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Page 26 of 54 Yang et al. Chem Synth 2023;3:7 https://dx.doi.org/10.20517/cs.2022.38

DIRECT SPIROLACTONIZATION REACTION USING VARIOUS REAGENTS IN
ORGANOCATALYTIC ASYMMETRIC CASCADE REACTIONS

The efficient construction of chiral spirolactones with broad structural diversity, including
spiropropyllactones, spirobutyrolactones and spirovalerolactones from simple substrates, would be valuable
for the development of new biologically active molecules.

To achieve this goal, in recent years, the use of readily available lactone-related frameworks as starting
materials for the organocatalyzed asymmetric domino annulation reaction is a straightforward strategy.
Despite the advancements, the structural diversity is limited by the choice of starting materials. In this
context, the eco-friendly, efficient methodologies for the rapid generation of skeletally-diverse chiral
spirolactone molecules remain highly desirable but challenging. In addition to utilizing the existing lactone
structure as the starting material, another synthetic route is the skeletal construction of the lactone
framework from various lactone construction precursors in a direct spirolactonization reaction, providing
the structurally and biologically interesting chiral spirolactones with good efficiency [Scheme 34].

Spirolactonization reaction of 3-olefinic oxindoles
Skeletal construction is an important method in synthetic communities for the rapid and reliable
[92]
construction of core frameworks with various functional groups. In 2018, Guo et al. developed a new and
promising Michael-initiated Pinnick oxidative spirolactonization reaction for the synthesis of potentially
bioactive chiral spirocyclic oxindole-lactone derivatives 68 in up to 97% yield with up to 99% ee [Scheme 35,
top]. The corresponding products 68 contain spirocyclic oxindole-paraconic esters and bear three chiral
stereocenters.

The mechanism of formation of the spirocyclic oxindole-lactones is presented [Scheme 35, bottom].
Initially, an organocatalytic asymmetric Michael addition of aliphatic aldehyde 67 with 3-olefinic oxindole
66 to generate intermediate 3-oxindolepropionic aldehyde A. Then, spirocyclic oxindole-lactone 68 was
g e n e r a t e d i n t h e p r e s e n c e o f s o d i u m c h l o r i t e v i a a s e q u e n t i a l t a n d e m P i n n i c k
oxidation/chlorination/substitution transformation.

Spirolactonization reaction of 3-hydroxyoxindoles
The spiro[oxindole-lactone] scaffolds are found in a wide range of biologically active natural products and
clinical pharmaceuticals [Figure 1]. Because of the correlation between molecular structure and biological
activity, it is strongly desired to develop efficient asymmetric synthetic methods for the construction of
spiro[oxindole-lactone] derivatives.

For many years, 3-hydroxyoxindoles 69 containing two reactive nucleophilic sites have been successfully
applied in the organocatalytic asymmetric synthesis of spiro[oxindole-lactone] scaffolds. Due to the
presence of the lone pair electron at the oxygen atom, they are a good candidate to react with electron-
deficient species via nucleophilic addition reactions. With the presence of the carbonyl group, the sequential
intramolecular nucleophilic lactonization reaction is expected via the acyl-transfer process [Scheme 36].
Various biselectrophilic species, such as α, β-unsaturated N-acylated succinimides, α, β-unsaturated
pyrazoleamides, α, β-unsaturated esters, α, β-unsaturated acyl phosphonates and α, β-unsaturated acyl
azoliums generated from enals and NHCs, have been explored over the past years.

The spirolactone is widely present in various natural products, e.g., fungi, plants, and marine species. Some
of these products show significant biological and pharmaceutical activities [Figure 1] [93,94] . To investigate the
diversity-oriented synthesis of the medicinally important spirolactone scaffolds, an efficient tandem
spirolactonization reaction of 3-hydroxyoxindoles 69 with olefinic azlactones 70 was reported by Cui et al.
[95]
for the synthesis of structurally diverse spirocyclic oxindole-lactones 71 [Scheme 37]. It is proceeded via the