of the Mannich reaction.
1.3.3. Other Functionalization of the α‐Position of Carbonyl Groups
Bifunctional organocatalysts are effective not only for the aldol and Mannich reactions but also for functionalization of the α‐position of carbonyl compounds. α‐Fluorination [21], α‐bromination [22], and α‐iodination [23] of aldehydes are successfully carried out by the use of organocatalyst. Azodicarboxylate is used in the α‐amination of aldehydes catalyzed by proline [24]. α‐Aminoxylation of carbonyls is catalyzed by proline [25] and proline salt [26] using nitrosobenzene as an electrophile. These reactions are summarized in the previous book [6].
1.3.4. Michael Reaction
Organocatalysts are also useful for the addition of carbonyl compounds to electron‐deficient alkenes, known as the Michael reaction. The reaction of aldehydes and nitroalkenes catalyzed by organocatalyst is a well‐investigated reaction. In 2005, diphenylprolinol silyl ether was applied to this reaction, which afforded a Michael product with excellent diastereo‐ and enantioselectivity (Eq. 1.12) [9]. It was also found that an acid additive accelerates the reaction, and the effect of the acid has been investigated in detail (Scheme 1.2) [27]. An enamine and a nitroalkene react to afford cyclobutane A and dihydro‐oxazine N oxide B as initial products, which were converted into the Michael product, and acid affects this conversion step.
As a Michael acceptor, not only nitroalkene but also vinyl sulfones [28], β‐substituted α‐nitroacrylates [29], dicyanoalkenes [30], and β‐substituted α‐cyano α,β‐unsaturated esters [31] can be successfully employed to afford the Michael products with excellent diastereo‐ and enantioselectivity (Eq. 1.13).
Scheme 1.2. The reaction mechanism of the Michael reaction of aldehyde and nitroalkene.
Source: Based on [27].
Low catalyst loading and the development of a reactive catalyst are important issues for the asymmetric synthesis of chiral molecules. For the Michael reaction of aldehydes and nitroalkenes, Wennemers reported a very active tripeptide catalyst H‐D‐Pro‐Pro‐Glu‐NH2, which catalyzes the Michael reaction of butanal and nitrostyrene in the presence of only 0.1 mol% of the catalyst (Eq. 1.14) [32]. This catalyst is a bifunctional catalyst, possessing a secondary amine moiety and an acid moiety.
1.3.5. Dienamine and Trienamine as an Intermediate [33]
Enamine chemistry was extended to dienamine chemistry: diarylprolinol silyl ether reacts with an α,β‐unsaturated aldehyde to generate an iminium ion, which is further converted into a dienamine. As dienamines are electron‐rich, they act as reactive dienes in the Diels‐Alder reaction. The 1,4‐position of the original aldehyde reacts with a dienophile. Jørgensen reported the reaction of a dienamine with azodicarboxylate, in which only the s‐cis dienamine from a mixture of s‐cis and s‐trans isomers reacts in a concerted fashion (Diels‐Alder reaction) to afford the product with excellent enantioselectivity (Eq. 1.15) [34].
A dienamine is successfully utilized in the enantioselective synthesis of a key intermediate of 14β‐steroids by the reaction of an enal with a cyclic dienophile in the presence of diphenylprolinol silyl ether (Eq. 1.16). This reaction allows easy access to an optically active steroid core with a variety of substituents in the A ring in high yields and up to more than 99% ee. (+)‐Estrone was efficiently synthesized by using this reaction as a key step [35].
This dienamine system was further extended to trienamine chemistry. Chen and Jørgensen reported the generation of an electron‐rich trienamine from a polyconjugated 2,4‐dienal. By a reaction with a dienophile, a cycloaddition reaction proceeded to afford a spirocyclic oxindole possessing a cyclohexene moiety with an exclusive β,ε‐regioselectivity and excellent stereoselectivity (Eq. 1.17) [36].
1.4. IMINIUM ION
1.4.1. Introduction of an Iminium Ion
MacMillan reported the Diels‐Alder reaction using a chiral imidazolidinone, which reacts with an α,β‐unsaturated aldehyde to afford an iminium ion. The iminium ion is a highly electron‐withdrawing group; its alkene has a lower LUMO level than the parent α,β‐unsaturated aldehyde. Thus, the Diels‐Alder reaction proceeds via the iminium ion intermediate not from the α,β‐unsaturated aldehyde. By the appropriate design of the chiral amine moiety, an enantioselective reaction can be realized. In fact, the chiral imidazolidinone catalyst afforded an excellent enantioselectivity (see above; Eq. 1.3) [4]. Many reactions have been developed involving the iminium ion as a key intermediate.
1.4.2. Two Reaction Paths
Two reaction paths, Diels‐Alder type reaction and Michael reaction, involve an iminium ion as a reactive intermediate [37]. These two reaction paths will be discussed in the reactions of cinnamaldehyde and cyclopentadiene catalyzed by diarylprolinol silyl ether (Table 1.1).
The Diels‐Alder reaction was catalyzed by diarylprolinol silyl ether 6, with trifluoromethyl groups on the aryl moiety (Figure 1.6) with a combination of a strong acid such as CF3CO2H [38].