English

• 1. Introduction

  Almost all diterpenoids are derived from cyclization and modification of geranylgeranyl pyrophosphate (GGPP) by enzymes. Due to the specificity of enzymes, it is rarely to find the same or similar ring system in polycyclic diterpenes. In the past few decades, chemists have isolated several classes of natural products with similar fused tetracyclic structures from different living organisms. Cycloamphilectanes and isocycloamphilectanes were extracted from sponges and tunicates in the ocean, while hydropyrene and hydropyrenol were isolated from fungi. Kempenes and rippertanes existed within termite bodies, and cephalotanes were obtained from Taxus plants (Fig. 1). Disregarding stereochemistry, these natural products all have a degree of symmetry, which was also shown in some synthetic works. On the other hand, in terms of planar structure only, the common ring system may bring some inspiration to each molecule’s synthesis.

  Figure 1

  

  Figure 1.  Representative molecules of these natural products and their core skeleton.

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  Biosynthetic pathways of these compounds differ greatly even though they have similar ring system, cycloamphilectanes, isocycloamphilectanes, hydropyrene and hydropyrenol with a 6/6/6/6 skeleton have distinct biosynthetic pathways (Scheme 1). As suggested by Garson [1], an unfrequent oxidation/isomerization/cyclization occurred to afford the bicyclic intermediate (7). Later gradual cyclization, addition of HCN equivalent and methyl shift furnish the final natural products such as 7,20-diisocyanoadociane (10). On the other side, the biosynthesis [2] of hydropyrene and hydropyrenol is supposed to begin with 1,10-cyclization of GGPP. Subsequent 1,3-H shift and cyclization deliver perhydropyrene (3). Reprotonation at C6 triggers the transannular cyclisation to set the unique carbon skeleton of hydropyrene (4) and hydropyrenol (5) that arise by final deprotonation or attack of water.

  Scheme 1

  

  Scheme 1.  Suggested biosynthetic pathways of four kinds of natural products.

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  Biosynthetic pathway of cephalotanes was not clearly advanced until the independent discovery of cephalotane diterpene synthase by Wang [3] and Dai [4] et al. in 2023. They isolated the diterpene synthase CharTPS7 and CsCTS of cephalotanes from Cephalotaxus harringtonia and Cephalotaxus sinensis, respectively. However, the conversion from cation 20 to 21 is still unclear, and Wang gave supporting evidence through quantum chemical calculations. The cephalotanes with numerous structures have undergone a long process of biosynthetic evolution in Cephalotaxus plants. Yue et al. [5] summarized the biosynthetic connections among the identified cephalotanes. Prestwich et al. [6] made a reasonable conjecture as to the biosynthetic pathway of kempanes and rippertanes. For cephalotanes, kempenes and rippertanes, a common start with 1,14-cyclization of GGPP produces the cationic intermediate 11. Its isomer with β-H at C14 was subjected to a process of epoxidation, ring-opening and cation cyclization to form intermediate 14. A tandem cyclization induced by proton then gives kempene-1 (15), meanwhile stepwise cyclizations and methyl shift provide rippertane (18). Direct cyclization of this cation 11 with C14-αH would generate the bicyclic intermediate 19. Subsequent Wagner−Meerwein 1,2-hydride and methyl migration produces 20. A plausible 1,7-hydride shift would furnish the supposed cationic intermediate 21, which would afford the tetracyclic system "cephalotene" (25) after a cascade of cyclization. An ambiguous ring contraction process in vivo delivers the cephalotanes (26) bearing 6/6/5/6 core.

  2. Chemical synthesis of highly fused tetracyclic diterpenoids

  These highly fused tetracyclic natural compounds generally have extremely complex ring systems, therefore presenting attractive targets to chemical synthesis. The compact and multifunctionalized ring framework render great challenges for their stereocontrolled total synthesis. At the same time, these challenges have forced chemists to devise new strategies and develop new methods to advancing their synthesis.

  Hydropyrene and hydropyrenol were not isolated until 2015, and there are no reports for their synthesis. However, several other kinds of natural products have been reported with the results of extensive chemical synthesis. We will now categorize them based on the research groups and provide a detailed account of their synthetic work.

  2.1 Total synthesis of cycloamphilectanes and isocycloamphilectanes

  Cycloamphilectanes and isocycloamphilectanes have a regular trans-fused 6/6/6/6 tetracyclic system. The complex structures and remarkable biological activities have attracted the attention of many synthetic chemists. They designed and used divergent strategies and methods to solve the difficulties caused by the crowded ring system. Diels−Alder reaction was often used to build the six-membered ring in diisocyanoadocianes. Corey [7], Miyaoka and Shenvi’s groups completed the construction of the ring system via using two consecutive Diels−Alder reactions respectively. Two systematic reviews had been summarized by Edenborough [8] and Shenvi [9]. In 2022, Vanderwal [10] detailed the development of his two-generation synthesis.

  2.1.1   Mander’s group

  In 2006, Mander’s group [11] completed the formal total synthesis of 7,20-diisocyanoadociane with the Birch reductive alkylation, BF₃·Et₂O-induced cyclization and intramolecular Michael reaction as key steps (Scheme 2). Birch reduction of methyl 2‑methoxy-5-methylbenzoate (27) with lithium liquid ammonia and in situ alkylation followed by BF₃·Et₂O-induced cyclization afforded 28 in 48% yield. The introduction of the propionyl side chain by Friedel−Crafts acylation of the styrene double bond in 28 went smoothly, and the subsequent process of Birch reduction, protection of resulting primary alcohol, reduction with LiAlH₄ and protection of secondary alcohol furnished benzoate 29. To avoid interfering with epoxidation, the MOM group was replaced by acetate, following epoxidation, BF₃·Et₂O-induced rearrangement, base-catalyzed hydrolysis as well as retro-aldol and Wittig reaction afforded ether 30. A modified Simmons−Smith methylenation was carried out. The resulting cyclopropane derivative was then treated with acid at reflux to give the desired aldehyde, which was converted to acid 31 by oxidation with NaClO₂. The benzoate group was replaced with TBS to operate the next Birch reduction. A sequence of Birch reduction, hydrolysis in acetic acid and isomerization provided enone 33, which was further converted to ketone 34 by another Birch reduction. Oxidative dehydrogenation using the Saegusa procedure followed by acylation with methyl cyanoformate and α-methylation prepared enone 35. For the further intramolecular Michael reaction, 35 was converted to dione 36 via a process of reduction with NaBH₄, deprotection and oxidation via Dess−Martin periodinane (DMP). The intramolecular Michael reaction was carried out smoothly under the (CH₂OH)₂/Et₃N conditions. Subsequent deoxygenation by applying the Barton−McCombie procedure afforded diester 37. Hydrolyzing the ester followed by treatment with oxalyl chloride afforded corresponding diacyl chloride, which was transformed into diacyl azide. In the end, Curtius rearrangement and following hydrolysis in concentrated HCl afforded the diamine 38 and completed the formal synthesis of 7,20-diisocyanoadociane (10).

  Scheme 2

  

  Scheme 2.  Mander’s formal synthesis of 7,20-diisocyanoadociane.

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  2.1.2   Miyaoka’s group

  Similar to the synthesis work of Corey, Miyaoka’s group [12] used sequential Diels−Alder (DA) reactions to complete the formal synthesis of 7,20-diisocyanoadociane (Scheme 3). They started their synthesis from the allylation of chiral lactone 39. The resulting product was converted to acetal 40 by additional four steps. A sequence of deprotection, addition with Grignard reagent, protection of primary and secondary alcohols separately, then afforded alkene 41 in 68% overall yield. In order to prepare the precursor of DA reaction, 41 was treated with NaH in refluxing DMSO and afforded the diene, which went further deprotection, oxidation by IBX and Grignard reaction to provide the desired alcohol 42. The intramolecular Diels−Alder reaction proceeded well and provided endo-type product cis-decalin 43 as the sole isomer after oxidation with IBX in DMSO. Aiming at the construction of the next diene, a process of reduction, TBS-protection, Tr-deprotection and oxidation gave aldehyde 44, which was then transformed to triene 45 via HWE reaction and further four steps. The second Diels−Alder reaction afforded the perhydropyrene derivative as a mixture (exo: endo = 5:6) and subsequent deprotection provided separable alcohol 46 in 28% yield. Its oxidation by IBX to give the aldehyde, which was then deformylated and isomerized at C11 by treatment with TBAF to afford diketone 47. A sequence of hydrogenation and isomerization afforded "Corey dione" 48.

  Scheme 3

  

  Scheme 3.  Miyaoka’s formal synthesis of (+)-7,20-diisocyanoadociane.

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  2.1.3   Shenvi’s group

  In 2016, Shenvi’s group [13] reported a concise and fully stereocontrolled synthesis of (+)-7,20-diisocyanoadociane (10) via a key Diels−Alder reaction and N-heterocyclic carbene-catalyzed cyclization (Scheme 4). Their synthesis started with the copper(Ⅱ) triflate-promoted intermolecular Diels−Alder reaction between the substituted Danishefsky [3]-dendralene 49 and dienophile component 50. Cyclohexanone 51 was obtained after elimination of the ethyl silyl ether. The following intramolecular Diels−Alder reaction proceeded in 1,2-DCB at 180 ℃, and auxiliary removal via heteroretroene/decarboxylation took place when temperature was increased to 200 ℃. A sequence of operation including methylation of the saturated ketone, hydrogenation of the enone, afforded ester 53, which was transformed to aldehyde 54 via reduction of ester and oxidation by DMP. Cyclization catalyzed by the N-heterocyclic carbene generated in situ from triazolium salt furnished the expected α‑hydroxy ketone, and samarium(Ⅱ) iodide-mediated deoxygenation then delivered ketone 55. Methylation and followed oxymercuration generated the equatorial, axial diol 56 as a single diastereomer. Finally, (+)-7,20-diisocyanoadociane 10 was obtained by stereoselective displacement using Sc(OTf)₃-catalyzed solvolysis with TMSCN.

  Scheme 4

  

  Scheme 4.  Shenvi’s synthesis of (+)-7,20-diisocyanoadociane.

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  2.1.4   Thomson’s group

  For the preparation of diverse polycyclic scaffolds from simple precursors, Thomson’s group [14] reported a powerful reaction sequence including stereoselective oxidative coupling of cyclic ketones via silyl bis-enol ethers and subsequent ring-closing metathesis (RCM) in 2018. Further utility of this strategy was demonstrated by a concise formal synthesis of the (+)-7,20-diisocyanoadociane (Scheme 5). Convergent and stereoselective oxidative coupling accomplished assembly of dienone 59 from chiral enones 57 and 58. Then RCM afforded the desired tricyclic dienone 60. Reductive hydrogenation saturated the three carbon-carbon double bonds and further Wittig reaction gave diene 61. A sequence of allyl oxidation and DMP oxidation converted diene 61 to dienone 62, which was transformed to "Corey dione" 48 via Ru-catalysed reductive coupling.

  Scheme 5

  

  Scheme 5.  Thomson’s formal synthesis of (+)-7,20-diisocyanoadociane.

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  2.1.5   Vanderwal’s group

  Vanderwal’s group [15,16] achieved the synthesis of (±)-7,20-diisocyanoadociane in 2016 and (+)-7,20-diisocyanoadociane in 2019 (Scheme 6), respectively. The chiral enone 63 underwent a stereocontrolled conjugate arylation followed by a enolate trapping with ethyl bromoacetate and Grignard addition to successfully yield lactone 64. It was transformed to tetracyclic styrene 65 by a process of epoxidation and Lewis acid-induced Meinwald rearrangement/Friedel–Crafts cyclodehydration. The conjugated aromatic system in 65 was saturated under Birch reduction conditions, and the lactone was simutaneously reduced to the lactol, affording compound 66 after hydrolysis of the initial reduction product. The rhodium-catalyzed heterogeneous hydrogenation reaction diastereoselectively saturated the double bond in enone 66 and generated a ketone with the lactol motif, which was transformed to 67 via subsequent proline-mediated intramolecular aldol condensation. Another heterogeneous enone hydrogenation performed in basic methanol, and the following methylation with AlMe₃ can delivered Shenvi diol 56 as a single diastereomer, which could be smoothly converted to (+)-10.

  Scheme 6

  

  Scheme 6.  Vanderwal’s synthesis of (+)-7,20-diisocyanoadociane.

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  The above strategies were summaried in Scheme 7.

  Scheme 7

  

  Scheme 7.  Summary of the synthesis of 7,20-diisocyanoadociane.

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  2.2 Chemical synthesis of kempenes and rippertanes

  Seven research groups including Dauben, Paquette, Burnell, Kato, Hong, Deslongchamps and Metz have synthesized kempene and its derivatives. In 1991, Dauben first completed the total synthesis of (±)-kempene-2. In 2011, Metz then developed the first enantioselective access to kempenes-1 and 2. In addition, his group also finished the synthesis of 3β‑hydroxy-7β-kemp-8(9)-en-6-one, a kempane isolated from the soldier defense secretion of the higher termites Nasutitermes octopolis.

  2.2.1   Dauben’s group

  In 1991, Dauben et al. [17] completed the first total synthesis of (±)-kempene-2 through intermolecular Diels−Alder cycloaddition, intramolecular aldol condensation and Ti⁰-induced McMurry coupling as the key reactions (Scheme 8). They started this synthesis with a Lewis acid-induced [4 + 2] reaction between 2,6-dimethyl-p-benzoquinone (68) and isoprene. After reduction by zinc in AcOH, the resulting regioisomeric cis-decalins was converted to 69 with trans-ring juncture in 13% yield. Stereoselective reduction of the less hindered carbonyl by L-selectride afforded the single axial alcohol, which was then protected as benzyl ether 70. Followed by Peterson-type homologation and hydrolysis, aldehyde 71 was obtained with a four-step yield of 50%. This compound was then converted to ketone 74 in 43% overall yield by an efficient sequence of Wittig reaction, hydroboration-oxidation of the terminal double bond, benzyl etherification, another hydroboration-oxidation and Swern oxidation. In order to perform the second intermolecular Diels−Alder reaction, 74 was treated with pyridinium bromide perbromide and the resulting bromides were heated to 120 ℃ under alkaline conditions to give dienophile 76 with bromo ketone 75, which was converted to 76 by dehaloganation with Bu₃SnH. The EtAlCl₂-promoted annulation with isoprene went smoothly. Dihydroxylation of the generated alkene 77 and removal of benzyl groups, tetrol 78 was obtained as a mixture of diastereomers. Their glycol moiety was cleavaged with NaIO₄, and the generated keto aldehyde 79 constructed the expected cyclopentenone by protonic acid-promoted intramolecular aldol condensation. Subsequent acetylation, hydrolysis and PCC oxidation furnished the tricyclic keto aldehyde 80. Its treatment with TiCl₃(DME)_1.5 and Zn−Cu in refluxing DME provided (±)-kempene-2 (81).

  Scheme 8

  

  Scheme 8.  Dauben’s synthesis of (±)-kempene-2.

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  2.2.2   Paquette’s group

  Using the palladium-catalyzed [3 + 2] cycloaddition reaction and intramolecular aldol condensation, Paquette’s group [18] constructed the skeleton of kempenes smoothly (Scheme 9). A sequence of monomethylation and Grignard reagent addition of 82 afforded 83 in 66% yield, which was stereoselectively converted to octalone 84 by a one-pot Birch-Michael reaction and aldol condensation under KOH conditions. To introduce the angular methyl group and adjust the position of the double bond in 84, Birch reduction was carried out again and the resulting ketone was transformed to keto ester 85 via condensation with dimethyl carbonate and oxidative dehydrogenation. The key [3 + 2] cycloaddition with [2-(acetoxymethyl)allyl]trimethylsilane went in an extremely high yield and afforded 86 as the only isomer because of the steric effect. The monotosylate 87 was furnished by the diol generated from 86 with LiAlH₄ in THF. A sequence of, reduction, hydroxyl protection (to 88) and ozonolysis delivered diketone 89, which was converted to 90 in 9% yield by KOH, alongside conjugated enone (50%). HF deprotection then generated hydroxykempenone 90 effectively. In addition, C3 β‑hydroxyl isomer (95) was achieved by a similar route (92 to 94).

  Scheme 9

  

  Scheme 9.  Paquette’s synthesis of the kempenes skeleton.

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  2.2.3   Burnell’s group

  Burnell’s group made many efforts in synthetic studies toward the kempane diterpenes. In 1997, they [19] accomplished the construction of the kempane diterpenes’ skeleton by the key intermolecular Diels−Alder reaction and Dieckmann condensation (Scheme 10). They began their synthetic studies with diene 96 which was prepared based on Corey’s work. Treating 96 with 68 in refluxing PhMe provided adduct 97 in a regio-, stereo-, and facially-selective manner. Then the exclusive axial addition of 97 with ethoxyacetylide afforded the corresponding alcohol. Subsequent removal of the silyl group with KF afforded a mixture of hemiacetal 98 and 99 in a 7:1 ratio. The mixture was converted to enone 100 by a sequence of reduction/solvolysis with zinc dust, epimerization by HCl in MeOH. The next stereoselective reduction by LiAlH(O-t-Bu)₃ and protection of the resulting hydroxyl provided MEM ether 101, the double bond of which was then diastereoselectivly saturated by dissolving-metal reduction. Further oxidation by PCC and reduction by L-selectride provided alcohol 103. Finally, Dieckmann cyclization of this β-ketoester under t-BuOK condition provided the pentacyclic target 104.

  Scheme 10

  

  Scheme 10.  Burnell’s synthesis of the kempenes skeleton in 1997.

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  In 2006, Burnell’s group [20] completed the synthesis of kempane’s skeleton using the key intermolecular Diels−Alder reaction and ring-closing metathesis (RCM) reaction (Scheme 11). As their work in 1997, the desired diene was prepared first. The lactone ring in 105 was cleaved by LiAlH₄ reduction. Subsequently, selective protection of the generated primary and secondary alcohols respectively as silyl and methyl ether afforded 106 in a good yield after desilylation. A process of Dess−Martin oxidation, Mannich reaction and Luche reduction gave alcohol 107 in moderate yield. Barton−McCombie reaction of 107 furnished the deoxygenation product 108 which was then converted to diene 109 by the following removal of dioxane group and formation of silyl enol ether. Intermolecular Diels−Alder reaction was next carried out as analogous to the previous work. The less hindered carbonyl in the adduct 110 was selectively reduced under Luche condition. With the following addition by allylmagnesium bromide and oxidation by DMP, hemiacetal 111 was furnished albeit in low yield. This compound cyclized in refluxing C₆D₆ to produce 112 by RCM in the presence of Grubbs Ⅱ catalyst, and the tetracyclic core of kempane diterpenes was thus completed.

  Scheme 11

  

  Scheme 11.  Burnell’s synthesis of the kempenes skeleton in 2006.

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  2.2.4   Kato’s group

  In 1998, Kato’s group [21] reported the biomimetic construction of kempane’s skeleton (Scheme 12). This synthesis began with the cyclization of geranylgeranoic acid chloride 113 in the presence of stannic chloride. A process involving elimination of chloride 114 and subsequent DIBAL-H reduction afforded the allyl alcohol, which was transformed to 115 by following TBHP epoxidation and acetylation. A six-membered ring in 116 was then formed via the treatment with BF₃·Et₂O in Et₂O. Protection as methoxymethyl (MOM) ether of the generated hydroxy group and subsequently hydrolysis of acetate furnished 117, where the β-OH could be converted to α-OH by additional PCC oxidation and NaBH₄ reduction. Selective epoxidation of the exocyclic double bond in 118 went well in the presence of TBHP and Ti(O-i-Pr)₄. After the hydroxyl protection, epoxide cleavage was performed smoothly by Al(O-i-Pr)₃ in PhMe. The resulting bis-MOM ether was converted to triol 120 by 2 mol/L HCl. Finally, treatment of the allyl chloride derived from 120 with AgClO₄ and t-BuCl in THF afforded 121 with the tetracyclic core of kempane.

  Scheme 12

  

  Scheme 12.  Kato’s biomimetic synthesis of the kempane skeleton.

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  2.2.5   Metz’s group

  Metz’s group [22-25] made great progress in building the skeleton of these compounds and completed the total synthesis of kempene-1, kempene-2 and 3‑epi-kempene-1.

  In 1993, Metz’s group [22] used the key photosantonin rearrangement reaction and intramolecular Diels−Alder cycloaddition to complete the skeleton construction of rippertane (Scheme 13). They began their synthesis with epimerizations of 122 at C6 and C11. Further photosantonin rearrangement of 123 proceeded to give hydroazulene 124 in 33% yield. Elimination of acetic acid followed by hydrogenolysis with CrCl₂ produced acid 125. Chemo- and stereoselective hydrogenation afforded 126 smoothly after esterification, which was converted to aldehyde 127 via a sequence of reduction (LiAlH₄) and oxidation (TPAP, NMO). Chain elongation of 127 to ester 128 was accomplished by a sequence involving a chemoselective Wittig reaction and the following hydrogenation. An additional adjustment of oxidation levels converted 128 to aldehyde 129. The six-membered ring in 130 was formed by an intramolecular vinylogous aldol reaction under basic conditions. Treating with LiBr in refluxing DMF, the mesylate derived from acylation of 130 with MsCl was converted to a mixture of isomeric dienones consisting mainly of 131, whose proportion could be enhanced by Rh-catalyzed isomerization. 1,2-Reduction of 131 and etherification with propargyl bromide provided 132, which effected base-catalyzed isomerization to the corresponding allenyl ether and subsequent [4 + 2] cycloaddition to generate the tetracyclic skeleton of rippertane. Finally, acid-catalyzed hydration and oxidation afforded the target lactone 134.

  Scheme 13

  

  Scheme 13.  Metz’s construction of the rippertanes skeleton.

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  Based on previous work, Metz’s group [23] accomplished the synthesis of 4-desmethyl-3α‑hydroxy-15-rippertene in 2009 (Scheme 14). This asymmetric synthesis started with chiral cyclohexanone 135 which was efficiently made from (–)-isopulegol in 4 steps. A Lewis acid assisted ring expansion of furnished cycloheptanone 136 which could be converted to diketone 137 by dihydroxylation as well as glycol cleavage. Further intramolecularly aldol condensation of 137 in refluxing t-BuOH, followed by a stereoselective allylation afforded 138. After Wacker oxidation with modified conditions, an additional aldol cyclization under microwave irradiation generated dienone 139. Reduction via LiAlH₄ in ether and subsequent etherification using propargyl bromide provided cycloaddition precursor 140, which was converted to enol ether 141 with complete diastereoselectivity under analogous microwave irradiation conditions. Acid-catalyzed hydration and TPAP oxidation afford lactone 142, which was converted to tetracyclic ketone 143 via a sequence of an α-hydroxylation with MoOPH, basic hydrolysis of the functionalized lactone, subsequent reduction and oxidative cleavage of the 1,2-diol moiety. A hydroxy‑directed 1,3-anti reduction afforded a diol; where chemoselective protection of C3 hydroxy gave 144. Eventually, a Barton−McCombie deoxygenation at C5 followed by acidic cleavage of MOM group furnished 4-desmethyl-3α‑hydroxy-15-rippertene(145).

  Scheme 14

  

  Scheme 14.  Metz’s synthesis of 4-desmethyl-3α‑hydroxy-15-rippertene.

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  In 2011, Metz’s group [24] completed the total synthesis of kempene-1, kempene-2 and 3‑epi-kempene-1 by tandem RCM reactions (Scheme 15). Inspired by Dauben, they started with oxazaborolidine·AlBr₃-catalyzed intermolecular enantioselective Diels−Alder reaction between 2,6-dimethyl-p-benzoquinone (68) and isoprene. Further reduction of enone moiety by zinc and AcOH followed diastereoselective reduction of the less hindered carbonyl by L-selectride and etherification with MOMCl afforded 146. This ketone was converted to aldehyde 147 by Peterson reaction and acidic hydrolysis of the resulting enol ether. One-carbon homologation with the ylide from (methoxymethyl)-triphenylphosphonium chloride furnished enol methylether 148, which was transformed to dimethyl acetal 149 by treatment with TsOH in refluxing MeOH, followed by TBS-protection of the alcohol moiety. A sequence of hydroboration/oxidation, Dess−Martin oxidation, formation of the trimethylsilyl enol ether, oxidative dehydrogenation and hydrolysis of the acetal converted 149 to aldehyde 150. Its Wittig reaction with isopropyl phosphorus ylide gave bicyclic enone 151. A conjugate addition with 1-lithio-1-propyne-AlMe₃ "ate" complex and the following chemoselective deprotection with 2N HCl afforded ketone 152 in 81% yield. Further α-alkylation with allyl iodide gave 40% of dienyne 154 diastereoselectivly and 52% of allyl ether 153, which could be transformed to 154 by a Claisen rearrangement in refluxing PhMe with 90% yield. The key tandem RCM reaction by the Grubbs-Ⅱ catalyst constructed the five- and seven-membered ring of tetracyclic product 155 in 92% yield. Quantitative deprotection with Bu₄NF in THF afforded alcohol 156, which was converted to (+)-kempene-1 (15) by further acetylation. Reduction of the carbonyl in 156 provided two isomeric diols 157 and 158, which were then converted by chemoselective acetylation to (+)-kempene-2 (159) and (+)-3‑epi-kempene-1 (160), respectively.

  Scheme 15

  

  Scheme 15.  Metz’s synthesis of kempene-1, kempene-2 and 3‑epi-kempene-1.

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  The same strategy was used by Metz in 2017 for the synthesis of 3β‑hydroxy-7β-kemp-8(9)-en-6-one [25].

  2.2.6   Hong’s group

  A brief synthesis of kempane’s skeleton was completed by Hong’s group [26] via intramolecular Diels−Alder cycloaddition of fulvenes and TiCl₂(i-OPr)₂ induced-Prins reaction (Scheme 16). Selective reduction of 161 with BH₃·SMe₂ and oxidation with PCC gave 162 in 68% yield. Stereoselective Michael reaction of 162 and methyl vinyl ketone (MVK) in the presence of (R)-2-benzhydrylpyrrolidine furnished 163 in 55% yield. Subsequent Horner−Wadsworth−Emmons reaction formed the conjugated diene structure in 164 under LDA conditions. This intermediate was then converted to the desired fulvene 165 in 85% yield. Treatment in refluxing PhMe, an endo-type Diels−Alder cycloaddition occurred to generate tricyclic ester 166 smoothly.

  Scheme 16

  

  Scheme 16.  Hong’s synthesis of the kempane skeleton.

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  Selective reduction of the methyl ester in compound 166 with DIBALH and DMP oxidation of the resulting alcohol produced aldehyde 167 in 71% yield. Final Prins cyclization induced by TiCl₂(i-OPr)₂ provided the kempene tetracycle 168.

  2.2.7   Deslongchamps’ group

  In 2006, Deslongchamps’ group [27] reported the synthesis of kempane derivatives utilizing the transannular Diels−Alder (TADA) strategy for making the functionalized tricyclic core followed by an aldol reaction (Scheme 17). Their investigation commenced with an alkylation reaction between allylic bromide 169 and the methylmalonate derivative under NaH, and the acyclic triene 170 was obtained in 92% yield. Stille coupling of this iodoester with vinyltributyltin gave the tetraene ester 171 quantitatively. After removing the silyl ether of 171, a RCM reaction gave the desired 13-membered macrocyclic triene 172 in 69% yield. The designed TADA reaction in PhMe afforded tricyclic alcohol 173 having a stereodefined [6.6.5] ring system as the only product in 93% yield. This alcohol was oxidized to the corresponding aldehyde by DMP, and subsequent Wittig reaction with methyltriphenylphosphonium iodide produced the diester which was then subjected to Krapcho decarboxylation protocol. The carboxylic ester of generated 174 was then transformed into the Weinreb derivative from N,O-dimethyhydroxylamine hydrochloride, which was subsequently converted into methyl ketone 175 with MeLi in THF. It was then subjected to a sequence of Bayer−Villiger oxidation along with the double epoxidation of the olefins, reduction of the resulting terminal epoxide with LiAlH₄ and followed by oxidation with DMP to afford diketone 176 in 35% overall yield. Finally, the intramolecular aldol reaction of 176 with K₂CO₃ in refluxing methanol smoothly delivered tetracyclic enone 177 in 70% yield.

  Scheme 17

  

  Scheme 17.  Deslongchamps’s synthesis of the kempane skeleton.

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  2.2.8   Snyder’s group

  In 2011, Snyder’s group [28] accomplished the first total synthesis of the unique terpene rippertenol, with two consecutive aldol condensations, an inverse-demand Diels−Alder (IDDA) reaction, and a ring expansion as key steps (Scheme 18). They began their synthesis with 178, obtained from 3-methylanisole in 6 steps on multigram scale. A sequence of α-methylation and copper(Ⅰ)-promoted conjugate addition with 178 provided ketone 179. Its treatment under PTSA effected a fully diastereocontrolled alkylation with β-keto chloride, deprotection of 1,3-dioxane, and aldol condensation sequence leading to bicyclic enone 180. Meanwhile, the second aldol condensation went well with t-BuOK in t-BuOH and THF to afford diene 181, after elimination of the generated tertiary alcohol using MsCl and Et₃N. Further IDDA reaction promoted by BF₃·OEt₂ furnished the desired tetracyclic product 182 along with the minor diastereomer. Takai olefination, followed by an acidic aqueous workup to deprotect the 1,3-dioxane group and subsequent hydrogenation using Wilkinson’s catalyst gave 183 with the high diastereoselectivity. Treatment of 183 with BF₃·OEt₂ and TMSCHN₂ in DCM completed the ring expansion to forge 184. A process of deoxygenation and deprotection afforded the rippertenol (185).

  Scheme 18

  

  Scheme 18.  Snyder’s synthesis of rippertenol.

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  The above strategies were summaried in Scheme 19.

  Scheme 19

  

  Scheme 19.  Summary of the synthesis of kempenes and rippertanes.

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  2.3 Chemical synthesis of cephalotanes

  From harringtonolide, the first member of cephalotanes, was discovered to now, > 100 natural products have been disclosed and our understanding of the evolution of secondary metabolites in Cephalotaxus genus was therefore intensified. Depending on the carbon number of these molecules, they are divided into four kinds: C₁₈-, C₁₉-, C₂₀-cephalotanes and C₁₉-dimers.

  Early synthetic chemists focused on the synthesis of harringtonolide [32-34]. In recent years, divergent strategies have been developed to synthesize those newly isolated diterpenoids. Particularly the use of Pauson−Khand reaction allowed efficient construction of the common B-C-D tricyclic skeleton, while giving more flexibilities to the more variable A ring. So far, a total of nine research groups have finished total synthesis of different cephalotanes. Those achievements from 1988 to 2021, had been summarized by Hua [29] and Chen et al. [30]. A systematic review by Yue [31] summarized about the isolation, biological activities, and chemical synthesis of these natural products.

  2.3.1   Zhai’s group

  In 2021, Zhai’s group [35] completed the first asymmetric total synthesis of (+)-mannolide C via Ru-complex catalyzed double RCM reactions as a critical method for the construction of tetracyclic skeleton (Scheme 20). This synthesis commenced with the Grignard addition of meso‑186 in the presence of CuI. Subsequent dehydration, partial reduction, intramolecular aldol reaction, mesylation and elimination process afforded cyclopentenone rac-187 in 64% overall yield. Stereoselective reduction of ketone group in Luche’s condition furnished allyl alcohol which was converted to (−)-187 by enzyme-mediated stereospecific resolution and DMP oxidation. Diastereoselective Michael addition of this chiral cyclopentenone and the following Wittig reaction with Ph₃P=CH₂OMe gave aldehyde 188 after hydrolysis of the resulting enol ether. Acetalization and regioselective epoxidation effectively protected the sensitive groups making the ozonolysis reaction successful. Follow-up double olefination of the generated bisaldehyde with Ph₃P=CH₂ smoothly furnished diene 189. A process of Zn(0)-mediated reductive epoxide deoxygenation, acidic acetal deprotection, nucleophilic addition with the organocerium reagent and DMP oxidation then afforded tetraene 190. Double RCM reactions with Hoveyda−Grubbs Ⅱ catalyst went well under microwave irradiation and provided tetracycle 191 in 70% yield. Its treatment with DBU in refluxing toluene led to C1 epimerization and AlMe₃ Michael addition of the resulting enone catalysed by Ni(acac)₂ provided ketone 192 as a single isomer. The pentacycle was thus constructed by a sequence of NaBH₄ reduction and K₂CO₃-promoted spontaneous δ-lactonization. Subsequent allylic oxidation with Mn(OAc)₃·2H₂O/TBHP furnished enone 193. Its α-methylation and formation of tosylhydrazone followed by catecholborane reduction produced alkene 194 in 48% overall yield. Diastereoselective dihydroxylation in acidic condition formed γ-lactone moiety. Finally, regioselective dehydration of the remaining alcohol with Burgess reagent afforded (+)-mannolide C (195).

  Scheme 20

  

  Scheme 20.  Zhai’s asymmetric total synthesis of (+)-mannolide C.

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  In 2022, Zhai et al. [36] accomplished the asymmetric total syntheses of cephanolides A–D via a palladium-catalyzed formal bimolecular [2 + 2 + 2] cycloaddition reaction as the essential step (Scheme 21). The 6–6 cis-fused bicycle 197 was constructed by a substrate-controlled diastereoselective intermolecular Diels–Alder reaction of dienophile from chiral cyclohexenol 196 and Danishefsky’s diene and the following deprotection and DMP oxidation. Dione 197 was transformed into a vinyl bromide via the chemoselective formation of a monohydrazone and following treatment with pyridinium tribromide. Subsequent stereoselective monoalkylation of enone moiety with 1-iodo-2-butyne and epimerization then gave bromoenyne 198 in moderate yield. Its tandem cyclization with trimethylsilylacetylene catalyzed by Pd(PPh₃)₂Cl₂ in DMF smoothly assembled the tetracyclic skeleton and provided 199 in 51% yield after Michael addition with Me₃Al. A reaction sequence of α-hydroxylation, reduction with NaBH₄, and lactonization delivered alcohol 200 in 43% overall yield. A Suárez oxidation constructed the THF ring, and the following sequence consisting of Friedel−Crafts (FC) acylation and spontaneous hydrolysis of formate intermediate generated from Baeyer−Villiger (BV) oxidative rearrangement furnished the desired hydroxyl group at benzene ring, therefore completing total synthesis of cephanolide A (201). Alternatively, ketoester 199 was stereoselectively reduced to alcohol 202, which was treated with NBS and PTSA to afford lactone 203 smoothly. It was then transformed to cephanolide D (204) by selective one-pot benzylic oxidations with Ru^Ⅱ-complex/PIDA and PCC as well as Pd-catalyzed methoxycarbonylation. Alcohol 202 can be converted to lactone 205 in acidic media, upon simutaneous loss of the TMS group. The same benzylic oxidations were used to afforde cephanolide C (206). A similar two-step sequence including FC formylation and BV oxidation with 205 then achieved total synthesis of cephanolide B (207).

  Scheme 21

  

  Scheme 21.  Zhai’s asymmetric total synthesis of cephanolides A–D.

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  2.3.2   Hu’s group

  Hu’s group developed a unified approach to synthesize many cephalotanes based on the rapid construction of cyclopentenone embedded in their skeletons by Pauson–Khand (PK) reaction.

  In 2021, Hu et al. [37] accomplished total syntheses of 3-deoxyfortalpinoid F, fortalpinoid A, and cephinoid H by a diastereoselective PK reaction as the key step to construct core tetracyclic skeleton of these Cephalotaxus norditerpenoids (Scheme 22). This synthesis began with a Michael addition–Dieckmann condensation between ethyl acetoacetate (208) and ethyl crotonate (209). The subsequent formation of enol isopropyl ether afforded β-keto ester 210. Its highly diastereoselective alkylation with the bromide and the following two-step reduction reactions smoothly provided diol 211. To avoid preferential oxidation of the allyl alcohol, its protection with TBSCl was executed. The ensuing oxidation by DMP as well as deprotection treatment then delivered aldehyde 212. A reaction sequence of Cu(OTf)₂-promoted acetalation in isopropanol and TEMPO-mediated oxidation led to the production of aldehyde 213. Its addition with valylene-derived lithium reagent afforded alcohol intermediate which was oxidized by DMP to deliver ketone 214. The designed PK reaction successfully built the desired tetracyclic skeleton. Subsequent addition of the resulting 215 with Weinreb amide smoothly generated the tertiary alcohol followed by protection with TMSOTf, thus giving 216. Its treatment with LiAlH₄ furnished the corresponding aldehyde which was converted to ketone 217 by a sequence of TBS protection, addition with vinylmagnesium bromide and DMP oxidation. The tropone 218 was smoothly obtained after a protocol of RCM and elimination the tertiary hydroxyl group. The next hydrolysis of the acetal moiety and oxidation by Ag₂CO₃/Celite successfully constructed the bridged lactone, therefore achieving the total synthesis of 3-deoxyfortalpinoid F (219). A inversion of the hydroxyl configuration in 218 by a two-step procedure including chlorination with MsCl and treatment with AgBF₄ was secured. The similar hydrolysis and oxidation process then provided fortalpinoid A (220). Starting from 218, a reaction sequence of chlorination, reduction, hydrolysis and oxidation also realized the synthesis of cephinoid H (221). The corresponding chiral diol (−)-211 was then prepared and the first asymmetric syntheses of these three natural products were thus accomplished.

  Scheme 22

  

  Scheme 22.  Hu’s total synthesis of 3-deoxyfortalpinoid F, fortalpinoid A and cephinoid H.

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  Based on the work described above, Hu et al. [38] achieved divergent synthesis of (−)-ceforalide B and (−)-cephanolides B-D (Scheme 23). This total synthesis started from a nucleophilic addition of in situ generated alkynyl lithium reagent from TMSCHN₂ to aldehyde 213. The resulting alcohol was oxidized by IBX in DMSO and afforded ketone 222. The subsequent Pauson−Khand reaction gave the desired tetracyclic ketone 223 with expected stereoselectivity. The proposed olefination/6π-electrocyclization/oxidative aromatization cascade was then carried out by Wittig reaction and oxidation with NMO. The similar cascade had been utilized in the synthesis of (±)-cephanolide B by Yang and Zhang et al. [39]. The resulting pentacyclic skeleton was converted to lactone 224 via oxidation of the acetal moiety under acidic conditions. Subsequent reductive decarbonylation and de-ethylation furnished (−)-cephanolide B (207). Following the above procedures, enone 215 was transformed to 225 with a Horner reagent. The site-selective benzylic oxidation enabled by Co(OAc)·4H₂O/TBAB/O₂/PPh₃/NHPI system gave (−)-cephanolide D (204) or (−)-ceforalide B (226) in different solvents. Meanwhile, 215 was also converted to the corresponding lactone 205. Its treatment with the similar aerobic oxidation condition achieved the synthesis of (−)-cephanolide C (206) eventually.

  Scheme 23

  

  Scheme 23.  Hu’s synthesis of (−)-ceforalide B and (−)-cephanolides B-D.

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  In 2023, Hu’s group [40] achieved the enantioselective total synthesis of cephalotanin B on the basis of their previous work (Scheme 24). This synthesis commenced with the asymmetric Michael addition of 227 and 228 under the control of a chiral thiourea catalyst. Dieckmann condensation of the resulting ketoester with an excellent ee and subsequent enol etherification furnished compound 229. Stereoselective alkylation with the bromide and reduction gave cyclohexenone 230. α-Chlorination of the carbonyl was executed via the formation of silyl enol ether and simultaneous protection of the hydroxyl group with TMSOTf. The desired ketone 231 was then obtained through a configuration inversion at the new stereocenter. After a series of transformations, aldehyde 232 was obtained in 52% overall yield. A five-step process similar to their work in 2021 was applied to construct the bridged acetal and introduce an alkynyl side chain, thus delivering enyne ketone 233. It was treated with Co₂(CO)₈ in PhMe to afford tetracyclic enone 234 as a sole diastereomer by the PK-deacyloxylation cascade. The bridged lactone moiety was then introduced by the treatment with TiCl₄ and DMP. The resulting compound was further converted to pentacyclic ketone 235 via stereoselective epoxidation, reduction as well as the formation of a THF ring and DMP oxidation. Under the LiTMP condition, 235 reacted with methyl acetate and provided the corresponding diester, which was converted to (−)-cephalotanin B (236) promoted by PTSA via the proposed sequence of epoxide opening/elimination/dual lactonization.

  Scheme 24

  

  Scheme 24.  Hu’s enantioselective synthesis of cephalotanin B.

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  2.3.3   Gao’s group

  In 2023, Gao et al. [41] achieved the asymmetric total syntheses of cephinoid P, cephafortoid A, 14‑epi-cephafortoid A and fortalpinoids M-N, P by a universal strategy including two crucial steps: a Nicholas/Hosomi−Sakurai (NHS) cascade reaction and an intramolecular PK reaction (Scheme 25). A five-step convensional modification of known chiral compound 237 delivered bridging lactone 238. Its anti-Markovnikov Wacker oxidation and nucleophilic addition of the resulting aldehyde with the alkynyl lithium with a chiral methyl group furnished the desired propargylic alcohol 239. The expected NHS reaction controlled by the interaction between the allylsilane and the C8 substituted group delivered cycloheptene Co-complex 240 as a single diastereomer in 78% yield. A three-step procedure was then carried out to convert the bridging lactone to the bulky isopropyl acetal group and obtain ketone 241 after Swern oxidation. The diastereoselective PK reaction promoted by tetramethyl thiourea (TMTU) proceeded uneventfully to provide pentacyclic product 242. On this basis, the first asymmetric total synthesis of (−)-cephinoid P (244) was achieved via three functional group transformations, including selective reduction of the cyclohexanone, oxidative cleavage of the exocyclic double bond, and δ-lactone formation. This C₁₉ Cephalotaxus diterpenoid was then utilized as a common precursor to finish total synthesis of other members in with lower oxidation state. Treatment with NaBH₄ thus afforded cephafortoid A (245) and 14‑epi-cephafortoid A (246) in 83% combined yield. In the meantime, removal of the hydroxyl group in cephinoid P via Barton–McCombie deoxygenation delivered (−)-fortalpinoid P (247). Its further reduction with NaBH₄ provided fortalpinoids N (248) and M (249) in 86% combined yield.

  Scheme 25

  

  Scheme 25.  Gao’s asymmetric syntheses of cephinoid P, cephafortoid A, 14‑epi-cephafortoid A and fortalpinoids M-N, P.

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  2.3.4   Sarpong’s group

  Sarpong’s group efficiently constructed the core skeleton of C18-benzenoid cephalotane-type norditerpenoids by intramolecular inverse-electron-demand Diels−Alder (IEDDA) cycloaddition and completed the total syntheses of (±)-cephanolides A-D via late-stage oxidations in 2021 [42]. On this basis they streamlined the synthetic route to cephanolides A-D via alkene difunctionalization, meanwhile some peripheral C-H functionalizations were developed to access five ceforalides in 2022 (Scheme 26) [43]. This improved synthesis began with subjecting alkene 250 to methylboration conditions and subsequent one-pot oxidation of the resulting boronic ester, which afforded alcohol 251 in 77% yield as a single isomer. Construction of the tetrahydrofuran ring in 252 was completed by configuration inversion of the hydroxyl group and Suárez oxidation as well as the following TMS cleavage. Barton–McCombie deoxygenation protocol then provided 253. The next process including regioselective thianthrenation (C13:C15 = 13:1), photocatalytic boronic esterification and subsequent one-pot oxidation of the resulting Bpin moiety furnish the C13-OH in cephanolide A (202). Its further treatment with PIDA afforded ceforalide H (256) in 78% yield. Meanwhile the above Cu-catalyzed methylboration of 250 delivered boronic ester 257 in 83% yield. Its treatment with PhLi in Et₂O and following photoinduced protodeboronation by PhSH as well as one-pot cleavage of the TMS group afforded alcohol 258 in 76% yield. InCl₃-catalyzed ionic deoxygenation and phthaloyl peroxide (PPO)-mediated hydroxylation provided cephanolide B and its constitutional isomer in 74% yield. On the other side, subjecting alcohol 258 to PCC for benzylic oxidation gave rise to cephanolide C (207) in 61% yield. A concise sequence of oximation, ortho-C–H methoxycarbonylation and ozonolysis was carried out to afford cephanolide D (205) in 18% overall yield. The synthesis of ceforalide D (260) was completed by a sequence including oxidation of the secondary alcohol, bromination of benzyl alcohol and subsequent reductive debromination as well as reduction of the ketone carbonyl group. Under different benzylic oxidation conditions, ceforalide D can be further converted to ceforalide C (261) or ceforalide F (262). Photoredox oxygenation of the previously generated boronic ester 255 using compact fluorescent light (CFL) afforded alcohol 263 stereoselectively, and final oxidation of the remaining Bpin moiety furnished ceforalide G (264) in 43% yield. Notably, Cai and co-workers developed an asymmetric IEDDA for the total synthesis of cephanolides A and B [44].

  Scheme 26

  

  Scheme 26.  Sarpong’s synthesis of cephanolides A-D and ceforalides.

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  2.3.5   Zhao’s group

  In 2024, Zhao’s group [45] completed the total syntheses of cephinoid H, fortalpinoid C, cephanolide E and their structural analogues by employing ring expansion strategy (Scheme 27). Their studies commenced with cephanolide B, a natural product prepared reliably in multigram-scale by their previously described method. Oxidative dearomatization of cephanolide B (208) as well as one-carbon introduction and ring expansion cascade successfully furnished 13-oxo-cephinoid H (266) and cephinoid H (222) in a ratio of 3.5:1. Halogen atoms with electron-withdrawing properties were introduced to the benzene ring so as to adjust the migratory aptitude. C15-halogen substituted cephanolide B (267 and 267′) were thus synthesized and subjected to the above similar dearomatization and ring expansion conditions, affording the corresponding products with an improved ratio of 1:3 (X = Cl) or 1:1 (X = Br) in 58% combined yield. Subsequent reductive dehalogenation smoothly delivered cephinoid H. Its regioselective oxidation by SeO₂ provided 7-oxo-cephinoid H (271), which was then converted to 7‑epi-fortalphinoid C (272) via NaBH₄. The configuration inversion of C7 hydroxy group was achieved through a Mitsunobu reaction and gave fortalphinoid C (273) for the first time. On the other hand, compound 267′ was converted to α-bromodienone 274 through oxidative dearomatization with water, protection of the resulting tertiary alcohol with chloro(chloromethyl)dimethylsilane and further Finkelstein reaction. The designed Ueno–Stork-type radical cyclization of 274 proceeded smoothly, yielding 275 with a C8 quartenary stereocenter in 70% yield. CN group was introduced as a one-carbon unit for ring expansion after a reduction of 275 with SmI₂. Selective reduction of 276 with Raney Ni and the desired Tiffeneau–Demjanov rearrangement proceeded when the resultant primary amine was oxidized by HNO₂, giving 277 as the main ring expansion product. C12-OH was smoothly installed with high regio-/diastereoselectivity via a oxidation of the enolate derived from ketone 277. The resulting alcohol was transformed to 278 through Fleming oxidation and dihydroxyl protection with TMSCl. A sequence of bromination, oxidation of the primary alkoxy silyl ether, oxa-alkylation and Fétizon oxidation converted 278 to lactone 279 in 35% overall yield. Stereoselective reduction of the C13-carbonyl group by Noyori hydrogenation gave diterpene cephanolide E (280) and its epimer 13‑epi-cephanolide E (281) eventually.

  Scheme 27

  

  Scheme 27.  Zhao’s synthesis of cephinoid H, fortalpinoid C and cephanolide E.

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  The above strategies were summaried in Scheme 28.

  Scheme 28

  

  Scheme 28.  Summary of the synthesis of benzenoid and troponoid cephalotanes (2021–2024).

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  3. Conclusion

  In the last few years, there has been an increase in the discovery of these kinds of fused tetracyclic diterpenoids. In addition, the pharmacology effect of these unique natural products is still understudied. Especially isocyanoterpenes (like cycloamphilectanes and isocycloamphilectanes) are often found to exhibit favourable biological activities. At the same time, since these kinds of natural products share similar structural characteristics, the respective synthetic work may enlighten each other. Although similar ring systems suggest a possibility to unify their chemical synthesis, the structural diversity within these classes poses a great challenge, particularly with a high level of efficiency. The pursue for highly versatile precursors, the development of novel strategies (i.e., biomimetic approach), new synthetic methodologies, and more extensive pharmacological research should be considered as future efforts.

  Declaration of competing interest

  The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

  CRediT authorship contribution statement

  Yun-Hong Yu: Writing – original draft. Yu Peng: Writing – review & editing, Supervision, Funding acquisition. Wei-Dong Z. Li: Writing – review & editing, Supervision.

  Acknowledgments

  Financial support was provided by the National Natural Science Foundation of China (No. 22471224). We would like to thank Analytical and Testing Center of Southwest Jiaotong University (SWJTU) for NMR test.

  
  
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• 

  Figure 1  Representative molecules of these natural products and their core skeleton.

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  Scheme 1  Suggested biosynthetic pathways of four kinds of natural products.

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  Scheme 2  Mander’s formal synthesis of 7,20-diisocyanoadociane.

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  Scheme 3  Miyaoka’s formal synthesis of (+)-7,20-diisocyanoadociane.

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  Scheme 4  Shenvi’s synthesis of (+)-7,20-diisocyanoadociane.

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  Scheme 5  Thomson’s formal synthesis of (+)-7,20-diisocyanoadociane.

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  Scheme 6  Vanderwal’s synthesis of (+)-7,20-diisocyanoadociane.

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  Scheme 7  Summary of the synthesis of 7,20-diisocyanoadociane.

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  Scheme 8  Dauben’s synthesis of (±)-kempene-2.

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  Scheme 9  Paquette’s synthesis of the kempenes skeleton.

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  Scheme 10  Burnell’s synthesis of the kempenes skeleton in 1997.

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  Scheme 11  Burnell’s synthesis of the kempenes skeleton in 2006.

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  Scheme 12  Kato’s biomimetic synthesis of the kempane skeleton.

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  Scheme 13  Metz’s construction of the rippertanes skeleton.

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  Scheme 14  Metz’s synthesis of 4-desmethyl-3α‑hydroxy-15-rippertene.

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  Scheme 15  Metz’s synthesis of kempene-1, kempene-2 and 3‑epi-kempene-1.

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  Scheme 16  Hong’s synthesis of the kempane skeleton.

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  Scheme 17  Deslongchamps’s synthesis of the kempane skeleton.

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  Scheme 18  Snyder’s synthesis of rippertenol.

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  Scheme 19  Summary of the synthesis of kempenes and rippertanes.

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  Scheme 20  Zhai’s asymmetric total synthesis of (+)-mannolide C.

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  Scheme 21  Zhai’s asymmetric total synthesis of cephanolides A–D.

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  Scheme 22  Hu’s total synthesis of 3-deoxyfortalpinoid F, fortalpinoid A and cephinoid H.

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  Scheme 23  Hu’s synthesis of (−)-ceforalide B and (−)-cephanolides B-D.

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  Scheme 24  Hu’s enantioselective synthesis of cephalotanin B.

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  Scheme 25  Gao’s asymmetric syntheses of cephinoid P, cephafortoid A, 14‑epi-cephafortoid A and fortalpinoids M-N, P.

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  Scheme 26  Sarpong’s synthesis of cephanolides A-D and ceforalides.

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  Scheme 27  Zhao’s synthesis of cephinoid H, fortalpinoid C and cephanolide E.

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  Scheme 28  Summary of the synthesis of benzenoid and troponoid cephalotanes (2021–2024).

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