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Yang et al. Chem Synth 2023;3:7 https://dx.doi.org/10.20517/cs.2022.38 Page 29 of 54

yields with excellent diastereoselectivities. However, no literature report regarding the catalytic asymmetric
synthesis of spirocyclic oxindole-lactones 71 was found, which creates great research potential for
asymmetric syntheses.

The α, β-unsaturated acyl phosphonates have been known as activated ester surrogates for the generation of
esters or amides due to the presence of the lability of the C-P bond. In 2017, Chen et al. developed a
[96]
highly enantioselective Michael/lactonization cascade reaction of 3-hydroxyoxindoles 69 with α, β-
unsaturated acyl phosphonates 72 in the presence of quaramide catalyst C19 under mild conditions (CAN,
25 °C). On the basis of the demonstrated protocol, a serial of spirocyclic oxindole-lactone derivatives 73
were obtained in moderate to excellent yields (up to 98%) with good to excellent diastereo- and
enantioselectivities (up to > 99:1 dr and 95% ee) under the optimal conditions [Scheme 38].

It is proposed that, with the dual activation of cinchonine-derived quaramide catalyst C19, Michael addition
of the 3-hydroxyoxindoles 69 to α, β-unsaturated acyl phosphonates 72 forms the chiral acyl phosphonate
intermediate B. Then, a favorable intramolecular cyclization reaction via the acyl-transfer led to the
formation of spirocyclic oxindole-lactones 73 with excellent yields and selectivities [Scheme 38].

The class of heterocyclic spiro known as oxindole-lactones possesses many biological activities, e.g., tumor
necrosis factor-α (TNFα) induced NF-κB inhibition, antibacterial, and antibiofilm activities [97,98] . Since
trifluoromethylated molecules have unique physical, chemical, and physiological properties [99-101] , it has been
well developed in chemical biology and drug discovery. The structure-activity relationships (SAR) could be
a good starting point for drug design. Hence the fusion of fluorinated lactones to oxindole will be discussed.

[102]
In this context, Yang et al. developed an organocatalytic Michael/lactonization of 3-hydroxyoxindoles 69
with 3-trifluoroethylidene oxindoles 74 in the presence of a cinchona-derived squaramide catalyst C20 for
the synthesis of heterocyclic spiro products 75 Scheme 39). The conversion of the chemically inert amide
moiety of oxindoles into the lactone was successfully achieved with the delivery of CF -containing spiro
3
oxindole-lactones 75 in moderate to excellent yields (up to 97%) and selectivities (up to 98:2 dr and 98% ee).
It was explained by the authors that the dual activation of chiral bifunctional squaramide-tertiary amine
catalyst C20 is critical for the generation of excellent stereoselectivities [Scheme 39].

In addition, the further late-stage modification of this asymmetric methodology was demonstrated by the
treatment of 75a with HCl/MeOH at ambient temperature for 4 h. The 3-hydroxy oxindole 76 was obtained
in 93% with 95% ee and 1.2:1 diastereoselectivity [Scheme 40].

Similar to α, β-unsaturated acyl phosphonates, the α, β-unsaturated N-acylated succinimides 77 can also
serve as biselectrophilic species in the spirolactonization reaction of 3-hydroxyoxindoles 69. In 2017, Ming
et al. utilized α, β-unsaturated N-acylated succinimides 77 as biselectrophilic synthons to undergo a
[103]
bifunctional squaramide-catalysed asymmetric Michael/cyclization cascade reaction of 3-hydroxyoxindoles
69, affording the desired spiro[oxindole-lactone] derivatives 78 bearing two contiguous stereocenters were
obtained in up to 89% with up to > 95:5 dr and up to 99% ee [Scheme 41].

The plausible mechanism for the formation of 78 was proposed [Scheme 41]. Based on the activation of
both substrates 69 and 77 with the bifunctional quinine-derived squaramide catalyst C21, the hydrogen
bond stabilized intermediate A was obtained. The nucleophilic addition of C3 in the deprotonated 3-
hydroxyoxindole 69 to the α, β-unsaturated N-acylated succinimide 77 via Michael addition gave
intermediate B. Then, intramolecular lactonization was achieved by nucleophilic substitution of an alkoxide