Chiral acyl donors

These chiral acyl donors can be used for quite effective kinetic resolution of racemic secondary alcohols. For example, enantiomeric aryl alkyl ketones are es-terified by the acyl pyridinium ion 8 with selectivity factors in the range 12-53 [10], In combination with its pseudo-enantiomer 9, parallel kinetic resolution was performed [11], Under these conditions, methyl l-(l-naphthyl)ethanol was resolved with an effective selectivity factor > 125 [12]. Unfortunately, the acyl donors 8 and 9 must be preformed, and no simple catalytic version was reported. Furthermore, over-stoichiometric quantities of either MgBr2 or ZnCI2 are required to promote acyl transfer. In 2001, Vedejs and Rozners reported a catalytic parallel kinetic resolution of secondary alcohols (Scheme 12.3) [13]. 

The improvement of the enantioselectivity E in kinetic resolution of a primary alcohol (10) through lipase-catalyzed transesterification was studied using a chiral acyl donor 11. The combination of the lipase, solvent and acyl donor was effective for the enantioselectivity.62... 

Figure 11 Representative kinetic resolution of primary alcohol ( )-10 using chiral acyl donor ( )-ll.

Reactions involving chiral acyl donors are kinetically more complex as the acyl donor will form diastereomeric acyl enzymes. The selectivity of the enzyme is in this case defined by four different transition states [8], two for each acyl donor one of which leads to the acyl enzyme whereas the other involves its breakdown. As seen in Scheme 4, the formation of the acyl enzymes is a competition between the two enantiomeric acyl donors (RCOOH and SCOOH) for the free enzyme (HO-Enz). For the breakdown of the acyl enzyme there is a different competitive situation without connection between the two acyl enzymes. The competition involves water and alcohol (in the cases of hydrolysis and esterification) and occurs independently at the two acyl enzymes (RCOO-Enz and SGOO-Enz). 

Scheme 4 A Lipase-catalyzed resolution of a chiral acyl donor (RCOOH and SCOOH) by esterification or hydrolysis (the reverse reaction). B The reaction goes through two diastereomeric acyl enzymes (RCOO-Enz and SCOO-Enz). The enantiomeric acyl groups R and S are shown in boldface.

The resolution of chiral acyl donors mainly involves carboxylic acids with the stereocenter at the a position. Candida rugosa lipase shows high enantioselectivity to many of these acids in contrast to C. antarctica lipase B. To compounds with an electron-withdrawing substituent at the stere(x enter, P. cepacia lipase shows a high selectivity as well. Two examples are presented in Scheme 8 [91,92]. 

Scheme 8 Kinetic resolution of chiral acyl donors by esterification [91] and hydrolysis [92].

Another approach for the coupled racemization step has been used for compounds having an acidic hydrogen on the stereocenter. Examples of such compounds are chiral acyl donors such as a-substituted esters which are prone to base-catalyzed racemization via an enolate intermediate. This approach has been frequently used and a few examples will be given here to illustrate the utility (Scheme 11). The first examples involve oxa-zolinones where it was found that porcine pancreatic lipase and lipase from Aspergillus sp. exhibited opposite enantiopreferences [106,107]. The remaining oxazolinone was spontaneously racemized via the enolate intermediate and both (l)- and (D)-iV-benzoyl amino acids could be produced this way in high chemical and optical yields. The p Ka values of thio esters are lower than those of oxo esters [108]. This has been used in the lipase-... 

The alcohol used as cosubstrate in lipase reactions with chiral acyl donors may act as an enantioselective inhibitor that will be detrimental to the enantiomeric excess. This has been reported for C. rugosa lipase-catalyzed kinetic resolution by esterification of 2-meth-ylalkanoic acids (Scheme 17) [134]. 

The power ofbiocatalysts for the production of chiral compounds can be elevated to a second stage when proper use of the process leads to a larger number of different enantioenriched products from the same reaction. Some efforts have been made in this direction because the enzyme can be selective to either nucleophile or acyl donor. The elegancy of the reaction is increased when the process is carried out for the resolution of both. Scheme 7.20 depicts this possibility [38]. 

The catalytic alcohol racemization with diruthenium catalyst 1 is based on the reversible transfer hydrogenation mechanism. Meanwhile, the problem of ketone formation in the DKR of secondary alcohols with 1 was identified due to the liberation of molecular hydrogen. Then, we envisioned a novel asymmetric reductive acetylation of ketones to circumvent the problem of ketone formation (Scheme 6). A key factor of this process was the selection of hydrogen donors compatible with the DKR conditions. 2,6-Dimethyl-4-heptanol, which cannot be acylated by lipases, was chosen as a proper hydrogen donor. Asymmetric reductive acetylation of ketones was also possible under 1 atm hydrogen in ethyl acetate, which acted as acyl donor and solvent. Ethanol formation from ethyl acetate did not cause critical problem, and various ketones were successfully transformed into the corresponding chiral acetates (Table 17). However, reaction time (96 h) was unsatisfactory. 

The one-pot dynamic kinetic resolution (DKR) of ( )-l-phenylethanol lipase esterification in the presence of zeolite beta followed by saponification leads to (R)-l phenylethanol in 70 % isolated yield at a multi-gram scale. The DKR consists of two parallel reactions kinetic resolution by transesterification with an immobilized biocatalyst (lipase B from Candida antarctica) and in situ racemization over a zeolite beta (Si/Al = 150). With vinyl octanoate as the acyl donor, the desired ester of (R)-l-phenylethanol was obtained with a yield of 80 % and an ee of 98 %. The chiral secondary alcohol can be regenerated from the ester without loss of optical purity. The advantages of this method are that it uses a single liquid phase and both catalysts are solids which can be easily removed by filtration. This makes the method suitable for scale-up. The examples given here describe the multi-gram synthesis of (R)-l-phenylethyl octanoate and the hydrolysis of the ester to obtain pure (R)-l-phenylethanol. 

Hence, a reaction of Type I will involve a racemic or achiral/me,t(9 nncleophile which will react enantioselectively with an achiral acyl donor in the presence of a chiral catalyst, while on the other hand, a reaction of Type II will associate an achiral nncleophile and a racemic or udm lmeso acyl donor in the presence of a chiral catalyst. In both cases, when a racemic component is implicated the process constitntes a KR and the maximum theoretical yield of enantiomerically pure product, given perfect enantioselectivity, is 50%. When an achiral/mera component is involved, then the process constitutes either a site-selective asymmetric desymmetrisation (ASD) or, in the case of tt-nucleophiles and reactions involving ketenes, a face-selective addition process, and the maximum theoretical yield of enantiomerically pure product, given perfect enantioselectivity, is 100%. 

In addition, Oriyama was the first to provide a practical protocol for the ASD of mei( -l,2-diols [179-182], Thus, employing just 0.5 mol% of (5)-proline-derived chiral diamine 56 in conjunction with benzoyl chloride as the stoichiometric acyl donor in the presence of EtjN, asymmetric benzoylation of a variety of me o-diols could be achieved with good to excellent enantioselectivities (66-96% ee) and 80% yields (Scheme 24) [179-182],... 

Another example showing the utility of 1 is the asymmetric hydrogenation of vinyl esters which usually are used as acyl donors in enzymatic resolution. In this transformation, vinyl esters are converted to ketones which then undergo asymmetric reductive acylation to give chiral esters as described in Scheme 1.13. The overall reaction thus corresponds to the asymmetric hydrogenation of vinyl ester to the corresponding alkyl esters. 

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... 

Several chiral racemic alkylamines have been successfully resolved using hydrolase-catalyzed acylation reactions with esters as acyl donors. A few examples are described here (Table 4.2). 

Schering Plough demonstrated the kinetic resolution of a secondary amine (24) via enzyme-catalyzed acylation of a pendant piperidine (Scheme 7.13) [32]. The compound 27 is a selective, non-peptide, non-sulfhydryl farnesyl protein transfer inhibitor undergoing clinical trials as a antitumor agent for the treatment of solid tumors. The racemic substrate (24) does not contain a chiral center but exists as a pair of enantiomers due to atropisomerism about the exocylic double bond. The lipase Toyobo LIP-300 (lipoprotein lipase from Ps. aeruginosa) catalyzed the isobu-tylation of the (+) enantiomer (26), with MTBE as solvent and 2,2,2-trifluoroethyl isobutyrate as acyl donor [32]. The acylation of racemic 24 yielded (+) 26 at 97% and (-) 25 at 96.3% after 24h with an E >200. The undesired enantiomer (25)... 

The resolution of chiral amines via lipase-catalyzed enantioselective acylation is now a major industrial process, but interest in adopting ionic liquid reaction media has been surprisingly scant. Interestingly, acids could be used as the acyl donor (Figure 10.15) rather than the usual activated ester in a range ofionic liquids. CaLB was employed as the biocatalyst, and water was removed to shift the equilibrium toward the product [130, 131]. The highest rates were found in [BMMIm][TfO], [EMIm][TfO], and [EMIm][BF4]. 

Racemization of (S)-l-phenylethanol in the presence of an Ru p-cymerie binu-clear complex and triethylamine was much faster in [BMIm][BF4] or [BMIm][PF,s] than in toluene [136]. A range of chiral alcohols (Figure 10.17) were resolved in the presence of this complex and immobilized PsL. The reactions were performed in [BM Im][PF6] with the activated ester 2,2,2-trifluoroethyl acetate as the acyl donor (Figure 10.17). A hydrogen donor was required to prevent the formation of partially oxidized byproducts. Enantiomerically pure acetates were isolated in high yield (>85%). 

The enantiopreference of the protease subtilisin in the acylalion of chiral alcohols is known to be opposite to that observed with lipases, providing for access to both enantiomers with DKR, depending on the enzyme used [137, 138, 139]. Acylation using 2,2,2-trifluoroethyl butyrate as the acyl donor was combined with in situ racemization, affording the corresponding esters in high yield and [135]. 

To test the feasibility of enzyme-catalyzed enantiosective reactions in solid/gas reactors and to evaluate the efficiency of the resolution obtained in the gas phase compared to liquid systems, resolution of racemic 2-pentanol, catalyzed by CALB, through alcoholysis with methyl propanoate as acyl donor has been investigated in both liquid media and the gas phase [24]. As CALB has an enantiopreference for R enantiomers of secondary alcohols, this last reaction leads to S-2-Pentanol. This compound is a chiral intermediate in the synthesis of several potential anti-Alzheimer s drugs that inhibit 3-amyloid peptide release and/or its synthesis [25]. The degree of enantioselectivity was measured by using the enantiomeric ratio E, which is defined as the ratio of the specificity constants kcat/KM for the enantiomers (R/S in this case). E can be determined from the enantiomeric excess of... 

In the first attempts to use a chiral a-sulfinyi ester enolate as donor in Michael additions to a -un-saturated esters, only low selectivities were observed.185 186 Better results are obtained when the a-lithio sulfoxide (174), a chiral acyl anion equivalent, is employed. Conjugate addition of (174) to cyclopent-enone derivatives occurs with reasonably high degrees of asymmetric induction, as exemplified by the preparation of the 11-deoxy prostanoid (175 Scheme 63).187 188 Chiral oxosulfonium ylides and chiral li-thiosulfoximines can be used for the preparation of optically active cyclopropane derivatives (up to 49% ee) from a, -unsaturated carbonyl compounds.189... 

The same concept is applicable to allylic alcohols, ketones, or ketoximes. Enol acetates or ketones were successfully converted in multi-step reactions to chiral acetates in high yields and optical yields through catalysis by Candida antarctica lipase B (CALB, Novozyme 435) and a ruthenium complex. 2,6-Dimethylheptan-4-ol served as a hydrogen donor and 4-chlorophenyl acetate as an acyl donor for the conversion of the ketones (Jung, 2000a). 

In a one-pot reaction, a series of ketones were converted to chiral acetates with the help of an achiral ruthenium complex and CALB at 1 atm of hydrogen gas in ethyl acetate. Molecular hydrogen was equally effective in the transformation of enol acetates to chiral acetates in the same catalyst system without addition of additional acyl donors (Jung, 2000b). 

Quite efficient nucleophilic catalysts with planar (21a-c) and axial (22a-d) chirality were recently developed by Fu et al. [17-22] and Spivey et al. [23-25], The ferrocene-derived catalysts developed by Fu (21a-c) were first tested in the kinetic resolution of aryl alkyl carbinols with diketene as the acyl donor. 

Later studies focused on the planar chiral DMAP derivative 21c as catalyst and use of acetic anhydride as an inexpensive and readily available acyl donor [19]. Under these conditions (2 mol% catalyst loading, r.t.) kinetic resolution of several racemic alcohols could be achieved with selectivity factors up to 52 (Scheme 12.7). As a consequence, enantiomerically highly enriched alcohols (> 95% ee) could be obtained at conversions only slightly above 50%. 

Catalytic kinetic resolution of amines has been a typical domain of enzymatic transformations. Attempts to use low-molecular-weight catalysts have notoriously been frustrated by the rapid uncatalyzed background reaction of the amine substrate with the acyl donor [40]. The first solution to this problem was recently developed by Fu, who used the planar chiral catalyst 21d and O-acyl azlactone 40 as the acyl donor (Scheme 12.19) [41]. In this process, the acyl transfer from the azlactone 40 to the nucleophilic catalyst 21d is rapid relative to both direct transfer to the substrate and to the transfer from the acylated catalyst to the substrate amine. Under these conditions, which implies use of low reaction temperatures, selectivity factors as high as 27 were achieved (Scheme 12.19) [41]. 

Primary alcohols have been successfully used as substrates for lipases. Monterde et. Al60 reported the resolution of the chiral auxiliary 2-methoxy-2-phenylethanol 1 via Candida antarctica lipase B (CAL-B)-catalyzed acylation using either vinyl acetate (R=H) or isopropenyl acetate (R= CH3) as acyl donor (cf. fig. 8) and the alkoxycarbonylation using diallyl carbonate as the alkoxycarbonylation agent in THF at 30 °C (cf. fig. 9). 

Figure 15 Gas chromatographic chiral separation of (left) racemic l-(4-methoxy-phenyl)ethanol 22 and its corresponding acetate 22a (reference) and (right) lipase-catalyzed transesterification of l-(4-methoxy-phenyl)ethanol 22 (4 hrs) using isopropenyl acetate as acyl donor in toluene as organic solvent ees= 99.9 eep= 87 conv. =53.4, E=141.

Diols of different structures such as the meso-diol 76 (Fig. 41), the C2-symmetric diol rac-79 (Fig. 42), the diol rac-82 in which the primary hydroxy group is protected (Fig. 43) and the unprotected diol rac-84 with a primary and secondary hydroxy group (Fig. 44) were used as substrates in the lipase-catalyzed transesterification using vinyl acetate as acyl donor in organic solvents with the aim to prepare chiral buildings blocks of high enantiomeric purity.86... 

The first enzymatic desymmetrizations of prochiral phosphine oxides was recently reported by Kielbasinski et al.88 Thus, the prochiral bis(methoxycarbonylmethyl)-phenylphosphine oxide 93 was subjected to the PLE-mediated hydrolysis in buffer affording the chiral monoacetate (RJ-94 in 72% ee and 92% chemical yield. In turn, the prochiral bis(hydroxymethyl)phenylphosphine oxide 95 was desymmetrized using either lipase-catalyzed acetylation of 95 with vinyl acetate as acyl donor in organic solvent or hydrolysis of 97 in phosphate buffer and solvent affording the chiral monoacetate 96 with up to 79% ee and 76% chemical yield. 

Acyl transfer to alcohols and amines is related mechanistically to ester hydrolysis but yields a complementary set of products that are useful in their own right and as chiral synthons for the preparation of more complex materials. Such transformations can be difficult to achieve in water, however, because the solvent, which is present in vast excess, can participate directly in the reaction as a reactant. Enzyme-like specificity is thus required to favor the bimolecular reaction between alcohol and ester and prevent spontaneous hydrolysis of the acyl donor. 

This means that the chiral catalyst participates in nucleophilic attack on an achiral acyl donor to afford a reactive chiral acyl salt. Nucleophilic attack on this salt by an appropriate nucleophile (an alcohol, amine or 7r-nucleophile) then provides the acylated product and regenerates the catalyst. This latter step determines the stereochemistry, but knowledge of the precise mechanism by which stereochemical information is transferred in most of these processes is still rather limited. 

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