Asymmetric Transfer Hydrogenation of gem‐Difluorocyclopropenyl Esters: Access to Enantioenriched gem‐Difluorocyclopropanes

Abstract

Catalytic enantioselective access to disubstituted functionalized gem-difluorocyclopropanes, which are emerging fluorinated motifs of interest in medicinal chemistry, was achieved through asymmetric transfer hydrogenation of gemdifluorocyclopropenyl esters, catalyzed by a Noyori-Ikariya (p-cymene)-ruthenium(II) complex, with (N-tosyl-1,2-diphenylethylenediamine) as the chiral ligand and isopropanol as the hydrogen donor. The resulting cis-gem-difluorocyclopropyl esters were obtained with moderate to high enantioselectivity (ee = 66-99 %), and post-functionalization reactions enable access to valuable building blocks incorporating a cis-or transgem-difluorocyclopropyl motif.

Recent Advances in Ru Catalyzed Transfer Hydrogenation and Its Future Perspectives

“…The presence of labile ancillary ligands also participates in enhancement of efficient TH capabilities. Additionally, these robust catalysts showed exceptionally good conversion of the ketones to the reduced products (14)(15)(16)(17)(18) in comparison with the commercially available [Ru(p-cymene) Cl 2 ] 2 and the "Hoveyda-Grubbs" catalysts, under identical catalytic conditions.…”

“…However, ent-47 under the kinetically controlled conditions and with proton transfer from the less hindered face at C1 yielded ent-48. The synthetic applications of these difluorocyclopropane was investigated further for the formation of a variety of nitrogen heterocycles as future building blocks in medicinal chemistry [15]. In-depth study of the pyrazole/phosphine-supported ruthenium complex in TH of olefins and alkynes under semi-hydrogenation conditions resulted in unusual Eselectivity.…”

The preparation and properties of 1,1-difluorocyclopropane derivatives

“…Although gem -difluorocyclopropanes contain a strained ring, they are kinetically stable under the conditions employed for many synthetically important reactions. These include the catalytic hydrogenolysis of benzyl ethers (H 2 , Pd) [ 72 ], DIBAL-H reduction of esters to form alcohols [ 73 ], oxidative cleavage of vinyl groups to form carboxylic acids (KMnO 4 ) [ 74 ], and the conversion of the acids into amines using the Curtius rearrangement (SOCl 2 , followed by Me 3 SiN 3 , thermolysis, and acid hydrolysis of the intermediate isocyanate, Scheme 29 ) [ 74 ]. Such transformations proceed with the conservation of the difluorocyclopropane unit and complement the methods for the cyclopropyl-ring synthesis discussed in the previous sections.…”

“…Consequently, the enantioselective functional group interconversions on prochiral or racemic difluorocyclopropane and difluorocyclopropene derivatives have provided important ways of obtaining enantiomerically pure cyclopropanes. The key reactions in this context are the enzyme-catalyzed formation and hydrolysis of esters and the hydrogenation of difluorocyclopropenes [ 73 , 79 ].…”

“…Cossy and co-workers have achieved the catalytic asymmetric transfer hydrogenation with isopropanol as reductant, in conjunction with a Noyori–Ikariya ruthenium-based homogeneous catalyst ( Scheme 36 ) [ 73 ].…”