Transition-Metal-Free Synthesis of Ynol Ethers and Thioynol Ethers via Displacement at sp Centers: A Revised Mechanistic Pathway

Gray, Vincent James; Cuthbertson, James D.; Wilden, Jonathan D.

doi:10.1021/jo500814y

Cited by 25 publications

(14 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1). The Michael addition reaction of thiols in peptides with compounds containing a carbon-carbon triple bond has been demonstrated previously (39,40). This suggests that PES and its derivates could react with thiol groups within proteins.…”

Section: Introductionmentioning

confidence: 76%

PES inhibits human-inducible Hsp70 by covalent targeting of cysteine residues in the substrate-binding domain

Yang

Gong

et al. 2021

Journal of Biological Chemistry

View full text Add to dashboard Cite

Hsp70 proteins are a family of ancient and conserved chaperones. They play important roles in vital cellular processes, such as protein quality control and the stress response. Hsp70 proteins are a potential drug target for treatment of disease, particularly cancer. PES (2-phenylethynesulfonamide or pifithrin-μ) has been reported to be an inhibitor of Hsp70. However, the mechanism of PES inhibition is still unclear. In this study we found that PES can undergo a Michael addition reaction with Cys-574 and Cys-603 in the SBDα of human HspA1A (hHsp70), resulting in covalent attachment of a PES molecule to each Cys residue. We previously showed that glutathionylation of Cys-574 and Cys-603 affects the structure and function of hHsp70. In this study, PES modification showed similar structural and functional effects on hHsp70 to glutathionylation. Further, we found that susceptibility to PES modification is influenced by changes in the conformational dynamics of the SBDα, such as are induced by interaction with adjacent domains, allosteric changes, and mutations. This study provides new avenues for development of covalent inhibitors of hHsp70.

show abstract

Section: Introductionmentioning

confidence: 76%

PES inhibits human-inducible Hsp70 by covalent targeting of cysteine residues in the substrate-binding domain

Yang

Gong

et al. 2021

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Therefore, phenylacetylenes substituted at the alkyne group were investigated experimentally . They are easy to handle at room temperature and there are simple methods available for their synthesis . To select which substituent at the triple bond is most effective, one can look at Figure , in which the results of B2LYPD/6–31G* calculations on the 1,1′ and 2,2′ dimerizations of 78·78 to give the diradicals 80 and the dicarbenes 81′ are compared .…”

Section: Resultsmentioning

confidence: 99%

Cyclic Compounds Incorporating Two or Four Alkyne Units in Close Proximity – Theory and Experiments

Gleiter

Haberhauer

2018

Eur J Org Chem

View full text Add to dashboard Cite

In the first part we summarize the results of experiments performed with medium‐sized cyclic compounds (10, 12, 14 ring size) incorporating either two opposite acetylene units or two buta‐1,3‐diyne units. The acetylene units in the 10‐membered rings react either thermally or with the aid of AuI catalysis to afford bicyclo[4.4.0]‐1,6‐diene rings. Reduction with H2/Pd or addition of I2 to 12‐membered rings containing two opposite buta‐1,3‐diyne units yield 5–6–5 cycles, whereas 14‐membered rings react with HCl to afford 5–8–5 or 6–6–6 rings. In the second part we discuss the results of calculations relating to 1,6‐transannular ring closure of cyclodeca‐1,6‐diyne derivatives in which the two triple bonds are each flanked either with two oxygen atoms or with two NH groups. For the resulting heterocycles, dicarbenes with singlet ground states are predicted. The extension of these model calculations led us to look at substituted phenylacetylenes (e.g., Ph–C≡C–OMe) for which dimerization to cyclobutadiene derivatives was predicted. This forecast could be verified by trapping the cyclobutadiene products with maleic acid.

show abstract

“…By generated potassium alkoxides in situ, the group also showed that a range of primary and secondary alcohols could be used to synthesise ynol ethers with greater scope (Scheme 2.7). 11 In this instance it was found that employing dimethylamine in THF was of great benefit as the reaction was complete in a matter of minutes.…”

Section: Scheme 26mentioning

confidence: 94%

The chemistry of ynol and thioynol ethers

Gray

Wilden

2016

Org. Biomol. Chem.

Self Cite

View full text Add to dashboard Cite

Alkynyl ethers and alkynyl thioethers ('ynol ethers' and 'thioynol ethers') are appealing building-blocks in synthetic chemistry due to their ease of manipulation and predictable reactivity. Until recently however, their potential has remained underexploited due to difficulties in preparation and isolation. Although recent advances in synthetic chemistry have highlighted various applications for ynol ethers, the equivalent thioynol examples have been rather less exploited despite a unique and fascinating reactivity profile. Although superficially the chemistry of alkynyl ethers and their sulfide counterparts are similar, close examination of their chemistry reveals important differences which can be exploited by the synthetic chemist. This review will examine the preparation of both classes of compound and examine their reactivity to highlight their powerful synthetic applications. Particular focus will be made of thiynol ethers whose chemistry exhibits some fascinating differences compared to their oxygen counterparts and have immense untapped potential for synthetic chemistry.

show abstract

Transition-Metal-Free Synthesis of Ynol Ethers and Thioynol Ethers via Displacement at sp Centers: A Revised Mechanistic Pathway

Cited by 25 publications

References 20 publications

PES inhibits human-inducible Hsp70 by covalent targeting of cysteine residues in the substrate-binding domain

PES inhibits human-inducible Hsp70 by covalent targeting of cysteine residues in the substrate-binding domain

Cyclic Compounds Incorporating Two or Four Alkyne Units in Close Proximity – Theory and Experiments

The chemistry of ynol and thioynol ethers

Contact Info

Product

Resources

About