Enzymatic acylation, alcohol

In contrast to the hydrolysis of prochiral esters performed in aqueous solutions, the enzymatic acylation of prochiral diols is usually carried out in an inert organic solvent such as hexane, ether, toluene, or ethyl acetate. In order to increase the reaction rate and the degree of conversion, activated esters such as vinyl carboxylates are often used as acylating agents. The vinyl alcohol formed as a result of transesterification tautomerizes to acetaldehyde, making the reaction practically irreversible. The presence of a bulky substituent in the 2-position helps the enzyme to discriminate between enantiotopic faces as a result the enzymatic acylation of prochiral 2-benzoxy-l,3-propanediol (34) proceeds with excellent selectivity (ee > 96%) (49). In the case of the 2-methyl substituted diol (33) the selectivity is only moderate (50). 

Cychc alcohols are excellent targets for enantioselective enzymatic acylations. For example, acylation of (65) with vinyl acetate catalyzed by Hpase SAM-II gives the (R),(3)-ester with 95% ee (81). Similarly (66), which is a precursor for seratonin uptake inhibitor, is resolved in a high yield and selectivity with Amano Hpase P (82). The prostaglandin synthon (67) is resolved by the same method into the optically pure alcohol in 35% yield (83). 

Another example of an enzymatic one-pot multiple Diels-Alder reaction is illustrated in Table 4.20 [83]. Racemic furfuryl alcohols 130 in the presence of ethoxy vinyl methyl fumarate 131 and enzyme TOYOBO-LIP undergo enzymatic acylation followed by kinetic enzymatic resolution to give the acyl derivatives 132 which then affords the adducts 133 and 134 by intramolecular Diels-Alder reaction 3-methyl-furfuryl alcohol 130 (R = Me) in acetone gives the best results. 

Gotor-Fernandez, V., ReboDedo, F. and Gotor, V. (2007) Preparation of chiral pharmaceuticals through enzymatic acylation of alcohols and amines, in Biocatalysis in the Pharmaceutical and Biotechnology Industry, (ed. R.M. Patel), Dekker, Taylor and Francis, New York, Chapter 7, pp. 203-248. 

The DKR of secondary alcohols can be efficiently performed via enzymatic acylation coupled with simultaneous racemization of the substrates. This method was first used by BackvaU for the resolution of 1-phenylethanol and 1-indanol [38]. Racemization of substrate 18 by a mthenium catalyst (Scheme 5.11) was combined with transesterification using various acyl donors and catalyzed by C.antarctica B Hpase. From aU the acyl donors studied, 4-chlorophenyl acetate was found to be the best. The desired product 19 was obtained in 80% yield and over 99% ee. 

The method is not restricted to secondary aryl alcohols and very good results were also obtained for secondary diols [39], a- and S-hydroxyalkylphosphonates [40], 2-hydroxyalkyl sulfones [41], allylic alcohols [42], S-halo alcohols [43], aromatic chlorohydrins [44], functionalized y-hydroxy amides [45], 1,2-diarylethanols [46], and primary amines [47]. Recently, the synthetic potential of this method was expanded by application of an air-stable and recyclable racemization catalyst that is applicable to alcohol DKR at room temperature [48]. The catalyst type is not limited to organometallic ruthenium compounds. Recent report indicates that the in situ racemization of amines with thiyl radicals can also be combined with enzymatic acylation of amines [49]. It is clear that, in the future, other types of catalytic racemization processes will be used together with enzymatic processes. 

Bellemin-Laponnaz S, Twedel J, Ruble JC, Breitling FM, Fu GC (2000) The kinetic resolution of allylic alcohols by a non-enzymatic acylation catalyst application to natural product synthesis. Chem Conunun 1009-1010... 

Analogous to the reactions of chiral alcohols, enantiomerically pure amines can be prepared by (D)KR of the racemate via enzymatic acylation. In the case of alcohols the subsequent hydrolysis of the ester product to the enantiomerically pure alcohol is trivial and is generally not even mentioned. In contrast, the product of enzymatic acylation of an amine is an amide and hydrolysis of an amide is by no means trivial, often requiring forcing conditions. 

P-Adrenergic-blocking agents, such as propranolol, have been synthesized by different chemoenzymatic methods where the key step to introduce the chirality is an enzymatic acylation or a hydrolysis process. The main reason to prepare these amino alcohols in optically pure form is due to the fact that the activity of these pharmaceuticals resides in the (S)-enantiomer. In Scheme 10.1 we have represented a chemoenzymatic approach that has been carried out for the preparation of this dmg where the key step is the resolution of the key intermediate 1-chloro-... 

The resolution of primary or secondary alcohols is easy by enzymatic acylation however, few examples have been described for the resolution of tertiary alcohols [26]. 

Although in recent years transesterification processes of racemic alcohols have received major attention, enzymatic acylation of amines for synthetic purposes is also being employed as a conventional tool for the synthesis of chiral amines and amides [31], using CALB as the biocatalyst in the majority of these reactions [31a]. The main difference between enzymatic acylation of alcohols and amines is the use of the corresponding acyl donor, because activated esters which are of utility... 

Kinetic optical resolution of racemic alcohols and carboxylic acids by enzymatic acyl transfer reactions has received enormous attention in recent years56. The enzymes generally employed are commercially available lipases and esterases, preferentially porcine liver esterase (PLE) or porcine pancreatic lipase (PPL). Lipases from microorganisms, such as Candida cylindracea, Rhizopus arrhizus or Chromobacterium viscosum, are also fairly common. A list of suitable enzymes is found in reference 57. Standard procedures are described in reference 58. Some examples of the resolution of racemic alcohols are given39. 

NPIL). The chiral triol was produced in a whole cell reduction process and was then selectively protected at the primary alcohol by enzymatic acylation using Novozyme 435 (CAL-B). Finally the key intermediate was produced by protecting the two secondary alcohols as they cleanly reacted with dimethoxypropane to give a crystalline product (>99 % ee, >99 % de, 96 % purity) which was subsequently used for Lipitor production (Figure 1.44). 

The application of enzymatic acylation for the resolution of racemic alcohols in organic solvent has shown to be an effective method to rapidly synthesize chiral alcohols. The racemic alcohols are treated with the lipase and acylating agent one enantiomer remains unconverted whereas the second enantiomer is esterified and easily separated by distillation (Scheme 7.2). Vinyl acetate or isopropenyl acetate are typical acylating agents, as the generated vinyl alcohol tautomerizes rapidly... 

Scheme 7.2 Resolution of racemic alcohols through enzymatic acylation.

Scheme 7.4 Resolution of racemic alcohol enzymatic acylation.

Scheme 7.8 Dynamic kinetic resolution of racemic alcohols by the combination of transition metal catalysis with enzymatic acylation.

Popular oxidation reactions of peptide alcohols such as the Parikh-Doering or Dess-Martin in addition to older oxidation reactions such as Collins, pyridinium chlorochromate, or Swern oxidation afford racemization free productsJ9121415 37-39 Oxidations using pyridinium dichromate results in racemization and low yields of product.[l3 Oxidation reactions have also been utilized in semisynthetic pathways of peptide aldehydes (1) peptide aldehydes are obtained through the enzymatic acylation of a peptide ester to an amino alcohol with subsequent oxidation of the peptide alcohol to afford the aldehyde, and (2) peptide aldehydes can also be obtained by direct enzymatic oxidation of the peptide alcohol by alcohol de-hydrogenaseJ40 41 ... 

In an alternate process, enantioselective enzymatic acylation of racemic a-methyl-l,3-benzodioxole-5-ethanol (55, Fig. 17) was developed using Amano lipase PS-30 (lipase from Pseudomonas cepacia) with vinyl acetate as acylating agent in n-hexane benzene (2 1). This process gave (+)-56 in 54% yield with 80% ee and (-)-57 in 46% yield with 96% ee After separation of alcohol (+)-56 from acetate (-)-57 by methanolysis in the presence of K2CC)3, the acetate was converted to alcohol (-)-56 in 95% yield with 96% ee Mitsunobu inversion of (-)-56 provided (+)-56 in 94% yield with 96% ee The conversion of (.S )-alcohol 56 to (-)-talampanel was carried out in 54% overall yield (Easwar and Argade, 2003). 

The kinetic resolution of racemic secondary alcohols by enzymatic acylation is a well-established method for obtaining optically pure alcohols or their esters in near-50% yield [293]. Coupling the enzymatic method with a catalytic redox ability of a Ru complex makes the process a dynamic kinetic resolution, increasing the theoretical yield from 50 to 100% [294]. Thus, a reaction system consisting of an achiral Ru catalyst for the chemical racemization of an alcoholic substrate, a suitable enzyme,... 

As an alternative to hydrolysis of the racemic ester in water, we investigated the possibility of resolving the alcohol (R,S)-5 obtained by the reduction of (R,S)-4, by enzymatic trans esterification in organic solvents as shown in Fig. 6. High rates and selectivities of enzymatic acylation of unhindered alcohols can be achieved in an organic solvent using vinyl acetate as an acyl donor [14]. 

During their studies on kinetic resolution (KR) of secondary alcohols, Connon et al. found that chiral pyridine catalyst 177 and its optimized analogue 178 promoted the synthetically useful KR of MBH adducts 179 derived from deactivated precursors (which were difficult to synthesize using catalytic asymmetric MBH reactions), allowing the convenient preparation of 179 in 62-90% ee and 82-97% ee, respectively (Scheme 2.87). This study also represents the first examples of effective non-enzymatic acylative KR of sec-sp -sp ... 

Attack of another alcohol R" -OH leads to a different ester R -CO-OR". This is an interesterification reaction, called enzymatic acyl transfer [13, 14]. 

Scheme 3.7 /Z-Stereoselective enzymatic acylation of terpene alcohols...

KR of racemic secondary alcohols by enzymatic acylation is a weU-established method for obtaining optically pure alcohols or their corresponding esters in nearly 50% yield [79]. However, coupling an enzymatic method with the catalytic redox ability of a transition metal complex can transform this process into a DKR [4d-gj. Secondary alcohols can be racemized by ehmination of Hj or metal hydride from the alcohol followed by re-addition. This pioneering work was reported in... 

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. 

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