Double kinetic resolution

Figure 11, Double kinetic resolution using enzymes with opposite enantioselectivity. PPL, porcine pancreatic lipase PLE, pig liver esterase.

Within limits, an increase in the steric bulk at the olefin terminus of allylic alcohols of the type R1 CH(OH)CH=CHR2 causes an increase in the rate of epoxidation of the more-reactive enantiomer, and a decrease in the rate for the less-reactive enantiomer, resulting in enhanced kinetic resolution334. However, complexes of diisopropyl tartrate and titanium tetra-terf-butoxide catalyse the kinetic resolution of racemic secondary allylic alcohols with low efficiency335. Double kinetic resolution techniques can show significant advantages over the simple Sharpless epoxidation techniques336. 

Double kinetic resolution. Davies et at.2 have noted that the enantiomeric selectivity of Sharplcss asymmetric epoxidation of an allylic alcohol can be enhanced in some cases by use of two kinetic resolutions. Thus epoxidation of the allylic alcohol 1 with (+)-DiPT as the chiral component (58% conversion) provides the epoxide 2 and the less reactive enantiomer (R) of I, which can be recovered and epoxidized with (—)-DiPT. Using this technique, the epoxide 3 was obtained from I in 86% ec. This strategy is... 

In 2005, Cong et al. developed a new method for the resolution of 2-octanol by combining a DKR with a double kinetic resolution. Indeed, the method was based on the feasibility of using the residue of one double kinetic resolution as the substrate of the next double kinetic resolution, etc., and recycling them to DKR. In these conditions, an 80% racemic substrate could be converted to enantiopure products as depicted in Scheme 3.31. 

Double kinetic resolution of 2-phenylpropan-1-ol with vinyl acetate using PPL as biocatalyst for the synthesis of (S)-turmenorol B. 

Two types of racemic 3-hydroxy phosphonates, in which the phosphono and hydroxy moiehes are separated hy double bond, were successfully resolved using a common enzyme-catalysed acetylation. Both acyclic 52 (Equation 28) and cyclic 54 (Equation 29) derivatives underwent easy acetylation under the kinetic resolution conditions to give the products in high yield and with almost full stereoselechvity. 

Kagan, H. B., New Approaches in Asymmetric Synthesis, 10, 175 Kinetic Resolution, 18, 249. Kalinowski, H.-O., Fast Isomerizations about Double Bonds, 7, 295. 

Many methods have been reported for the enantioselective synthesis of the remaining PG building block, the (J )-4-hydroxy-cyclopent-2-enone. For example, the racemate can be kinetically resolved as shown in Scheme 7-28. (iS )-BINAP-Ru(II) dicarboxylate complex 93 is an excellent catalyst for the enantioselective kinetic resolution of the racemic hydroxy enone (an allylic alcohol). By controlling the reaction conditions, the C C double bond in one enantiomer, the (S )-isomer, will be prone to hydrogenation, leaving the slow reacting enantiomer intact and thus accomplishing the kinetic resolution.20... 

Asymmetric Synthesis Using a Chiral Molybdenum Catalyst In olefin metathesis, a double bond is cleaved and a double bond is formed. Thus, a chiral carbon center is not constructed in the reaction. To realize the asymmetric induction by ring-closing metathesis, there are two procedures a kinetic resolution and desym-metrization of symmetric prochiral triene. Various molybdenum complexes are synthesized in order to explore the viabihty of these approaches (Figure 6.2). 

Langlois and co-workers (179) found the same exo stereochemical preference through double asymmetric induction of a related ene-lactone (1 )-145 with their well-explored and efficient camphor-derived oxazoline nitrone (150-146 (Scheme 1.32). They found the cycloaddition components form a matched pair and allowed kinetic resolution of the racemic lactone in up to 70% enantiomeric excess (ee). They suggest the selectivity for exo adduct 147 arises through destabilization of the endo transition state by a steric clash between dipolarophile ring hydrogens and the bornane moiety. 

Efficient kinetic resolution of chiral unsaturated secondary alcohols by irreversible enzyme-mediated acylation (with vinyl acetate as acylating agent, a crude preparation of Pseudomonas AK, and hexane as solvent) is possible, provided one relatively large and one small substituent are attached to the carbinol carbon. However, the method can be used to resolve substrates that are not amenable to asymmetric epoxidation (see examples 23, 25, 27, 29, where the double bond is either deactivated by an electron-withdrawing substituent, or is of the propargyl alcohol type). Acylation of the / -enantiomer consistently proceeds faster than that of the 5-enantiomer. An example of an allenic alcohol was also reported248. 

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 Sharpless epoxidation is sensitive to preexisting chirality in selected substrate positions, so epoxidation in the absence or presence of molecular sieves allows easy kinetic resolution of open-chain, flexible allylic alcohols (Scheme 26) (52, 61). The relative rates, kf/ks, range from 16 to 700. The lower side-chain units of prostaglandins can be prepared in high ee and in reasonable yields (62). A doubly allylic alcohol with a meso structure can be converted to highly enantiomerically pure monoepoxy alcohol by using double asymmetric induction in the kinetic resolution (Scheme 26) (63). A mathematical model has been proposed to estimate the degree of the selectivity enhancement. 

Scheme 81 shows a highly enantioselective C—C bond formation in the BINAP-Pd(II) diacetate-catalyzed reaction of aryl triflate and 2,3-dihydiofuran (193). A BINAP-Pd(0) species generated by the action of a tertiary amine on the Pd(II) complex is the actual catalyst. Enhancement of the enantioselectivity through kinetic resolution of the intermediate is indicated by the double-bond isomer having opposite absolute configuration at the arylated carbon. / -Substituted 2-pyrrolines may also be used as olefinic substrates. 

The reaction with N-Boc-pyrrolidine may be taken a step further by inducing a double C-H insertion sequence [27]. This results in the formation of the elaborate C2-symmetric amine 35 as a single diastereomer with control of stereochemistry at four stereogenic centers. The enantiomeric purity of 35 is higher than that obtained for the single C-H insertion products, presumably because kinetic resolution is occurring in the second C-H insertion step. 

A small, structurally distinct class of 1 -substituted allylic alcohols consists of those that are conformationally restricted by incorporation into a ring system. These allylic alcohols may be further subdivided into two types, depending on whether the double bond is endocyclic or exocyclic. For allylic alcohols with endocyclic double bonds, kinetic resolution gives 2-cyclohexen-l-ol (71) with 30% ee [14], (4a.S, 2/ )-4a-methyl-2,3,4,4a,5,6,7,8-octahydro-... 

R)-lrans-Verbenol (77) is epoxidized five times as fast as (S)-/rarcs-verbenol when (+)-DlPT is used in the catalyst [77]. For allylic alcohols with an exocyclic double bond, kinetic resolution gives 2-methylenecyclohexanol (78) with 80% ee in 46% yield when (-)-DIPT is used [119]. 

---