Kinetic resolution, of alcohols

Scheme 5.11 Dynamic kinetic resolution of alcohol 18 by combination of enzymatic transesterification and ruthenium-catalyzed racemization.

The low-temperature method is effective not only in the kinetic resolution of alcohols but also in the enantioface-selective asymmetric protonation of enol acetate of 2-methylcyclohexanone (15) giving (f )-2-methylcyclohexanone (16). The reaction in H2O at 30°C gave 28% ee (98% conv.), which was improved up to 77% ee (82% conv.) by the reaction using hpase PS-C 11 in /-Pt20 and ethanol at 0°C. Acceleration of the reaction with lipase PS-C 11 made this reaction possible because this reaction required a long reaction time. The temperature effect is shown in Fig. 14. The regular temperature effect was not observed. The protons may be supplied from H2O, methanol, or ethanol, whose bulkiness is important. 

Scheme 10.6 Mechanism of aerobic oxidation catalysed by complex 13 [23] Table 10.2 Oxidative kinetic resolution of alcohols using (-)-sparteine [25]...

Axially chiral Pd-NHC complexes reported by Shi and co-workers [26-28] have shown high selectivity in the oxidative kinetic resolution of alcohols without the need of addition of a chiral base. Enantiomeric excesses of up to 99% were obtained (Scheme 10.7). 

Scheme 10.7 Oxidative kinetic resolution of alcohols using chiral bis-NHC hgands [26-28] 10.3.1.2 Anaerobic Oxidation...

The empirical observation that (—)-sparteine 55 is necessary for catalysis implicates a base-promoted pathway in the mechanism. In the first step, a palladium alk-oxide is formed after alcohol binding, followed by p-hydride elimination of the alkoxide to yield a ketone product. On the basis of a kinetic study of the enantio-selective oxidation of 1-phenylethanol, it was revealed that (—)-sparteine plays a dual role in the oxidative kinetic resolution of alcohols, as a ligand on palladium and an exogeneous base " ... 

Lipase Catalyzed Kinetic Resolution of Alcohols via Chloroacetate Esters (-)-(lR,2S)-trans-2-Phenylcyclohexano1 and (+)-(lS,2R)-trans-2-Phenyl cyclohexanol... 

Even more interesting is the oxidative kinetic resolution of alcohols under aerobic conditions. The system Pd(lI)/sparteine/02 was reported to convert a racemic alcohol with high selectivity into the ketone and the alcohol [97-99]. This has also been shown to work with palladium carbene complexes (Scheme 16). 

Moreover, the already known abihty of iridium compounds to catalyze hydrogen transfer reactions has been excellently applied in Oppenauer-type and domino-type reactions for valuable organic chemicals and further developments, including asymmetric variants to kinetic resolution of alcohols and fine chemicals, can be expected. 

I.4.2. Enzymatic Kinetic Resolution of Alcohols and Carboxylic Acids... 

Compared to the chemo-catalyzed kinetic resolution of alcohols, there are few reports of similar reactions for amines. Building on other work, one elegant example from Berkessel uses bifunctional organocatalysts to enantioselectively hydrolyze a racemic azlactone, and the dynamic kinetic resolution (DKR) is achieved by in-situ acid-catalyzed racemization of the azlactone under mild conditions to give product N-acylarnino esters in, for example, 72% ee and 96% conversion with phenylalanine [6]. 

LIPASE-CATALYZED KINETIC RESOLUTION OF ALCOHOLS VIA CHLOROACETATE ESTERS (-)-(1R,2S)-trans-2-PHENYLCYCLOHEXANOL AND (+)-(1S,2R)-trans-2-PHENYLCYCLOHEXANOL... 

Fig. 3. Peptide-based catalysts for kinetic resolution of alcohols...

For examples of kinetic resolution of alcohols using chiral acylating agents, see Evans DA, Anderson JC, Taylor MK (1993) Tetrahedron Lett 34 5563-5566 Vedejs E, Chen X (1997) J Am Chem Soc 119 2584-2585... 

To recycle a valuable amine acylation catalyst, Janda and co-workers10 attached a proline-based catalyst to a polymeric support for the enan-tioselective kinetic resolution of alcohols (entry 6). The resin-bound catalyst behaves similarly to the soluble catalyst, providing good yields of secondary alcohols and their corresponding esters with good to excellent enantioselectivities for various substrates. 

Steric effects were evaluated by a study of the DMAP-catalysed acylation of 1 y, 2y and 3y alcohols by acetic, propionic, isobutyric, isovaleric, and pivalic anhydrides in CH2C12 at 20 °C. In all cases the reaction kinetics could be described by rate laws containing a DMAP-catalysed term and an uncatalysed (background) term. Steric effects were evident in both reactions, but were generally greater for the DMAP-catalysed reaction. For example, the uncatalysed reactions between cyclohexanol and acetic and pivalic anhydrides differed about 500-fold, but for the corresponding DMAP-catalysed reactions the factor was 8000-fold. The implications of these findings for the kinetic resolution of alcohols were discussed.32... 

Other centrally chiral amine catalysts reported for kinetic resolution of alcohols include the (S)-prolinol-derived dihydroisoindolines 12a,b (Scheme 12.4), devel-... 

It is especially worth noting that a method for non-enzymatic resolution of amines by acylation has also been developed. It is hoped that selectivity factors and ease of operation achieved in the kinetic resolution of alcohols will soon by possible with amines also. 

Kinetic resolution of alcohols Several peptide coupling... 

Martm-Matute B, Edin M et al (2004) Highly compatible metal and enzyme catalysts for efficient dynamic kinetic resolution of alcohols at ambient temperature. Angew Chem Int Ed... 

Figure 5.15 a Generic scheme of dynamic kinetic resolution of alcohols b example of the resolution of a racemic 8-aminotetrahydroquinoline, where the racemization iscatalyzed by the organic ketone 8-aza-l-tetralone (the racemization cycle is highlighted in gray). 

Fig. 12.14 Chiral nitroxyl radical 34 for oxidative kinetic resolution of alcohols.

It is worth mentioning the emergence of sequential catalytic processes involving a ruthenium-catalyzed step followed by a catalytic enzymatic transformation. This strategy has been developed by the groups of J.E. Backvall, and M.-J. Kim and J. Park especially for the dynamic kinetic resolution of alcohols (Scheme 50) [107-109]. 

Another important difference between (dynamic) kinetic resolution of alcohols and amines is the ease with which the acylated product, an ester and an amide, respectively, is hydrolyzed. This is necessary in order to recover the substrate enantiomer which has undergone acylation. Ester hydrolysis is generally a facile process but amide hydrolysis, in contrast, is often not trivial. For example, in the BASF process [28] for amine resolution by lipase-catalyzed acylation the amide product is hydrolyzed using NaOH in aq. ethylene glycol at 150 °C (Fig. 9.18). In the case of phenethylamine this does not present a problem but it will obviously lead to problems with a variety of amines containing other functional groups. 

Lipases are of remarkable practical interest since they have been used in numerous biocatalytic applications, such as kinetic resolution of alcohols and carboxyl esters (both in water and in non-aqueous media) [1], regioselective acylations of poly-hydroxylated compounds, and the preparation of enantiopure amino acids and amides [2, 3]. Moreover, lipases are stable in organic solvents, do not require cofactors, possess broad substrate specificity, and exhibit, in general, a high enantioselectivity. All these features have contributed to make hpases the class of enzyme with the highest number of biocatalytic applications carried out in neat organic solvents. 

---