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Enantioselective intramolecular addition of a heteroatom pronucleophile to a carbon–carbon double bond is a powerful strategy for the construction of useful heterocyclic frameworks containing a stereogenic center. Asano and Matsubara reported the enantioselective cycloetherification via oxa‐Michael addition mediated by cinchona alkaloid‐thiourea catalyst 2h (Scheme 3.15) [37]. The reaction provided an efficient access to enantio‐enriched 2‐substituted tetrahydrofurans and tetrahydropyrans in a highly enantioselective manner.

Scheme 3.15. Enantioselective cycloetherification via oxa‐Michael addition catalyzed by 2h.

Source: Based on [37].

The same group developed two types of intriguing cascade processes that involve the enantioselective intramolecular oxa‐Michael addition. One is the enantioselective synthesis of spiroketals through the intramolecular hemiacetalization followed by oxa‐Michael addition catalyzed by Takemoto’s catalyst ent‐2a (Scheme 3.16) [38]. The authors suggested that the enantioselectivity of the reaction is largely attributed to the oxa‐Michael addition step while the diastereoselectivity is determined through the kinetic resolution of the chiral hemiacetal intermediates.

Scheme 3.16. Enantioselective synthesis of spiroketals.

Source: Based on [38].

The other process is the enantioselective synthesis of tetrahydropyrans with two stereogenic centers one of which is a tetrasubstituted one [39]. This method features an enantioselective oxa‐Michael addition and dynamic kinetic resolution (DKR) involving reversible generation of chiral cyanohydrins 15 (Scheme 3.17). Amine‐thiourea 2o efficiently catalyzed the reaction to furnish the desired products in high yields with high diastereo‐ and enantioselectivities.

Scheme 3.17. Enantioselective synthesis of tetrahydropyrans with two stereogenic centers. Source: Based on [39].

Takemoto and co‐workers investigated the enantioselective intramolecular oxa‐Michael addition of α,β‐unsaturated amides and esters [40]. Because of the low reactivity of these Michael acceptors, the reaction with the conventional catalysts was rather sluggish. In contrast, catalyst 2p having a strong hydrogen bond donor unit efficiently promoted the reaction to provide the corresponding isoxazolidines in high yields with high enantioselectivities (Scheme 3.18). This catalyst system was also applicable to the synthesis of dihydrobenzofuran derivatives.

Scheme 3.18. Enantioselective intramolecular oxa‐Michael addition of α,β‐unsaturated amides catalyzed by 2p. Source: Based on [40].

Ghorai and co‐workers reported the enantioselective intramolecular oxa‐Michael addition of 4‐hydroxy cyclohexadienones 16 generated in situ via dearomatization of phenols [41]. The reaction was efficiently catalyzed by cinchona‐squaramide 2q, providing enantio‐enriched tetrahydrofurans attached to a cyclohexadienone moiety in spiro fashion (Scheme 3.19). The products were easily transformed into chromans without disturbing the enantiomeric purity by treating with a Lewis acid.

Scheme 3.19. Enantioselective intramolecular oxa‐Michael addition of in situ generated 4‐hydroxy cyclohexadienone via dearomatization of phenol catalyzed by 2q. Source: Based on [41].

Chiral bifunctional catalysts can also be applied to aza‐Michael addition reactions. For instance, Ghorai and co‐workers developed the intramolecular aza‐Michael addition of enamines to several Michael acceptors including ketones, esters, thioesters, and Weinreb amide [42]. The reaction proceeded efficiently by using cinchona alkaloid‐squaramide 2r as a catalyst to provide enantio‐enriched dihydroisoquinoline derivatives (Scheme 3.20).

Scheme 3.20. Enantioselective intramolecular aza‐Michael addition of enamines catalyzed by 2r. Source: Based on [42].

On the other hand, Dixon and co‐workers developed one‐pot catalytic enantioselective synthesis of 2‐pyrazolines, which involves the intermolecular aza‐Michael addition of hydrazone derivatives (Scheme 3.21) [43]. In this reaction, newly developed cinchona alkaloid‐derived 2s, which possesses a 3,5‐dichlorobenzoylamide moiety as a single hydrogen bond donor, was the optimum catalyst.

Scheme 3.21. One‐pot catalytic enantioselective synthesis of 2‐pyrazolines.

Source: Based on [43].

As an example of addition reactions of sulfur nucleophiles, Ellmann and co‐workers reported the enantioselective addition of thioacids to trisubstituted nitroalkenes catalyzed by cinchona alkaloid‐squaramide 2t (Scheme 3.22) [44]. This transformation constitutes the first example of nucleophilic addition to a trisubstituted nitroalkene followed by the enantioselective protonation.

Scheme 3.22. Enantioselective addition of thioacids to trisubstituted nitroalkenes catalyzed by 2t.

Source: Based on [44].

Liu, Li, and co‐workers developed the enantioselective addition of thiols to in situ generated ortho‐quinone methides 17 (Scheme 3.23) [45]. Cinchona alkaloid‐squaramide 2u was employed as a catalyst and water was used as a solvent. The control experiments suggested that water–oil biphase was crucial to achieve both high yields and high stereoselectivity in this reaction.

Scheme 3.23. Enantioselective addition of thiols to in situ generated ortho‐quinone methides catalyzed by 2u.

Source: Based on [45].