Chiral direction strategy

Chirality-Directed Self-Assembly An Enabling Strategy for Ligand Scaffold Optimization... 

In the previous chapter we discussed various reagent-based strategies for the enantioselective formation of chiral centres. The next two chapters are also concerned with reagent-directed strategy but with an important difference. The source of asymmetry is used in a much lower concentration it is a catalyst. We may put in a few milligrams of an optically active compound and get out grams or even kilograms of enantiomerically pure product. This chapter concerns the formation of C-O and C-N bonds, the next the formation of C-H and C-C bonds. 

The use of enantioselective lithiation to generate axial chirality directly is in its infancy. However, several strategies are available for the conversion of planar or... 

As shown in Scheme 2, our first approach for construction of the labile iso-chromanone core 3 relied on an innovative orf/io-lithiation strategy. It was envisioned that in conjunction with an appropriate chiral-directing group, a suitable electrophile (5) might be introduced in the orf/io-position of the meta-lated aromatic 4. The resulting product would then be further transformed into the desired heterocycle 3. Notably, this route is very flexible by allowing the addition of various electrophiles in a modular fashion. Also, it starts from a 3-methylsalicylic acid derivative (4) that already contains almost the complete aromatic substitution pattern of the ajudazols. 

The strategy of the catalyst development was to use a rhodium complex similar to those of the Wilkinson hydrogenation but containing bulky chiral ligands in an attempt to direct the stereochemistry of the catalytic reaction to favor the desired L isomer of the product (17). Active and stereoselective catalysts have been found and used in commercial practice, although there is now a more economical route to L-dopa than through hydrogenation of the prochiral precursor. 

Direct addition of Grignard reagents to Zincke-derived chiral pyridinium salts such as 99, meanwhile, allowed subsequent reduction to 1,2,3,6-tetrahydropyridines (e.g., 100, Scheme 8.4.32). This strategy provided entry to asymmetric syntheses of (-)-lupetidin and (+)-solenopsin. Tetrahydropyridines prepared by reduction of chiral... 

Upon removal of the auxiliary, an enantioenriched product could be obtained. The application of chiral auxiliary-based methods to Simmons-Smith cyclopropanation not only provided a useful synthetic strategy, but it also served to substantiate earlier mechanistic hypotheses regarding the directing influence of oxygen-containing functional groups on the zinc reagent [6dj. 

The main strategy for catalytic enantioselective cycloaddition reactions of carbonyl compounds is the use of a chiral Lewis acid catalyst. This approach is probably the most efficient and economic way to effect an enantioselective reaction, because it allows the direct formation of chiral compounds from achiral substrates under mild conditions and requires a sub-stoichiometric amount of chiral material. 

To date, direct asymmetric synthesis of optically active chiral-at-metal complexes, which by definition leads to a mixture of enantiomers in unequal amounts thanks to an external chiral auxiUary, has never been achieved. The most studied strategy is currently indirect asymmetric synthesis, which involves (i) the stereoselective formation of the chiral-at-metal complex thanks to a chiral inductor located either on the ligand or on the counterion and then (ii) removal of this internal chiral auxiliary (Fig. 4). Indeed, when the isomerization of the stereogenic metal center is possible in solution, in-... 

The strategy for the asymmetric reductive acylation of ketones was extended to ketoximes (Scheme 9). The asymmetric reactions of ketoximes were performed with CALB and Pd/C in the presence of hydrogen, diisopropylethylamine, and ethyl acetate in toluene at 60° C for 5 days (Table 20) In comparison to the direct DKR of amines, the yields of chiral amides increased significantly. Diisopropylethylamine was responsible for the increase in yields. However, the major factor would be the slow generation of amines, which maintains the amine concentration low enough to suppress side reactions including the reductive aminafion. Disappointingly, this process is limited to benzylic amines. Additionally, low turnover frequencies also need to be overcome. 

Whilst the addition of a chiral NHC to a ketene generates a chiral azolium enolate directly, a number of alternative strategies have been developed that allow asymmetric reactions to proceed via an enol or enolate intermediate. For example, Rovis and co-workers have shown that chiral azolium enolate species 225 can be generated from a,a-dihaloaldehydes 222, with enantioselective protonation and subsequent esterification generating a-chloroesters 224 in excellent ee (84-93% ee). Notably, in this process a bulky acidic phenol 223 is used as a buffer alongside an excess of an altemativephenoliccomponentto minimise productepimerisation (Scheme 12.48). An extension of this approach allows the synthesis of enantiomericaUy emiched a-chloro-amides (80% ee) [87]. 

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