Synthesis of Chiral Nonracemic α-Difluoromethylthio Compounds with Tetrasubstituted Stereogenic Centers via a Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation

Abstract

The synthesis of chiral, nonracemic difluoromethylthio (SCF 2 H) compounds that contain a tetrasubstituted stereogenic center is reported. Racemic α-SCF 2 H-β-ketoallylesters 5 were initially prepared by an electrophilic difluoromethylthiolation of β-ketoallylesters 6, followed by a Pd-catalyzed Tsuji decarboxylative asymmetric allylic alkylation (DAAA) to provide a wide variety of chiral, nonracemic α-allyl-α-SCF 2 H-ketones (4) with high enantiopurity. This strategy can be extended to the enantioselective synthesis of chiral, nonracemic α-allyl-α-trifluoromethylthio(SCF 3 )-ketones (7).

Asymmetric Electrophilic Difluoromethylthiolation of Indanone-Based β-Keto Esters Using Difluoromethanesulfonyl Hypervalent Iodonium Ylides

“…Methyl 2-((difluoromethyl)thio)-6-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate ( 3a ) [23,24,25]. Yellow oil (24.2 mg, 45%, 88% ee).…”

“…The synthesis of enantioenriched molecules featuring a SCF 2 R motif directly linked to the chiral center is an issue worth consideration in the context of designing new chiral drugs. Asymmetric synthesis of trifluoromethylthiolated compounds have been investigated [6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22], and very recently Shibata and co-workers published the asymmetric synthesis of α-tri- and difluoromethylthio allyl ketones via electrophilic difluoromethylthiolation of β-keto esters using difluoromethanesulfonyl hypervalent iodonium ylide 1a followed by a Pd-catalyzed Tsuji decarboxylative asymmetric allylic alkylation (DAAA, Scheme 1a) [23]. However, there is no report describing the asymmetric synthesis of difluoromethylthio compounds via a direct difluoro- methylthiolation reaction.…”

Asymmetric Difluoromethylthiolation of Carbon Nucleophiles with Optically Pure Difluoromethylthiolating Reagents Derived from Camphorsultam

“…Over the past few years, several difluoromethylthiolating reagents 1 — 8 have been developed (Figure ), thus allowing efficient construction of C(sp 2 )‐ SCF 2 H and C(sp 3 )‐SCF 2 H bonds under mild conditions. Nevertheless, few methods that can stereoselectively build chiral carbon center bearing a SCF 2 H group have been reported . To the best of our knowledge, only two such transformations have been described previously, both by Shibata and coworkers.…”

Enantioselective Benzylation and Allylation of α-Trifluoromethoxy Indanones under Phase-Transfer Catalysis

“…Later, Shen and co-workers reported a method to construct chiral trifluoromethoxyl compounds by the Ni-catalyzed enantioselective Suzuki–Miyaura coupling of secondary benzyl bromides in good to high enantioselectivity (Scheme 1b) [44]. We developed a strategy for the synthesis of chiral, non-racemic α-OCF 3 -ketones with a tetrasubstituted carbon center via a Pd-catalyzed enantioselective Tsuji-allylation reaction with high enantioselectivity (Scheme 1c) [45,46]. Very recently, Liu and co-workers reported the Pd-catalyzed enantioselective intramolecular trifluoromethoxylation reaction of alkenes using CsOCF 3 to furnish OCF 3 -compounds with a chiral stereogenic center (Scheme 1d) [47].…”