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Page 12 of 54 Yang et al. Chem Synth 2023;3:7 https://dx.doi.org/10.20517/cs.2022.38

Scheme 12. α, β-unsaturated butyrolactones/valerolactones 27 as 2C synthons for construction of spirobutyrolactone/valerolactones.

report is still limited.

Due to the inherent inertness of the α, β-unsaturated esters, there is no literature report regarding the
catalytic asymmetric synthesis. Hence, it is critical to develop a novel organocatalytic system for it. In 2022,
[54]
our group established a highly efficient strategy for the synthesis of complicated bispiro[butyrolactone-
pyrrolidine-indanedione] hybrids 30 in up to 89% yield with excellent selectivity (> 20:1 dr) with three-
component reaction of α, β-unsaturated butyrolactones/valerolactones 27, ninhydrin 28 and proline or
thioproline 29 [Scheme 13].

Initially, the intermediate azomethine ylides A was generated in situ by the reaction of ninhydrin 28 and
f
p r o l i n e o r t h i o p r o l i n e 29, o l l o w e d b y t h e c y c l i z a t i o n a d d i t i o n o f α , β - u n s a t u r a t e d
butyrolactones/valerolactones 27 to obtain the final spiro product 30.

It is happy to find out that many of the natural products, e.g., parthenolide, dehydrocostus lactone, and
costunolide, could be used as the substrates for described cyclization to give corresponding chiral
parthenolide-fused product 30f, dehydrocostus lactone-fused products 30g-30h, and costunolide-fused
product 30i with good yields (73%-81%) and enantioselectivity (> 20:1 dr).

The preliminary anti-cancer activity of three selected compounds 30f-h was performed [Scheme 14]. On the
basis of the initial biological experiments results, 30f and 30g show significant cytotoxicity to the A549 cells
and the K562 cells by inducing apoptosis of tumor cells. Thus, further optimization of the structure and
biological data might make them potential candidates for drug discovery.

3-Alkenyl-5-arylbutenolides as 2C synthons
Due to the significant steric hindrance between the two vicinal spiro-quaternary chiral centers, especially in
a constrained ring system, it is a great challenge to chemically synthesize such moiety. Hence, it is important
to develop an efficient method for the synthesis of vicinal spiro-quaternary chiral centers.

Recently, 3-alkenyl-5-arylbutenolides serving as efficient 2C synthons have been used to generate highly
[55]
functionalized spiro heterocyclic derivatives under organocatalytic conditions. Wang et al. have
developed a highly diastereo- and enantioselective [3 + 2] cycloaddition of N-2,2,2-trifluoroethylisatin
ketimines 32 as efficient azomethine ylide precursors with 3-alkenyl-5-arylbutenolides 31 as efficient 2C
synthons with thiourea-tertiary amine C10 as the catalyst (1 mol%) [Scheme 15].

In this reaction, the tertiary amine of the catalyst C10 activates the N-2,2,2-trifluoroethylisatin ketimines 32
via hydrogen bonding and simultaneously the 3-alkenyl-5-arylbutenolides 31 gets activated by thiourea
group through hydrogen bonding. This process allows the rapid synthesis of spiro[pyrrolidin-3,20-
oxindoles] 33 bearing four consecutive stereocenters, including sterically congested two vicinal quaternary