Resin Glycosides from Convolvulaceae Family: An Update

Resin glycoside is a type of secondary metabolite isolated commonly from the Convolvulaceae family. It consists of oligosaccharides conjugated to organic acids with a larger percentage having a macrocyclic structure. The resin glycosides reported in this review is classified mostly based on the number of sugar units constructing the structure, which is correlated to the biological properties of the compounds. According to preliminary reviews, the protocols to isolate the compounds are not straightforward and require a special technique. Additionally, the structural determination of the isolated compounds needs to minimize the structure for the elucidation to become easier. Even though resin glycosides have a complicated structural skeleton, several total syntheses of the compounds have been reported in articles published from 2010 to date. This review is an update on the prior studies of the resin glycosides reported in 2010 and 2017. The review includes the classification, isolation techniques, structural determination, biological properties, and total synthesis of the resin glycosides.


Introduction
Resin glycosides are a class of natural products comprising oligosaccharides and organic acids, which are mostly obtained from the plants of the Convolvulaceae family [1,2]. The structures of these compounds are intramolecular macrocyclic esters formed through an intramolecular cyclization of the oligoglycosidic acid containing hydroxy fatty acids. However, several resin glycosides have acyclic aglycone [3][4][5] instead of forming macrocyclic structures, which are mostly acylated at the sugar moiety with varied organic acids [6][7][8][9][10]. The classification of this compound is based on the various number of sugar units inherent in the structure, which also form an ester-type dimer that makes the categorization process even larger. The unique structure of resin glycosides is also related to the biological properties of the compounds. Resin glycosides have broad biological properties, such as cytotoxic activities, MDR modulating properties, α-glucosidase inhibitory potential, antimicrobial activity, anti-metastatic activity, antiproliferative activity, neuroprotective and anticonvulsant activities [10][11][12][13][14][15][16]. Others include a sedative effect and GABA release, anti-inflammatory, antidepressant effect, anti-diarrhea, anti-bacteria, antimalaria, and downregulation of aquaporin 3 [15,[17][18][19][20][21][22]. The isolation and characterization of this compound are somehow not straightforward. Therefore, special protocols are required to make successful isolation [23,24]. Mostly, the simplification of the resin glycoside structure through hydrolysis is required prior to the structural elucidation. Even though the structure of resin glycoside itself seems complicated, several total syntheses with numerous synthetic strategies have been reported and described in the present review.
A review of resin glycosides from the Convolvulaceae family in this review is an update to the prior review published in 2010 and 2017 [1,2]. The review in 2010 described

Monosaccharides
The monosaccharide group, which consists of an aglycone as a decanoic acid (C-10) and one sugar group of either quinovose or fucose attached to C-7 of the decanoic acid, has the simplest structure. Fucose sugar is found in the compound of maltifidinic acid E (1) (Figure 1) isolated from the Quamoclit × multifida plant [26]. Meanwhile, the quinovose sugar is located in the compound of quamoclinic acid B (2) and operculinic acid K (3) (Figure 1) from the Quamoclit pennata [27] and Operculina macrocarpa plants [28]. Both quamoclinic acid B (2) and operculinic acid K (3) are diastereoisomers with methine carbon at C-7. The difference was found by measuring their optical rotation, where the compound (2) and compound (3) (3) was characterized as 7R-hydroxydecanoic acid 7-O-β-D-quinovopyranoside. This compound is rarely found as an aglycone or acyl side chain in the glycosidic resins of Convolvulaceae [28].
Molecules 2022, 27, x FOR PEER REVIEW 8 β-D-quinovopyranoside. This compound is rarely found as an aglycone or acyl side c in the glycosidic resins of Convolvulaceae [28].

Trisaccharides
Cuses-5-7 (4-6) ( Figure 2) were trisaccharide-type resin glycosides isolated from Cuscuta chinensis plant, where the three compounds are the result of a reductive amina reaction of a trisaccharide glycoside resin with p-anisidine [4]. The reaction was ca out because the glucose in the first sugar unit group on the anomeric carbon was not tected, easily underwent tautomerization, and was difficult to purify. For phytochem studies, the ethanol fraction containing the resin glycoside was reduced with p-anisi in order to protect the reducing sugar, thereby leading to an aminoalditol deriv grouped into disaccharide-type resin glycoside.

Trisaccharides
Cuses-5-7 (4-6) ( Figure 2) were trisaccharide-type resin glycosides isolated from the Cuscuta chinensis plant, where the three compounds are the result of a reductive amination reaction of a trisaccharide glycoside resin with p-anisidine [4]. The reaction was carried out because the glucose in the first sugar unit group on the anomeric carbon was not protected, easily underwent tautomerization, and was difficult to purify. For phytochemical studies, the ethanol fraction containing the resin glycoside was reduced with p-anisidine in order to protect the reducing sugar, thereby leading to an aminoalditol derivative grouped into disaccharide-type resin glycoside. reaction of a trisaccharide glycoside resin with p-anisidine [4]. The reaction was car out because the glucose in the first sugar unit group on the anomeric carbon was not tected, easily underwent tautomerization, and was difficult to purify. For phytochem studies, the ethanol fraction containing the resin glycoside was reduced with p-anisi in order to protect the reducing sugar, thereby leading to an aminoalditol deriva grouped into disaccharide-type resin glycoside. Cuses-3 (7) and cuses-4 (8) (Figure 3) are trisaccharide-type resin glycosides isol from Cuscuta chinensis [4]. The glucose, as the first sugar unit, was exposed and un tected, which led to tautomerism, resulting in α and β-anomers. Similarly, dichondr (9) (Figure 3), a trisaccharide-based resin glycoside isolated from the Dichondra repens, unprotected glucose in the first sugar unit. In its structure, the aglycone was attache the second sugar unit, rhamnoside [3]. Poranic acid A-B (10-11) and A (12), isolated f Porana duclouxii [5], and stansoic acid A (13) (Figure 3), obtained from Ipomoea stans showed a different structure. The trisaccharide has an aglycone attached to the first su unit group, hence, there is no unprotected sugar unit in the structure, and it resists tomerism. The last four compounds have a sugar skeleton of 11-O-α-Rha-(1 → 2)-Glc-(1 → 2)-O-β-Qui-(1 → 11)-aglycone. Cuses-3 (7) and cuses-4 (8) (Figure 3) are trisaccharide-type resin glycosides isolated from Cuscuta chinensis [4]. The glucose, as the first sugar unit, was exposed and unprotected, which led to tautomerism, resulting in α and β-anomers. Similarly, dichondrin C (9) (Figure 3), a trisaccharide-based resin glycoside isolated from the Dichondra repens, was unprotected glucose in the first sugar unit. In its structure, the aglycone was attached to the second sugar unit, rhamnoside [3]. Poranic acid A-B (10-11) and A (12), isolated from Porana duclouxii [5], and stansoic acid A (13) (Figure 3), obtained from Ipomoea stans [16], showed a different structure. The trisaccharide has an aglycone attached to the first sugar unit group, hence, there is no unprotected sugar unit in the structure, and it resists tautomerism. The last four compounds have a sugar skeleton of 11
Molecules 2022, 27, x FOR PEER REVIEW 11 that is bound to the second sugar unit (glu″) at C-3 (ester-1,3″). The structural diffe is only found in the placement of nilic acid (Nla) and methyl butyric acid (Mba) at C-C-3 in the third sugar unit (rha‴). The tetrasaccharide-based resin glycoside, stansinic acid I (44), has a structure Qui with acyclic inolic acid, which acts as the aglycone [17]. The structure is similar to that of tyrian acid VI (48) (Figure 4). This compound was obtained from Ipomoea tyrianthina, whe difference was only in the absence of the methyl butyric acid (Mba) group at C-2 i second sugar unit (Rha‴).
The other series of tricolorins was also found from Ipomoea tricolor, which are tricolorin K-M (45-47) (Figure 4) [12]. These resin glycosides share the same oligosaccharide framework as tricolorins A-D [73], which is 11 with a macrocyclic aglycone that is bound to the second sugar unit (glu") at C-3 (ester-1,3"). The structural difference is only found in the placement of nilic acid (Nla) and methyl butyric acid (Mba) at C-2 and C-3 in the third sugar unit (rha ).
The tetrasaccharide-based resin glycoside, stansinic acid I (44), has a structure of 11-O- Qui with acyclic jalapinolic acid, which acts as the aglycone [17]. The structure is similar to that of tyrianthinic acid VI (48) (Figure 4). This compound was obtained from Ipomoea tyrianthina, where the difference was only in the absence of the methyl butyric acid (Mba) group at C-2 in the second sugar unit (Rha ).
Wolcottinoside I (49) (Figure 4) isolated from Ipomoea wolcottiana [8] has a similar structure to ipomotaoside C-D compound (37)(38) obtained from Ipomoea batatas [18]. The difference between both compounds is the absence of a dodecanoyl side group (Dodeca) at C-2 in the third sugar unit Rha and an octanoyl group (Octa) at C-4 in the fourth sugar unit Rha.

Pentasaccharides
Acutacosides A-B (50-51) ( Figure 5) are resin glycosides containing a pentasaccharide core in their structure [8]. These compounds were isolated from Argyreia acuta and have the same structural framework that is characterized by the presence of similar carbon signals in the 13 C-NMR, particularly of the chemical shift from 177 to 41 ppm. The oligosaccharide core of these compounds is 11 fucopyranoside with an intramolecular aglycone 1,2"-ester. The only difference is that acutacoside A (50) and acutacoside B (51) have decanoic and dodecanoic groups, respectively. Acutacosides C-E (52-54) [36] were isolated, where the structures had the same framework as acutacosides A-B (50)(51). However, the first sugar unit of acutacosides C-E (52-54) was glucose, while for acutacosides A-B (50-51) it was fucose. The difference between the structure of acutacosides C-E (52-54) was in the position of the cinnamoyl acid (Cna) and the dodecanoyl (Dodeca) groups at C-2, C-3, and C-4 of the fourth sugar unit (rha ). Acutacosides F-I (55-58) [37] have the same oligosaccharide core as acutacosides A-B (50-51); the difference is in the presence of organic acid groups, namely, methyl butyric acid (Mba), cinnamic acid (Cna), dodecanoyl (Dodeca), and butyl (Bu) at the third (Rha ) and fourth (Rha ) sugar units.
Calysepins I-VII (168-174) ( Figure 6) has a structural skeleton of β-D-glucopyra- [61]. The aglycone of 11S-jalpinolic acid forms a lactone that is attached to the C-2 of the glucose (glc‴). The difference between the calysepins I-VII (168-174) is in the variety of organic acids, namely methyl butyric acid (Mba) and Nilic acid (Nla). In 2012, albinosides I-III (59-61) ( Figure 5) were isolated from Ipomoea alba. Based on GC-MS analysis, these resin glycosides revealed the presence of sugar units of rhamnose (Rha), quinovose (Qui), and glucose (Glc) in a ratio of 2:2:1 [38]. HMBC analysis was used to determine the location of the aglycone in the structure. Based on the HMBC analysis, macrolactone was located at C-2, while the aglycone of albinoside I (59) was found in the terminal sugar unit of rhamnose (Rha), which was shown through a correlation of H-2 (5.60) with C-1 (173.5) of convolvulinic acid. The macrolatone of albinoside II (60) is located at C-3 on the terminal sugar unit rhamnose (Rha) with a correlation of H-3 (5.66), as well as C-1 (171.1) of convolvulinic acid. For albinoside III (61), the macrolactone is located at C-3 of the second sugar unit, and glucose (Glc) is indicated by a correlation between H-3 (5.78) and C-1 (173.0) jalapinolic acid. Based on its oligosaccharide core, albinoside IV (62) [7] has the same sugar framework as albinoside I (59). However, there is a tigloyl (Tig) group in albinoside IV (62) ( Figure 5) that is attached to the third sugar unit, known as rhamnose (Rha ). Albinoside V (63) ( Figure 5) has the same framework as the albinoside II (60). The difference between albinoside V (63) and albinoside II (60) with albinoside I (59) and albinoside III (61) is in the second sugar unit, whereby glucose is replaced with rhamnosyl sugar; hence, the oligosaccharide core becomes 11 [7].
Arvensis K-L (82-83) ( Figure 5) were found in the plants of Convolvulus arvensis [40]. Both compounds have the same oligosaccharide core, which is glucosyl- The acyclic aglycone contains different structures, where arvensis L (83) has a common aglycone, and 11S-hydroxyhexadecanoic acid (or 11S-jalapinolic acid), while arvensis K (82) has a new aglycone with an additional one carbon, which is 11S-hydroxyheptadecanoic acid.
Calonyctins found in Ipomoea muricata are of the tetrasaccharide and pentasaccharide type [23]. The pentasaccharide-typed resin glycosides of calonyctins B-C (97-98) ( Figure 5) have the structural framework as the oligosaccharide core of rhamnosyl- Figure 5) is only different in its fourth sugar, in which quinovose is replaced with fucose. Calonyctins B-D (97-99) have a macrocyclic aglycone of jalapinolic acid and are attached to C-3 in the second sugar unit, qui" (ester-1,3" type).
All plant parts of Calystegia hederacea were found to produce four glycosidic acids, namely, calyhedic acids A-D [44]. However, of these four resin glycosides, only calyhedic acid A (100) ( Figure 5) belongs to the type of pentasaccharide group with a composition of three glucoses, one quinovose, and one rhamnose sugar unit, accompanied by an acyclic aglycone 12-hydroxyhexadecanoic acid.
Both compounds have differences in the location of the nilic acid (Nla) group, which is attached to the sugar rhamnose unit at its C-2 or C-3 [30]. Meanwhile, calysolin V-VI (105-106) ( Figure 5) has a β-D-glucopyranosyl- The difference between the structures is in the calysolin V (105), which has a tiglic acid group (tig) on C-3 of glucose (glc"), as opposed to calysolin VI (106). Another difference is that there is a methyl butyric acid (Mba) group on the C-4 glucose unit (glc ) in calysolin VI (106), which was absent in calysolin V (105) [46].
Evolvulic acid A (107) and evolvulin I-III (108-110) ( Figure 5) have the same oligosaccharide core as β- [47,48]. These compounds are found in Evolvulus alsinoides plants. The most interesting fact about these compounds is the presence of a novel aglycone, which is a 3,11,14-trihydroxyhexadecanoid acid unit, a new fatty acid derivative obtained from nature. The absolute configuration of the aglycone was determined by the Mosher method using an MTPA reagent. Meanwhile, the aglycone was derived as 3S,11R, and 14R-trihydroxyhexadecanoid acid [47].
The two new glycoside resins obtained by the plant Ipomoea pes-caprae, ipomeolides A and B (111-112) ( Figure 5), had an unusual structure with the aglycone of 11R-jalapinolic acid [49]. The configuration of macrolactones with 11R has not been reported, where the majority of resin glycosides have an 11S configuration. Both compounds have an oligosaccharide core rhamnosyl- [50]. The difference between these merremin compounds is found in the attachment position of the lactone aglycone. Macrocyclic aglycones of merremins A-D (113-116) are attached in the C-2 second sugar (1,2"-ester type). Meanwhile, merremin E (117) has its aglycone attached to the C-3 second sugar (1,3-ester type), with the presence of an acylic aglycone in the merremins F-G (118-119) structure.

Bidesmosides
Jalapinoside B (223) (Figure 8) was isolated from the methanolic extract of the roots of Ipomoea purga [16]. Structurally, this compound is categorized as resin glycoside in the macrocylic bidesmoside class and is characterized by the presence of additional sugar units attached to the aglycone outside the main framework of the oligosaccharide core. This core is similar to the hexasaccharide of multifidin VII (194). Jalapinoside B (223) contains two aglycones and one macrocyclic aglycone 11S-convolvulinic acid (1,3″-lactone) attached to the skeleton of the main oligosaccharide. The second aglycone is an aglycone placed outside the oligosaccharide framework, which has an additional sugar unit of quinovose at the decanoic acid (C-7), which is structurally similar to the monosaccharidetype resin glycoside, quamoclinic acid B (2). Therefore, the framework to the jalapinoside The isolation of resin glycoside from Ipomoea batatas resulted in four murasakimasarins I-IV (124-127) ( Figure 5) [52]. The difference in the structures of these compounds is in the first sugar unit, which built the oligosaccharide core. The first sugar unit in Murasakimasarin I (124) and murasakimasarin II-IV (125-127) are glucose and fucose, respectively. For example, murasakimasarin II (125) has an oligosaccharide core of glucosyl- The macrocyclic aglycone of murasakimasarins I-III (124-126) is attached to the C-2 of the second sugar unit (ester-1,2" type). In contrast to murasakimasarin IV (127), its aglycone is attached to the C-3 of the second sugar unit (ester-1,3" type).
The pentasaccharide core of wolcottinosides III-IV (157-159) ( Figure 5 which is almost similar to arboresins 1-6 with a difference in the last sugar unit (glc ) [24]. According to the report, the last sugar unit does not have a branch at C-3 of Rha" but forms a linear pentasaccharide. Furthermore, wolcottinoside V (158) has a different oligosaccharide core of glucosyl- which is similar to intrapilosine VII (112). The macrolactonization of wolcottinosides III-V (157-159) took place at the C-2 of the second sugar unit. These three compounds were found in the plant Ipomoea wolcottiana.
The new resin glycoside compound (160) ( Figure 5), isolated from the Ipomoea maxima plant, was named compound 1 by the first author [57]. Moreover, compound 1 (160) was reported to have an oligosaccharide core of rhamnosyl- ) similar to the aquaterins series [29].

Bidesmosides
Jalapinoside B (223) (Figure 8) was isolated from the methanolic extract of the roots of Ipomoea purga [16]. Structurally, this compound is categorized as resin glycoside in the macrocylic bidesmoside class and is characterized by the presence of additional sugar units attached to the aglycone outside the main framework of the oligosaccharide core. This core is similar to the hexasaccharide of multifidin VII (194). Jalapinoside B (223) contains two aglycones and one macrocyclic aglycone 11S-convolvulinic acid (1,3"-lactone) attached to the skeleton of the main oligosaccharide. The second aglycone is an aglycone placed outside the oligosaccharide framework, which has an additional sugar unit of quinovose at the decanoic acid (C-7), which is structurally similar to the monosaccharidetype resin glycoside, quamoclinic acid B (2). Therefore, the framework to the jalapinoside B
tone-1,3‴, while in unit B, the structure has an acyclic aglycone, with the connecting site between the C-1 aglycone and C-4 qui′ (unit A). The difference between these three compounds is the variety of organic acids.
Wolcottine I (261) (Figure 9) is a dimeric ester-type resin glycoside obtained from Ipomoea wolcottina [24]. The oligosaccharide core of this compound is similar to operculinic acid C (168), a tetrasaccharide with the structural skeleton of 11-O-α-L-rhamnopyranosyl- The 11S-jalapinolic acid aglycone in unit A forms a macrocylic lactone 1,3″, while the oligosaccharides in unit B are attached to the C-11 of the acyclic aglycone, with the connecting site between the C-1 aglycone and the C-3 sugar Rha″ unit A.  This classification comprises several pieces of information with a particular species of plants responsible for producing a specific group of resin glycosides. For example, the Operculina and Jalapae species only produced hexasaccharides-typed resin glycosides, while Porana and Dichondra had trisaccharides and tetrasaccharides groups. Meanwhile, the Ipomoea species is the only species that produced a wide range of resin glycosides, from trisaccharides to octasaccharides, down to the dimer class. The distribution of resin glycosides in several species is shown in Table 2.
Three dimeric esters of resin glycosides were isolated tyrianthins C-E (257-259) (Figure 9) from Ipomoea tyrianthina [17]. The tetrasaccharides core in units A and B is similar to the skeleton of tyrianthinic acid VI (48), which is 11 In unit A, the aglycone, 11S-hydroxyhexadecanoic acid forms a macrocylic lactone-1,3 , while in unit B, the structure has an acyclic aglycone, with the connecting site between the C-1 aglycone and C-4 qui (unit A). The difference between these three compounds is the variety of organic acids.
The Ipomoea stans plant produced a resin glycoside, stansin A (260) (Figure 9), which was classfied into the dimeric ester type because it has two trisaccharide units, which are esterified with hexadecanoic acid [16]. The trisaccharide core of this compound is 11-O-α- which is similar to the core stansoic acid A (13). In unit A, the 11S-hydroxyhexadecanoic acid aglycone forms a macrocylic lactone-1,3 . Meanwhile, there is an acyclic aglycone in unit B, with the linking site of the C-1 aglycone (unit B) attached to the C-4 of rhamnose (unit A).
Wolcottine I (261) (Figure 9) is a dimeric ester-type resin glycoside obtained from Ipomoea wolcottina [24]. The oligosaccharide core of this compound is similar to operculinic acid C (168), a tetrasaccharide with the structural skeleton of 11 The 11S-jalapinolic acid aglycone in unit A forms a macrocylic lactone 1,3", while the oligosaccharides in unit B are attached to the C-11 of the acyclic aglycone, with the connecting site between the C-1 aglycone and the C-3 sugar Rha" unit A.
This classification comprises several pieces of information with a particular species of plants responsible for producing a specific group of resin glycosides. For example, the Operculina and Jalapae species only produced hexasaccharides-typed resin glycosides, while Porana and Dichondra had trisaccharides and tetrasaccharides groups. Meanwhile, the Ipomoea species is the only species that produced a wide range of resin glycosides, from trisaccharides to octasaccharides, down to the dimer class. The distribution of resin glycosides in several species is shown in Table 2.

Isolation Techniques
The previous reviews described the use of various processes to obtain resin glycosides from plants. However, this review analysed the steps in the isolation of resin glycosides from Convolvulaceae plants.
Step 1: Maceration of the plant using methanol at room temperature (1 month).

2.
Step 2: Extraction of water suspension from the methanol extract with subsequent ethyl acetate and butanol. 3.
Step 3: Separation and purification of ethyl acetate fraction using subsequent silica gel column chromatography, using gradient mixtures of CHCl 3 -MeOH-H 2 O and HPLC, and using 95% and 90% MeOH as an eluent producing calysolin IX and compound 1, respectively. [14] 2 Ipomoea tricolor Seeds 1.
Step 1: Maceration of the plant using n-hexane at room temperature. 2.
Step 2: Treatment of the hexane extract with chloroform and analysis of the crude by TLC and HPLC with a standard resin glycoside, tricolorin A. This step was carried out to identify the lipophilic resin glycoside mixtures. 3.
Step 3: Separation and purification of the hexane extract by preparative HPLC using the peak-shaving and heart cutting techniques to obtain ten eluates of resin glycosides. [12] 3 Ipomoea muricata Seeds 1.
Step 2: Extraction of water suspension in the acetone/water extract with subsequent petroleum ether and ethyl acetate. 3.
Step 3: Separation and purification of the ethyl acetate fraction using silica gel column chromatography, eluting with CHCl 3 /MeOH mixtures, preparative HPLC (MeCN-H 2 O), or NH 2 column chromatography and eluting with MeOH/H 2 O to yield resin glycosides. All compounds were further purified by Sephadex LH-20. [23]
Step 1: Maceration of the plant using subsequent n-hexane and chloroform at room temperature. 2.
Step 3: Analysis of the crude using RP-HPLC on the C-18 column for comparison with reference compounds. 4.
Step 1: Maceration of the plant using subsequent chloroform at room temperature. 2.
Step 2: Separation of chloroform extract with open silica gel column chromatography with a gradient of MeOH in CHCl 3 . 3.
Step 1: Maceration of the plant using subsequent ethyl acetate at room temperature (six weeks). 2.
Step 2: Separation of ethyl acetate extract using silica gel column chromatography eluted with hexane-EtOAc. 3.
Step 3: Separation of fraction five using silica gel column chromatography, with hexane-EtOAc for elution. 4.
Step 1: Maceration of the plant using subsequent n-hexane, dichloromethane, and methanol at room temperature. 2.
Step 2: Separation of methanolic extract with C-18 silica gel column chromatography over the reversed-phase (C18) with a gradient of CH 3 OH in H 2 O for elution. 3.
Step 4: Purification of a more polar chromatographic fraction using preparative HPLC using an Ultrasil ODS column (10 mm i.d. × 300 mm, 5 µm, Altex), eluting with a mixture of CH 3 CN-H 2 O (7:3), at a flow rate of 1 mL/min at 25 o C and detection with UV at 215 nm. Chromatographic peaks were collected and reinjected until pure. This technique afforded pure resin glycosides. [17] 8 Operculina macrocarpa Root 1.
Step 1: Percolation of the plant using subsequent n-hexane, dichloromethane, and methanol at room temperature.

2.
Step 2: Suspending the methanolic extract with water and sonication of the suspension.
Step 4: Liquid-liquid partion of the supernatant with butanol and evaporation of the fraction to obtain resin glycosides. [28]

Structural Determination
The structural determination of resin glycosides has been described in preliminary reviews thoroughly [1,2]. In this review, the sequence of the general structural determination of resin glycosides will still be explained based on the reports, even though the majority are mostly similar to the ones reported in the prior reviews.
The absolute configuration of the sugars is determined by comparing their specific rotations and GC-MS data with the given standards. The relative configuration of the β-configuration is determined via the large coupling constants of the anomeric protons (J = 7.5, 8.0, 8.5 Hz). The α-configuration was determined via the chemical shifts of C-5 in the carbon NMR, while the Mosher method was used for the 11S-configuration [42].
An infrared experiment was used to determine the main functionalities present in the resin glycoside structure. The three functional groups contained in the infrared spectrum are hydroxyl, alkyl, and carbonyl groups [8,36,37,57]. Ultraviolet experiments showed that resin glycoside absorbs at a wavelength of 280 nm [36].
Mass spectroscopy, including ESI-MS, FAB-MS, HRAPCI-MS [57], APCI-MS [57], can be used to analyse fragments obtained during the experiments to erase overall structural determination [29,42,65]. Furthermore, the NMR experiment is one of the most powerful methods used in the structural elucidation of resin glycoside. All protons and carbons of the structure are characterized by ID and 2D-NMR. The presence of sugars can be determined by analysing the anomeric signals in the proton and carbon NMR. Meanwhile, carboxyl groups in the structure are evaluated through carbon NMR. All sugar connectivity's in the structure, including the ester location, are determined using 1 H-NMR, 13 C-NMR, HSQC, COSY, and HMBC. TOCSY was also used in the structural determination [41]. However, it is not mandatory but can be added to the manuscript if the discussion is unusually long or complex. The steps in the structural elucidation of resin glycosides are described in Table 5, which presents the structural determination steps of eight representatives of the resin glycosides, including monosaccharide-, trisaccharide-, tetrasaccharide-, pentasaccharide-, hexasaccharide-, heptasaccharide-, bidesmoside-, and ester dimer-based resin glycosides.  HPLC analysis and optical rotations: revealing that the hexose unit belonged to D-glucose, and the three 6-deoxyhexose units belonged to two D-quinovose and one rhamnose. NMR data and EIMS data: determining the aglycone to be the (11S)-jalapinolic acid (Jal) (after alkaline and acid hydrolyses). 8.
HMBC-3: Determining the lactonization position to be H-2 of β-Glc, which indicated that the compound contained a 22-membered ring, and this was inferred by the correlation from H-2 of β-Glc (δ H 5.67) to C-1 of Jal (δ C 174). The compound contained an additional acetyl group (Ac) for the correlation between methyl (δ H 4.75) and the carbonyl (δ C 171.2). The additional HMBC correlations from δ H 5.48 (H-4 of Rha) to δ C 171.2 (C-1 of Ac) indicated that the OH-4 of Rha was acylated by the acetyl group. [23]
An optimized total synthesis of the 22-membered ring of analogue (273) and ipomoeassin F was reported in 2020 [11]. The dissacharide core of the synthetic target was built from the glucose donor (262) and fucose acceptor (263) mediated by TMSOTf to obtain dissacharide (264). The deprotection of two levulinoyl groups using NH 2 NH 2 .H 2 O, AcOH in Pyridine led to a diol that was ready to be subsequently incorporated by the tiglate group (Mukaiyama method) and was sylilated using TESOTf to produce compound (267) in good yield. This compound was further converted to diol (268) using TFA in chloroform before it was conjugated with 4-oxo-10-undecenoic acid and mediated by EDC. The product (269)/(270) was then cyclized through ring-closing metathesis followed by hydrogenation to produce the cyclic product (271)/(272). The hydroxy group was then esterified using the Mukaiyama method with cinnamic acid, followed by TES and TBS deprotections to obtain the desired analogue (273)/ipomoeassin F (274), as shown in Scheme 1.
assin F was reported in 2020 [11]. The dissacharide core of the synthetic target was built from the glucose donor (262) and fucose acceptor (263) mediated by TMSOTf to obtain dissacharide (264). The deprotection of two levulinoyl groups using NH2NH2.H2O, AcOH in Pyridine led to a diol that was ready to be subsequently incorporated by the tiglate group (Mukaiyama method) and was sylilated using TESOTf to produce compound (267) in good yield. This compound was further converted to diol (268) using TFA in chloroform before it was conjugated with 4-oxo-10-undecenoic acid and mediated by EDC. The product (269)/(270) was then cyclized through ring-closing metathesis followed by hydrogenation to produce the cyclic product (271)/(272). The hydroxy group was then esterified using the Mukaiyama method with cinnamic acid, followed by TES and TBS deprotections to obtain the desired analogue (273)/ipomoeassin F (274), as shown in Scheme 1.
The synthetic approach in the total synthesis of tricolorin A (tetrasaccharide) was interrupted using the Pummerer reaction-mediated (IPRm) glycosylation method toward the construction of complex oligosaccharides and glycoconjugates [94]. IPRm was applied to connect two disaccharide fragments (280 and 287) and also to build them individually. Fragment (280) was constructed from the OPSB glycosyl donor and the SPTB glycosyl acceptor (278), as shown in Scheme 2. The acceptor (278) was synthesized via the subsequent deacetylation of rhamnoside (275) and isopropylidenation leading to (276) with free hydroxyl groups at position four. The obtained compound was esterified with (S)-(+)-2methylbutyric acid in the presence of EDCI and DMAP to give a high yield (277). The following ketal deprotection and acylation of the hydroxyl group at position two resulted in the SPTB glycosyl acceptor (278) that was ready to be glycosylated with the OPSB donor The synthetic approach in the total synthesis of tricolorin A (tetrasaccharide) was interrupted using the Pummerer reaction-mediated (IPRm) glycosylation method toward the construction of complex oligosaccharides and glycoconjugates [94]. IPRm was applied to connect two disaccharide fragments (280 and 287) and also to build them individually. Fragment (280) was constructed from the OPSB glycosyl donor and the SPTB glycosyl acceptor (278), as shown in Scheme 2. The acceptor (278) was synthesized via the subsequent deacetylation of rhamnoside (275) and isopropylidenation leading to (276) with free hydroxyl groups at position four. The obtained compound was esterified with (S)-(+)-2methylbutyric acid in the presence of EDCI and DMAP to give a high yield (277). The following ketal deprotection and acylation of the hydroxyl group at position two resulted in the SPTB glycosyl acceptor (278) that was ready to be glycosylated with the OPSB donor using the IPRm method. The glycosylation produced (279) that was further selectively oxidized using m-CPBA to produce the high-yield SPSB donor (280).  Fragment (287) was prepared from the SPSB donor (281), as shown in Scheme 3. This donor was glycosylated with methyl 11(S)-jalapinolate (282) in the presence of triflic anhydride and 2,6-di-tert-butyl-4-methylpyridine (DTBMP) to obtain compound (283). The deacetylation, isopropylidenization, IPRm glycosylation, and safonification resulted in the aliphatic chain-bearing disaccharide (286). The macrolactonization of (286) was found to be critical in the overall synthesis. Meanwhile, the use of 2,2′-pyridyl disulfide and triphenylphosphine gave a 19-membered ring, and 74% yield of the macrolactone (287).  Fragment (287) was prepared from the SPSB donor (281), as shown in Scheme 3. This donor was glycosylated with methyl 11(S)-jalapinolate (282) in the presence of triflic anhydride and 2,6-di-tert-butyl-4-methylpyridine (DTBMP) to obtain compound (283). The deacetylation, isopropylidenization, IPRm glycosylation, and safonification resulted in the aliphatic chain-bearing disaccharide (286). The macrolactonization of (286) was found to be critical in the overall synthesis. Meanwhile, the use of 2,2 -pyridyl disulfide and triphenylphosphine gave a 19-membered ring, and 74% yield of the macrolactone (287).  Fragment (287) was prepared from the SPSB donor (281), as shown in Scheme 3. This donor was glycosylated with methyl 11(S)-jalapinolate (282) in the presence of triflic anhydride and 2,6-di-tert-butyl-4-methylpyridine (DTBMP) to obtain compound (283). The deacetylation, isopropylidenization, IPRm glycosylation, and safonification resulted in the aliphatic chain-bearing disaccharide (286). The macrolactonization of (286) was found to be critical in the overall synthesis. Meanwhile, the use of 2,2′-pyridyl disulfide and triphenylphosphine gave a 19-membered ring, and 74% yield of the macrolactone (287).  After obtaining fragments (280) and (287), the last step was to combine both using IPRm glycosylation, as shown in Scheme 4. However, this step only yielded moderate results and about 74% when it was run under −78 o C conditions. The replacement of SPSB-based (289) donors with OPSB-based (290) increased the yield to 92%. A subse-quent desopropylidenization, de-benzylidenization, and debenzylation led to the desired tricolorin A (293). After obtaining fragments (280) and (287), the last step was to combine both using IPRm glycosylation, as shown in Scheme 4. However, this step only yielded moderate results and about 74% when it was run under −78 o C conditions. The replacement of SPSBbased (289) donors with OPSB-based (290) increased the yield to 92%. A subsequent desopropylidenization, de-benzylidenization, and debenzylation led to the desired tricolorin A (293).

Scheme 4. Synthesis of tricolorin A (293).
Total synthesis of the most complex resin glycosides, which were isolated to the datecalysolin IX 27-membered ring, macrolactone was carried out using intramolecular glycosylation during the ring-closing step [91]. This approach aimed to reduce the steps in the synthesis with the retrosynthetic analysis consisting of three fragments, namely, the glycosyl donor (301), glycosyl acceptor (298), and disaccharide unit. Fragment (298) was synthesized from the jalapinolic ester (294) and was previously prepared from undecyne and hexanal, as shown in Scheme 5. The reaction of (294) and 6-deoxyglucal (295) stereoselectively conjugated using oxone, followed by zinc chloride, led to the opening of the oxirane ring to produce β-glycoside (296) with the free OH group at the C-2 position suitable for the next glycosylation step. The glycosylation step was carried out using trichloroacetimidate in the presence of catalytic amounts of TMSOTf to produce disaccharide (298) in 83% yields.
Before it was conjugated with (301), the protecting groups of OH and COOH were deprotected to produce intermediate (302), as shown in Scheme 7. The product (302) was conjugated with (301) by placing the bulky protected group of tert-butyldimethylsilyloxy at a neighbouring C-3 position to prevent intramolecular esterification between the free OH and COOH of (302). By applying this strategy, (304) could be successfully combined with fragment (301) using DIC/DMAP to obtain (303).

Scheme 4. Synthesis of tricolorin A (293).
Total synthesis of the most complex resin glycosides, which were isolated to the date-calysolin IX 27-membered ring, macrolactone was carried out using intramolecular glycosylation during the ring-closing step [91]. This approach aimed to reduce the steps in the synthesis with the retrosynthetic analysis consisting of three fragments, namely, the glycosyl donor (301), glycosyl acceptor (298), and disaccharide unit. Fragment (298) was synthesized from the jalapinolic ester (294) and was previously prepared from undecyne and hexanal, as shown in Scheme 5. The reaction of (294) and 6-deoxyglucal (295) stereoselectively conjugated using oxone, followed by zinc chloride, led to the opening of the oxirane ring to produce β-glycoside (296) with the free OH group at the C-2 position suitable for the next glycosylation step. The glycosylation step was carried out using trichloroacetimidate in the presence of catalytic amounts of TMSOTf to produce disaccharide (298) in 83% yields. The regioselective intramolecular glycosylation of (303) was undertaken to produce compound (306), as shown in Scheme 8. The introduction of the disaccharide unit has not been reported in due course. Fragment (301) was synthesized using the same method as the synthesis of fragment (298), which involved glucal (299) and thioglycoside (300), as shown in Scheme 6. Scheme 5. Synthesis of disaccharide (298). Scheme 6. Synthesis of disaccharide (301). Scheme 7. Synthesis of (303). Before it was conjugated with (301), the protecting groups of OH and COOH were deprotected to produce intermediate (302), as shown in Scheme 7. The product (302) was conjugated with (301) by placing the bulky protected group of tert-butyldimethylsilyloxy at a neighbouring C-3 position to prevent intramolecular esterification between the free OH and COOH of (302). By applying this strategy, (304) could be successfully combined with fragment (301) using DIC/DMAP to obtain (303). The regioselective intramolecular glycosylation of (303) was undertaken to produce compound (306), as shown in Scheme 8. The introduction of the disaccharide unit has not been reported in due course.

Scheme 8. Synthesis of (306).
Two interrupted Pummerer reactions mediated with (IPRm) glycosylations were developed in the synthesis of resin glycoside [95]. This made it easy for the latent glycosides to oxidize the active glycosyl donors for the subsequent glycosylations with high efficacy. Murucoidins IV and V were synthesised through the application of the IPRm glycosylations and a sequential transient protection−glycosylation−deprotection protocol. Murucoidins IV and V were assembled in a convergent manner via a [3 + 2] IPRm glycosidic coupling and a macrolactonization.
Two interrupted Pummerer reactions mediated with (IPRm) glycosylations were developed in the synthesis of resin glycoside [95]. This made it easy for the latent glycosides to oxidize the active glycosyl donors for the subsequent glycosylations with high efficacy. Murucoidins IV and V were synthesised through the application of the IPRm glycosylations and a sequential transient protection−glycosylation−deprotection protocol. Murucoidins IV and V were assembled in a convergent manner via a [3 + 2] IPRm glycosidic coupling and a macrolactonization.
There were efficient syntheses of the three macrocyclic lactone units by the use of a Keck macrolactonization approach [92]. The Keck macrolactonization is a carbodiimidepromoted esterification to form a macrolactone in the presence of a nitrogenous base. This reaction was applied in the preparation of macrolactones. The synthesis of macrolactone (315) started from allyl 3-O-PMB-a-L-rhamnopyranoside (307), as shown in Scheme 9. The overall reaction involved protection, deprotection, and glycosylation. The activation of anomeric hemiacetal was carried out using trichloroacetonitrile (CCl 3 CN) and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) to produce trichloroacetimidate (309). The glycosilation steps (309) and (310) involved the Schmidt condition of a catalytic amount of trimethylsilyl trifluoromethane-ulfonate (TMSOTf) and the furnishing of disaccharide lipid (311) in a 97% yield. Macrolactonization took advantage of the Keck method using DCC/DMAP/PPTS. Intermediate (335) was synthesized through subsequent Lev protection and TBS deprotection before it was glycosylated with donor (333), as shown in Scheme 11. Finally, fragments (335) and (329) were combined through inverse O-glycosilation to produce a 96% yield of octasaccharide (336). Global deprotection of the groups in (336) was carried out to obtain batatin VI (337). Xie et al. (2010) reported a total synthesis of batatoside L (362) [93], which was carried out using a convergent strategy between fragments (358) and (360) through glycosylation. The Corey-Nicolaou macrolactonization method was involved in the formation of macrocyclic subunit (358). Four glycosyls trichloroacetimidate donors (350), (351), (343), and (345), and one L-rhamnosyl acceptor (348) were used in the preparation of fragments (360) and (356). The acyl groups serving as the necessary neighbouring participatory groups were incorporated at the 2-OH position of each donor to ensure that the desired 1,2-trans stereoselectivity was obtained for the glycosylation process. Subsequential protection followed by activation (imidation) was involved in the formation of fragment (343) from (338). Similar steps were used in the formation of (345). In addition, the (348) compounds were prepared through the aminolysis of intermediate (345), followed by respective esterification and desylilation, as shown in Scheme 12. Macrolactone (358) was synthesized using the Schmidt glycosylation method, as shown in Scheme 13. A chiral hydroxy ester (349) was glycosylated with (350) and (351) using the activating agent TMSOTf. The deacetylation process was problematic in determining the condition of DBU in methanol:dichloromethane (40 °C). This is because it resulted in the desired product that was ready to be glycosylated with donor (343) and the TMSOTf-activated step. The process was followed by the saponification of product (355) Scheme 12. Preparation of monosaccharide building blocks.
Macrolactone (358) was synthesized using the Schmidt glycosylation method, as shown in Scheme 13. A chiral hydroxy ester (349) was glycosylated with (350) and (351) using the activating agent TMSOTf. The deacetylation process was problematic in determining the condition of DBU in methanol:dichloromethane (40 • C). This is because it resulted in the desired product that was ready to be glycosylated with donor (343) and the TMSOTf-activated step. The process was followed by the saponification of product (355) into (338) before the application of Corey-Nicolaou's lactonization protocol using 2,20-pyridyl disulfide ((PyS)2) and triphenylphosphine (Ph3P). This was conducted in the highly dilute toluene (7.5 × 10 −4 M) upon heating for 5 days to obtain compound (357). The product was then desylilated to obtain fragment (358), which was coupled to (360). A total synthesis of tricolorin F (377) was then attempted, as shown in Scheme 16. The synthesis was initiated from the starting material donor (371), which was initially Scheme 13. Formation of macrolactone framework.
In preparing the exocyclic dirhamno-pyranose fragment (360), the imidate donor (345) was glycosylated with (348) and catalyzed by TMSOTf to produce intermediate (359). This compound was then concerted to imidate over two steps resulting in (360), which was coupled to fragment (358) through TMSOTf-activated glycosylation, followed by a global deprotection to give batatoside L (362), as shown in Scheme 14.
Synthesis of a disaccharide constituent of tricolorin A (370) and tricolorin F was successfully carried out through the MeOTf-promoted intermolecular glycosylation of dodecyl thioglycosyl donors [96]. Son et al. (2009) studied the intramolecular glycosyation using racemic: a mixture with MeOTf as a catalyst. The result showed that the R isomer went through glycosylation easier than the S isomer. Furthermore, the studies were applied to the synthesis of the disaccharide of tricolorin A and the total synthesis of tricolorin F.
In the synthesis of disaccharide and tricolorin A (370), the D-fucosyl donor (363) was conjugated to enantiomerically pure (S)-methyl 11-jalapionate using MeOTf. The resulting product was then safonified and condensed to the glucosyl donor (368) to obtain a low-yield product (369). This compound was then cyclized through MeOTf-activated glycosylation to produce (370) as a disaccharide constituent of tricolorin A, as shown in Scheme 15. yield by 72%. The intramolecular glycosylation of compound (375) was undertaken using a similar MeOTf-activated glycosylate to give compound (376) at a 72% yield. This product was then deprotected globally to produce the desired tricolorin F (377). In the synthesis of ipomoeassin A-F and analogues, macrocyclic rings were obtained through the ring-closing metathesis (RCM) method [97]. The C-sylillated strategy was applied successfully to synthesize the synthetic target. One of the precursors was the syllilated cinnamic acid (382), which was synthesized through the hydroalumination of (378), followed by the addition of iodine and subsequent O-silylation under standard conditions to produce product (379), which was subsequently converted to (382) through three reaction steps, as shown in Scheme 17. Lithium for the halogen exchange triggered a retro-Brook rearrangement that installed the C-silyl substituent and released the primary alcohol in (380), which was then oxidized to the corresponding acid (382) in an excellent overall yield.
The new strategy was used to esterify the sylillated cinnamic acid (382) by alcohol (383). Furthermore, the Yamaguchi method was used to analyse product (384), and after the PMB deprotection of the 4-oxo-8-nonenoic acid ester segments, diene (386) was produced. This was followed by a macrocycle using the commercial "second-generation" ruthenium alkylidene complex (387). After the hydrogenation and syllil processes, OPMB deprotection, ipomoeassin A (392), and B (390) were obtained. A similar strategy was also applied to the synthesis of ipomoeassin C-F, as shown in Scheme 18.

Summary
This updated review shows that resin glycosides are a class of natural products with unique structures, comprising sugar units and the aglycone. The number of sugar unit and the variety of the aglycone, including the organic acids, make a large variation in the

Summary
This updated review shows that resin glycosides are a class of natural products with unique structures, comprising sugar units and the aglycone. The number of sugar unit and the variety of the aglycone, including the organic acids, make a large variation in the structure of resin glycoside. The review on the structural diversity of resin glycosides revealed that the pentasaccharides-typed resin glycosides are the dominant compounds discovered in the Convolvulaceae family, followed by the hexasaccharide type. The most complex structure of resin glycosides was found in the group of the oligomer ester. Meanwhile, the monosaccharide-typed resin glycoside made it the simplest structure of all. The unique structure of the resin glycosides is associated with the varied biological properties of the compounds, covering cytotoxic activities, MDR modulating properties, α-glucosidase inhibitory potential, antiviral, anti-metastatic, and anti-proliferative activities. It also covers the neuroprotective and anticonvulsant activities, sedative effect, GABA release, anti-inflammatory, antimycobacterial, antidepressant, anticonvulsant, antimalarial, antidiarrhoea, downregulation aquaporin 3, and antibacterial activities. Among all of the activity, resin glycosides are known to be a good MDR modulator when they are combined with resistant drugs and have the potential to be explored more in the future. The isolation and structural characterization of resin glycosides shown in this review provide useful information. For the chemical synthesis part, the review gave information for the chemical access to the resin glycoside, and it can possibly stimulate new synthetic strategies in the future, including strategies for glycosylation to make an oligosaccharide core, cyclization, including macrolactonization, to make a macrocyclic core and also in the selection, protection, and deprotection of the hydroxyl groups during synthesis.