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Page 2 of 54 Yang et al. Chem Synth 2023;3:7 https://dx.doi.org/10.20517/cs.2022.38

Keywords: Chiral spirolactones, spirocyclic stereocenter, spirolactonization reaction, natural products and
bioactive molecules, organocatalytic asymmetric cascade reaction

INTRODUCTION
The biological activities of privileged natural products are usually linked with their characteristic moiety and
[1,2]
well-defined stereo-structure . This observation has provided the impetus to develop highly stereoselective
synthetic strategies for the privileged target structure. Spirolactones, including spiropropyllactones,
spirobutyrolactones and spirovalerolactones, are the structural motifs frequently found in many natural
products and biologically active molecules [Figure 1] . The essential moiety of these compounds is the
[3-5]
spiro-lactone core with various degrees of substitution. Due to their biological activities, these compounds
have drawn much attention from chemists and biologists. However, many challenges need to be addressed,
e.g., (a) control of stereogenic spirocenter; (b) incorporation of suitable functional groups into the newly
formed ring system for the possible late-stage chemical modification and derivatization. Although several
reports have been published in the past few years, the developing efficient methods to access chiral
spirolactones with high structural diversity from readily available starting materials remain a challenging
but highly desirable goal.

The environmentally friendly, metal-free organocatalysis, usually under simple and mild reaction
conditions, has been the frontier topic due to the described advantages [6-15] . In particular, organocatalytic
asymmetric synthesis was awarded the 2021 Nobel Prize in Chemistry, which has been demonstrated as one
of the most efficient methods for synthesizing chiral compounds. Thus, novel strategies for the
organocatalytic asymmetric synthesis of chiral spirolactones are urgently needed. To address the
aforementioned challenges, numerous elegant transformations have been developed for the organocatalytic
asymmetric construction of this prominent structural motif, which usually employs the two major
organocatalytic asymmetric synthetic approaches: the first approach takes advantage of the presence of the
existing lactone structure and focuses on its functionalization; the second approach is the lactone
framework constructed from various precursors in a direct spirolactonization reaction.

Despite ongoing progress, to the best of our knowledge, a comprehensive review article is lacking to
summarize the recent advances in catalytic asymmetric synthesis of chiral spirolactones. Herein, we review
for the first time the recent advances in organocatalytic asymmetric cascade reactions for synthesis of chiral
spirolactone skeletons, including spirobutyrolactones and spirovalerolactones. This review is summarized
and classified according to the two major organocatalytic asymmetric synthetic routes: (i) using the lactone-
related frameworks as building blocks; and (ii) direct spirolactonization reaction using various reagents.
Discussions of the asymmetric catalytic mechanisms and related transformations are also described. Finally,
the remaining challenges in organocatalytic asymmetric synthesis of chiral spirolactones are also touched
on, which will enlighten the future development of this research area.

USING THE LACTONE-RELATED FRAMEWORKS AS BUILDING BLOCKS IN
ORGANOCATALYTIC ASYMMETRIC CASCADE REACTIONS
The novel skeleton could be obtained by the chemical recombination [16-20] of stereo-chemically rich scaffolds
from different sources via complexity-generating transformations, which might exhibit unexpected or new
bioactivities. Thus, the construction of these three-dimensional chiral spirolactone skeletons is highly
desired in the pharmaceutical and organic synthetic community. The use of readily available lactone-related
frameworks as building blocks in organocatalytic asymmetric cascade reactions is promising, which enables
the construction of this type of potentially bioactive compound in one step [Scheme 1].