Resolution catalytic kinetic

Separation of Enantiomers Synthetic Methods, First Edition. Edited by Matthew Todd. 

As summarized in Table 3.1, catalysts 1-11 have provided good-to-excellent results for the KR of a wide range of unsaturated (functionalized) alcohols, such as benzylic, allylic and propargylic alcohols. 

In addition, Shiina et al. [34] have developed the first KR of secondary benzyhc alcohols with free carboxyhc acids as acylation agents catalysed by (-l-)-benzotetramizole 10, which allowed good selectivity factors of up to 94 to be 

In 2006, Pfaltz et al. demonstrated that boron-bridged anionic bisoxazoline C2-symmetric ligands could be successfully employed in the copper(II)-catalysed benzoylation of pyridyl alcohols, providing selectivity factors of up to 125 [36]. In 

In addition, a chiral 1,2-diamine derived from L-proUne was investigated as a catalyst for the KR of primary alcohols with acyl chlorides by Oriyama et al. [50], providing the highest selectivity factors of up to 16 in the case of glycerol derivatives as substrates. Chiral Ph-BOX-Cu(II) complex 17 has also been successfully 

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Catalytic kinetic resolution can be the method of choice for the preparation of enantioenriched materials, particularly when the racemate is inexpensive and readily available and direct asymmetric routes to the optically active compounds are lacking. However, several other criteria-induding catalyst selectivity, efficiency, and cost, stoichiometric reagent cost, waste generation, volumetric throughput, ease of product isolation, scalability, and the existence of viable alternatives from the chiral pool (or classical resolution)-must be taken into consideration as well... 

Furthermore, the same methodology was used for an approach towards enantiopure PGFla (2-46) through a catalytic kinetic resolution of racemic 2-43 using (S)-ALB (2-37) (Scheme 2.10) [14]. Reaction of 2-35, 2-36 and 2-43 in the presence of 2-37 led to 2-44 as a 12 1 mixture of diastereomers in 75 % yield (based on malonate 2-36). The transformation proceeds with excellent enantioselectivity thus, the enone 2-45 obtained from 2-44 shows an ee-value of 97 %. 

Keywords Catalytic metathesis, Enantioselective synthesis, Catalytic kinetic resolution, Catalytic carbomagnesation, Catalytic rearrangement, 2-Substituted chromenes, Catalytic m aero cyclization... 

Enantioselective Synthesis of Unsaturated Heterocycles by Tandem Catalytic RCM-Catalytic Kinetic Resolution... 

The resolution of rac-20 represents a less common form of catalytic kinetic resolution (parallel kinetic resolution) [9]. In conventional kinetic resolution, one substrate enantiomer reacts preferably to leave behind the unreacted isomer in high optical purity (e.g., rac-18 (k)-19 in Scheme 4). In this instance, both starting material enantiomers undergo catalytic alkylation to give constitutional isomers. Since both enantiomers are consumed simultaneously, as the reaction proceeds, the amount of slow enantiomer (relative to the unreacted fast enantiomer) does not increase. Therefore, product ee remains high, even at relatively high conversions. 

Catalytic RCM and another Zr-catalyzed process, the kinetic resolution of cyclic allylic ethers, joined forces in our laboratories in 1995 to constitute a fully-cata-lytic two-step synthesis of optically pure 2-substituted chromenes. These structural units comprise a critical component of a range of medicinally important agents (see below). Our studies arose from unsuccessful attempts to effect the catalytic kinetic resolution of the corresponding chromenes [13] a representative example is illustrated in Eq. 3. 

The synthetic versatility and significance of the Zr-catalyzed kinetic resolution of exocyc-lic allylic ethers is demonstrated by the example provided in Scheme 6.9. The optically pure starting allylic ether, obtained by the aforementioned catalytic kinetic resolution, undergoes a facile Ru-catalyzed rearrangement to afford the desired chromene in >99% ee [20], Unlike the unsaturated pyrans discussed above, chiral 2-substituted chromenes are not readily resolved by the Zr-catalyzed protocol. Optically pure styrenyl ethers, such as that shown in Scheme 6.9, are obtained by means of the Zr-catalyzed kinetic resolution, allowing for the efficient and enantioselective preparation of these important chromene heterocycles by a sequential catalytic protocol. 

Related catalytic enantioselective processes It is worthy of note that the powerful Ti-catalyzed asymmetric epoxidation procedure of Sharpless [27] is often used in the preparation of optically pure acyclic allylic alcohols through the catalytic kinetic resolution of easily accessible racemic mixtures [28]. When the catalytic epoxidation is applied to cyclic allylic substrates, reaction rates are retarded and lower levels of enantioselectivity are observed. Ru-catalyzed asymmetric hydrogenation has been employed by Noyori to effect the resolution of five- and six-membered allylic carbinols [29] in this instance, as with the Ti-catalyzed procedure, the presence of an unprotected hydroxyl function is required. Perhaps the most efficient general procedure for the enantioselective synthesis of this class of cyclic allylic ethers is that recently developed by Trost and co-workers, involving Pd-catalyzed asymmetric additions of alkoxides to allylic esters [30]. 

This section will only discuss examples of catalytic kinetic resolution, DKR, desymmetrization and asymmetrization. Deracemization will not be considered because, although an important developing technology, examples of its application to the production of chiral late-stage intermediates in API production have yet to appear. 

Enzymes such as pig liver esterase have been successfully applied in enantioselective hydrolysis of allenyl esters on a scale of 2 mmoles131. This provides the enantiomerically enriched allene-carboxylic acid as well as the ester of opposite configuration, by what is in fact a catalytic kinetic resolution (6-90% oy). Conversely, partial enantioselective esterification of /1-hydroxy-allenes (3-72% oy) employing lipases has been reported132,133. 

Catalytic Kinetic Resolution Through Mo-Catalyzed ARCM.210... 

The catalytic kinetic resolution of various dienes through ARCM can be carried out in an efficient manner at 22 °C in the presence of 5 mol %4a [10]. As the data in Scheme 1 illustrate, 1,6-dienes 5-7 are resolved with excellent levels of enan-tiocontrol (krei>20) [11]. Chiral complex 4a readily promotes the resolution of allylic ethers 8-10 as well [12]. 

Most recent studies indicate that ARCM can be used to synthesize small and medium ring N-containing unsaturated heterocycles in high yield and with excellent ee through catalytic kinetic resolution and asymmetric synthesis [19]. As the representative data in Scheme 10 illustrate, levels of enantioselectivity can vary depending on the nature of the arylamine (compare 44 to 46). As the synthesis of 48 indicates (cf. Scheme 10), the facility and selectivity with which medium ring unsaturated amines are obtained by the Mo-catalyzed protocol is particularly noteworthy. 

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]. 

Catalytic Kinetic Resolution through Mo-Catalyzed ARCM... 

The chiral amide approach has also been applied to the catalytic kinetic resolution of racemic epoxides. For example, exposure of the tricyclic epoxide 90 with 10 mo % 86 and stoichiometric LDA at 0°C led to the recovery of the chiral spiro[4.5]decenol 91 with 90% ee and in 45% isolated yield, compared to the theoretical 50% maximum <02OL3777>. This halfway barrier... 

The chiral lithium amide 18 has also been used for catalytic kinetic resolution of epoxides117. Epoxide 104 was subjected for kinetic resolutions under the conditions shown in Scheme 75, which resulted in roughly enantiopure epoxide and allylic alcohol. 

Hoveyda and co-workers have developed chiral catalysts for asymmetric alkene metathesis. They have demonstrated that with their chiral molybdenum catalyst asymmetric syntheses of dihydrofurans through catalytic kinetic resolution by RCM and enantioselective desymmetrization by RCM are feasible processes (Scheme 40) <1998JA9720>. The use of Schrock s molybdenum catalysts for asymmetric alkene metathesis has been reviewed <2001CEJ945>. 

Table 5 Catalytic kinetic resolution of chiral aminopentenes [101,163,171]...

LaDS, Alexander JB,CefaloDR,GrafDD,HoveydaAH, SchrockRR(1998) Mo-catalyzed asymmetric synthesis of dihydrofurans. Catalytic kinetic resolution and enantioselec-tive desymmetrization through ring-closing metathesis. J Am Chem Soc 120 9720-9721... 

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