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Yang et al. Chem Synth 2023;3:7 https://dx.doi.org/10.20517/cs.2022.38 Page 21 of 54

Scheme 26. Organocatalyzed Mannich/cyclization reaction of isothiocyanato butyrolactone 48 with N-tosylimines 52. This figure is
used with permission from Wiley-VCH Verlag [80] .

Following the work of Jiang et al. , the reaction of isothiocyanato thiobutyrolactone 48 as a nucleophilic
[80]
cascade with alkylidene pyrazolones 54 was explored for the squaramide-catalyzed enantioselective
synthesis of bispirocyclic bispiro[pyrazolone-thiobutyrolactone] skeletons 55 via cascade
Mannich/cyclization reaction. A range of structurally diverse products 55 bearing three contiguous
stereocenters including two quaternary spiro stereocenters was obtained in up to 90% yield with up to > 20:1
[81]
dr and > 99% ee [Scheme 27A] .
As for the reaction mechanism, we speculated that the tertiary amine of the catalyst C16 activates the
isothiocyanato thiobutyrolactone 48 via hydrogen bonding and simultaneously the alkylidene pyrazolones
54 gets activated by squaramide through hydrogen bonding. The hydrogen bond interaction between the
three components locked their conformation and played a critical role in the stereoselectivity of this
cyclization reaction [Scheme 27A]. To further highlight the synthetic value of this method, the amenability
to gram-scale synthesis provided many opportunities for possible industrial applications [Scheme 27B].

To check the potential application of the demonstrated asymmetric synthesis, the reaction of 55e with MeI
and K CO in acetone led to the formation of methylated analog 56 without damage to the two quaternary
3
2
spiro stereocenters [Scheme 27C]. Notably, there are two privileged substructures, butyrolactone and
pyrazolone [82-87] , in one spirocyclic molecular structure of 55, which may potentially be useful in medicinal
chemistry.