2-cyclohexenones kinetic resolution

We have recently discovered that phosphoramidite 18 is also an excellent ligand for copper-catalyzed kinetic resolution of chiral 2-cyclohexenones (Scheme 7.15). Chiral 2-cyclohexenones are attractive building blocks for a variety of natural products, but their synthesis usually requires multistep routes from chiral starting materials [65]. The development of the new kinetic resolution was the product of two impor-... 

Tab. 7.3. Kinetic resolution of 5-substituted 2-cyclohexenones 53-56 according to Scheme 7.15 (s stereoselectivity factor).

Scheme 7.15. Enantioselective kinetic resolution of 5-substituted 2-cyclohexenones.

In an ideal kinetic resolution (common in enzyme-catalyzed processes), one enantiomer of a racemic substrate is converted tvhile the other is unreactive [70]. In such a kinetic resolution of 5-methyl-2-cyclohexenone, even with 1 equivalent of Me2Zn, the reaction should virtually stop after 50% conversion. This near perfect situation is found with ligand 18 (Fig. 7.10) [71]. Kinetic resolutions of 4-methyl-2-cyclohexenone proceed less selectively (s = 10-27), as might be expected from the lower trans selectivity in 1,4-additions to 4-substituted 2-cyclohexenones [69]. 

The kinetic resolution of 5-hydroxymethyl-2-cyclohexenone towards the total synthesis of penienone, a fungal metabolite of Penicillium sp. no. 13 [89], has been performed by using Lipase PS from B. cepacia for the acetylation of the (S)-enantiomer, leaving the desired (/ )-alcohol. As a main problem inherent with enzymatic kinetic resolutions, the reaction yielded both products in a 1 1 mixture... 

In addition to the simple and reagent-induced diastereoselectivity observed in the reaction of thiols with unsaturated compounds, an interesting kinetic resolution takes place when racemic 5-trimethylsilyl-2-cyclohexenone is treated with 0.55 equivalents of 4-methylbenzenethiol in the presence of cinchonidine12. The reaction results in the formation of the tram-adduct tram-14 as the major product together with small amounts of the m-addition product cis-14 and unreacted starting cyclohexenone that is partially resolved. 

This approach was also successfully applied to the kinetic resolution of 5-/crf-butyl-2-cyclo-hexenonel3. Thus, cinchonidine catalyzed addition of thiophenol to racemic enone 15 in benzene affords the mms-addition product tram-16 contaminated with small amounts of the r/y-adduct and unreacted, partially resolved cyclohexenone. The latter has 20% ee and 29% when the thiol/enone ratio is 0.5 and 0.4, respectively. 

Kinetic Resolution and Desynnnetrization. A variety of substituted 2-cyclohexenones are obtained in enantiomerically pure form employing chiral copper phosphoramidite catalyst for kinetic resolution (eq 5) (> 99% ee at 52% conversion, selectivity S > 200). The enantioselective desymmetrization of methylidene epoxycycloalkanes is also reported. ... 

Ligands of type 1 have also led to interesting results in kinetic resolutions during Cu-catalyzed reactions of dialkyIzinc with cycloalkene oxides (eq. (1)) [18] and cyclohexenones [19]. On the other hand, monophosphonites bearing a fused 1,4-dioxane ring behave moderately in the Rh-catalyzed hydrosilylation of ketones (up to ca. 56 % ee) [20] cf. Section 2.6 Finally, a phosphapallada-cyclic complex has been reported as an exceptionally fast catalyst for the hydroarylation of norbomene (TONs up to 10 °) but with low ees (< 25 %) [21]. 

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