4.1 Serendipitous Discovery and High-Throughput
Screening (HTS)
Enabled by modern technology, such as automated robotic systems, it is possible to
accelerate the process of trial-and-error experimentation to generate results rapidly.
For example, Macmillan has used high-throughput screening and GC-MS as a
means to analyse product formation, leading to a discovery of a novel Ir-catalysed
α-amino C-H photoredox arylation, terming the procedure ‘accelerated serendipity’
(Fig. 5) [31]. While this transformation was racemic, the growing availability of
high-throughput screening (HTS) platforms has meant that this paradigm has begun
to impact asymmetric catalysis.
Examples of rapid screening platforms in asymmetric catalysis have been applied
by de Vries and Lefort to transition metal-catalysed asymmetric hydrogenations.
Here, the in situ synthesis of 32 BINOL-derived phosphoramidite ligands and
64 hydrogenation reactions were carried out by Premex 96-multireactor within
2 days (Fig. 6a) [32]. Feringa, de Vries and Minnaard also applied this approach
to rhodium-catalysed asymmetric addition of arylboronic acids by synthesizing
20 chiral phosphoramidite ligands in situ and used them in the subsequent reaction
giving up to 87% ee of the desired product (Fig. 6b) [33]. The modular nature of
phosphoramidite ligands makes such an approach feasible, since a library of candidate ligands can be synthesized with relative ease.
The ability to screen multiple reactions at a time is a promising approach;
however, the reliable analysis of reaction progress, product formation and selectivity
is equally as important. The traditional approach of experimentally quantifying
enantioselectivity using chiral high-performance liquid chromatography (HPLC)
becomes the bottleneck. Recent advances in ee determination have aimed to make
HTS of chiral catalysts more attractive. With supercritical fluid chromatography,
Regalado and Welsh (at Merck) have shown that the ee of 50 different scalemic
mixtures can be analysed in less than a minute each on customized short chiral
columns (1–2 cm) [34]. Others have developed, to a certain extent, more specialized
(in a sense, less widely used) systems. Anslyn and co-workers have developed a
circular dichroism-based host-guest system to determine the ee of vicinal diols,
α-hydroxyacids, vicinal diamines, cyclohexanones, amines, α-chiral aldehydes,
carboxylates, amino acids and secondary alcohols within Æ7% or lower average
error (Fig. 7a) [35]. For chiral amines and amino acids, a few other methods have
been developed to analyse their ee values [36] such as the use of nuclear magnetic
resonance (NMR) and fluorescence detection of chiral boronate and amine assembly
by Anzenbacher (Fig. 7b) [37],
19 F NMR probing of a chiral palladium pincer
complex with chiral amines developed by Zhao and Swager [38] (Fig. 7c) while a
DNA biosensor to detect the chiral amino acid derivative tyrosinamide developed by
Heemstra (Fig. 7d) [39].
Despite the early promise of HTS approaches for chiral catalyst discovery, some
drawbacks remain. Firstly, specialized tools or chemical systems are often required
for screening and analysis. Secondly, there is no guarantee that screening will yield
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R. Ardkhean et al.
Screening (HTS)
Enabled by modern technology, such as automated robotic systems, it is possible to
accelerate the process of trial-and-error experimentation to generate results rapidly.
For example, Macmillan has used high-throughput screening and GC-MS as a
means to analyse product formation, leading to a discovery of a novel Ir-catalysed
α-amino C-H photoredox arylation, terming the procedure ‘accelerated serendipity’
(Fig. 5) [31]. While this transformation was racemic, the growing availability of
high-throughput screening (HTS) platforms has meant that this paradigm has begun
to impact asymmetric catalysis.
Examples of rapid screening platforms in asymmetric catalysis have been applied
by de Vries and Lefort to transition metal-catalysed asymmetric hydrogenations.
Here, the in situ synthesis of 32 BINOL-derived phosphoramidite ligands and
64 hydrogenation reactions were carried out by Premex 96-multireactor within
2 days (Fig. 6a) [32]. Feringa, de Vries and Minnaard also applied this approach
to rhodium-catalysed asymmetric addition of arylboronic acids by synthesizing
20 chiral phosphoramidite ligands in situ and used them in the subsequent reaction
giving up to 87% ee of the desired product (Fig. 6b) [33]. The modular nature of
phosphoramidite ligands makes such an approach feasible, since a library of candidate ligands can be synthesized with relative ease.
The ability to screen multiple reactions at a time is a promising approach;
however, the reliable analysis of reaction progress, product formation and selectivity
is equally as important. The traditional approach of experimentally quantifying
enantioselectivity using chiral high-performance liquid chromatography (HPLC)
becomes the bottleneck. Recent advances in ee determination have aimed to make
HTS of chiral catalysts more attractive. With supercritical fluid chromatography,
Regalado and Welsh (at Merck) have shown that the ee of 50 different scalemic
mixtures can be analysed in less than a minute each on customized short chiral
columns (1–2 cm) [34]. Others have developed, to a certain extent, more specialized
(in a sense, less widely used) systems. Anslyn and co-workers have developed a
circular dichroism-based host-guest system to determine the ee of vicinal diols,
α-hydroxyacids, vicinal diamines, cyclohexanones, amines, α-chiral aldehydes,
carboxylates, amino acids and secondary alcohols within Æ7% or lower average
error (Fig. 7a) [35]. For chiral amines and amino acids, a few other methods have
been developed to analyse their ee values [36] such as the use of nuclear magnetic
resonance (NMR) and fluorescence detection of chiral boronate and amine assembly
by Anzenbacher (Fig. 7b) [37],
19 F NMR probing of a chiral palladium pincer
complex with chiral amines developed by Zhao and Swager [38] (Fig. 7c) while a
DNA biosensor to detect the chiral amino acid derivative tyrosinamide developed by
Heemstra (Fig. 7d) [39].
Despite the early promise of HTS approaches for chiral catalyst discovery, some
drawbacks remain. Firstly, specialized tools or chemical systems are often required
for screening and analysis. Secondly, there is no guarantee that screening will yield
162
R. Ardkhean et al.