Aust. J. Chem., 1975,28, 2035-41

Synthesis of p-Orcinol meta-Depsides

John A. Elix and Susan Norfolk

Chemistry Department, Australian National University, P.O. Box 4, Canberra, A.C.T. 2600.

Abstract

The total syntheses of the lichen depsides, decarboxythamnolic, thamnolic, hypothamnolic and haemathamnolic acid are described.

p-Orcinol meta-depsides form a small group of lichen metabolites where the B-ring component1 comprises a p-orcinol nucleus which has undergone further oxidation (hydroxylation) and is linked at the 5'-position in depside formation. Thamnolic

acid (1) and hypothamnolic acid (2) are well known lichen metabolite^'^^ but haema- thamnolic acid (3)3 was only isolated in 1967 from the African lichen, Pertusaria rhodesiaca Vainio. The structure of this depside was established by examination of its spectroscopic properties and by degradative experiments.

Culberson, C. F., 'Chemical and Botanical Guide to Lichen Products' (University of North Carolina Press: Chapel Hill 1969); 'Supplement to Chemical and Botanical Guide to Lichen Products' Byrologist, 1970, 73, 177-377.

Asahina, Y., and Shibata, S., 'Chemistry of Lichen Substances' (Japanese Society for Promotion of Science: Tokyo 1954)

Harper, S. H., and Letcher, R. M., J. Chem. Soc., C, 1967, 1603.

3. A. Elix and S. Norfolk

In view of the ease with which thamnolic acid (1) decarboxylates4 it is difficult to ascertain whether the fourth member of this group, decarboxythamnolic acid (4), is a true metabolite or whether it is an artefact of the extraction or identification pro- ~edure . ' .~ Compound (4) has only been reported to occur together with thamnolic acid.

Due to the multiplicity of reactive functional groups in these depsides, they have not previously been synthesized. However, two of the corresponding methyl esters, dimethyl thamnolate and dimethyl hypothamnolate, have been prepared by the classical route to depsides.','

Discussion

The successful synthesis of these depsides was achieved by direct condensation of appropriately substituted aromatic carboxylic acids and phenols with trifluoroacetic anhydride. Potentially reactive phenol and carboxyl groups were protected by 0-benzylation. We and others have successfully employed this route previously in the synthesis of natural deps ide~ .~ - l~

The mononuclear precursors for these depsides were derived from various orcinol derivatives by straightforward procedures (Scheme 1). Thus transesterification of ethyl 4-benzyloxy-2-hydroxy-3,6-dimethylbenzoate'2 (5) and methyl 2-hydroxy-6- methoxy-4-methylbenzoate13 (6) in the presence of sodium benzyloxide and benzyl alcohol led to the formation of the corresponding benzyl esters (7) and (8). Benzyl haematommate (benzyl 3-formyl-2,4-dihydroxy-6-methylbenzoate) (10) was obtained from benzyl orsellinate12 (9) by formylation with titanium(1v) chloride and dichloro- methyl methyl ether. In a similar manner benzyl 2-hydroxy-6-methoxy-4-methyl- benzoate (8) was converted into benzyl 3-formyl-2-hydroxy-6-methoxy-4-methylben- zoate (1 I), this formylating reagent favouring attack ovtho to the phenolic hydroxyl group.14

Nuclear hydroxylation of the esters (7) and (10) with alkaline potassium per- sulphate solution led to the formation of benzyl 4-benzyloxy-2,5-dihydroxy-3,6- dimethylbeilzoate (12) and benzyl 3-formyl-2,4,5-trihydroxy-6-methylbenzoate (13) respectively. Benzyl 3-formyl-2-hydroxy-6-methoxy-4-methylbenzoate (1 1) was sub- sequently oxidized to give 3-benzyloxycarbonyl-2-hydroxy-4-methoxy-6-methyl- benzoic acid (14) by treatment with sodium chlorite, a reagent which is effective in oxidizing aromatic aldehydes to give the corresponding carboxylic acids in the presence of free phenolic

Asahina,Y., and Hiraiwa, M., Ber. Deut. Chem. Ges., 1939, 72, 1402. Asahina, Y., and Nuno, M., J. Jap. Bot., 1964, 39, 313. Bendz, G., Santesson, J., and Wachtmeister, C. A., Acta Chem. Scand., 1965, 19, 1250. Asahina, Y., Aoki, M., and Fuzikawa, F., Ber. Deut. Chem. Ges., 1941, 74, 824. Aghoramurthy, K., Seshadri, T. R., and Venkatasubramanian, G. B., Tetrahedron, 1957, 1, 310. Brown, C. J., Clark, D. E., Ollis, W. D., and Veal, P. L., Proc. Chem. Soc., 1960, 393.

lo Neelakantan, S., Padmasani, R., and Seshadri, T. R., Tetrahedron, 1965, 21, 3531. l1 Elix, J. A., Aust. J. Chem., 1974, 27, 1767. lZ Elix, J. A,, and Norfolk, S., Aust. J. Chem., 1975, 28, 399. l 3 Asahina, Y., and Ihora, S., Ber. Deut. Chem. Ges., 1929, 62, 1196. l4 Cresp, T. M., Sargent, M. V., Elix, J. A,, and Murphy, D. P. H., J. Chem. Soc., Perkin Trans. I , 1973, 340. l5 Lindgren, B. O., and Nilsson, T., Acta Chem. Scand., 1973, 27, 888.

Synthesis of p-Orcinol meta-Depsides

The preparation of 3-formyl-2-hydroxy-4-methoxy-6-methylbenoic acid (15) has been described previously.12

~ ~ 0 , ~ - OH- I

Depside ester formation between acid (15) and benzyl3-formyl-2,4,5-trihydroxy-6- methylbenzoate (13), and between the carboxylic acid (14) and the phenolic esters (12) and (13), was achieved by treatment with trifluoroacetic anhydride and yielded benzyl haemathamnolate (16), dibenzyl 4'-0-benzylhypothamnolate (17) and dibenzyl thamnolate (1 8), respectively. Hydrogenolysis of esters (16)-(18) over palladized

J. A. Elix and S. Norfolk

carbon produced the depsides haemathamnolic acid (3), hypothamnolic acid (2) and thamnolic acid (1) in high yield.

0 J&-~@:~~~~~ hfeo#~ro.,@co2cH2F%

Me0 OH HO PhCH20 OH

CHO CHO C02CH2Ph Me

(16) (17)

- +. XeO OH

OH HO OH

Me0

Scheme 2

Furthermore, thamnolic acid (1) was converted into decarboxythamnolic acid (4) according to the method of Asahina and Hiraiwaa4 The observed properties of these

Synthesis of j?-Orcinol meta-Depsides

synthetic compounds were consistent with those described in the literature for the natural metabolites.

Mass Spectra

Mass spectrometry is a highly sensitive and often diagnostic means of identifying lichen metabolite^.^^^^^,^^^^' As a result the fragmentation of this group of depsides under electron impact was of considerable interest.

Apart from decarboxythamnolic acid (4), the depsides did not exhibit molecular ions in the positive ion spectra. However, the acids (1)-(3) did exhibit peaks due to the corresponding decarboxy ions and moreover the actual fragmentations were indicative of the structure of the component A- and B-rings (Scheme 2).

Experimental P.m.r. spectra were recorded at 100 MHz on a Jeol JNM-MH-100 spectrometer and chemical

shifts were measured on the 6 scale relative to tetramethylsilane as an internal standard. Mass spectra were determined on a Varian MAT CH7 instrument operating at 70 eV. Melting points are uncorrected. Microanalyses were carried out by the A.N.U. Microanalytical Laboratory under the direction of Dr J. E. Fildes and Miss B. Stevenson. Preparative-layer chromatograms were carried out on thick-layer plates (100 cm by 20 cm by 0.1 cm) with silica gel (Merck PF2J4+366) as adsorbent. Bands were detected by exposure to short-wavelength ultraviolet light. Light petroleum refers to that fraction boiling between 60 and 80".

Ethyl 4-benzyloxy-2-hydroxy-3,6-dimethylbenzoate12 (9.7 g) was added to a solution prepared from sodium (0.15 g) and benzyl alcohol (90 ml), and stirred at 120' for 20 h in an atmosphere of nitrogen. The resulting mixture was cooled and poured into cold dilute hydrochloric acid. The resulting suspension was extracted with ether, the ethereal solution washed in turn with water and ammonium chloride solution, and then dried (MgS04). The ether was evaporated and the benzyl alcohol distilled under reduced pressure (1.0 mm). The residue was then applied to a column of silica gel (5 cm by 10 cm) and eluted with 7.5 % ethyl acetate-light petroleum. Benzyl4-benzyloxy-2- hydroxy-3,6-dimethylbenzoate (7) (8.8 g, 75 %) crystallized from acetone-cyclohexane as colourless prisms, m.p. 115-1 17' (Found: C, 76.2; H, 6.2. Cz3H2204 requires C, 76.2; H, 6.1 %). P.m.r. (CDC13) 6 2.15,2.47 (each 3H, s, ArCH,), 5.07, 5.36 (each 2H, s, 0CH2), 6.32 (lH, s, H5), 7.34 (10H, bs, O C H ~ C ~ H J ) and 11.59 (lH, s, OH).

This benzyl ester was prepared from the corresponding methyl ester1, by the method described above. Benzyl 2-hydroxy-6-methoxy-4-methylbenzoate (8) (73%) crystallized from n-hexane as colourless needles, m.p. 54' (Found: C, 70.7; H, 6.0. C16H1604 requires C, 70.6; H, 5.9%). P.m.r. (CDC13) 6 2.28 (3H, s, ArCH,), 3.83 (3H, s, OCH,), 5.43 (2H, s, 0CH2), 6.27, 6.48 (each 1H, s, H3,5), 7.37-7.55 (5H, m, 0CH2C6H5) and 11.59 (IH, s, OH).

A solution of benzyl orsellinate (3.9 g) in 1,l-dichloromethyl methyl ether (3.75 ml) and dichloro- methane (80 ml) was cooled to - 10'. A solution of titanium(1v) chloride (6.6 ml) in dichloromethane (20 ml) was then added with stirring over 1 h. The reaction was stirred at this temperature for a further 10 min and then poured into cold dilute hydrochloric acid and extracted with ether. The combined ethereal extract was washed with water, dried (MgS04) and concentrated. The residue was applied to a column of silica gel (5 cm by 15 cm) and eluted with 7.5% ethyl acetatelight

l6 Huneck, S., Djerassi, C., Becher, D., Barber, M., Ardenne, M, von, Steinfelder, K., and Tiimrnler, R., Tetrahedron, 1968, 24, 2707. l 7 Santesson, J., Ark. Kemi, 1969, 30, 363.

J. A. Elix and S. Norfolk

petroleum. The faster moving band yielded benzyl 3-formyl-2,4-dihydvoxy-6-methylbenzoate (10) (1.3 g, 30 %) which crystallized from cyclohexane in pale yellow needles, m.p. 92' (Found: C, 66.8; H, 5.0. C16Hl4O5 requires C, 67.1; H, 4.9%). P.m.r. (CDCl,) 62.46 (3H, s, ArCH,), 5.40 (2H, s, 0CH2), 6.25 (lH, s, H 5), 7.41 (5H, S, 0CH2C6H5), 10.32 (lH, s, CHO), 12.44, 12.91 (each lH, s, OH).

This compound was obtained by formylation of benzyl 2-hydroxy-6-methoxy-4-methylbenzoate in the manner described above. Benzyl3-formyl-2-hydroxy-6-methoxy-4-methylbenzoate (11) (59%) was crystallized from cyclohexane to form colourless plates, m.p. 107-109° (Found: C, 68.0; H, 5.3. Cl7Hl6O5 requires C, 68.0; H, 5.4%). P.m.r. (CDCl,) 6 2.55 (3H, s, ArCH,), 3.83 (3H, s, OCH,), 5.33 (2H, s, 0CH2), 6.24 (lH, s, HS), 7.20-7.44 (5H, m, OCHZCsH5), 10.07 (lH, s, CHO) and 12.41 (lH, s, OH).

A solution of benzyl 4-benzyloxy-2-hydroxy-3,6-dimethylbenzoate (3.5 g) and sodium hydroxide (2.2 g) in water (10 ml) and dioxan (90 ml) was cooled and stirred while a saturated aqueous solution of potassium persulphate (2.9 g) was added slowly such that the temperature remained between 0-10". The resulting solution was stored at 0" for 16 h and then acidified to pH 6 by addition of concentrated hydrochloric acid. Unchanged starting material was then extracted with ether (recovered 3.3 g). The aqueous layer was acidified by further addition of hydrochloric acid and then stirred and warmed to 90" for 0.5 h. After cooling, the solution was extracted with ether, the ethereal solution dried (MgS04) and the solvent removed. The residue was adsorbed on a silica gel plate (20cm by 20 cm) and eluted with 20% ethyl acetate-light petroleum. One major band developed and this yielded benzyl4-benzyloxy-2,5-dihydroxy-3,6-dimethylbenzoate (12) (0.08 g, 38 %) which crystallized from n-hexane-cyclohexane as colourless needles, m.p. 80" (Found: C, 73.2; H, 6.0. C23H2205 requires C, 73.0; H, 5.9%). P.m.r. (CDClj) 6 2.22,2.42 (each 3H, s, ArCH,), 4.92, 5.41 (each 2H, s, OCH,), 7.41 (lOH, s, 0CH2C6H5) and 11.22 (IH, s, bonded OH).

This compound was obtained by oxidation of benzyl 3-formyl-2,4-dihydroxy-6-methylbenzoate in the manner described above. Benzyl 3-formyl-2,4,5-trih~oxy-6-methylbenzoae (13) (47%) crystallized from n-hexane-cyclohexane as yellow needles, m.p. 127" (Found: C, 63.4; H, 5.0. C16H1406 requires C, 63.6; H, 4.7%). P.m.r. (CDCI,) 6 2.48 (3H, s, ArCH,), 5.44 (2H, s, OCH,), 7.42 (5H, s, 0CH2C6H5), 10.34 (lH, S, CHO) and 12.30, 12.73 (each lH, s, bonded OH).

3-Benz~~loxycavbonyl-2-hydroxy-4-methoxy-6-methylbenzoic Acid (14)

A solution of benzyl 3-forinyl-2-hydroxy-6-methoxy-4-methylbenzoate (2.5 g) in 50% aqueous dioxan (500 ml) containing sulphamic acid (1.0 g) was stirred while a solution of sodium chlorite (0.9 g) in water (15 rnl) was added. Stirring was continued for a further 1 h, and then the mixture extracted with ether, and the ethereal extract washed with water and dried (MgSO,). The solvent was removed and the residue recrystallized from benzene-cyclohexane to give 3-benzyloxycavbonyl-2- hydroxy-4-methoxy-6-methylbenzoic acid (14) (1.7 g, 65 %) as colourless plates, m.p. 131-133" (Found: C, 64.6; H, 5.1. CI7Hl606 requires C, 64.6; H, 5.1 %). P.m.r. (CDCI,) 8 2.59 (3H, s, ArCH,), 3.87 (3H, s, OCH,), 5.42 (2H, s, OCH3, 6.37 (lH, s, H5), 7.43 (5H, bs, 0CH2C6H5) and 12.47 (lH, s, bonded OH).

Synthesis of Depsides

The general procedure for the preparation of depsides has been described previously.11J2

Thamnolic Acid (I)

Dibenzyl thamnolate (18) (7.5 %) was eluted with 20% chloroform-toluene and recrystallized from ethyl acetate to form yellow prisms, m.p. 163" (Found: C, 65.6; H, 5.0. C33H28011 requires C, 66.0; H, 4.7%). P.m.r. (CDCI,) 6 2.45, 2.58 (each 3H, s, ArCH3), 3.83 (3H, s, OCH,), 5.36 (4H, bs, OCH,), 6.31 (lH, s, H5), 7.33 (lOH, bs, OCHZC.&~), 10.28 (lH, s, CHO), and 11.65, 12.58, 12.66 (each lH, s, OH).

Synthesis of b-Orcinol meta-Depsides

Thamnolic acid (1) (89%) crystallized from acetone as a pale yellow powder, m.p. 220-222" (dec.) alone, or admixed with a portion of authentic material (lit.ls~lg 223' dec.); mass spectrum m/e 376 (0.25 %), 332 (0.36), 226 (6), 209 (15), 208 (6), 192 (5), 191 (43), 190 (9), 182 (16), 169 (7), 168 (67), 167 (40), 166 (24), 165 (68), 164 (53), 150 (5), 139 (6), 138 (13), 137 (5), 136 (20), 122 (16), 121 (24), 109 (5), 94 (5), 93 (8), 77 (5), 69 (6), 67 (5), 66 (7), 65 (lo), 53 (ll) , 51 (7), 44 (100) and 43 (9) with metastable peaks at 191.4, 1746, 147.8, 133.8, 116.2, 114.0, 112.9, 106.1 and 99.8.

Hypothamnolic Acid (2)

Dibenzyl 4'-0-benzylhypothamnolate (17) (46%) was eluted with 20% chloroform-toluene and obtained as a colourless oil (Found: C, 71.2; H, 5.5. C4&6010 requires C, 71.0; H, 5.4%). P.m.r. (CDCl,) G 2.16, 2.38,2.46 (each 3H, s, ArCH3), 3.86 (3H, s, OCH,), 4.84 (2H, s) and 5.38 (4H, s, OCH,), 6.26 (lH, s, H5), 7.28-7.52 (15H, m, 0CH,C6H,) and 11.62, 11.73 (each lH, s, OH).

Hypothamnolic acid (2) (95%) crystallized from 80% acetone-water as colourless needles, m.p. 224-225" (dec.) (lit.687 225-227' dec., 217-218" dec.) (Found: C, 55.9; H, 4.6. Calc. for C19H18010: C, 56.2; H, 4.5%). Mass spectrum m/e 362 (1.6%), 318 (4), 226 (1.6), 209 (12), 198 (2.2), 191 (32), 182 (14), 180 (6), 166 (ll) , 165 (loo), 164 (35), 155 (6), 154 (58), 153 (16), 152 (8), 139 (lo), 138 (21), 137 (lo), 136 (20), 135 (9), 125 (7), 121 (14), 109 (12), 108 (IS), 107 (13), 95 (7), 94 (5), 93 (9), 80 (8), 79 (13), 78 (6), 77 (19), 71 (7), 69 (9), 67 (13), 66 (7), 65 (lo), 57 (13), 55 (12), 53 (lo), 52 (5), 51 (9), 44 (100) and 41 (14) with metastable peaks at 174.6, 163.6, 147.8, 120.6, 119.8 and 112.9.

Haemathamnolic Acid (3)

Benzyl haemathamnolate (16) (5 %) was eluted with 20% chloroform-toluene and recrystallized from chloroform-cyclohexane to form pale yellow prisms, m.p. 208-210" (Found: C, 62.9; H, 4.8. C26H2Z010 requires C, 63.1 ; H, 4.5 %). P.m.r. (CDCl,) 6 2.52, 2.54 (each 3H, s, ArCH,), 3.92 (3H, s, 0CH3), 5.39 (2H, s, OCH,), 6.28 (lH, s, H5), 7.38 (5H, S, OCHZC6H5), 10.21, 10.32 (each lH, s, CHO) and 12.60, 12.64, 12.70 (each lH, s, OH).

Haemathamnolic acid (3) (95 %) crystallized from acetone as pale yellow prisms, m.p. 199-201' (dec.) (lit.3 202-204' dec.) (Found: C, 56.1 ; H, 4.0. Calc. for C1gH16010 : C, 56.4; H, 4.0%). Mass spectrum mle 360 (O.12%), 210 (3.4), 209 (1.6), 194 (16), 193 (loo), 192 (7), 191 (20), 168 (8), 167 (6), 166 (12), 165 (4), 164 (5), 163 ( 4 , 138 (5), 135 (5), 134 (5), 122 (5), 121 (61, 108 (61, 107 (61, 91 (6), 79 (19), 78 (5), 77 (16), 69 (7), 67 (8), 66 (6), 65 (19), 63 (5), 53 (7) and 51 (9) with a metastable peak at 189.0.

Manuscript received 1 April 1975

l8 Koller, G., and Hamburg, H., Monatsh. Chem., 1935, 65, 375. l9 Asahina, Y., and Hiraiwa, M., Ber. Deut. Chem, Ges., 1936, 69, 330,