Desymmetrization Diels-Alder reaction

Keywords Anthracyclines Desymmetrization Diels-Alder reactions ... 

Stereoselective epoxidation of alkenes, desymmetrization of maso-TV-sulfonylaziri-dines, Baeyer-Villiger oxidation of cyclobutanones, Diels-Alder reactions of 1,2-dihydropyridines, and polymerization of lactides using metal complexes of chiral binaphthyl Schiff-base ligands 03CCR(242)97. 

Keywords Ene reaction, Hetero-Diels-Alder reaction, Ene cyclization, Desymmetrization, Kinetic resolution. Non-linear effect. Asymmetric activation, Metallo-ene, Carbonyl addition reaction, Aldol-type reaction. Titanium, Aluminum, Magnesium, Palladium, Copper, Lanthanides, Binaphthol, Bisoxazoline, Diphosphine, TADDOL, Schiff base. 

Figure 7.1. Desymmetrization of approach to Diels-Alder reaction ...

The diol 4 had never been described in the literature before we used it in the synthesis of 1. Initially, we tried to synthesize it using an enantioselective Diels-Alder reaction between a chiral fumarate equivalent 5 (Scheme 10.1) and butadiene 6, followed by double-bond dihydroxylation [41]. However, a more effective protocol for large-scale synthesis could finally be based on the procedure shown in Scheme 10.2, leading to enantiomericaUy pure (lS,2S)-cyclohex-4-ene-1,2-dicarboxylic acid 7 [42]. Here, a Bolm desymmetrization of tetrahydrophthahc anhydride 8 using quinine leads to monoester 9 in 89% ee. The monoester 9, in turn, can be epimerized to the trans isomer 10 which is hydrolyzed to obtain 7, after crystallization. This intermediate is the starting material for the synthesis of 4 and of other conformationally constrained DCCHD to be used as monosaccharide mimics [43, 44]. Our current best protocol for the large-scale synthesis of 7 is reported at the end of this chapter. 

For a smooth transition from the previous section, we will continue by discussing the work of Sun and coworkers, who reported their efforts on the application of a new directing group in an organocatalyzed MCR in 2013 [25]. The rarely used oxetane proved to be the ideal hydrogen-bond acceptor that supports the formation of the desired transition state. The previously used ethers already exhibited some desired directing effects and delivered perfect diastereoselectivity (>95 5 dr), but proved ineffective for enantioselectivity (<5% ee). By employing the oxetane, however, the envisioned aza-Diels-Alder reaction proceeded as intended with excellent diastereo (>99 1 dr) and enantioselectivity (99% ee). The proposed transition state of this desymmetrization clarifies the selectivity of the reaction the chiral phosphoric acid allows the amine to approach only from the front face (Scheme 14.10). 

The first clear attempt to address the stereochemical problem presented by the juvabiones was reported by Birch. The plan was to use enone 33 to desymmetrize the 4-substituted cyclohexanone intermediates encountered thus far. The vicinal stereocenters in enone 33 were to be derived from 34 via a retro-aldol condensation. As we will see, 34 was to be prepared via a Diels-Alder reaction, a reaction that frequently has been used to establish vicinal stereochemistry with a high degree of selectivity. 

Precursor of Useful Chiral Ligands. OPEN is widely used for the preparation of chiral ligands. Organometallic compounds with these ligands act as useful reagents or catalysts in asymmetric induction reactions such as dihydroxylation of olefins, transfer hydrogenation of ketones and imines, Diels-Alder and aldol reactions, desymmetrization of meso-diols to produce chiral oxazolidinones, epoxidation of simple olefins, benzylic hydroxylation, and borohydride reduction of ketones, imines, and a,p-unsaturated carboxylates. ... 

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