the past decades, transition‐metal catalysis has emerged as a powerful tool for the construction of complex molecules. Also, rigid and strained chiral scaffolds have been synthesized in a straightforward manner under catalytic routines. Across these molecules, spirocompounds represent an important structural family with diverse and specific biological activity. In the following pages, it will be demonstrated how transition metals have overcome the synthetic issues connected to the assembly of the rigid all‐substituted quaternary sprirocenter. Drawbacks of some transition‐metal‐based catalytic systems remain the relatively low stability under aerobic conditions, while the most recent transformations have found important applications in concert with organocatalytic approaches. The section has been divided into three subcategories according to the involved reactions: [3+2] cycloaddition, [4+2] cycloaddition, and miscellaneous reactions.
3.2.1 Organometallic [3+2] Cycloaddition Strategies to Construct Spiro Compounds
In 2014, Franz and coworkers reported the asymmetric annulations of alkylidene oxindole 1 and allyl silane 2 for the synthesis of spirocyclic oxindole 3 (Scheme 3.1) [8]. The reaction was conducted in the presence of ScCl3 and the chiral (R,S)‐indapybox ligand 4 and was proposed to proceed by the formation of β‐silyl carbocation 5 through a Michael/1,2‐silyl shift/cyclization sequence.
Mechanistically, NaBArF played a dual role in the process, primarily is responsible to generating a cationic scandium complex and secondly is stabilizing the β‐silyl carbocation 5. Remarkably, this transformation represents the first example of a [3+2] annulation process involving allylsilanes and unsaturated carbonyl compounds to furnish chiral cyclopentanes in high yields (73–99%) and good to excellent stereocontrol (6 : 1–>20 : 1 dr and 64–99% ee).
Arai, Yamanaka, and coworkers presented in 2015 a [3+2] cycloaddition mediated by Cu(OTf)2 and the chiral PyBidine ligand 13 for the synthesis of a variety of functionalized spiro[pyrrolidin‐3,3′‐oxindole]s 14 (Scheme 3.2) [9]. The catalytic system, which was previously used for the endo‐selective [3+2] cycloaddition of iminoesters with nitroalkenes [10], furnished the spiranic products in excellent yields (83%–>99%) and high stereoselectivities (5 : 1–>20 : 1 and 91%–98% ee).
Scheme 3.1 Scandium‐catalyzed enantioselective carboannulation between alkylidene oxindole and allylsilanes.
Source: Modified from Ball‐Jones et al. [8].
Scheme 3.2 Copper‐catalyzed asymmetric [3+2] cycloaddition between alkylidene oxindole and imino esters.
Source: Modified from Arai et al. [9].
In the same year, the group of Yu and Deng reported the first asymmetric 1,3‐dipolar cycloaddition of azomethine ylides 23 with α‐alkylidene succinimides 24 to obtain dispiropyrrolidine derivatives 25 in good yields (up to 90%) and high stereoselectivities (>20 : 1 dr and 87–96% ee) (Scheme 3.3) [11]. The methodology uses catalytic amounts of chiral N,O‐ligand 26 in the presence of Cu(OAc)2 to impart high stereocontrol over the [3+2] cyclization process. The catalytic system was also applied for the synthesis of pyrrolidinyl‐spirooxindole skeletons with excellent diastereo‐ and enantiocontrol.
Later on, the authors extended the application of their catalytic system (using a different ligand) to the 1,3‐dipolar cycloaddition of azomethine ylides to 5‐alkylidene thiazolidine‐2,4‐diones for the synthesis of spirocyclic pyrrolidine‐thiazolidinediones [12].
Shortly after, Feng, Liu, and coworkers reported that a combination of Mg(OTf)2 and the chiral N,N′‐dioxide ligand 34 is a highly effective catalytic system for the asymmetric [3+2] cycloaddition of methyleneindolinones 1 with N,N′‐cyclic azomethine imines 35 to produce pyrazolidine‐based spirooxindoles 36 [13]. This strategy allows the construction of valuable contiguous tertiary and quaternary stereocenters (Scheme 3.4).
Scheme 3.3 Copper‐catalyzed asymmetric construction of dispiropyrrolidine skeletons via 1,3‐dipolar cycloaddition between azomethine ylides and α‐alkylidene succinimides.
Source: Modified from Yang et al. [11].
A weak positive nonlinear effect was observed between the enantiomeric excess of the product 36 and the chiral ligand 34. Hence, the authors suggest the presence of both monomeric and oligomeric catalytic species in the reaction medium, with the monomeric complex being more active. Subsequently, an asymmetric [3+2] cycloaddition of methyleneindolinones with nitrones was also reported by the same authors using the combination of chiral N,N′‐dioxide ligand and Co(BF4)2·H2O to synthesize spirooxindole derivatives in good yield and excellent diastereo‐ and enantiocontrol [14].
In 2016, Cramer and coworkers reported the [3+2] annulation between alkynes 47 and cyclic sulfonimines 46 catalyzed by a chiral Rh complex for the synthesis of spirocyclic sultams 44 (Scheme 3.5) [15]. The methodology involves the use of a chiral cyclopentadienyl ligand 45. Under the optimized reaction conditions, the enantioenriched sultams are obtained in good to excellent yields (50–99%) and enantioselectivites (75–90%). The proposed catalytic cycle is initiated by the C–H activation of the sulfonimine 46, which is directed by the N‐sulfonyl imino group, to generate the rhodacycle 48. Alkyne migratory insertion of intermediate 48 followed by the addition to the imine bond generates the spiro compound 44. Low regioselectivities were observed in the case of unsymmetrical aryl alkynes 47. This is the major limitation of this process.
Scheme 3.4 Magnesium‐catalyzed asymmetric [3+2] cycloaddition between methyleneindolinones and N,N′‐cyclic azomethine imines.