Ephedrine asymmetric protonation

Among the very few papers published after the above review appeared, two deserve some comment. The asymmetric protonation of the lithium enolate of a thiopyranic thioester by an ephedrine-derived chiral aminoalcohol described by Ward and coworkers leads to the desired enantiomer in 99% yield and 82% e.e., provided the reaction was performed in carefully designed conditions (Scheme 79)373. 

Figure 3. Transition states involved in the asymmetric protonation of a photodienol induced by ( —)-ephedrine.

Procter reported a solid-phase variant of Fukuzawa s asymmetric y-butyr-olactone synthesis (see Chapter 5, Section 5.2) that involves the intermolecular reductive coupling of aldehydes and ketones with a,p-unsaturated esters, immobilised using an ephedrine chiral resin 12.44 For example, treatment of acrylate 13 and crotonate 14 with cyclohexanecarboxaldehyde, employing Sml2 in THF, with tert-butanol as a proton source, gave lactones 15 and 16, respectively, in moderate yield and good to high enantiomeric excess (Scheme 7.11).44 The ephedrine resin 12 can be conveniently recovered and recycled.45... 

In a more recent study, the enamide photocyclization with very similar photosubstrates was examined in the presence of chiral amino alcohols and chiral amines as asymmetric inductors [47]. The achieved enantioselectivities are in the same range as the ones reported by Ninomiya and Naito, but in this approach the asymmetric induction was more effective for the cis products. In cyclopentane at — 40°C, 0.1 equivalents of the most effective inductor, (— )-ephedrine (entity, gave the cis cyclization products with up to 37% ee and the trans products with only 2% ee. The role of the chiral inductor as a Br0nsted acid was supported by flash photolysis experiments. The presence of the chiral amino alcohol led to an increase in the rate of disappearance of a transient that was assigned to the primary cyclization intermediate of type 29, i.e., the chiral inductor accelerates the protonation/deprotonation sequence that reestablishes the aromatic ring. 

For example, treatment of acrylate and crotonate ephedrine resins 150 and 151, with cyclohexanecarboxaldehyde 149, employing Sml2 in THF with f-butanol as a proton source, gave 152 and 153 respectively, in moderate yield and good to high enantiomeric excess (Scheme 34). The process can be considered an example of an asymmetric catch-release process, where a substrate immobilized using a chiral support captures a reactive intermediate, in this case a ketyl radical anion, from solution [23]. The chiral support controls the asymmetry of the capture step and leads to a diastereomeric, resin-bound intermediate that breaks down to release a non-racemic product. 

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