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Yang et al. Chem Synth 2023;3:7 https://dx.doi.org/10.20517/cs.2022.38 Page 23 of 54

Scheme 28. Butyrolactone-derived imino esters 57 as C-N-C synthons for construction of chiral spirobutyrolactones.

In 2013, a rosin-based thiourea C9 catalyzed formal 1,3-dipolar cycloaddition of butyrolactone-derived
cyclic imino esters 57 and methyleneindolinones 58 as dipolarophiles was reported by Wang et al.
[Scheme 29] . It is proposed that, with the dual activation of rosin-based thiourea C9, this process provides
[88]
a series of highly functional spiro[butyrolactone-pyrrolidin-oxindole] tricyclic skeletons 59 containing four
contiguous stereocenters and two spiro-quaternary carbon with excellent yields and stereoselectivities (up
to 97% yields, > 20:1 dr and > 99% ee).

In recent years, bispirocyclic scaffolds, which consist of three closed rings with two rigid spirocenters, have
been found in many natural products that exhibit important biological activities. Asymmetric 1,3-dipolar
cyclization reactions to construct these bispirocyclic scaffolds are highly attractive but extremely
challenging. In this context, organocatalytic 1,3-dipolar cycloaddition of butyrolactone-derived cyclic imino
esters 57 with alkylidene pyrazolones 60 in the presence of catalyst C17 in ether at ambient temperature
gave highly functionalized bispiro products 61 in high yields (up to 93% yield) and excellent
[89]
stereoselectivities (> 20:1 dr and > 99% ee, Scheme 30) . Various highly functionalized
bispiro[butyrolactone-pyrrolidin-pyrazolone] scaffolds 61 containing two quaternary spirocenters have
been successfully obtained in a single reaction. Due to the extensive biological activities of the three
structural motifs of butyrolactone, pyrrolidine, and pyrazolone, the author believes that the resulting
bispiro[butyrolactone-pyrrolidin-pyrazolone] scaffolds 61 could potentially display enhanced or new
bioactivities.

It was explained by the authors that both the intermolecular H-bonding between the catalyst and two
substrates as well as the chiral environment created by the bifunctional squaramide catalyst C17 are critical
for the generation of excellent stereoselectivities [Scheme 30].

Dihydrocoumarins and lactones are synthetically useful compounds with various bioactive derivatives and
exist in many natural products. Both types of heterocyclic systems occupy a prominent position among the
extraordinary richness of various heterocyclic systems. Recently, utilizing butyrolactone-derived cyclic
[90]
imino esters 57 and α, β-unsaturated butenolides 62 as starting materials, Kowalczyk-Dworak et al. have
developed an organocatalytic approach for the preparation of spiro[butyrolactone-pyrrolidin-
dihydrocoumarin] scaffolds 63 with structural complexity and diversity [Scheme 31].

There are two critical annulation processes in the reported synthesis. The first one is the [3 + 2]-dipolar
cycloaddition for the construction of a pyrrolidine ring. The second one is the nucleophilic addition-
elimination, which led to the butenolide-ring-opening and introduction of a dihydrocoumarin framework
in 63. The polycyclic products 63 have been isolated and characterized in excellent yields and
stereoselectivity due to the efficiencies of the bifunctional quinine-derived thiourea catalyst C18
[Scheme 31].