One-Pot Absolute Stereochemical Identification of Alcohols via Guanidinium Sulfate Crystallization

Article abstract of DOI:10.1021/acs.orglett.9b03792

A novel technique for the absolute stereochemical determination of alcohols has been developed that uses crystallization of guanidinium salts of organosulfates. The simple one-pot, two-step process leverages facile formation of guandinium organosulfate single crystals for the straightforward determination of the absolute stereochemistry of enantiopure alcohols by means of X-ray crystallography. The strong hydrogen bonding network drives the stability of the crystal lattice and allows for a diverse range of organic alcohol substrates to be analyzed.

Full text of DOI:10.1021/acs.orglett.9b03792

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
One-Pot Absolute Stereochemical Identification of Alcohols via
Guanidinium Sulfate Crystallization
Beau R. Brummel, Kinsey G. Lee, Colin D. McMillen, Joseph W. Kolis,* and Daniel C. Whitehead*
Department of Chemistry, Clemson University, Clemson, South Carolina 29634, United States
S
* Supporting Information
ABSTRACT: A novel technique for the absolute stereochemical
determination of alcohols has been developed that uses
crystallization of guanidinium salts of organosulfates. The simple
one-pot, two-step process leverages facile formation of guandinium
organosulfate single crystals for the straightforward determination
of the absolute stereochemistry of enantiopure alcohols by means
of X-ray crystallography. The strong hydrogen bonding network
drives the stability of the crystal lattice and allows for a diverse range of organic alcohol substrates to be analyzed.
he identity of the absolute stereochemistry of a
compound is essential to a number of different disciplines
(ECCD) which then can be used to empirically predict the
absolute stereochemistry of the chiral substrate. A variety of
chiral organic compounds including carboxylic acids,3a−e 1,2-
diols, 1,2-diamines, 1,2-aminoalcohols,3f epoxy alcohols,3g 1,n-
glycols,3h amines,3i−j cyanohydrins,3k and sulfoxides3l have
been successfully identified using this method. Despite the
wide range of chiral substrates tolerated under this approach,
the strategy requires the nontrivial synthesis of the porphyrin
tweezer probes, and each different chiral functional group
demands different tweezers for analysis. The approach also
involves the use of specialized analytical equipment (circular
dichroism) which may not be universally available and is often
complicated by the need for derivatizations of the analyte
samples.
Another strategy for absolute stereochemical determination
is the competing enantioselective conversion (CEC) method.4
In this technique, both enantiomers of a kinetic resolution
reagent are reacted with the target enantiopure compound.
The conversion of this reaction is measured, and the faster
reacting substrate-reagent pair is then determined via NMR,
TLC, or GC analysis. The absolute stereochemical assignment
is deduced by comparing the kinetic resolution results to an
empirical mnemonic. Although this method has successfully
identified amines,4a−c oxazolidinones, lactams,4d and chiral
alcohols,4e−h each class of substrates requires its own unique
suitable catalyst or reagent capable of kinetic resolution.
Another common method for chiral identification is the
advanced Mosher ester analysis or the use of other chiral
derivatizing agents (CDAs) in order to solve the absolute
stereochemistry via NMR spectroscopy. Methods that utilize
NMR spectroscopy require a transformation of the chiral
molecule to two different species which can be differentiated
by their NMR spectra. The differences in chemical shifts (Δδ)
of the two species (diastereomers or conformers) along with
T
in organic chemistry including synthetic, pharmaceutical, and
biological processes. The task of assigning the absolute
stereochemistry of a small organic molecule, as opposed to
measuring the enantiomeric excess (ee) or enantiomeric ratio
(e.r.) of a scalemic sample, often can be very difficult.1
Resolution techniques, such as chiral high-performance liquid
chromatography (HPLC), have allowed for the evaluation of
the enantiomeric purity (ee or e.r.) of a sample to be
completed with relative ease. Nonetheless, determining with
certainty which enantiomer has been generated or isolated
remains a daunting challenge.
Indeed, the critical importance of chiral identification has led
to the development of a range of techniques for the assignment
of absolute stereochemistry.2−6 The most popular practices
include chiroptical spectroscopy, stereoselective reactions,
NMR spectroscopy, and X-ray crystallography. Advances in
circular dichroism (CD) by a Nakanishi,2a Harada,2a Berova,2b
and Stephens,2c among others has made it a promising tool for
the determination of the absolute configuration of target
molecules.2 Circular dichroism can be coupled with electronic
transitions, electronic CD (ECD), to examine chiral substrates
containing electronic chromophores capable of absorbing
visible light.2a−c If the chiral molecule lacks an electronic
chromophore, circular dichroism can be coupled with
vibrational transitions (VCD) or Raman scattering known as
vibrational Raman optical activity (VROA).2d−f The major
disadvantage of these chiroptical methods is that they cannot
directly assign the absolute configuration of chiral molecules.
Theoretical methods must be used to predict the chiroptical
properties of the targeted molecule followed by comparative
analysis of the experimental and predicted chiroptical spectra
to then infer the absolute stereochemistry. More recently,
Borhan and co-workers have developed a series of metalated
bis-porphyrin tweezers that are capable of binding chiral
substrates.3 The induced helicity of the tweezer-substrate
complex is measured using exciton coupled circular dichroism
Received: October 24, 2019
© XXXX American Chemical Society
A
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Letter
model substrates can then be compared to assign the absolute
configuration. Development of CDA agents that can afford the
required transformation have been ongoing since the
introduction of Mosher’s acid in the 1970s.5 CDA agents
react with the chiral substrate of interest and form a covalent
bond, while chiral solvating agents (CSAs) such as ion-pairing
or metal complexes interact with the chiral molecule through a
noncovalent interaction.5c,d Both typically depend on the use
of enantiomerically pure reagents for derivatization/coordina-
tion and the use of model compounds for comparison.5 The
major disadvantage of NMR-based methods is the need for
enantiomerically pure CDA/CSA agents to transform the
target analyte and the requirement that the functional group
undergoing derivatization must typically be on or proximal to
an asymmetric center.
proceeds in one pot and only requires a cheap and
commercially available sulfur trioxide−pyridine complex and
guanidinium chloride. Finally, the chiral material of interest is
readily recoverable after derivatization by means of a simple
hydrolysis step. This method would also be useful as a strategy
for assigning relative stereochemistry.
This methodology (Scheme 1) for stereochemical analysis of
small organic molecules begins with the sulfation of a
Scheme 1. Enantiomeric Identification
While these pioneering examples have aided in the
determination of the absolute stereochemistry of organic
molecules, they are not without drawbacks. We describe,
herein, an approach using the facile formation of guanidinium
sulfate single crystals for the direct determination of the
absolute and relative stereochemistry of enantiopure alcohols
or other simple nucleophiles, via X-ray crystallography. X-ray
crystallography is commonly viewed as the most reliable and
definite method to assign the absolute configuration of chiral
molecules; however, the generation of single crystals suitable
for analysis can be very challenging, especially when
considering small organic compounds.6 Historically, this
challenge has been overcome by the formation of derivatives
that are crystalline6a−g or, recently, employing host−guest
chemistry using crystalline sponges6h or frameworks.6i The
methodology described herein combats challenges of crystal-
lization by employing a guanidinium sulfate network which
promotes the formation of large, high quality crystals. While
these approaches clearly depend on obtaining a single crystal of
the target material, the phenomenon of anomalous dispersion
has become a useful tool for the unambiguous assignment of
absolute configuration.6a−e Modern diffractometers with
sensitive detection and advanced software can now be used
to routinely assign absolute stereochemistry with complete
reliability. The method works best when there is at least one
heavy atom (Z > 14) present. In this paper we employ sulfur as
a suitable heavy atom in all of our crystals making the method
amenable to X-ray instruments utilizing either Mo or Cu
radiation sources.
nucleophilic group (i.e., an alcohol) on the substrate of
interest. The sulfated organic compound can then be
combined with guanidinium chloride to form a guanidinium
sulfate salt as a well-formed, large, three-dimensional single
crystal containing a strong network of hydrogen bonding. This
easily formed, high-quality organic crystal can then be used in
an X-ray diffraction experiment, from which the crystal
structure can be determined and the absolute stereochemistry
of the parent substrate can be assigned. Lastly, the sulfate
group can be readily removed by simple hydrolysis for
subsequent recovery of the chiral organic analyte without
erosion of the enantiopurity of the compound.
The driving force of the crystal lattice formation in these
large organic crystals is the ample amount of hydrogen
bonding that takes place between the organic sulfate and
guanidinium pair (Figure 1). Ward and co-workers have
demonstrated that planar trigonal guanidinium ions are ideally
configured to form hydrogen bonds with multiple organo-
sulfonate donors.7 Thus, the pairing forms not only stable
anion−cation interactions but also bridging linkers between
Our approach is inspired by the work of Ward et al., who
first observed that the guanidinium salts of organosulfonates
−
(i.e., RSO3 ) readily form high quality single crystals over a
wide range of structural types because of extensive hydrogen
bonding between the sulfonate and guanidinium.7 We adapted
−
this approach to related organosulfates (i.e., R−OSO3 ) as
described herein and find that the crystal growth can often be
very straightforward in many cases because of similar hydrogen
bonding. The H-bonding networks readily form the same
patterns as in the Ward compounds, leading to high quality,
well-formed crystals. The technique has several advantages in
comparison to other methods for absolute stereochemical
determination including that it is definite and requires no
predictive model or empirical mnemonics, it can unambigu-
ously identify all stereocenters that are present in the chiral
molecule along with their relative orientation, and it does not
require the chiral center to be coincident with the
derivatization site. While the method still depends on a
derivatization step, it bears mentioning that the derivatization
Figure 1. Formation of salts of guanidinium organosulfates via
hydrogen bonding interactions. (a) Schematic of the sulfated (R)-1-
phenylethanol substrate. (b) Hydrogen bonding about the guanidi-
nium cation hydrogen bond donor (the majority of the organosulfate
anion is omitted for clarity). (c) Hydrogen bonding about the sulfate
anion hydrogen bond acceptor. (d) Packing of molecules viewed
along the b-axis. (e) Pleated 2-D sheets of guanidinium cations and
organosulfate anions viewed along the c-axis.
B
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Letter
organosulfonates.7a,b This combined effect creates an environ-
ment highly favorable for the growth of large single crystals of a
wide range of organic compounds.7b−g Furthermore, the
sulfonate−guanidinium hydrogen bonding network typically
forms 1-D ribbons which pair to form pleated 2-D sheets.7 In
these sheets, the organic groups have numerous options in
which they can position themselves relative to the hydrogen
bonding sheets and this packing is typically dependent on the
size of the organic functional groups. The ability to tune the
overall geometry and the dihedral angle of the ribbons
maximizes the hydrogen bonding, steric efficiency, and van
der Waals interaction of the organic groups. This flexibility
leads to a remarkable range of organic substrates that readily
grow as high-quality, single crystals. The organosulfates of the
present study present the same combination and quantity of
hydrogen bond donors and acceptors as in the sulfonate
systems. Additionally, the high degree of hydrogen bonding
drives the stability of the crystal lattice and enables relatively
straightforward growth of single crystals from common, simple
solvents, avoiding excessive experimental problems. Since
many substrates of interest do not crystallize well as neutral
molecules, the sulfate group plays a dual role in providing both
the driving force for crystallization and the source of the
anomalous dispersion to enable the stereochemical assign-
ments.
The first step of our approach toward absolute stereo-
chemical determination is the sulfation of a nucleophilic group
on the chiral substrate of interest. Initially, we targeted alcohols
to demonstrate the overall strategy, as they represent a large
percentage of significant chiral compounds and they are known
to undergo facile sulfation. In addition, in contrast to amines
for example, there are relatively few methods for stereo-
chemical resolution or identification of alcohols. Several
sulfation reagents were examined, but it was found that a
suspension of sulfur trioxide/pyridine (SO3·Pyr) in DCM is
the most satisfactory (see Supporting Information (SI) for
optimization studies). A slight excess (1.3 equiv) of SO3·Pyr
allows for 100% conversion of a wide range of alcohols to their
respective sulfate pyridinium complex within 24 h (Scheme 2).
Scheme 3. Enantioretentive Hydrolysis
a
Enantiomeric excess (% ee) determined by chiral HPLC.
Table 1. Stereochemical Identification by X-ray
a
Crystallography
space
group
abs. str. param.
chirality
substrate
R1
flack
identified
1 (R)
2 (S)
P21
P21
P21
P212121
P212121
P3221
C2221
P21
P1
P21
P212121
P1
P212121
C2
P21
P21
P21
0.0270
0.0253
0.0496
0.0358
0.0338
0.0766
0.0340
0.0375
0.0554
0.0350
0.0228
0.0290
0.0329
0.0298
0.0490
0.0270
0.0794
0.02(2)
0.00(2)
0.01(4)
0.02(5)
0.00(3)
0.05(4)
0.03(2)
0.00(3)
0.02(2)
0.05(3)
0.00(1)
0.06(6)
−0.01(3)
0.07(3)
0.06(5)
0.04(2)
−0.10(4)
R
S
R,S,R
R,S,R
S,S
R,S,S
R,R,R,S
S
R
R
S,S
R,R
S
R
S
3 (−)
4 (L)
5 (−)
6 (−)
7 (−)
8 (S)
9 (R)
10 (R)
11 (S,S)
12 (R,R)
13 (S)
14 (D)
15 (S)
16 (D)
17 (−)
R,S,S,R,S
S,R,S,R
a
Complete refinement details are given in the SI.
stereochemistry of (R)-1-phenylethanol (1) and (S)-1-phenyl-
enthanamine (2). Although 2 was the only amine substrate
that was investigated, we were pleased to see that the same
sulfation conditions afforded the sulfated amine and the critical
hydrogen bonding network persisted in the crystal lattice,
making this technique suitable for the stereochemical
identification of amines as well. For completeness we also
examined the opposite enantiomers of these systems with the
same success. Next, we explored the absolute stereochemical
assignment of more structurally complex alcohols. For
instance, we were able to readily sulfate, crystallize, and assign
a series of terpenoid natural products including (−)-isopulegol
(3), L-menthol (4), (−)-nopol (5), (−)-borneol (6),
(−)-isopinocampheol (7), and (−)-perillyl alcohol (8). Simple
aliphatic chiral alcohols such as (R)-2-butanol (9) and (R)-2-
octanol (10), as well as two diols (11, 12), were also readily
sulfated, and their absolute stereochemical identity was
assigned. The assignment of (S)-2-phenylpropan-1-ol (13)
demonstrates that the chiral center of interest does not need to
reside directly on the carbinol moiety. This is also evident in
the terpenoid examples 5 and 8. The process is also compatible
with relatively sensitive molecules including those bearing
enolizable chiral centers like the one resident in (+)-methyl-D-
lactate (14). Propargylic alcohols also proceed well in the
process allowing for the assignment of (S)-3-butyne-2-ol (15).
Furthermore, substrates with acid-labile groups such as acetals
in the protected sugar 16 and esters/lactones in the Corey
lactone benzoate (17) are well tolerated and can be easily
identified. The latter two substrates further highlight the ability
of this method to identify more complex molecules which have
multiple stereocenters and whose chiral centers are not
Scheme 2. One-Pot Guanidinium Sulfate Crystallization
a
1
Conversion determined by H NMR spectroscopy.
Once the sulfated product is formed, the guanidinium
crystallization step proceeds straightforwardly as desired. The
unpurified sulfate pyridinium complex is then subjected to 1
equiv of guanidinium chloride and a common alcohol solvent
to solubilize the components of the mixture. Slow evaporation
of this solution resulted in high-quality, large, single crystals of
the organosulfate guanidinium salt. We then unambiguously
established the structural and enantiomeric identity of the
target molecule using single crystal X-ray diffraction employing
the anomalous dispersion method. After successful identi-
fication, the original chiral sample can be recovered in excellent
yields and enantioselectivity via simple hydrolysis (Scheme 3).
This facile two-step, one-pot process was effectively
employed on a suite of chiral molecules shown in Table 1
and Figure 2. First, we successfully assigned the absolute
C
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Figure 2. Scope of alcohol substrates crystallized as guanidinium organosulfate salts, with the anionic organosulfate moieties shown as 50%
probability ellipsoids from the single crystal structure refinements. Carbon atoms are gray, oxygen atoms are red, sulfur atoms are yellow, and
nitrogen atoms (in 2 only) are blue.
coincident with the sulfated alcohol moiety. The structural
diversity of the 17 substrates in this study which were
successfully assigned with 100% accuracy demonstrates the
versatility and reliability of this strategy for absolute stereo-
chemical determination. The main limitation of the method-
ology is our current inability to apply the strategy for the
identification of chiral tertiary alcohols due to the reluctance of
these species to undergo sulfation under the present conditions
employed. We probed two such substrates: (−)-linalool and
(+)-terpinen-2-ol. In the former case, we observed incomplete
sulfation (i.e., 50% conversion) and successfully grew crystals
from the crude reaction mixture after treatement with
guanidinium chloride. Nevertheless, the resulting crystals
were of insufficient quality for X-ray analysis. In the latter
case, the sulfation attempt failed. Finally, our strategy failed to
return X-ray quality crystals for one 1° alcohol substrate,
(−)-citronellol, despite successful sulfation and crystallization.
Further investigations to probe the limitations and potential of
this method are ongoing in our laboratory. Studies include the
optimization of this strategy for the stereochemical determi-
nation of other important functional groups.
utilizing X-ray equipment readily available to most research
universities and pharmaceutical laboratories. The two-step
method takes advantage of the highly flexible hydrogen
bonding network present between the sulfated organic
compound and the guanidinium moiety. This favorable lattice
allows for facile generation of large, high-quality crystals from a
diverse range of substrates that otherwise may be recalcitrant
toward facile crystallographic analysis. The sulfate group
provides sufficient anomalous dispersion such that the absolute
stereochemistry can be assigned unambiguously. This
technique has a number of advantages in comparison to
other methods, including operational simplicity, low cost, and
easy-to-interpret, absolute results. While the 17 substrates
assigned in this report demonstrate the ability of this chiral
identification technique, we hope to build on these compelling
preliminary results in the near future.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b03792.
By means of our straightforward strategy, the absolute
stereochemistry of target compounds can be obtained from a
small amount of sample (less than 50 mg) in less than 48 h,
General procedures, optimization of sulfation and
desulfation protocols, tabular summary of X-ray
D
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1
crystallography data, H and 13C NMR data for sulfate
Absolute Configuration for erythro and threo Diols, Amino Alcohols,
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pyridinium complexes (PDF)
Accession Codes
CCDC 1954250−1954266 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: kjoseph@clemson.edu (J.W.K.).
*E-mail: dwhiteh@clemson.edu (D.C.W.).
ORCID
Daniel C. Whitehead: 0000-0001-6881-2628
Notes
(4) (a) Wagner, A. J.; David, J. G.; Rychnovsky, S. D. Determination
of Absolute Configuration Using Kinetic Resolution Catalysts. Org.
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Rychnovsky, S. D. Nanomole-Scale Assignment of Configuration for
Primary Amines Using a Kinetic Resolution Strategy. J. Am. Chem.
Soc. 2012, 134, 20318−20321. (c) Burtea, A.; Rychnovsky, S. D.
Determination of the Absolute Configuration of Cyclic Amines with
Bode’s Chiral Hydroxamic Esters Using Competing Enantioselective
Conversion Method. Org. Lett. 2017, 19, 4195−4198. (d) Perry, M.
A.; Trinidad, J. V.; Rychnovsky, S. D. Absolute Configuration of
Lactams and Oxazolidinones Using Kinetic Resolution Catalysts. Org.
Lett. 2013, 15, 472−475. (e) Wagner, A. J.; Rychnovsky, S. D.
Determination of Absolute Configuration of Secondary Alcohols
Using Thin-Layer Chromatography. J. Org. Chem. 2013, 78, 4594−
4598. (f) Wagner, A. J.; Miller, S. M.; King, R. P.; Rychnovsky, S. D.
Nanomole-Scale Assignment and One-Use Kits for Determining the
Absolute Configuration of Secondary Alcohols. J. Org. Chem. 2016,
81, 6253−6265. (g) Burns, A. S.; Wagner, A. J.; Fulton, J. L.; Young,
K.; Zakarian, A.; Rychnovsky, S. D. Determination of the Absolute
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the Tobey Beaudrot Endowment (Clemson
University) for partial support of this work.
■
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