*2.1. Limonoids*

Limonoids are natural tetranortriterpenoids containing a four-ring structure with a 17*β*-furyl ring mainly distributed in the Meliaceae and Rutaceae families [18]. In the mangrove flora, they are especially abundant and structurally diversified in the genus *Xylocarpus moluccensis* and *X. grantum* (family Meliaceae). Up to 2021, approximately 2700 limonoids have been identified. Moreover, owing to their widespread distribution and substantial content in Meliaceae plants, and active biosynthetic pathways, more than 1600, including 30 types of unique rearrangemen<sup>t</sup> skeletons, have been isolated and identified in the last 10 years [19]. Among them, nearly 233 new limonoids with 14 kinds of novel skeletons were isolated from mangrove *Xylocarpus*.

Thaixylomolin A (**1**), isolated from the seeds of a Thai mangrove *Xylocarpus moluccensis* collected at the Trang province, was obtained similar to the cleavage of C-6/C-7 by Baeyer–Villiger (BV) oxidation [20], and then the oxidized C-6 formed an unusual 6- oxabicyclo[3.2.1]octan-3-one motif with C-1 [21]. In 2016, the same research group isolated another analogue from *X. moluccensis*, thaixylomolin R (**2**) [22], whose C-8 is decarboxylated compared with **1** (Figure 1).

**Figure 1.** Structures of compounds **1** and **2**.

Xylomexicanin F (**3**) [23], hainangrantums I and J (**4** and **5**) [24] (Figure 2) are the second examples of a limonoid with an unusual 9, 10-*seco* and C-9-C-30 linkage, isolated from the seeds of the Chinese mangrove *X. granatum*. Among them, **3** showed moderate activity against the A549 and RERF cell lines with IC50 values of 18.83 *μ*M and 15.83 *μ*M, respectively. However, the first reported analogue, xylogranatin D, was concluded as an artifact [25,26].

**Figure 2.** Structures of compounds **3**–**5**.

Chemical investigation of the seeds from a Trang (Thailand) mangrove *X. moluccensis* yielded five structurally intriguing limonoids, namely, trangmolins A–E (**6**–**10**) [27] (Figure 3). Notably, compounds **6**–**8** consist of unprecedented ring A/B-fused bicyclic moieties, and compound **10** represents the first example of the oxidative cleavage of the C2-C3 bond among limonoids. In 2021, a trangmolin A derivative krishnolide J (**11**) was isolated from seeds of the India Krishna mangrove *X. moluccensis* [28]. The biosynthetic origins of **6**–**11** could be traced back to a proposed andirobin-type limonoid with 1,2-bisketone groups [18]. Taking andirobin as the starting point, scientists from the Wu group proposed a biosynthetic pathway characterized by a highly divergent biosynthetic assembly line (Scheme 1) [27]. The three forks of the biosynthetic pathway obtain C-1/C-30 linkage (**6**–**8**, **11**), C-3/C-30 linkage (**9**), and C-2/C-30 linkage (**10**) based on the main mechanisms of electro- and nucleophilic enzymatic cascade reactions. The diverse cyclization patterns of **6**–**11** reveal the remarkable structural plasticity of rings A and B in limonoid biosynthesis.

**Figure 3.** Structures of compounds **6**–**11**.

Andhraxylocarpins A–E (**12**–**16**) (Figure 4) were isolated and identified as three new types of limonoids from the seeds of two true mangroves, *X. granatum* (collected at the estuary of Krishna, India) and *X. moluccensis* (collected in the estuary of Godavari, India), respectively [29]. Among them, andhraxylocarpins A and B (**12** and **13**) contain an unprecedented 9-oxa-tricyclo-[3.3.2.17,10]undecan-2-ene motif, andhraxylocarpins C-D (**14** and **15**) harbor a rare (Z)-bicyclo[5.2.1]dec-3-en-8-one substructure, and andhraxylocarpin E (**16**) possesses a unique tricyclo[3.3.1.13,6]decan-9-one scaffold. In 2016, trangmolin F (**17**), which shared the same A/B fused carbobicyclic with **16**, was obtained from *X. moluccensis* by the same group [27] Wu et al. suggested a mexicanolide with a *Δ*8,30 double bond, derived from an andirobin by C-2/C-30 linkage and previously discovered among the genus *Xylocarpus*, may be the precursor of **12**–**16** [29] (Scheme 1). The presence of bridging rings (C10–C1–C2) in mexicanolide-type limonoids makes C-3 and C-30 close to each other in space, which leads to their coupling.

**Scheme 1.** Proposed biosynthetic pathway for compounds **6**–**20** [21,27,29,30].

**Figure 4.** Structures of compounds **12**–**17**.

Krishnadimer A (**18**) (Figure 5) is the first dimeric limonoid isolated from the seeds of *X. moluccensis* with an unprecedented axial chirality architecture, with the C2-symmetric architecture, with a *P*-configured central axis at the C15, C15--positions of the monomeric units, represents a milestone during decades of work on natural limonoids [30]. It could be obtained by the intermolecular oxidative coupling of the phargmalin-class limonoid, which can be derived from andirobin through C-2/C-30 and C-1/C-29 linkage. (Scheme 1) The semisynthesis of the dimer was successfully conducted. Subsequently, eight new limonoid dimers of four skeletons (two symmetric and two nonsymmetric) were designed and synthesized by oxidative carbon-carbon radical coupling [31].

**Figure 5.** Structures of compounds **18**–**20**.

Two unprecedented limonoids, thaixylomolins B and C (**19** and **20**) (Figure 5), coisolates with **1** [21], are limonoids containing a unique pentasubstituted pyridine scaffold that might be generated by aromatization into a pyridine ring from a phargmalin-class limonoid. (Scheme 1) Thaixylomolin B (**19**) exhibited inhibitory activity against nitric oxide production in lipopolysaccharide and IFN*γ*-induced RAW264.7 murine macrophages with an IC50 value of 84.3 *μ*M.

Two pyridine-containing limonoids, xylogranatopyridines A (**21**) and B (**22**) (Figure 6), were isolated from the twigs and leaves of *X. granatum*, collected from the seashore of Dongzhai, Hainan Province [32]. Compared to **21**, xylogranatopyridine B (**22**) possesses an unprecedented rearranged A-ring. Prexylogranatopyridine, a co-occurrence of limonoid with an unusual C-8-C-30 linkage, could be the common biosynthetic precursor of **21** and **22** (Scheme 2). Xylogranatopyridine A (**21**) exhibited significant inhibitory activity against protein tyrosine phosphatase 1B (PTP1B) with an IC50 value of 22.9 *μ*M.

**Figure 6.** Structures of compounds **21** and **22**.

**Scheme 2.** Proposed biosynthetic pathway for compounds **21**–**24 [23,32,33]**.

An unusual tetranortriterpenoid, xylomexicanins E (**23**) (Figure 7), which is the first example of limonoid with azaspiro skeleton between B (pyrrolidine) and C rings, was isolated from the seeds of the Chinese mangrove, *X. granatum* [23]. The plausible biosynthetic routes are proposed, as shown in Scheme 2, starting from the limonoid prexylogranatopyridine.

**Figure 7.** Structures of compounds **23**–**25**.

Further investigation of the seeds from the *X. granatum* led to the isolation of two new tetranortriterpenoids, xylomexicanins I and J (**24** and **25**) [33] (Figure 7). Notably, **24** represents an unprecedented limonoid with a bridged skeleton between the B- and C-rings, contrasting with analogues possessing bridged A- and B-rings (**25**). Wu et al. proposed that **24** was obtained from the same natural precursor as **22** after an enolate addition to the allylic alcohol moiety between C-3 and C-11 (Scheme 2).

Three new limonoids, entitled xylomolones A–C (**26**–**28**, respectively, Figure 8) were discovered from the seeds of the Thai mangrove *X. moluccensis*, as well as a vital biosynthetic precursor, xylomolone D (a new C11-terpenic acid methyl ester) [34]. Compared to **26**, compound **27** is the first 9,10-*seco* limonoid with a 3,4-dihydro-2H-pyran motif and possesses the reversed alignment of ring A. For the biosynthesis of xylomolone C (**28**), a five-membered A-ring could be built through a benzylic acid-like rearrangement, forming an unusual 3-oxabicyclo[3.2.1]octan-2,7-dione motif; the C-2 is excluded from the A-ring in the rearrangemen<sup>t</sup> process. Wu et al. proposed a novel convergen<sup>t</sup> strategy for limonoid biosynthesis (Scheme 3).

**Figure 8.** Structures of compounds **26**–**28**.

**Scheme 3.** Proposed biosynthetic pathway for compounds **26**–**28** [34].
