Chiral amplification with a stereodynamic triaryl probe: Assignment of the absolute configuration and enantiomeric excess of amino alcohols

Article abstract of DOI:10.1021/ja907741v

(Figure Presented) A stereodynamic, axially chiral triaryl probe is locked into a single conformation upon condensation with two amino alcohol substrates. The well-defined chiral amplification in the diimines formed results in intense Cotton effects at high wavelengths that can be used for in situ CD analysis of the absolute configuration and ee of cyclic and acyclic substrates.

Full text of DOI:10.1021/ja907741v

Published on Web 10/26/2009
Chiral Amplification with a Stereodynamic Triaryl Probe: Assignment of the
Absolute Configuration and Enantiomeric Excess of Amino Alcohols
Marwan W. Ghosn and Christian Wolf*
Department of Chemistry, Georgetown UniVersity, Washington, D.C. 20057
Received September 11, 2009; E-mail: cw27@georgetown.edu
Scheme 2. Central-to-Axial Chirality Induction Using Amino
Alcohols 4-12 and Triaryl Probe 1
Chiroptical spectroscopy has been applied extensively in the
stereochemical analysis of chiral compounds. In particular, the efficacy
of methods based on circular dichroism has received increasing
attention in recent years.1 Induced circular dichroism (ICD) has been
used to probe the orientation of guest molecules in cyclodextrin and
calixarene inclusion complexes2 or to analyze the structure of chiral
ion pairs3 and supramolecular assemblies.4 The covalent linkage of a
chiral compound to a porphyrin, phthalocyanine or other chromophoric
moieties has been reported to generate strong Cotton effects,5 which
provides a means to determine the chirality of UV-silent substrates.6
In particular, the covalent attachment of a conformationally flexible
biphenyl unit to chiral amino acids, carboxylic acids and alcohols
followed by isolation and CD analysis has been shown to allow a
reliable assignment of the absolute configuration.7 The formation of
hydrogen bond adducts8 and metal complexes9 can provide an entry
to in situ analysis that avoids elaborate workup procedures.
In analogy to other 1,8-diarylnaphthalenes, 1 can be expected to
undergo facile rotation about the two aryl-aryl bonds at room
temperature.14 Accordingly, the enantiomeric anti-isomers of this triaryl
rapidly interconvert via the thermodynamically less stable meso syn-
intermediate. We envisioned that imine formation with amino alcohols
would disturb this equilibrium and strongly favor population of a single
diastereomer by intramolecular hydrogen bonding (Scheme 2).
Compared to ICD analysis of amines, amino acids, carboxylic acids
and alcohols, only few methods for the determination of both the
absolute configuration and enantiomeric composition of amino alcohols
have been developed.10 Remaining drawbacks of some of these
protocols are elaborate derivatization and purification steps prior to
CD analysis, generation of modest Cotton effects at low wavelengths,
and narrow application scope. Furthermore, the use of a stereodynamic
chromophoric sensor that undergoes rapid racemization via rotation
about a chiral axis for both quantitative ICD sensing of the ee and
simultaneous determination of the absolute configuration of amino
alcohols has not been reported to date. This may be partly attributed
to the difficulty of designing a stereolabile probe that is suitable for
distinct chiral amplification and predictable chiroptical properties upon
binding to a chiral substrate.
Figure 1. UV and CD analysis of the imines obtained with 4 using 1 and
salicylaldehyde. (Left) UV plot of 1 titrated with (R)-4 in CHCl3, reaction
concentration was 0.02 M, UV concentration was 10.0 × 10-3 M. Pure 1
(red), 1 equiv of 4 after 5 min (green), 2 equiv after 5 and 10 min (both
light blue) and 18 equiv after 5 min (dark blue). (Right) CD plot of the
diimine obtained from (R)-4 in CHCl3 (green) and (S)-4 (red) both (5.0 ×
10-4 M), and the (R)-4 derived salicylidenimine (blue, 5.0 × 10-3 M).
Scheme 1. Synthesis of Stereodynamic Sensor 1
Indeed, titration of 1 with either enantiomer of amino alcohol 4
showed a new characteristic UV absorption band above 400 nm and
MS and NMR analysis proved quantitative diimine formation in
chloroform within 5 min (see Figure 1 and Supporting Information).15
The corresponding CD spectra show that reaction with this simple
acyclic amino alcohol results in a remarkably strong Cotton effect and
similar results were obtained with several other substrates (see
Supporting Information). Since it is known that salicylaldehyde can
be used for CD analysis of the absolute configuration of amines and
amino acids, we employed both 1 and free salicylaldehyde in CD
sensing experiments of 4.16 CD and NMR analysis showed that the
reaction with salicylaldehyde requires significantly more time and is
still not complete after 90 min. The corresponding salicylidenimine
remains CD silent above 300 nm in chloroform and ethanol even at
10-fold concentration. Apparently, the strong Cotton effect at high
wavelengths and the short condensation reaction time are due to the
unique structure of sensor 1.
We now introduce a simple, time-efficient CD method based on an
axially chiral reporter molecule that provides information on the
enantiomeric excess and the absolute configuration of amino alcohols.
We realized that the unique structure of 1,8-diarylnaphthalenes provides
an excellent opportunity to design a sensor that carries a chromophoric
binding pocket and that has the ability to transform a binding event
with a chiral substrate into a strong CD signal. In continuation of
previously conducted studies with stereodynamic chiral biaryls and
triaryls11 and 1,8-diheteroarylnaphthalene-derived sensors,12 we de-
cided to prepare 1,8-bis(3′-formyl-4′-hydroxyphenyl)naphthalene, 1.13
Suzuki coupling of boronic acid 2 with 1,8-diiodonaphthalene
gave 3 which was easily deprotected to afford 1 in 48% overall
yield (Scheme 1).
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C O M M U N I C A T I O N S
We were able to grow single crystals of the diimines 13 and 14
produced from 1 and amino alcohols 4 and 5. Crystallographic analysis
of the orange crystals of 13 and 14 proved that the central chirality of
the substrates induces a rigid, axially chiral triaryl scaffold. Condensa-
tion of 1 and the (S)-enantiomer of 4 and 5 resulted in well-defined
amplification of chirality and the sensor was found to adopt a (P,P)-
conformation that is stabilized by intramolecular hydrogen bonding
(Figure 2 and Supporting Information). Importantly, we obtained
(R,R,M,M)-13 when (R)-4 was employed in the same experiment. As
expected, the two phenyl rings in these crowded structures are not
perfectly coplanar but slightly splayed. The splaying angle (the angle
between the two phenyl planes) in (R,R,M,M)-13 and (S,S,P,P)-13 is
15.9°. The salicylidenimine rings are also not perfectly orthogonal to
the naphthalene ring but afford a torsion angle of -52.6° and +52.1°,
respectively. Finally, (R,R,M,M)-13 and (S,S,P,P)-13 show opposite
twisting which is expressed by the angle between the two phenyl-
naphthalene bonds viewed along the naphthalene plane. The twisting
angles are -14.6° and +14.7°. The separation of the centroids of the
two phenyl rings was determined as 3.392 and 3.391 Å, which enforces
strong π-π-interactions between the two salicylidenimine units. The
CdN· · ·HOCphenyl hydrogen bonding lengths are 1.692 and 1.649 Å
and the CaliphOH· · ·OCphenyl hydrogen bonds are 1.899 and 2.011 Å,
respectively. The sense of asymmetric induction and the three-
dimensional arrangement including bond angles and hydrogen bond
lengths in (S,S,P,P)-14, which was obtained from (S)-5, closely match
those discussed for (S,S,P,P)-13 (see Supporting Information). This
parallel behavior underscores the generality of the chiral amplification
process shown in Scheme 2.
time-efficient ICD assay reveals the absolute configuration of the major
enantiomer and gives accurate ee’s that are generally within 6% of
the actual values.
In conclusion, we have introduced sensor 1, which can be easily
prepared in two steps, for enantioselective CD analysis of chiral amino
alcohols. This stereodynamic probe combines several attractive
features: (1) the generation of intense Cotton effects at high wavelength
reduces interference with chiral impurities and is a general requisite
for ee quantification; (2) fast diimine formation followed by in situ
CD measurements allows time-efficient analysis and eliminates the
need for elaborate purification steps; (3) the operational simplicity of
the CD assay provides an entry toward automation and high throughput
screening; (4) only minute sample, sensor and solvent amounts are
needed; (5) the sensor provides information about the absolute
configuration and enantiomeric composition of cyclic and acyclic
substrates based on well-defined chiral amplification.
Acknowledgment. This material is based upon work supported
by the NSF under CHE-0910604.
Supporting Information Available: Experimental procedures and
CD, MS and X-ray analyses of the diimines. This material is available
free of charge via the Internet at http://pubs.acs.org.
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(15) NMR and MS reaction monitoring did not show any sign of the monoimine
indicating that the second condensation step is faster than the first.
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Figure 2. X-ray structures of (R,R,M,M)-13 and (S,S,P,P)-13. Outside: view
into the cleft; Inside: view along the naphthalene plane. Selected crystal-
lographic separations [Å]: (R,R,M,M)-13: N1· · ·H1 1.692, H2 · · ·O1′ 1.899;
(S,S,P,P)-13: N1· · ·H1 1.649, H2 · · ·O1′ 2.011.
This arrangement allows the two imino alcohol moieties in 13 and
14 to participate in four hydrogen bonds while the alkyl groups occupy
the sterically least hindered positions and the hydrogens attached to
the chiral center are directed toward the more sterically crowded areas
close to the salicylidenimine planes. The high degree of central-to-
axial chirality induction and the corresponding strong CD signals are
thus a result of concurrent optimization of hydrogen bonding and
minimization of steric interactions. The stereodynamic sensor is
effectively locked into a single conformation which is known to favor
intense Cotton effects.17 The sense of axial chirality and the sign of
the observed ICD signal which can be attributed to exciton coupling
of the proximate cofacial salicylidenimine chromophores are ultimately
controlled by the central chirality of the substrate.18 The sign of the
CD spectrum can therefore be used to determine the absolute
configuration of the amino alcohols shown in Scheme 2 (see Supporting
Information).
(17) The amino diols 10 and 11 show weak CD signals, probably due to
competitive hydrogen bonding of the two available hydroxyl groups.
(18) Salicylidenimines can form a CD active quinoid-like tautomer. The ICD
observed with 1 is more likely a result of ECCD. NMR and X-ray analysis
do not show the quinoid structure. The phenolic C-O bond lengths in 13
and 14 are 1.357 and 1.361 Å, which is close to the value in phenol (1.349
Å); the C-O bond length in quinone is 1.294 Å. Ligtenbarg, A. G. J.; Hage,
R.; Meetsma, A.; Feringa, B. L. J. Chem. Soc., Perkin Trans. 2 1999, 807.
To evaluate the practical use of our sensor, scalemic samples of
2-aminopropanol, 2-aminobutanol and 2-hydroxypropylamine, 4-6,
covering a wide ee range were analyzed (Supporting Information). In
all cases, diimines were formed within 5 min and analyzed without
further purification. The results obtained by our in situ CD sensing
method were in excellent agreement with the theoretical ee’s. This
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