Parallel chiral reagents

In one version, classical derivatization using a chiral reagent or NMR shift agent is simply parallelized and automated by the use of flow-through cells, with about 1400 ee measurements being possible per day with a precision of +5%. In the second embodiment, illustrated here in detail, a principle related to that of the MS system described in Section III.C is applied 98). Chiral or mexo-substrates are labeled to produce /. sewiio-enantiomers or psendo-meso-compo md that are then used in the actual screen. Application is thus restricted to kinetic resolution of racemates and... 

From these studies it has been shown that for a successful and efficient parallel kinetic resolution the following guidelines need to be adhered to a) derivatisation with two complementary chiral reagents have to occur without mutual interference [17] b) both reactions need to occur with similar but preferably equal rate and have complementary stereocontrol and c) afford distinct and easily separable products. 

The development of new methodologies for asymmetric synthesis is of crucial importance and in this context the new strategy of parallel kinetic resolution (PKR), whereby both enantiomers of a racemic mixture can be converted to useful products via simultaneous reaction with two different chiral reagents, is particularly promising. Pedersen and co-workers have recently reported the first asymmetric Horner-Wadsworth-Emmons procedure that allows the parallel kinetic resolution of racemic aldehydes. These workers have used two alternative approaches. In the first approach (Scheme... 

Divergent RRM Using Two Chiral Reagents Parallel Kinetic Resolution (PKR) 253... 

A few vinylzinc reagents have been added to aldehydes in the presence of chiral sulfur-containing ligands. As an example, Seto et al. reported, in 2005, the synthesis of dipeptide A-acylethylenediamine-based ligands by parallel... 

The stereochemistry of addition of organometallic reagents to chiral carbonyl compounds parallels the behavior of the hydride reducing agents, as discussed in Section 5.3.2. Organometallic compounds were included in the early studies that established the preference for addition according to Cram s rule.118... 

The sense of the enantiofacial selection was predictable from the model complex of organolithium, imine and chiral diether 28, where the migrating C—Li bond is parallel to the 7T-system of the a,/3-unsaturated imine (Figure 4). From the favored complex the R group of the organolithium reagent is transferred to the less hindered face of the double bond of the unsaturated imine. 

Historically, the methods used for ring closure of linear precursor peptides via amide bond formation evolved in parallel to the methods applied in segment condensations from the azide and active ester procedures to the use of coupling reagents such as DCC in the presence of additives, or of the more recently developed phosphonium and uronium/gua-nidinium reagents. In all cases the choice of method is mainly dictated by the epimerization problem when chiral amino acids act as the carboxy component in the cyclization reaction, and by other side reactions. 

Most work on this subject is based on the use of alcohols as reagents in the presence of enantiomerically pure nucleophilic catalysts [1, 2]. This section is subdivided into four parts on the basis of classes of anhydride substrate and types of reaction performed (Scheme 13.1) - desymmetrization of prochiral cyclic anhydrides (Section 13.1.1) kinetic resolution of chiral, racemic anhydrides (Section 13.1.2) parallel kinetic resolution of chiral, racemic anhydrides (Section 13.1.3) and dynamic kinetic resolution of racemic anhydrides (Section 13.1.4). 

In a parallel study, it was found that chelating chiral diamines 208 or 209 are well suited as ligands to promote Kumada-type couplings of primary and secondary alkyl halides 202 with aryl Grignard reagents 203 (entry 4) [281]. This reaction was applicable to alkyl bromides and alkyl iodides, while alkyl chlorides gave only low yields. Acetal and ester functions are tolerated. A notable feature is the stereoretentive arylation of fra s-a-bromo acetals with excellent diastereo-selectivity. The involvement of radicals is supported by the stereoconvergent formation of cxo-phenvI norbornane from both endo- or exo-bromonorbomane (cf. Part 1, Fig. 9) and radical 5-exo cyclizations (see below). 

Another breakthrough came several years later, when the photoadduct of trans stilbene with chiral bomyl methyl fumarate 82 was obtained with a hi diastereomeric excess [60]. Here again, a model involving an approach of t reagents in parallel planes was proposed to explain the observed stereoselectivi (Scheme 19). In an attempt to increase the observed de, the cycloaddition reacti of dibomyl fumarates was examined, but a far lower selectivity was observe On this basis, a multistep process was proposed with control of the asymmet induction by the rate of cyclization of the 1,4-biradical intermediates. The natii of the substituents, however, the complexity of the reaction mixture, and the lc chemical yields of the chiral adducts are major limitations for synthetic applic tions [61]. 

As a part of ongoing efforts to synthesize a potent, orally active anti-platelet agent, xemilofiban 1 [1], development of an efficient chemoenzymatic process for 2, the chiral yS-amino acid ester synthon (Fig. 1) was proposed. The scheme emphasized the creation of the stereogenic center as the key step. In parallel with the enzymatic approach, chemical synthesis of the / -amino acid ester synthon emphasized formation of a chiral imine, nucleophilic addition of the Reformatsky reagent, and oxidative removal of the chiral auxiliary. This chapter describes a selective amida-tion/amide hydrolysis using the enzyme Penicillin G amidohydrolase from E. coli to synthesize (R)- and (S)-enantiomers of ethyl 3-amino-5-(trimethylsilyl)-4-pen-tynoate in an optically pure form. The design of the experimental approach was applied in order to optimize the critical reaction parameters to control the stereoselectivity of the enzyme Penicillin G amidohydrolase. 

With a parallel kinetic resolution, the two reactions should not interfere with one another. In the example above, both reactions were acylations but the use of stoichiometric reagents meant that the right acylating group was attached to the right enantiomer. Even here, Vedejs does not rule out a small amount of leakage between the paths (once the chiral DMAP is liberated it can get in on the act with the other pathway). A PKR becomes more difficult if, in addition to the reactions being related, they are also catalytic. 

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