Pentacyclic Triterpenoids Isolated from Celastraceae: A Focus in the 13C-NMR Data

The Celastraceae family comprises about 96 genera and more than 1.350 species, occurring mainly in tropical and subtropical regions of the world. The species of this family stand out as important plant sources of triterpenes, both in terms of abundance and structural diversity. Triterpenoids found in Celastraceae species display mainly lupane, ursane, oleanane, and friedelane skeletons, exhibiting a wide range of biological activities such as antiviral, antimicrobial, analgesic, anti-inflammatory, and cytotoxic against various tumor cell lines. This review aimed to document all triterpenes isolated from different botanical parts of species of the Celastraceae family covering 2001 to 2021. Furthermore, a compilation of their 13C-NMR data was carried out to help characterize compounds in future investigations. A total of 504 pentacyclic triterpenes were compiled and distinguished as 29 aromatic, 50 dimers, 103 friedelanes, 89 lupanes, 102 oleananes, 22 quinonemethides, 88 ursanes and 21 classified as others.

PCTTs are structurally diverse compounds and are therefore classified according to their main skeletal structure. The main classes found in Celastraceae family possess friedelane, oleanane, lupane, ursane and quinonemethide skeletons. Quinonemethides are chemomarkers of this family are found exclusively in these species [13]. These PCTTs can occur as alcohols, ketones, carboxylic acids, lactones, aldehydes, epoxides, esters, or even glycosylated derivatives. Furthermore, these PCTTs can be sub-classified as seco, generally due to the opening of one of their rings, the most common being the ring 'A' opening between carbons 3 and 4, and sub-classified as nor when there is a lack of any of the methyl groups that constitute the basic skeleton. opening between carbons 3 and 4, and sub-classified as nor when there is a lack of any of the methyl groups that constitute the basic skeleton.
This review aims to present the PCTTs reported for species of the Celastraceae family in the 21st century, exhibiting from which species they were isolated and contributing to the chemical characterization process of these compounds listing their 13 C NMR data. The information about the PCTTs was obtained from SciFinder, Scopus, and Web of Science, using as key search terms: "Celastraceae and triterpenes", "Celastraceae and compounds", "Celastraceae and phytochemistry" and "Celastraceae and metabolites". Articles with only ethnopharmacological information and data from in vitro and in vivo tests involving extracts or isolated substances were excluded. The period covering from January 2001 to September 2021 was considered since the group has already developed a free online database (in Portuguese) for the previous years [23]. This review reports a total of 504 pentacyclic triterpenoids, 29 aromatics (A), 50 dimers (D), 103 friedelanes (F), 89 lupanes (L), 102 oleananes (O), 22 quinonemethides (Q), 88 ursanes (U) and 21 classified as others. Table S1 (supplementary material) summarizes all these PCTTs, as well as the plant species and parts from which they were isolated.

Pentacyclic Triterpenoids (PCTTs)
PCTTs consist of 30 carbon atoms (six isoprene units) distributed over five fused rings (named A, B, C, D and E). This ring arrangement yields five six-membered rings or four six-membered rings fused to a 5-membered ring, numbered as shown in Figure 1 [24]. As terpenes, the biosynthesis of PCTTs starts by the coupling of active isoprene units. Initially, there is an electrophilic condensation of IPP (isopentenyl diphosphate), with DMAPP (dimethylallyl diphosphate), yielding the precursor of monoterpenes, geranyl diphosphate (GPP). The addition of IPP to GPP generates farnesyl diphosphate (FPP), which is the precursor of sesquiterpenes. Then a tail-tail condensation of two FPP molecules leads to squalene, after the release of a diphosphate unit and a 1,3-alkyl shift ( Figure 2) [25].
The biosynthesis of PCTTs continues with the oxidation of squalene, catalyzed by squalene epoxidase, forming 2,3-oxidosqualene. This intermediary assumes the "chairchair-chair-boat" conformation and after a sequence of cyclizations yields the dammarenyl cation, which then undergoes a rearrangement forming the baccharenyl cation. From the baccharenyl cation, the key step in PCTTs biosynthesis occurs, characterized by the formation of the lupanyl cation ( Figure 3) [25,26]. Through a sequence of carbocation rearrangements (1,2-shifts), involving hydride, methyl, and ringopening shifts, the lupanyl cation yields the different PCTTs skeletons, which then could As terpenes, the biosynthesis of PCTTs starts by the coupling of active isoprene units. Initially, there is an electrophilic condensation of IPP (isopentenyl diphosphate), with DMAPP (dimethylallyl diphosphate), yielding the precursor of monoterpenes, geranyl diphosphate (GPP). The addition of IPP to GPP generates farnesyl diphosphate (FPP), which is the precursor of sesquiterpenes. Then a tail-tail condensation of two FPP molecules leads to squalene, after the release of a diphosphate unit and a 1,3-alkyl shift ( Figure 2) [25].
The biosynthesis of PCTTs continues with the oxidation of squalene, catalyzed by squalene epoxidase, forming 2,3-oxidosqualene. This intermediary assumes the "chairchair-chair-boat" conformation and after a sequence of cyclizations yields the dammarenyl cation, which then undergoes a rearrangement forming the baccharenyl cation. From the baccharenyl cation, the key step in PCTTs biosynthesis occurs, characterized by the formation of the lupanyl cation ( Figure 3) [25,26]. Through a sequence of carbocation rearrangements (1,2-shifts), involving hydride, methyl, and ring-opening shifts, the lupanyl cation yields the different PCTTs skeletons, which then could oxidize, reduce, and isomerize, leading to the formation of the different currently known PCTTs [25,26].
The most powerful spectroscopic method in the structural elucidation of PCTTs is 13 C Nuclear Magnetic Resonance (NMR). Comparison of experimental 13 C NMR chemical shifts with literature data is a useful tool in identifying the basic skeleton of these compounds. Through this data, it is possible to make predictions about the influence of a functional group on the chemical displacement of carbons from its basic skeleton [27]. According

Quinonemethides and Aromatics
Quinonemethides are compounds isolated exclusively in species of the Celastr family, and can also be found in the form of dimers or trimers [31]. Hypotheses about origin assume that they are formed from friedelane derivatives, which are transp from the leaves to the roots, where they are converted into quinonemethides [32]. are characterized as 24-nor-triterpenoids, due to the absence of methyl 24, and also have functional oxygenated groups attached to carbons 2 and 3 [33]. Aromatic ske PCTTs are a subgroup of quinonemethides, which are characterized by the aromatic the A ring.    In the 13 C NMR spectra of the quinonemethides, signals are observed in the characteristic carbonyl region, between δ C 170-200 ppm, and in the typical olefinic carbon region, around δ C 110-160 ppm. (d)
Characteristic 13 C-NMR signals of the class of lupanes are those in the olefinic region, which appear around δC 109 (C-29) and δC 150 ppm (C- 20), and signals from the methine
In the 13 C-NMR spectrum, the signals that characterize oleananes are those related to the double bond carbon atoms. For the most common oleananes with double bond between carbons 12 and 13, the chemical shifts are observed around δ C 122 (C-12) and δ C 145 ppm (C-13), except for those that have substituents close to these carbons [27].

Ursanes
Ursanes differ structurally from oleananes only by the position of methyl group 29, which is attached to carbon 19, in a β position. In the structure of ursanes, methyl group 30 is found in α position. Rings A/B, B/C and C/D have trans configuration, while rings D/E have cis configuration, like oleananes. The most common ursanes also present a double

Conclusions
This review describes 504 pentacyclic triterpenoids isolated from Celastraceae species, classified as aromatics (29), dimers (50), friedelanes (103), lupanes (89), oleananes (102), quinonemethides (22), ursanes (88) and others (21). The data reported highlights the abundance and structural diversity of pentacyclic triterpenes isolated from plants of this family. The chemical complexity of these compounds helps to rationalize the various biological properties associated with these plant species, as well as these pure metabolites. The compilation of PCTTs 13 C-NMR data presented in this review represents a contribution to the structural elucidation of new compounds of this class of terpenes.
Supplementary Materials: The following are available online, Table S1: Pentacyclic triterpenoids isolated from Celastraceae species (2001-2021) .  Data Availability Statement: The information about the PCTTs was obtained from SciFinder, Scopus, and Web of Science, using as key search terms: "Celastraceae and triterpenes", "Celastraceae and com-pounds", "Celastraceae and phytochemistry" and "Celastraceae and metabolites".