Facile Construction of Structurally Diverse Thiazolidinedione-Derived Compounds via Divergent Stereoselective Cascade Organocatalysis and Their Biological Exploratory Studies

In
this article, we present a new approach by merging two powerful
synthetic tactics, divergent synthesis and cascade organocatalysis,
to create a divergent cascade organocatalysis strategy for the facile
construction of new “privileged” substructure-based
DOS (pDOS) library. As demonstrated, notably 5 distinct molecular
architectures are produced facilely from readily available simple
synthons thiazolidinedione and its analogues and α,β-unsaturated
aldehydes in 1–3 steps with the powerful strategy. The beauty
of the chemistry is highlighted by the efficient formation of structurally
new and diverse products from structurally close reactants under the
similar reaction conditions. Notably, structurally diverse spiro-thiazolidinediones
and -rhodanines are produced from organocatalytic enantioselective
3-component Michael–Michael–aldol cascade reactions
of respective thiazolidinediones and rhodanines with enals. Nevertheless,
under the similar reaction conditions, reactions of isorhodanine via
a Michael–cyclization cascade lead to structurally different
fused thiopyranoid scaffolds. This strategy significantly minimizes
time- and cost-consuming synthetic works. Furthermore, these molecules
possess high structural complexity and functional, stereochemical,
and skeletal diversity with similarity to natural scaffolds. In the
preliminary biological studies of these molecules, compounds 4f, 8a, and 10a exhibit inhibitory
activity against the human breast cancer cells, while compounds 8a, 9a, and 9b display good antifungal
activities against Candida albicans and Cryptococcus
neoformans. Notably, their structures are different from
clinically used triazole antifungal drugs. Therefore, they could serve
as good lead compounds for the development of new generation of antifungal
agents.