Catalytic Asymmetric Synthesis. Группа авторов

Nonactivated ketones such as cyclohexanone are also employed as Michael donors in the reaction of α,β‐unsaturated aldehydes catalyzed by a combination of diphenylprolinol silyl ether and hydroxyproline (or pyrrolidine), to afford the Michael products with excellent enantioselectivity (Eq. 1.22) [47]. The key nucleophile is not an enamine but an enolate, which is generated from a secondary amine by combination with p‐nitrophenol (Eq. 1.23) [48].

(1.22)

(1.23)

1.5. DOMINO REACTION

      1.5.1. Introduction of Domino (Cascade and Tandem) Reactions

Domino reactions offer a powerful way to construct complex structures in a single reaction vessel; each reaction occurs as a consequence of the intermediates generated in previous steps without changing any reaction conditions [49]. Most of the asymmetric domino reactions are composed of two reactions occurring one after the other. Organocatalysts can also be effective in domino reactions [50]. List [51], MacMillan [52], and Jørgensen [44] reported the domino iminium/enamine reaction at the same time in 2005. List reported conjugate reduction−Michael cyclization of enal enones, in which treatment of the enal enone with Hantzsch dihydropyridine in the presence of a catalytic amount of MacMillan’s catalyst provided cyclic keto aldehydes with excellent enantioselectivity (Eq. 1.24). MacMillan reported an iminium/enamine domino reaction employing several nucleophiles and electrophiles catalyzed by MacMillan’s catalyst (Eq. 1.25). Jørgensen reported that a domino reaction of conjugate addition of thiol and amination, which was catalyzed by diarylprolinol silyl ether, afforded 1,2‐aminothiol derivatives in nearly optically pure form (Eq. 1.26).

(1.24)

(1.25)

(1.26)

      1.5.2. Enders’ Work

In 2006, Enders reported a seminal paper on organocatalyst‐mediated domino reaction (Eq. 1.27) [53]. He reported an excellent domino reaction catalyzed by diphenylprolinol silyl ether, wherein three reactions such as Michael/Michael/intramolecular aldol condensation reactions take place in one pot to provide cyclohexene carbaldehydes bearing four stereogenic centers with excellent stereocontrol. Rather complex skeletons were synthesized only by mixing the substrates via a domino reaction.

Enders’ group reported many useful domino reactions [54]. For instance, functionalized complex tricyclic polyethers were synthesized by one‐pot quadruple domino oxa‐Michael/Michael/Michael/aldol condensation/hetero‐Diels‐Alder reaction in nearly enantiomerically pure form (Eq. 1.28) [55]. Tetracyclic pyridocarbazole derivatives were synthesized by the three‐component triple cascade reaction such as Diels‐Alder/aza‐Michael/intramolecular aldol condensation reactions with excellent enantioselectivity (Eq. 1.29) [56].

(1.27)

(1.28)

(1.29)

1.6. DOMINO REACTION AND TOTAL SYNTHESIS

      Many domino reactions have been developed that use organocatalysts. Domino reaction catalyzed by organocatalysts can generate complex structures in a single reaction vessel. This is a very powerful method for the synthesis of natural products and drugs [57]. Organocatalytic domino reactions have been successfully applied to natural product synthesis. In this section, selected domino reactions will be described with an application to total synthesis.

      1.6.1. Steroid Skeleton

Hong reported the synthesis of a steroid skeleton by a one‐pot reaction starting from an α,β‐unsaturated aldehyde and a nitroalkane (Eq. 1.30). A domino Michael/Michael reaction proceeded, followed by aldol and Henry reaction in a one‐pot operation, to afford a steroid skeleton with excellent enantioselectivity [58].

(1.30)

      1.6.2. α‐Skytanthine and Quinine

Ishikawa reported a domino Michael reaction/hemiacetal formation/dehydration for the synthesis of C4‐alkyl substituted chiral piperidines using diphenylprolinol silyl ether (Eq. 1.31) [59]. This is a formal aza [3+3] cycloaddition reaction with aliphatic α,β‐unsaturated aldehydes and thioamide derivatives. Thioamide is a reactive nucleophile. The reaction proceeded efficiently, and only 0.1 mol % catalyst loading is sufficient for a multigram‐scale synthesis to complete within a suitable reaction time. This reaction was applied to the total synthesis of several alkaloids such as α‐skytanthine [59a] and quinine [59b].

(1.31)

      1.6.3. (+)‐Lycoposerramine Z

Bradshaw and Bonjoch reported a domino Michael/aldol (Robinson annulation)/aza‐Michael reaction to afford a substituted