Please cite this article in press as: Minus et al., Reengineering a Reversible Covalent-Bonding Assembly to Optically Detect ee in b-Chiral Primary
Article
Reengineering a Reversible Covalent-Bonding
Assembly to Optically Detect ee in b-Chiral
Primary Alcohols
Matthew B. Minus,1 Aaron L. Featherston,2 Sooyun Choi,2 Sam C. King,3 Scott J. Miller,2,
*
SUMMARY
The Bigger Picture
Controlling the synthesis of
stereogenic centers is key in the
development of therapeutics and
biomaterials. High-throughput
experimentation (HTE), coupled
with modern data analysis
The use of parallel synthesis protocols for asymmetric reaction discovery has
increased the need for new methods to rapidly determine enantiomeric excess
(ee) values. Most chirality sensing is performed on stereocenters that are a (i.e.,
proximal) to the target functional group. Finding a general approach to detect
more distant point chirality would increase the substrate scope of such assays.
Herein, we demonstrate a design principle to ‘‘reach out’’ to more distant ster-
eocenters, in this case b-chirality in primary alcohols. Therefore, we see the
design principles established in this work as a step forward in sensing distant
point chirality and, eventually, multi-stereocenter relationships.
methods such as machine
learning, can potentially enable
the discovery of new asymmetric
catalysts. However, these
methods demand large sample
numbers—upward of 104
INTRODUCTION
The utilization of designed and synthesized drugs for medicinal applications has played
a critical role in increasing the average human lifespan.1–3 Around 50% of all drugs
contain at least one stereocenter.4 Thus, the need to create chiral molecules continues
to inspire the synthetic community.5–7 As such, the ever-increasing demand for asym-
metric synthetic methods, in turn, increases the need for analytical techniques.
reactions for training. While
parallel synthesis techniques are
capable of producing enough
reactions to satisfy these
demands, enantiomeric excess
(ee) analysis on that scale is a
current challenge. Therefore, our
group and others are developing
optical ee sensors for high-
throughput screening. We
Modern methods for catalyst discovery, such as high-throughput experimentation,
accelerate the discovery of ideal asymmetric transformations.8,9 These methods
call for measuring the enantiomeric excess (ee) in hundreds, if not thousands, of
reactions.5 Analyzing the ee of 1,000 samples by high-performance liquid chroma-
tography (HPLC) can take anywhere from 2 to 10 min per optimized run depending
on the column and solvent system. Because HPLC analysis by nature is serial and not
parallel, it would take 33–167 h (i.e., 1 week) to analyze 1,000 reactions. Thus, many
groups are creating rapid optical methods to determine ee, and assays for several
classes of functional groups have been created.10,11
present herein a general principle
for developing chirality sensors for
stereocenters that are remote
from common organic functional
groups. These new analytical
methods, and advances
Our group has developed a series of ee assays that target chiral amines,12 carboxylic
acids,13 ketones,14 and alcohols.15 Zonta has recently developed sensors for chiral
sulfonamides and amides,14 and Anzenbacher,16 Pu,17 Wolf,18 and You,19 along
with others,20 have also reported several chirality sensors.21 Nearly without excep-
tion, the stereocenter in the chiral analyte is a, i.e., as proximal as possible, to the
functional group being analyzed. Thus, armed with the ability to determine the ee
of stereocenters proximal to many common functional groups, we are working to
build assemblies that can sense stereocenters that are more remote from their
functional groups. Finding methods to detect elements of chirality distal from
functional groups will increase the substrate scope and utility of the optical methods.
presented herein, would bridge
that gap between big data
analysis and asymmetric catalysis,
granting access to the next
generation of chiral materials and
medicines.
Chem 5, 1–11, December 12, 2019 ª 2019 Elsevier Inc.
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