Total Synthesis of Terpenes and Their Biological Significance: A Critical Review

Terpenes are a group of natural products made up of molecules with the formula (C5H8)n that are typically found in plants. They are widely employed in the medicinal, flavor, and fragrance industries. The total synthesis of terpenes as well as their origin and biological potential are discussed in this review.

In recent years, small subgroups of novel terpenes and terpenoids have been isolated or synthesized, providing more potentially chemotherapeutic terpene compounds for clinical trials [13]. Various terpenes and terpenoids, mainly monoterpenes and sesquiterpenes, can be continuously emitted from specialized storage organs in leaves, stems, and trunks of trees, while others are synthesized de novo after invasion of a pathogen to defend the plants [14][15][16][17]. Many volatile terpenoids such as menthol and perillyl alcohol are used as raw materials for spices, flavorings, fuels, and cosmetics. They are also used as pesticides, industrial raw materials, etc., such as pyrethrin and limonoids, which are often used as insecticides [18].
As deduced from their various structures, terpenes and terpenoids have been reported to exhibit diverse biological activities. Among them, the beneficial effects of terpene and terpenoid compounds on human health have been attracting the attention of numerous researchers, and their roles in various human disease processes, such as inflammatory diseases, tumorigenesis, and neurodegeneration, have been studied using cell and animal

Menthol
Menthol (15) is a main volatile oil component of a small number of aromatic plants that have been shown to have antibacterial, anti-inflammatory, and anticancer properties [36]. These plants are also utilized as insect repellents and fumigants [37]. Menthol (15), neomenthol (17), isomenthol (16), and neoisomenthol (18) are some of the eight chiral centers forms known as "menthols." Mentha piperita and Mentha arvensis are the most common plants from which menthol (15) is extracted. Scheme 1. Synthesis of bromo-methyl-butene derivatives.

Menthol
Menthol (15) is a main volatile oil component of a small number of aromatic plants that have been shown to have antibacterial, anti-inflammatory, and anticancer properties [36]. These plants are also utilized as insect repellents and fumigants [37]. Menthol (15), neomenthol (17), isomenthol (16), and neoisomenthol (18) are some of the eight chiral centers forms known as "menthols". Mentha piperita and Mentha arvensis are the most common plants from which menthol (15) is extracted.
Pd as well as Ni precursors are filled with phosphoglutamic acid and acidic support (HPA-MM). For the synthesis of menthol, these catalysts have been used in citral and citronellal hydrogenations. The conversion of citral (9) to menthols (15)(16)(17)(18) was catalyzed by a stable proportion of metallic and acidic positions, which increased selectivity. The strongest menthol selectivity was achieved by medium Bronsted and robust Lewis acidic sites that were preoccupied with Ni intermediate-containing metal sites. Optimized conditions (8 wt%, P 0.5-1.0 MPa and T = 80 °C ) were helpful for obtaining the highest menthol selectivity (Scheme 2) [38]. Scheme 2. Total synthesis of menthol.

9-Hydroxy-Isoegomaketone
9-hydroxy-isoegomaketones (25) originate from the dried leaves of Perillae Folium belonging to the Perilla. frutescens varieties frutescens, P. frutescens var. acuta, and P. frutescens var. crispa (Lamiaceae). They devour a bitter flavor and deep possession, performing on catalyzed cycloisomerizationsulfonyl migration cascade was carried out in the presence of JohnPhosAuNTf 2 in dichloromethane. The N-alkylated pyrrolyl sulfonates have been synthesized with good efficiency by JohnPhosAuNTf 2 . The coupling of (30,31) with the unprotected aniline boronic acid gave the aniline pyrrole derivatives (32) in a good yield from tosylate (30) but a lower yield from (31). Macrolactamization, as well as intramolecular Heck addition involving oxidation, and reduction of the resultant vinyl at the terminal site, were carried out to complete the synthesis. According to Zakarian's conditions, macrolactam synthesis was simple and achieved a good overall yield, furnishing rhazinilam (34), which was quantitatively produced by hydrogenation of the latter under standard conditions (Scheme 4) [53]. alkaloid subfamily. Rhazya stricta, Kopsia sp., and Melodinus Australia are anticancer alkaloids having IC50 values in the range of 0.6−1.2 μM that have been extracted from the deserts of the Arabian Peninsula, Iraq, and Oceania [52]. N-ArSO2-or N-OMePhSO2 glycine containing methyl ester derivatives, as well as tertiary butyl having ethylidene iodoheptanoate containing moiety, were used to make two linear precursors (28,29) in three steps. Starting with each derivative, the gold-catalyzed cycloisomerizationsulfonyl migration cascade was carried out in the presence of JohnPho-sAuNTf2 in dichloromethane. The N-alkylated pyrrolyl sulfonates have been synthesized with good efficiency by JohnPhosAuNTf2. The coupling of (30,31) with the unprotected aniline boronic acid gave the aniline pyrrole derivatives (32) in a good yield from tosylate (30) but a lower yield from (31). Macrolactamization, as well as intramolecular Heck addition involving oxidation, and reduction of the resultant vinyl at the terminal site, were carried out to complete the synthesis. According to Zakarian's conditions, macrolactam synthesis was simple and achieved a good overall yield, furnishing rhazinilam (34), which was quantitatively produced by hydrogenation of the latter under standard conditions (Scheme 4) [53].

Angustilodine
Indole alkaloids belonging to monoterpene, Angustilodine (100), isolated from the leaves of the Alstonia angustiloba, a Malayan species, were isolated by Kam and Choo [66]. Morita and coworkers evaluated alkaloids from the same plant in 2008 and identified alstilobanine E, an N-dimethyl analog of angustilodine (99). They were determined to have mild relaxant effectiveness against phenylephrine-induced cardiac ring contractions in thoracic rats [67].

Pleurolactone
J. K. Liu et. al. proposed the extraction of pleurolactone (109), a novel menthanecontaining monoterpenoid, from the fungus Pleurotus eryngii in 2013 [69]. Pleurolactone (109) has four contiguous stereocenters and a hexahydrobenzofuran structure. They suppress nitric oxide synthesis in macrophages that have been stimulated by lipopolysaccharide.

Abiespiroside A
Abiespiroside A (120), which was extracted from the Chinese fir Abies delavayi, has inhibitory effects against nitric oxide generation, which is a therapeutic incentive for inflammatory ailments such as arthritis [71]. Beshanzuenones D (122) and C (121) were extracted from the shed trunk of Abies beshanzuensis, a Chinese fir leaf. With IC50 values of 59.7 and 40.4 M, however, they were shown to inhibit PTP 1B (protein tyrosine phosphatase 1B), the main target for the cure of obesity and type 2 diabetes [72].

Abiespiroside A
Abiespiroside A (120), which was extracted from the Chinese fir Abies delavayi, has inhibitory effects against nitric oxide generation, which is a therapeutic incentive for inflammatory ailments such as arthritis [71]. Beshanzuenones D (122) and C (121) were extracted from the shed trunk of Abies beshanzuensis, a Chinese fir leaf. With IC 50 values of 59.7 and 40.4 M, however, they were shown to inhibit PTP 1B (protein tyrosine phosphatase 1B), the main target for the cure of obesity and type 2 diabetes [72].

Cyperolone
Cyperolone (139) is a bicyclo [4.3]nonane sesquiterpene that is cis-fused. Hikino et al. were the first to isolate cyperolone (139) from LINNE Cyperus rotundus (Nutgrass Japanese) in 1966 [74]. Traditional oriental medicine has long used the rhizomes of Japanese nutgrass to treat a variety of ailments, including menstrual abnormalities and reproductive conditions [75].
Under basic parameters, (R)-(-)-carvone (125) is oxidized to chlorohydrin (126) and then degraded. Since the hydrolysis stage produced only moderate yields, we found this two-step diol (127) route to be superior to alternative sequences as it was scalable and yield-reliable. The use of pyridinium chlorochromate undergoes oxidative rearrangement to compound (128), the cyclicenone, following selective protection as the triisopropylsilyl ether of the primary hydroxyl group. The Grignard reagent, which is synthesized from propargyl bromide, was smoothly coupled with tertiary hydroxyl, giving siloxy enyne (129).
The benzyloxymethyl ether was used to protect 2-methylcyclopenta-1, 3-dione (140) in its enol state. Following that, an aldol reaction with vinylogous ester having ketone (141) to produce tertiary alcohol (142) as a diastereomer. The silacycle (143) was created simultaneously from a diastereomeric mixture and heated up to 40 • C for 15 h. Purification and desilylation resulted in a high yield of the required Diels-Alder intermediate, racemic compound (144), as a single diastereomer. When the tertiary alcohol is silylated, the cyclopentenone is activated intramolecularly, and after deprotonation is confined as the silyl enol ether.
The methyl ester had to be converted to the main alcohol. Worldwide lithium aluminum hydride reduction (LAH), undergoing TBS (tertiary butyldimethylsilyl ether) protection of the newly yielded primary alcohol, and C10 ketone reoxidation provided the most straightforward transition, yielding molecule (145) in overall good yield (65%). Barton's technique was used to make vinyl iodide (146). The crude allylic alcohol was produced by Bouvealt aldehyde and simultaneous reductions, which was then oxidized with m-perchloro benzoic acid (m-CPBA) to create epoxide (147) in a satisfactory yield, which was oxidized to a lactone (150) by White's FePDP with H 2 O 2 as the stoichiometric scavenger after being handled with TFA and reduced into acid (149) (Scheme 11) [78].

Dysidavarone A
Lin et al. reported in 2012 that dysidavarone A (162), a new sesquiterpenoid quinone, was isolated and structurally elucidated from Dysidea avara, a marine sponge gathered along Yongxing Island located in the sea of South China. With IC50 values of 9.98 and 21.6 mm, these natural marine compounds have exhibited inhibitory efficacy against PTP1B (proteintyrosine phosphatase 1B) [79]. PTP1B is a main adverse regulator in leptin and insulin signaling pathways, as well as a positive regulator in malignancy and cancer development [80]. Scheme 11. Total synthesis of (±)-illisimonin A.

Dysidavarone A
Lin et al. reported in 2012 that dysidavarone A (162), a new sesquiterpenoid quinone, was isolated and structurally elucidated from Dysidea avara, a marine sponge gathered along Yongxing Island located in the sea of South China. With IC 50 values of 9.98 and 21.6 mm, these natural marine compounds have exhibited inhibitory efficacy against PTP1B (proteintyrosine phosphatase 1B) [79]. PTP1B is a main adverse regulator in leptin and insulin signaling pathways, as well as a positive regulator in malignancy and cancer development [80].
Under the Birch condition, the crucial reductive alkylation of enone (151) with molecule (152) went quickly and effectively, yielding the predicted coupling compound (153) in an 81% yield as the only diastereomer. Deprotection in the molecule (153) of the TBS group resulted in the production of hemiacetal (154) in a 98% yield. To directly synthesize the quinone system, hemiacetal (154) was allowed to be treated with an O 2 balloon (molecular oxygen) in acetonitrile at room temperature for 15 h in N, N -bis (salicylidene)ethylene diaminocobalt(II) (salcomine), yielding the required quinone (155) (86%). The formation of methoxyquinone (156) in high yield was achieved by reacting quinone (155) with five equivalents of LiN (SiMe 3 ) 2 in the presence of two equivalents of CuBr•Sme 2 in a diluted THF solution from 40 • C to r.t. for 48 h (84%).
Total synthesis of product (173), rumphellaone A, started from a molecule having (R)- (164), which was obtained via O-iodo benzyl bromide alkylation, coupling with HC 2 Si(Me 3 ) 3 via Sonogashira, and TMS deprotection from commercially accessible (R)-163 (methyl heptenol). In a 75% average yield, the major diastereomer of cyclobutane (166) was achieved with (97.3:2.7 er). The stereoselective reduction of the double bond of the cyclobutane (166) was subsequently investigated under various conditions, including Pd-catalyzed hydrogenation and cleavage of (C-H and C-C) bond of the benzylic ether, which simultaneously yielded alcohol (167). Following acetal and ketone protection, aryl ring cleavage oxidatively generated cyclobutane derivatives (168) (carboxylic acid), which were almost quantitatively yielded after methylation and ketone protection. The requisite trans-geometry at the ring containing cyclobutane moiety was accomplished via epimerization of ester on the α-position, providing pure trans- (170), yielding 86% in epimerization hydrolysis.

Thapsigargin
Thapsigargin (186) was discovered in 1978, although it was used as a popular folk medicine in prehistoric eras. Thapsigargin (186) is a classic target for total synthesis as it is common oxidizing species of the ancient guaianolide family [85]. The prodrug derivative of thapsigargin (186) in latestage clinical trials is currently being used for several tumors. Thapsigargin (186) is a robust antagonist against the protein SERCA-pump with promise to be used in a scope of healing areas [86][87][88].
To make decalin (176), we started via Robinson annulation between (+)-(175) (dihydro carvone) and (174) (ethyl vinyl ketone). After the annulation event, exposing the mixture to an O 2 atmosphere leads to installation of the alcohol at the C-6 (

Thapsigargin
Thapsigargin (186) was discovered in 1978, although it was used as a popular folk medicine in prehistoric eras. Thapsigargin (186) is a classic target for total synthesis as it is common oxidizing species of the ancient guaianolide family [85]. The prodrug derivative of thapsigargin (186) in latestage clinical trials is currently being used for several tumors. Thapsigargin (186) is a robust antagonist against the protein SERCA-pump with promise to be used in a scope of healing areas [86][87][88].
To make decalin (176), we started via Robinson annulation between (+)-(175) (dihydro carvone) and (174) (ethyl vinyl ketone). After the annulation event, exposing the mixture to an O2 atmosphere leads to installation of the alcohol at the C-6 (Ƴ-position) diastereoselectively. In one step, in a sequence involving bromination and elimination, dienone (177) from decalin (176) was efficiently obtained in an 85% yield. Diol (178) was obtained in a 60% yield by hydrolysis of (177) with Burgess solution and dihydroxylation via chemoselective/diastereoselective 5:1 ratio with AD-mix-α of terminal olefin. This step was responsible for the following oxidation with the diol (178) at C-8.
Selective protection of primary alcohol, simultaneously involving CH allylic oxidation via diastereoselectivity with SeO2, provided allylic alcohol (179). Mitsunobu inversion with butyric acid led to the simple fitting of the butyrate (180) with the preferred stereochemical geometry at C-8 after the allylic alcohol (179) was synthesized. Interestingly, at trans-synthesis, at C-11 the major targeted stereoisomer reacted favorably, leading to a diastereomerically 10:1 dr abundant product (180). Enone (181) was obtained at 50% by irradiating compound (180), by 0.01 M in CH3COOH via a mercury lamp. The required αoctanoylated enone (182) was obtained by treating enone (181) with KMno4 in benzene refluxing in octanoic and octanoic anhydride.
While efficient, dihydroxylation of α-octanoylated enone (182) with stoichiometric OsO4 was difficult due to the prolonged approach to adding C-6 and C-7 oxygen atoms. After many experiments, it was observed that using the Upjohn method employing citric acid made the reaction catalytic at 50 °C. Molecule (183) was synthesized in a 33% yield under these reaction conditions, coupled with TBS tetraol (23%). Lactonization under Parikh-Doering conditions yielded lactone (184) via the reasonably stable lactol, possibly via the intermediacy of a lactol. The penultimate product (185), as the final natural product, is known to be potentially noxious at a very low quantity; lactone (184) was chosen as the synthesis's end point. Using zinc borohydride conversion and esterification through anhydride of benzoyl chloride/angelic acid, an analytically pure compound (186) was prepared from lactone (184) (Scheme 14) [89].
-position) diastereoselectively. In one step, in a sequence involving bromination and elimination, dienone (177) from decalin (176) was efficiently obtained in an 85% yield. Diol (178) was obtained in a 60% yield by hydrolysis of (177) with Burgess solution and dihydroxylation via chemoselective/diastereoselective 5:1 ratio with AD-mix-α of terminal olefin. This step was responsible for the following oxidation with the diol (178) at C-8.
Selective protection of primary alcohol, simultaneously involving CH allylic oxidation via diastereoselectivity with SeO 2 , provided allylic alcohol (179). Mitsunobu inversion with butyric acid led to the simple fitting of the butyrate (180) with the preferred stereochemical geometry at C-8 after the allylic alcohol (179) was synthesized. Interestingly, at trans-synthesis, at C-11 the major targeted stereoisomer reacted favorably, leading to a diastereomerically 10:1 dr abundant product (180). Enone (181) was obtained at 50% by irradiating compound (180), by 0.01 M in CH 3 COOH via a mercury lamp. The required α-octanoylated enone (182) was obtained by treating enone (181) with KMno 4 in benzene refluxing in octanoic and octanoic anhydride.
While efficient, dihydroxylation of α-octanoylated enone (182) with stoichiometric OsO 4 was difficult due to the prolonged approach to adding C-6 and C-7 oxygen atoms. After many experiments, it was observed that using the Upjohn method employing citric acid made the reaction catalytic at 50 • C. Molecule (183) was synthesized in a 33% yield under these reaction conditions, coupled with TBS tetraol (23%). Lactonization under Parikh-Doering conditions yielded lactone (184) via the reasonably stable lactol, possibly via the intermediacy of a lactol. The penultimate product (185), as the final natural product, is known to be potentially noxious at a very low quantity; lactone (184) was chosen as the synthesis's end point. Using zinc borohydride conversion and esterification through anhydride of benzoyl chloride/angelic acid, an analytically pure compound (186) was prepared from lactone (184) (Scheme 14) [89].

α-Ekasantalic Acid
Illicium lanceolatum produces tricyclane sesquiterpenoids [90]. Sesquiterpenoids contain the tricyclane ring [tricycle [2.2.1.02,6] heptane] in their configuration. Antitumor, antifungal, and bactericidal activities were found in them. They are attached to tubulin and are responsible for initiating the G2/M cell cycle and leukemia cells (HL-60); they suppress migration of MCF-7 breast tumor cells and MDA-MB-231 by attacking the β-catenin pathway, an antagonist of D2 and 5-HTreceptors [91][92][93][94]. They are also proven to have antibacterial properties against the oral pathogen Porphyromonas gingivali as well as moderate activity against Helicobacter pylori [95]. Their derivatives included the proapoptotic cytotoxin with selectivity for cancer cells over healthy cells at sub-µM dosage, as well as longicyclene, a metabolite that reduces the SOS effect caused by biochemical mycotoxins [96,97].
The sodium carboxylate salt (188) was selectively acquired by treating cycloadduct (187) with sodium isopropoxide. Regioselective ring opening of acid anhydride occurs due to steric factors. Because of the methyl substituent, the bulky CH(Me) 2 O − (isopropoxide anion) resists targeting the carboxyl group adjoined to the quaternary carbon. Furthermore, the epimerized ester group is sterically less hindered and hence a thermodynamically favorable exo-site under various basic reaction conditions. Bromide (190) is produced by treating sodium carboxylate salt (188) with Br 2 /H 2 O. The reaction proceeds via Br + synthesis on the alkene's sterically less hindered face, by a nucleophilic carboxylate interaction on the backside.
In tetrahydrofuran, treatment of bromide (190) with K + (Me) 3 CO − led to enolization of the noncyclic ester, intramolecular cyclization, and removal of potassium bromide, giving intermediate (191). Under acidic conditions, the noncyclic ester was selectively hydrolyzed in intermediate (191) to only become a molecule (192). In the pivotal step, alcohol (193) was obtained by reducing the carboxylic acid function in the molecule (192) with borane. To make bisalcohol (195), alcohol (193) was converted to iodide (194), which was then treated with LiAlH 4 . Because aldehydes were more reactive than ketones in Wittig reactions, we reduced the bisalcohol (195) to compound (197) by PCC (Swern oxidation) to chemically differentiate the two hydroxyl groups.
Keto ekasantalic acid ethyl ester (198) was obtained by treating the compound (197) with the relevant Wittig substrate and hydrogenating the obtained alkene. The five-keto group was reduced by converting it to thione (199) via Lawesson's reagent, then reducing it with NiCl 2 and NaBH 4 to obtain the compound (200). The hydrolysis of (200) resulted in the formation of α-ekasantalic acid (201). This is the first time that (±)-α-ekasantalic acid (201) has been synthesized entirely. In the whole synthesis of α-santalene (202), as a target molecule, the compound (200) is a recognized precursor to synthesizing significant active molecules (Scheme 15) [92].

Crotogoudin
Crotogoudin (214), a cytotoxic diterpene isolated from local Croton plants, was isolated by a Madagascan-French group in 2010 [98]. This genus species has long been used

Crotogoudin
Crotogoudin (214), a cytotoxic diterpene isolated from local Croton plants, was isolated by a Madagascan-French group in 2010 [98]. This genus species has long been used in ethnomedicine around the world and is a rich source of secondary metabolites having a vast range of biological activity, as well as a source of interest for synthetic chemists [9]. Crotogoudin is a diterpene from the rare 3,4-secoatisane family that has displayed cytotoxicity with an IC 50 of 40 µM against the human lymphocytic leukemia (K562) cell line and 139 µM against rat hepatocytes, and is also used for the cure of fungal infections, fever, sexually transmitted disorders, malaria, diabetes, inflammation, cancer, and digestive problems [99,100].
A progressive methylation/allylation technique was used to make the (S)-carvone derivative (203). After conjugate reduction with L-Selectride ® (C 12 H 28 BLi) and oxidative work-up, the corresponding ketone (204) is obtained, which would then be deprotonated and treated with Comins' reagent to yield vinyl triflate (205). Heck reaction of vinyl triflate (205) with ethyl acrylate as the cross-coupling partner generates an ethyl enoate (206). Ester allyl group (206) was transformed into the propyl hydroxy group. This was obtained by hydroboration of the allyl group chemoselectively in the vicinity of the isopropenyl moiety using Wilkinson's catalyst (C 54 H 45 ClP 3 Rh) (207), a well-known catalyst for the hydrogenation of unsaturated hydrocarbons/catecholborane, by oxidation of the alkylborane. Then, saponification of the intermediate hydroxy ester delivered acid (208) in an 83% yield. After warming molecule (208) in (MeCH 2 CO) 2 to 180 • C for 5 d, benzannulated bis-propionate bicycle (209) was produced in an 82% yield.
Tetramethylguanidine (210), a strong nucleophilic base for alkylations, was utilized to selectively cleave the phenyl propionate in a molecule (209). This opened the route for position-specific oxidative dearomatization, which formed dienone (211). The intention was to perform a [4+2] cycloaddition of cyclohexadiene (211) with ethylene diastereoselectively. Under pressure (70 bar) and 140 • C for 5 d, undergoing cycloaddition generated tricycle (212) (6:1) in a 90% yield. The dimethyl ketal and propionyl groups were both removed by Wittig olefination, which was carried out by acid hydrolysis of the ketone group.

Waihoensene
The diterpene waihoensene (230) was isolated from Podocarpus totara, a native plant by the Weavers group in 1997 in New Zealand, and exhibited anticancer activity mainly towards (A-549) lung cells [102,103]. Waihoensene contains a tetracyclic joined ring framework imbedded in it, with six stereocenters, four of which are quaternary stereocenters, leading to the discovery of various types of drugs [104,105].
Starting with the commercial substrate (216), the synthetic chiral process was initiated. The quaternary site was inserted into molecule (216) through alkylation employing propargylic triflate (217), which generated vinylogous ester (218) in an 80% yield. The addition of lithiated (219) to molecule (218), vinylogous ester, was succeeded by an in situ elimination process, yielding enone (220) in an 89% yield. Through a radical cyclization reaction, the required hydrindane scaffold (221) was formed at C-7 (diastereomeric mixture) in 95%. By equilibration, the required stereochemistry of the methyl group at C-7 was achieved via destannylation of hydrindane (221) and later treated with NaOH in MeOH, yielding 97% of the desired cis-geometry (222) in an 88% yield.
The reduction in 1,3-allyl strain is responsible for the high preference for the desired structure of the C-7-methyl-group in the compound (222). The ketone compound (222) was defunctionalized by transferring it to hydrazone (223) and then reducing it with catechol borane to yield compound (224). Deprotection under Birch conditions, Doering-Parikh oxidation to the appropriate aldehyde, and Bestmann-Ohira alkynylation were used to convert it into alkyne (226). The precursor for the reaction of Pauson-Khand is alkyne (226), which was reacted with Co 2 (CO) 8 (dicobalt octacarbonyl) to generate the cobalt-alkyne framework. Under stressful situations, this key intermediate was cyclized and carbon monoxide was inserted to give 46% of the target product (227) and therefore deliver the fully formed nucleus of waihoensene (230).

Leonuketal
Leonuketal (246) has 8, 9-Seco labdane tetracyclic terpenoid with a large number of geometric and stereochemical structures, due to a C-C breakage process during synthesis. Peng and colleagues extracted leonuketal from Leonurus japonicas (Chinese liverwort) and found that it has a strong vasodilating activity, with EC50 values of 2.32 μM, against which KCl activation leads to the narrowing of the rat aorta [107].

Leonuketal
Leonuketal (246) has 8, 9-Seco labdane tetracyclic terpenoid with a large number of geometric and stereochemical structures, due to a C-C breakage process during synthesis. Peng and colleagues extracted leonuketal from Leonurus japonicas (Chinese liverwort) and found that it has a strong vasodilating activity, with EC 50 values of 2.32 µM, against which KCl activation leads to the narrowing of the rat aorta [107].
Treatment of epoxide (231) with in situ-generated Cp 2 TiCl 2 efficiently afforded bicyclic ketone (232) after acidic hydrolysis. The stiffness produced by the auxiliary ring may have increased the diastereoselectivity seen for the synthesis of compound (233), encouraging the equatorial method of L-selectride and inhibiting ketone ring flipping. Over two processes, compound (233) was reduced to tosyl hydrazone, which was then treated with MeLi, yielding alkyne (235) in an 89% yield. This process most likely began with the formation of vinyl lithium (234), which was then β-eliminated. The iodide obtained from intermediate (23) was made in three processes, first with the hydroxymethylation of the alkyne (236), then mesylation, and finally iodination. Alkyne (239) was obtained in an 85% yield by treating β-ketoester (238) with NaBH 4 /NaH and the iodide generated from intermediate (237). Alkyne (239) was a combination of C-10 epimers, and the C-11 ketone would contain four diastereomers if reduced. As an alternate spiroketalization substrate, deprotection of TBS and lactonization of the alkyne (239) yielded cyclic β-keto (enol) lactone (240). Treatment of lactone (240) with PPTA and AuCl•DMS consistently produced spiroketal (241) in a 65% yield.

Epoxyeujindole A
Nakadate et al. reported the extraction of epoxyeujindole A (265), a structurally complicated anominine from Eupenicillium javanicum, in 2011 [109]. Through a biomimetic synthesis, epoxyeujinode A (265) has a heptacyclic structure [110]. It has anti-inflammatory properties [111]. To set the first stereocenter, the conjugate addition of CuTC, Me3Al (247) with phosphoramidite ligand (R, S, S)-(248) occurred. The resulting enolate was initiated in situ with methyl lithium and HMPA before being quenched with allyl iodide (249), giving ketone (250), with excellent enantioselectivities. Allyl iodide (249) was a suitable substitute for methyl vinyl ketone. The epoxidation of the alkenyl silane involving m-CPBA was followed by TFA resulting in the equivalent diketone, which proceeded with aldol condensation employing MeONa to give enone (251) in a 53% total yield. This product (251) was treated with a well-known three-step mechanism to obtain iodide (252). In the case of reaction scalability/purification, the Luche protocol was more effective than conventional radical protocols. This mixture of diastereomeric acetal (1.4:1) at C-20 was smoothly transformed to the thermodynamically more stable compound (253) by exposing it to MsOH in ethanol. Treatment with LiHMDS affected regioselective deprotonation (254). The Li enolate was masked by PhNTf2 to give triflate (254) in an 87% yield, which was subsequently iodinated via Ph3P, I2, and imidazole, followed by Stille-Migita coupling [Bu3SnCH2OH, Pd(PPh3)4, LiCl] to yield allyl iodide (255). The insertion of the two-carbon unit at C9 was accomplished using a Nozaki-Hiyama-Kishi coupling (LiI, CrCl2) with acetaldehyde, which resulted in alcohol (256) in a 67% yield as a single diastereomer. Under the coupling conditions, alcohol (256) tends to cyclize to make an acetal bridged. As a result, 2,6-lutidine is significant as a buffering agent. For the cross-coupling, NaHCO3 was employed as a weak base. A three-step strategy was used to convert aldehyde (259) to tertiary alcohol (260) with high overall (85%) efficiency. Due to the deprotonation of the methyl ketone substrate, the second methyl addition required the use of a Ceric reagent. The steps of acid hydrolysis via TPAP oxidation yielded compound (261) in a 95% yield; the benzylic tertiary hydroxyl was tolerated under these conditions. When compound (261) was exposed to BF3 •OEt2, a ring closing occurred, yielding hexacycle (264) in a 65% yield. The vinylogous reaction of Friedel-Crafts can happen mainly to the intermediacy To set the first stereocenter, the conjugate addition of CuTC, Me 3 Al (247) with phosphoramidite ligand (R, S, S)-(248) occurred. The resulting enolate was initiated in situ with methyl lithium and HMPA before being quenched with allyl iodide (249), giving ketone (250), with excellent enantioselectivities. Allyl iodide (249) was a suitable substitute for methyl vinyl ketone. The epoxidation of the alkenyl silane involving m-CPBA was followed by TFA resulting in the equivalent diketone, which proceeded with aldol condensation employing MeONa to give enone (251) in a 53% total yield. This product (251) was treated with a well-known three-step mechanism to obtain iodide (252). In the case of reaction scalability/purification, the Luche protocol was more effective than conventional radical protocols. This mixture of diastereomeric acetal (1.4:1) at C-20 was smoothly transformed to the thermodynamically more stable compound (253) by exposing it to MsOH in ethanol. Treatment with LiHMDS affected regioselective deprotonation (254). The Li enolate was masked by PhNTf 2 to give triflate (254) in an 87% yield, which was subsequently iodinated via Ph 3 P, I 2 , and imidazole, followed by Stille-Migita coupling [Bu 3 SnCH 2 OH, Pd(PPh 3 ) 4 , LiCl] to yield allyl iodide (255). The insertion of the two-carbon unit at C9 was accomplished using a Nozaki-Hiyama-Kishi coupling (LiI, CrCl 2 ) with acetaldehyde, which resulted in alcohol (256) in a 67% yield as a single diastereomer. Under the coupling conditions, alcohol (256) tends to cyclize to make an acetal bridged. As a result, 2,6-lutidine is significant as a buffering agent. For the cross-coupling, NaHCO 3 was employed as a weak base. A three-step strategy was used to convert aldehyde (259) to tertiary alcohol (260) with high overall (85%) efficiency. Due to the deprotonation of the methyl ketone substrate, the second methyl addition required the use of a Ceric reagent. The steps of acid hydrolysis via TPAP oxidation yielded compound (261) in a 95% yield; the benzylic tertiary hydroxyl was tolerated under these conditions. When compound (261) was exposed to BF 3 •OEt 2 , a ring closing occurred, yielding hexacycle (264) in a 65% yield. The vinylogous reaction of Friedel-Crafts can happen mainly to the intermediacy of intermediates (262) and (263). The heptacyclic framework of the natural product was produced through Prins cyclization by reinstalling the hemiacetal function group via DIBAL-H reduction by treating TsOH. In an 84% yield, reductive desulfonation happens with Mg in methanol-produced epoxyeujindole A (265) (Scheme 19) [112].
The requisite bicyclo[3.2.1]-octane functional moiety (277) was made from enol triflate (276). Competitive breakdown of the C16-C17 of exomethylene function in enol triflate (276) resulted in attenuation of this alkene's reactivity, which was accomplished through allylic oxidation of compound (277) with SeO 2 /t-BuOOH, which transformed the resulting alcohol into bis-silylated species (278). After reductive workup with dimethylsulfide, bissilylated species (278) were carefully exposed to O 3 in the presence of C 5 H 5 N, yielding lactol (279). Using NaBH 4 for the reductive workup instead of (Me) 2 S to directly convert secondary ozonide to a lactone (280) produced mainly lactol (279). At 50 • C, lactol (279) was exposed to a mixture of LiBH 4 in diglyme and produced the required finding. The synthesis was subsequently easily completed by simultaneously removing both protecting silyl groups and selectively oxidizing the CH 2 =CHCH 2 OH with MnO 2 giving sculponeatin N (281) in a 95% yield (Scheme 20) [114]. yielding lactol (279). Using NaBH4 for the reductive workup instead of (Me)2S to directly convert secondary ozonide to a lactone (280) produced mainly lactol (279). At 50 °C , lactol (279) was exposed to a mixture of LiBH4 in diglyme and produced the required finding. The synthesis was subsequently easily completed by simultaneously removing both protecting silyl groups and selectively oxidizing the CH2=CHCH2OH with MnO2 giving sculponeatin N (281) in a 95% yield (Scheme 20) [114].

Canataxpropellane
Canataxpropellane (305), which belongs to the complex taxane group, was isolated from Taxus Canadensis. Diterpene containing highly oxygenated moieties belongs to one of the most complicated and sophisticated organic compounds interminably identified for the treatment of various cancers [115]. Canataxpropellane (305) is made up of a heptacyclic carbon structure [5,5,5,4,6,6,6]. In only two CH 2 groups, it is highly functionalized and extremely oxidized, containing five hydroxyl groups and one ketone group [116].

Crotophorbolone
Crotophorbolone (348) was isolated in 1934 as a phorbol degradation compound, and its structure was identified in 1969 [118,119]. It was isolated in 2010 from Euphorbia Fischeriana Steud, widely utilized in conventional Chinese treatment to treat edema, ascites, and cancer [120,121].
The C14 substituent once again regulated the exclusive stereoselectivity in generating the C-8 center of a molecule (310). The conjugated C11 and C12 bonds underwent Birch reduction after the TIPS protection of molecule (312) to generate ketone (313). The sterically lithiated vinyl ether (314) was then equatorially added to the C-9 ketone (313), yielding the pentasubstituted cyclohexane (315).
The acetylation of two-hydroxy groups of the molecule (324) undergoes simultaneously to obtain the molecule (325). By p-allyl synthesis and site-selective reduction of acetate to the less congested primary site, a reagent combination of Pd°/KOAc rapidly converted the disubstituted olefin (325) into the trisubstituted olefin (326). The more exposed hydroxy group at C-20 of the ensuing diol (327) was terminated regioselectively with a hindered TIPS moiety after saponification, leading to the synthesis of molecule (328), and the residual hydroxy group at C-5 of (328), undergoing chlorination, yielding molecule (329). When molecule (329) was treated with substrate (330), CuTC, and K2CO3/DMF in [Pd(PPh3)4], the C-C synthesis carried on even at 0 °C , yielding (331) with no geometrical change.

Crotophorbolone
Crotophorbolone (348) was isolated in 1934 as a phorbol degradation compound, and its structure was identified in 1969 [118,119]. It was isolated in 2010 from Euphorbia Fischeriana Steud, widely utilized in conventional Chinese treatment to treat edema, ascites, and cancer [120,121].
The C14 substituent once again regulated the exclusive stereoselectivity in generating the C-8 center of a molecule (310). The conjugated C11 and C12 bonds underwent Birch reduction after the TIPS protection of molecule (312) to generate ketone (313). The sterically lithiated vinyl ether (314) was then equatorially added to the C-9 ketone (313), yielding the pentasubstituted cyclohexane (315).
When activated with CSA, the C-9 alcohol at the axial position of molecule (315) exchanged acetals with the C-13 di-methyl acetal to form oxa-bicyclo[2.2.2]octane (316) (1:1 dr at C-13 ). The O, Se acetal at C-9 was synthesized by converting the vinyl ether at C-9 of molecule (316). Thus, m-CPBA chemoselectively oxidized (316) vinyl ether to molecule (317) carboxylic acid via hydroxyl ketone. Following mesylation of molecule (317), the mesyloxy-carbonyl of the molecule (318) was transformed into the Aryl-Se function (320) in a one-pot reaction using photoirradiation and Barton ester in (PhSe) 2 . The three carbon extensions from (322) aldehyde produced from SO 3 •C 6 H 5 N-oxidation was followed through nucleophilic attack of vinyl lithium (323), resulting in the synthesis of the molecule (324).
The acetylation of two-hydroxy groups of the molecule (324) undergoes simultaneously to obtain the molecule (325). By p-allyl synthesis and site-selective reduction of acetate to the less congested primary site, a reagent combination of Pd • /KOAc rapidly converted the disubstituted olefin (325) into the trisubstituted olefin (326). The more exposed hydroxy group at C-20 of the ensuing diol (327) was terminated regioselectively with a hindered TIPS moiety after saponification, leading to the synthesis of molecule (328), and the residual hydroxy group at C-5 of (328), undergoing chlorination, yielding molecule (329). When molecule (329) was treated with substrate (330), CuTC, and K 2 CO 3 /DMF in [Pd(PPh 3 ) 4 ], the C-C synthesis carried on even at 0 • C, yielding (331) with no geometrical change.
The reaction mixture containing RCEM was cooled to 78 • C before adding boron tribromide to eradicate the O-methyl moiety and yielded the desired phenol product (353). To enhance the whole effectiveness of synthesis, we added a premixed LiAlH 4 /AlCl 3 mixture to perform a stereoselective double reduction of the diketone molecule at 1, 3 positions, which was the final transformation in the one-pot reaction involving demethylation, RCEM, and double reduction. At room temperature, compound (353) underwent RDOD reaction, inserted two methoxy groups successfully into the phenol ortho site to make the equivalent diene moieties (355).

1-Hydroxytaxinine
1-Hydroxytaxinine (394), derived from Taxus cuspidata Japanese yew, is cytotoxic and has human epidermoid KB carcinoma cells and murine leukemia L1210 cells of IC50 values 6.9 and 4.6 mg/mL, respectively [127]. This natural substrate is a component of the taxane diterpenoids family, which comprises over 400 congeners [128]. Many compounds in this class have been tried in clinical trials to treat various malignancies [129].
Methyl ester (372) underwent saponification with aqueous lithium hydroxide after the protection of acetonide at the subsequent vicinal diol (371). The activated ester was prepared with iBuOCOCl and NMM and converted instantly into α-alkoxy acyl telluride of molecule (373) via attacking of the TePh anion formed by (PhTe)2 and NaBH4. The adduct (377) was created through radical coupling between the A-ring (374) and the C-ring (375), followed by oxidative olefin regeneration at C-8.
The treatment of the compound having an A-ring (374) and two equivalent C-rings (375) with three equivalents of Et3B in C6H6 at 50 °C open to the air affected the synthesis of the C-8 and C-9 bond, and then DDQ was added to the mixture to yield adduct (377) as a major C-9 isomer in a 65% yield. The formation of ethyl radical by O2/Et3B stimulates the homolytic breakdown of the C-Te bond to produce acyl radical, which undergoes unprompted CO discharge to yield the α-alkoxy A radical (374). Following 1, 4-radical addition, the 1, 2-diols of A (374), were protected by the acetonide group, redefining the absolute C-9 geometry, as C-ring in a molecule (375) comes from the opposite side of the hindered C-10 substituent of A (374).
Following that, Et3B captures the resulting radical intermediate to produce the boron enolate B (381), and the oxidation of DDQ yields the enone (384). Enantiopure molecule (384) was achieved by recrystallizing the obtained enone (377) in (96% ee). The C8-quaternary center was stereoselectively inserted from the enone (377) before the synthesis of a substrate (378) for another significant radical reaction by the 1, 4-addition of CH3MgBr in the presence of Me2S/CuI in C6H5CH3. Alcohol (378) was produced via the NaBH4 reduction of the C-4 ketone in one step.
The secondary alcohol of molecule (378) was then consecutively reacted with Et3N, DBU, and MsCl, leading to the synthesis of α, β-unsaturated nitrile (379) by removal of mesylate. With diisobutylaluminum hydride, the nitrile (378) was reduced to the equivalent imine (379) and the subsequent acidic workup effectively hydrolyzed the C-2 imine Scheme 23. Total synthesis of atropurpuran.

1-Hydroxytaxinine
1-Hydroxytaxinine (394), derived from Taxus cuspidata Japanese yew, is cytotoxic and has human epidermoid KB carcinoma cells and murine leukemia L1210 cells of IC 50 values 6.9 and 4.6 mg/mL, respectively [127]. This natural substrate is a component of the taxane diterpenoids family, which comprises over 400 congeners [128]. Many compounds in this class have been tried in clinical trials to treat various malignancies [129].
Methyl ester (372) underwent saponification with aqueous lithium hydroxide after the protection of acetonide at the subsequent vicinal diol (371). The activated ester was prepared with iBuOCOCl and NMM and converted instantly into α-alkoxy acyl telluride of molecule (373) via attacking of the TePh anion formed by (PhTe) 2 and NaBH 4 . The adduct (377) was created through radical coupling between the A-ring (374) and the C-ring (375), followed by oxidative olefin regeneration at C-8.
The treatment of the compound having an A-ring (374) and two equivalent C-rings (375) with three equivalents of Et 3 B in C 6 H 6 at 50 • C open to the air affected the synthesis of the C-8 and C-9 bond, and then DDQ was added to the mixture to yield adduct (377) as a major C-9 isomer in a 65% yield. The formation of ethyl radical by O 2 /Et 3 B stimulates the homolytic breakdown of the C-Te bond to produce acyl radical, which undergoes unprompted CO discharge to yield the α-alkoxy A radical (374). Following 1, 4-radical addition, the 1, 2-diols of A (374), were protected by the acetonide group, redefining the absolute C-9 geometry, as C-ring in a molecule (375) comes from the opposite side of the hindered C-10 substituent of A (374).
Following that, Et 3 B captures the resulting radical intermediate to produce the boron enolate B (381), and the oxidation of DDQ yields the enone (384). Enantiopure molecule (384) was achieved by recrystallizing the obtained enone (377) in (96% ee). The C8-quaternary center was stereoselectively inserted from the enone (377) before the synthesis of a substrate (378) for another significant radical reaction by the 1, 4-addition of CH 3 MgBr in the presence of Me 2 S/CuI in C 6 H 5 CH 3 . Alcohol (378) was produced via the NaBH 4 reduction of the C-4 ketone in one step.
The secondary alcohol of molecule (378) was then consecutively reacted with Et 3 N, DBU, and MsCl, leading to the synthesis of α, β-unsaturated nitrile (379) by removal of mesylate. With diisobutylaluminum hydride, the nitrile (378) was reduced to the equivalent imine (379) and the subsequent acidic workup effectively hydrolyzed the C-2 imine at C-2 and acetal at C-1 to yield the required ketoaldehyde (380). At 50 • C in the presence of pyridine in THF, keto-aldehyde (380) was treated with 4 equivalents of TiCl 4 and 10 equivalents of Zn to form a compound (381).
The unprotected top surface of the hydrazone (385) underwent 1, 2-reduction, which resulted in the removal of a p-tolyl sulfinate. Following the rearrangement of allylic diazene the hydrogen atom was shifted at C-3 from the bottom surface, and the olefin site was altered, resulting in the selective production of the molecule (386) (47%), and its epimer C-3-epi-(386) in a 21% yield. The dihydroxylation of the disubstituted C-5 olefin of the diene (386) proceeded stereoselectively from the bottom site via catalytic OsO 4 and stoichiometric NMO to give diol (387). Using the Yamaguchi reagent system, the less-hindered C-5 OH of diol (387) was transformed into the compound (389), cinnamoyl ester, while the remaining C-4 hydroxyl group of compound (389) underwent oxidation of ketone at C-4, by treating with PCC.
The chemo-and stereoselective nucleophilic addition of MeMgBr to the C-4 ketone (390) yielded compound (391) without altering the C-13 carbonyl, C-2, and C-5 acyloxy groups. Before dehydration, the acetonide group of C-9 and C-10 diol were substituted for the two acetyl groups in a single pot by successive treatment with CF 3 CO 2 H/MeOH and Ac 2 O. Through the Wagner-Meerwein rearrangement, activation of the C-1 bridgehead hydroxy group (392) triggered C-11 migration from C-15 to C-1.
In the presence of Me 2 HSiCl and imidazole, we protected the sterically hindered C-1 OH of a hydroxy group (392) as a dimethyl silyl ether, and molecule (393) was reacted with the Burgess mixture and then with HF•C 6 H 5 N. This allowed for the synthesis of the desired product (394), 1-hydroxytaxinine, in a 56% yield (Scheme 24) [130].
Compound (398)  Chemoselective hydrogenation of the C-9 and C-18 olefin in a molecule (403) using Wilkinson's reagent at 1K pressure of H 2 in toluene, following diastereoselective hydroboration oxidation of the enone with BH 3 •THF in a one-pot step, yielded diol (404) with a 71% total yield. Following treatment with five equivalents of 2-iodoxybenzoic acid in DMSO at 80 • C, molecule (404) was obtained (30%).
When diol (404) was treated with five equivalents of IBX in DMSO at 80 • C for 2 h, quenching with Na 2 S 2 O 3 /NaHCO 3 at the same time, molecule (407) was synthesized in a 72% yield as a major intermediate. Ketone
The synthesis of asperolide C (427) began with the synthesis of compound (414) vinyl ketone, which was prepared in three steps from commercially available δ-butyrolactone. Vinyl ketone (414) is converted into enol silane (415), and the silyl group is exchanged with the triflate (416). Under ordinary circumstances, the formation of enol silane (415) is impeded by the polymerization of vinyl ketone (414). When a molecule containing vinyl ketone (414) was added to a premixed solution of tertiary butyl dimethyl silyl chloride and LiHMDS in THF at −78 • C, using HMPA as a cosolvent, the required intermediate was produced in a 95% yield and had remarkable Z-selectivity, having a diastereomeric ratio of 95:5.
Under Johnson and Braun conditions, cross-coupling of enol triflate (416) and boronic acid (417) was attained by using 10 mol% of [Pd(dppf)Cl 2 ] as a catalyst in combination with 10 mol% of AsPh 3 as a co-ligand and Cs 2 CO 3 as a base to produce the desired product (418) in a 62% yield (10:1). Diene (418) of terminal olefin was hydroborated with 9-BBN, and trialkyl borane was subjected to Suzuki coupling with vinyl iodide (419) to yield polyene in 61%. Re-introducing the re-covered starting substrate resulted in allylic alcohol (420) in an 81% overall yield.
Under normal circumstances, a reaction of allylic alcohol (420) with 3.2 mol% of [Ir(cod)C 2 ] and 12.8 mol% of molecule (421) as catalyst precursors and 16 mol% of Zn(OTf) 2 as a Lewis acid gives decalin (422), with remarkable stereoselectivity 9:1 d.r. in a 73% yield. Deprotection of decalin (422) was followed by stepwise oxidation of the primary hydroxy group in the production of asperolide C (427). The resulting carboxylic acid was reacted with trimethylsilyl diazomethane to give the appropriate methyl ester in a 62% yield.
The exomethylene group was epoxidized with newly produced DMDO at 200 • C, yielding oxirane (423) in a moderate yield. At 0 • C, exposure to trifluoroacetic acid in anhydrous CH 2 Cl 2 resulted in selective epoxide opening and rapid cyclization to yield lactone (424). Lemieux-Johnson oxidation yielded aldehyde (425) in an 81% yield after masking the main hydroxy group in (424) with a TBS ether. The treatment of a mixture of aldehyde (425) in THF at −20 • C with 1.25 equivalents of tBuOK followed by the addition of 1.25 equivalents of iodomethane to 0 • C resulted in aldehyde (426) as a single isolable intermediate. The first overall synthesis of asperolide C (427) was accomplished by Pinnick oxidation of aldehyde (426) to the appropriate carboxylic acid in a 76% yield and the breakdown of the TBS group in a 74% yield (Scheme 26) [141].

Salvinorin A
Salvinorin A (449) belongs to neoclerodane diterpene, was isolated from Mexican medicinal herb Salvia divinorum [142]. The most potent naturally occurring hallucinogen in humans is neoclerodane diterpene, which is also a robust and highly selective k-opioid receptor (KOR) agonist [143,144]. Salvinorin A (449) is a promising new therapeutic target for the treatment of CNS diseases, pain, depression, and drug addiction [145].

Scheme 26.
Total synthesis of asperolide C.

Salvinorin A
Salvinorin A (449) belongs to neoclerodane diterpene, was isolated from Mexican medicinal herb Salvia divinorum [142]. The most potent naturally occurring hallucinogen in humans is neoclerodane diterpene, which is also a robust and highly selective k-opioid receptor (KOR) agonist [143,144]. Salvinorin A (449) is a promising new therapeutic target for the treatment of CNS diseases, pain, depression, and drug addiction [145].
With the help of DBU, stability between molecules (440) and (441) could be efficiently achieved, allowing for the complete conversion of molecule (440) into C8 epimer (441) before the IMDA phase, which was achieved by the chromatographic fractionation of these enantiomers.

Propindilactone G
Sun and coworkers extracted Propindilactone G (474), a novel category of nortriterpenoids from several Schisandracea plants [147]. Propindilactone G (473) has a distinct 5/5/7/6/5 pentacyclic core with seven stereocenters, three of which are quaternary centers (C-9, C-10, and C-13). The species is found throughout North America and South-East Asia, and it is utilized in prudent Chinese herb treatments for liver protection and regulating the immune system. Biological tests revealed that these nortriterpenoids have promising anti-HIV potential [148].
Asymmetric Diels-Alder reactions are used to synthesize ester (453) from diene (450) and dienophile (451). The requisite Diels-Alder reaction could be effectively accomplished in Hayashi's ligand (452), resulting in the synthesis of (-)-ester (453) in an 88% yield with a high ee of 98%. Furthermore, in two steps, aldehyde (453) was added with Scheme 27. Total synthesis of salvinorin A. 6. Triterpenoids 6.1. Propindilactone G Sun and coworkers extracted Propindilactone G (474), a novel category of nortriterpenoids from several Schisandracea plants [147]. Propindilactone G (473) has a distinct 5/5/7/6/5 pentacyclic core with seven stereocenters, three of which are quaternary centers (C-9, C-10, and C-13). The species is found throughout North America and South-East Asia, and it is utilized in prudent Chinese herb treatments for liver protection and regulating the immune system. Biological tests revealed that these nortriterpenoids have promising anti-HIV potential [148].
Asymmetric Diels-Alder reactions are used to synthesize ester (453) from diene (450) and dienophile (451). The requisite Diels-Alder reaction could be effectively accomplished in Hayashi's ligand (452), resulting in the synthesis of (-)-ester (453) in an 88% yield with a high ee of 98%. Furthermore, in two steps, aldehyde (453) was added with MeMgBr in Al(Me) 3 to create alcohol function, which was subsequently oxidized with DMP in NaHCO 3 and CH 2 Cl 2 to yield keto ester (454) in 74% overall yield.
Keto ester (454) treated with MeMgBr yielded a lactone moiety, which was oxidized by treatment with KHMDS in P(OMe) 3 /O 2 in THF, which was further treated with TESCl, yielding product (455) in a 76% total yield. Further treatment of molecule (455) with dibromo carbene obtained from CHBr 3 /tBuOK led to the synthesis of dibromide (456) as a pair of diastereoisomers (1:1), which was then treated in acetone with AgClO 4 to provide the cycloheptenone-based vinyl bromide (457) in a 57% yield.
Vinyl bromide (457) was combined with acetylene-TMS in the presence of i-Pr 2 NH and Pd(PPh 3 ) 2 Cl 2 /CuI to produce enone (458) in an 88% yield. The treatment of enone (458) with (3-methyl but 3 en-1-yl) MgBr − (459) in cerium trichloride resulted in enyne (460) as a single isomer in an 81% yield. Enyne (460) was treated with 0.5 equivalents of Co 2 (CO) 8 in the presence of celite in toluene under reflux to prepare the cyclopentenone subunit with an all-carbon quaternary stereogenic center. The desired product (461) was produced in a 67% yield, along with its C-13 diastereoisomer in a 24% yield. When a product (461) was treated with silver fluoride, dienone (462) was produced in an 85% yield after the silyl groups were removed. The treatment of dienone (462) with Pd(OH) 2 /C in the existence of triethylamine at hydrogen balloon pressure triggered a reductive isomerization, yielding dienone derivative (463) in a 98% yield. Then, further treatment of dienone (463) with m-CPBA in CH 2 Cl 2 yielded epoxide (464) in a 73% yield as a single stereoisomer. In the presence of Et 3 N, epoxide (464) was first treated with acetic anhydride, and the resultant acetate was reacted with LiHMDS to commence a Dieckmann condensation, yielding lactone (465) in a 76% yield.
To obtain the stereo-and chemoselective synthesis of molecule (466), intermediate (465) was first dehydrated with Martin's sulfuran, and then the resulting unsaturated lactone (466) was subjected to both Pd-catalyzed hydrogenation at the (C-1, C-2) double bond and hydrogenolysis for opening the epoxide ring, yielding product (467) in 56% overall yield.
The synthesis of molecule (470) can be accomplished through an intermolecular oxidative coupling of conjugated enol silane (468) with enol silane A (469). We demonstrated that using CAN, an oxidant allowed this coupling to continue smoothly, yielding (470) as two pairs of diastereoisomers in a 92% yield. This reaction was taken out in 2, 6 ditertiary butyl pyridine at −50 • C to −300 • C in MeCN, yielding inseparable products (472) and (473) in 60% yields, which were then reacted with OsO 4 , yielding propindilactone G (474) in an 81% yield in the presence of NMMO as a co-oxidant (Scheme 28) [149].

Rhabdastrellic Acid A
The main constituents of the isomalabaricane triterpenoids are rhabdastrellic acid A (487) and stelletin E (488), which belong to marine natural products that continue to arouse curiosity due to their extremely specific anticancer effects [150]. The nanomolar mean GI50 doses of these selective apoptosis inducers inhibiting the NCI-60 tumor cell lines panel are remarkable [151].

Scheme 28.
Total synthesis of propindilactone G.

Rhabdastrellic Acid A
The main constituents of the isomalabaricane triterpenoids are rhabdastrellic acid A (487) and stelletin E (488), which belong to marine natural products that continue to arouse curiosity due to their extremely specific anticancer effects [150]. The nanomolar mean GI 50 doses of these selective apoptosis inducers inhibiting the NCI-60 tumor cell lines panel are remarkable [151].
Using dichloro methyllithium as a carbon source, the ketone was homologated to an α, β unsaturated aldehyde in (477), a diastereoselective reduction of lithium acetylide, simultaneously following protection of the pivalate by completing the synthesis of the major cycloisomerization starting material (478) in an 80% yield. When pivalate (478) was treated with a cationic gold (I) catalyst in Selectfluor ® , the desired functionalization and annulation occurred with excellent productivity, resulting in the formation of the C-ring-α-fluoro enone as a major stereoisomer.
The separation of α-fluoro hydrazone (480) in an 81% yield was made possible by an in situ synthesis of the equivalent p-toluene sulfonyl hydrazone. Under usual conditions, the exposure of molecule (480) to triethylamine in MeOH spontaneously produced azo alkene (482), followed by stereospecific reduction of H 2 to the appropriate side by retro-ene rearrangement of allylic diazene (480). Reductive zirconation and Cu-catalyzed coupling with acetyl AcCl could be used to achieve the required transformation. After extensive optimization, the required C-C bond of deconjugated enone (483) was obtained in a 64% yield. Triketone (484) was produced as a single constitutional isomer via relay hydroboration from the ketone, followed simultaneously by deprotection of the silyl moiety with CF 3 COOH and two-fold total oxidation. Bromination using the Vilsmeier reagent produced electrophile (485) as a single geometrical and constitutional isomer. Stille coupling of vinyl bromide with tetraenylstannane (486) resulted in a 45% overall yield, with rhabdastrellic acid A having methyl ester from triketone (484), with the isomeric methyl ester of stelletin E (488) in an (8:1) ratio. After saponification with trimethyl tin hydroxide, the desired product (±)-rhabdastrellic acid (487) was achieved with a 98% yield (Scheme 29) [152]. Scheme 29. Total synthesis of (±)-rhabdastrellic acid A.

Asiaticoside
Asiaticoside (497) is an ursane-type triterpene glycoside derived from the tropical plant Centella asiatica (L.), sometimes known as Indian pennywort or Gotu kola. It has been used as a cure-all since prehistoric times, but most notably for the treatment of skin diseases and dermatoses such as burns, excoriations, and hypertrophic scars [153]. Asiaticoside may promote collagen synthesis by activating the Smad pathway or inhibiting glycogen-phosphorylase [154,155].

Asiaticoside
Asiaticoside (497) is an ursane-type triterpene glycoside derived from the tropical plant Centella asiatica (L.), sometimes known as Indian pennywort or Gotu kola. It has been used as a cure-all since prehistoric times, but most notably for the treatment of skin diseases and dermatoses such as burns, excoriations, and hypertrophic scars [153]. Asiaticoside may promote collagen synthesis by activating the Smad pathway or inhibiting glycogen-phosphorylase [154,155].
The 28-carboxyl group of a molecule ursolic acid (489) was acetylated with benzoyl bromide in the presence of n-Bu 4 NBr and K 2 CO 3 , succeeded by oxidation with Dess-Martin and oxime formation (H 2 NOH•HCl, NaOAc, MeOH, CH 2 Cl 2 ) to provide molecule (490) in an 87% yield (three steps). By following Baldwin's approach, we added NaOAc and Na 2 PdCl 4 to a molecule (490) in AcOH solution at r.t. under argon, stirred for 3 d. The Pd 2+ ursane oxime C-23 angular methyl composite resulted in a yellow solid. The C-23 Pd-linkage was oxidized with lead tetraacetate following reduction with NaBH 4 to obtain the desired 23-O-acetyl-3-acetoxy oxime (491) in a 66% yield after acetylation [(CH 3 CO) 2 CO, DMAP, Et 3 N] (over three steps).

Schiglautone A
Ruan and coworkers reported schiglautone A (524), which has a new skeleton, in 2011 after identifying novel triterpenoids as possible therapeutic approaches from Schisandra glaucescens [157]. The structure of compound (524) is comprised of a cyclohexylfused bicyclo[6.4.1]tridecane carbon skeleton with a rare bridgehead δ-alkene and six chiral carbons, three of which are quaternary [158].

Schiglautone A
Ruan and coworkers reported schiglautone A (524), which has a new skeleton, in 2011 after identifying novel triterpenoids as possible therapeutic approaches from Schisandra glaucescens [157]. The structure of compound (524) is comprised of a cyclohexyl-fused bicyclo[6.4.1]tridecane carbon skeleton with a rare bridgehead δ-alkene and six chiral carbons, three of which are quaternary [158].
Schisandraceae plants are mostly utilized in conventional Chinese medicine to treat several ailments, including cough, chronic diarrhea, premature ejaculation, and drowsiness [159,160]. Schisandra triterpenoids have gained increasing consideration from the synthetic community because of their unique framework and essential biological properties, leading to elegant syntheses of their scaffolds and target complexes [161,162].
The effectiveness of this cyclization was greatly increased by changing to carbonate (502). Because of the steric hindrance of the angular Me moiety at C-19, the successive epoxidation happened with perfect face selectivity, yielding molecule (503) in 86% as a major diastereomer. Following Ley-Griffith oxidation, Meerwein-Ponndorf-Verley reduction was used to invert the configuration at C-3, leading to the formation of an alcohol mixture in 72% total yield preferring the axial isomer. The unification of the benzyl ether (503) and methyl acrylate progressed easily utilizing Gansauer's modified technique [0.5 equivalents of Cp 2 TiCl 2 , 2 equivalents of Zn, 2.5 equivalents of 2, 4, 6-collidine•HCl] for reductive epoxidation, yielding the homologated lactone (504) in a 91% yield. Following reduction by LiAlH 4 , Swern conditions were used to produce simultaneous oxidation of the two resulting hydroxyl functionalities, yielding ketoaldehyde via an Et 3 N-facilitated breakdown of the di-alkoxy sulfonium intermediate.
Following chemoselective Grignard addition and silylation, molecule (505) was obtained as insignificant mixtures (1:1) at C-17 in a 67% yield (two steps). Instead, the O-allylation intermediate (507) was synthesized by treating with allyl iodide and LiHMDS at −40 • C and then undergoing Claisen rearrangement at 120 • C to provide the transconfigured diene at C-9 and C-14 in an 85% yield. The expected tricyclic product (508) was obtained in a 65% yield with 15mol% of Grubbs (II) catalyst and stoichiometric concentrations of tetra-fluorobenzoquinone for oxidation of the ruthenium hydride complexes.
The 1, 2-addition by MeLi and Dauben-Michno oxidation of the resulting tertiaryallylic alcohol yielded molecule (509) in a 60% yield, followed by Jones oxidation. At the convex side of the C-13 and C-17 double bond, the vinyl cuprate underwent Michael addition, produced from the organo lithium (511). The direct usage of a secondary alkyl cuprate generated from a Grignard molecule (512) resulted in the synthesis of the molecule (513) and its C-20 epimer with a combined yield of 72%. Through the centrality of the cyclic chromate ester (514), PCC oxidants yielded the aldehyde (515) in a 68% yield. The Z-configured alkene (518) was produced in an 84% yield as a sole isomer by the Horner-Wadsworth reaction of molecule (515) with (517), catalyzed by KHMDS/18 C-6 (516). The Z-configured alkene (518) was initially treated at 78 • C with methyl acrylate, ICl, and LiHMDS to produce α-iodoketone in situ, which was then used to implant the bridgehead alkene.

Walsucochins B
Walsucochins B (543) is a C24 nortriterpenoid with a phenyl acetylene group joined to a five-membered contracted circle. Yue and colleagues extracted it in 2007 from the twigs and leaves of Cochinchinensis Walsura [164]. Walsucochin B (543) contains a 6/5/6/6 attached ring framework with four continuous stereocenters (including two quaternary centers) and a chiral hydroxyl functional moiety. The cell protection effect of novel C24 nortriterpenoids in contrast to H2O2-prompted PC12 cell destruction is substantial. Scheme 31. Total synthesis of (±)-schiglautone A.

Walsucochins B
Walsucochins B (543) is a C 24 nortriterpenoid with a phenyl acetylene group joined to a five-membered contracted circle. Yue and colleagues extracted it in 2007 from the twigs and leaves of Cochinchinensis Walsura [164]. Walsucochin B (543) contains a 6/5/6/6 attached ring framework with four continuous stereocenters (including two quaternary centers) and a chiral hydroxyl functional moiety. The cell protection effect of novel C 24 nortriterpenoids in contrast to H 2 O 2 -prompted PC1 2 cell destruction is substantial.
Allylic alcohol (530) undergoes oxidation with DMP to yield an unstable, α, β-unsaturated aldehyde. The aldehyde was promptly reacted with 1, 3-propane dithiol in the presence of Et 2 O•BF 3 at 0 • C, yielding dithiane (531) in two steps in an 83% yield. The reaction of allylic bromide (532) with the organolithium generated from the reaction of dithiane (531) with n-BuLi resulted in the required polyolefin epoxide (533) in an 86% yield. Following dedithianation of molecule (533) with CaCO 3 and I 2 at 0 • C gives the α, β-unsaturated ketone (534) in an 82% yield, while the epoxy functional moiety was retained. The alcohol (536) was obtained in a 71% yield after reduction of ketone (534) asymmetrically with intermediate (535), R-CBS mixture. In a 98% yield, acetylation happened for the protection of alcohol (536), to give the necessary main cyclization intermediate (537) in the (1:4) mixture. The inseparable diastereomeric combination of a molecule (537) could be transformed to the respective core tetracyclic skeleton (538) as a single diastereoisomer in a 62% yield by cationic polyolefin cyclization in dichloromethane in DEAC at 78 • C for 10 h. TBSOTf was used to protect alcohol (538), and ether, leading to synthesized molecule (539) in a 96% yield. The radical bromination of the C-20 methyl of the molecule (539), with NBS and AIBN in carbon tetrachloride at reflux, following oxidation with DMSO, yielded intermediate (540) in a 73% yield (two processes). In a one-pot Gilbert-Seyferth homologation/hydrolysis sequence, (MeO) 2 P(O)CN 2 C(O)-CH 3 (541) and K 2 CO 3 in methanol transform aldehyde (540) to phenyl acetylene and the MeCO function was also eliminated to provide alcohol (542) in a 76% yield.

Rubriflordilactone A
Sun and coworkers indicated the isolation of rubriflordilactone A (566) from Schisandra rubriflora in 2006, which has a long history of use in Chinese herbal medicine and has promising anti-HIV activity. Rubriflordilactone A (566) is a triterpenoid, having a heptacyclic framework with a multisubstituted arene motif [166].

Rubriflordilactone A
Sun and coworkers indicated the isolation of rubriflordilactone A (566) from Schisandra rubriflora in 2006, which has a long history of use in Chinese herbal medicine and has promising anti-HIV activity. Rubriflordilactone A (566) is a triterpenoid, having a heptacyclic framework with a multisubstituted arene motif [166].
Heating triene (562) in dimethyl sulfoxide at 145 • C in an air environment influenced the 6π electrocyclization and aromatization in one step, yielding arene (563) in a 73% yield. After aqueous workup, arene (563) was treated with hindered LiAlH(Ot-Bu) 3 to effectively separate the two carbonyl lactones, yielding a combination of its ring-opened aldehyde form and six-membered lactol. When the aldehyde/lactol mixture was exposed to Et 2 NSF 3 , the yielded fluoride (564) in 62% (total yield from 563) was produced as a stimulated "donor" for the following C-glycosylation. Fluoride (564) was discovered to be unreactive, contrary to siloxy furan; only allyl tri-methyl silane may attack it after BF 3 •OEt 2 activation. In the presence of boron trifluoride etherate, this stannane (565) smoothly interacted with fluoride (564) to generate rubriflordilactone A (566) in a 66% yield as a major identifiable diastereomer (Scheme 33) [167].
Hydrindane protection of molecule (590) gave the analogous SEM ether (591) which further underwent Pd-catalyzed allylation giving hydrindanone (593). Disclosure of ketone (593) to K-Selectride gives rise to diastereoselective reduction of the carbonyl functionalities. After the Lemieux-Johnson breakdown of the terminal alkene and Cr-accelerated oxidation of the molecule lactol to lactone (594) for the insertion of the C-3 methyl group, the reaction of the Li-enolate with methyl iodide gives rise to a major diastereomer (595). Lactone (595) undergoes reduction with LiAlH 4 , following silylation and chemoselective oxidation under optimized Swern conditions, yielding a competent approach to aldehyde (596).
Finally, a -step procedure comprising Wittig olefination, oxidation, and chemoselective deprotection yielded trans-hydrindanone (597), which allows 5 out of the 10 stereo-centers. Treatment of trans-hydrindanone (597) to alkenyl lithium (598) instantaneously led to epoxidation (599). This two-step procedure gave metathesis substrate (599) as the only stereoisomer in a remarkable yield of 71%. The subsequent RCM proceeded smoothly in the Grubbs II to yield cyclo-octene (600). The double bond of alkene (600) underwent hydrogenation upon being treated with excess HMPA/TASF in the presence of MS at higher temperatures, which was quickly unmasked by the analogous secondary alcohol. Following hydrogenation, under the previous conditions, furnished "nitidasol" (601). This intermediate (601), a biosynthetic starting substrate of nitidasin, is potentially being recruited as a natural product. Then finally, the oxidation of nitidasol (601) by using NMO/TPAP gave nitidasin (602) (Scheme 35) [173].

Cerorubenic Acid-III
Cerorubenic acid-III (625), which belongs to the sesterterpenoid with a unique tetracyclo[8.4.1.0.0]pentadecane framework, was first extracted by Naya and coworkers in 1983 from Ceroplastes Maskell Rubens, insect secretions [174]. It plays a main role in the communication of insects [175]. On a number of cell lines, it also displayed remarkable but inert cytotoxic effects with an IC 50 range of 0.057-3.4 µM in vitro. It also influences the transcriptional level of multiple pathways associated with cell survival, such as in apoptosis, cell cycle, and inflammation [176].
The organocatalytic Michael addition of substrate (603) to methyl vinylketone (604) was stimulated by employing 5 mol% of proline-derived initiator (605) together with ethyl 3, 4-dihydroxy benzoate (606) as a 20 mol% of cocatalyst. Then, intramolecular aldol condensation and dehydration were performed by employing i-PrOH and LiOHsynthesized molecule (607) in a 72% yield (93% de). The silyl enol ether treated with n-BuLi, followed by setting up the consequential enolate with the aldehyde (609) in the presence of zinc bromide, was reduced simultaneously via DIBAL-H to synthesize the stable diol (610) in a 50% yield from the molecule (607). Treatment of diol (610) underwent treatment with TsOH in acetone following TBAF in addition to giving intermediate (611) in an 85% yield. Intermediate (611) underwent oxidative rearrangement via VO(acac) 2 and TBHP in CH 2 Cl 2 , following one-pot protection of hydroxyl function by the acetyl group, synthesizing the key starting molecule (612) in a 71% yield.
Starting molecule (612) underwent type-II-[5+2] cyclo-addition by using TMP in an airtight tube with heating, yielding molecule (613) as a single stereoisomer in a 72% yield. The primary hydroxyl group in compound (618) was protected by TBS, following tosylation of the C 24 -OH functional moiety and elimination of the TBS in a one-pot step undergoing oxidation via DMP, yielding compound (619) in a 55% yield. The desired transannular cyclization of compound (619) using tBuOK in t-butanoic acid delivers cyclopropyl aldehyde (621) diastereoselectively in a 78% yield. The reaction progressed through a cationic conduit via intermediate (620), with the attacking of enolate at the C-24 cation steadied by the contiguous vinyl moiety. Huang's variation of Wolff-Kishner was used to alter the formyl group of cyclopropyl aldehyde (621) to a methyl group, following simultaneous deprotection via acetic acid to make the diol (622). Chemoselective acetylation of the sterically less-hindered -OH group in diol (622), monitored by DMP using a one-pot method and following base-intermediated exclusion, furnished the enone (623) in an 80% yield.
Diol (627) then underwent oxidation of alcohol using IBX in dichloro-ethane, undergoing heating/hydrolysis of the acetate function giving ketone diol (628) (82%). Treatment of ketone diol (628) with 2, 6-lutidine, and t-Bu 2 Si(OTf) 2 resulted in the synthesis of cyclic silyl ether (629) (92%). Using 2, 4-di-tertiary butyl pyridine and Tf 2 O successfully provided compound (630) in excellent productivity. Elimination of the silyl motif under mild conditions via TBAF with acetic acid and successive IBX-oxidation of primary alcohol yielded aldehyde (632). TMSOTf stimulated the Prins cyclization between aldehyde (632) and intermediate (633) to achieve the stereoselective synthesis of the 2, 6 cis-tetrahydro pyran group. The elimination of the TfO group of compound (634) via PPh 3 and Pd(OAc) 2 in the presence of HCOOH and Et 3 N delivered compound (635) in an 87% yield. The conversion of compound (635) to the final product (637) was succeeded via variation of Tong's two-step procedure.

Leucosceptroids A
In 2010, Li and coworkers described the separation of leucosceptroids A and their analogs (657) from Leucosceptrum canum, which belongs to glandilar trichomes [182]. The preliminary biological potential has shown that these sesterterpenoids have potent antifeedant properties against the cotton bollworm and beet armyeorm, and antifungal effects against four strains of agricultural fungal pathogen, including Rhizoctonia Solani and Colletotrichum Musae [183][184][185].
Reduction of a secondary alcohol (649) with Me4NB(Oac)3H gave diol (650), which led to regioselective acetylation and subsequent oxidation of hydroxyl group to yield ketone (651) in 69%. The reduction in ketone (651) with LiBH4 provided the alcohol with the desired stereochemistry, and the resulting diol was oxidized selectively with IBX to form ketone (652) after TMSCl protection. The SmI2-interceded cyclization of ketone (652) gave the preferred triol (653) as the only product after desilylation in an 89% yield (overall).

Leucosceptroids A
In 2010, Li and coworkers described the separation of leucosceptroids A and their analogs (657) from Leucosceptrum canum, which belongs to glandilar trichomes [182]. The preliminary biological potential has shown that these sesterterpenoids have potent antifeedant properties against the cotton bollworm and beet armyeorm, and antifungal effects against four strains of agricultural fungal pathogen, including Rhizoctonia Solani and Colletotrichum Musae [183][184][185].
Reduction of a secondary alcohol (649) with Me 4 NB(Oac) 3 H gave diol (650), which led to regioselective acetylation and subsequent oxidation of hydroxyl group to yield ketone (651) in 69%. The reduction in ketone (651) with LiBH 4 provided the alcohol with the desired stereochemistry, and the resulting diol was oxidized selectively with IBX to form ketone (652) after TMSCl protection. The SmI 2 -interceded cyclization of ketone (652) gave the preferred triol (653) as the only product after desilylation in an 89% yield (overall).
Following iso-propenyl addition to commercially available cyclopentenone to yield (669), treatment with TIPSOTf and KHMDS at 78 °C in THF resulted in a (2.5:1) mixture of regioisomeric silyl enol ethers, with (670/671) favored. Compound (673) was obtained in a 38% yield after further exposure to SnCl4 in methylene dimethyl-malonate (672). Using trimethyl orthoformate, ethylene glycol, and p-TsOH•H2O in hot toluene at 90 °C led to the ketone inside (674) being protected as a ketal, and epimers of the α-carbon were induced to generate compound (674) as a single stereoisomer in an 86% yield. Allylic chlorination with trichloroisocyanuric acid (TCCA) was followed by NaH-activated intramolecular cyclization. After that, an extensive reduction of both esters with LiAlH4 yielded (675). The addition of Dess-Martin periodinane resulted in a 65% total yield of aldehyde (676).
By adopting the Bestmann modification to the Seyferth-Gilbert homologation, deprotonating the newly generated terminal alkyne, and adding electrophile (679), compound (680) was synthesized from a mixture of diastereomers. The Zn powder in acetic acid reductively cleaved iodo-ether. The resulting product (681) was then hydrogenated with Pd/C putrefying through quinoline to give the cis-alkene (682) a whole yield of 88% from the compound (680). Crude dicarbonyl (683) was produced directly in good yield using Dess-Martin periodinane following a standard workup with saturated aqueous Na-HCO3 and Na2S2O3 solutions. After treating dicarbonyl (683) with SmI2 in THF at r.t., the desired diol (684) emerged as a single diastereomer. Scheme 39. Total synthesis of (-)-aplysinoplide B.
Following iso-propenyl addition to commercially available cyclopentenone to yield (669), treatment with TIPSOTf and KHMDS at 78 • C in THF resulted in a (2.5:1) mixture of regioisomeric silyl enol ethers, with (670/671) favored. Compound (673) was obtained in a 38% yield after further exposure to SnCl 4 in methylene dimethyl-malonate (672). Using trimethyl orthoformate, ethylene glycol, and p-TsOH•H 2 O in hot toluene at 90 • C led to the ketone inside (674) being protected as a ketal, and epimers of the α-carbon were induced to generate compound (674) as a single stereoisomer in an 86% yield. Allylic chlorination with trichloroisocyanuric acid (TCCA) was followed by NaH-activated intramolecular cyclization. After that, an extensive reduction of both esters with LiAlH 4 yielded (675). The addition of Dess-Martin periodinane resulted in a 65% total yield of aldehyde (676).
By adopting the Bestmann modification to the Seyferth-Gilbert homologation, deprotonating the newly generated terminal alkyne, and adding electrophile (679), compound (680) was synthesized from a mixture of diastereomers. The Zn powder in acetic acid reductively cleaved iodo-ether. The resulting product (681) was then hydrogenated with Pd/C putrefying through quinoline to give the cis-alkene (682) a whole yield of 88% from the compound (680). Crude dicarbonyl (683) was produced directly in good yield using Dess-Martin periodinane following a standard workup with saturated aqueous NaHCO 3 and Na 2 S 2 O 3 solutions. After treating dicarbonyl (683) with SmI 2 in THF at r.t., the desired diol (684) emerged as a single diastereomer.
Following the production of a molecule (685) from diol (684) by using excess N-bromo succinimide in the presence of H 2 O facilitated the formation of bromohydrin (686), which was entirely stereo-and regioselective. Then, adding a base yielded the anticipated β-disposedepoxide of a molecule (687) in a 65% yield. N-BuLi-promoted halo ether ring-opening following silyl deprotection yielded (688), whereas later, base-promoted etherification yielded (689) in a 96% yield. Double Swern oxidation was followed by DMP/PCC ketal breakdown and FeCl 3 to give (690) in a 48% total yield. Finally, employing a mixture of 2.1 equivalents of LaCl 3 •2LiCl and 2.1 equivalents of MeMgBr in THF at −78 • C, a regio-selective addition of the Me group yielded manginoid A (691) as a single stereoisomer in a 42% yield (Scheme 40) [194].

Myrotheciumone A
Myrotheciumone A (707) was extracted by Lin et al. from Roridum Myrothecium, an endophytic fungus, Ajuga decumbens (Medicinal herb) in 2014 [199]. Myrotheciumone A (707) exhibited anticancer activity of IC 50 values (5.36−7.56 µM) and prompted the PARP [poly (ADP-ribose) polymerase] breakdown in a time-and dose-dependent way [200]. It also displayed cell-specific cytotoxicity by prompting apoptosis to the targeted tumor cell relatively more than healthy cells and promoting the escape of cytochrome-C from mitochondria [201].

Merochlorin A
Merochlorin A (728) contains a tetracyclic ring skeleton that comprises a highly congested bicyclo[3.2.1]octane motif including four contiguous stereocenters, a resorcinol fragment, and a bridgehead chlorine. The groups of Fenical and Moore stated the separation of a unique class of meroterpenoids from the Action-mycetes strain (CNH 189) from sediments near the beach of Oceanside, California in 2012 [203]. Merochlorin A (728) was discovered to show in vitro antibiotic evaluation against dificile, having MIC values of 0.15-0.3 μM, and several multi-drug resistant S. aureus with MIC values ranging from 2-4μM, which are two protruding pathogens in control for hospital acquired disinfections [204].

Merochlorin A
Merochlorin A (728) contains a tetracyclic ring skeleton that comprises a highly congested bicyclo[3.2.1]octane motif including four contiguous stereocenters, a resorcinol fragment, and a bridgehead chlorine. The groups of Fenical and Moore stated the separation of a unique class of meroterpenoids from the Action-mycetes strain (CNH 189) from sediments near the beach of Oceanside, California in 2012 [203]. Merochlorin A (728) was discovered to show in vitro antibiotic evaluation against dificile, having MIC values of 0.15-0.3 µM, and several multi-drug resistant S. aureus with MIC values ranging from 2-4µM, which are two protruding pathogens in control for hospital acquired disinfections [204].
PCC initiation for oxidation of ketol (723) yielded the resultant diketone. The diketone was found to be reactive on silica and prone to undergoing a retro Claisen sequence. Nevertheless, using PCC as an oxidant facilitated its clean and prompt separation by filtration with celite and gave the diketone purity (94% yield). Deprotonation with LDA at −78 • C following via the addition of molecule (724) yielded enone (725), which was further reacted with Brassard's diene (726) in toluene at 110 • C. After acidic workup and filtration through silica gel, the crude Diels-Alder mixture underwent oxidation via Saegusa Ito to provide monomethylated merochlorin A (727) in 48% productivity (four steps). In conclusion, heating monomethylated merocholin A (727) at 135 • C for 4 h with lithium chloride in DMF gave (-)-merochlorin-A (728) in a 70% yield (Scheme 43) [205].
Cytosporins A-D (732-736) belong to the class of benzophenone hemiterpene conjugated heterodimers, featuring an unprecedented strained seven-to-eight-membered ring structure. Cytosporins A-D (732-736) have to be made via a unified starting material (731), obtained from monodictyphenone, an unusual natural compound (729) by the insertion of the densely functionalized hemiterpene core through chemoselective prenylation and stereoselectively dihydroxylation. The intramolecular lactonization of the starting molecule (731) would directly convert it to be cytosporin-B (732), while cytosporin-A (734) might be accessible from the starting molecule (731) through the reduction of carboxylic acid and etherification. Furthermore, cytosporins C-D (735, 736) could be easily inferred from cytosporin-A (734) by a simple reduction of carbonyl (Scheme 44) [213].

Taondiol
Taondiol (751) was extracted from marine algae (Atomaria taonia) by Gonzalez et al. in 1971 [214]. Fenical and his group in 1980 reported metabolites of algae from Zonale Stypopodium, and also isolated taondiol, an optical antipode that was reported by the Gonzalez. The enantiomers (+)-taondiol and (-)-taondiol are naturally occurring, contradictory to their origin in marine algae [215]. Taondiol is a basic congener of the Stypopodium class, consisting of a benzopyran moiety. These marine alkaloids exhibit cytotoxic and ichthyotoxic activities. They also exhibit diverse lethargic activities and narcosis at 10 µg/mL intensities [216].
The synthetic order was initiated by the selective protection of ketal of the Wieland Miescher ketone derivative (737) by ethylene glycol. A Robinson-type annulation was then stimulated on the bicyclic part to achieve the tricyclic diterpene scaffold. Using 1 chloro 3-pentanone/KOt-Bu succeeded by an intramolecular aldol condensation provided enone (738) in an 83% yield through thermodynamically controlled alkylation (two steps). The tricyclic moiety, which underwent reductive methylation on enone derivative (738) was conceded via Li/MeI/NH 3 to afford ketone (739) in an 80% yield. Ketone (739) underwent LAH reduction, progressed by benzylation of the alcohol, giving the tricyclic benzyl compound (740) which further led to acid-accelerated deketalization to synthesize molecule (741) in a 90% yield. α-methylation of ketone (742) was then conceded out with LDA and MeI, following epimerization at the newly formed stereocenter by reacting with NaOMe in MeOH to achieve the single diastereomer of molecule (743) in an 80% yield. The second-last step was Nozaki-Yamamoto homologation on ketone (743) to achieve the unsaturated aldehyde (744), which upon Luche reduction delivered the desired tricyclic alcohol (745) in a 57% yield.
Hydroxyquinol (746) involving the Friedel−Crafts mechanism with diterpenoid (745) employing BF 3 ·OEt 2 promptly synthesized a pentacyclic meroterpenoid scaffold (747) by sequential C−C/C−O formation in a 70% yield. A prominent observation was the selective cyclization at the olefin through the requisite hydroxyl group. That could be endorsed to the intramolecular hydrogen interaction in the middle of the other hydroxy and its contiguous methoxy moiety that prevents its contribution to the cyclization reaction. Deoxygenation of pentacyclic scaffold (747) was then succeeded by transforming the hydroxyl scaffold into triflate via triflic anhydride to achieve the triflate (748) in an 85% yield, following Pd(PPh 3 ) 4 -mediated reduction of triflate to synthesize (749) in a 60% yield.
The upcoming step was the demethylation of the methoxy group in intermediate (749). Unfortunately, the common procedures of demethylation through EtSH/NaH and BCl 3 , BBr 3 failed to deliver the preferred demethylated yield. We obtain demethylation upon applying Yamamoto's procedure through B(C 6 F 5 ) 3 /tri-ethylsilane to achieve the silyl ether and then deprotection of the silyl ether with TBAF to achieve the required demethylated yield. Finally, hydrogenolysis of a molecule (750) using H 2 /Pd(OH) 2 synthesized (+)-taondiol (751) in a 58% yield (Scheme 45) [217].

Conclusions
Terpenoids, also known as isoprenoids, are a diverse group of compounds that are necessary to all living things. Future work focused at improving both screening methodologies for plant terpenoid lead compounds and novel approaches to understand complex biochemical processes of preexisting prospects will surely increase the rate of development and accessibility of plant terpenoids for medical use. The biggest and most diversified collection of naturally occurring substances is comprised of terpenes, sometimes referred to as terpenoids. They are divided into the categories of mono, di, tri, tetra, and sesquiterpenes according to the number of isoprene units they contain. They are mostly present in plants and constitute the majority of essential oils made from plants. The total Scheme 46. Total synthesis of dysideanone B.

Conclusions
Terpenoids, also known as isoprenoids, are a diverse group of compounds that are necessary to all living things. Future work focused at improving both screening methodologies for plant terpenoid lead compounds and novel approaches to understand complex biochemical processes of preexisting prospects will surely increase the rate of development and accessibility of plant terpenoids for medical use. The biggest and most diversified collection of naturally occurring substances is comprised of terpenes, sometimes referred to as terpenoids. They are divided into the categories of mono, di, tri, tetra, and sesquiterpenes according to the number of isoprene units they contain. They are mostly present in plants and constitute the majority of essential oils made from plants. The total synthesis, origin, and biological potential of several hemiterpenes, monoterpenes, sesquiterpenoids, diterpenoids, triterpenoids, sesterterpenoids, and meroterpenoids are covered in this review.