Regioselective routes to orthogonally-substituted aromatic MIDA boronates

Close, Adam J.; Kemmitt, Paul D.; Roe, S. Mark; Spencer, John

doi:10.1039/c6ob01141a

Cited by 19 publications

(8 citation statements)

References 33 publications

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“…For example, many standard oxidations (Figure 5a), reductions (Figure 5b), and protecting group manipulations (Figure 5c) are well-tolerated. 145–151 Numerous other common synthetic transformations leave MIDA boronates intact, including aldol reactions, 145 carbonyl olefination reactions, 145 Mitsunobu reactions, 145 electrophilic substitution reactions, 149, 152 hydroborations and –stannylations, 151 Diels Alder cycloadditions (Figure 5j), 151, 153 and cyclopropanations. 147 A variety of transition metal-catalyzed reactions are also well-tolerated (Figure 5g), including Heck reactions, 147, 154 Grubbs metathesis, 147 Sonagashira couplings, 151 and Suzuki cross-couplings.…”

Section: Advances Towards a General Platform For Iterative Small Molementioning

confidence: 99%

Towards the generalized iterative synthesis of small molecules

2018

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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.

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Section: Advances Towards a General Platform For Iterative Small Molementioning

confidence: 99%

Towards the generalized iterative synthesis of small molecules

2018

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“…There are numerous examples of generating boronate esters from boronic acids and MIDA described in the literature. − A traditional method is to perform the reaction in a toluene/DMSO mixture at reflux in order to solubilize the MIDA and in which the water formed as a byproduct is azeotropically distilled off. The derivatization reaction described here looks to perform the reaction in only DMSO without the need to remove the water byproduct via glassware setup, i.e.…”

Section: Methodsmentioning

confidence: 99%

Trace Level Quantification of Derivatized Boronic Acids by LC/MS/MS

Baldwin

North

Eisenbeis

2019

Org. Process Res. Dev.

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Boron-containing compounds are often controlled as potentially mutagenic impurities based on ICH M7 guidance in drug substances. Herein, we describe a simple method to derivatize a subset of organoborons, non-nitrogencontaining aryl boronic acids, in order to quantify trace levels remaining in a drug substance using LC/MS/MS. Through this derivatization we are able to increase the sensitivity, demonstrate linearity, and spiked analyte recovery in matrix down to low parts per million (ppm) levels. The feasibility of this method is proven as three different examples are described, two in which one boronic acid may be present in a drug substance and one where two boronic acids may be present in the final product.

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“…6 We have recently reported procedures for forming poylsubstituted aromatics, mainly based on a MIDA boronatesubstituted aryl scaffold. 7,8 Our aim was to synthesise analogues of the type I and II ( Fig. 3) as useful 1,2,3,4-and 1,2,4,5substituted building blocks.…”

Section: Introductionmentioning

confidence: 99%

Elaboration of tetra-orthogonally-substituted aromatic scaffolds towards novel EGFR-kinase inhibitors

Jones

Ocasio

et al. 2016

Org. Biomol. Chem.

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Nitration of three regioisomers of bromo-fluorobenzaldehyde proceeds regioselectively, notably with H2SO4/HNO3 at 0 °C. The thereby synthesized tetrasubstituted aromatics, endowed with orthogonal substituents, can be elaborated via Pd-catalysed coupling, reduction and reductive amination reactions. As a test-case, these compounds were converted into EGFR inhibitors related to Gefitinib, whose activity was rationalised by docking studies.

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Regioselective routes to orthogonally-substituted aromatic MIDA boronates

Cited by 19 publications

References 33 publications

Towards the generalized iterative synthesis of small molecules

Towards the generalized iterative synthesis of small molecules

Trace Level Quantification of Derivatized Boronic Acids by LC/MS/MS

Elaboration of tetra-orthogonally-substituted aromatic scaffolds towards novel EGFR-kinase inhibitors

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