Abstract:The Suzuki–Miyaura cross-coupling is one of the most often utilized reactions in the synthesis of pharmaceutical compounds and conjugated materials. In its most common form, the reaction joins two sp2-functionalized carbon atoms to make a biaryl or diene/polyene unit. These substructures are widely found in natural products and small molecules and thus the Suzuki–Miyaura cross-coupling has been proposed as the key reaction for the automated assembly of such molecules, using protecting group chemistry to affect… Show more
“…Simple filtration through silica gel enabled a Csp 3 cross coupling of the remaining secondary boronic acid in the presence of Ag 2 O, creating a defined polyarylated structure. 115 …”
Section: Many Customized Iterative Synthesis Methods Have Already Beementioning
Small molecules have extensive untapped potential to benefit society, but access to this potential is too often restricted by limitations inherent to the customized approach currently used to synthesize this class of chemical matter. In contrast, the “building block approach”, i.e., generalized iterative assembly of interchangeable parts, has now proven to be a highly efficient and flexible way to construct things ranging all the way from skyscrapers to macromolecules to artificial intelligence algorithms. The structural redundancy found in many small molecules suggests that they possess a similar capacity for generalized building block-based construction. It is also encouraging that many customized iterative synthesis methods have been developed that improve access to specific classes of small molecules. There has also been substantial recent progress toward the iterative assembly of many different types of small molecules, including complex natural products, pharmaceuticals, biological probes, and materials, using common building blocks and coupling chemistry. Collectively, these advances suggest that a generalized building block approach for small molecule synthesis may be within reach.
“…Simple filtration through silica gel enabled a Csp 3 cross coupling of the remaining secondary boronic acid in the presence of Ag 2 O, creating a defined polyarylated structure. 115 …”
Section: Many Customized Iterative Synthesis Methods Have Already Beementioning
Small molecules have extensive untapped potential to benefit society, but access to this potential is too often restricted by limitations inherent to the customized approach currently used to synthesize this class of chemical matter. In contrast, the “building block approach”, i.e., generalized iterative assembly of interchangeable parts, has now proven to be a highly efficient and flexible way to construct things ranging all the way from skyscrapers to macromolecules to artificial intelligence algorithms. The structural redundancy found in many small molecules suggests that they possess a similar capacity for generalized building block-based construction. It is also encouraging that many customized iterative synthesis methods have been developed that improve access to specific classes of small molecules. There has also been substantial recent progress toward the iterative assembly of many different types of small molecules, including complex natural products, pharmaceuticals, biological probes, and materials, using common building blocks and coupling chemistry. Collectively, these advances suggest that a generalized building block approach for small molecule synthesis may be within reach.
“…[2] In this context, the oxidative addition step is generally selectivity-controlling. [8] As such, ag eneral and predictive coupling protocol would be highly desired, particularly if paired with operational simplicity. [2,3] Fore xample,w hile [PdCl 2 {P(o-tol) 3 } 2 ]-catalyzed Kumada coupling of A gave selective C À Br functionalization, the introduction of two methyl groups ortho to C À Br (B)d iminished selectivities,t hus resulting in mixtures under otherwise identical reaction conditions ( Figure 1).…”
While chemoselectivities in Pd 0 -catalyzed coupling reactions are frequently non-intuitive and aresult of acomplex interplay of ligand/catalyst, substrate,and reaction conditions, we herein report ageneral method based on Pd I that allows for an apriori predictable chemoselective C sp 2 À C sp 2 coupling at C À Br in preference to C À OTfand C À Cl bonds,regardless of the electronic or steric bias of the substrate.T he C À Cb ond formations are extremely rapid (< 5min at RT)a nd are catalyzedbyanair-and moisture-stable Pd I dimer under openflask conditions.
“…After a filtration through a small silica plug and the last coupling step, triarylated product 53 could be isolated in 32% overall yield (over 70% per cross-coupling step) (Scheme 49) [93].
…”
Section: Regio- and Chemoselectivity At The Nucleophilic Coupling Parmentioning
Sequential and iterative Pd-catalyzed cross-coupling reactions can be performed in which the order of C–C bond formations can be controlled either by the attenuated leaving groups of the multireactive substrate or by specific catalyst/ligand combinations. This tutorial review gives an overview about recent developments in this field and the various strategies used for the assembly of oligoarenes and -alkenes.Graphical abstract
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