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Yang et al. Chem Synth 2023;3:7 https://dx.doi.org/10.20517/cs.2022.38 Page 33 of 54

In this context, in 2020, the synthesis of highly functionalized spirooxindoles 85 was reported by Wang
[112]
et al. via the asymmetric allylic alkylation-cyclization of 3-hydroxyoxindoles 69 with MBH carbonates 84
in the presence of catalyst C23 in DMC at 5 °C. Due to the presence of α-methylene-γ-lactone decorated
moiety in products 85, there is a possibility for the late-stage chemical modification after spirooxindoles 85
were obtained in good yields with diastereo- and enantioselectivities. It is proposed that nucleophilic
addition (allylic alkylation) of 3-hydroxyoxindole 69 to MBH carbonates 84, which was activated by the
cinchona alkaloid C23, followed by an intramolecular lactonization to afford the desired spirooxindoles 85
[Scheme 44A].

The potential of this methodology was demonstrated by the facile transformation for the construction of
fused butenolide derivatives and their analogues. The cyclization product 85 was unexpectedly isomerized
to the fused butenolide 86 in the presence of Pd-C/H in 41% yield. A CuCl-NaBH complex can
2
4
successfully reduce 85 to the expected fused dihydrofuran-2(3H)-one derivative 87 in 38% yield and > 99:1
dr [Scheme 44B].

Another organocatalytic synthesis of optically active spirocyclic spirooxindole scaffolds 90 bearing α-
methylene-γ-lactone motifs was reported by Jayakumar et al. . Instead of 3-hydroxyoxindoles 69, 3-OBoc-
[113]
protected oxindoles 88 were employed as a nucleophile, which avoided the possible dimerization of 3-
hydroxyoxindole 69 under basic conditions as well as competitive C,O-alkylation. Furthermore, the
alkylated product 90 was obtained under trifluoroacetic acid conditions, which is an important supplement
to the above-mentioned Wang’s strategy [Scheme 45] .
[112]

Recently, the N-heterocyclic carbene (NHC)-catalyzed reaction via radical intermediate has been well
developed and used as a powerful strategy for the synthesis of highly modified molecules [114-116] . A variety of
heterocycles including spiro compounds have been successfully synthesized in the presence of N-
heterocyclic carbene (NHC) based organocatalysis. Besides the above-mentioned α, β-unsaturated
substrates, the α, β-unsaturated aldehydes were also known as 3-carbon nucleophilic partners with 3-
hydroxyoxindoles 69 for the synthesis of spiro compounds via the Michael addition/lactonization sequence.

In this context, in 2017, the N-heterocyclic carbene C25-catalyzed oxidative [3 + 2] annulation of 3-
hydroxyoxindoles 69 and α, β-unsaturated aldehydes 91 was reported by Chen et al. in 2017 [Scheme 46,
[117]
top]. Both challenging alkyl enals and aryl enals 91 worked well under the optimal conditions to give the
corresponding spirooxindole lactones 92 in good yields with excellent diastereo- and enantioselectivities.

The cyclization was proposed to proceed via radical/radical cross-coupling of homoenolate and enolate, and
the single electron transfer is the key step for NHC-catalyzed annulation reaction [Scheme 46, bottom].
Furthermore, both enolate and homoenolate radicals were observed by EPR spectra.

As a continuation of the research, the oxidative N-heterocyclic carbine C25-catalyzed [3 + 2] annulation of
β, β-disubstituted enals 93 and 3hydroxyoxindole nucleophiles 69 was achieved via catalytic coupling of two
[118]
tertiary radicals . The spirocyclic oxindole-lactones 94, bearing two contiguous tetrasubstituted
stereocenters, were obtained in good yields with excellent diastereoselectivities and good
enantioselectivities. This is an important alternative synthetic method to the previously reported NHC
catalysis strategy [Scheme 47] .
[117]

The α, β-unsaturated acyl azolium intermediate [119,120] (electrophile) is an important intermediate in this N-
heterocyclic carbene (NHC)-catalysis. This type of intermediate could be easily obtained from the reaction