Spiro Compounds. Группа авторов

responsible for controlling the stereochemistry of the product 116. A variety of chiral β‐lactones were obtained in excellent yield (80–96%) with very high diastereo‐ and enantioselectivity (>20 : 1 dr and 88–97% ee).

Scheme 3.10 Ni‐catalyzed asymmetric Diels–Alder/[3,3]sigmatropic rearrangement cascade between methyleneindolinones with 1‐thiocyanatobutadienes.

      Source: Modified from Zhou et al. [20].

In 2015, Tanaka and coworkers outlined an enantioselective [2+2+2] cycloaddition approach to construct spiro‐cyclohexadienes 123, starting from terminal alkynes 124, acetylenedicarboxylates 125, and cyclopropylideneacetamides 126 (Scheme 3.12) [23].

Scheme 3.11 Scandium‐catalyzed asymmetric cycloaddition between ketenes and isatins.

      Source: Modified from Hao et al. [22].

Scheme 3.12 Rhodium‐catalyzed [2+2+2] cycloadditions between alkynes and cyclopropylideneacetamides.

      Source: Based on Yoshida et al. [23].

      In the reported reaction mechanism, a rhodium(I)/(S)‐binap cationic complex is responsible for the excellent stereocontrol (96%–>99% ee), affording the spiro cyclohexadiene products 123 in moderate to good yield (31–76%). Mechanistically, the reaction proceeds through the formation of intermediate 127 by coupling the two terminal alkynes 124 and 125 with cyclopropylideneacetamides 126 in the presence of Rh(I) complex. Regioselective insertion of 126 produces the intermediate 127 which undergoes direct reductive elimination to furnish the final spiranic product 123. In a subsequent report, the authors extended the scope of the [2+2+2] cycloaddition to 1,6‐enynes instead of alkynes [24].

In 2018, the group of Rios reported an enantioselective synthesis of spiropyrazolones 135 by a formal [6+2] cycloaddition reaction (Scheme 3.13) [25]. The method relies on the catalytic synergistic activation of the seven‐membered pyrazolone derivatives 136 by Pd along with the activation of enals 137 by the chiral secondary amine 138. Specifically, the reaction is initiated by the simultaneous formation of highly active Pd‐complex 139 and the chiral iminium ion intermediate 140. Stereoselective interception of the iminium ion by the nucleophilic Pd‐complex 139 provides the enamine intermediate 141 bearing the Pd‐coordinated allyl cation. Intramolecular ring closing between the enamine moiety and allyl cation in 141 furnishes the final spiranic products 135. The [5,5]spiropyrazolone products are obtained in good yields (54–79%), moderate to good diastereoselectivities (3.2 : 1 to 20 : 1), and excellent enantiocontrol (93%–>99%).

Scheme 3.13 Synergistic palladium/chiral secondary amine‐catalyzed formal ring contraction for the enantioselective synthesis of spiropyrazolones.

      Source: Modified from Meazza et al. [25].

3.3 Organocatalytic Methodologies

      The versatility and robustness of the different organocatalytic activation modes have been implemented in a number of stereoselective cascade processes, addressing the requests of atom and step economy of modern synthetic chemistry. Remarkably, organocatalysts are generally robust, readily available, and their easy scaffold modifications allow the straightforward generation of different structural variants for the development of highly diversified asymmetric transformations. In this scenario, organocatalytic methodologies represent a powerful strategy for the preparation of complex spiro compounds with high optical purity. The section has been divided into four subsections according to the involved reactions: [3+2] cycloadditions, [4+2] cycloadditions, [4+3]‐, [2+2] cycloadditions and switchable strategies, and miscellaneous reactions.

      3.3.1 Organocatalytic [3+2] Cycloaddition Strategies to Construct Spiro Compounds

The group of Glorius envisaged an a³–d³ umpolung reactivity strategy of β,β‐disubstituted enals to construct spirocyclic oxindoles 146 bearing two highly congested contiguous quaternary carbon centers (Scheme 3.14) [26]. In this manner, the diastereoselective annulations of a variety of isatins 147 with β,β‐disubstituted enals 148 were successfully developed under N‐heterocyclic carbene catalysis 149. The use of a pivalic acid as Brønsted acid cocatalyst revealed crucial in order to ensure high yields and diastereoselectivities (8 : 1–>20 : 1 dr and 68–98% yields). Moreover, the authors carried out an enantioselective variant using a chiral NHC catalyst where the acid cocatalyst also had a beneficial effect on the reaction enantioselectivity (one example, 84% ee). The authors proposed that after the formation of Breslow intermediate, the acid cocatalyst stabilizes the intermediate 150 via two hydrogen bonds, promoting the diastereoselective formation of the adduct 151. Subsequently, intramolecular attack of the alkoxide moiety at the carbonyl group in 151 affords the desired spirooxindole 146 and regenerates the NHC catalyst.

Scheme 3.14 Conjugate umpolung of β,β‐disubstituted enals and isatins promoted by N‐heterocyclic carbene/Brønsted acid dual catalysis.

      Source: Modified from Li et al. [26].

Substrates that bear multiple nucleophilic and electrophilic sites are highly useful syntons to rapidly generate architecturally complex molecules and bioactive compound libraries. In this context, Sun and coworkers reported a method for the construction of five‐membered spirocyclic oxindoles 160 based on a Michael–Mannich cascade reaction of a ketimine intermediates, characterized by a dichotomous reactivity profile, with methyleneindolinones 1 (Scheme 3.15) [27]. The one‐pot