Dynamic Kinetic Resolution-Enabled Highly Stereoselective Nucleophilic Fluoroalkylation to Access Chiral β-Fluoro Amines

Abstract

β-Fluorinated amine is highly desirable for biological and pharmaceutical science, because replacing a C–H bond with a C–F bond can change the physical and chemical properties of the parent molecule to a large extent but not significantly alter its overall geometry. Herein, the highly stereoselective nucleophilic monofluoromethylation of imines have been developed. It is proposed that the chelated transition state enables the chiral induction by the dynamic kinetic resolution of the chiral α-fluoro carbanions.

Reagent-Controlled Highly Stereoselective Difluoromethylation: Efficient Access to Chiral α-Difluoromethylamines from Ketimines

“…Although 5i , 5j and 5k were parallel with the previous preliminary results [ 20 ], the process for the corresponding HCF 2 -products is vague. To obtain the difluoromethylation products, 5b could undergo deprotection of the silyl group with aqueous acid to yield NH- 6b in full conversion.…”

“…To obtain the difluoromethylation products, 5b could undergo deprotection of the silyl group with aqueous acid to yield NH- 6b in full conversion. The absolute configuration of 6b was reported by our group [ 20 ], and those of the others were assigned by analog. The process of a reductive alkyl C-S bond cleavage with magnesium and an N-S bond cleavage with triflic acid could afford 7b in 69% overall yield ( Scheme 2 ), which implied the products could be modified diversely, and provided the possibility of accessing chiral amine derivatives, especially those molecules with bioactivities.…”

“…In addition, the possible kinetic interpretation of the reaction with enamidation substrates was proposed [ 24 , 25 ]. The nucleophilic addition of monofluoromethyl phenyl sulfoximine to ketimines requires the preproduction of PhSO(NTBS)CHF − [ 20 , 26 ], while the version of difluoromethyl phenyl sulfoximine was achieved in high yield and stereoselectivity by in situ production of PhSO(NTBS)CF 2 − in the presence of strong bases. We analyzed the possible reaction process in the system, and it was summarized in Scheme 3 b.…”

“…For instance, Hu group reported the stereoselective addition reaction between tert -butyl sulfinyl protected imines and phenyl difluoromethyl sulfone or TMSCF 2 H to generate the enantiomerically enriched α-difluoromethyl amine [ 14 , 15 ] (shown in Figure 1 C(i)), which served as an example of substrate-controlled Mannich addition. Recently, we have been devoted to the development of nucleophilic fluoroalkylation by using fluoroalkyl sulfoximine reagents [ 16 , 17 , 18 , 19 , 20 ]. In this context, we were interested in developing a reagent-controlled stereoselective Mannich reaction instead of a substrate-controlled version [ 21 , 22 , 23 ].…”

Synthesis of Pyrazolesulfoximines Using α-Diazosulfoximines with Alkynes

“…N-Boc and N-TBDPS derivatives 1a and 2a were carried through an acetylation and diazo transfer sequence (Scheme ). Deprotonation of the methylsulfoximines with lithium amide bases and quenching with ethyl acetate gave β-ketosulfoximines 3a and 4a . Installation of the diazo group by a Regitz diazo transfer required different conditions dependent on the N-substituent.…”