Resolution of Secondary Alcohols

The ester was most easily separated from the alcohol by distillation. The (S)-alcohol was also recovered in 36% yield. Further stereoselective transformations on the (R)-ester resulted in an efficient synthesis of (R)-methadone, the pharmacologically active enantiomer. 

Additionally, the same researchers studied the enantiopreference of GALA and CALB across a variety of racemic ethyl 3-hydroxy-3-(furyl/thienyl)propanoates. The separation of enantiomers at the maximum theoretical yield was achievable because of the high enantioselectivity displayed ( 200). An interesting inverted enantiopreference of GALA was reported despite its low enantioselectivity (E = 14-54) the behaviour of GALA and CALB depends on the substrate structure [12]. 

Difficult-to-resolve secondary alcohols that generally require high enzyme loading, long reaction time and achieve only moderate E values were successfully resolved using a novel lipase panel containing 23 enzymes. The superiority of these novel enzymes over GALB has been demonstrated [14]. 

Not only was excellent ee ( 99%) obtained under mild reaction conditions, but the biocatalyst was found to be quite stable and could be re-used several times with little decrease in performance. 

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The second group of studies tries to explain the solvent effects on enantioselectivity by means of the contribution of substrate solvation to the energetics of the reaction [38], For instance, a theoretical model based on the thermodynamics of substrate solvation was developed [39]. However, this model, based on the determination of the desolvated portion of the substrate transition state by molecular modeling and on the calculation of the activity coefficient by UNIFAC, gave contradictory results. In fact, it was successful in predicting solvent effects on the enantio- and prochiral selectivity of y-chymotrypsin with racemic 3-hydroxy-2-phenylpropionate and 2-substituted 1,3-propanediols [39], whereas it failed in the case of subtilisin and racemic sec-phenetyl alcohol and traws-sobrerol [40]. That substrate solvation by the solvent can contribute to enzyme enantioselectivity was also claimed in the case of subtilisin-catalyzed resolution of secondary alcohols [41]. 

The complex Pd-(-)-sparteine was also used as catalyst in an important reaction. Two groups have simultaneously and independently reported a closely related aerobic oxidative kinetic resolution of secondary alcohols. The oxidation of secondary alcohols is one of the most common and well-studied reactions in chemistry. Although excellent catalytic enantioselective methods exist for a variety of oxidation processes, such as epoxidation, dihydroxy-lation, and aziridination, there are relatively few catalytic enantioselective examples of alcohol oxidation. The two research teams were interested in the metal-catalyzed aerobic oxidation of alcohols to aldehydes and ketones and became involved in extending the scopes of these oxidations to asymmetric catalysis. 

In 2003, Sigman et al. reported the use of a chiral carbene ligand in conjunction with the chiral base (-)-sparteine in the palladium(II) catalyzed oxidative kinetic resolution of secondary alcohols [26]. The dimeric palladium complexes 51a-b used in this reaction were obtained in two steps from N,N -diaryl chiral imidazolinium salts derived from (S, S) or (R,R) diphenylethane diamine (Scheme 28). The carbenes were generated by deprotonation of the salts with t-BuOK in THF and reacted in situ with dimeric palladium al-lyl chloride. The intermediate NHC - Pd(allyl)Cl complexes 52 are air-stable and were isolated in 92-95% yield after silica gel chromatography. Two diaster corners in a ratio of approximately 2 1 are present in solution (CDCI3). 

Interestingly, the scope of the reaction using this catalyst can be extended to oxidative kinetic resolution of secondary alcohols by using (-)-sparteine as a base (Table 10.2) [25]. The best enantiomeric excess of the alcohol was obtained when a chiral enantiopure base and an achiral catalyst were used. The use of chiral enantiopure catalyst bearing ligand 17 led to low enantioselectivity. 

Zhu, Y-.Z., Fow, K.L., Chuah, G.K. and Jaenicke, S., Dynamic kinetic resolution of secondary alcohols combining enzyme-catalyzed transesterification and zeolite-catalyzed racemisation. Chem. Eur. J. 2007, 13, 541. 

Van Nispen, S.E.G.M., van Buijtenen, J., Vekemans, J.A.J.M., Meuldijk, J. and Hulshof, L.A., Efficient dynamic kinetic resolution of secondary alcohols with a novel tetrafluorosuccinato ruthenium complex. Tetrahedron Asymm., 2006, 17, 2299. 

Verzijl, G.K.M., de Vries, J.G. and Broxterman, Q.B., Removal of the acyl donor residue allows the use of simple alkyl esters as acyl donors for the dynamic kinetic resolution of secondary alcohols. Tetrahedron Asymm., 2005, 16, 1603. 

Janssen, A. J. M. Klunder, A. J. H. Zwanenburg, B. Resolution of secondary alcohols by enzyme-catalyzed transesterification in alkyl carboxylates as the solvent. Tetrahedron 1991, 47, 7645-7662. 

Monoacylation of achiral and meso diols has been a popular strategy for introducing asymmetry and, in addition to kinetic resolutions of secondary alcohols, a... 

The groups of Sigman and Stoltz have concurrently published the palladium-catalyzed oxidative kinetic resolution of secondary alcohols using molecular oxygen as the stoichiometric oxidant. Both communications also described a single example of a diol desymmetrization using a palladium catalyst in the presence of (—(-sparteine [Eqs. (10.42) ° and (10.43) ] ... 

Scheme 1.3 Lipase-catalyzed resolution of secondary alcohols.

Oxidative kinetic resolution of secondary alcohols mediated with a catalytic amount of optically active binaphthyl-type iV-oxyl has been performed with high selectivity". Also, it has mediated oxidative asymmetric desymmetrization of primary alcohols with good selectivity (equation 25)". ... 

A similar carbonylative coupling reaction was applied to the kinetic resolution of secondary alcohols [63]. In the presence of a Pd catalyst ligated by chiral oxazolinylferrocenylphosphine, the pentavalent Ph3Bi(OAc)2 and carbon monoxide effectively benzoylated secondary alcohols, and up to 48% enantiomeric excess (ee) was attained (Scheme 47). Although the enantioselectivity is not satisfactory, this is a unique new procedure for the kinetic resolution. 

Scheme 47 Kinetic resolution of secondary alcohols by carbonylative coupling reaction of Ph3Bi (OAc)2...

Polymers derived from natural sources such as proteins, DNA, and polyhy-droxyalkanoates are optically pure, making the biocatalysts responsible for their synthesis highly appealing for the preparation of chiral synthetic polymers. In recent years, enzymes have been explored successfully as catalysts for the preparation of polymers from natural or synthetic monomers. Moreover, the extraordinary enantioselectivity of lipases is exploited on an industrial scale for kinetic resolutions of secondary alcohols and amines, affording chiral intermediates for the pharmaceutical and agrochemical industry. It is therefore not surprising that more recent research has focused on the use of lipases for synthesis of chiral polymers from racemic monomers. 

Although many publications have covered the enantioselectivity of lipases in the deacylation step, their enantioselectivity in the acylation step (i.e., towards the acyl donor) has received much less attention. Generally, the selectivity of lipases towards racemic esters or acids is low to moderate [75-77]. Directed evolution and site-directed mutagenesis lead to a significant increase in the selectivity of the wild-type enzymes [78-80]. However, the enantiomeric ratios attained are still well below those typically obtained in kinetic resolutions of secondary alcohols. 

Whereas resolutions of secondary alcohols by hydrolase-catalyzed acylation in organic solvents often proceed with high E-values (see Section 4.2.1.2), primary alcohols are much more difficult to resolve. There are, however, many examples of successful resolutions of primary alcohols, and a selection of these will be described here. 

Vedejs and co-workers have explored the use of chiral phosphines as acyl transfer catalysts. The viability of this approach was proven when phosphine 1 was shown to catalyze the resolution of secondary alcohols with promising selectiv-ities (Scheme 2) [10,11]. 

Scheme 4. Planar chiral DMAP analog 10 as a catalyst for kinetic resolution of secondary alcohols...

A new class of chiral 4-A,A-dialkylaminopyridine acyl-transfer catalysts has been developed that are capable of exploiting both van der Waals (jt) and H-bonding interactions to allow remote chiral information to control stereochemically the kinetic resolutions of secondary alcohols with moderate to excellent selectivity (S = 6-30). Catalysts derived from (.S )- , -diarylprolinol (89 Ar = Ph, 2-naphthyl) in combination with isobutyric anhydride were found to possess high activity and selectivity across a broad range of substrates 89... 

Chiral A-salicylidene vanadyl carboxylates are efficient catalysts for asymmetric aerobic oxidation of a-hydoxy esters and amides with divergent substituents. These catalysts have been explored for the kinetic resolution of secondary alcohols also. The stereochemical origin of the almost total asymmetric control has been probed.262... 

The standard in the field was set with the following racemic resolution of secondary alcohols the transesterification of vinyl acetate to (S)-O-acetyl phenylethanol was catalyzed at room temperature by (isopropylamino)cyclopentadienylruthenium chloride and CALB with 97% yield and > 99% e.e. A reaction temperature of 25 °C, a reaction time of 30 h, and use of molecular sieve 4 A as a water trap, sodium carbonate as base, and vinyl acetate as acyl donor, are all major improvements over the previous state-of-the-art (Choi, 2002). 

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]. 

Toda, F., Matsuda, S., and Tanaka, K. (1991) Efficient Resolution of Secondary Alcohols, Cyanohydrins, and Glycerol Acetates by Complexation with the Host Derived from Tartaric Acid, Tetrahedron Asymm., 2, 983-986. 

Rate of complex formation between chiral alcohols and DBTA monohydrate in hexane suspension is quite slow (see Figure 1) and numerous separation steps are necessarry for isolation of the alcohol isomers (filtration of the diastereoisomeric complex then concentration of the solution, decomposition of the complex, separation of the resolving agent and the enantiomer, distillation of the product). To avoid these problems, alternative methods have been developed for complex forming resolution of secondary alcohols. In a very first example of solid phase one pot resolution [40] the number of separation steps was decreased radically. Another novel method [41] let us to increase the rate of complex forming reaction in melt. Finally, first examples of the application of supercritical fluids for enantiomer separation from a mixture of diastereoisomeric complexes and free enantiomers [42, 43] are discussed in this subchapter. 

An attractive method for the determination of the enantiomeric excess of substrates and products resulting from the enzyme-catalyzed kinetic resolution of secondary alcohols is chiral gas chromatography (GC).48,49 This sensitive method is quick, simple to carry out and unaffected by the presence of impurities in the analyzed sample, therefore, isolation and purification of the analyzed sample is not required. Very small sample size is required for the analysis hence, reactions can be done on small scale. 

Ghanem, A. Schurig, V. Entrapment of Pseudomonas cepacia lipase with cyclodextrin in sol-gel application to the kinetic resolution of secondary alcohols. Tetrahedron Asymmetry 2003, 14, 2547-2555. 

Ghanem, A. The utility of cyclodextrins, sol-gel procedure and gas chromatography in lipase-mediated enantioselective catalysis kinetic resolution of secondary alcohols. PhD Thesis, University of Tubingen, 2002. 

Dynamic kinetic resolutions of secondary alcohols and amines have been achieved by the combination of biocatalysts with metal catalysts.12 For example, a metal catalyst was used to racemize the substrate, phenylethanol, and a lipase was used for the enantioselective esterification as shown in Figure 12. The yield was improved from 50% in kinetic resolution without racemization of the substrate to 100% with metal catalyzed racemization. 

Kinetic resolution of secondary alcohols has been efficiently achieved using a vana-dium(V) complex and oxygen as a stoichiometric oxidant. The ligand architecture allows access to both enantiomers of a secondary alcohol by choice of ligand stereoisomer. The mild reaction conditions and chemoselectivity of the catalyst system provide access to a range of a-hydroxy esters in high yields and excellent enantioselectivities. 

Pd(II) catalysts have been widely used for aerobic oxidation of alcohols. The catalytic systems Pd(OAc)2-(CH3)2SO [14] and Pd(OAc)2-pyridine [15] oxidize allylic and benzylic alcohols to the corresponding aldehydes and ketones. Secondary aliphatic alcohols, with relatively high water solubility, have been oxidized to the corresponding ketones by air at high pressure, at 100 °C in water, by using a water-soluble bathophenanthroline disulfonate palladium complex [PhenS Pd(OAc)2] [5d]. The Pd catalyst has also been successfully used for aerobic oxidative kinetic resolution of secondary alcohols, using (-)-sparteine [16]. 

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