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.


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  12 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  12 double bond moves to  13 (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.  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.
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.
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 1a can be explained by two routes, both converging at intermediate A and evolving to 20, 21 via 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 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 NaBH 4 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. 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). 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 OsO 4 /NaIO 4 treatment [84,85]. First, ozonolysis of 1a was performed under different conditions, such as type of solvent (hexane, methanol, CH 2 Cl 2 ), 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 CH 2 Cl 2 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 OsO 4 /NaIO 4 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).
Ambrox (30) and ambracetal (40) are perfume fixatives with a powerful amber-type aroma. Their syntheses were carried out alternatively from methyl trans-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 Schemes 7 and 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)  14 selective hydrogenation with diimide, followed by a C12-C13 degradation of the resulting 14,15-hydrogenated derivative with OsO 4 /NaIO 4 . Oxidation of 25 with Jones reagent followed of cyclization with p-TsOH in toluene at reflux stereoselectively yielded the -lactone 27 with the most stable cis interannular linkage. Its reduction with LiAlH 4 followed by kinetically controlled cyclization with p-TsOH/CH 3 NO 2 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). In the second route hydroxyolefin 31, obtained by reductive ozonolysis from 1a/2a, was treated with p-TsOH in CH 3 NO 2 at room temperature and subsequently with LiAlH 4 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 CH 3 NO 2 to yield the alcohol 33 (Scheme 8).     Allylic oxidation of 34 at C7 with SeO 2 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 ,-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 NaBH 4 afforded the diol 47, which was acetylated yielding 48. Exposure of 48 to thiophenol and boron trifluoride etherate in CH 2 Cl 2 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).
Considering their interesting properties, the podolactones nagilactone F (63) and LL-Z1271 (62) have been synthesized from a mixture of 1, 2 (Schemes 13 and 14) [95]. Now the key steps are a -lactonization in order to form the C ring, -lactonization and finally 14-hydroxylation. 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 HIO 4 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 CH 2 N 2 followed by treatment with mercuric acetate (2.0 equiv.) in toluene at reflux gave the derivative 53 as an 8:1 mixture (    ). This mixture was reduced with NaBH 4 /DMF in the presence of an excess of bubbling O 2 , 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 SeO 2 led to the -hydroxylactone 61 permitting firstly -lactone closure and subsequently allylic oxidation at C14. Then the antibiotic LL-Z1271 (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  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 podolactonetype tetracyclic skeleton from a norlabdadienedioic acid. This synthetic scheme was also used by the authors to improve podolactone LL-Z1271 synthesis.   [98], and sugikurojin A (80), isolated from Cryptomeria japonica [99], from trans-communic acid (1) is shown in Schemes 16 and 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. Epoxidation of ester 1a by mCPBA followed by treatment with HIO 4 in THF led to aldehyde 25, whose treatment with MeMgBr and further oxidation with Jones reagent gave methylketone 71. Reaction of 71 with Me 2 CO 3 and NaH in benzene afforded the -ketoester 72. Treatment of 72 with Mn(OAc) 3 ·2H 2 O (4.0 equiv.) and LiCl (3.0 equiv.) in Ac 2 O 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 Et 3 SiH and CF 3 COOH was obtained silylether 75, whose treatment with LiAlH 4 in THF at reflux afforded 19-hydroxyferruginol (76) (Scheme 16).
Heating of silylether 75 with Na 2 CrO 4 and NaOAc in Ac 2 O-AcOH led to 7-oxoderivative 77. Compound 77 was refluxed with LiAlH 4 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).

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.