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Page 16 of 54 Yang et al. Chem Synth 2023;3:7 https://dx.doi.org/10.20517/cs.2022.38

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As a complementary above-mentioned organocascade strategy, in 2013, Li et al. reported a highly
enantioselective double-Michael addition reaction by reaction of benzofuranones 36 containing a
dinucleophilic center with divinyl ketones 39 in the presence of tertiary amine-thiourea Cinchona alkaloid
organocatalyst C11 for the construction of a spirobenzolactone scaffolds 40 in very good yields (up to 99%),
up to 19:1 dr and 92% ee [Scheme 19A]. A broad substrate scope of spirobenzolactones 40 was obtained.

It was proposed that the tertiary amine of the catalyst C11 activates the divinyl ketone 39 via hydrogen
bonding and simultaneously the benzofuranone 36 gets activated by thiourea 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. The origin of stereoselectivity was explored
and determined by density functional theory (DFT) calculations [Scheme 19A].

To demonstrate the synthetic utility of this process, the enantiomerically enriched compound 40a obtained
by this method can be easily converted into oxime derivative 41 in one step without any loss of
enantiomeric excess [Scheme 19B], which is an essential structural motif in a great number of drug
molecules [62,63] .

Benzolactone-chromones as 4C synthons
In 2020, our group developed a novel benzolactone-chromone building block 42 and successfully applied it
to the organocatalytic Mannich/cyclization reactions of acceptor/donor-based species to give the chiral
spirolactone derivatives with excellent structural complexity and diversity, thus facilitating the search for
new bioactive entities. After careful analysis of the property of the structure, it is believed that this strategy
benefits from the initial intermolecular Michael reaction followed by another intramolecular Michael
reaction. The counterbalancing of the lower electrophilicity of these unactivated chromones is critical to
facilitate the expected cyclization reaction [Scheme 20].

Due to the special structure of hexahydroxanthone, which contains four or more contiguous stereocenters,
it represents a prominent structural motif in many natural products and pharmacologically active
compounds. In this context, in 2020, a quinine-derived thiourea C12-catalyzed inter-/intramolecular
Michael cycloaddition reaction of bifunctional benzolactone-chromone synthon 42 with benzolactone-
derived olefins 1 was reported by Zhang et al. [Scheme 21] . All the desired products 43, potentially useful
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in medicinal chemistry, were obtained in good yields (up to 80%) with high diastereoselectivities (up to
> 20:1 dr) and enantioselectivities (up to > 99% ee).

Bifunctional benzolactone-chromone synthon 42 was well-tailored to first act as a nucleophilic donor and
then to originate as a Michael acceptor; after the conjugate addition, an in situ generated intermediate able
to continue the intramolecular Michael cycloaddition.

α-Keto lactones as C-O synthons
The spiro-bis-lactone is a crucial synthetic motif found in natural products and biologically active molecules
[Figure 1] [65-70] . Benzolactone-2-one derivatives are typical α-keto lactones, which can serve as a new kind of
versatile C-O synthons to react with electron-rich species in annulation, and have attracted much attention
in recent years. Treatment of benzolactone-2-ones 43 with NHC-catalyzed generation of homoenolate
equivalents from enals 44 in the presence of a convenient catalyst provided a straightforward strategy for the
synthesis of spiro-bis-lactones 45 [Scheme 22A] .
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