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[3+2] annulation to form spirocyclic sultams.

      Source: Modified from Pham and Cramer [15].

In the same year, the group of Zhao reported the asymmetric [3+2] cycloaddition of p‐quinone methides 54 with vinyl cyclopronanes 55 and epoxides 56 (Scheme 3.6) [16]. The reaction proceeds through a 1,6‐conjugate addition of Pd‐activated vinyl cyclopronanes 55 and epoxides 56 to p‐quinone methides 54 followed by the annulation event. Ferrocene‐based chiral phosphine 57 was the ligand of choice for the annulations of epoxides, while chiral spiro phosphene 58 was found to be optimal in the case of vinyl cyclopropanes, obtaining in both the cases the products 61‐65 in good to high yields (71–98%) and excellent stereocontrol (3 : 1–>20 : 1 dr and 51–99% ee).

Scheme 3.6 Palladium‐catalyzed stereoselective 1,6‐conjugate addition/annulation of vinyl epoxides/cyclopropanes to p‐quinone methides.

      Source: Modified from Ma et al. [16].

In 2018, the group of Enders established the first Cu‐catalyzed enantioselective Kinugasa/Michael domino reaction for the synthesis of spirocyclic β‐lactams 66 by desymmetrization of prochiral cyclohexadienone 67 with nitrones 68 (Scheme 3.7) [17]. Cu(OTf)₂ and indane‐BOX ligand 69 was found to be the optimal catalytic system for the reaction. Mechanistically, the reaction starts with the formation of Cu‐acetylide intermediate 70 which underwent [3+2] cycloaddition with nitrones 68 to form Cu‐bound isoxazoline intermediate 71. A rearrangement of the intermediate 71 affords the tethered four‐membered copper enolate intermediate 72, which subsequently participates in desymmetric Michael addition to afford the spirocyclic β‐lactams 66 in a highly enantio‐ and diastereoselective fashion (>20 : 1 dr and 82–96% ee).

Scheme 3.7 Copper‐catalyzed asymmetric synthesis of spirocyclic β‐lactams through Kinugasa/Michael domino sequence.

      Source: Modified from Shu et al. [17].

In 2018, Waldmann and Antonchick reported the enantioselective synthesis of spirotropanyl oxindoles 78 by a bimetallic relay strategy (Scheme 3.8) [18]. Transient azomethine ylides 79 were generated from E‐oximino α‐diazo ketones 80 in the presence of an achiral Rh(II) complex, which subsequently underwent intermolecular [3+2] cycloaddition with 3‐alkenyloxindole 81 catalyzed by the chiral N,N‐dioxide Nd(III) Lewis acid complex. The products are obtained in high yields (54–97%) with high enantio‐ and diastereoselectivity (3.2 : 1 dr and 77%–>99% ee).

      3.2.2 Organometallic [4+2] Cycloaddition Strategies to Construct Spiro Compounds

In 2015, Liu, Feng, and coworkers reported a regio‐ and enantioselective aza‐Diels–Alder reaction of 3‐vinylindoles 90 with isatin‐derived ketimines 91 (Scheme 3.9) [19]. The reaction uses Ni(II) complex together with the chiral N,N′‐dioxide ligand 92, providing a wide range of spiroindolones 93 in good to high yields (75–96%), high enantioselectivities (62–94% ee), and complete diastereocontrol. Mechanistically, the reaction commenced by the activation of isatin‐derived ketimines 91 by the chiral L‐PiPr₂/Ni(II) complex through coordination with the two carbonyl groups, via a lowering LUMO strategy. The 2,4,6‐triisopropylaniline moieties in the chiral N,N′‐dioxide ligand 92 ensured the Si‐face approach of the 3‐vinylindoles 90, providing the product exclusively in exo fashion.

Scheme 3.8 Bimetallic relay catalysis for the enantioselective synthesis of the spirotropanyl oxindole.

      Source: Modified from Jia et al. [18].

Recently, the same group established the asymmetric Diels–Alder reaction/[3,3]sigmatropic rearrangement cascade of methyleneindolinones 1 with 1‐thiocyanatobutadienes 101 for the synthesis of spiranic cyclohexenyl isothiocyanates 102 (Scheme 3.10) [20]. The reaction uses Ni(II) complex and the chiral N,N′‐dioxide ligand 103, providing a range of spiro cyclohexenyl isothiocyanates in high yields (64–97%) with excellent diastereo (>15 : 1 in all the cases) and enantioselectivities (65–94% ee). Mechanistically, the reaction involves the initial activation of methyleneindolinones 1 by the chiral L‐PiPr₂/Ni(II) complex through coordination with the two carbonyl groups, generating intermediate 104. Subsequently, the 1‐thiocyanatobutadienes 101 participates in a stereoselective quasi‐concerted Diels–Alder cycloaddition from the Re face of 104 to afford intermediate 105, which further undergoes a suprafacial [3,3]sigmatropic rearrangement to furnish the final product 102. Interestingly, the authors applied the developed method to the gram‐scale synthesis of NITD609, an antimalarial active spirocyclic indole. Shortly after, the same group also developed a catalytic asymmetric Diels–Alder reaction for the synthesis of optically pure spiro[cyclohexane‐oxindoline] derivatives using Zn(OTf)₂ and a chiral N,N′‐dioxide ligand [21].

Scheme 3.9 Regio‐ and enantioselective aza‐Diels–Alder reactions of 3‐vinylindoles.

      Source: Modified from Zheng et al. [19].

      3.2.3 Organometallic Miscellaneous Strategies to Construct Spiro Compounds

The following reports are based on the construction of strained small ring spirocyclic scaffolds and on the utilization of merged metal‐ and organocatalytic strategies. The first example deals with an enantioselective [2+2] cycloaddition of disubstituted ketenes 114 and isatins 115 for the synthesis of spirocyclic β‐lactones 116, reported by the group of Feng in 2014 (Scheme 3.11) [22]. The method utilizes Sc(OTf)₃ as Lewis acid

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