Acylative Dynamic Kinetic Resolution of Secondary Alcohols: Tandem Catalysis by HyperBTM and Bäckvall’s Ruthenium Complex

Abstract

Non-enzymatic dynamic kinetic resolution (DKR) of secondary alcohols by enantioselective acylation using an isothiourea-derived HyperBTM catalyst and racemization of slowly reacting alcohol by Bäckvall’s ruthenium complex is reported. The DKR approach features high enantioselectivities (up to 99:1), employs easy-to-handle crystalline 4-nitrophenyl isobutyrate as the acylating reagent, and proceeds at room temperature and under an ambient atmosphere. The stereoinduction model featuring cation−π system interactions between the acylated HyperBTM catalyst and π electrons of an alcohol aryl subunit has been elaborated by DFT calculations.

Two-Step Kinetic Resolution of Racemic Secondary Benzylic Alcohols Using the Combination of Enantioselective Silylation and Acylation: One-Pot Procedure Catalyzed by Chiral Guanidine

“…Scheme , 17.0 mg, 28% yield, >99:1 er; HPLC (IC-3, i -PrOH/ n -hexane = 1/100, flow rate = 0.5 mL/min, λ = 254 nm) t R = 14.5 min (major), 17.7 min (minor). Absolute configuration was determined by the comparison of the HPLC elution order in ref : 1 H NMR (500 MHz, CDCl 3 ) δ 7.26–7.22 (m, 1H), 7.17–7.13 (m, 2H), 7.10 (d, J = 7.5 Hz, 1H), 5.85 (q, J = 6.5 Hz, 1H), 2.57 (sep, J = 7.0 Hz, 1H), 2.36 (s, 3H), 1.52 (d, J = 6.5 Hz, 3H), 1.19 (d, J = 7.5 Hz, 3H), 1.16 (d, J = 6.5 Hz, 3H); 13 C­{ 1 H} NMR (126 MHz, CDCl 3 ) δ 176.3, 141.9, 138.0, 128.44, 128.35, 126.7, 122.9, 71.9, 34.1, 22.3, 21.4, 18.91, 18.86.…”

“…Analytical Data of Compounds (R)-4b, (R)-8a, 8b, and (R)-8d−8l. (R)-1-Phenylpropyl isobutyrate ((R)-4b): 20 Table 2, entry 5, 15.9 mg, 39% yield, >99:1 er; HPLC (IC-3, i-PrOH/n-hexane = 1/30, flow rate = 0.5 mL/min, λ = 254 nm) t R = 11.7 min (major), 13.0 min (minor). Absolute configuration was determined by the comparison of the HPLC elution order in ref 20: 1 H NMR (500 MHz, CDCl 3 ) δ 5H),5.66 (dd,J = 7.5,6.5 Hz,1H), 2.58 (seq, J = 7.0 Hz, 1H), 1.91 (ddq,J = 7.5,7.5,14.0 Hz,1H),1H),1.19 (d,J = 7.0 Hz,3H),1.15 (d,J = 6.5 Hz,3H), 0.89 (t, J = 7.5 Hz, 3H); 13 C{ 1 H} NMR (126 MHz, CDCl 3 ) δ 176.…”

Cooperative Palladium/Isothiourea Catalyzed Enantioselective Formal (3+2) Cycloaddition of Vinylcyclopropanes and α,β‐Unsaturated Esters

“…The effect of salt additives (20-30 mol %) on the stereoselectivity of the reaction was further investigated with (R)-BTM 6 instead of (S)-TM•HCl 7 (entries [11][12][13][14][15][16][17][18][19]. Salts containing halide ions led to high diastereoselectivity, irrespective of the nature of the cation (entries [11][12][13][14] with LiCl being optimal.…”

“…As a final optimization step, toluene, THF and EtOAc were selected for an extended solvent screen. In the presence of 30 mol % LiCl, THF and EtOAc gave the product with improved enantioselectivity (> 90 : 10 er, en- tries 17,18), with a combination of EtOAc and THF in a 3 : 2 ratio proving optimal, furnishing the product in > 90 % conversion, 95 : 5 dr and 94 : 6 er (entry 19). To demonstrate the practicality of the developed cooperative catalysis process, the reaction was performed at gram scale, giving cyclopentane 4 (1.49 g) in 78 % isolated yield and excellent diastereo-and enantioselectivity (95 : 5 dr, 93 : 7 er).…”

“…A combination of isothiourea and palladium catalysts has also been used to promote tandem allylic amination/ [2,3]-sigmatropic rearrangements, [16] while cooperative ruthenium and isothiourea catalysts have been used to facilitate the DKR of secondary alcohols. [17] In these processes, catalyst deactivation through isothiourea coordination with the transition-metal co-catalyst was avoided successfully, but irreversible binding has been observed with gold, resulting in isolable chiral Au I and Au III -isothiourea complexes. [18] Among the potential substrates for palladium-catalyzed transformations, vinylcyclopropanes (VCPs) have been widely explored, particularly in formal (3+2) cycloadditions since the seminal work by Tsuji and co-workers.…”