Reduction organocatalytic asymmetric conjugate

The asymmetric organocatalytic enantioselective conjugate hydrogen transfer reaction is clearly inspired by the mode of action in biological processes, in which reductions are accomplished by enzymes using hydride reduction cofactors like NADH. 

Asymmetric Organocatalytic Reduction of Olefins 395 Table 11.1 Organocatalytic reduction of conjugated aldehydes by Hantzsch ester 4 [14]. 

A successful asymmetric organocatalytic based C=0 reduction with the Hantzsch ester was not reported until very recently. Terada and Toda developed a relay catalysis that combined Rh(ll) and a chiral phosphoric acid catalyst in a one-pot reaction (Scheme 32.15). In this reaction sequence, a rhodium carbene (I) forms in the first step and is followed with an intramolecular cyclization to afford carbonyl ylide intermediate II or oxidopyrylium III. These intermediates are protonated by 7 to yield the chiral ion pair between isobenzopyrylium and the conjugate base of 7 (IV). Intermediate IV is further reduced in situ by Hantzsch ester Id to produce the isochroman-4-one derivative 67, which is finally trapped with benzoyl chloride to afford the chiral product 68. Surprisingly, the reaction sequence proceeds well to give racemic product even without the addition of chiral 7, while giving rise to the desired product with high enantioselectivity in the presence of chiral Br0nsted acid 7 [38]. 

As detailed in Sections 42.2 and 42.3, both covalent and non-covalent organocatalytic activation modes have provided efficient strategies to design asymmetric MCRs. A quite recent study by Zhou and list has demonstrated the feasibility of combining asymmetric Bronsted acid catalysis with aminocatalysis to design even more sophisticated reaction sequences toward the synthesis of useful complex molecules. Specifically, they developed a highly enantioselective approach to pharmaceutically relevant 3-substituted cyclohexylamines from 2,6-diketones 223 via an aldolization/dehydration/conjugate reduction/reductive amination domino... 

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