DKR of Alcohols

In 1996, Williams and colleagues described the first examples of DKRs based on the use of a combination of enzymes and metal catalysts, which involved a lipase-palladium combination for the DKR of allyl acetates, and a 

Chirality from Dynamic Kinetic Resolution By Helene Pellissier Helene Pellissier 2011 

One of the useful strategies for enhancing the enzyme enantioselectivity is the use of structurally-modified substrates. In this way, various substrates, such as jS-hydroxyacids, diols and hydroxyaldehydes were protected by Park s group 

Another novel ruthenium-based catalytic system, such as TosN(CH2)2NH2] RuCl(p-cymene)/TEMPO, capable of promoting the in situ racemisation during enzymatic resolution, was reported by Sheldon s group and employed for the DKR of 1-phenylethanol, providing the corresponding acetate in 76% yield and enantioselectivity of 99% ee by using Novozym 435. The only side product observed was acetophenone, formed by oxidation of the substrate by 

The asymmetric synthesis of chiral fluoroorganic compounds plays an important role in the development of medicines, agrochemicals and materials due to the influence of fluorine s unique properties.In this context, Backvall s 

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DKR of alcohols with cymene-ruthenium catalyst 3 in [BMIm]PFg... 

The (5 )-selective DKR of alcohols with subtilisin was also possible in ionic liquid at room temperature (Table 14). " In this case, the cymene-ruthenium complex 3 was used as the racemization catalyst. In general, the optical purities of (5 )-esters were lower than those of (R)-esters described in Table 5. 

Kim and Park subsequently reported that ruthenium pre-catalyst 2 racemizes alcohols within 30 min at room temperature [53]. However, when combined with an enzyme (lipase) in DKR at room temperature, very long reaction times (1.3 to 7 days) were required, in spite of the fact that the enzymatic KR takes only a few hours (Scheme 5.24). Despite these compatibility problems, their results constituted an important improvement, since chemoenzymatic DKR could now be performed at ambient temperature to give high yields, which enables non-thermostable enzymes to be used. More recently, we communicated a highly efficient metal- and enzyme-catalyzed DKR of alcohols at room temperature (Scheme 5.24) [40, 54]. This is the fastest DKR of alcohols hitherto reported by the combination of transition metal and enzyme catalysts. Racemization was effected by a new class of very... 

Naturally occurring Upases are (R)-selective for alcohols according to Kazlauskas rule [58, 59]. Thus, DKR of alcohols employing lipases can only be used to transform the racemic alcohol into the (R)-acetate. Serine proteases, a sub-class of hydrolases, are known to catalyze transesterifications similar to those catalyzed by lipases, but, interestingly, often with reversed enantioselectivity. Proteases are less thermostable enzymes, and for this reason only metal complexes that racemize secondary alcohols at ambient temperature can be employed for efficient (S)-selective DKR of sec-alcohols. Ruthenium complexes 2 and 3 have been combined with subtilisin Carlsberg, affording a method for the synthesis of... 

DKR of alcohol acetylation One-pot t-BuOH Organometallic Ruthenium catalyst for alcohol CA lipase + ROAc 22... 

DKR of alcohol acetylation One-pot C6H12 or CH2C12 and Al, Ir, or Rh catalysts for secondary alcohol Pseudomonas sp. lipase or 21... 

The development of a large-scale process for the DKR of alcohols using various lipases in combination with a range of ruthenium catalysts has been demonstrated. The reactions can be carried at concentrations up to 1M with lower catalyst loadings (Pamies, and Backvall, 2003b). The process for the preparation of (R)-3,5-bis-trifluoromethyl-phenylethan-l-ol using [RuCl2(p-... 

Scheme 2.90 Titanium-catalysed DKRs of alcohols, ethers and acetals.

In 2007, Park s group showed that one of the two carbonyl ligands of Backvall s catalyst could easily be replaced with triphenylphosphane with the aid of trimethylamine A-oxide to give a novel analogue of Backvall s catalyst, depicted in Scheme 4.12. Interestingly, this catalyst promoted the racemisa-tion of alcohols at room temperature in the presence of a catalytic amount of silver oxide. The catalytic species were stable in air and reusable at least ten times for the DKR of alcohols, although stoichiometric amounts of Ag20 were required. The DKR of phenylethanol under these conditions is described in Scheme 4.12. 

In the same context, another racemisation ruthenium catalyst, bearing a benzyloxy function, was synthesised by the same group and was successfully applied to similar reactions, providing the DKR of a wide range of functionalised alcohols in excellent yields and enantioselectivities (>99% ee). The corresponding polymer-supported derivative was also synthesised and tested as a recyclable catalyst for the aerobic DKR of alcohols (Scheme 4.13) its... 

Scheme 4.9 DKR of alcohols with a pentaphenylcyclopentadienylruthemum chloride catalyst.

Scheme 4.14 DKR of alcohols with an in situ generated ruthenium catalyst.

Scheme 4.15 DKRs of alcohols with Shvo s catalyst.

In 2004, Kita s group reported a combination of the domino reaction concept and the DKR protocol, comprising the first lipase-catalysed domino process that combined the DKR of alcohols by using 1-ethoxyvinyl esters and... 

Scheme 4.27 DKR of alcohols with subtilisin-ruthenium combination.

Scheme 4.34 DKR of alcohols with an analogue of BackvaU s catalyst.

It has been demonstrated that the combination of metal-catalysed racemisation and enzymatic kinetic resolution is a powerful method for the synthesis of optically active compounds from racemic alcohols and amines. There are many metal complexes active for racemisation, but the conditions for enzymatic acylation often limit the application of the metal complexes to DKR. In the case of DKR of alcohols, complementary catalyst systems are now available for the synthesis of both (R)- and (5)-esters. Thus, (R)-esters can be obtained by the combination of an R-selective lipase, such as CAL-B or LPS, and a racemisation catalyst, whereas the use of an A-selective protease, such as subtilisin, at room temperature provides (5)-esters. The DKR of alcohols can be achieved not only for simple alcohols but also for those bearing various additional functional groups. The DKR of alcohols has also been applied to the synthesis of chiral polymers and coupled to tandem reactions, producing various polycyclic compounds. 

The first broadly applicable and highly practical type of DKR of alcohols in organic media was developed by the Backvall group [13, 14] by using the Shv6 ruthenium complex 14 as an efficient and enzyme-compatible metal-based redox catalyst for in situ racemization of alcohols. Notably, this (nonchiral) ruthenium catalyst does not require base and ketone additives for efficient racemization. This racemization... 

Scheme 8.16 Enzymatic DKR of alcohols with Backvall s catatyst.

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