Alkyl sulfinates as cross-coupling partners for programmable and stereospecific installation of C(sp(3)) bioisosteres

In recent years, a variety of cycloalkyl groups with quaternary carbons, in particular cyclopropyl and cyclobutyl trifluoromethyl groups, have emerged as promising bioisosteres in drug-like molecules. The modular installation of such bioisosteres remains challenging to synthetic chemists. Alkyl sulf...

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Published inNature chemistry Vol. 15; no. 4; pp. 550 - 559
Main Authors Zhou, Min, Tsien, Jet, Dykstra, Ryan, Hughes, Jonathan M. E., Peters, Byron K., Merchant, Rohan R., Gutierrez, Osvaldo, Qin, Tian
Format Journal Article
LanguageEnglish
Published BERLIN NATURE PORTFOLIO 01.04.2023
Nature Publishing Group
Subjects
Aromatic compounds
Biochemistry
Chemical reactions
Chemistry
Chemistry, Multidisciplinary
Coupling (molecular)
Cross coupling
Installation
Ligands
Optimization
Organic compounds
Pharmaceutical sciences
Physical Sciences
Reagents
Regioselectivity
Scaffolds
Science & Technology
Solvation
Sulfur
Tetrahydrofuran
SIGMA-SULFURANE
ENANTIOSELECTIVE SYNTHESIS
2-PYRIDYL SULFOXIDE
CONVENIENT PREPARATION
CONFIGURATION
ARYL
LIGAND
GRIGNARD-REAGENTS
COMPLETE RETENTION
ORGANOLITHIUMS
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Summary:In recent years, a variety of cycloalkyl groups with quaternary carbons, in particular cyclopropyl and cyclobutyl trifluoromethyl groups, have emerged as promising bioisosteres in drug-like molecules. The modular installation of such bioisosteres remains challenging to synthetic chemists. Alkyl sulfinate reagents have been developed as radical precursors to prepare functionalized heterocycles with the desired alkyl bioisosteres. However, the innate (radical) reactivity of this transformation poses reactivity and regioselectivity challenges for the functionalization of any aromatic or heteroaromatic scaffold. Here we showcase the ability of alkyl sulfinates to engage in sulfurane-mediated C(sp(3))-C(sp(2)) cross-coupling, thereby allowing for programmable and stereospecific installation of these alkyl bioisosteres. The ability of this method to simplify retrosynthetic analysis is exemplified by the improved synthesis of multiple medicinally relevant scaffolds. Experimental studies and theoretical calculations for the mechanism of this sulfur chemistry reveal a ligand-coupling trend under alkyl Grignard activation via the sulfurane intermediate, stabilized by solvation of tetrahydrofuran.
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M.Z., J.T. and T.Q. performed experiments. R.D. and O.G. performed DFT theoretical studies. J.M.E.H., B.K.P., R.R.M. and T.Q. designed and supervised the project; M.Z., J.T., R.D., J.M.E.H., B.K.P., R.R.M., O.G. and T.Q. wrote the paper.
Author contributions
ISSN:1755-4330
1755-4349
DOI:10.1038/s41557-023-01150-z