Resolution of Alcohols by Oxidation

2 Armstrong, A. (2007) Oxidation reactions, in Enantiosdective Organocatalysis Reactions and Experimental Procedures (ed. P.I. Dalko), Wiley-VCH Verlag GmbH, Weinheim, ch. 12, pp. 403 24. 

32 Nieto, N., Munslow, I.J., Barr, Benet-Buchholz, J., and Vidal-Ferran, A. (2008) Org. Biomol. Chem.. 6. 2276-2281. 

55 Solladie-Cavallo, A., Jierry, L, Norouzi-Arasi, H., and Tahmassehi, D. (2004) 

73 Vega-Perez, J.M., Vega Holm, M Luisa Martinez, M., Blanco, E and Iglesias-Guerra, F. (2009) Eur. J. Org. Chem., 6009-6018. 

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Figure 16.2-37. Resolution of alcohols by enantioselective oxidation using quinohemoprotein dehydrogenases (QHDH) from different microorganisms.

Scheme 10.6 Mechanism of aerobic oxidation catalysed by complex 13 [23] Table 10.2 Oxidative kinetic resolution of alcohols using (-)-sparteine [25]...

Axially chiral Pd-NHC complexes reported by Shi and co-workers [26-28] have shown high selectivity in the oxidative kinetic resolution of alcohols without the need of addition of a chiral base. Enantiomeric excesses of up to 99% were obtained (Scheme 10.7). 

The empirical observation that (—)-sparteine 55 is necessary for catalysis implicates a base-promoted pathway in the mechanism. In the first step, a palladium alk-oxide is formed after alcohol binding, followed by p-hydride elimination of the alkoxide to yield a ketone product. On the basis of a kinetic study of the enantio-selective oxidation of 1-phenylethanol, it was revealed that (—)-sparteine plays a dual role in the oxidative kinetic resolution of alcohols, as a ligand on palladium and an exogeneous base " ... 

Enantioselective ring opening of epoxides was attained with (salen)Cr(III) complex (191) [68]. Cyclopentene derivatives (190) were converted with Me3SiN3 to azide-alcohols (192) in 80-90% yields up to 98% ee (Scheme 16.56). Kinetic resolution of racemic styrene oxide was performed in 98% ee. This reaction was applied to practical synthesis of enantiopure cyclic 1,2-aminoalcohols by reduction of the azide products by Pt02-catalyzed hydrogenation [69], to synthesis of cyclopentenone derivatives [70] to formal synthesis of bioactive compound Balanol [71], and to solid-phase synthesis of peptides [72]. 

For a long time, kinetic resolution of alcohols via enantioselective oxidation or via acyl transfer employing, for example, lipases along with dynamic kinetic resolution have been the biocatalytic methods of choice for the preparation of chiral alcohols. In recent years, however, impressive progress has been made in the use of alcohol dehydrogenases (ADHs) and ketor-eductases (KREDs) for the asymmetric synthesis of alcohols by stereoselective reduction of the corresponding ketones. Furthermore, recent remarkable multienzymatic systems have been successfully applied to the deracemisation of alcohols via stereoinversion based on an enantioselective oxidation followed by an asymmetric reduction. 

Andersson also showed that, in addition to meso-desymmetrization, kinetic resolution of some cyclic epoxides by use of the first-generation catalyst was also possible, giving both epoxides and allylic alcohols in good yields (Scheme 7.51) [108], Kozmin reported the effective use of the same catalyst in the desymmetrization of diphenylsilacyclopentene oxide. The resulting products could be used in the ster-eocontrolled syntheses of various acyclic polyols (Scheme 7.52) [109]. 

In 2003, Sigman et al. reported the use of a chiral carbene ligand in conjunction with the chiral base (-)-sparteine in the palladium(II) catalyzed oxidative kinetic resolution of secondary alcohols [26]. The dimeric palladium complexes 51a-b used in this reaction were obtained in two steps from N,N -diaryl chiral imidazolinium salts derived from (S, S) or (R,R) diphenylethane diamine (Scheme 28). The carbenes were generated by deprotonation of the salts with t-BuOK in THF and reacted in situ with dimeric palladium al-lyl chloride. The intermediate NHC - Pd(allyl)Cl complexes 52 are air-stable and were isolated in 92-95% yield after silica gel chromatography. Two diaster corners in a ratio of approximately 2 1 are present in solution (CDCI3). 

Interestingly, the scope of the reaction using this catalyst can be extended to oxidative kinetic resolution of secondary alcohols by using (-)-sparteine as a base (Table 10.2) [25]. The best enantiomeric excess of the alcohol was obtained when a chiral enantiopure base and an achiral catalyst were used. The use of chiral enantiopure catalyst bearing ligand 17 led to low enantioselectivity. 

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