Synthesis of Limonoid Natural Products

Abstract

Limonoid natural products are a large family of oxygenated terpenoid compounds that are best known as secondary metabolites found in citrus fruit. The diverse array of significant bioactivities associated with limonoids has stimulated targeted synthetic investigations that are often confounded by complex three‐dimensional landscapes and dense functionalization within a compact molecular framework. This Microreview aims to delineate the various structural subcategories of the limonoid aglycon class as well as provide an overview of synthetic efforts invested toward the laboratory preparation of these fascinating molecules.

The Chemistry and Pharmacology of Citrus Limonoids

“…The chemistry of CLs both in a historical perspective [29] and for structural classification purposes [37] has been masterfully treated in recent reviews. Briefly, CLs are classified in the enlarged class of the terpene family of natural products.…”

“…In the latter case, it is a common practise to relate the structure of limonoids to an archetypal limonoid scaffold from which actual limonoids may be formally derived modifying cycles and/or introducing or modifying functional groups and substituents. This reference compound (16, Figure 2) consists of four rings condensed in steroid-like manner and designated A through D [37]. At the C-17 position, a furan ring is attached while five methyls are positioned at C-4, two β-and one α-hydrogens at C-8, C-10, and C-13 respectively.…”

“…may be considered compound 16's closest parent hydrides (cf. the dammarane (17) and lanostane (18) The term "protolimonoid" [37,41] to indicate reference molecular entities like 16 should be discouraged since properly called protolimonoids (also named protomeliacins or melianes [42]) are (a) naturally occurring compounds; (b) bear an intact (eventually oxygenated) dammarane-like C-17 side chain [43]; and (c) seem to be biogenetically related to limonoids as biochemical precursors [42][43][44], while the synthetic compound 16 [41] that bears a furan ring at position C-17 has not been detected in the plant kingdom.…”

“…The proposed biogenetic relationships between compounds 1-15 are graphically summarized in Figure 3 and briefly described in the next section. The reader may also find further details on the biosynthesis of these secondary metabolites in excellent recent reviews [37,43]. …”

“…Hence, a comprehensive medicinal chemistry tools and analysis methodology are employed herein to assess the various limonin biosynthetic products. Degraded limonoids (e.g., isobenzofuranones sharing structural features with limonoids [91]) and other tetranortriterpenoids extracted from different genera and/or not belonging to the limonin biosynthetic group will not be considered and hence readers are rather directed to relevant recent reviews [15,37,[92][93][94][95][96][97][98][99][100][101].…”