Design and Synthesis of a Series of Novel Macrocycle Janus Kinase 2 Inhibitors

Wang, Yanling; Ge, Huan; Wang, Disha; He, Huan; Lü, Li; Diao, Yanyan; Shen, Zihao; Zhu, Lili; Li, Shiliang; Zhao, Zhenjiang; Li, Honglin

doi:10.1002/cjoc.201900316

Cited by 3 publications

(4 citation statements)

References 21 publications

(22 reference statements)

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“…Wang et al used this kind of reaction for the synthesis of 38 by using tris(dibenzylideneacetone)dipalladium(0) as a catalyst and Xantphos as an ligand (Scheme ). The desired product was isolated with a yield of 28% …”

Section: Macrocyclization Reactionsmentioning

confidence: 99%

“… a Example for a macrocyclization through A, Suzuki reaction; B, Heck reaction; C, Buchwald-Hartwig amination …”

Section: Macrocyclization Reactionsmentioning

confidence: 99%

“…The desired product was isolated with a yield of 28%. 82 As already mentioned above, the mean yields for the Suzuki coupling were quite low. The reason for this unsatisfying yield was probably due to a strategy in which the boronic acid was generated in situ and a potential improvement could be separating the introduction of the boronic acid and the crosscoupling step.…”

Section: Collins Et Al Established the Macrocyclization Efficiency Indexmentioning

confidence: 99%

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Synthetic Opportunities and Challenges for Macrocyclic Kinase Inhibitors

2021

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Macrocycles are typically cyclic variants of inhibitors derived from uncyclized canonical molecules or from natural products. For medicinal chemistry, drug-like macrocycles have received increasing interest over the past few years, since it has been demonstrated that macrocyclization can favorably alter the biological and physiochemical properties as well as selectivity in comparison to the acyclic analogue. Recent drug approvals such as Lorlatinib, glecaprevir, or voxilaprevir underline the clinical relevance of drug-like macrocycles. However, the synthesis of drug-like macrocycles can be challenging, since the ring-closing reaction is generally challenging with yields depending on the size and geometry of the bridging linker. Nevertheless, macrocycles are one opportunity to expand the synthetic toolbox for medicinal chemistry to provide bioactive molecules. Therefore, we reviewed the past literature of drug-like macrocycles highlighting reactions that have been successfully used for the macrocyclization. We classified the cyclization reactions by their type, ring-size, yield, and macrocyclization efficiency index.

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Section: Macrocyclization Reactionsmentioning

confidence: 99%

“… a Example for a macrocyclization through A, Suzuki reaction; B, Heck reaction; C, Buchwald-Hartwig amination …”

Section: Macrocyclization Reactionsmentioning

confidence: 99%

Section: Collins Et Al Established the Macrocyclization Efficiency Indexmentioning

confidence: 99%

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Synthetic Opportunities and Challenges for Macrocyclic Kinase Inhibitors

2021

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“…[ 16 ] However, the synthesis of macrocyclic compounds is generally full of challenges. [ 17 ] It is inevitable to considerate the competition of forming the linear products during the macromolecular cyclization. One effective strategy is to decrease the concentration of substrates to make the intramolecular cyclization efficiency more advantageous in the competition with the intermolecular reaction.…”

Section: Background and Originality Contentmentioning

confidence: 99%

Synthesis of Donor‐Acceptor π‐Conjugated Macrocycles by Post‐Functionalization^†

2021

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Main observation and conclusion In this paper, two novel donor‐acceptor (D‐A) macrocyclic compounds 5 and 7 were successfully synthesized by post‐functionalization of a planar dimer macrocycle (1) and a highly twisted trimer macrocycle (2), respectively, via controllable oxidation of methoxy groups and condensation between diketones and phenylenediamine in succession. Compared with unembellished 9,10‐dimethoxyphenanthrene, the resultant dibenzo[a,c]phenazine motif is electron‐deficient rather than electron‐rich, yielding two D‐A π‐conjugated macrocycles with more contractive energy gaps. Density functional theory (DFT) calculations further support the unequivocal evidence of the D‐A properties of macrocycles 5 and 7. The difference of their photophysical properties was investigated by the aid of ultraviolet‐visible absorption and fluorescence spectrophotometers. Furthermore, the stacking patterns of 7 and its contrast π‐conjugated macrocycle trimer (2) were compared via the analysis of X‐ray single crystal, in which the electron‐deficient dibenzo[a,c]phenazine unit provides extra interaction sites, resulting in orderly arrangement of 7 in the solid state.

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