From the start of a synthetic chemist’s training,
experiments
are conducted based on recipes from textbooks and manuscripts that
achieve clean reaction outcomes, allowing the scientist to develop
practical skills and some chemical intuition. This procedure is often
kept long into a researcher’s career, as new recipes are developed
based on similar reaction protocols, and intuition-guided deviations
are conducted through learning from failed experiments. However, when
attempting to understand chemical systems of interest, it has been
shown that model-based, algorithm-based, and miniaturized high-throughput
techniques outperform human chemical intuition and achieve reaction
optimization in a much more time- and material-efficient manner; this
is covered in detail in this paper. As many synthetic chemists are
not exposed to these techniques in undergraduate teaching, this leads
to a disproportionate number of scientists that wish to optimize their
reactions but are unable to use these methodologies or are simply
unaware of their existence. This review highlights the basics, and
the cutting-edge, of modern chemical reaction optimization as well
as its relation to process scale-up and can thereby serve as a reference
for inspired scientists for each of these techniques, detailing several
of their respective applications.
A nanogram-to-gram workflow has been established for the identification and development of synthetic transformations which are enabling in Fragment-Based Drug Discovery (FBDD). In this study, we disclose a method for the synthesis of privileged sp2–sp3 architectures via direct cross-dehydrogenative coupling of heterocycles.
A combined experimental and computational investigation on the Ag-catalysed decarboxylation of benzoic acids is reported herein. The present study demonstrates that a substituent at the ortho position exerts dual effects in the decarboxylation event. On one hand, ortho-substituted benzoic acids are inherently destabilised starting materials compared to their meta- and para-substituted counterparts. On the other hand, the presence of an ortho-electron-withdrawing group results in an additional stabilisation of the transition state. The combination of both effects results in an overall reduction of the activation energy barrier associated with the decarboxylation event. Furthermore, the Fujita-Nishioka linear free energy relationship model indicates that steric bulk of the substituent can also exert a negative effect by destabilising the transition state of decarboxylation.
A visible-light-mediated photocatalytic umpolung synthesis of 1,3-diamines from in situ-generated imines and dehydroalanine derivatives is described. Pivoting on a key nucleophilic addition of photocatalytically generated α-amino radicals to electron-deficient alkenes, this three-component coupling reaction affords 1,3-diamines efficiently and diastereoselectively. The mild protocol tolerates a wide variety of functionalities including heterocycles, pinacol boronates, and aliphatic chains. Application to biologically relevant α-amino-γ-lactam synthesis and extension to 1,3-aminoalcohols is also demonstrated.
An in depth meta analysis of 131 fragment-to-lead case-studies has shown the importance of synthetic methods that allow carbon-centred synthetic elaboration in the presence of polar pharmacophores.
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