Combined Ruthenium(II) and Lipase Catalysis for Efficient Dynamic Kinetic Resolution of Secondary Alcohols. Insight into the Racemization Mechanism

Abstract

Pentaphenylcyclopentadienyl ruthenium complexes (3) are excellent catalysts for the racemization of secondary alcohols at ambient temperature. The combination of this process with enzymatic resolution of the alcohols results in a highly efficient synthesis of enantiomerically pure acetates at room temperature with short reaction times for most substrates. This new reaction was applied to a wide range of functionalized alcohols including heteroaromatic alcohols, and for many of the latter, enantiopure acetates were efficiently prepared for the first time via dynamic kinetic resolution (DKR). Different substituted cyclopentadienyl ruthenium complexes were prepared and studied as catalysts for racemization of alcohols. Pentaaryl-substituted cyclopentadienyl complexes were found to be highly efficient catalysts for the racemization. Substitution of one of the aryl groups by an alkyl group considerably slows down the racemization process. A study of the racemization of (S)-1-phenylethanol catalyzed by ruthenium hydride eta(5)-Ph(5)CpRu(CO)(2)H (8) indicates that the racemization takes place within the coordination sphere of the ruthenium catalyst. This conclusion was supported by the lack of ketone exchange in the racemization of (S)-1-phenylethanol performed in the presence of p-tolyl methyl ketone (1 equiv), which gave <1% of 1-(p-tolyl)ethanol. The structures of ruthenium chloride and iodide complexes 3a and 3c and of ruthenium hydride complex 8 were confirmed by X-ray analysis.

Recent trends in whole cell and isolated enzymes in enantioselective synthesis

“…Metals such as rhodium, iridium and ruthenium are known to racemise secondary alcohols, for the in situ conversion of unwanted enantiomers to products, but only a few of these metals have proved compatible with enzymatic reaction conditions, and these have been reviewed. 250,[272][273][274][275][276][277][278][279][280][281] The first example of a chemoenzymatic DKR of secondary alcohols was reported by Williams; a ruthenium catalyst was combined with a lipase to produce enantiopure acetate of 1-phenyl ethanol in 81% conversion and 96% e.e. 278 Bäckvall made significant improvements to this procedure by using immobilised Candida antarctica Lipase B and a ruthenium complex.…”

“…250,[272][273][274][275][276][277][278][279][280][281] It should be noted that vinyl acetate is incompatible with the ruthenium complexes explored, while isopropenyl acetate can be used with the majority of monomeric ruthenium complexes. p-Chlorophenyl acetate is the best acyl donor for the dimeric ruthenium complexes.…”

Ruthenacycles and Iridacycles as Catalysts for Asymmetric Transfer Hydrogenation and Racemisation

“…Bäckvall and co-workers initially used the Shvo catalyst 4a (Fig. 2) for the racemisation reaction, but later developed monomeric equivalents such as 5 that were even more active as racemisation catalyst [28]. This DKR has been further developed by Verzijl and co-workers leading to its application in a large-scale process at DSM [29].…”

Design and asymmetric synthesis of chiral diaryliodonium salts

“…30 The alcohol was mesylated to (R)-6 in 99% yield and used in alkylation of 2-iodophenol, to deliver the desired iodoarene 7 without loss of enantiomeric excess (Scheme 5b). Unfortunately, all attempts to synthesize the target I from 7 using the TsOH protocol (see Scheme 4b) were unsuccessful, possibly due to sluggish oxidation caused by steric hindrance from the orthosubstituent.…”

“…Prepared by kinetic resolution of rac-4 following a modified literature procedure: 30 To a flame dried 250 mL round bottom flask was loaded racemic 2-octanol (12.21 mL, 76.79 mmol), isopropenyl acetate (10.0 mL, 92.14 mmol), Na 2 CO 3 (1.59 g, 15.0 mmol) and i-Pr 2 O (120 mL). The flask was purged with argon and CALB (300 mg) was added.…”