Enantioselective Construction of Tertiary Fluoride Stereocenters by Organocatalytic Fluorocyclization.

Qiang Wang,Fahmi Himo,Kálmán J Szabó,Lars Eriksson,Martin Hedberg,Marvin Lübcke,Maria Biosca

doi:10.1021/jacs.0c09323

Qiang Wang, Fahmi Himo + Show 5 more

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https://doi.org/10.1021/jacs.0c09323

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Abstract

1,1-Disubstituted styrenes with internal oxygen and nitrogen nucleophiles undergo oxidative fluorocyclization reactions with in situ generated chiral iodine(III)-catalysts. The resulting fluorinated tetrahydrofurans and pyrrolidines contain a tertiary carbon–fluorine stereocenter. Application of a new 1-naphthyllactic acid-based iodine(III)-catalyst allows the control of tertiary carbon–fluorine stereocenters with up to 96% ee. Density functional theory calculations are performed to investigate the details of the mechanism and the factors governing the stereoselectivity of the reaction.

Highlights

Carbon−fluorine bonds frequently occur in drug substances, agrochemicals, and substances used for medical diagnostics.[1−3] The predominant structures are aryl fluorides and trifluoromethylated arenes.[4,5] In contrast, alkyl fluoride motifs are far less abundant in small molecules relevant for life sciences
Recent studies have highlighted the beneficial properties of alkyl fluorides for the modification of molecular conformation, polarity, acid−base properties, and electronic interactions based on gauche/anomeric effects.[6−14] There are a few examples of marketed alkyl fluoride drugs, such as macrolide antibiotics solithromycin, fluticasone, and sofosbuvir, which are used for treatment of asthma and hepatitis C (Figure 1a).[4]
We have developed a new method for the synthesis of chiral tetrahydrofurans and pyrrolidines with endocyclic tertiary C−F stereocenters

Summary

■ INTRODUCTION

Carbon−fluorine bonds frequently occur in drug substances, agrochemicals, and substances used for medical diagnostics.[1−3] The predominant structures are aryl fluorides and trifluoromethylated arenes.[4,5] In contrast, alkyl fluoride motifs are far less abundant in small molecules relevant for life sciences. Enantioselective construction of tertiary fluorides is considered to be challenging but relevant for drug design (Figure 1a) and for modern synthetic methodology development.[15] many excellent techniques were reported for the synthesis of these species,[41−51] relatively few methods are based on hypervalent iodine reagents.[32,37,38,52−54] Jacobsen and co-workers presented studies on asymmetric aziridination[38] and 1,2difluorination reactions[32,37] (Figure 1b) leading to tertiary fluorides. The reactivity and selectivity in these types of fluorocyclization reactions have been unexplored

■ RESULTS AND DISCUSSION

■ CONCLUSIONS

■ ACKNOWLEDGMENTS

■ REFERENCES