Dynamic Kinetic Resolution of γ-Substituted Cyclic β-Ketoesters via Asymmetric Hydrogenation: Constructing Chiral Cyclic β-Hydroxyesters with Three Contiguous Stereocenters

Abstract

An efficient asymmetric hydrogenation of racemic γ-substituted cyclic β-ketoesters via dynamic kinetic resolution to provide chiral cyclic β-hydroxy esters with three contiguous stereocenters is reported. Using a chiral spiro iridium catalyst (R)-5 (Ir-SpiroSAP), a series of racemic γ-aryl/alkyl substituted cyclic β-ketoesters were hydrogenated to the corresponding chiral cyclic βhydroxy esters in high yields (84−97%) with good to excellent enantioselectivities (69−>99% ee) and cis,cis-selectivities (up to >99:1).

Highly Efficient Asymmetric Hydrogenation Catalyzed by Iridium Complexes with Tridentate Chiral Spiro Aminophosphine Ligands

“…55 In addition, we used (R)-6e for hydrogenation of various racemic γ-aryl/alkyl cyclic β-ketoesters rac-40 to prepare cyclic β-hydroxy esters 41 with three contiguous stereocenters in high yields with good to excellent enantioselectivities (69−>99% ee) and cis,cis-selectivity up to >99:1. 56 These reactions provide an efficient approach to natural products such as (+)-waihoensene 57 and (−)-podocarpic acid 58 (Figure 8b).…”

“…One of the products, ( S )-1-benzyl-3-(( R )-1-hydroxyethyl)­pyrrolidin-2-one (R 1 = Me, R 2 = Bn), is a key intermediate in the synthesis of the fluoroquinolone antibiotic premafloxacin . In addition, we used ( R )- 6e for hydrogenation of various racemic γ-aryl/alkyl cyclic β-ketoesters rac - 40 to prepare cyclic β-hydroxy esters 41 with three contiguous stereocenters in high yields with good to excellent enantioselectivities (69–>99% ee) and cis , cis -selectivity up to >99:1 . These reactions provide an efficient approach to natural products such as (+)-waihoensene and (−)-podocarpic acid (Figure b).…”

Iodine‐Catalyzed α‐Hydroxylation of β‐Dicarbonyl Compounds

“…Preparation of Substrate 1 p. [22] A reaction mixture of methyl 1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (1.02 g, 5 mmol) and aniline (0.93 g, 10 mmol) in p-xylene (5 mL) was heated to reflux under a nitrogen atmosphere for 14 h. The solvent was removed under reduced pressure, and the resulting residue was treated with water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layer was dried over anhydrous Na 2 SO 4 , concentrated, and purified through silica gel column chromatography to afford substrate 1 p. [23] To a solution of diethyl malonate (0.8 g, 5 mmol) in anhydrous THF (10 mL) at 0 °C was added NaH (60 %, 0.2 g, 5 mmol). After stirred for 0.5 h, the resulting mixture was treated dropwise with methyl iodide (1.42 g, 5.5 mmol) at the same temperature, and then stirred at room temperature for 12 h. The reaction was quenched with sat.…”

“…[22] 14 h; eluent: CH 2 Cl 2 /PE 50 : 50; yield: 1280 mg, 97 %; white solid, mp 141-142 °C; 1 H NMR (400 MHz, DMSO-d 6 , mixture of tautomers, *peaks of the minor one): δ 14.83* (s, 0.1H), 10.18 (s, 0.9H), 9.41* (s, 0.1H), 7.91 (dd, J = 7.6, 1.2 Hz, 0.9H), 7.70-7.67 (m, 3H), 7.40-7.31 (m, 4.1H), 7.14* (t, J = 7.2 Hz, 0.1H), 7.07 (t, J = 7.2 Hz, 0.9H), 3.74 (dd, J = 10.4, 5.6 Hz, 0.9H), 3.07-3.04 (m, 1.8H), 2.87* (t, J = 7.6 Hz, 0.2H), 2.68* (t, J = 7.6 Hz, 0.2H), 2.42-2.29 (m, 1.8H); 13 Diethyl 2-methylmalonate (1 q). [23] 24 h; eluent: CH 2 Cl 2 /PE 20 : 80; yield: 793 mg, 91 %; colorless oil; 1 H NMR (CDCl 3 , 400 MHz): δ 4.24-4.16 (m, 4H), 3.43 (q, J = 7.6 Hz, 1H), 1.42 (d, J = 7.6 Hz, 3H), 1.27 (t, J = 7.6 Hz, 6H); 13 Diethyl 2-ethylmalonate (1 r). [24] 4 h; eluent CH 2 Cl 2 /PE 25 : 75; yield: 465 mg, 49 %; colorless oil; 1 H NMR (CDCl 3 , 400 MHz): δ 4.20 (q, J = 6.8, 0.8 Hz, 4H), 3.25 (t, J = 7.6 Hz, 1H), 1.97-1.90 (m, 2H), 1.27 (t, J = 7.2 Hz, 6H), 0.97 (t, J = 7.6 Hz, 3H); 13 Diethyl 2-propylmalonate (1 s).…”

Catalytic Asymmetric Construction of Chiral Amines with Three Nonadjacent Stereocenters via Trifunctional Catalysis

“… , The construction of these stereocenters is typically accomplished one by one in different steps, a major contributing factor to complex and lengthy synthetic routes. The development of new methods to construct multiple stereocenters in a streamlined stereoselective fashion is a highly important and challenging task. − Single-step construction of cyclic structures containing multiple stereocenters is often realized by catalytic asymmetric cycloaddition reactions. , However, catalyst-promoted single-step construction of complex structures containing multiple stereocenters is an ideal approach that has rarely been reported. − Davis and co-workers reported a chiral Rh 2 ( S -DOSP) 4 -catalyzed asymmetric reaction of methyl aryldiazoacetates 4 with pyrrolidine 5 that produced chiral pyrrolidines 6 with 1,2,4-stereocenters (Scheme a) . In that reaction, the chiral Rh catalyst achieved efficient chiral recognition of pyrrolidine 5 in addition to promoting a highly stereoselective C–C bond forming reaction in a single transition state.…”