Ionic asymmetric reductions

Free-radical reductions mediated by chiral stannanes, germanes, and silanes may occur with enantioselectivities in excess of 99% ee. Owing to the involvement of radical intermediates and the mild reaction conditions, this process is applicable for a large variety of simple or even complex target molecules that are incompatible to asymmetric reductions that require ionic reaction conditions. 

Numerous studies have demonstrated the solvent influence on enzyme enan-tioselectivity, and sometimes the enantiopreference may even be reversed by medium engineering. For instance, the enantioselectivity of asymmetric reduction of prochiral ketones catalyzed by T. ethanolicus ADH can be controlled by changing the reaction medium containing either organic solvents or ionic liquids [93]. Reversal of the enantioselectivity was reported for S. cerevisiae-catalyzed reduction of hydrophobic phenyl w-propyl ketone by means of the... 

Schiirmann, M., Lutje-Spelberg, (., Pitner, W.R., and Weuster-Botz, D. (2009) Wholecell biocatalysis evaluation of new hydrophobic ionic liquids for efficient asymmetric reduction of prochiral ketones. Enzyme Microb. Technol., 45, 310-316. 

Matsuda T, Yamagishi Y, Koguchi S, Iwai N, Kitazume T. An effective method to use ionic liquids as reaction media for asymmetric reduction by Geotrichum candidum. Tetrahedron Lett. 2006 47 4619 1622. 

The simple piperidine alkaloid coniine (for selected asymmetric syntheses of coniine see [22, 81-85]) offered a preliminary test case for hybrid radical-ionic annulation in alkaloid synthesis. From butyraldehyde hydrazone and 4-chloro-iodobutane (Scheme 4), manganese-mediated photolysis afforded the acyclic adduct in 66% yield (dr 95 5) the cyclization did not occur in situ [69, 70]. Nevertheless, Finkelstein conditions afforded the piperidine, and reductive removal of the auxiliary afforded coniine in 34% overall yield for four steps. This reaction sequence enables a direct comparison between radical- and carbanion-based syntheses using the same retrosynthetic disconnection an alternative carbanion approach required nine to ten steps [81, 85]. The potential for improved efficiency through novel radical addition strategies becomes quite evident in such comparisons where multifunctional precursors are employed. 

Jessop and coworkers investigated the asymmetric hydrogenation of tiglic acid using Ru-tolBINAP as a catalyst in wet [bmim][PFs] [115, 116]. Extraction of the product with SCCO2 from the ionic liquid containing the catalysts provided the extremely pure product from the CO2 effluent, in which neither the ionic liquid nor catalyst was contaminated at all. In this way a conversion of up to 99% and an ee-value of 90% were obtained. The recovered ionic liquid catalytic solution was reused up to four times without any reduction of the conversion and enantioselectivity (Scheme 7.44). 

Application of subcritical gaseous CO2 to an organic liquid causes the liquid phase to expand noticeably, due to extensive dissolution of the CO2 into the liquid phase (131). This expansion is accompanied by a reduction in the liquid phase viscosity, an increase in the solubility of H2 in the liquid, and an increase in the mass transfer rates from the gas to liquid phase. There is evidence that this can affect the enantioselectivity of reactions in viscous liquids. The enantioselectivity of asymmetric hydrogenation of unsaturated carboxylic acids in a viscous ionic liquid was shown to be strongly affected by CO2 expansion of the liquid, the enantioselectively being improved for one substrate (atropic acid) and decreased for another (tiglic acid). The results were explained in terms of the solubility and rate of transfer of H2 gas into the expanded ionic liquid (23). The same effect was not observed in expanded methanol. 

Biphasic systems that include ionic liquids can also be applied to whole-cell biocatalysis. The ability of these solvents to act as a substrate reservoir and in situ extracting agent was demonstrated by an efficient asymmetric ketone reduction. 4-Chloroacetophenone was reduced to the key pharmaceutical intermediated (k)-l-(4-chlorophenyl) ethanol using Lactobacillus kefir cells in ILs. The indigenous cellular cofactor regeneration system remained active, which allowed high product concentrations without cofactor supplementation [34]. 

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