Absolute configuration for 1, n-glycols: A nonempirical approach to long-range stereochemical determination

Article abstract of DOI:10.1021/ja2119767

The absolute configurations of 1,n-glycols (n = 2-12, 16) bearing two chiral centers were rapidly determined via exciton-coupled circular dichroism (ECCD) using a tris(pentafluorophenyl)porphyrin (TPFP porphyrin) tweezer system in a nonempirical fashion devoid of chemical derivatization. A unique "side-on" approach of the porphyrin tweezer relative to the diol guest molecule is suggested as the mode of complexation.

Full text of DOI:10.1021/ja2119767

Communication
pubs.acs.org/JACS
Absolute Configuration for 1,n-Glycols: A Nonempirical Approach to
Long-Range Stereochemical Determination
Xiaoyong Li, Carmin E. Burrell, Richard J. Staples, and Babak Borhan*
Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, United States
S
* Supporting Information
ABSTRACT: The absolute configurations of 1,n-glycols
(n = 2−12, 16) bearing two chiral centers were rapidly
determined via exciton-coupled circular dichroism
(ECCD) using a tris(pentafluorophenyl)porphyrin
(TPFP porphyrin) tweezer system in a nonempirical
fashion devoid of chemical derivatization. A unique “side-
on” approach of the porphyrin tweezer relative to the diol
guest molecule is suggested as the mode of complexation.
Figure 1. Zinc TPFP porphyrin tweezers A and B.
1,n-Glycols are widely present in natural products and as
synthetic intermediates, yet the determination of their absolute
stereochemistry presents a considerable challenge. NMR
analysis1 and exciton-coupled circular dichroism (ECCD) of
dibenzoates2 or cyclic derivatives3 of diols are the most
common techniques for determining the configurations of 1,2-
and 1,3-glycols. Nonetheless, these approaches are not suitable
for acyclic long-chain diols separated by more than four
carbons. This is due to the flexible nature of the derivatized
molecules, which adopt multiple conformations in solution.
Moreover, they also lack internuclear coupling in NMR since
the asymmetric centers are far apart. With the exception of
Molinski’s elegant tactic4 that restricts the orientation of the
linear chain to a stretched-out zigzag motif through interactions
of the glycol with liposomes, there are no other methods that
can interrogate the absolute stereochemistry of two remote
centers simultaneously. In the latter system, the ECCD of
porphyrin-derivatized 1,n-glycols provides a solution for a
subset of diols (n = 5, 7, 9). Herein we demonstrate a different
approach that utilizes the porphyrin tweezer methodology to
address the absolute stereochemical determination of glycols
with up to 14 carbons between the two chiral centers.
The porphyrin tweezer methodology has been successfully
employed to elucidate the absolute stereochemistry of amines,5
alcohols,6 and carboxylic acids.7 In our efforts to determine the
absolute configuration of 1,2-diols, we developed a highly
fluorinated zinc porphyrin tweezer, Zn-TPFP-C5-tz (A),8 that
can bind strongly with hydroxyl groups because of the
enhanced Lewis acidity of the metal centers (Figure 1). We
realized that the success of the fluorinated tweezer was solely
due to its ability to limit the number of conformations upon
complexation with its chiral guest molecule as a result of its
tighter binding profile. A was successfully used to determine the
absolute stereochemistry of threo and erythro vicinal diols,
amino alcohols, and diamines via ECCD.8 This porphyrin
tweezer also demonstrated good binding affinity with epoxidic
O atoms, facilitating the assignment of chiral 2,3-epoxy alcohols
with different substitution patterns.9
The flexible skeletons of acyclic molecules with remote
stereochemistry present a major challenge for ECCD analysis as
a result of multiple conformations in solution, which
complicates configurational analyses. We envisaged that the
strong complexation of A with diols would rigidify the
supramolecular assembly, reduce the number of conformations,
and thus facilitate the stereochemical differentiation at each
asymmetric center, leading to predictable ECCD spectra.
Chiral diols 1 and 3−13 were synthesized (>95% ee) by
known methodologies10 [see the Supporting Information (SI)],
and diol 2 was obtained from Acros. The diols were then
subjected to ECCD measurement. As expected, diols 1−13
bound well with tweezer A in hexane at 0 °C (as evident from
UV−vis analysis) to form a 1:1 supramolecular complex (as
shown by Job’s plot analysis; see the SI), resulting in an intense
ECCD curve arising from the porphyrin Soret band. The
expected ECCD signs in Table 1 were based on our previous
rationalization for 1,2-diols,8 which can be summarized as
follows. Binding interactions invariably occur between the
hydroxyl groups at the two stereogenic carbons and the Zn
centers of the porphyrins.11 It is assumed that independent
steric differentiation at each asymmetric center proceeds
through the binding of the porphyrin moiety opposite the
largest substituent on the chiral center, the methyl group in
most cases for the compounds in Table 1. As a result, the
methyl groups are anti to the bound porphyrin rings and are
not involved in the steric differentiation process. The remaining
two substituents on the chiral carbon, the H and the alkyl chain,
are the steric discriminants that project toward the bulky
porphyrin. As such, the porphyrin ring slides toward the smaller
H atom and away from the larger alkyl chain, resulting in a
helicity that culminates in the predicted ECCD.
Received: January 14, 2012
© XXXX American Chemical Society
A
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Journal of the American Chemical Society
Communication
approaches to “tighten” the complex. The first approach
entailed the use of fluorinated porphyrin tweezers, which would
increase the binding affinity of the zincated porphyrins with the
guest molecules. This was successfully applied for the absolute
stereochemical determination of 1,2-diols. In our second
approach, we shortened the linker connecting the two
porphyrin rings, resulting in a less flexible porphyrin tweezer.
We successfully showed that this C3 porphyrin tweezer is less
apt to stabilize multiple conformations.12 To determine the
absolute stereochemical determination of 1,n-diols, we
envisaged that combining these two features would give a
porphyrin tweezer system that is not only capable of strong
binding with the diols but also less flexible, leading to
stabilization of predominately one bound conformation.
Zn-TPFP-C3-tz (B) was synthesized following procedures
similar to those reported previously (λmax = 415 nm, ε = 670
000 cm−1 M−1 in hexane).8 Binding of B with diols 1−13
yielded surprisingly strong ECCD signals, which gratifyingly
were consistent in all cases with the predicted signs (Table 1).
Complexation of B with diols 2, 5, and 10 (problematic diols
with A) produced the expected results across a large range of
diol concentrations (5−100 equiv of diol; see Figure S4 for 5
and 10).
Table 1. ECCD Data for 1,n-Glycols in Hexane with
Tweezers A and B
a
The strongest ECCD amplitude was observed with 40 equiv
of diol in most cases, so this was chosen as the optimal amount
for use with B. Because of the low solubility of diol 11 (which
precipitated under the standard conditions), the ECCD analysis
was performed in a mixed solvent system (5% CH2Cl2 in
hexane) at slightly elevated temperature (5 °C) after screening
for the optimal conditions. The relatively low CD amplitude of
11 in comparison with other diols (A = +55) is ascribed to
competitive binding of CH2Cl2 with B. We previously
postulated the binding of heteroatom-containing solvents
with the fluorinated porphyrins due to the highly Lewis acidic
nature of the Zn metallocenter (chiral 1,2-diols complexed with
B are ECCD-silent in coordinating solvents such as CH2Cl2,
CHCl3, CH3CN, THF, and Et2O).8
a
A tweezer:substrate ratio of 1:40 and a tweezer concentration of 2.5
mM at 0 °C in hexane were used, unless otherwise indicated.
b
c
Tweezer:substrate ratio = 1:100. Tweezer:substrate ratio = 1:60 in
Having at hand a system that can report the absolute
stereochemistry of remotely spaced diols, we turned our
attention to developing a better understanding of the binding
mode for short- and long-chain diols with B. Two points are
important to note: (1) the C3 tweezer seemingly can bind a
variety of methylene-spaced diols in the same manner, thus
leading to consistent results; (2) the C3 tweezer, with its
shortened linker, not only binds well-spaced diols just as well as
the C5 tweezer but also yields stronger ECCD amplitudes in
comparison. These two points did not seem to fit the
conventional binding mode developed previously for A,
which assumed that the two porphyrins approach the guest
molecule in a “head-on” fashion (Figure 2a). In such a scenario,
5% CH2Cl2/hexane at 5 °C.
A general trend could be ascertained, indicating that (R,R)-
diols exhibit positive ECCD spectra upon complexation with
tweezer A (Table 1). However, several complications were
noticed. First, although complex 2/A was expected to give a
negative ECCD signal, a positive signal was observed. Second,
complicated ECCD curves were obtained for complexes 5/A
and 10/A. We also observed a switch in the sign of the ECCD
spectrum (from negative to positive) when >20 equiv of diol 5
was added (Figure S1a in the SI). For complex 10/A, three
peaks were seen when 5−100 equiv of the diol was added to
the tweezer solution (Figure S1b).
These observations suggest the possible presence of multiple
competing ECCD-active conformations. although their UV−vis
profiles did not reflect this speculation, essentially exhibiting the
same features as other diols. Altering the solvent (methyl-
cyclohexane or CH2Cl2) or the temperature (room temperature
or −10 °C; Figure S3) did not result in any improvement with
the problematic diols. At this juncture, we were in need of a
more robust supramolecular host for reliable absolute stereo-
chemical determination of long-chain chiral diols.
The inconsistencies observed with A were attributed to its
flexible nature, which presumably would allow the host/guest
system to search multiple conformations. We had two
Figure 2. Complexation patterns for 1,n-diols with tweezers: (a) head-
on; (b) side-on.
B
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Journal of the American Chemical Society
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the porphyrins of the tweezer are arranged face-to-face, and
binding of longer diols leads to a greater separation of the two
aromatic rings. It would be difficult to rationalize why
shortening the linker length (as in B) would lead to more
consistent results, especially with longer-chain diols.
Alternatively, we have postulated a “side-on” approach in
which the diols are stretched out in their most energetically
stable, zigzag conformation and the porphyrins of the tweezer
approach the hydroxyls from the side (Figure 2b). In this
manner, the linker behaves as a hinge that allows the
porphyrins to slide across each other. Shorter diols lead to a
smaller angle and larger stretched out diols to a larger angle
between the coupling porphyrins. Interestingly, the strength of
the ECCD coupling depends on the angle of the coupling
electric-dipole transition moments, which for vicinal 1,2-diols it
approaches a maximum at 70°.13 While this dependence has
not been previously demonstrated for the systems studied here,
one could postulate that an angle dependence for 1,n-glycols
bound to the porphyrin tweezer could also affect the ECCD
amplitude. The side-on approach could well explain why larger
separated hydroxyl groups lead to larger ECCD amplitudes (see
Table 1), as they would lead to a larger angle between the
coupling porphyrin rings (it should be noted that the binding
constants for diols of different lengths are similar: Ka = 3200
M−1 for 5 and 3750 M−1 for 10; see Figure S5). More
importantly, the interchromophoric distance predicted by the
side-on approach would not change greatly for longer diols.
This is suggested by the small observed difference in λmax for
binding short versus long diols (1.3 nm for 1,6-diol 5 vs 3 nm
for 1,12-diol 10). The correlation of λmax with the porphyrin
interchromophoric distance is the result of two opposing
effects.8 The binding of electron donors such as hydroxyl
groups with the Zn2+ causes a bathochromic shift. Conversely,
the closer proximity of the two chromophores as a result of the
coordination of the guest molecule leads to a hypsochromic
shift. Therefore, the magnitude of the bathochromic shift is
dependent on the nature of the coordinating element and how
close the two porphyrin rings are to each other.14
Modeling of 5 (a 1,6-diol) binding with B in a side-on
approach leads to a 6 Å separation of the two porphyrin rings,
whereas modeling of 10 (a 1,12-diol) gave a separation of only
7 Å. This is in contrast to the head-on approach, which would
clearly separate the porphyrin rings much more with the longer
diols (∼7 Å for 5 vs 16 Å for 10). The similar red shifts for
short and long chiral diols in UV−vis titrations of B in hexane
(see the SI) suggest that the interchromophoric distance does
not change to a large extent, providing further proof for the
proposed side-on binding of B with 1,n-diols.
A more detailed analysis of the side-on approach necessitates
a difference in the binding conformations with the host
porphyrin tweezers for diols separated by even or odd numbers
of methylenes. For diols with an even number of intervening
carbons (even-n diols), the most stable trans, all-staggered
conformation (energy-minimized structure; Figure 3 top) has
the terminal methyl groups pointing in opposite directions.
Since the porphyrins approach the hydroxyl groups opposite
the methyl substituents at the chiral centers, in the most stable
zigzag conformation, the porphyrins approach the hydroxyls
from opposite sides of the chain in the side-on approach. The
crystal structure of diol 10 (Figure 3 bottom) shows the same
orientation of the hydroxyl groups as postulated above for the
bound system. Considering our previously developed mne-
monic for steric differentiation described above, we can easily
Figure 3. (top) Energy-minimized trans, all-staggered conformation of
10 and (bottom) its corresponding crystal structure. The arrows
denote the putative approach of the porphyrins anti to the methyl
substituents at the two chiral centers; thus, the porphyrins approach
the diol from opposite faces of the molecule.
rationalize the observed helicity of the bound complexes. For
even-n (R,R)-diols, P1 would rotate counterclockwise toward
the smaller H atom and away from the larger alkyl chain, and
similarly, P2 would rotate clockwise to minimize the steric
repulsion with the bulky alkyl chain (Figure 4). Overall, a
Figure 4. Proposed side-on binding of tweezer B with even-n diols. P1
and P2 approach the hydroxyls anti to the methyl groups and sterically
differentiate between the smaller H and the larger alkyl chain, leading
to the observed helicity. As anticipated, a positive ECCD was obtained
for complexation of diol 5 with B.
clockwise (positive) helicity of P1 relative to P2 and a positive
ECCD spectrum would be observed.15 It should be noted that
the steric differentiation depends on the sizes of the
substituents at the chiral center and not necessarily the
Cahn−Ingold−Prelog priority. For example, (R,R)-12 leading
to a negative ECCD couplet also follows these rules. The
change in priority (Me vs benzyl) leads to the assignment of
substrate 12 as 2R,11R, while its pseudoenantiomer 9 is also
assigned as 2R,11R. Nonetheless, one would expect substrates 9
and 12 to yield opposite ECCD spectra given the sizes of the
substituents on the chiral center, as indeed they do.
For odd-n diols, the most stable trans, all-staggered
conformation (Figure 5a) would lead to a steric clash of
bulky P1 and P2, since they would approach the diol from the
same face (the methyl groups at the end of the chain are syn to
each other). Alternatively, the second most stable trans, all-
staggered conformation, which results from a 60° rotation
about the C−C bond, disposes the methyl groups anti to each
other and thus would accommodate the side-on binding of P1
and P2 (Figure 5b). Interestingly, both of these staggered
conformations postulated for odd-n diols are observed in the
crystal structure of diol 8 (Figure 5). Stereochemical differ-
C
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Journal of the American Chemical Society
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Generous support was provided by an NSF-CAREER Grant
(CHE-0094131). The authors thank Ms. Sumira Stein for her
work in making diol 9 and Dr. Chrysoula Vasileiou (MSU) and
Professor Daniel Whitehead (Clemson University) for critical
and illuminating discussions.
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entiation as described above for even-n diols leads to the
observed ECCD of the odd-n diols.
The latter suppositions were further substantiated by
conformational searches using molecular mechanics, which
showed a clear preference for positive helicity for the R,R
supramolecular assembly among the low-energy conformers
examined (see the SI). Conformational searches also favored
the slipped cofacial geometry of the porphyrin tweezer (see
Figures S17−S20 and further discussion in the SI). Although
we favor the side-on approach for binding with B, we cannot
preclude the possibility of head-on binding for smaller diols
that could be accommodated with the short C3 linker.
In conclusion, we have established a new supramolecular
host system that is capable of binding a variety of 1,n-diols in a
predictable manner and leads to reliable interrogation of
absolute stereochemistry. We postulate that the tweezer host
system can provide consistent results for a host of different diol
lengths by its tendency to bind in a side-on fashion. This, we
believe, is a result of having limited the porphyrin tweezer’s
conformational freedom through two distinct pathways. First,
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improved binding affinity for the bound diol. Second,
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conformational flexibility of the complex. The combination of
these factors leads to a consistent binding motif that enables
predictable assignment of chirality. Further application of this
method to complex diol molecules has revealed promising
results and will be reported in due course.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental and modeling procedures and results and
crystallographic data (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
babak@chemistry.msu.edu
■
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dx.doi.org/10.1021/ja2119767 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX