Communic acids: occurrence, properties and use as chirons for the synthesis of bioactive compounds.

Communic acids are diterpenes with labdane skeletons found in many plant species, mainly conifers, predominating in the genus Juniperus (fam. Cupresaceae). In this review we briefly describe their distribution and different biological activities (anti- bacterial, antitumoral, hypolipidemic, relaxing smooth muscle, etc.). This paper also includes a detailed explanation of their use as chiral building blocks for the synthesis of bioactive natural products. Among other uses, communic acids have proven useful as chirons for the synthesis of quassinoids (formal), abietane antioxidants, ambrox and other perfume fixatives, podolactone herbicides, etc., featuring shorter and more efficient processes.

1. Introduction

Communic acids are a group of diterpenic natural products [1,2,3,4] with a labdane skeleton containing three double bonds and a carboxyl group at position 19 (Figure 1). Five communic acids have been described to date that differ in the location of the double bonds and the orientation of the carboxyl group: trans-communic acid (1) with the double bonds located in positions 8(17), 12 and 14, with Δ12 double bond E stereochemistry, and axial carboxyl group orientation, cis-communic acid (2) the Z isomer of the former, mirceocommunic acid (3), also named isocommunic acid, regioisomer of the former, where the Δ12 double bond moves to Δ13(16), 4-epi-trans-communic acid (4), a C4 epimer of 1 and ent-trans-communic acid (5) is the (−) enantiomer of 1. Of these, the most abundant in Nature is 1.

Figure 1

Structure of the communic acids.

2. Sources

Communic acids are widely distributed in Cupresaceae species, especially in the genus Juniperus. Although there are species that contain several of them, the most common case is the presence of only one. A tertiary mixture of 1–3 is found in Juniperus nana Willd. [5], J. communis [6] and J. oxycedrus [7]. A binary mixture of 1–2 is found in J. chinensis Linn [8,9,10], J. phoenicea [11], J. thurifera var. africana [11], J. foetidissima [12], J. sabina [13], Cryptomeria japonica [14], Platycladus orientalis [15], Sabina vulgaris [16], Podocarups imbricatus BI [17], Agathis vitiensis, A. macrophylla and A. lanceolata [18], Thuja occidentalis L. [19], and Hermas villosa [20] whereas a mixture of 3–4 is found in J. excelsa [21]. Trans-communic acid (1) was isolated from Entada abyssinica [22], Thujopsis dolabrata [23,24,25], Pinus luchuensis [26], Chamaecyparis obtusa Endl. [27,28,29], Thuja standishii [30,31], Araucaria angustifolia [32], Chamaecyparis formosensis [33], Porella navicularis [34], J. oxycedrus [35], J. drupaceae Labill [36], Sciadopitys verticillata [37], Fritillaria thunbergii [38], Cunninghamia unicanaliculata var. pyramidalis [39], Chromolaena collina [40], Cupressus sempervirens [41,42], J. communis [43], Chloranthus spicatus [44], Sabina vulgaris Antoine [45], Torreya jackii [46], Dacrydium pierrei [47], J. phoenicea [48], Calocedrus formosana [49], Fleischmannia multinervis [50], Cretan propolis [51], Libocedrus chevalieri [52], Pinus densiflora [53], and Mikania aff. jeffreyi [54], Chamaecyparis lawsoniana [55]. Cis-communic acid (2) was detected in Larix dahurica [56], Pseudotsuga wilsoniana [57], and Cladonia rangiferina L. Web. [58].

Myrceocommunic acid (3) was isolated from Juniperus oxycedrus [59]. Moreover the main component of diterpene acids in Cunninghamia lanceolata (Lamb.) Hook was 4-epi-trans-communic acid (5) [60]. Additionally polymers of 1 and of their derivatives have been found in resins of different Agathis species [61,62] and in sandarac resin [63].

Although these acids have been isolated from different parts of the plant (fruits, wood, bark, leaves, roots, etc.), they are mainly founded in leaves, fruits, and bark.

3. Biological Activity

The three communic acids 1–3 exhibited strong cytotoxic activity in a brine shrimp bioassay (LD50 0.16 μg/mL) [46]. Trans-communic acid (1) and cis-communic acid (2) and plant extracts containing them were also active against different microorganisms such as Staphylococcus aureus, both standard ATCC strain and clinical isolates [55,64,65,66,67,68,69], S. epidermidis ATCC 12228 [70], Aspergillus fumigatus and Candida albicans [62]. Moreover, both acids have shown cytotoxic activity against BSC-1 cells [71]. Other activities described for 1 are: antimycobacterial (Mycobacterium aurum, M. phlei, M. fortuitum and M. smegmatis) [72], antitumoral [35,73], relaxant [74], hypolipidemic [75], testosterone 5α-reductase inhibitory [76], anti-inflammatory and antioxidant [77].

4. Chemical Reactivity

Years ago, Pascual-Teresa et al. [78,79] described two studies based on the oxidation of the lateral chain of methyl esters of communic acids 1a–3a. First, the functionalization of the side chain by selective epoxidation [78], and later the singlet oxygen addition [79] was studied. In both cases the relative reactivity of the three double bonds was determined for each compound. Epoxidation of 1a and 2a with m-chloroperbenzoic acid mainly afforded a mixture of 12,13-epopxy derivatives 6–9 together with a mixture of 14- and 15-m-chlorobenzoates 10–11 (Figure 2). The epoxidation of 3a with mCPBA gave methyl (8R)-8,17-epoxy-8,17-dihydromirceocommunate (12, 5%) and methyl 13,16-epoxy-13,16-dihydromirceocommunate (13, 19%), recovering 24% yield of 3a. This result indicates greater reactivity at the trisubstituted double bond for 1a and 2a and terminal double bond on the side chain for 3a.

Figure 2

Structures of the products obtained by epoxidation and singlet oxygen oxidation of 1a–3a.

The singlet oxygen addition to 1a led principally to the 12-hydroxyderivatives 12R (15, 19%) and 12S (16, 5%) together with minor proportions of the 12,15-dioxyderivative 14 (6%) and the tertiary alcohol 17 (4%), whereas in the case of 3a afforded the only the 15,16-dioxyderivative 18 (12%).

Compound 1a preferably underwent ene-reactions of the singlet oxygen on the trisubstituted double bond with syn stereospecificity, in accordance the with point established by Schulte-Elte [80]. Thus, the reaction produced mainly alcohols 15–17 and a minor proportion of the 12,15-dioxyderivative 14, coming from a Diels-Alder reaction. In the case of methyl isocommunate 3a, which does not have trisubstituted double bond and where the monosubstituted dienic system adopts the cisoid conformation with relative ease, the reaction that takes place with singlet oxygen is the Diels-Alder cycloaddition, slowly yielding a small amount of 15,16-dioxyderivative 18 due to the tendency of 3a to polymerize.

Furthermore, another oxygenation procedure, i.e., the oxymercuration-demercuration (OM-DM) reaction of methyl esters of trans- and cis-communic acids (1a–2a) was studied [81,82,83]. Treatment of 1a with mercuric acetate (1:2) in THF/H2O and the subsequent reduction of mercurials with NaBH4 afforded compounds 19–22 (Scheme 1).

Scheme 1

OM-OD reaction for compound 1a. OD reaction with NaBH4.

Compound 19 is the product corresponding to the OM-DM at C14-C15 double bond. The formation mechanism of compounds 20, 21 is shown in Scheme 2. The formation of tetrahydrofuran derivatives 20–21 from 1acan be explained by two routes, both converging at intermediate A and evolving to 20, 21via radical processes. In the first route, A results from the formation of mercurinium ion on the 14,15 double bond, followed by 1,4 addition of water at C12, and heterocyclization by attack of the hydroxy group on the other mercurinium ion formed on the 8,17 double bond. In a second possible route, A is obtained by the hydration of the 8,17 double bond on the β face, followed by attack of the hydroxy group on carbon C12 on the mercurinium ion of the monosubstituted double bond. Both routes converge at the organomercurial A, whose reduction with NaBH4 in basic medium leads to the formation of a bis-radical intermediate, that by direct cyclization between carbons C13 and C17 originates 20, and by reaction with atmospheric oxygen leads to 21.

Scheme 2

Mechanism of formation of compounds 20, 21.

When the OM-OD reaction of compound 1a was carried out using Na(Hg) as the demercuriating agent (Scheme 3), the products obtained were 19, 23–24 and there was no evidence of the formation of either pimarane 20 or endoperoxide 21. That is due to the fast reduction of the intermediate radicals coming from the corresponding type A organomercurials by sodium amalgam (Scheme 3).

Scheme 3

OM-OD reaction for compound 1a. OD reaction with Na(Hg).

Another interesting reaction from the synthetic point of view is the oxidative degradation of the C12,C13 double bond of either cis-, trans-communic acids or their methyl esters. This transformation opens the possibility of using them in the preparation of bioactive molecules. In order to find appropriate experimental conditions for regioselective oxidative cleavage of the C12,C13 double bond in presence of the 8(17) and 14,15 ones, two methods of double bond cleavage were tried on 1a–2a: Ozonolysis and OsO4/NaIO4 treatment [84,85]. First, ozonolysis of 1a was performed under different conditions, such as type of solvent (hexane, methanol, CH2Cl2), temperature (room temperature, 0 °C, −78 °C) and different ozone stream flows. Better selectivity towards the C12,C13 double bond degradation was observed when the reaction was carried out at −78 °C in CH2Cl2 yielding aldehyde-esters 25 and 26 (Scheme 4). The ozonolysis of isomer 2a under the same conditions also led to preferential attack on the C12,C13 double bond giving rise to the same products (Scheme 4).

Scheme 4

Ozonolysis of 1a–2a.

The outcome of the reaction of 1a–2a with OsO4/NaIO4 is, however, strongly dependent on experimental conditions. Thus, when the temperature was kept at 0 °C to 10 °C, only 26 was detected, whereas mixtures of 25 and 26 were isolated when the temperature was 25 °C or higher (Scheme 5).

Scheme 5

Oxidation of 1a–2a with OsO4/NaIO4.

5. Use of Communic Acids as Starting Materials for the Synthesis of Compounds of High Added Value

Communic acids 1–3 possess a labdane diterpene structure functionalised with a carboxylic group at C19, an exocyclic methylene at C8,C17 and a side chain dienic system appropriate for the preparation of a great variety of bioactive terpenoids, such as perfume fixatives [ambrox (30) and ambracetal (40)], antitumoral quassinoids [bruceantin (52)], antifungal podolactones [nagilactone F (63) and oidiolactone C (69)], and abietanes [19-hydroxyferruginol (76) a target for tolerance after transplant and in autoimmune diseases], and sugikurojin (80)] (Scheme 6).

Scheme 6

Compounds synthesized from communic acids 1–3.

Ambrox (30) and ambracetal (40) are perfume fixatives with a powerful amber-type aroma. Their syntheses were carried out alternatively from methyltrans-communate (1a) or methyl cis-communate (2a) or a mixture of the two [86,87]. Two different routes to ambrox from 1a/2a are showed in Scheme 7 and Scheme 8. The key steps of these syntheses are selective degradation of the side chains, stereoselective formation of the tetrahydrofuran ring and reduction of the axial methoxycarbonyl group. In the first synthesis the transformation of 1a and/or 2a to aldehyde 25 was done using two different methods: (a) carefully controlled ozonolysis of 1a and/or 2a at low temperature or (b) Δ14 selective hydrogenation with diimide, followed by a C12–C13 degradation of the resulting 14,15-hydrogenated derivative with OsO4/NaIO4. Oxidation of 25 with Jones reagent followed of cyclization with p-TsOH in toluene at reflux stereoselectively yielded the γ-lactone 27 with the most stable cis interannular linkage. Its reduction with LiAlH4 followed by kinetically controlled cyclization with p-TsOH/CH3NO2 at room temperature gave the tetrahydrofurane derivative 28 with the suitable trans stereochemistry. The conversion of the hindered methoxycarbonyl group into the methyl group was carried out in three steps by reduction of ester 28, oxidation of the resulting alcohol to aldehyde 33 and finally reduction under Huang-Minlon conditions led to the target 30 (Scheme 7).

Scheme 7

Synthesis of ambrox 30.

Scheme 8

Synthesis of ambrox.

In the second route hydroxyolefin 31, obtained by reductive ozonolysis from 1a/2a, was treated with p-TsOH in CH3NO2 at room temperature and subsequently with LiAlH4 to give the alcohol 33. Oxidation of 33 with Jones reagent led to the aldehyde 29 whose reduction under Huang Minlon conditions yielded ambrox (30). This route was improved and shortened by direct conversion of 1a/2a into diol 32 by reductive ozonolysis followed of cyclization with p-TsOH in CH3NO2 to yield the alcohol 33 (Scheme 8).

Mixtures of 1–3 from Juniperus communis fruits are of great interest because they are byproducts of gin manufacturing. Scheme 8 and Scheme 9 show the syntheses of ambrox and ambracetal from a mixture of methyl esters of 1–3. The key intermediate in both processes is methyl ketone 34. This compound was obtained efficiently by a chemoselective reduction of the dienic system of a mixture of 1a–3a with Na/t-BuOH at room temperature and subsequent oxidation with OsO4/NaIO4. The transformation of 34 to trihydroxy derivative 35 was carried out by stereoselective epoxidation with m-CPBA at room temperature followed by reduction with LiAlH4 in THF at reflux. Stereo-selective cyclization of 35 with p-TsOH/CH3NO2 at room temperature led to 36, which was transformed in ambrox 30 following the experimental procedure outlined in Scheme 7.

Scheme 9

Synthesis of ambrox.

For ambracetal (40) synthesis, treatment of methyl ketone 34 with a catalytic amount of OsO4 in a refluxing mixture of t-BuOH/pyridine/H2O and trimethylamine oxide as co-oxidant, afforded the tetracyclic ester 37 (Scheme 10). Conversion of the methoxycarbonyl group into the methyl group was carried out as shown in Scheme 6.

Scheme 10

Synthesis of ambracetal.

An approach to compound 51, an intermediate in the synthesis of the antitumor agent bruceantin (52) has been developed from the communic acids 1–3 (Scheme 11 and Scheme 12) [88] via the methyl ketone 34.

Scheme 11

Synthesis of the tetracyclic intermediate 45.

Scheme 12

Synthesis of the intermediate 51 (precursor of bruceantin 52).

Allylic oxidation of 34 at C7 with SeO2 at 60 °C and subsequent protection of the alcohol obtained with TBSCl yielded keto-ester 37 with high stereoselectivity. Subsequent condensation of the kinetic enolate of 41 with glyoxal dimethylacetal followed by mesylation and elimination with DBU led to the α,β-unsaturated ketone 42. Chemoselective reduction of 42 with Raney nickel and subsequent ozonolysis afforded diketone 43. At this point, an intramolecular aldol condensation gave the tricyclic ketone 44, whose hydrocyanation with potassium cyanide, diethylaluminium cyanide and 18-crown-6 ether led with high stereoselectivity to an epimer mixture of acetals (45a–b) (6:1) (Scheme 11). Isomer 45a was used to complete the synthetic sequence (Scheme 11). Thus, reduction of 45a, first with DIBAL and then with NaBH4 afforded the diol 47, which was acetylated yielding 48. Exposure of 48 to thiophenol and boron trifluoride etherate in CH2Cl2 at room temperature yielded thioacetal 49. This compound was obtained as an epimeric mixture and the thioether groups were sequentially removed with mercury (II) chloride and mercury oxide in acetonitrile/methanol (1:1) at room temperature. Compound 51 was finally obtained as an epimer mixture after reductive desulfurization of 50 using nickel boride (Scheme 12).

Podolactones are nor-or bisnorditerpenic compounds isolated mainly from different plants of the genus Podocarpus (family Podocarpaceae) [89], and filamentous fungi (Oidodendrum truncatum [90], Aspergillus wentii [91], and Acrostalamus sp. [92]). These molecules present a wide range of biological activity, including antitumoral, insecticidal, antifeedant, allelopathic, and fungicidal activities, special attention being paid to their the antifungal activity. In this regard, LL-Z1271α (62) and oidolactone C (69) exhibited potent antifungal activities [93,94].

Considering their interesting properties, the podolactones nagilactone F (63) and LL-Z1271α (62) have been synthesized from a mixture of 1, 2 (Scheme 13 and Scheme 14) [95]. Now the key steps are a δ-lactonization in order to form the C ring, γ-lactonization and finally 14-hydroxylation.

Scheme 13

Synthesis of nagilactone F, LL-Z1271γ and LL-Z1271α.

Scheme 14

Synthesis of nagilactone F, LL-Z1271γ and LL-Z1271α.

The synthesis begins with the degradation of the side chain of the acids 1,2 by a different procedure to those previously described. Thus, oxidation with m-CPBA of the starting material and subsequent treatment of the crude product with HIO4 led to the aldehyde 25 with good yield (73%). Compound 25 was better obtained by potassium permanganate oxidation and subsequent periodic degradation (80%). Oxidation of 25 to a carboxylic acid and esterification with CH2N2 followed by treatment with mercuric acetate (2.0 equiv.) in toluene at reflux gave the derivative 53 as an 8:1 mixture (Δ8:Δ7). This mixture was reduced with NaBH4/DMF in the presence of an excess of bubbling O2, producing lactone 54 (75%), dienolide 55 (15%) and the starting product 56 (5%). This mixture was dehydrogenated with DDQ and PTSA to give an 8:3:1 mixture of 57–59.

The methyl ester 57 was hydrolyzed almost quantitatively with concentrated sulphuric acid to obtain the acid 60. The treatment of 60 with lead tetraacetate under argon atmosphere and ten with SeO2 led to the δ-hydroxylactone 61 permitting firstly γ-lactone closure and subsequently allylic oxidation at C14. Then the antibiotic LL-Z1271α (62) was prepared by treatment of 61 with methanol acidified with a drop of sulphuric acid. Moreover, treatment of 61 with isopropylmagnesium bromide at 0 °C yielded 83% of condensation products, being the most of the α isomer (90%), nagilactone F (63).

Related with the above-mentioned podolactone syntheses, the first synthesis of the antifungal oidiolactone C (69) was carried out from trans-communic acid (1) (Scheme 14) [96,97]. The key step of the synthesis is a new bislactonization reaction catalyzed by Pd(II), giving rise to the podolactone-type tetracyclic skeleton from a norlabdadienedioic acid. This synthetic scheme was also used by the authors to improve podolactone LL-Z1271α synthesis.

The selective ozonolysis of 1 and subsequent oxidation with Jones reagent, double esterification with diazomethane and allylic oxidation with SeO2/t-BuOOH yielded 36% of the hydroxydiester 64. Elimination of the trifluoroacetate of 64 with Pd(PPh3)4 led to diene 56, whose hydrolysis with sodium propanethiolate afforded diacid 65. Two different procedures were employed to carry out the double lactonization. First, the selective methylation of the carboxyl group at C12 with MeOH in the presence of 1,1′-carbonyldiimidazole and then iodolactonization under Barrett’s conditions after strict deoxygenation of the reaction medium furnished the iodo derivative 67 (80% yield) along with a 20% yield of dilactone 66. Iodo derivative 67 was exclusively converted in dilactone 66 by reaction with AgNO3/H2O/acetone (84% yield). Dilactone 66 was directly obtained from diacid 65 through a novel dilactonization process by treatment with substoichiometric Pd(II) (25%) and p-benzoquinone in a mixture of acetic acid and acetone as solvent (56%). The 9,11 double bond in diene-dilactone 68 was obtained, via the corresponding lithium enolate of 66 after adding phenylselenenyl chloride, and oxidation of the 11α-phenylseleno derivative to corresponding selenoxide by hydrogen peroxide with concomitant syn-elimination. Treatment of 68 with dimethyldioxirane afforded the natural oidiolactone C (69). Additionally, 62 was prepared by allylic oxidation as indicated in Scheme 15.

Scheme 15

Synthesis of oidiolactone C and LL-Z1271α.

Synthesis of the phenol abietane diterpenes 19-hydroxyferruginol (76), isolated from Podocarpus ferrugineus [98], and sugikurojin A (80), isolated from Cryptomeria japonica [99], from trans-communic acid (1) is shown in Scheme 16 and Scheme 17, respectively [100]. The key steps of these procedures are the side chain degradation and the elaboration of the aromatic C ring by Mn(III) cyclization.

Scheme 16

Synthesis of 19-hydroxyferruginol (76).

Scheme 17

Synthesis of sugikurojin (80).

Epoxidation of ester 1a by mCPBA followed by treatment with HIO4 in THF led to aldehyde 25, whose treatment with MeMgBr and further oxidation with Jones reagent gave methylketone 71. Reaction of 71 with Me2CO3 and NaH in benzene afforded the β-ketoester 72. Treatment of 72 with Mn(OAc)3·2H2O (4.0 equiv.) and LiCl (3.0 equiv.) in Ac2O at 120 °C for 12 h led to the methyl O-acetyl salicylate 73 (74% yield). Transformation of 73 in abietane 74 was carried out by the addition of MeMgBr in excess. When this compound was treated with Et3SiH and CF3COOH was obtained silylether 75, whose treatment with LiAlH4 in THF at reflux afforded 19-hydroxyferruginol (76) (Scheme 16).

Heating of silylether 75 with Na2CrO4 and NaOAc in Ac2O-AcOH led to 7-oxoderivative 77. Compound 77 was refluxed with LiAlH4 in THF giving sugikurojin A (80). An alternative route to compound 80 from 75 involved the removal of the silyl group and further acetylation and oxidation to obtain ketone 79, which was then transformed into 80 (Scheme 17).

6. Conclusions

This paper reveals the occurrence of the communic acids in fam. Cupresaceae especially in genus Juniperus. Furthermore they constitute appropriate building blocks for the efficient preparation of interesting bioactive natural products as ambrox, nagilactone F, bruceantin, 19-hydroxyferruginol and others.