Asymmetric Oxidation Synthesis of Modafinil Acid by Use of a Recyclable Chiral‐at‐Metal Complex

Abstract

The enantioselective oxidation synthesis of chiral modafinil acid and its analogues with high enantiomeric excess has been developed by means of a chiral‐at‐metal strategy. Treatment of ruthenium complexes cis‐[Ru(bpy)2Cl2] or Δ/Λ‐[Ru(bpy)2(MeCN)2](PF6)2 (bpy is 2,2′‐bipyridine) with the appropriate prochiral thioether ligands afforded thioether complexes rac‐1, Δ/Λ‐1, rac‐2, Δ/Λ‐2, rac‐3, and Δ/Λ‐3. Diastereoselective oxidation of the thioether complexes in situ produced the corresponding sulfoxide complexes rac‐1a, Δ/Λ‐1a, rac‐2a, Δ/Λ‐2a, rac‐3a, and Δ/Λ‐3a. The configuration at the metal center in each case is stable during the coordination and oxidation reactions, and dictates the chirality of the sulfoxide ligand in the oxidation process. The chiral modafinil acids were obtained with ee values greater than 98 % upon their removal from the corresponding sulfoxide complexes in the presence of TFA/MeCN. Moreover, the chiral ruthenium precursors Δ/Λ‐[Ru(bpy)2(MeCN)2](PF6)2 are recyclable and reusable with complete retention of the configurations.

Chiral Recognition and Dynamic Thermodynamic Resolution of Sulfoxides by Chiral Iridium(III) Complexes

“…The N1 and N2 atoms are at trans position with the angle of N1–Ir1–N2 = 170.4(2)°; this is consistent with its parent. The Ir1–S1 distance of 2.357(1) Å is in accord with the reported distance for the Ir­(III) sulfoxide complexes. , The S–O bond distance of 1.499(3) Å is consistent with that reported in sulfoxide complexes. ,− A pair of enantiomers Δ- R and Λ- S are found in the crystal structure; thus, the complex is racemate. Two pairs of diastereomers Δ- R and Δ- S , and Λ- R and Λ- S , would be generated when rac - trans ( N )-[(Ir­(ppy) 2 Cl) 2 ] reacted with rac -HLO- i Pr in the experimental conditions.…”

“…That is, the Δ Ir­(III)-centered configuration favors the R configuration sulfoxide while the Λ configuration center prefers the S configuration sulfoxide, leading to enantioselective recognition between the metal center receptors and chiral sulfoxides. These are consistent with the previous observations in Ru­(II) sulfoxide complexes by Meggers’ group and our group. ,, To understand this selectivity, a density functional theory (DFT) calculation was carried out for Ru­(II) and LO- i Pr complexes by Meggers’ group, and they found that the Λ- S enantiomer is more stable than the Δ- S enantiomer . As shown in Figure , the O2 of the sulfoxide group is hydrogen bonded to the C22–H of the pyridine ring (C22···O2 = 3.197 Å, H22···O2 = 2.338 Å, ∠C22–H–O2 = 153.6°); the i Pr group is far from the α-H of the pyridine ring to relieve the steric congestion and forms C–H···π interaction (2.92 Å) with the ppy ligand to stabilize the diastereomer.…”

Efficient Generation of Singlet Oxygen and Photooxidation of Sulfide into Sulfoxide via Tuning the Ancillary of Bicyclometalated Iridium(III) Complexes

“…Although many methodologies have been developed for preparation of chiral sulfoxides ,, and Andersen’s method is often employed to generate enantiopure sulfoxides, they still suffer from a lack of generality; the experimental procedures were tedious, and an organometallic reagent need to be used. The aerobic photo-oxidation protocol for sulfide is quantitative, chemoselective, and functional-group tolerant.…”

Octahedral Ruthenium Complex with Exclusive Metal-Centered Chirality for Highly Effective Asymmetric Catalysis

“…In pioneering work, Fontecave reported that Λ- and Δ-[Ru­(2,9-dimethyl-1,10-phen­anthroline)­(MeCN) 2 ] 2+ catalyze the oxidation of organic sulfides to their sulfoxides, albeit with a maximum of just 18% ee . Much higher enantio­selectivities for the synthesis of sulfoxides were achieved by Ye using chiral-at-metal Λ- and Δ-[Ru­(2,2′-bipyridine) 2 ­(pyridine) 2 ] 2+ as recyclable chiral auxiliaries . Hartung and Grubbs reported a chiral-at-ruthenium catalyst for diastereo- and enantio­selective ring-opening/cross-metathesis.…”