LITMIR.BIZ

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href="#ulink_dff1b591-24d2-594a-8d3d-bce0f298df95">Eq. 1.32). (+)‐Lycoposerramine Z was synthesized from this intermediate [60].

(1.32)

      1.6.4. Estradiol Methyl Ether

Bicyclo[4.3.0]none derivatives, which are C and D rings of the steroids, were synthesized as a single isomer with excellent enantioselectivity by diphenylprolinol silyl ether mediated Michael reaction of nitroalkane possessing a diketone moiety and an α,β‐unsaturated aldehyde, followed by aldol reaction (Eq. 1.33). This domino reaction was used as a key reaction for the total synthesis of estradiol methyl ether, which was synthesized using five reaction vessels with four purifications [61].

(1.33)

      1.6.5. MacMillan’s Alkaloid Synthesis

MacMillan reported the domino Diels‐Alder reaction/β‐elimination of methyl selenide/aza‐Michael reaction to afford a spiroindoline intermediate (Eq. 1.34). The first Diels‐Alder reaction and the third aza‐Michael reaction were catalyzed by the same MacMillan’s catalyst via an iminium ion as an intermediate, and an excellent enantioselectivity was obtained. From the intermediate, (‐)‐strychnine, (‐)‐akuamicine, (+)‐aspidospermidine, (+)‐vincadifformine, (‐)‐kopsinine, and (‐)‐kopsanone were synthesized efficiently [62].

(1.34)

      1.6.6. Prostaglandin E₁ Methyl Ester

A domino Michael/Henry reaction of succinaldehyde and nitroalkene in the presence of diphenylprolinol silyl ether proceeded to afford substituted cyclopentanecarbaldehyde, which was further treated with Horner‐Wadsworth‐Emmons reagent to provide a cyclopentane derivative with excellent enantioselectivity in a one‐pot operation (Eq. 1.35). This is a key intermediate for the synthesis of prostaglandin E₁ methyl ester, which was synthesized using a total of three reaction vessels [63].

(1.35)

      1.6.7. Corey Lactone

Nonactivated ketones are useful Michael donors for the Michael reaction of α,β‐unsaturated aldehydes catalyzed by diphenylprolinol silyl ether (see above; Eq. 1.22) [47]. When ethyl 4‐oxo‐2‐pentenoate was employed as a nucleophile, a domino Michael/Michael reaction proceeded to afford a trisubstituted cyclopentanone in nearly enantiomerically pure form (Eq. 1.36). By using this reaction as a key step, a one‐pot, 152‐minute total synthesis of Corey lactone was realized [64]. Latanoprost [64b] and clinprost [65] were also synthesized by using the same key reaction.

(1.36)

1.7. COMBINATION OF TWO CATALYSTS

      In the previous sections, asymmetric reactions using a single chiral organocatalyst were described. By the use of two catalysts, synergistic effects would be expected [66]. A combination of organocatalyst with another catalyst can be used to realize asymmetric reactions, which are difficult to achieve by using a single catalyst. Some of the successful reactions will be discussed in this section.

      1.7.1. Combination of Two Organocatalysts

Rovis reported a domino Michael/benzoin reaction of 1,3‐diketones and α,β‐unsaturated aldehydes by using a combination of diarylprolinol silyl ether and N‐heterocyclic carbene catalyst (Eq. 1.37) [67]. This is a formal [3+2] cycloaddition reaction that affords highly functionalized cyclopentanone derivatives with excellent enantioselectivity. When only diarylprolinol silyl ether was employed as a single catalyst, first Michael reaction proceeded to afford the Michael product with lower enantioselectivity, because of the retro‐Michael reaction. A combined use of the two catalysts not only provided the formal [3+2] cycloaddition products but also realized excellent enantioselectivity.

(1.37)

Luo reported a unique two‐catalyst cooperative system of a chiral primary amine and a ketone for the asymmetric α‐hydroxylation of β‐ketocarbonyls with H₂O₂ (Eq. 1.38) [68]. A chiral primary amine not only reacts with β‐ketocarbonyl to generate an enamine, it also reacts with 2,2,2‐trifluoroacetophenone to generate a chiral ketimine, which reacts further with H₂O₂ to afford an oxaziridine intermediate. The chiral enamine–chiral oxaziridine coupling provided α‐hydroxylated β‐ketocarbonyls in excellent yield with excellent enantioselectivity.

(1.38)

      1.7.2. Combination of Organocatalyst and Metal Catalyst

      Metal catalysts are widely used in organic synthesis, and a combination of metal catalyst with enamine and iminium ion intermediates opens a new avenue for the synthetic organic chemistry [69]. However, there are limitations to the use of organocatalysts and metal catalysts cooperatively. In organocatalytic reactions involving an enamine as an intermediate, water would be generated in the reaction, and organometallic catalysts have to act efficiently under these reaction conditions. Moreover, the organocatalyst is usually an amine, and metal catalysts also have to catalyze the reaction in the presence of organo amine catalyst. In spite of these limitations, several successful reactions have been developed using a combination of organocatalyst and metal catalyst.

       1.7.2.1. Enamine and Metal Catalyst

MacMillan reported α‐trifluoromethylation (Eq. 1.39) [70], α‐arylation (Eq. 1.40) [71], and α‐vinylation [72] of aldehydes with iodonium salts catalyzed by a combined use of MacMillan’s catalyst and copper catalyst. In the α‐trifluoromethylation reaction, Togni’s reagent is employed as CF₃ source. In the α‐arylation reaction, Cu(I) reacts with diaryliodonium salts to generate aryl‐Cu(III) species, which react with an enamine to generate η¹

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