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Page 46 of 54 Yang et al. Chem Synth 2023;3:7 https://dx.doi.org/10.20517/cs.2022.38

In 2012, the enantioselective annulation of enals 125 with isatins 106 in the presence of cooperative catalysis
[137]
NHC/Lewis acid (LiCl) in THF at ambient temperature was reported by Sun et al. for the synthesis of
spirocyclic oxindole-lactone products 126 [Scheme 62].

It was proposed that the initial activation of 125 with NHC catalyst C33, while the isatins 106 was activated
by LiCl at the same time. Those two activated substrates were further stabilized by the π-π stacking and O-
Li-O covalent bonds. The alkali salt significantly enhances the enantioselectivity by securing the
confirmation of substrates to give the spirocyclic oxindole-lactone products 126 [Scheme 62, bottom].

More importantly, the total synthesis of Maremycin B was successfully achieved in a few steps via the
described highly selective formal [3 + 2] annulation methodology, which is a great example of the possible
application for chemists [Scheme 63].

Due to the electronegativity of the fluorine atom, the sigma bond between carbon and fluoride is generally
considered the strongest single bond for the carbon atom. Thus, the reduction of fluorocarbons or the
transformation of fluorocarbons into non-fluorinated organic molecules under mild conditions is extremely
challenging but still has drawn much attention.

In 2018, the reaction of γ-fluoroenals 130 with isatins 106 in the presence of chiral NHC catalyst C34 in
toluene at 0 °C gave spirocyclic oxindole-pentenelactone scaffolds 131 in up to 91% yield with up to > 99%
[139]
ee [Scheme 64] .
Upon the activation of the γ-fluoroenals 130 with in situ generated NHC, the Zwitterion intermediate I was
obtained. Followed by the 1,2-H shift and tautomerization, along with the cleavage of the C-F bond,
intermediate III was obtained. Sequential 1,5-H shift, base-promoted hydrogen abstraction and [4 + 2]
cyclization gave the final spiro product 131. It is worth mentioning that the C-F bond cleaved without the
help transition-metal catalyst and elevated temperature was not required. To further understand the
mechanism, Density functional theory (DFT) calculations were performed to elucidate the C-F bond
cleavage process [Scheme 64].

In 2015, an NHC C25-catalyzed annulation of 106 and aldehyde 132 in THF was developed by Cheng
[140]
et al. . The corresponding spirocyclic oxindole-pentenelactones 133 were obtained in moderate to good
yields and enantioselectivities [Scheme 65].

It is proposed that the addition of in situ generated NHC to 132 initially gives the vinyl Breslow
intermediate A, which decomposes to the NHC-bound unsubstituted dienolate B in the presence of base.
Subsequently, the γ-addition of the dienolate intermediate B to the isatin 106 affords the acyl azolium
adduct C. Finally, the lactonization leads to the desired spirocyclic oxindolodihydropyranone 133 and
regenerates the NHC catalyst C25 [Scheme 65].

CONCLUSION AND OUTLOOK
The catalytic asymmetric synthesis of chiral spirolactone skeletons is an important topic in synthetic
chemistry and medicinal chemistry. This review has summarized the efficient organocatalytic asymmetric
cascade reactions for the synthesis of desired chiral spirolactone molecules with structural diversity and
complexity. However, this research is still in its early stage. The below-listed challenges need to be addressed
as well. (a) The organocatalytic asymmetric cascade synthesis of chiral spirolactone scaffolds is confined to
the two major organocatalytic asymmetric synthetic routes as discussed above. Thus, the constructed