Achiral Trisubstituted Thioureas as Secondary Ligands to Cu^I Catalysts: Direct Catalytic Asymmetric Addition of α‐Fluoronitriles to Imines

Abstract

Thioureas have emerged as effective hydrogen‐bonding catalysts over the last two decades, and they are broadly utilized in asymmetric catalysis. We report that achiral trisubstituted thioureas function as beneficial secondary ligands to CuI catalysts, thereby enabling highly diastereo‐ and enantioselective addition of α‐fluoronitriles to imines. The structure of the thiourea significantly affects the reaction outcome, and kinetic experiments indicate that the thioureas enhance the stereocontrol by binding to the CuI complex. The reaction products can be readily transformed into valuable β‐amino acid derivatives bearing a fluorinated tetrasubstituted stereogenic center.

Direct Catalytic Asymmetric Addition of α‐Fluoronitriles to Aldehydes

“… [8] In our continuing efforts to develop the reaction based on in situ‐generated α‐cyanocarbanions, we documented that α‐fluoronitriles are complementary pronucleophiles for the addition of activated imines to provide acyclic scaffolds with a tetrasubstituted fluorine‐containing stereogenic center (Scheme 1 c). [9] Although a similar strategy was later adopted by Wolf et al. using α‐fluoronitriles and activated imines derived from oxindoles to deliver highly congested substructures, [10] construction of the corresponding α‐fluoro‐β‐hydroxyl analogs using aldehydes instead of imines as electrophiles remained an unmet challenge.…”

Recent Advances in Catalytic Enantioselective Synthesis of Fluorinated α‐ and β‐Amino Acids

“…Recently, the Shibasaki group accomplished a highly stereoselective direct addition of α‐fluoronitriles 138 to N ‐diphenylphosphinoyl ( N ‐Dpp) aldimines 139 by using a soft Lewis acid/thiourea/Brønsted base cooperative catalysis (Scheme 31). [80] A combination of 5 mol% [Cu(CH 3 CN) 4 ]PF 6 ligated chiral diphosphine 126 with 6 mol% achiral trisubstituted thiourea 140 was identified to be effective catalytic system and afforded the desired α‐fluoro‐β‐amino nitriles 141 featuring a fluorine‐containing tetrasubstituted stereocenter in up to 99% yield, >20:1 dr and 99% ee. Control experiment demonstrated that the addition of thiourea was indispensable for achieving high diastereoselectivity, and the thiourea structure greatly affected the yield and diastereoselectivity.…”

Recent Progress in the Asymmetric Syntheses of α‐Heterofunctionalized (Masked) α‐ and β‐Amino Acid Derivatives

“…Given the power of asymmetric organo‐ and transition metal‐catalysis to accomplish a multitude of asymmetric C–C‐bond forming reactions, it comes as no surprise that such methods have also been heavily exploited to access chiral β‐AA derivatives. [ 33–42 ]…”

“…[ 35 ] Very recently, the same group also succeeded in engaging simple α‐fluoro nitriles 63 for Mannich reactions, giving the nitriles 64 which could then be converted into the free α‐F‐β‐AA 65 (Scheme 12C). [ 36 ]…”

“…Over the years, Shibasaki's group contributed like maybe no other to the development of robust and highly selective metal‐catalyzed Mannich type approaches using diversely functionalized enolate precursors (see also Scheme 12 for the already discussed synthesis of α‐halogenated‐β‐AA via Mannich reactions). [ 35,36,54 ] With respect to the synthesis of α‐OH‐β‐AA derivatives, they succeeded in controlling the addition of the free‐OH‐containing amide 105 to various imines 57 by using a chiral indium catalyst system (Scheme 21A). [ 54a ] The resulting pyrrole‐amides 106 could then be transferred into the esters 107 straightforwardly.…”