Di-, tri-, and sesterterpenoids, a structural feature of which is a furan ring or a derivative of it, are interesting as promising compounds for medical application. The furan ring in these natural terpenoids is transformed into a butenolide or dihydrofuran moiety. The transformation of the ring leads to the manifestation of new or enhanced biological activity of the original native terpenoid. Therefore, examples of the modification of furanoterpenoids are becoming more common.

Herein we review the structure and biological activity of plant furanolabdanoids and present schemes for the total synthesis of metabolites from terpenoids and chemical modifications of several available metabolites.

Plant Furanoditerpenoids. Furanolabdanoids are produced by plants of the families Acanthaceae, Alismaceae, Annonaceae, Apocynaceae, Asteraceae, Caprifoliaceae, Cistaceae, Euphorbiaceae, Lamiaceae, Pinaceae, Potamogetonaceae, Scrophulariacea, and Zingiberaceae.

Lambertianic acid (1) was first isolated from oleoresin of Pinus lambertiana Dogl. [1] and occurs in oleoresin of long-needle pines P. sibirica [2], P. koraiensis [3], and P. wallichiana [4]. Cones of P. lambertiana contained significant amounts of 1 (up to 25 % of total acids) [5]. Acid 1 and its methyl ester 2 [2] occurred also in needles and needle-less shoots of P. sibirica [6]. Acid 1 has been isolated from other plants, e.g., Gutierrezia dracunculoides [7], Sciadopitys verticillata [8], Platycladus orientalis [9], Biota orientalis [10], Thuja orientalis [11], and Caesalpinia echinata [12]. Investigations of the pharmacological activity of 1 revealed its antidepressant activity with a sedative component [13]. The significant potential of 1 as an allergy treatment agent was noted [11]. Data on its action on allergy mediators, including the inhibition of interleukine- 6 (IL-6), prostaglandin D2 (PGD2), and leukotriene C4 (LTC4) production; cyclooxygenase-2 (COX-2) expression; and β-hexosaminidase degranulation into PMA were obtained. The methyl ester of 1 (2) exhibited stimulating antidepressant properties [14].

figure a
figure b

Oleoresin of P. sibirica and the medicinal plant Biota orientalis yielded products of oxidative metabolism at the C-13 atom, i.e., pinusolic acid (3) and pinusolide (4) [9, 15, 16]. Compound 4 was characterized as a new thrombocyte aggregation factor (TAF) antagonist [15–17]. IC50 values from 19 to 5 μM for thrombocyte aggregation caused by TAF upon lowering its concentration from 500 to 5 nM were obtained in tests using rabbit thrombocytes. The ED50 value in vivo was 1.1 mg/kg for i.v. injection and 69.0 mg/kg for per os administration. The anti-leukemia and prophylactic potential of 4 was studied in vitro on the BJAB Burkitt lymphoma cell line [18]. Furthermore, it was found that 4 ex vivo overcame the anthracycline resistance of primary lymphoblasts obtained from patients with a high risk of acute lymphoblastic leukemia (ALL) and a weak response to chemotherapy [18]. The neuroprotective activity of 4 and 15-methoxypinusolic acid 5 (from Biota orientalis) were investigated [19].

Extracts of aquatic plants of the genus Potamogeton possess antiviral, antibacterial, and antitumor activity. The plants produce diterpenoids of the labdane and ent-labdane types. Potamogetonin (6) [20] and ketofuran 7 [21] were isolated from P. ferrugineus Hagstr. and P. nodosus Poir., respectively.

Substituents in ring B are found in a large number of biologically active labdane-type metabolites. These include solidagenone (8) from Solidago chilensis Meyen. [22]; hedychenone (9) [23], 9-hydroxyhedychenone (10) [24], 7-hydroxyhedychenone (11) [25], and coronarin A (12) [26] (from Hedychium spp.); (+)-leoheterin (13) [27] (Leonurus sp.); and hispanolone (14) [28–30], hispanone (15) [30, 31] (from Ballota spp. and Leonurus sp.), and (+)-austrochaparol (16) [32] from Acritopappus spp. Metabolites of Hedychium coronarium Koen. (ginger lily) exhibited cytotoxic activity against human tumor cells [Colo-205 (colon cancer), L-431 (skin cancer), MCF-7 (breast cancer)]. Compound 10 was the most active [24]. Flowers of the medicinal plant Hedychium spicatum afforded metabolites that showed antihyperglycemic activity, among which 9, butenolide derivatives spicatanol (17) and the methyl ether of spicatanol (18), 7-hydroxyhedychenone (11), and hedychialactone B (19), which contains an exocyclic double bond, are notable. All components and the extract inhibited 𝛼-glucosidase. Metabolite 17 had the lowest inhibiting concentration (IC 34.1 μg/mL) [33]. Subsequent research on the extracts of this plant isolated cytotoxic metabolites such as coronarin E (20), which is a furanolabdanoid that is unsubstituted in ring B, and the 6-ketosubstituted labdanoids yunnancoronarin D (21) and 7-hydroxyhydichinal (22) [34]. New cytotoxic labdanoids with a transformed furan group (23 and 24) in addition to metabolites 19 and 20 were isolated from H. coronarium [35]. Hedychenone (9), coronarin E (20), hedychialactone B (19), coronarin D (25), and villosin (26) inhibited significantly the accumulation of nitric oxide (produced in vivo by oxidation of L-arginine by NO-synthase) through the inhibition of iNOS induction in macrophages activated by lipopolysaccharide [37]. The butenolide (–)-lagerstronolide (27), which was isolated from leaves of the medicinal plant Lagerstroemia lancasteri, was also characterized as having anti inflammatory activity [38]. Antihypertensive, sedative, and uterotonic properties were found for metabolites of Leonurus spp., i.e., 12, 14, 15, and sibiricinones A (28) and B (29) [39].

The metabolite of Leonurus heterophyllus Sw. prehispanolone (30) (a transformation product of 14) was characterized as a selective TAF antagonist [40]. The plant Renealmia exaltata (Zingiberaceae) produced cytotoxic butenolides with exocyclic double bonds, pacovatinins A–C (31–33) [41]. Introduction of a hydroxyl into the C-3 position (32) reduced significantly the cytotoxicity. Pacovatinins A (31) and B (32) had the E-configuration of the C-12,13 double bond; pacovatinin C, the Z-configuration. (+)-Zerumin B (34), which occurs in various plants, was isolated from several derivatives of labdanoid hydroxylactones [42, 43]. A structural feature of this metabolite is the presence of a 12𝛼-hydroxy group. It exhibited cytotoxic activity against various human tumor cells and was selective against MCF-7 breast tumor cells (IC50 0.59 μM) [44].

figure c

Medicinal plants of the genus Marrubium sp. produce a rich assortment of labdanoids. The principal constituents are marrubiin (35), marrubiinic acid (36), and marrubenol (37) [45], which possessed significant analgesic activity in vivo in the acetic-acid writhing test [46].

figure d

The previously known nepetaefuran (38) [47] and sciadin (39) [48] are other notable polyfunctional metabolites and derivatives of labdane acids.

Bark of the plant Neouvaria acuminatissima afforded the cytotoxic metabolites acuminolide (40) and 17-O-acetylacuminolide (41), which contain 𝛽-substituted γ-hydroxybutenolide and 8𝛼, 12-epoxide fragments in their structures [49]. Despite the similar structures of the compounds, they exhibited selective cytotoxicity for different tumor cells. Medicinal plants of the family Labiatae, Phlomis, and Eremostachys, which are widely represented in the flora of Central Asia and China, yielded the sweet diterpene glycosides baiyunoside (42), phlomisoside I (43), and phlomisoside II (44) in addition to the corresponding phlomisoic acid glycosides phlomisoside III (45), phlomisoside IV (46), and eremostachiin (47) [50, 51].

Thus, furanolabdanoids exhibit various biological activities. Labdanoids modified in ring B are characterized by broad spectra of pharmacological activity. Compounds that are inhibitors of 𝛼-glucosidase (9–11 and 17–19) and promising analgesics (35–37) have been isolated. Compounds with a transformed furan ring (4 and 30) were characterized as TAF antagonists and are promising antitumor agents.

Approaches to the Synthesis of Furanolabdanoids. The significant biological activity of furanolabdanoids is responsible for the interest in developing methods for total synthesis of these compounds. The principal preparation methods are based on transformations of available diterpenoids and monoterpenoids.

Sclareol in the Synthesis of Labdane Diterpenoids. The available labdane diterpenoid (–)-sclareol (48) (isolated from Salvia sclarea) was used in the synthesis of several furanolabdanoids. Scheme 1 illustrates the synthesis of (+)-coronarin E (20) from 48 [52]. The rate-limiting step was periodate cleavage of 48, which occurred with formation of the corresponding acetoxy acid (30 % sclareolide was also formed). Subsequent methylation by dimethylsulfate and thermal elimination of the C-8 acetoxy group produced 49 as the main product (the 𝜟7,8- and 𝜟8,9-isomers were also detected). Reduction to the corresponding alcohols, Swern oxidation, and reaction of aldehyde 50 with 3-lithiofuran afforded the coupling products as a mixture of diastereomers 51a and b. Elimination of the hydroxyl formed coronarin E (20).

scheme 1

Scheme 1

The γ-acetoxybutenolide (+)-lagerstronolide [(+)-27] was synthesized starting with (+)-13-epi-sclareol (52) (Scheme 2) [53]. Oxidation of 52 by KMnO4 in neutral solution and reduction of the keto-derivative led to a mixture of C-13 epimeric diols 54, acetylation of which formed a mixture of the corresponding epimeric acetates 55. Elimination of the acetoxy group in the bicyclic system by pyrolysis over silica gel gave a mixture of olefins 56. Subsequent hydrolysis of the secondary acetoxy group afforded an inseparable mixture of alcohols 57, oxidation of which produced a difficultly separated mixture of keto-olefins 53a–c. Epoxidation of the double bond allowed unreacted 53a to be isolated. The next synthesis steps included formation of the butenolide ring in the side chain by oxidation of silylenol ether 58 into hydroxyketone 59 and treatment with ketene according to Bestman to produce butenolide 60. Photochemical oxidation of furan derivative 61 by singlet oxygen led to hydroxybutenolide 62, acetylation of which gave (+)-lagerstronolide [(+)-27], the optical isomer of the natural compound (-–)-lagerstronolide [(–)-27]. The overall yield of (+)-27 calculated as (+)-13-epi-sclareol (52) was about 10 %.

scheme 2

Scheme 2

(–)-Sclareol (48) was used to synthesize leoheterin (13), sibiricinone A (28), and sibiricinone B (29) [54–56]. The starting material in the syntheses was 6,7-disubstituted ketone 63, which was obtained from methylketone 64 [55]. Treatment of 63 with lead tetraacetate in MeOH produced a mixture of acetoxy- and methoxy-derivatives 65 and 66. Basic hydrolysis of 65 led to hydroxyketone 67 with a small impurity of acid 68. Treatment of 67 with ketene according to Bestman gave key lactone 69. Scheme 3 presents the synthesis conditions for natural labdanoids 13, 28, and 29.

scheme 3

Scheme 3

Sclareolide in the Synthesis of Labdane Diterpenoids. Several schemes for the total synthesis of furanolabdanoids are based on the use of the natural metabolite (+)-sclareolide (77), which is obtained by oxidative cleavage of several available labdane terpenes such as (–)-sclareol (48), (+)-cis-abienol, or (–)-labdanic acid. Scheme 4 shows the synthesis of coronarin A (12) from sclareolide (77) [57]. Hydride reduction of 77 produced diol 78, treatment of which with acetic anhydride in collidine transformed it into a mixture of acetates with exo- (79a) and endocyclic (79b and c) double bonds (3:1:1 ratio). Allylic hydroxylation of 79a–c led to 7𝛼-hydroxybicyclane 80, oxidation of which produced the corresponding 7-keto derivative 81, reduction of which gave 7𝛽-hydroxybicyclane 82 (natural configuration). Silyl protection of the alcohol afforded 83, deacetylation of which produced 84. Oxidation of 84 produced the unstable aldehyde 85 (75 % yield from 80), reaction of which with 3-lithiofuran gave furanolabdanoids 86a and b (mixture of diastereomers). Removal of the silyl protection afforded corresponding alcohols 87a and b, dehydration of which led smoothly to coronarin A (12).

scheme 4

Scheme 4

It was demonstrated [58] that a more convenient method for introducing the C-11 = C-12 double bond in the syntheses of coronarins A (12) and E (20) was to heat the corresponding hydroxy-derivatives 51a and b or 87a and b in alcohols in the presence of HMPA.

Villosin (26) was synthesized from (+)-sclareolide (77) [59]. The key step was formation of the (E)-(1-alkenyl)- 2(5H)-furanones from the aldehydes (Scheme 5). Aldol condensation of aldehyde 50 with dibutylboron-2-furanolate that was generated in situ occurred regioselectively to form diastereomeric alcohols 88a and b (3.8:1), the mesylates of which (89a and b) transformed smoothly into butenolide 26.

scheme 5

Scheme 5

An effective method for preparing coronarin E (20) from metabolite 77 was proposed (Scheme 6) [60]. Opening of the lactone ring of sclareolide by 3-lithiofuran led to hydroxyketone 90. Then, selective introduction of the exocyclic double bond, reduction of ketone 91, bromination of alcohols 51a and b, and elimination under basic conditions followed.

scheme 6

Scheme 6

The total synthesis of the antitumor diterpenoid (+)-zerumin B (34) that was based on metabolite 77 was reported [61, 62]. The first step involved regioselective formation of the 𝛼-substituted γ-hydroxybutenolide moiety, which included [1, 4] O → C migration of the triisopropylsilyl group in 92a or b (obtained from pure alcohols 51a or b) and subsequent oxidation by singlet oxygen of substituted 2-triisopropylsilyl-3-(𝛼-hydroxy)alkylfurans 93a and b (Scheme 7) [61]. The resulting silyl esters 94a and b were hydrolyzed in situ to the corresponding γ-hydroxybutenolides (+)-zerumin B (34) and (+)-12-epizerumin B (95). A diastereo-divergent synthesis of zerumin (34) and its 12-epimer 95 using the reaction of aldehyde 50 with 2-isopropylsiloxy-3-lithio- or 2-isopropylsiloxy-3-[tri(isopropyloxy)titanium]furans (96a and b) as the key step was described [62]. The reaction of 50 with 96a in THF produced a mixture of 93a and b, from which 12(S)-isomer 93a was easily isolated (65 % yield). Condensation of 50 with 96b gave primarily 12(R)-isomer 93b (72 % yield). Further oxidation by dimethyldioxirane in Me2CO and hydrolysis produced pure γ-hydroxybutenolides 34 or 95.

scheme 7

Scheme 7

Aldehyde 50 that was obtained from sclareolide was used successfully in the total synthesis of (+)-hedychialactone A (pacovatinin A, 31) (Scheme 8) [63]. Horner–Wadsworth–Emmons olefination of 50 led to a mixture of E- and Z-butyrolactones 97 and 98. Allylic oxidation of both compounds by SeO2 produced 7𝛼-hydroxylabdanoids 99 and 100. Sequential Swern oxidation of alcohols 99 and 100 and reduction of ketones 102 and 103, which exhibited significant cytotoxicity against five human tumor cell lines, was used to prepare 7𝛽-hydroxy-derivatives 31 or 101.

scheme 8

Scheme 8

Acuminolide (40) and 17-O-acetylacuminolide (41) were also synthesized from (+)-sclareolide (77) (Scheme 9) [64]. Diol 78 was converted into epoxide 104 using selective protection of the primary alcohol. Then, the furan ring was introduced (compounds 106a and b; 46 % and 32 % yields). Treatment of the (12S)-hydroxy-derivative (106a) with p-toluenesulfonic acid in nitromethane gave exclusively tricyclane 107a, reaction of which with singlet oxygen in the presence of base formed epimeric hydroxybutenolides acuminolide (40) and 15-epi-acuminolide (108a) (70:30 ratio). 17-O-Acetylacuminolide (41) was obtained from 107a according to a scheme including acylation at the C-17 position and reaction of 107b with singlet oxygen. Metabolite 41 was formed in a mixture with 16-epi-17-O-acetylacuminolide (108b) (66:34 ratio) [64].

scheme 9

Scheme 9

Larixol in the Synthesis of Labdane Diterpenoids. Larixol (109) is an available sap constituent of various larch species. The syntheses of furanoditerpenoids hedychenone (9) and yunnancoronarin A (21) that are substituted in ring B were described [65]. Epoxidation of larixol (109) using oxone led to 8,17-epoxide 110 that was smoothly reduced to triol 111. Oxidation of 111 by an excess of sodium periodate in the presence of a catalytic amount of osmium oxide gave a mixture of aldehydes 112 and 113a and b. Elimination of the acetoxy group from the triethylsiloxyaldehyde that was formed in situ from 112 produced decaline aldehyde 114 with an exomethylene double bond (Scheme 10), reaction of which with 3-lithiofuran and dehydration of the resulting mixture of alcohols gave furanolabdanoid 115, which was transformed into ketone 116. Isomerization of the endocyclic double bond produced metabolite 9 (22 % overall yield from 109), from which metabolite 21 was obtained.

scheme 10

Scheme 10

Other Terpenoids in the Synthesis of Furanolabdanoids. Many studies were focused on the development of preparation methods for key optically active bicyclic aldehydes suitable for further coupling reactions with furan derivatives. Thus, an effective synthesis of aldehyde 50 and correspondingly (+)-coronarin E (20) from (+)-manool (117) was described [66]. The available drimane-type diterpenoid (±)-albicanol was used as the starting material for synthesizing (+)-coronarin A (14), (+)-coronarin E (20), and austrochaparol (16) [67]. (+)-Albicanol (118) (prepared by lipase cleavage of the racemate) was oxidized by Dess–Martin periodinane to aldehyde 119. Olefination of the aldehyde by 𝛽-furylmethylheteroaromatic sulfone 120 or 121 according to Julia produced a mixture of (+)-trans-coronarin E (20, 11 %) and (+)-cis-coronarin E (122, 77 %) (Scheme 11), which were hydrogenated to (+)-15,16-epoxy-8,13,14-labdatriene (123) (isolated from the marine sponge Cacospongia sp. [68]). Allylic oxidation of 123 produced metabolite 16. Allylic oxidation of 20 led to alcohol 124, from which metabolite 12 was obtained.

scheme 11

Scheme 11

The synthesis of methyl lambertianate (2) from the methyl ester of agatic acid (126) and metabolite 1 from podocarpic acid (127) was reported (Scheme 12) [69, 70].

scheme 12

Scheme 12

The use of C–C bond-forming reactions of trans-decaline-type ketones with organolithium compounds was proposed for the synthesis of labdanoids substituted in ring B. Such ketones included 11-nordrim-7-en-9-one (128), which was easily obtained from (R)-carvone (129) [31]. Scheme 13 shows that ketone 128 was used in the synthesis of hispanone (15). Reaction of 128 with 3-(2-lithioethyl)furan gave coupling product 130, rearrangement and oxidation of which produced (+)-hispanone (15) that was identical to the natural compound.

scheme 13

Scheme 13

Transformations of Furanolabdanoids. Synthesis of Natural Metabolites from Furanolabdanoids. A structural analysis of furanolabdanoids and the availability of several metabolites led to the conclusion that their synthetic transformations were promising for preparing compounds that were structurally analogous to several natural metabolites and other practically valuable compounds. Thus, treatment of methyl lambertianate (2) with acid formed methyl spongia-13(16),14-dien-18-oate (131) (Scheme 14) [71].

scheme 14

Scheme 14

Lambertianic acid (1) isomerized smoothly through the action of p-toluenesulfonic acid in refluxing benzene to phlomisoic acid (132), the aglycon of plant glycosides 45–47 (Scheme 14) [72]. Methyl lambertianate (2) underwent an analogous transformation to form 133 [73].

A practical synthesis of the diterpenoid pinusolide (4) (Scheme 14) that included oxidative methoxylation of 2 by chloramine B [or N-bromosuccinimide (NBS)] and subsequent treatment of diterpenoid 2,5-dimethoxydihydrofurans 134 with HCl was described [18].

The synthesis of the valuable diterpenoid prehispanolone (30) from hispanolone (14) was reported (Scheme 15) [74]. Regioselective deprotonation and silylation of protected prehispanolone 135 produced trimethylsilyl derivative 136, from which butenolide 137 was obtained. Intramolecular addition gave a mixture of 13(R)- and 13(S)-diastereomers (–)-138a and (+)-138b (1:1 ratio). Reduction of (–)-138a gave lactol 139 and then thioacetal 140. Its oxidation into sulfoxides 141 and removal of the benzenesulfonyl group afforded (–)-prehispanolone (30).

scheme 15

Scheme 15

The transformation of coronarin E (20) into natural antioxidants [75, 76] chinensines A–E (142–146) was investigated [60]. Silylation of 20 formed regioisomers 147 and 148 (3:1) (Scheme 16). Cycloaddition of singlet oxygen gave chinensines A and B (142 and 143). Reduction of 142 produced villosin (26), subsequent reduction of which led to chinensine C (144). [4 + 2]-Cycloaddition of singlet oxygen to lactol 144 synthesized 145 and 146

scheme 16

Scheme 16

Synthetic Transformations of Furanolabdanoids. We examined transformations of native metabolites that occurred mainly with retention of the labdanoid structure without including [4 + 2]-cycloaddition reactions of the furan moiety.

Modification of Furanolabdanoids on the Decaline Skeleton. The significant pharmacological activity of furanolabdanoids substituted in ring B stimulated interest in the corresponding modifications. Transformations in ring B were studied with respect to lambertianic acid (1), its ester (2), pinusolide (4), and hispanolone (14). The preparation of 9-𝛼-cyanoderivatives of labdanoids 149–151 from 14 [77] included treatment with a catalytic amount of I2 to give hispanone (15) [29]. Acetoxylation of 15 formed a mixture of epimeric 6-acetoxy-derivatives 152a and b (5:2), treatment of which with KCN gave Michael reaction products 149 (45 %) and 150 (9 %) (Scheme 17). Compounds 149 and 150 and reduction product 151 showed significant growth inhibition of pathogenic plant fungi [77].

scheme 17

Scheme 17

Scheme 17 A series of oxygen-containing derivatives of labdanoids 1 and 2 that became the subjects of further structural transformations were synthesized by an assortment of oxidants that affected selectively the exomethylene double bond. Hydroxylation of 1 by KMnO4 in basic solution produced a mixture of 8,17-dihydroxy acid 153 (59 %) and 8,12-epoxy acid 154 (5.5 %) (Scheme 18) [78]. Periodate oxidation of 153 gave hydroxyaldehyde 155, acid treatment of which (through a ketoacid step) afforded phenanthro[1,2-b]furan 156, a structural analog of furanoabietanes, which occur among the active principles of Tanshen, a Chinese-medicine cardioactive agent [79].

scheme 18

Scheme 18

Oxidation of methyl lambertianate (2) by KMnO4 under interphase catalysis conditions formed ketone 157 (21 %), 8𝛼,12𝛼-epoxylabdanoid 158a (39 %), and its 12-diastereomer 158b (11 %) (Scheme 19) [80, 81].

scheme 19

Scheme 19

Diterpene alkaloids of the new structural types 159 and 160 were synthesized by transformation of 157 and 158a (Scheme 20). Reductive amination by methylamine of ketone 157 led to a mixture of 17-nor-8𝛼-methylaminolabdanoid 161 and alcohol 162. Intramolecular Mannich aminomethylation of diterpenoid amine 161 using formaldehyde produced furobenzazocine derivative 159. Transformation of labdanoid 158a into furobenzazocine 160 included its oxidation into aldehyde 163, reductive amination into amine 164, and a Mannich reaction [81].

scheme 20

Scheme 20

Derivatives and analogs of pinusolide (4) (primarily functionalized on ring B) were synthesized [17]. Data on the in vitro inhibitory activity against TAF were obtained. Epoxidation or hydroxylation of the exomethylene double bond and isomerization of the ring B double bond did not increase the inhibitory activity. 17-Nor-8-oxopinusolide showed the greatest activity (IC50 of 0.25 μM) that was comparable with that of 4.

Modification of Furanolabdanoids in the Furan Ring. Formylation of methyl lambertianate (2) under Vilsmeier–Haack reaction conditions formed 16-formyl- and 15-formyllabdatrienoates 165 and 166 (10:1, 77 % yield) (Scheme 21) [82]. Formylation of 133 produced tetracyclic isospongiane-type diterpenoid 169 [83] in addition to formyllabdatrienes 167 and 168 (79 and 8 % yields).

scheme 21

Scheme 21

Treatment of methyl 16-formyllambertianate (165) with ammoniacal I2 in THF led smoothly to 16-cyanolabdatriene 170 (Scheme 22), reaction of which with the zinc enolate of ethylbromoacetate produced enaminoester 171, which was hydrolyzed to 𝛽-ketoester 172 [84].

scheme 22

Scheme 22

16-Cyanolabdatriene 170 was used to develop a route to 16-(1,2,4-oxadiazol-3-yl)-15,16-epoxylabdatrienoates 173a–c (through amidooxime 174) (Scheme 22). The products showed high cytotoxicity against human tumor cells (CCID50 of 0.08 μM) [85].

The aminomethyl substituents in the furan rings of metabolites 1 and 2 were introduced in several ways. These included reduction of the oxime of methyl 16-formyllambertianate (175) [86], reductive amination of methyl 16-formyllambertianate (165), or Mannich aminomethylation of methyl lambertianate (2) [87]. Oximation of 165 occurred quantitatively to give pure (E)-oxime 175, reduction of which led to methyl 16-aminomethyllambertianate 176 (97 % yield) (Scheme 23). Reductive amination of aldehyde 165 by benzylamine and amino-acid derivatives afforded aminomethyl derivatives 177 [87]. Amides of labdanoids that were prepared via condensation of amine 176 with N-Boc-protected of ω-amino acids exhibited high cytotoxicity in CEM-13, MT-4, and U-937 tumor models (CCID50 values of the most active compounds were 3.9–9.9 μM). Derivatives of 177 were used for further transformations [73].

scheme 23

Scheme 23

Hybrid structures with a tetrahydro-𝛽-carboline group were synthesized from methyl 16-formyllambertianate (165) (Scheme 23) [88, 89]. The Pictet—Spengler reaction was used as the synthetic tool. The synthesis included reductive amination by tryptamine of aldehyde 165 to give indoloterpenoid 178 and subsequent condensation with formaldehyde to form𝛽-carboline 179.

An Erlenmeyer reaction of diterpene aldehyde 165 with an acid group formed labdanoid 5(4H)-oxazolone 180 (76 % yield) as the pure isomer with the Z-configuration of the double bond (Scheme 24) [90]. Condensation of azlactone 180 with amines or 𝛼-amino-acid esters (leucine and isoleucine) synthesized 4-substituted carbamoylvinylbenzamides 181 (69–91 % yields) or esters of terpenoid 2-benzoylaminoacryloylamino acids 182 (62–78 % yields). Hydrolysis of 180 produced 𝛼-acylamino acid 183. 16-Carbamoylvinylbenzamides 181 acted as correctors for cytostatic polychemotherapy [91].

scheme 24

Scheme 24

Labdanoid alkynes 184, 185a and b, and 186a and b were synthesized (Scheme 25) [92, 93]. Their Cu(I)-catalyzed 1,3-dipolar cycloaddition reactions with mono- and diazides were investigated. The reaction of alkynes 185a and b with benzylazide formed a mixture of diastereomeric labdatrienes 187a and b. Oxidation of the stereoisomeric alcohols by Dess– Martin periodinane produced 1′-keto-derivative 188 (65 % yield). Dehydration of 187a and b led to E-triazolylvinyllabdanoid 189 (49 % yield). Alkynes 184, 185a and b, and 186a and b and triazolyl-substituted labdanoids were significantly cytotoxic in CEM-13, MT-4, and U-937 human tumor cell models (CCID50 of the most active compound 188 was 7–12 μM) [93].

scheme 25

Scheme 25

Oxidative coupling of methyl phlomisoate (133) with terminal olefins synthesized 16-alkenyl-substituted labdatrienes (Scheme 26) [94]. The Pd(OAc)2–Cu(OAc)2-catalyzed reaction of 133 with styrene in the presence of benzoquinone in a mixture of propionic acid and ether did not stop at the singly coupled products but proceeded to the formation of 15,16-distyryl-derivative 190. The reaction time had to be increased to 80 h for complete reaction of 133 with methylacrylate. The ratio of formed products 191, 192, 193 changed with time. The values were 6:8:1, respectively, after 10 h; 2:1:1, after 30 h [94].

scheme 26

Scheme 26

An approach to the preparation of diterpenoid pyrrolidin-2-ones was proposed (Scheme 27) [95]. Treatment of methyl lambertianate (2) with lead tetraacetate gave stereoisomeric 2,5-diacetyldihydrofurans 194, reaction of which with primary amines or o-phenylenediamine produced (5H)-pyrrol-2-ones 195.

scheme 27

Scheme 27

Diterpene analogs of levetiracetam were synthesized because of the significant interest directed at 1,3-disubstituted (5H)-pyrrol-2-ones as antiepileptic agents (Scheme 27) [96]. Oxidative methoxylation products 134 of methyl lambertianate were used as starting materials (Scheme 14). The reaction of 134 with glycine or 𝛼-aminobutyric acid gave labdanoid N-(1-carboxymethyl)- (196) or N-(1-carboxypropyl)-(5H)-pyrrol-5-ones (197), treatment of which with trimethylchlorosilane in MeOH and subsequent (without isolation) reaction with ammonia afforded corresponding amides 198 or 199 (Scheme 27). The overall yields of the terpenoid 2-(2-oxo-2,5-dihydropyrrol-1-yl)acetamides calculated for methyl lambertianate (2) were 48 % and 42 %, respectively. Hydrogenation of 198 and 199 was accompanied by reduction of the exomethylene double bond in the terpene skeleton and formed epimeric 2-(2-oxopyrrolidin-1-yl)acetamides 200a and b or 201a and b. Compounds 198, 199, and 200a were patented as anticonvulsants [97, 98]. Analgesic activity was found for 200a [98].

Intramolecular photochemical [2 + 2]-cycloaddition involving the furan ring and the exomethylene double bond of 2 was described [99, 100]. The main reaction product was pentacyclic oxide 202. As it turned out, the reaction was reversible. The degree of conversion of 2 depended on the solvent and varied in the order hexane < MeCN (0.4 %) < C6H6 (10 %) < Me2CO (35 %). Irradiation of 2 in Me2CO by a high-pressure Hg lamp formed an equilibrium mixture of four compounds, i.e., oxide 202, dioxide 203, [2 + 2]-cycloaddition product of 2 to Me2CO 204, and starting 2 in a 1:0.8:0.7:8 ratio. Irradiation of 202 in Me2CO gave dioxide 203, which was a stable compound. Irradiation of methyl 16-formyllambertianate (165) in a mixture of hexane and Et2O gave 205 (22.5 % yield) (Scheme 28) [82].

scheme 28

Scheme 28

[2 + 2]-Cycloaddition of furanolabdanoid 206 with a C-12 ketone formed a mixture of regioisomeric pentacyclanes 207 and 208 [101].

Photochemical transformations of hispanolone (14) resulted in the formation of -lactone 209 (60 % yield) [102].

This transformation is a rare example of photochemical transformations of 𝛽-hydroxyketones into -lactones. The structure of 209 was proved by converting it to reduction product 210 (Scheme 28). In conclusion, it is noteworthy that the presented information indicated that research on plant furanolabdanoids is highly promising. New sources of furanoditerpenoids are being discovered. These include woody (various Pinus species, plants of the species Biota orientalis), bushy (Phlomis spp., Renealmia spp., and Eremostachys spp.), and herbaceous plants [ginger, horehound, turmeric, goldenrod, galangal (Alpinia), and ginger lily (Hedychium)]

Studies of the biological activity of furanolabdanoids are expanding. Selective inhibitors of NO production (that inhibit induction of iNOS in macrophages activated by lipopolysaccharide), TAF antagonists, 𝛼-glucosidase inhibitors, and cytotoxic agents were found among such metabolites in the last decade.

The valuable pharmacological properties of these diterpene metabolites stimulated great interest in the development of their total syntheses. The starting materials have been primarily available diterpenoids such as sclareol, sclareolide, and larixol. Effective methods for preparing several valuable metabolites such as pinusolide, villosin, acuminolide, and hedychenone were proposed.

Modified derivatives of lambertianic acid, hedychenone, and coronarins A and E are highly interesting in the discovery of new agents with high biological activity and for solving problems of synthetic organic chemistry.