Hydrogen-bond-assisted helical folding of propeller-shaped molecules: Effects of extended π-conjugation on chiral selection, conformational stability, and exciton coupling

Article abstract of DOI:10.1002/ejoc.201101351

Cooperative interaction between multiple chiral centers dictates the absolute handedness of structural folding. We have designed and prepared a series of chiral C₃-symmetric tris(N-salicylidenamine) derivatives that adopt three-blade propeller-like conformations. Synthetic access to an expanded family of such constructs was aided by enzymatic resolution and C-C cross-coupling reactions of aryl-substituted chiral propargylic alcohol derivatives. These key structural components were integrated into molecular propellers of predetermined helical screw sense. Through comparative studies on a homologous set of molecules, we found that installation of phenylene-ethynylene-derived π-conjugation profoundly affected the stabilities of the helically folded structures, as evidenced by UV/Vis and circular dichroism (CD) studies. Increasing the number of hydrogen bonds through additional substitution also enhanced the populations of the folded conformations in solution. In addition to introducing steric bias to control structural folding, linearly π-conjugated groups function as spatially well-defined chromophores that give rise to characteristic exciton-coupled circular dichroism. Absolute configurations of chiral centers could thus be further confirmed by comparing the torsional relationships between pairs of chromophores on adjacent subunits, which are fully consistent with the computationally predicted structural models. Twist to fold: Chiral alcohol groups effectively direct the absolute helicities of three-bladed propeller-shaped C₃-symmetric molecules through tight O-H...O-H contacts. The stabilities of the conformations of these systems depend upon the numbers of hydrogen bonds and the steric bulk of the π-conjugated substituents on thestereogenic centers. Copyright

Full text of DOI:10.1002/ejoc.201101351

FULL PAPER
DOI: 10.1002/ejoc.201101351
Hydrogen-Bond-Assisted Helical Folding of Propeller-Shaped Molecules:
Effects of Extended π-Conjugation on Chiral Selection, Conformational
Stability, and Exciton Coupling
Elizabeth A. Opsitnick,[a] Xuan Jiang,[a] Andrew N. Hollenbeck,[a] and Dongwhan Lee*[a]
Keywords: Helical structures / Conformation analysis / Chiral induction / Hydrogen bonds / Exciton coupling
Cooperative interaction between multiple chiral centers dic-
tates the absolute handedness of structural folding. We have
designed and prepared a series of chiral C3-symmetric tris(N-
salicylidenamine) derivatives that adopt three-blade propel-
ler-like conformations. Synthetic access to an expanded fam-
ily of such constructs was aided by enzymatic resolution and
denced by UV/Vis and circular dichroism (CD) studies. In-
creasing the number of hydrogen bonds through additional
substitution also enhanced the populations of the folded con-
formations in solution. In addition to introducing steric bias
to control structural folding, linearly π-conjugated groups
function as spatially well-defined chromophores that give
C–C cross-coupling reactions of aryl-substituted chiral pro- rise to characteristic exciton-coupled circular dichroism. Ab-
pargylic alcohol derivatives. These key structural compo- solute configurations of chiral centers could thus be further
nents were integrated into molecular propellers of predeter-
mined helical screw sense. Through comparative studies on
a homologous set of molecules, we found that installation of
phenylene-ethynylene-derived π-conjugation profoundly af-
fected the stabilities of the helically folded structures, as evi-
confirmed by comparing the torsional relationships between
pairs of chromophores on adjacent subunits, which are fully
consistent with the computationally predicted structural
models.
multiple noncovalent interactions between non-neighboring
positions along the rigid backbone helps guide the forma-
tion of robust secondary structures in solution. Existing
paradigms in such endeavors focus predominantly on the
formation of helical objects that present functional groups
on the convex or concave side of the cavity to assist self-
association,[7] guest recognition,[1q,7h,7g,8–13] or catalysis.[14]
As shown in Scheme 1, spiral folding of a linear foldamer
A could proceed in either a right- or a left-handed manner
to furnish helical objects of opposite handedness (i.e., P or
M conformations). Positioning of chiral auxiliaries, typi-
cally in the form of pendant aliphatic chains[7e,13d,13f,15–18]
or twisted arene–arene backbone skeletons,[19] can poten-
tially bias this process toward one screw sense over the
other.
Introduction
Spontaneous folding of well-designed linear molecules
gives rise to compact secondary structures that are stabi-
lized by multiple noncovalent bonds.[1–3] As is exemplified
by naturally occurring macromolecules such as proteins,
polynucleic acids, and polysaccharides, restriction of bond
rotations around the molecular backbones of such con-
structs often helps simplify the reaction coordinates of the
structural folding process. In addition, the intricate side
chain–side chain and/or backbone–side chain interactions
provide energetic bias toward the desired conformation
against potentially competing species.[4] Particularly useful
in this context is the concept of negative design,[5] in which
energy-destabilizing structural motifs are intentionally in-
troduced in order to increase the penalty of “misfolding”
and thereby to define a steeper energy landscape that will
quickly converge to the correctly folded structure. This de-
sign principle has frequently been applied to the de novo
construction of proteins[6] and their synthetic mimetics.[1–3]
Foldamers represent an emerging class of synthetic mole-
Scheme 1. Structural folding of a linear foldamer A to adopt either
cules that are designed to fold into well-defined three-di- a right-handed P conformation or a left-handed M conformation.
mensional (3D) structures.[1–3] Here, strategic placement of
We have recently shown that intuitive chiral induction
models developed for linear foldamers can readily be
[a] Department of Chemistry, Indiana University
adapted for dendritic structures that spontaneously fold to
adopt propeller-shaped geometries.[20] As shown in
Scheme 2, close steric contacts between the three mobile
components (“blades”) constituting the stereodynamic
800 East Kirkwood Avenue, Bloomington, Indiana 47405, USA
Fax: +1-812-855-8300
E-mail: dongwhan@indiana.edu
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101351.
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Helical Folding of Propeller-Shaped Molecules
structure B dictate that their tilting motions proceed in a
unidirectional fashion to provide either a right-handed P
conformer or a left-handed M conformer.[21,22] Classical ex-
amples of such stereodynamic systems include C3-symmet-
ric triarylcarbonium and triarylcyclopropenium cations, in
which torsional motions occurring at different parts of the
molecule are correlated through tight van der Waals con-
tacts.[23] In inorganic systems with threefold symmetry, sim-
ilar structural interconversions between the P and M iso-
mers occur through concerted tilting motions of bulky li-
gands.[24]
Figure 1. Chemical structure of (S,S)3-2 and space-filling models
of M and P helical conformations obtained by hydrogen-bonding-
assisted structural folding.[20] The “misfolded” P chiral conforma-
tion suffers from steric congestion between phenyl groups that con-
verge at the molecular core. As a consequence, it is energetically
destabilized with respect to the M conformer, which is the “cor-
rectly folded” form of the molecule (NOTE: these conformers are
not mirror images of one another but are diastereomeric and there-
fore differ in energy).
Scheme 2. Stereochemical interconversion of the propeller-shaped
molecule B between a right-handed P conformer and a left-handed
M conformer. Structural folding proceeds through concerted tilting
motions of three “blades”, which correspond to the three aryl
groups that are attached directly to the C3-symmetric molecular
core of tris(N-salicylidenamine) shown below the schematic dia-
gram. For achiral tris(N-salicylidenamine)s with R = H, the M and
P conformations are enantiomers and isoenergetic. For chiral
tris(N-salicylidenamine)s with R ϶ H, the M and P conformations
are not mirror images of one another but are diastereomeric, and
therefore differ in energy.
This stereoinduction model immediately established a di-
rect correlation between the absolute configuration (either
R or S) of the chiral centers at the dendritic termini and
the preferred screw sense (either P or M) of the folded mo-
lecule. DFT single-point energy (SPE) calculations on
We postulated that the introduction of steric bias at such model compounds and TD-DFT analysis of experimentally
intersubunit contacts should dictate the absolute screw determined CD spectra fully supported the validity of our
sense, either P or M, of structural folding, and that this initial proposal of central-to-helical chirality transfer.[20]
process could be assisted by the principles of negative de-
In order to develop these stereoinduction models, to re-
sign.[5] Our first-generation molecular prototypes – (S,S)3-2 fine them further, and to obtain direct experimental evi-
(Figure 1) and its mirror-image isomer (R,R)3-2 – were thus dence for assignation of absolute screw sense by exciton-
constructed with the use of tris(N-salicylidenamine)[20,25–27] coupled circular dichroism (ECCD),[28] we decided to ex-
as the C3-symmetric core and three 2,6-disubstituted aryl plore an expanded family of chiral tris(N-salicylidenaniline)
groups as the blades. Through the installation of bulky molecules. In addition to enhancing the stability of the pre-
phenyl groups as part of the chiral secondary alcohol ferred helical conformation in solution, extended π-conju-
groups at the “wingtips”, we wished to enhance repulsive gation installed at the wingtip chiral groups of these mole-
van der Waals interactions in the misfolded conformations cules enables them to function as spatially well-defined
so that the correctly folded structure would be further stabi- chromophores with low excitation energies. Notably, the
lized in the relative energy scale. As shown in Figure 1, in ECCD spectral patterns arising from well-defined pairwise
the choice between the right-handed and the left-handed spatial relationships of these extended π-conjugated substit-
structure, (S,S)3-2 preferentially adopts the M conforma- uents are fully consistent with computational models and
tion, in which phenyl groups point away from the center of further support the validity of our chiral induction model.
the molecule in order to avoid undesired steric congestion. A systematic analysis on the effects of i) the sizes of the
The mirror-image relationship dictates that its enantiomer chiral substituents, ii) the number of hydrogen bonds, and
(R,R)3-2 should prefer the right-handed P conformation, iii) solvent environments on the structural folding of these
which was also confirmed experimentally.
new chiral tris(N-salicylidenamine)s constitutes the main
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topic of this contribution. As in the de novo design of pro- substitution on the 3- and 5-positions should enhance steri-
teins,[5b] destabilization of an undesired interaction becomes cally unfavorable contacts between the wingtip groups. It
as important as stabilization of a desired interaction in our was anticipated that the increasing energy penalty of over-
synthetic systems, the details of which are provided in the crowding in such π-extended groups should enhance the
following sections.
bias toward the M over the P conformer further, which is
evident from comparison of the geometry-optimized mod-
els of (S,S)3-2 (Figure 1) and (S,S)3-4 (see Figures 2 and 3).
Consistently with our intuitive prediction, the energy differ-
ence between the P and M conformers, calculated at the
PM3 level, increases significantly from 8.7 kcalmol–1 for
(S,S)3-2 to 17.8 kcalmol–1 for (S,S)3-4 (Table S1 in the Sup-
porting Information).[29]
Results and Discussion
Design Principles – “Negative Design” in the Promotion of
Chiral Bias
The DFT energy-minimized structure of (S,S)3-2 served
as the logical starting point in our structural reengineering
directed towards systematic modulation of the conforma-
tional stability and chiral bias. As shown in Figure 1, the
preference of (S,S)3-2 for the M conformation originates
from the unfavorable steric interactions between the phenyl
groups in the competing P conformation, which account
for an 8.7 kcalmol–1 energy difference as estimated by
PM3-level calculations.[29] In the disfavored P conforma-
tion, the phenyl rings on the wingtip alcohol groups point
toward the center of the molecule (Figure 1). We thus rea-
soned that either linear extension at the para-position or
Figure 2. Space-filling models of PM3 geometry-optimized struc-
tures of (S,S)3-4 and cartoon-type renditions to describe the propel-
ler-like arrangements of three aniline rings which are unidirection-
ally tilted either in left-handed fashion (for the M helix) or in right-
handed fashion (for the P helix) (NOTE: these conformers are not
mirror images of one another but are diastereomeric, and therefore
differ in energy). In the case of the M helix (left), the six (phenyl-
ethynyl)phenyl groups on the wingtip alcohol groups all point away
from the molecular core. Upon reversal of the helical screw sense,
however, these groups converge to create highly congested steric
environments both above and below the core plane of the P helix
shown on the right. The tert-butyl groups on the para-positions of
the aniline rings are removed for clarity in this drawing.
Figure 3. Chemical structures of the chiral tris(N-salicyliden-
amine)s 1–7 and of the subunit model compound 8. The symbol
(S)3- here denotes the presence of three S chiral alcohol groups in
the molecule; (S,S)3- for six such groups. Note that (R,R)3-4 is the
enantiomer of (S,S)3-4 (shown in Figure 2), and therefore has six
R chiral alcohol groups.
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Helical Folding of Propeller-Shaped Molecules
A series of chiral tris(N-salicylidenamine) derivatives – different para-substituents on the phenyl group, including
compounds 3–7 (Figure 3) – and the chiral subunit model F and Cl, had previously been screened in kinetic resolu-
8 were thus identified as logical synthetic targets in which tions of propargylic alcohols with the aid of Novo-
variations were made in i) the number, ii) the absolute con- zyme 435.[33d] In each case, the R alcohol was selectively
figuration, and iii) the steric bulk of the substituents on the esterified to leave behind the S alcohol with good yield (30–
wingtip chiral alcohol groups engaged in intramolecular hy- 47%; max theoretical yield = 50%) and enantioselectivity
drogen bonds. We anticipated that comparative spectro- (Ͼ98%). Encouraged by these precedents, we reasoned that
scopic studies on these new molecules and on the previously a para-iodo substituent on the phenyl ring should not
reported 1 and 2[20] (see Figures 1 and 3) should help in change the selectivity toward esterification of the R alcohol
the construction of more comprehensive structure–property and decided to employ 4-iodobenzaldehyde and ethynyl-
models for chiral induction and conformational stability.
magnesium bromide to prepare rac-10 as the key intermedi-
ate in our synthesis (Scheme 4).
Chiral Alcohols as Key Synthetic Intermediates
Optically active secondary propargylic alcohols are use-
ful synthons for chemical synthesis.[30] Typical strategies to
access these chiral building blocks include i) asymmetric ad-
dition of acetylides to aldehydes or ketones,[30d,31] ii) asym-
metric reductions of ketones,[32] and iii) enzymatic resolu-
tion of racemic alcohols.[33]
Asymmetric additions of terminal acetylides to a series
of alkyl or aryl aldehydes with the aid of a catalytic system
consisting of zinc triflate and optically active N-methyleph-
edrine provide high yields and high enantioselectivi-
ties.[30d,31e,34] Although this method has shown that enantio-
selectivities are high for aromatic aldehydes (94–96%), the
yields are considerably lower (ca. 50%) than in the case of
aliphatic aldehydes (Ͼ90%).[34a] For the preparation of
large quantities of chiral building blocks for our chemistry,
enzymatic resolution of racemic alcohols thus became an
appealing method. The reactions could be carried out under
standard benchtop conditions without the requirement for
strictly anhydrous reaction media. In addition, the resin-
bound enzyme could be recovered and recycled without sig-
nificant diminution of its reactivity and selectivity. One of
the most attractive aspects of this method is that both R
and S enantiomers could be accessed with use of one en-
zyme (vide infra), rather than by use of two different, and
costly, catalysts for each enantiomer, as would be necessary
with asymmetric addition or reduction protocols.
Scheme 4. Synthetic routes to the enantiomeric pair of protected
propargylic alcohol derivatives (S)-12 and (R)-12. Note the formal
change in R vs. S assignment upon silylation of the ethynyl group
of 11.
A lipase isolated from Candida antarctica, known com-
mercially as Novozyme 435, is an effective catalyst in the
resolution of aryl propargylic alcohols.[33] With this enzyme
and vinyl acetate, the R alcohol is selectively esterified to
leave the S alcohol behind (Scheme 3).
After enzymatic resolution and subsequent functional
group transformation, each enantiomer (i.e., R and S) could
be elaborated further by standard cross-coupling reactions
at the para-position to install ethynylenearyl moieties with
different branching patterns. One of the most attractive fea-
tures of this synthetic plan is its inherent modularity,
through which a diverse array of π-extended chiral propar-
gylic alcohols could be i) readily accessed from a common
synthetic precursor, and ii) quickly integrated into the C3-
symmetric synthetic targets (Figure 3) through a finite
number of synthetic operations.
Scheme 3. Enzymatic resolution of aryl propargylic alcohols. The
assignment of the absolute configuration here is based on R = 4-
X-C6H5.
Access to Chiral Building Blocks – Enzymatic Resolution
and Extension of π-Conjugation
This enzymatic protocol has proven to be selective for
A one-pot reduction/oxidation of 4-iodobenzoic acid was
the resolution of racemic aryl alcohols.[33b,33d,33f] Several carried out in quantitative yield to furnish 9 (Scheme 4).[35]
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Addition of ethynylmagnesium bromide to 9 yielded rac-10 (R)-12 in a similar manner. The latter compound was pre-
in good yield (78%), and this compound was enzymatically pared by acetylation and TMS-protection of (S)-10 as
resolved to afford the R ester 11 and the S alcohol 10. We shown in Scheme 4 and subjected to cross-coupling with
anticipated that the iodo substituent at the para-position phenylacetylene followed by deprotection to furnish (S)-14.
of rac-10 should have little effect on the enantioselective
Synthesis of the branched phenylene(ethynylene) frag-
esterification of the R alcohol, as established for structur- ment (R)-20 (Scheme 6), for incorporation into (S)3-5 and
ally related compounds.[33d] Enzymatic resolution with No- (S,S)3-6 (Figure 3), began with a Sonogashira–Hagihara
vozyme 435 was thus carried out with rac-10 under stan- coupling between tribromobenzene and 2-methylbut-3-yn-
dard conditions (benzene, T = 30 °C) and the progress of 2-ol (15).[40] The presence of the OH group in this “acetone-
the asymmetric esterification reaction with vinyl acetate was protected” acetylene equivalent aided the separation of 16
monitored by chiral HPLC. The purity of (R)-10 was veri- from doubly and triply coupled byproducts as well as unre-
fied after isolation and subsequent hydrolysis of the ester acted starting materials, each of which has distinctively dif-
(R)-11. The chiral HPLC chromatogram of (R)-10 was ferent polarity. The monocoupling product 16 was isolated
compared to that of rac-10 and found to represent Ͼ99% ee and subjected to coupling with an excess amount (3 equiv.)
(Figure S2 in the Supporting Information). The purity of of phenylacetylene to obtain 17. The tertiary alcohol group
the unreacted (S)-10, after isolation by column chromatog- in 17 was removed by treatment with KOH in toluene at
raphy, was also checked by chiral HPLC.[36] Although the reflux to yield the free alkyne 18, which was subjected to
purities of (R)-10 and (S)-10 were confirmed by chiral cross-coupling with (S)-12. Removal of the trimethylsilyl
HPLC, it was necessary to verify the absolute configuration and acetyl groups from the coupling product (S)-19 com-
of each enantiomer. For this purpose, Mosher’s ester pleted the synthesis of (R)-20.
method[37] was used to convert each alcohol into the corre-
sponding (R)- and (S)-MTPA [α-methoxy-α-(trifluoro-
methyl)phenylacetic acid] esters. These compounds were an-
1
alyzed by H NMR spectroscopy (Table S2 in the Support-
ing Information) to establish fully the absolute stereochem-
istries depicted in Scheme 3 and Scheme 4.
For subsequent chemical transformations with C–C
coupling, the ethynyl group of (R)-11 needed to be pro-
tected in order to prevent self-coupling under Sonogashira–
Hagihara reaction conditions. Typical protocols employing
deprotonation with nBuLi and subsequent trapping with
TMSCl proved inefficient,[38] but treatment with CF3TMS
in the presence of a catalytic amount of CsF[39] proceeded
cleanly to convert (R)-11 into the desired product (S)-12 in
good yield (80%) [Note: the change in the R to the S as-
signment here is the result of silylation of the ethynyl end
of the molecule, which reverses the Cahn–Ingold–Prelog
Scheme 6. Installation of branched π-conjugation onto the chiral
priority around the stereogenic center]. Under stringently propargylic alcohol.
oxygen-free conditions, cross-coupling between (S)-12 and
phenylacetylene furnished (S)-13 (Scheme 5).
Construction of Chiral Blades for C3-Symmetric Propeller-
Shaped Molecules
With efficient synthetic routes for the propargylic
alcohols (R)-14, (S)-14, and (R)-20 established, we pro-
ceeded to prepare a series of “propeller blades”. The design
of the molecules 21–25 (Figure 4) specifically took account
of
i) mono- (21 and 24) versus disubstitution (22, 23, and 25)
on the aniline ring to set the number of chiral centers and
hydrogen bonds (Figure 3),
ii) absolute configurations (i.e., R vs. S) of the chiral alcohol
groups to control the preferred directionality of folding
(Figure 1), and
Scheme 5. Installation of linear π-conjugation on an enantiomeric
pair of aryl propargylic alcohols.
iii) linear (21, 22, and 23) versus branched (24 and 25)
Removal of the trimethylsilyl and acyl groups was conve- elongation of π-conjugation to modulate the degree of steric
niently achieved in a one-step procedure with K2CO3 in a bias for asymmetric folding (Figure 1 and Figure 2)
mixed solvent (THF/MeOH) to afford (R)-14. The synthesis in the resulting C3-symmetric chiral molecules listed in Fig-
of the enantiomeric alcohol (S)-14 was carried out from ure 3.
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Helical Folding of Propeller-Shaped Molecules
Scheme 7. Synthetic routes to monosubstituted and disubstituted
anilines and their incorporation into the chiral tris(N-salicyliden-
amine)s.
Hydrogen-Bonding-Assisted Structural Folding
In CDCl3 at T = 298 K, compounds 1–7 (Figure 3) each
1
show a simple H NMR pattern consistent with molecular
threefold symmetry. A set of doublets at 14.01–13.34 ppm
and 9.64–8.77 ppm, assigned to the Nenamine–H and Cvinyl
–
H protons, respectively, is consistent with the keto–enamine,
rather than enol–imine, description of the core tautomer-
ism.[20,25–27] This assignment is supported further by the
carbonyl 13C NMR resonances at ca. 185 ppm observed ac-
ross the entire series 1–7, and by their achiral analogues, for
which X-ray structures are available.[25a–25c,25e–25g] In par-
ticular, the observation of only one set of N–H and C–H
resonances in each case here supports the notion that each
solution population is dominated by a single geometrical
isomer of pseudo-C3 symmetry, which maximizes the
number of energy-stabilizing N–H···O hydrogen bonds at
the core and O–H···O–H hydrogen bonds between the wing-
tip alcohol groups (Figure 3). Synthesis of tris(N-salicylid-
enamine)s lacking such noncovalent interactions often re-
sults in inseparable mixtures of two isomers as shown in
Equation (1).[26,27]
Figure 4. Chemical structures of chiral amine derivatives.
Preparation of these chiral anilines was achieved in a
straightforward manner through cross-coupling reactions
between the propargylic alcohols and either monoiodoanil-
ine (26) or diiodoaniline (27). As summarized in Scheme 7,
route I was taken for (S)-21 and (S)-24, which were sub-
jected to efficient triple Schiff base condensation reactions
with 1,3,5-triformylphloroglucinol (28) to furnish (S)3-3
and (S)3-5 (Figure 3), respectively. The asymmetrically 2,6-
disubstituted aniline (S)-22 was prepared by consecutive
cross-coupling of the diiodoaniline 27 with propargyl
alcohol and with (R)-14, and carried forward to the triple
condensation product (S)3-7 (Scheme 7, route II). With the
2,6-disubstituted anilines (S,S)-23, (R,R)-23, and (S,S)-25,
route III was followed to prepare the triple Schiff base ad-
ducts (S,S)3-4, (R,R)3-4, and (S,S)3-6, respectively.
(1)
When the reactions were carried out in EtOH at reflux,
In order to probe hydrogen-bonding assisted structural
the aromatic-rich triple Schiff base condensation products folding in solution further, a 2D-ROESY NMR spectrum
precipitated out of the polar reaction mixtures. In most for (S)3-7 in CDCl3 at 298 K was obtained (Figure 5). Mul-
cases, analytically pure products could be isolated by simple tiple crosspeaks were observed between Cvinyl–H/Nenamine
–
filtration and repeated washing, without resort to chroma- H at the tris(N-salicylidenamine) core and O–H protons of
tographic separation.
both primary and secondary propargylic groups. In ad-
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dition, crosspeaks of opposite phase were observed for and CD studies to probe its consequences on i) the elec-
OH···OH, relative to those of CH···OH and NH···OH, indi- tronic structures of the [n,π]-conjugated molecular cores,
cating chemical exchange in solution.[41] These spectro- and ii) interchromophore electronic coupling between π-ex-
scopic signatures give support for the formation of a helical tended wingtip groups that are brought into close proximity
conformation in solution that brings adjacent (but belong- through O–H···O–H hydrogen bonds between the wingtips.
ing to different peripheral aryl groups) wingtip OH groups
As shown in Figure 6, the UV/Vis spectrum of (S,S)3-4
into close proximity, to effectively “flatten” the entire struc- in CHCl3 is characterized by broad longer-wavelength ab-
ture and to establish conformationally rigid spatial relation- sorptions at λ = 400–450 nm and intense high-energy tran-
ships. 2D-ROESY NMR studies on the phenyl-substituted sitions at λ = 270–310 nm. Extensive TD-DFT studies on
analogue[20] provided evidence of similar structural folding the parent (S,S)3-2 system (with the simple phenyl group as
in solution.
substituent on the wingtip alcohol group) have previously
established that the features at λ = 400–450 nm are associ-
ated with the [n,π]-conjugated tris(N-salicylidenaniline)
core part of the molecule.[20] In support of this notion, the
UV/Vis spectra of (S,S)3-2 and (S,S)3-4 are essentially
superimposable in this energy window (Figure 6, a). On
the other hand, the intensities (ε
=
2.0ϫ105 to
2.2ϫ105 m–1 cm–1) of the shorter wavelength absorptions of
(S,S)3-4 at λ = 270–310 nm are markedly enhanced and
slightly red-shifted from those of (S,S)3-2, suggesting that
they originate from the (phenylethynyl)phenyl fragments at-
tached to the wingtip alcohol groups. Indeed, (S)3-3 dis-
plays very similar absorptions at λ = 270–310 nm but with
half the intensities (ε = 8.4ϫ104 to 1.1ϫ105 m–1 cm–1) of
(S,S)3-4 (Figure 6, a), which establishes a direct correlation
between the molar absorptivity and the number of the local
chromophores [i.e., six for (S,S)3-4 vs. three for (S)3-3]
Figure 5. 2D-ROESY spectrum of (S)3-7 in CDCl3 at T = 298 K,
and a close-up view of the chemical structure with protons contrib-
uting to ROE and TOCSY-relayed ROE cross-peaks labeled with
symbols that correspond to the assigned resonances in the 1-D
spectra.
Across the entire series 1–7, the formation of intramo-
lecular O–H···O hydrogen bonds is manifested most promi-
nently by the propargylic O–H proton resonances at δ =
6.09–6.25 ppm, which are shifted significantly downfield in
relation to that (δ = 2.27 ppm) of the model compound 8.
A narrow distribution of this parameter (Δδ = 0.16 ppm
over eight different systems) indicates that the introduction
of bulky aryl groups at the wingtips does not deleteriously
affect the stabilities of the conformations of the folded
forms. This observation further supports the computational
models shown in Figures 1 and 2. In the “correctly folded”
form, substituents at the para-positions of the wingtip
phenyl rings point away from the molecular cores and
therefore should not deleteriously affect the thermodynamic
stabilities of the systems. The spatial arrangements of these
π-extended groups and their collective effects on the pre-
ferred handedness of the propeller-shaped molecular cores
were probed further by UV/Vis and CD spectroscopy.
Figure 6. a) UV/Vis spectra of (S,S)3-2 (green), (S)3-3 (black), and
(S,S)3-4 (blue) in CHCl3. b) CD spectra of (S,S)3-4 (blue) and
(R,R)3-4 (red) in CHCl3, along with schematic presentations of pre-
ferred handedness of folding. See Figure 8 for the assignment of
absolute screw sense from the bisignate CD feature across λ =
Conformational Bias and Asymmetric Folding Probed by
UV/Vis and CD Spectroscopy
With 1H NMR spectroscopic evidence for structural
folding in solution in hand, we decided to employ UV/Vis 292 nm. T = 298 K.
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Helical Folding of Propeller-Shaped Molecules
within the molecule. Effective decoupling between the elec-
tronic structure of the molecular core (responsible for the
absorption at λ = 400–450 nm) and the peripheral π-conju-
gation (responsible for the absorption at λ = 270–310 nm)
is thus confirmed in a straightforward manner. The absence
of direct conjugation between the two chromogenic compo-
nents was fortuitous for simplification of our subsequent
data analysis.
The CD spectrum of (S,S)3-4 in CHCl3 (Figure 6, b) has
positive Cotton signals at the longer-wavelength end. Under
similar conditions, the enantiomeric (R,R)3-4 produces a
mirror-image spectrum and hence a reversal in this signal
(Figure 6, b). Our previous benchmark TD-DFT studies
have established that this CD feature signifies the predomi-
nance of one screw sense of the propeller molecule, which
for (S,S)3-2 in solution is the M conformer.[20] Such an as-
signment is now further validated by the bisignate CD fea-
ture of (S,S)3-4 toward the shorter-wavelength end (with
positive band at λ = 308 nm and negative band λ =
283 nm). A detailed analysis of the interchromophore exci-
ton coupling, which is responsible for this phenomenon, is
provided in the following section.
Figure 7. CD spectra of (S,S)3-2, (S,S)3-4, and (S,S)3-8 in CHCl3
at T = 298 K.
The enhanced conformational stability of (S,S)3-4 rela-
An effective transfer of the S central chirality present at tive to (S,S)3-2 thus derives not so much from the stabiliza-
the peripheral wingtips to the M helical chirality of the pro- tion of the preferred conformer as from the destabilization
peller-shaped molecular core is maintained across the entire of the less-preferred conformer, which is the hallmark of
series 1–7, as reflected in the consistently positive Cotton negative design. A similar increase in Δε415 was also ob-
signals at λ Ͼ 350 nm (Figure S3 in the Supporting Infor- served upon installation of 3,5-bis(ethynylenephenyl) sub-
mation). Although such a correlation supports the general stituents on the (S,S)3-4 system to produce the sterically
applicability of the chiral induction model shown in Fig- more congested (S,S)3-6 (see Figure S3a in the Supporting
ures 1 and 2, the absolute magnitude of this signature fea- Information). The larger positive Cotton effects observed
ture depends critically on the structural contexts in which for (S)3-3 (Δε415 = 31 m–1 cm–1) and (S)3-5 (Δε415
=
the individual chiral fragments are located. As shown in 33 m–1 cm–1) relative to (S)3-1 (Δε415 = 19 m–1 cm–1) also
Scheme 2, chiral tris(N-salicylidenaniline)s can switch be- corroborate this structure–property model (see Figure S3b).
tween the M and P conformations through correlated tilt-
In addition to specific chemical structures, the sheer
ing motions of the peripheral aryl groups. The CD signal number of chirality-transferring groups within a molecule
from the core chromophore thus reflects the difference in plays a critical role in the selection and stabilization of the
the relative stabilities of the two conformations of opposite preferred conformation. As shown in Figure 3, (S,S)3-4 and
screw sense, which is determined both by the size and by (S)3-7 have the same number of O–H···O–H hydrogen
the number of chiral groups that are brought into close bonding contacts but different numbers of chiral prop-
proximity upon structural folding.
argylic alcohol groups. For both systems, positive Cotton
As shown in Figure 7, the CD signal intensity of (S,S)3- effects were observed in the longer-wavelength end. The
4 at 415 nm (Δε415) in CHCl3 is 50 m–1 cm–1, which is about magnitude of this signal, however, essentially increases five-
2.5 times larger than that (21 m–1 cm–1) of (S,S)3-2 under fold from Δε415 = 9 m–1 cm–1 for (S)3-7 (with three chiral
similar conditions. These two molecules have structural alcohol groups) to Δε415 = 50 m–1 cm–1 for (S,S)3-4 (with six
skeletons that are identical except for the substituents on chiral alcohol groups) (Figure S3). This phenomenon re-
the wingtip alcohol groups: linearly π-extended (phenyl- flects an increased steric bias towards the M conformation
ethynyl)phenyl for (S,S)3-4 versus simple phenyl for (S,S)3- with increasing number of pairwise contacts between chiral
2 (Figure 3). In the preferred M conformation adopted both wingtip groups upon structural folding.
by (S,S)3-2 and by (S,S)3-4, these aryl groups point away
The stereoinduction mechanism discussed above operates
from the molecular cores (see Figures 1 and 2) and are through tight O–H···O hydrogen bonding networks that ef-
therefore less likely to affect the overall stabilities of the fectively transmit point chirality present at the molecular
molecules. In the competing P conformation (denoted the perimeter to the helical twisting of the molecular core. The
“misfolded” form in our design rationale; Figure 1), how- importance of such noncovalent contacts as “conduits” for
ever, they converge at the congested molecular cores. As a intramolecular chirality transfer was probed by solvent-de-
consequence, the energy penalty becomes more severe for pendent CD studies. As shown in Figure 8, the positive
the bulkier (phenylethynyl)phenyl groups in (S,S)3-4 than Cotton effects (Δε420) of the compound (S,S)3-4 show a sys-
for the simple phenyl groups in (S,S)3-2 (see Figures 1 and tematic decrease in signal intensity with increasing solvent
2).[42]
donor number (DN).[43] This observation corroborates the
Eur. J. Org. Chem. 2012, 708–720
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715

E. A. Opsitnick, X. Jiang, A. N. Hollenbeck, D. Lee
FULL PAPER
notion that disruption of the intramolecular O–H···O con- between two equivalent (= energetically degenerate) chro-
tacts by Lewis basic (and also hydrogen-bond accepting) mophores, the excited states split into two energy levels to
solvents leads to an effective “unfolding” of the molecule broaden the UV/Vis absorption band. A more pronounced,
with loss of well-defined secondary structures. Intriguingly, and thus practically useful, signature of this phenomenon
a further increase in DN led to an inversion of the sign in is “splitting” of the CD signal as shown in Figure 7. The
the Cotton effect of (S,S)3-4 in DMF, DMA, and DMSO change in the sign of such a coupled CD signal, either posi-
(Figure 8). Similar behavior had previously been reported tive-to-negative (positive CD couplet) or negative-to-posi-
for (S,S)3-2,[20] and was interpreted as the consequence of tive (negative CD couplet), correlates directly with the abso-
O–H···(solvent)n interactions in strong donor solvents that lute sense of torsion between two electric transition dipoles
provide sufficient steric bias to reorient the electronic tran- that are brought into close proximity in space.[28] This exci-
sition dipoles and give rise to pseudo-mirror image CD sig- ton chirality rule establishes a robust structure–spectra rela-
nals. Qualitatively consistent solvent-dependent spectral tionship that has been used extensively in the stereochemi-
changes were observed for (S,S)3-6, (S)3-3, and (S)3-5 (Fig- cal analysis of natural products,[28] and chiral alcohols,
ure S5), which suggests a general applicability of this empir- amines, and aminols.[44,45] A particularly relevant example
ical model for chiral tris(N-salicylidenaniline)s.
in this context is the use of ECCD to assign the absolute
directionality of unidirectional rotary movements of molec-
ular motors constructed with sterically overcrowded alk-
enes.[22,46]
The CD couplet of (S,S)3-4 is centered at λ = 292 nm
(Figure 7), which is close to the λmax = 279 nm of the di-
phenylacetylene π–π* transition.[47,48] Exciton coupling here
thus arises from two (phenylethynyl)phenyl chromophores
that are brought into close proximity through O–H···O–H
contacts (Figure 2). The experimentally observed positive
CD couplet (Figure 7) of (S,S)3-4 thus dictates a positive
chirality (= clockwise torsional relationship) of two electric
transition dipoles, each of which lies parallel to the long
axis of the π-conjugation (Figure 9, a). This spectroscopic
Figure 8. a) Solvent-dependent changes in the CD spectrum of
(S,S)3-4 at T = 298 K. Because of strong background absorption,
data in nitrobenzene were obtained only at Ͼ420 nm. b) Plots of
Δε420 (Δε at 420 nm) of (S,S)3-4 versus donor number (DN) for
solvents including chloroform (1), benzene (2), dichloromethane
(3), toluene (4), nitrobenzene (5), dioxane (6), acetone (7), ethyl
acetate (8), THF (9), DMF (10), DMA (11), and DMSO (12).
Exciton-Coupled Circular Dichroism (ECCD)
A salient feature of the CD spectrum of (S,S)3-4 (Fig-
ure 6) is the bisignate pattern that changes its sign from posi-
tive to negative toward the shorter-wavelength end of the
spectral window. The reference system (S,S)3-2 shows a sim-
ilar change in the sign of the Cotton effects (Figure 7). The
crossover wavelength of λ = 267 nm for (S,S)3-2, however,
lies closer to the high-energy end without full development
of the negative band, thus making the bisignate feature less
pronounced. A linear elongation of the π-conjugation in
(S,S)3-4, on the other hand, produces significant red shifts
in this spectral region (Figure 6, b) to reveal a well-defined
bisignate CD couplet across λ = 292 nm (Figure 7), which
is characteristic of exciton coupling.
Figure 9. Bisignate CD curves arising from exciton coupling of two
identical chromophores with a) positive and b) negative chirality,
as defined by the spatial relationship between the two interacting
electric transition dipoles μ1 and μ2. Shown next to each CD curve
are space-filling models of a) (S,S)3-4 and b) (R,R)3-4, and cartoon-
type representations highlighting the relative orientations of the
Exciton coupling results from through-space interaction
between multiple chromophores that have strong electric di-
pole-allowed transitions.[28] When such interactions occur coupled π–π* transitions of the diphenylacetylene chromophores.
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Helical Folding of Propeller-Shaped Molecules
interpretation is fully consistent with the PM3 energy-mini- synthetic strategy facilitated the incorporation of a wide
mized structure of (S,S)3-4 shown in Figure 2. For the enan- range of steric and electronic controller groups on a versa-
tiomeric (R,R)3-4, this spatial relationship is reversed to a tile chiral scaffold that guides hydrogen bonding with pre-
negative chirality (Figure 9, b), which translates to the ex- ferred handedness. The stability of a cyclic array of O–
perimentally observed negative CD couplet (Figure 6, b).
H···O–H contacts located in such a structural setting is rein-
Comparative CD spectroscopic studies on the series forced further by molecular threefold symmetry, the abso-
(S,S)3-4, (S)3-7, and (S,S)3-8 further sharpened our under- lute screw sense (i.e., P vs. M) of which is dictated by the
standing of the exciton coupling. The model compound absolute configuration (i.e., R vs. S) of the chiral alcohol
(S)3-7 also has (phenylethynyl)phenyl fragments as in groups. Phenyleneethynylene-based π-conjugated substitu-
(S,S)3-4, but their large spatial separation produces a ents attached to these stereogenic centers support well-de-
weakly coupled CD signal with ACD (= amplitude of the fined electric transition dipoles, the torsional relationships
CD exciton couplet = difference in Δε between the peak of which assisted assignment of the absolute screw sense of
and the trough) = 40 m–1 cm–1, in comparison with ACD
=
structural folding by exciton-coupled bisignate CD signals.
Our comparative spectroscopic studies have established
340 m–1 cm–1 in the case of (S,S)3-4 (Figure S3a in the Sup-
porting Information). The C2-chiral subunit model (S,S)- that this central-to-helical chirality transfer model is gen-
8 has two (phenylethynyl)phenyl fragments across the 2,6- erally applicable to a large set of tris(N-salicylidenaniline)
diethynylphenylene backbone, but no exciton-coupled fea- derivatives, the conformational stabilities of which depend
ture was observed in its CD spectrum (Figure 7). In the critically on i) the number of hydrogen bonds and ii) the
absence of an appropriate conformational lock, the mole- steric demands of the extended π-conjugation introduced at
cule samples a large conformational space through unre- the chiral “wingtips”. In particular, the principles of nega-
stricted C–C bond rotations. Consequently, (S,S)-8 fails to tive design were successfully implemented here to enhance
produce a well-defined absolute sense of twist that is critical the solution populations of individual helical conforma-
for exciton coupling. In a similar fashion, chiral secondary tions by destabilizing “misfolded” conformations.
structures display stronger ECCD intensities relative to
their random-coil analogues.[13d,18f,19b]
The strongly coupled CD signal of (S,S)3-4 thus arises
Experimental Section
from close positioning of multiple π-extended chromo-
phores that are brought into conformationally rigid chiral
environments through a tight O–H···O–H hydrogen bond-
ing network (Figure 2). In support of this notion, a simi-
General: All reagents were obtained from commercial suppliers and
used as received unless otherwise noted. All air-sensitive manipula-
tions were carried out under nitrogen by standard Schlenk-line
larly intense (ACD = 300 m–1 cm–1) positive CD couplet was techniques. Tetrahydrofuran and dichloromethane were saturated
with nitrogen and purified by passage through activated Al2O3 col-
umns under nitrogen (Innovative Technology SPS 400).[49] Com-
pounds (S)3-1,[20] (S,S)3-2,[20] 9,[35a] 16,[40] 26,[50] 27,[51] and 28[26a]
were synthesized by literature procedures.
observed for (S,S)3-6 containing additional 3,5-bis(phenyl-
ethynyl) substituents (Figure S3a in the Supporting Infor-
mation). Apparently, the meta linkage in the branched π-
conjugation in (S,S)3-6 gives rise to π–π* transitions that
are localized to the (phenylethynyl)phenyl fragment as in
(S,S)3-4, and produces similar exciton-coupled CD patterns.
As shown in Figure 8, the solvent-dependent changes in
the ECCD signal of (S,S)3-4 at the shorter-wavelength end
(reflecting changes in the interchromophore coupling at the
“propeller blade tips”) correlate nicely with changes in the
Cotton effects in the longer-wavelength region (reflecting
changes in the handedness of the “propeller core”). This
observation is a compelling manifestation of the principle
that local bond twisting motions can be correlated and ef-
fectively transmitted to remote locations with the molecule
through rigid π-skeletons.
Physical Measurements: Proton nuclear magnetic resonance (1H
NMR) spectra were measured with
a Varian INOVA-400
(400 MHz) or Varian Gemini 2000 (300 MHz) NMR spectrometer
at T = 298 K unless otherwise noted. Carbon nuclear magnetic
resonance (13C NMR) spectra were measured with a Varian IN-
OVA-400 (100 MHz) spectrometer at T = 298 K unless otherwise
noted. 1H NMR and 13C NMR spectra were acquired as solutions
in CDCl3 and are reported in parts per million (ppm) downfield
(δ) from tetramethylsilane with use of residual chloroform (CHCl3)
as an internal standard set to δ = 7.26 ppm (for 1H NMR) and
77.16 ppm (for 13C NMR). Proton NMR spectroscopic data are
reported in the form: δ (multiplicity, coupling constants, number of
protons). High-resolution mass spectral (HR-MS) data were ob-
tained with a Thermo Electron Corporation MAT 95XP-Trap in-
strument. MALDI-TOF mass spectroscopic data were collected
with a Bruker Biflex III instrument. FT-IR spectra were recorded
with a Nicolet 510P FT-IR spectrometer with EZ OMNIC ESP
software. UV/Vis spectra were recorded with an Agilent 8453 UV/
Vis spectrophotometer with ChemStation. Circular dichroism spec-
tra were recorded with a Jasco J-715 circular dichroism spectrome-
ter. Chiral HPLC was monitored with a Waters dual λ absorbance
detector with a chiral column [Regis, Pirkle Covalent, (S,S)-Whelk-
O 1, 25 cmϫ4.6 mm].
Conclusions
We have prepared a series of chiral tris(N-salicyliden-
aniline)s and have investigated their solution dynamics lead-
ing to helical folding. The assembly of these C3-symmetric
propeller-shaped molecules was aided by synthetic access to
new chiral propargylic alcohols through enzymatic kinetic
(2E,4E,6E)-2,4,6-Tris[(4-tert-butyl-2-{(S)-3-hydroxy-3-[4-(phenyl-
resolution and C–C cross-coupling reactions. Notably, this ethynyl)phenyl]prop-1-ynyl}phenylamino)methylene]cyclohexane-
Eur. J. Org. Chem. 2012, 708–720
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717

E. A. Opsitnick, X. Jiang, A. N. Hollenbeck, D. Lee
FULL PAPER
1,3,5-trione [(S)3-3]: An EtOH (8.2 mL) solution of (S)-21 (0.250 g,
0.66 mmol) was purged with N2 for 10 min. A portion of 28
(0.035 g, 0.17 mmol) was added and the mixture was heated at re-
flux for 12 h. A yellow solid was isolated by filtration and washed
with pentanes to afford (S)3-3 (0.167 g, 77%). 1H NMR (300 MHz,
CDCl3): δ = 14.60 (d, J = 13.2 Hz, 3 H), 8.77 (d, J = 13.4 Hz, 3
H), 7.69 (d, J = 8.1 Hz, 6 H), 7.58 (d, J = 8.3 Hz, 6 H), 7.52–7.50
(m, 6 H), 7.38–7.27 (m, 18 H), 6.23 (d, J = 5.4 Hz, 3 H), 5.84 (d,
J = 5.6 Hz, 3 H), 1.26 (s, 27 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 217.2, 184.6, 148.5, 147.8, 141.3, 137.9, 131.9, 131.7, 128.5 (2
peaks), 127.6, 127.0, 123.3, 123.1, 113.0, 106.7, 97.5, 89.7, 89.3,
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64.7, 34.6, 31.2, 29.8 ppm. FT-IR (thin film on NaCl): ν = 3366,
˜
3059, 2964, 2902, 2865, 2183, 1618, 1597, 1451, 1345, 1300, 1231,
984, 754 cm–1. MS (MALDI-TOF) calcd. for C90H75N3O6Na
1316.555 [M + Na]+; found 1316.631.
(2E,4E,6E)-2,4,6-Tris[(4-tert-butyl-2,6-bis{(S)-3-hydroxy-3-[4-(phen-
ylethynyl)phenyl]prop-1-ynyl}phenylamino)methylene]cyclohexane-
1,3,5-trione [(S,S)3-4]: An EtOH (6.0 mL) solution of (S,S)-23
(0.250 g, 0.41 mmol) was purged with N2 for 10 min. A portion of
28 (0.022 g, 0.10 mmol) was added and the mixture was heated at
reflux for 16 h. A yellow solid was isolated by filtration and washed
with EtOH to furnish (S,S)3-4 (0.11 g, 53%). 1H NMR (400 MHz,
CDCl3): δ = 13.34 (d, J = 13.5 Hz, 3 H), 9.39 (d, J = 13.3 Hz, 3
H), 7.54 (d, J = 8.2 Hz, 12 H), 7.49 (s, 6 H), 7.39 (d, J = 8.4 Hz,
12 H), 7.36 (dd, J = 8.0, 1.6 Hz, 15 H), 7.25–7.19 (m, 15 H), 5.53
(s, 6 H), 1.33 (s, 27 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
185.1, 151.9, 148.6, 140.5, 138.4, 131.7, 131.6, 131.2, 128.3, 127.0,
123.3, 123.1, 113.8, 106.4, 96.6, 89.9, 89.3, 82.7, 64.4, 34.7, 31.2,
[2]
[3]
[4]
29.9 ppm. FT-IR (thin film on NaCl): ν = 3368, 3059, 2964, 2903,
˜
[5]
[6]
2868, 2217, 1602, 1570, 1507, 1432, 1402, 1365, 1301, 1233, 1097,
1027, 984, 910, 841, 785, 754, 733, 689, 645, 596, 464 cm–1. MS
(MALDI-TOF) calcd. for C141H105N3O9Na 2008.782 [M + Na]+;
found 2008.031.
(1S,1ЈS)-3,3Ј-(1,3-Phenylene)bis{1-[4-(phenylethynyl)phenyl]prop-2-
yn-1-ol} [(S,S)-8]: A Teflon screw-capped tube was loaded with 1,3-
diiodobenzene
(0.13 g,
0.39 mmol),
Pd(PPh3)4
(0.009 g,
0.008 mmol), and CuI (0.002 g, 0.012 mmol). The reaction vessel
was evacuated and back-filled three times with N2. A portion of
Et3N (6 mL) was added under N2. The vessel was sealed and the
reaction mixture was stirred at room temp. for 16 h. Flash column
chromatography on SiO2 (hexanes/EtOAc 2:1, v/v) afforded (S,S)-
8 as a peach solid (0.19 g, 88%). 1H NMR (300 MHz, CDCl3): δ
= 7.60–7.53 (m, 13 H), 7.45 (dd, J = 7.8, 1.6 Hz, 2 H), 7.37–7.28
(m, 7 H), 5.70 (d, J = 6.1 Hz, 2 H), 2.27 (d, J = 6.1 Hz, 2 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 140.5, 135.1, 132.1, 132.0, 131.8,
129.7, 128.6, 128.5, 126.8, 123.7, 123.3, 122.8, 90.1, 89.2, 89.1, 86.1,
[7]
64.9 ppm. FT-IR (thin film on NaCl): ν = 3300, 2201, 1635, 1594,
˜
1507, 1476, 1406, 1299, 1183, 1037, 987, 906, 844, 790, 753, 683,
517 cm–1. MS (HR-CI) calcd. for C40H26O2 [M]+ 538.1933; found
538.1921.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details for synthesis and additional spectro-
scopic data.
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Acknowledgments
This work was supported by the National Science Foundation
(NSF) (CAREER CHE 0547251) and the U.S. Army Research Of-
fice (W911NF-07-1-0533). We thank Dr. András Olasz for assist-
ance in computational studies.
718
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Received: September 15, 2011
Published Online: December 2, 2011
720
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Eur. J. Org. Chem. 2012, 708–720