Large-scale ruthenium- and enzyme-catalyzed dynamic kinetic resolution of (rac)-1-phenylethanol

Abstract

The scale-up of the ruthenium-and enzyme-catalyzed dynamic kinetic resolution (DKR) of (rac)-1-phenylethanol (2) is addressed. The immobilized lipase Candida antarctica lipase B (CALB) was employed for the resolution, which shows high enantioselectivity in the transesterification. The ruthenium catalyst used, (η 5 -C 5 Ph 5 )RuCl(CO) 2 1, was shown to possess very high reactivity in the "in situ" redox racemization of 1-phenylethanol (2) in the presence of the immobilized enzyme, and could be used in 0.05 mol% with high efficiency. Commercially available isopropenyl acetate was employed as acylating agent in the lipase-catalyzed transesterifications, which makes the purification of the product very easy. In a successful large-scale DKR of 2, with 0.05 mol% of 1, (R)-1-phenylethanol acetate (3) was obtained in 159 g (97% yield) in excellent enantiomeric excess (99.8% ee).

Chemoenzymatic Dynamic Kinetic Resolution of Alcohols and Amines

“…Under optimized conditions, (R)-1-phenylethyl acetate (159 g, 97 %, Ͼ99 % ee) was obtained from 1-phenylethanol (122 g, 1.00 mol) in the presence of 6a (0.05 mol-%) and sodium carbonate (20 mol-%) at 70°C for 20 h. [23] Scheme 12. Large-scale DKR of 1-phenylethanol.…”

6.08 Acylation-Type Reactions: Synthesis of Esters via Acyl Transfer

“…The obtained selectivity (ee ¼ 97%) and yield (87% ¼ 1.43 kg) for (R)-1-phenylethanol acetate were still good on large scale. 147 To date catalysts are mostly identified through trial and error approaches or by using time consuming screening methods, but the investigation of processes for chemical recognition of the substrate by the catalyst have become more important. In the cases of Birman's amide-based catalysts 127/128 and Schreiner's peptide catalyst 238 94 computations were able to shed some light onto the selective acyl transfer process.…”

“…147 At 1 mol scale, applying 0.05 mol% of ruthenium catalyst 359 and small amounts of enzyme after 20 h at 40°C, 159 g (97% yield) of (R)-1-phenylethanol acetate (99% ee) were isolated. 147 The high efficiency was proved by carrying the reaction out at a 10 mol scale.…”

“…147 At 1 mol scale, applying 0.05 mol% of ruthenium catalyst 359 and small amounts of enzyme after 20 h at 40°C, 159 g (97% yield) of (R)-1-phenylethanol acetate (99% ee) were isolated. 147 The high efficiency was proved by carrying the reaction out at a 10 mol scale. The catalysts loadings of the ruthenium-complex 359 (0.01 mol%) and the biocatalyst were lowered and the reaction was performed in a more highly concentrated reaction mixture.…”

Tuning of the Electronic Properties of a Cyclopentadienylruthenium Catalyst to Match Racemization of Electron‐Rich and Electron‐Deficient Alcohols

“…In particular catalysts 4 and 7 give fast racemization reactions at room temperature and these systems have been applied to DKR reactions of various secondary alcohols [12,13] and they allow for scale-up to 100 g-1 kg scales. [14] Recently, Kim and Park reported on substituent effects on the catalytic activity of [{h 5 -Ar 4 C 4 COC(=O)Ar}Ru-(CO) 2 Cl] in racemization of secondary alcohols. [15] Results and Discussion Herein, we report on the synthesis and applications of a new series of electron-deficient and electron-rich analogues of catalyst 4.…”