The synthesis of natural acetylenic compounds from Stereum hirsutum

Article abstract of DOI:10.1002/(SICI)1522-2675(19990908)82:9<1418::AID-HLCA1418>3.0.CO;2-O

The regioselective synthesis of two new acetylenic compounds, sterehirsutinol (1) and sterehirsutinol (2), isolated recently from culture medium of the fungus Stereum hirsutum, is reported.

Full text of DOI:10.1002/(SICI)1522-2675(19990908)82:9<1418::AID-HLCA1418>3.0.CO;2-O

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Helvetica Chimica Acta ± Vol. 82 (1999)
The Synthesis of Natural Acetylenic Compounds from Stereum hirsutum
by Abdellatif Fkyerat, Guy-Marie Dubin, and Raffaele Tabacchi*
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Institut de Chimie de lꢀUniversite de Neuchatel, Avenue de Bellevaux 51, CH-2000 Neuchatel
The regioselective synthesis of two new acetylenic compounds, sterehirsutinal (1) and sterehirsutinol (2),
isolated recently from culture medium of the fungus Stereum hirsutum, is reported.
Introduction. ± Stereum hirsutum is a basidiomycete involved in esca, one of the
most destructive diseases of grapevine [1]. To find an alternative control method as
efficient as the highly toxic sodium-arsenite treatment, the search for a pathogenically
active secondary metabolite was necessary. From the culture medium of Stereum
hirsutum, a series of new acetylenic compounds was isolated [2]. The structure of
sterehirsutinal (1), and sterehirsutinol (2) were elucidated by spectroscopic analysis
and by comparison with the biogenetically related frustulosin. Thus, to confirm their
structures and to obtain higher quantities of material for bioassays, 1 and 2 were
synthetized starting from the commercially available hydroquinone (3).
Results and Discussion. ± A similar synthetic strategy applied previously for
siccayne [3], eutypine [4], and frustulosin [5], compounds containing the same
alkenynyl side chain, was followed for the synthesis of 1 and 2. retro-Synthetic analysis
suggested that 1 could be prepared by coupling the alkynyl chain with a dihalogeno-
benzene derivative. The latter compound could be obtained in two steps from
hydroquinone (3). Thus, the 2,5-dibromobenzene-1,4-diol (4) was prepared by
bromination of 3 with Br2 in AcOH (Scheme 1). Compound 4 has been prepared
previously from benzoquinone in HBr and Br2 [6], but this method gave a mixture of
the mono and dibromo derivatives, which were difficult to separate. The carboxal-
dehyde function was introduced into 4 by Duffꢀs reaction [7], with hexamethylene-
tetramine (HMTA) in trifluoroacetic acid ( ! 5).
To avoid the cyclization reaction leading to a benzofurane derivative [3 ± 5], the
phenolic OH groups of 5 had to be protected. Because of the instability of the ortho-

Helvetica Chimica Acta ± Vol. 82 (1999)
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Scheme 1
OH acetylenic compounds under acidic conditions, the appropriate OH-protecting
group was the methoxymethyl (MOM) group which could be hydrolyzed under mild
conditions. Under standard protection conditions (dimethoxymethane and P2O5 in
CH2Cl2 at room temperature), only one of the two phenolic OH groups (OH C(3)) of
5 reacted to give the mono-protected compound 8 (see below, Scheme 2). At higher
temperature, a second MOM group was introduced, however, selectively at the
aldehyde moiety due to the delocalization of the CHˆO bond, to give the enone 6.
Under the same conditions, 2,5-dihydroxybenzaldehyde could be protected at the two
phenolic positions. This result suggests that the steric hindrance of the Br-atoms
influences the reaction at the aldehyde group; such an unexpected reaction has
previously been described for the intramolecular cyclization in the synthesis of
heterocycles [8].
Since the enone 6 could be easily hydrolyzed to give back the starting material 5, we
decided to continue the synthesis of 1 and 2 via this intermediate. The alkynyl side
chain was introduced easily at position 6 of 6 ( ! 7); unfortunately, no alkynylation of
6 occurred at position 3, even at high temperature (908) (Scheme 1). This result forced
us to modify the experimental conditions for the protection of the phenolic OH groups
of 5. Thus, 5 was first protected at position 3 in acidic medium to give 8 and then at
position 6 in basic medium to give 9 (Scheme 2). The dibromobenzaldehyde 9 then
underwent the desired coupling reactions with 2-methylbut-3-yn-2-ol in the presence of
dichlorobis(triphenylphosphine)palladium ([PdCl2(PPh3)2) and Et3N in DMF at 608
for 3 h to give the bis(hydroxyalkynyl)benzaldehyde 10. Temperature and reaction
time were crucial in the coupling step. At higher temperature or after more than 3 h at

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Helvetica Chimica Acta ± Vol. 82 (1999)
608, benzofurancarboxaldehyde 11 was obtained as the major product. The aldehyde
group of 10 seems to play the role of catalyst for the deprotection of the adjacent
phenolic group, which cyclized to 11. Finally, the difficult deprotection and dehydration
of 10 was accomplished in a one-pot reaction in anhydrous toluene at 608, in the
presence of TsOH and molecular sieves, to give sterehirsutinal (1) with moderate yield.
Sterehirsutinol (2) was obtained in quantitative yield by reduction of 1 with NaBH4 at
708. Coupling of aldehyde 9 with 2-methylbut-3-yn-2-ol, followed by dehydration of
the intermediate 10, was preferred to the direct coupling of 9 with 2-methylbut-1-en-3-
yne, because of the instability and low boiling point of the eneyne [9].
Scheme 2
We would like to thank Dr. S. Claude for his assistance in NMR spectroscopy. The financial support from
the Swiss National Science Foundation (grant No. 20.46920.96) and OFES, European project (grant 95.0064
UE:FAIR1-CT95-0654), are gratefully acknowledged.
Experimental Part
General. All commercially available chemical reagents were used without further purification. CH2Cl2 was
distilled over CaH2 and toluene over P2O5. M.p.: Gallenkamp M FB-595-010M. TLC: Aluminium sheets coated
with silica gel 60 F254 (Merck). Prep. column chromatography (CC): silica gel (0.063 ± 0.200 mm; 60 Merck). FT-
IR: Perkin-Elmer 1720X; samples were measured as thin films on NaCl disks, unless otherwise indicated; in
cm 1. 1H-NMR: Bruker AMX 400; d in ppm relative to SiMe4 as internal standard, J in Hz. MS: electron-impact

Helvetica Chimica Acta ± Vol. 82 (1999)
1421
ionization (EI) or desorption chemical ionization (DCI); Nermag-R-30-10 spectrometer. The microanalyses
were performed at the Laboratory for Organic Chemistry, ETH Zurich.
2,5-Dibromobenzene-1,4-diol (4). A soln. of Br2 (16 g, 0.1 mol) in AcOH (10 ml) was added dropwise to a
soln. of hydroquinone (ˆ benzene-1,4-diol; 3; 5.5 g, 0.05 mol) in AcOH (40 ml). The mixture was stirred at r.t.
for 1 h, H2O was added, and the brown solid was filtered and crystallized from H2O: 4 (4.8 g, 36%). White
needles. M.p. 190 ± 1918. FT-IR: 3268 (OH), 3094, 3050, 2784, 2076, 1703, 1638, 1515, 1423, 1234, 1222, 1196,
1116, 1061, 863. 1H-NMR (400 MHz, CDCl3): 7.62 (s, arom. H); 6.88 (s, OH). 13C-NMR (CDCl3): 146.91 (C(1),
C(4)); 119.18 (C(3), C(6)); 108.56 (C(2), C(5)). Anal. calc. for C6H4Br2O2: C 26.90, H 1.50, Br 59.65; found:
C 26.85, H 1.60, Br 59.92.
2,5-Dibromo-3,6-dihydroxybenzaldehyde (5). A mixture of 4 (2.68 g, 0.01 mol), hexamethylenetetramine
(ˆ 1,3,5,7-tetraazatricyclo[3.3.1.13,7]decane; 1.4 g, 0.01 mol) in CF3COOH (20 ml) was heated under reflux for
16 h. The solvent was evaporated and the residual oil diluted in H2O (1000 ml) and heated at 608 for 6 h. The
mixture was extracted with AcOEt (5 Â 100 ml), the org. layer washed with sat. NaCl soln. (10 Â 100 ml), dried
(MgSO4), and evaporated, and the residual brown oil crystallized from AcOEt/hexane: 5 (2.3 g, 78%). Yellow
solid. FT-IR: 3456, 3067, 2922, 2855, 1646, 1437, 1261, 1233, 1181, 1143, 852, 721, 560, 506, 496. 1H-NMR
(400 MHz, CDCl3): 12.04 (s, OH); 10.16 (s, CHO); 7.81 (br. s, OH); 7.38 (s, arom. H). 13C-NMR (CDCl3):
‡
208.16; 197.07 (CHO); 153.84; 146.58; 127.92 (C(4)); 117.02; 112.21; 110.33. EI-MS: 296 (100, M ), 266, 39, 07,
187, 157, 131, 88, 73, 70. 61.
2,5-Dibromo-6-hydroxy-3-(methoxymethoxy)benzaldehyde (8). To a soln. of 5 (1.5 g, 5 mmol) and
CH2(OMe)2 (excess, 10 ml) in dry CH2Cl2 (10 ml), P2O5 (3.5 g) was added portionwise. After 2 h, more P2O5
(2 g) was added and stirred until 5 disappeared (TLC monitoring). The mixture was diluted with CH2Cl2,
washed with 1n aq. NaOH and sat. aq. NaCl soln., dried (MgSO4), and evaporated. The yellow solid was
purified by CC (AcOEt/hexane 1 :9): yellow 8 (1.34 g, 80%). FT-IR: 3443 (OH), 3082, 3002, 2942, 2829, 1650,
1473, 1436, 1417, 1401, 1291, 1272, 1250, 1205, 1161, 1149, 1087, 1017, 942, 919, 879, 822, 760, 733. 1H-NMR
(CDCl3): 12.25 (s, OH); 10.34 (s, CHO); 7.64 (s, H C(4)); 5.16 (s, CH2); 3.53 (s, Me). 13C-NMR (CDCl3): 197.55
(CHO); 155.50; 147.10; 129.07 (C(4)); 117.80; 117.04; 110.58; 96.39 (CH2); 56.64 (Me). DCI-MS: 354 ([M ‡
‡
‡
NH4] ), 340 (M ), 310, 275, 185, 157, 133, 88, 73, 70, 61. Anal. calc. for C9H8Br2O4: C 31.80, H 2.37, Br 47.01;
found: C 31.96, H 2.48, Br 47.01.
2,5-Dibromo-4-(methoxymethoxy)-6-[(methoxymethoxy)methylene]cyclohexa-2,4-dien-1-one (6) was pre-
pared as described for 8, but at reflux temp. in CH2Cl2. Yield: 75%. 1H-NMR (CDCl3): 7.41 (s, H C(3)); 5.40
(s, CH); 5.37 (d, J ˆ 13.2, 1 H, CH2OCHˆC(6)); 5.33 (d, J ˆ 13.2, 1 H, CH2OCHˆC(6)); 5.17 (d, J ˆ 6.80, 1 H,
CH2O C(4)); 5.15 (d, J ˆ 6.80, 1 H, CH2O C(4)); 3.63 (s, Me); 3.52 (s, Me). 13C-NMR (CDCl3): 175.93 (CO);
148.45; 145.48; 122.50; 121.65 (C(3)); 112.73; 109.35; 96.01 (CH2); 95.83 (CH); 84.55 (CH2); 56.46 (Me); 55.81
(Me). Anal. calc. for C11H12Br2O5: C 34.40, H 3.15, Br 41.61; found: C 34.40, H 3.21, Br 41.52.
5-Bromo-2-(3-hydroxy-3-methylbut-1-ynyl)-4-(methoxymethoxy)-6-[(methoxymethoxy)methylene]cy-
clohexa-2,4-dien-1-one (7) was prepared as described for 10. Yield: 81%. FT-IR: 3442, 2981, 2933, 2832, 1739,
1589, 1486, 1458, 1411, 1381, 1350, 1323, 1285, 1245, 1208, 1195, 1155, 1099, 1059, 1031, 998, 961, 881, 813.
1H-NMR (CDCl3): 7.20 (s, H C(3)); 5.37 (s, CH); 5.34 (d, J ˆ 16.1, 1 H, CH2OCHˆC(6)); 5.29 (d, J ˆ 16.1,
1 H, CH2OCHˆC(6)); 5.16 (d, J ˆ 9.7, 1 H, CH2O C(4)); 5.11 (d, J ˆ 9.7, 1 H, CH2O C(4)); 3.61 (s, Me);
3.51 (s, Me); 1.61 (s, 2 Me). 13C-NMR (CDCl3): 171.16 (CO); 148.94; 147.73; 121.74; 121.20; 111.15; 99.37; 95.99
(CH); 95.85 (CH2); 84.24 (CH2); 65.69; 65.50; 56.40 (Me); 55.70 (Me); 31.33 (2 Me).
2,5-Dibromo-3,6-bis(methoxymethoxy)benzaldehyde (9). To a soln. of 8 (1.35 g, 4 mmol) in DMF (20 ml)
at 08 under N2, a 60% NaH suspension in mineral oil (0.21 g, 4.4 mmol) was added portionwise. After 10 min,
chloromethyl methyl ether (0.334 ml, 4.4 mmol) was added dropwise and stirred at r.t. for 2 h. The soln. was
poured into H2O and extracted with AcOEt, the org. layer washed with sat. NaCl soln., dried (MgSO4), and
evaporated, and the residual yellow oil submitted to CC (silica gel, hexane/AcOEt 95 :5): 9 (74%). White solid.
FT-IR: 2996, 2963, 2938, 2871, 2834, 1771, 1699, 1660, 1575, 1537, 1485, 1463, 1453, 1438, 1381, 1278, 1237, 1207,
1157, 1090, 996, 939, 920, 887, 868, 827. 1H-NMR (CDCl3): 10.23 (s, CHO); 7.56 (s, H C(4)); 5.24 (s, CH2); 5.06
(s, CH2); 3.62 (s, Me); 3.51 (s, Me). 13C-NMR (CDCl3); 190.02 (CHO); 151.21; 149.86; 131.31; 123.72 (C(4));
‡
117.78; 113.60; 101.53 (CH2); 95.64 (CH2); 58.26 (Me); 56.62 (Me). EI-MS: 384 (68, M ), 353 (35), 338 (100),
324 (24). Anal. calc. for C11H12Br2O5: C 34,40, H 3.15, Br 41.61; found: C 34.60, H 3.21, Br 41.44.
2,5-Bis(3-hydroxy-3-methylbut-1-ynyl)-3,6-bis(methoxymethoxy)benzaldehyde (10). A soln. of 9 (192 mg,
0.5 mmol), 2-methylbut-3-yn-2-ol (0.200 ml, 2 mmol), [PdCl2(PPh3)2] (70 mg, 0.1 mmol), CuI (19 mg,
0.1 mmol), and Et3N (0.28 ml, 2 mmol) in DMF (2 ml) was heated at 608 under N2 for 1 h. The mixture was
then diluted in H2O and extracted with AcOEt, the org. layer washed twice with 2% aq. HCl soln. and twice with
sat. NaCl soln., dried (MgSO4), and evaporated, and the residual brown oil submitted to CC (silica gel, hexane/

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Helvetica Chimica Acta ± Vol. 82 (1999)
AcOEt 1:1): 10 (140 mg, 72%). Brown oil. FT-IR: 3407 (OH), 2981, 2935, 2832, 1699¹ 1649, 1585, 1462, 1376,
1324, 1271, 1237, 1205, 1156, 1072, 1036, 1009, 982, 956, 925, 878. 1H-NMR (CDCl3): 10.40 (s, CHO); 7.29
(s, H C(4)); 5.17 (s, CH2); 5.16 (s, CH2); 3.56 (s, Me); 3.50 (s, Me); 2.86 (s, OH); 1.62 (s, Me); 1.60 (s, Me).
13C-NMR (CDCl3): 190.01 (CHO); 154.29; 154.21; 130.95; 124.43 (C(4)); 118.56; 115.50; 106.35; 100.85; 100.59
(CH2); 99.65; 95.48 (CH2); 74.95; 65.48; 58.09 (MeO); 56.43 (MeO); 31.13 (2 Me); 31.09 (2 Me).
6-(3-Hydroxy-3-methylbut-1-ynyl)-2-(1-hydroxy-1-methylethyl)-5-(methoxymethoxy)benzofuran-7-carbox-
aldehyde (11) was obtained as major product under the conditions described for 10, but at higher temp. Yield:
60%. FT-IR: 3449 (OH), 2981, 2934, 1690, 1645, 1607, 1450, 1369, 1261, 1224, 1205, 1153, 1118, 1072, 1046, 1015,
1
998, 969, 934, 848. H-NMR (CDCl3): 10.61 (s, CHO); 7.46 (s, H C(4)); 6.53 (s, H C(3)); 5.24 (s, CH2); 3.56
(s, MeO); 1.69 (s, 4 Me). 13C-NMR (CDCl3): 190.66 (CO); 167.18; 154.03; 147.58; 130.53; 120.93; 114.04 (C(4));
105.34; 99.86 (C(3)); 96.13 (CH2); 74.52; 68.64; 65.77; 60.39; 56.37; 31.19 (2 Me); 28.35 (2 Me).
2,5-Dihydroxy-3,6-bis(3-methylbut-3-en-1-ynyl)benzaldehyde (1). A soln. of 10 (223 mg, 0.57 mmol) in
toluene (5 ml) was stirred at 608 for 5 h in the presence of a catalytic amount of TsOH. The soln. was diluted
with AcOEt, washed with sat. NaCl soln., dried (MgSO4), and evaporated, and the residue purified by CC (silica
gel, AcOEt/hexane 1:4): 1 (25 mg, 25%). 1H-NMR (CDCl3): 11.70 (s, OH); 10.30 (s, CHO); 7.27 (s, arom. H);
5.42 (m, OH, 2 CH2); 2.06 (t, Me); 2.02 (t, Me). 13C-NMR (CDCl3): 196.47 (CHO); 157.84, 150.22 (C(2), C(5));
127.17 (C(4)); 126.08; 125.52 (CH2); 124.01 (CH2); 118.40; 115.43; 111.61; 105.91; 98.71; 82.91; 23.95 (Me); 23.86
(Me).
3-(Hydroxymethyl)-2,5-bis(3-methylbut-3-en-1-ynyl)benzene-1,4-diol (2). A soln. of 1 (7 mg, 0.03 mmol) in
MeOH (5 ml) was cooled at 708, and excess of NaBH4 was added portionwise. After 10 min, the yellow color
disappeared, and the soln. was diluted with H2O/10% HCl soln. 5 : 1. The resulting soln. was extracted with
AcOEt (3 Â 10 ml), the extract washed with NaCl, dried (MgSO4), and evaporated, and the residue purified by
CC (silica gel, hexane/AcOEt 4 : 1): 2 (6 mg, 86%). White solid. 1H-NMR (CDCl3): 6.91 (s, arom. H); 6.32
(s, OH C(arom.)); 5.41 (m, CH2); 5.31 (m, CH2); 4.91 (d, CH2OH); 2.41 (t, CH2OH); 2.01 (m, 2 Me).
13C-NMR (CDCl3): 149.70; 148.98; 126.31; 126.03; 125.75; 123.63 (CH2); 123.31 (CH2); 116.30 (C(6)); 111.74;
‡
110.26; 102.75; 98.49; 82.06; 79.83; 60.66 (CH2OH); 23.28 (2 Me). EI-MS: 268 (54, M ), 250 (100), 235 (7), 221
(7), 207 (8), 193 (6), 179 (25), 178 (32).
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Received May 29, 1999