Functionalization of (2S)‐Isopropyl‐5‐iodo‐2,3‐dihydro‐4(H)‐pyrimidin‐4‐ones by a Suzuki–Miyaura Cross‐Coupling Reaction Using Aryltrifluoroborate Salts: Convenient Enantioselective Preparation of α‐Substituted β‐Amino Acids

Abstract

A simple protocol for the Pd(OAc)2‐catalyzed cross‐coupling reaction of 1‐benzoyl‐(2S)‐isopropyl‐5‐iodo‐2,3‐dihydro‐4(H)‐pyrimidin‐4‐ones with potassium aryltrifluoroborates was developed. The reaction is performed at 110 °C with a ligand‐free catalyst. In all cases, complete conversion of the 1‐benzoyl‐(2S)‐isopropyl‐5‐iodo‐2,3‐dihydro‐4(H)‐pyrimidin‐4‐onesand aryltrifluoroborates into the C–C coupling products was observed within 30–360 min. It is noteworthy that a largevariety of groups present in the potassium aryltrifluoroborates (–CF3, –OMe, –SEt, –CN, –CHO, –Cl, –Cbz, –NCbz,–OH, –CO2H) could be tolerated. Hydrogenation of the endocyclic double bonds in the Suzuki–Miyaura products followed by acid hydrolysis afforded highly enantioenrichedα‐aryl‐substituted β‐amino acids.

Asymmetric Synthesis of Netarsudil: A New Therapeutic for Open-Angle Glaucoma

“…The six-step synthetic route originates from the 2,4-dimethylbenzoate phenyl acetic acid starting material. The (S)-stereocenter is set using the chiral enolate of the Evans (R)-4-benzyloxazolidin-2-one chiral auxiliary to direct alkylation of N-Boc 1-aminomethyl benzotriazole (11) incorporating the β-amino arm. Hydrolytic removal of the auxiliary and coupling the (S)-N-Boc α-aryl β-amino acid with 6-aminoisoquinoline using 2,2,2-trichloro-1,1-dimethylethyl chloroformate as the activating agent is accomplished in good yield and excellent ee.…”

“…Stefani and co-workers prepared α-aryl β-amino acids by developing a Suzuki-Miyaura, Pd(OAc) 2 -catalyzed cross-coupling reaction using potassium aryltrifluoroborates and substituted 5-iodo-2,3dihydro-5(H)-pyrimidin-4-ones. 11 Williams and co-workers also used palladium-catalyzed allylic substitution to prepare various α-aryl analogs of the β 2 amino acid class. 12 A few catalytic asymmetric approaches have been reported including a Hantzsch ester induced conjugate reduction of β-nitro acrylates to the corresponding β-nitro esters and a rhodium-carbenoid-induced C-H activation/insertion of Nprotected methylamines.…”

Fundamental Developments of Chiral Phase Chromatography in Connection with Enantioselective Synthesis of β‐Amino Acids

“…For instance, the synthesis of α‐aryl‐substituted β‐amino acids was developed by reaction of the chiral iodo‐pyrimidinone ( S )‐ 15 obtained from ( S )‐asparagine, with a potassium aryl‐trifluoroborate via a Suzuki‐Miyaura coupling (17 examples). Subsequently, diastereoselective catalytic hydrogenation of the ( S )‐aryl‐dihydropyrimidinones, ( S )‐ 16 , therefore gave rise to perhydropyrimidin‐4‐ones (2 S ,5 S )‐ 17 with generation of a new stereogenic centre (Figure ) …”

Looking for Treasure in Stereochemistry-Land. A Path Marked by Curiosity, Obstinacy, and Serendipity

“…Subsequently, Sonogashira coupling of the halogenated heterocyclic enones with various terminal alkynes produced 1-benzoyl-2­( S )-isopropyl - 5-alkynyl-2,3-dihydro-4­( H )-pyrimidin-4-ones in good yields. Hydrogenation of the unsaturated C–C moieties in the Sonogashira products followed by acid hydrolysis afforded highly enantioenriched α-substituted β-amino acids (Scheme ). , …”