On the other hand, when a mixture of cinnamaldehyde and cyclopentadiene was treated with diphenylprolinol silyl ether 5 (Figure 1.6) with a combination of p‐nitrophenol or NaOAc, Michael products were obtained with excellent enantioselectivity without formation of the Diels‐Alder products [39]. Iminium ions are key intermediates in both reactions.
As the pyrrolidine moiety of catalyst 6 is more electron deficient than that of catalyst 5 because of the electron‐withdrawing CF3 group, the LUMO of the iminium ion generated from 6 is lower than that of the iminium ion generated from 5. The Diels‐Alder reaction proceeds smoothly when the LUMO of the dienophile is lower. Thus, the Diels‐Alder reaction proceeded in the case of 6 (Scheme 1.3). On the other hand, in the Michael reaction (Scheme 1.4), after the formation of the iminium ion, counterion (OH−) reacts with p‐nitrophenol to generate phenoxide, which reacts with cyclopentadiene to generate an anion of cyclopentadiene. This anionic nucleophile reacts with the iminium ion to afford the Michael product. For the generation of anionic nucleophile, the nucleophile is limited to the active methylene compounds, and a strong acid cannot be employed.
TABLE 1.1. The two reaction paths in the reaction of cinnamaldehyde and cyclopentadiene
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| 3 | 4 | |||||||
| Catalyst | Solvent | Additive | Yield/% | a:b | ee/% | Yield/% | exo/endo | ee/% |
| 5 | MeOH | p‐nitrophenol | 84 | 70 : 30 | 92 | 0 | ||
| 5 | MeOH | NaOAc | 81 | 64 : 36 | 92 | 0 | ||
| 5 | toluene | 0 | 0 | |||||
| 6 | toluene | CF3CO2H | 0 | 80 | 85 : 15 | 97/88 | ||
Figure 1.6. Diarylprolinol silyl ether in this study.
Scheme 1.3. The reaction mechanism of the Diels‐Alder reaction.
Scheme 1.4. The reaction mechanism of the Michael reaction.
1.4.3. Diels‐Alder Type Reaction
The Friedel‐Craft reaction belongs to the Diels‐Alder type set of reactions, and pyrroles, indoles, and aniline react readily with α,β‐unsaturated aldehydes in the presence of MacMillan’s catalyst to afford the products with excellent enantioselectivity (Eq. 1.18) [40]. [3+2] Nitrone cycloaddition also belongs to this type of reaction [41].
1.4.4. Michael Reaction
Active methylene compounds such as nitroalkanes (Eq. 1.19), malonates, and β‐keto esters are suitable Michael donors in the Michael reaction using α,β‐unsaturated aldehydes as a Michael acceptor, catalyzed by diphenylprolinol silyl ether catalyst [42].
Oximes, such as benzaldehyde oxime, also act as suitable Michael donors to afford β‐hydroxy carbonyl compounds after hydrogenolysis (Eq. 1.20) [43]. Given that asymmetric oxy‐Michael reactions are difficult because of the facile retro‐Michael reaction, this two‐step reaction is synthetically useful.
Thiol is also a good Michael donor and chiral β‐thio aldehydes were obtained with excellent enantioselectivity [44].
Aza‐Michael reactions were also reported using thiazoles, tetrazoles, and succinimides, and the products were generated with excellent enantioselectivity [45].
Construction of a C–P bond by the Michael reaction was reported. Asymmetric hydrophosphination proceeded by a reaction of diphenylphosphine and α,β‐unsaturated aldehydes catalyzed by diarylprolinol silyl ether (Eq. 1.21) [46].