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Page 4 of 54 Yang et al. Chem Synth 2023;3:7 https://dx.doi.org/10.20517/cs.2022.38

of Salvia pachyphylla, inhibits the growth of human cancer cells. Bis-diterpene ferrubietolide, which was
isolated from one type of mahogany-dysoxylum lenticellare, was used as the pesticide. Abiesinol E, a
member of the spiro-biflavonoid family, has antitumor-initiating effects [21-23] . It is a challenging task to
perform asymmetric synthesis on a highly substituted spirocyclic ring, especially the quaternary chiral
carbon.

Due to the well-known β-electrophilicity of benzolactone-derived olefins, they have become elegant
spirobenzolactone scaffolds for organocatalytic asymmetric cascade annulation strategies. Nucleophilic
addition of β-electrophilicity of benzolactone-derived olefins with electron-rich Michael acceptor via an
intramolecular cycloaddition gave the spirolactone annulation product in one shot [Scheme 2]. Many
different electron-rich substrates have been explored over the past few years.

In the past few years, several chiral phosphines catalyzed transformations have been noted [24-31] , including
the asymmetric synthesis of complicated chiral spirocyclic complex structures. In this context, in 2013,
[32]
Albertshofer et al. reported an efficient organocatalytic asymmetric [3 + 2] cycloaddition reaction between
benzolactone-derived olefins 1 and a phosphonium ylide, derived from diverse Morita-Baylis-Hillman
c a r b o n a t e s 2 u n d e r c h i r a l p h o s p h i n e c a t a l y s i s t o p r o v i d e h i g h l y c o m p l e x c h i r a l
spirocyclopentenebenzolactone scaffolds 3 with excellent enantioselectivity [Scheme 3]. Three continuous
stereocenters, including one all-carbon spiro carbon center, were built in a single step. It is believed that the
C -symmetric phospholane C1 plays a critical role as an efficient nucleophilic catalyst for the described
2
transformation.

[33]
Later on, Wang et al. applied another organocatalytic asymmetric roadmap to diverse
spirocyclopentenebenzolactones 5 and 7 catalyzed by a chiral phosphine C2 by employing benzolactone-
derived olefins 1 and two types of allenic esters 4 and 6. In these reactions, γ-addition products 5 and α-
addition products 7 can be obtained in high yields and with excellent enantioselectivities, respectively
[Scheme 4].

The reaction started from the formation of a zwitterionic intermediate derived from the chiral phosphine
and allenoate (4 or 6). Intermediate acted as a 1,3-dipole and underwent a [3 + 2] cycloaddition with
benzofuranone 1 to give a product 5 via γ-addition or product 7 via α-addition. The DFT calculations
disclosed the origins of the regioselective outcomes for this phosphine-catalyzed [3 + 2] cycloaddition
reaction.

The tetrahydroquinoline scaffolds [34-36] can usually be found in natural products and drug molecules. Many
of them have been used as therapeutic agents due to their biological activities. In the last few years, the
application of squaramide organocatalysts in asymmetric catalysis resulted in the significant development of
stereoselective cascade cycloaddition reactions.

In this context, in 2022, Zhang et al. developed an asymmetric catalytic cascade reaction of benzolactone-
[37]
derived olefins 1 and α, β-unsaturated ketones 9, merging the spiro-tetrahydroquinoline with
spirobenzolactone into a single new skeleton through asymmetric catalytic cascade reactions catalyzed by a
quinine-derived chiral bifunctional squaramide organocatalyst C3. A series of differently substituted
spiro[benzolactone-tetrahydroquinoline] hybrids 9 was smoothly obtained with high yields and excellent
diastereoselectivities and enantioselectivities (up to 99% yield, > 20:1 dr, and > 99% ee) under mild reaction
conditions.