Azlactone kinetic resolution

Moreover, it is possible to open racemic azlactones by acyl bond cleavage to form protected amino acids in a dynamic kinetic resolution process. As azlactones suffer a fast racemization under the reaction conditions, eventually all starting material is converted [115]. 

Liang J, Ruble JC, Fu GC (1998) Dynamic kinetic resolutions catalyzed by a planar-chiral derivative of DMAP enantioselective synthesis of protected a-amino acids from racemic azlactones. J Org Chem 63 3154—3155... 

Dynamic Kinetic Resolution (DKR) of Azlactones Thioureas Can Act as Oxyanion Holes Comparable to Serine Hydrolases... 

Scheme 3 Example for the dynamic kinetic resolution of azlactones...

Berkessel and co-workers have demonstrated the utility of the bifunctional cyclohexane-diamine catalysts in the dynamic kinetic resolution of azalactones (Schemes 60 and 61) [111, 112]. The authors proposed that the urea/thiourea moiety of the catalyst coordinates and activates the electrophilic azlactone. The allyl alcohol nucleophilicity is increased due to the Brpnsted base interaction with the tertiary amine of the catalyst. 

Berkessel and co-workers extended the synthetic applicability of hydrogenbonding thiourea catalyst 78 in the DKR of azlactones to the kinetic resolution (KR) of structurally related, but configurationally stable 4,5-dihydro-l,3-oxazine-6-... 

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]. 

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]. 

The planar chiral DMAP derivative 79a proved successful also in the dynamic kinetic resolution of racemic azlactones by ring-opening with alcohols (Scheme... 

Additions to prochiral ketenes [13.2] Desymmetrization of meso-diols [13.3] Dynamic kinetic resolution of azlactones rearrangement of O-acyl azlactones, O-acyl oxindoles, O-acyl benzofuranones [13.6]... 

Scheme 4. Dynamic kinetic resolution of azlactones 6 by alcoholytic ringopening, effected by the bifunctional organocatalysts 8...

Chromatography) (equation 82). These complexes are used as enantioselective nucleophilic catalysts for reactions such as the rearrangements of O-acylated azlactones, oxindoles, and benzofuranones, and the kinetic resolution of secondary alcohols via acylation. X-ray crystal structures have been obtained for iV-acylated derivatives of (366), allowing for characterization of a likely intermediate along the catalytic pathway. 

In this chapter, we attempt to review the current state of the art in the applications of cinchona alkaloids and their derivatives as chiral organocatalysts in these research fields. In the first section, the results obtained using the cinchona-catalyzed desymmetrization of different types of weso-compounds, such as weso-cyclic anhydrides, meso-diols, meso-endoperoxides, weso-phospholene derivatives, and prochiral ketones, as depicted in Scheme 11.1, are reviewed. Then, the cinchona-catalyzed (dynamic) kinetic resolution of racemic anhydrides, azlactones and sulfinyl chlorides affording enantioenriched a-hydroxy esters, and N-protected a-amino esters and sulftnates, respectively, is discussed (Schemes 11.2 and 11.3). 

Fu has demonstrated that a dynamic kinetic resolution using the nonenzy-matic catalyst (12.95) can be achieved. The azlactone (12.114) is very prone to racemisation, whilst the ring-opened product (12.115) is stable under the reaction conditions. Thus the product is formed by methanolysis under dynamic resolution conditions (see Section 3.1), albeit with moderate enantioselectivity so far. 

Tertiary phosphines are known to behave as Lewis bases in acylation reactions that proceed through a nucleophilic activation mechanism (see Section 4.06.7 for possible mechanisms operating in organocatalyzed polymerization). Their use as nucleophilic catalysts in enantioselective processes, which include the addition of alcohols to ketenes, the rearrangement of O-acylated azlactones, and the kinetic resolution of alcohols, is also well documented. " ... 

Thiourea catalyst turned out to be effective for the kinetic resolution Berkessel et al. have found enantioselective dynamic kinetic resolution of azlactones, leading to natural and unnatural amino acid derivatives with excellent enantioselectivity. On treatment of an azlactone with allyl alcohol in the presence of 5 mol% of (9) led to the ring opening and the corresponding ester was obtained in high ee. NMR spectroscopic experiments elucidated the formation of a substrate-catalyst complex (19) (Figure 2.21) [113]. 

Squaramide-based dimeric cinchona alkaloid organocatalysts have also been described [92] and shown to be highly suitable for the dynamic kinetic resolution of racemic azlactones (Scheme 6.43). The dimeric squaramide derivatives were free from self-association, as indicated by the observation that the enantioselectivity was not influenced to any significant extent by the concentration of the dimeric squaramide, in contrast to the monomeric species that showed a decline in ee upon an increase in concentration. 

Scheme 10.33 Dynamic kinetic resolution of racemic azlactones.

Considering that the a-proton-exchange of racemic azlactones occurred rapidly in the presence of a tertiary amine base. Song and coworkers demonstrated enan-tioselective synthesis of a-deuterated a-amino acids via dynamic kinetic resolution (DKR) of azlactones with EtOD using cinchona-derived dimeric squaramide catalyst 33 (Scheme 10.34) [112]. The authors noted that by increasing the amount of EtOD, the level of deuterium incorporation increased, whereas the enantioselectivity decreased. By using 50 equivalents of EtOD, the products were obtained with... 

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