchange between
the bound and unbound species. Calculation of the binding
constants yielded values similar to those calculated for 42.38
An unshifted peak at -2 ppm was assigned to those isomers
that do not bind well to C60. Interestingly, the relative ratio of
the more tightly binding isomer increased as more C60 was
added, demonstrating the ability of this system to adapt to an
appropriate guest. On the basis of the change in the chemical
shift of these two peaks, binding constants of 2550 ( 240 M-1
(Table 1, entry 5) and 5790 ( 1200 M-1 (entry 6) were
calculated for the less-upfield and more-upfield peaks, respec-
tively. The average high-temperature binding constant of 830
( 90 M-1 (entry 12), which was determined by performing the
titration on the coalesced peak at 90 °C, was similar to the value
of 920 ( 100 M-1 found for 42 (entry 11).
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A R T I C L E S
Lippert et al.
Figure 4. 1H NMR titrations of NVOC bisporphyrin bullvalene 1 with C60 (a) before and (b) after UV irradiation.
1
Table 1. Binding Constants Calculated for Bisporphyrin Bullvalone
of the system. H NMR binding studies have clearly demon-
strated that 1 adapts its structure in response to increasing
concentrations of C60 to form those isomers with more favorable
binding properties. Photolysis of the NVOC carbonate halts the
facile Cope rearrangements, allowing for the isolation of these
adapted structures. UV and 1H NMR binding experiments have
provided compelling evidence of the ability of appropriately
functionalized bullvalenes to serve as dynamic combinatorial
libraries. These studies introduce the unique and far-reaching
potential enabled by a versatile synthetic platform of highly
functionalized bullvalene derivatives.
41, Isobutyl Carbonate Bisporphyrin Bullvalene 41, and NVOC
Bisporphyrin Bullvalene 1 before and after Photocleavage
entry
cmpd
∆δ (ppm)a
T (°C)
Kb (M-1
)
method
1
2
3
4
5
6
7
8
41
41
42
42
1
1
-
25
25
25
25
25
25
25
25
25
90
90
90
2700 ( 120d
2800 ( 210d
3030 ( 430d
6770 ( 1800d
2550 ( 240
5790 ( 1200
3270 ( 670
7580 ( 1930
7490 ( 440
570 ( 650d
920 ( 100d
830 ( 90
UV
0.23
0.24
0.27
0.24
0.27
0.24
0.27
-
NMR
NMR
NMR
NMR
NMR
NMR
NMR
UV
1 + hνb
1 + hνb
1 + hνc
41
9
10
11
12
0.10
0.13
0.13
NMR
NMR
NMR
Experimental Procedures
42
1
Titrations and Photocleavage of NVOC Bisporphyrin
Bullvalene 1. A 1.8 × 10-3 M stock solution of NVOC bispor-
phyrin bullvalene 1 in C6D5CD3 was prepared, and 100 µL aliquots
(1.8 × 10-7 mol) were added to seven NMR tubes (10 mm). An
appropriate aliquot of a stock solution of C60 (2.3 × 10-3 M) in
C6D5CD3 was added to each NMR tube, giving mixtures with 0,
0.5, 1, 1.5, 2, 2.5, and 3 equiv of C60. All of the NMR tubes were
diluted with additional C6D5CD3 to a final volume of 400 µL. The
chemical shift of the upfield N-H proton of the porphyrin was
monitored. Plots of ∆δ versus [C60]t/[BP]t were plotted (Figure S2
in the Supporting Information), and the binding constant (Kb) and
the chemical shift at saturation of binding sites (∆δmax) were
evaluated by a nonlinear least-squares fitting approach using the
following equation:47
a Change in the chemical shift of the peak used to calculate Kb upon
the addition of 3 equiv of C60. b After photolysis. c Major bullvalone
fraction isolated after photolysis. d Data from ref 38.
obtained by spectrophotometric titration of the isolated fraction
1
(entry 9) and the value obtained by H NMR titration for the
higher-binding isomer of 1 after the photocleavage (entry 8)
provide a compelling demonstration of the ability of ap-
propriately functionalized bullvalenes to rapidly discover op-
timized host-guest complexes.
Conclusions and Future Prospects
In summary, we have developed a versatile 10-step synthesis
of elaborately functionalized bullvalenes, including NVOC
bisporphyrin bullvalene 1 and NVOC bisallyl bullvalene 2, from
readily available cycloheptadienone. A late-stage cross-metath-
esis strategy was used to append porphyrin units to the bull-
valene scaffold and could allow for the production of a wide
variety of other bullvalene derivatives with elaborate function-
alities and recognition motifs. Furthermore, the formation of
the bullvalene as an enol carbonate of the static bullvalone
presents an ideal platform to which a number of chemical
mechanisms could be introduced to modulate the dynamic nature
∆δmax [C60]
1
∆δ )
+ 1 +
(
{
2
[BP]
Kb[BP]
2
1/2
[C60]
[C60]
[BP]
1
+ 1 +
- 4
(
)
}
[
]
[BP]
Kb[BP]
where ∆δ ) δobs - δ0, [C60] is the total concentration of C60 in
solution, and [BP] is the total concentration of the bisporphyrin in
solution. The appearance of multiple peaks upon the addition of
(47) Cao, Y.; Xiao, X.; Lu, R.; Guo, Q. J. Mol. Struct. 2003, 660, 73–80.
9
15798 J. AM. CHEM. SOC. VOL. 132, NO. 44, 2010

Synthesis of Phototrappable Shape-Shifting Molecules
A R T I C L E S
C60 indicates the presence of several complexes that are in fast
exchange with their respective unbound isomer (Figure S1). The
binding constants at 25 °C were calculated by monitoring the shifts
of two separate complexes that appeared as separated, distinct peaks.
The titration was also performed at 90 °C, where coalescence of
the peaks was observed (Figure S1). The seven NMR tubes were
exposed to UV irradiation at 365 nm for 17 h. Upon completion of
the photolysis, NMR spectra were recorded from the seven samples
at 25 and 90 °C (Figure S3), and binding constants were determined
as above (Figure S4).
Isolation and Spectrophotometric Titration of an Adapted
Isomer. The major band from each of the tubes containing 2.0,
2.5, and 3.0 equiv of C60 was isolated by PTLC after photolysis. A
solution of this isolated fraction48 (1650 µL, 1.89 × 10-6 M) in
spectral-grade toluene was added to a quartz cuvette, and the
∆A ) ∆Amax (1 + K [C ] + [BP]K ) - (1 + K [C ] +
{
[
b
60
b
b
1/2
60
[BP]K )2 - 4K [C ][BP]
/2K [BP]
2
]
}
b
b
60
b
where ∆A ) Aobs - A0, [C60] is the total concentration of C60 in
solution, and [BP] is the total concentration of the bisporphyrin in
solution.
Acknowledgment. Financial support for this work was provided
by the Camille and Henry Dreyfus Foundation (New Faculty Award
to J.W.B.). J.W.B. is a Fellow of the Packard Foundation, the
Beckman Foundation, and the Sloan Foundation and a Cottrell
Scholar of the Research Corporation. A.N. was supported by the
Ono Corporation. Unrestricted support from Amgen, AstraZeneca,
Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, and Roche
is gratefully acknowledged. We thank Juthanat Kaeobamrung for
the synthesis of intermediates and Yuko Iwamoto for synthetic
protocols for the porphyrin.
absorbance was measured upon the addition of 1.2-120 µL aliquots
-3
(1200 µL total) of a stock solution of C60 (2.63 × 10
M in
toluene) to both the sample and the reference cuvette (Figure S5).
Plots of ∆A at 422 nm versus [C60] were analyzed after dilution
corrections, and the binding constant (Kb) and absorbance at
maximum saturation of binding sites (∆Amax) were evaluated by a
nonlinear least-squares fitting approach using the following
equation:39a
Supporting Information Available: Detailed experimental
procedures, spectral characterization, and binding data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(48) MALDI MS (m/z): calcd for a bisporphyrin bullvalone isomer
(C157H177N10O5)+, 2282.39; found, 2282.22.
JA107314P
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