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1.7.3. Two Chiral Catalysts
In the synthesis of molecules with two chiral centers, there are four possible isomers. When one chiral catalyst controls one chiral center and the second chiral catalyst controls the second chiral center independently with minimal matched/mismatched interactions, all four isomers can be synthesized with high selectivity. However, the realization of this concept is very difficult. Recently, excellent catalyst systems have been reported for this type of the reaction.
Carreira reported a stereodivergent α‐allylation of branched aldehydes by the reaction of allylic alcohols and α,α‐disubstituted acetaldehydes (Scheme 1.6) [85]. Products bearing quaternary stereocenters in a vicinal relationship to tertiary stereocenters are obtained in good yields with excellent selectivities. Cinchona‐alkaloid‐derived primary amine (A1 and A2) and chiral iridium (ligand: L) were used as catalysts. The amine catalyst reacts with an aldehyde to generate an enamine, which controls the enantioface selectivity of the aldehyde, while iridium catalyst generates a chiral π‐allyl complex in which two distinct and highly face‐selective catalytic cycles are merged to provide access to all possible stereoisomers of a target compound in enantiomerically pure form.
The author also extended this reaction to the stereodivergent α‐allylation of linear aldehydes with dual chiral iridium catalyst and diphenylprolinol silyl ether catalyst [86].
Dong reported a stereodivergent synthesis of γ,δ‐unsaturated aldehydes via alkyne hydrofunctionalization starting from α‐branched aldehydes and alkynes using Rh catalyst with a chiral bisphosphine ligand (L) and a chiral primary amine catalyst (A) (Scheme 1.7) [87]. An alkyne isomerizes into an allene by Rh catalyst and it is further converted into π‐allyl Rh complex with a chiral ligand. Chiral amine reacts with an aldehyde to generate a chiral enamine, which reacts with a chiral π‐allyl Rh complex. All possible stereoisomers were obtained with high enantio‐, diastereo‐, and regioselectivity.
Scheme 1.6. Stereodivergent α‐allylation of branched aldehydes using allyl alcohols.
Source: [85]/American Association for the Advancement of Science.
Scheme 1.7. Stereodivergent α‐allylation of branched aldehydes using an alkyne.
Source: Based on [87].
1.8. CONCLUSION
After the discovery of the proline‐mediated intermolecular aldol reaction and organocatalyst‐mediated Diels‐Alder reaction in 2000, the basic concept of reactions involving an enamine and an iminium ion has become established. Since these first reactions, domino reactions using organocatalysts have developed dramatically and complex skeletons have been constructed with excellent enantioselectivity in a single pot. The application of organocatalyst‐mediated reactions to total syntheses of natural products and drugs is another recent advancement. Combination of organocatalyst and other catalysts is another developing field, and many successful reactions have been reported. Given that enamines and iminium ions are useful intermediates, many reactions involving these intermediates await to be developed. I hope this chapter will encourage further development in organocatalytic reactions.
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