Kinetic Optical Resolution

On the basis of the desymmetrization concept, the kinetic optical resolution of a racemic substrate [66] can be recognized as an intermolecular version of desymmetrization. The kinetic resolution of a racemic allylic ether by the glyoxylate-ene reaction also provides efficient access to remote but relative [64] asymmetric induction. The reaction of allylic ethers catalyzed by the (f )-BINOL-derived complex (1) provides the 2R,5S)-syn products with 99 % diastereoselectivity and 95 % ee (Sch. 18). The high diastereoselectivity, coupled with the high ee, strongly suggests that the cata-lyst/glyoxylate complex efficiently discriminates between the two enantiomeric substrates to accomplish the effective kinetic resolution. In fact, the relative rates of the reactions of the enantiomers, calculated by use of the equation  

---

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. 

The kinetic optical resolution [32] of a racemic substrate might be considered as an intermo-lecular version of desymmetrization. In principle, the kinetic resolution of a racemic allylic ether... 

Scheme 8C.12. Kinetic optical resolution in asymmetric carbonyl-ene reaction catalyzed by BINOL-Ti complex.

On the basis of the desymmetrization concept, the kinetic optical resolution of a racemic substrate [42a, 42b] might be recognized as an intermolecular version of the desymmetrization. The kinetic resolution of a racemic allylic ether by the glyoxylate-ene reaction also provides an efficient access to remote but relative... 

Reactive ketenes (usually generated in situ by treating an appropriate acyl chloride with a base) undergo the [2 + 2] cycloaddition with fluorinated imine to afford the mixture of stereoisomers of p-lactam 67 (Scheme 2.31). Then the kinetic optical resolution is performed on the product to obtain pure enantiomers. 

BINOL-Ti-catalyzed carbonyl-ene reaction of glyoxylate has also been applied to the asymmetric desymmetrization of prochiral ene substrates with planar symmetry and kinetic optical resolution of racemic ether. As shown in Scheme 14.55, optically active products can be obtained with extremely high enantiomeric excesses [140]. The asymmetric desymmetrization of meso olefin derivative via BINOL-Ti-catalyzed carbonyl-ene reaction of formaldehyde, vinyl and alkynyl analogs of glyoxylates has been applied to the synthesis of isocarbocycline analogs [141]. 

The Salen motif has been widely utilized as a ligand for transition metals. Jacobsen et al. reported that chiral salen-cobalt complex (Co-salen) could be utilized as a Lewis acid catalyst for hydrolytic kinetic optical resolution of racemic... 

Prior to our work, Hawkins and Meyer had performed the kinetic optical resolution of the inherently chiral fiillerene D2-C76 by employing the asymmetric Sharpless osmylation reaction [17]. A comparison of the circular dichroism (CD) spectra reported by I wkins and Meyer for the C76 enantiomers that they obtained [17] to those of a variety of optically active, covalent derivatives of C76, prepared by us [18] revealed a large, unexpected difference in the magnitude of the Cotton effects. Whereas our covalent C76 derivatives displayed bands reaching Ae values up to 250 M cm , the enantiomers of the pure hillerenes reported by Hawkins and Meyer displayed bands widi Ae values up to only 32 M cm [17, 19]. In order to reinvestigate the chiroptical... 

Chiral sulphoxides are the most important group of compounds among a vast number of various types of chiral organosulphur compounds. In the first period of the development of sulphur stereochemistry, optically active sulphoxides were mainly used as model compounds in stereochemical studies2 5 6. At present, chiral sulphoxides play an important role in asymmetric synthesis, especially in an asymmetric C—C bond formation257. Therefore, much effort has been devoted to elaboration of convenient methods for their synthesis. Until now, optically active sulphoxides have been obtained in the following ways optical resolution, asymmetric synthesis, kinetic resolution and stereospecific synthesis. These methods are briefly discussed below. 

Mikolajczyk and coworkers have summarized other methods which lead to the desired sulfmate esters These are asymmetric oxidation of sulfenamides, kinetic resolution of racemic sulfmates in transesterification with chiral alcohols, kinetic resolution of racemic sulfinates upon treatment with chiral Grignard reagents, optical resolution via cyclodextrin complexes, and esterification of sulfinyl chlorides with chiral alcohols in the presence of optically active amines. None of these methods is very satisfactory since the esters produced are of low enantiomeric purity. However, the reaction of dialkyl sulfites (33) with t-butylmagnesium chloride in the presence of quinine gave the corresponding methyl, ethyl, n-propyl, isopropyl and n-butyl 2,2-dimethylpropane-l-yl sulfinates (34) of 43 to 73% enantiomeric purity in 50 to 84% yield. This made available sulfinate esters for the synthesis of t-butyl sulfoxides (35). 

Optically active selenoxides are known to be unstable toward racemization. An optically active selenoxide having a steroidal frame was obtained for the first time by Jones and co-workers in 1970.7 Enantiomeric selenoxides were prepared by Davis et al. in 1983,8 and an enantiomerically pure selenoxide was isolated for the first time by us in 1989.9 Many optically active selenoxides, which are kinetically stabilized by bulky substituents, were synthesized over the last two decades, and their stereochemistry and stability toward racemization were studied.3,5,10 Recently, some optically active selenoxides, which were thermodynamically stabilized by the intramolecular coordination of a Lewis base to the selenium atom, have been isolated. Optically active selenoxides 1 and 2 were obtained by optical resolution on chiral columns, and their stereochemistry and stability toward racemization under various conditions were clarified (Scheme 1).11,12... 

Approaches to oseltamivir phosphate (1) that were independent of ( )-shikimic acid as the raw material were also evaluated. The furan-ethyl acrylate Diels-Alder approach is shown in Scheme 7.8 (Abrecht et al., 2001, 2004). The zinc-catalyzed Diels-Alder reaction between furan and ethyl acrylate was heated at 50°C for 72 h to provide a 9 1 mixture favoring exo-isomer rac-43 over the enJo-isomer. The enJo-isomer was kinetically preferred, but with increased reaction times an equilibrium ratio of 9 1 was achieved favoring the thermodynamically preferred exo-isomer rac-43. The optical resolution of rac-43 was achieved via enantioselective ester hydrolysis using Chirazyme L-2 to give (—)-43 in 97%... 

Contrary to the optical resolutions described in Sections 2.1.1.-2.1.3., which depend on the solubility or chromatographic properties ( Thermodynamic resolution ), the kinetic resolution rests on rate differences shown by the enantiomers when reacted with an optically active reagent. In the ideal case, only one enantiomer is converted into the envisaged product and the other enantiomer is unchanged. In this way, optical resolution is reduced to the more simple separation of two different reaction products. In practice, only two methods of kinetic resolution are reasonably general and reliable the Sharpless epoxidation of allylic alcohols and the enzymatic transesterification of racemic alcohols or carboxylic acids. 

Yeast-mediated reductions predominantly form a single enantiomer and it is often difficult to find conditions which produce the opposite stereoisomer selectively. It has, however, been possible to obtain both enantiomers in 50% yield in 100% via enzymatic optical resolution. Chiral fluorinated secondary alcohols possessing the mono-, di- and/or trifluoromethyl group have been prepared by enzyme-catalyzed kinetic resolutions [27]. 

The kinetic results for the lipase-catalysed enantioselective hydrolysis of the esters (236)-(240) can be interpreted in terms of frontier orbital localization.213 The porcine pancreatic lipase (PPL)-mediated optical resolution of 18 racemic esters can be explained by a mechanistic model involving a W-shaped active conformation of the substrate lying in a diastereo-discriminating plane.214... 

Stereoselective enzymatic hydrolyses of esters represent a further type of biotransformation that has been used for the synthesis of optically active organosilicon compounds. The first example of this particular type of bioconversion is illustrated in Scheme 15. Starting from the racemic (l-acetoxyethyl)silane rac-11, the optically active (l-hydroxyethyl)silane (5)-41 was obtained by a kinetic racemate resolution using porcine liver esterase (PLE E.C. 3.1.1.1) as the biocatalyst7. The silane (5)-41 (isolated with an enantiomeric purity of 60% ee bioconversion not optimized) is the antipode of compound (R)-41 which was obtained by an enantioselective microbial reduction of the acetylsilane 40 (see Scheme 8). 

The enantioselective hydrolysis of the racemic 2-acetoxy-l-silacyclohexane rac-78 represents a further example of an enzymatic kinetic racemate resolution (Scheme 15). Hydrolysis of this compound in the presence of porcine liver esterase (PLE E.C. 3.1.1.1) yielded the optically active 1-silacyclohexan-2-ol (S)-43 which was isolated with an enantiomeric purity of 93% ee7. Similar results were obtained when using a crude lipase preparation from Candida cylindracea (CCL E.C. 3.1.1.3) as the biocatalyst... 

Enantioselective enzymatic transesterifications have been used as a complementary method to enantioselective enzymatic ester hydrolyses. The first example of this particular type of biotransformation is the synthesis of the optically active 2-acetoxy-l-silacyclohexane (5 )-78 (Scheme 19). This compound was obtained by an enantioselective transesterification of the racemic l-silacyclohexan-2-ol rac-43 with triacetin (acetate source) in isooctane, catalyzed by a crude lipase preparation from Candida cylindracea (CCL, E.C. 3.1.1.3)62. After terminating the reaction at 52% conversion (relative to total amount of substrate rac-43), the product (S)-78 was separated from the nonreacted substrate by column chromatography on silica gel and isolated in 92% yield (relative to total amount of converted rac-43) with an enantiomeric purity of 95% ee. The remaining l-silacyclohexan-2-ol (/ )-43 was obtained in 76% yield (relative to total amount of nonconverted rac-43) with an enantiomeric purity of 96% ee. Repeated recrystallization of (R)-43 led to an improvement of enantiomeric purity by up to >98% ee. Compound (R)-43 has already earlier been prepared by an enantioselective microbial reduction of the l-silacyclohexan-2-one 42 (see Scheme 8)53. The l-silacyclohexan-2-ol (R)-43 is the antipode of compound (.S j-43 which was obtained by a kinetic enzymatic resolution of the racemic 2-acetoxy-l-silacyclohexane rac-78 (see Scheme 15)62. For further enantioselective enzymatic transesterifications of racemic organosilicon substrates, with a carbon atom as the center of chirality, see References 64 and 70-72. 

---