Dihydrophenanthrene and phenanthrene mimics of natural compounds - Synthesis and antialgal activity

Article abstract of DOI:10.1023/A:1005463802388

9,10-Dihydrophenanthrenes and phenanthrenes, mimics of natural compounds with strong antialgal activity, have been synthesized through cross-coupling of 1-(2-iodo-5-methoxy)-phenylethanol with variously substituted iodobenzenes. The synthetic compounds, bearing a hydroxyl or a methoxyl group at C-2 and a methyl in the C ring, were tested against the green alga Selenastrum capricornutum. All compounds, except 2-methoxy-7- methylphenanthrene, caused inhibition of algal growth by more than 70% at 10^-4 M, and many of them retained this strong activity at 10^-5 M.

Full text of DOI:10.1023/A:1005463802388

Journal of Chemical Ecology, Vol. 26, No. 3, 2000
DIHYDROPHENANTHRENE AND PHENANTHRENE
MIMICS OF NATURAL COMPOUNDS—SYNTHESIS
AND ANTIALGAL ACTIVITY
M. DELLAGRECA,1 A. FIORENTINO,2 P. MONACO,1
A. POLLIO,3 L. PREVITERA,1,* and A. ZARRELLI1
1Dipartimento di Chimica Organica e Biologica, Universita
Via Mezzocannone 16, I-80134 Napoli, Italy
2Dipartimento di Scienze della Vita, II Universita
di Napoli
Via Arena, I-84100 Caserta, Italy
` Federico II
`
3Dipartimento di Biologia Vegetale, Universita
Via Foria 223, I-80139 Napoli, Italy
` Federico II
(Received March 15, 1999; accepted October 18, 1999)
Abstract—9,10-Dihydrophenanthrenes and phenanthrenes, mimics of natural
compounds with strong antialgal activity, have been synthesized through
cross-coupling of 1-(2-iodo-5-methoxy)-phenylethanol with variously substi-
tuted iodobenzenes. The synthetic compounds, bearing a hydroxyl or a
methoxyl group at C-2 and a methyl in the C ring, were tested against the
green alga Selenastrum capricornutum. All compounds, except 2-methoxy-
7-methylphenanthrene, caused inhibition of algal growth by more than 70%
4
5
at 10 M, and many of them retained this strong activity at 10 M.
Key Words—Juncus effusus, phenanthrenes, 9,10-dihydrophenanthrenes,
cross-coupling, algicides, Selenastrum capricornutum.
INTRODUCTION
Algal bloom is symptomatic of the later stages of eutrophication of waterbodies,
and although the reduction of nutrients remains the most effective method for
the control of the algal growth, in many cases, as in the waters receiving sewage
effluents or nutrients from agriculture, the use of algicides becomes a necessity.
There is a conflict between the need for powerful algicides and the require-
ment of safe and harmless compounds (Milne and Callow, 1985). None of the
*To whom correspondence should be addressed.
587
0098-0331 00 0300-0587$18.00 0  2000 Plenum Publishing Corporation
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/
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588
DELLAGRECA ET AL.
six active ingredients (Anderson and Dechoretz, 1984) currently used for algal
control in waters for fishing, aquaculture, irrigation, and swimming can be uti-
lized in large-scale treatments in natural environments owing to their harmful
effects on aquatic fauna.
In connection with a study of the allelopathic interactions of macrophytes
and microalgae (DellaGreca et al., 1995a), we have isolated from the wetland
plant Juncus effusus 25 free and 9 glucosylated 9,10-dihydrophenanthrenes (Del-
laGreca et al., 1992, 1993, 1995b,c, 1997). From the same species, some corre-
sponding phenanthrenes have also been isolated (Shima et al., 1991). Many of
the free compounds are strongly active against the green alga Selenastrum capri-
cornutum (DellaGreca et al., 1996), one of the organisms recommended for the
standard algal assay procedure developed for aquatic systems (Pipe and Shubert,
1984). Some of these compounds, in contrast, are inactive at the same concen-
trations against the brine shrimp Artemia salina. On this basis, we planned a
synthesis of 9,10-dihydrophenanthrenes and phenanthrenes, mimics of the natu-
ral compounds, with a hydroxyl or a methoxyl group at the C-2 position of the
A ring and a methyl in the C ring, to test them as algicides.
The synthesis was based on the cross-coupling of 1-(2-iodo-5-methoxy)-
phenylethanol with various substituted iodobenzenes by zerovalent nickel (Sem-
melhack et al., 1981).
METHODS AND MATERIALS
Chemicals. 3-Hydroxyacetophenone and iodobenzenes were obtained com-
mercially (Aldrich).
General Experimental Procedures. NMR spectra were recorded at 400
1
MHz for H and 100 MHz for 13C on a Bruker AC 400 spectrometer in CDCl3
—
solutions. One-bond and long-range H C COSY experiments were performed
with the XHCORR microprogram by using delays corresponding to JC, H 160
Hz and 8 Hz, respectively. HPLC was performed on a Varian Vista 5500 by
using an UV detector.
Synthesis of 1-(2-iodo-5-methoxy)-phenylethanol (1). To a solution of 3-
hydroxyacetophenone (2) (2.7 g; 20 mmol) in EtOH (6 ml) and 2 N NaOH (10
ml), Me2SO4 (5 ml) was added after 10 min, and the reaction mixture was kept
at room temperature for 4 hr. Acidification by 2 N H2SO4 and extraction with
Et2O gave 3-methoxyacetophenone (3) (3.0 g), which, dissolved in MeOH (10
ml), was directly reduced by NaBH4 excess. After 1 hr, AcOH was added, and
the mixture was extracted with Et2O to give 1-(3-methoxy)-phenylethanol (4)
quantitatively. That compound (3.0 g; 20 mmol), dissolved in CH2Cl2 (20 ml),
was treated with I2 (5.1 g; 20 mmol) and CF3COOAg (4.5 g; 20 mmol). After
2 hr, aq 10% NaHSO3 was added, and extraction with CH2Cl2 gave a crude
product that was chromatographed on silica gel (hexane–Et2O 4 : 1) to afford

SYNTHESIS OF ANTIALGAL COMPOUNDS
589
FIG. 1. Intermediates in the synthesis.
1
pure 1 (4.97 g; 18 mmol; 90%): H NMR d 7.66 (1H, d, J 8.4 Hz, H-3), 6.59
(1H, dd, J 2.1 and 8.4 Hz, H-4), 7.18 (1H, d, J 2.1 Hz, H-6), 5.03 (1H, q,
J
6.4 Hz, H-7), 1.46 (3H, d, J 6.4 Hz, H-8), 3.82 (3H, s, OMe); 13C NMR
d 148.6 (C-1), 85.3 (C-2), 139.7 (C-3), 115.4 (C-4), 160.4 (C-5), 112.0 (C-6),
73.6 (C-7), 23.7 (C-8), 55.4 (OMe).
Synthesis of 2-Hydroxy-9,10-dihydrophenanthrene (7b) and 2-Hydrox-
yphenanthrene (8b) (Figures 1 and 2). To a 50-ml three-necked flask, zinc dust
(392 mg, 6 mmol washed with 2 N HCl, H2O, EtOH, Me2CO, and Et2O and
dried in oven at 120 C), NiCl2 (784 mg, 6 mmol), PPh3 (6.3 g, 24 mmol), and
dry DMF (10 ml) were added. The mixture was warmed at 40 C under N2 and
stirred for 1 hr; a solution of 1 (834 mg, 3 mmol) and iodobenzene (612 mg,
3 mmol) in dry DMF (5 ml) was added at once, and the reaction mixture was
kept at 40 C for 6 hr. 2 N NH4OH was added, and the mixture was extracted
with Et2O. After evaporation, the residue was chromatographed on silica gel
(benzene–Et2O 19 : 1) to afford biphenyl 5a (320 mg, 1.4 mmol, 47%): 1H NMR
d 6.86 (1H, dd, J 2.4 and 8.3 Hz, H-5), 7.16 (1H, d, J 8.3 Hz, H-6), 7.22–7.44
′ ′
(6H, m, H-3, H-2 –H-6 ), 5.00 (1H, q, J 6.4 Hz, H-7), 1.40 (3H, d, J 6.4
Hz, H-8), 3.88 (3H, s, OMe); 13C NMR d 132.8 (C-1), 144.4 (C-2), 110.3 (C-3),
159.4 (C-4), 112.9 (C-5), 131.1 (C-6), 66.5 (C-7), 25.1 (C-8), 55.3 (OMe), 140.6
(C-1 ), 128.1 (C-2 and C-6 ), 129.5 (C-3 and C-5 ), 126.6 (C-4 ).
′ ′ ′ ′ ′ ′
FIG. 2. Synthetic phenanthrenes and 9,10-dihydrophenanthrenes.

590
DELLAGRECA ET AL.
To a solution of 5a (320 mg, 1.4 mmol) in dry xylene (1 ml), I2 (20 mg,
0.08 mol) was added, and the mixture was kept at 140 C for 6 hr. Addition of
10% aq NaHSO3 and extraction with Et2O gave a residue that, chromatographed
1
on silica gel (hexane), 6a (252 mg, 1.2 mmol, 86%): H NMR d 6.93 (1H, dd,
J
′ ′
2.3 and 8.3 Hz, H-5), 7.11–7.45 (7H, m, H-3, H-6, H-2 –H-6 ), 6.74 (1H,
dd, J 10.8 and 17.5 Hz, H-7), 5.71 (1H, dd, J 1.8 and 17.5 Hz, H-8), 5.22
(1H, dd, J 1.8 and 10.8 Hz, H-8), 3.90 (3H, s, OMe); 13C NMR d 133.7 (C-
1), 136.7 (C-2), 110.5 (C-3), 158.9 (C-4), 113.5 (C-5), 131.2 (C-6), 135.3 (C-7),
114.7 (C-8), 55.3 (OMe), 140.5 (C-1
C-5 ), 126.6 (C-4 ).
A sample of 6a (120 mg, 0.57 mmol) in dry benzene (6.5 ml) under an argon
′ ′ ′ ′
), 127.9 (C-2 and C-6 ), 129.8 (C-3 and
′
′
atmosphere was irradiated with a 450-W Hanovia lamp at room temperature for
30 min under magnetic stirring. Chromatography on silica gel (hexane–benzene
19 : 1) gave 7a (63 mg, 0.30 mmol) along with unreacted 6a (52 mg). After
purification by HPLC-NH2 (hexane–isopropyl ether 99.8 : 0.2), 7a had: 1H NMR
d 6.84 (1H, d, J 2.3 Hz, H-1), 6.88 (1H, dd, J 2.3 and 8.4 Hz, H-3), 7.73
(1H, d, J 8.4 Hz, H-4), 7.67 (1H, d, J 8.1 Hz, H-5), 7.25 (3H, m, H-6, H-7
and H-8), 2.91 (2H, brs, H-9 and H-10); 13C NMR d 112.3 (C-1), 161.0 (C-2),
113.5 (C-3), 124.9 (C-4), 123.0 (C-5), 126.5 (C-6), 127.0 (C-7), 128.0 (C-8),
29.5 (C-9), 29.1 (C-10), 139.0 (C-1a), 127.5 (C-4a), 136.5 (C-5a), 134.5 (C-8a)
55.2 (OMe).
To a solution of 7a (105 mg, 0.5 mmol) in dry CH2Cl2 (5 ml) cooled at
70 C, BBr3 (350 ml) was added. Addition of 1 N NaHCO3 after 3 hr and
extraction with CHCl3 gave a residue that was purified by preparative TLC
(hexane–Et2O 1 : 1) to give 7b (69 mg, 0.35 mmol, 70%): 1H NMR d 6.73 (1H,
d, J 2.5 Hz, H-1), 6.79 (1H, dd, J 2.5 and 8.3 Hz, H-3), 7.66 (1H, d, J
8.3 Hz, H-4), 7.67 (1H, d, J 8.1 Hz, H-5), 7.23 (3H, m, H-6, H-7, and H-8),
2.86 (4H, brs, H-9 and H-10); 13C NMR d 113.9 (C-1), 155.0 (C-2), 115.0 (C-
3), 125.2 (C-4), 123.0 (C-5), 126.6 (C-6), 127.0 (C-7), 128.1 (C-8), 29.3 (C-9),
29.0 (C-10), 139.2 (C-1a), 127.9 (C-4a), 136.1 (C-5a), 134.2 (C-8a).
A sample of 6a (120 mg, 0.57 mmol) in dry benzene (6.5 ml) was irradiated
with a 450-W Hanova lamp for 25 min at room temperature under magnetic
stirring in the presence of atmospheric oxygen. Chromatography on silica gel
(hexane) afforded 8a (64 mg, 0.31 mmol), unreacted 6a (50 mg), and 7a (3
1
mg). 8a had: H NMR d 7.32 (1H, d, J 1.6 Hz, H-1), 7.31 (1H, dd, J 1.6
and 8.4 Hz, H-3), 8.62 (2H, d, J 8.4 Hz, H-4 and H-5), 7.64 (1H, ddd, J
1.4, 8.3, 8.4 Hz, H-6), 7.58 (1H, ddd, J 1.4, 8.3 and 8.4 Hz, H-7), 7.91 (1H,
dd, J 1.4 and 8.3 Hz, H-8), 7.74 (2H, d, J 9.6 Hz, H-9 and H-10), 3.99 (3H,
s, OMe); 13C NMR d 117.1 (C-1), 158.3 (C-2), 108.7 (C-3), 124.3 (C-4), 122.2
(C-5), 126.5 (C-6), 126.7 (C-7), 128.6 (C-8), 127.6 (C-9), 125.6 (C-10), 133.5
(C-1a), 124.8 (C-4a), 130.4 (C-5a), 131.1 (C-8a), 55.4 (OMe).
BBr3 (350 ml) treatment of 8a (105 mg, 0.50 mmol) in dry CH2Cl2 (5 ml)

SYNTHESIS OF ANTIALGAL COMPOUNDS
591
1
at 70 C for 3 hr gave 8b (71 mg, 0.36 mmol): H NMR d 7.26 (1H, d, J
1.5 Hz, H-1), 7.25 (1H, dd, J 1.5 and 8.4 Hz, H-3), 8.58 (2H, d, J 8.4 Hz,
H-4 and H-5), 7.63 (1H, ddd, J 1.4, 8.3, 8.4 Hz, H-6), 7.55 (1H, ddd, J 1.4,
8.3 and 8.4 Hz, H-7), 7.91 (1H, dd, J 1.4 and 8.3 Hz, H-8), 7.73 (1H, d, J
9.6 Hz, H-9), 7.62 (1H, d, J 9.6 Hz, H-10); 13C NMR d 116.7 (C-1), 154.2
(C-2), 111.8 (C-3), 124.5 (C-4), 122.1 (C-5), 126.0 (C-6), 126.7 (C-7), 128.6 (C-
8), 127.7 (C-9), 125.6 (C-10), 133.8 (C-1a), 124.7 (C-4a), 130.6 (C-5a), 131.3
(C-8a).
Synthesis of 2-Hydroxy-7-methyl-9,10-dihydrophenanthrene (7h) and 2-
Hydroxy-7-methylphenanthrene (8h). A solution of 1 (3 mmol) and 4-
iodotoluene (3 mmol) in dry DMF (5 ml) was added to the mixture of the active
nickel complex prepared as above reported. Work-up after 9 hr at 35 C and
chromatography on silica gel (benzene–Et2O 19 : 1) gave biaryl 5d (266 mg, 1.1
mmol, 37%): 1H NMR d 6.97 (1H, dd, J 2.7 and 8.4 Hz, H-5), 7.24–7.35 (6H,
′ ′
m, H-3, H-6, H-2 –H-6 ), 5.11 (1H, q, J 6.5 Hz, H-7), 1.50 (3H, d, J 6.5
Hz, H-8), 2.52 (3H, s, Me), 3.98 (3H, s, OMe); 13C NMR d 132.5 (C-1), 144.7
(C-2), 110.6 (C-3), 159.4 (C-4), 113.1 (C-5), 131.3 (C-6), 66.6 (C-7), 25.1 (C-8),
55.4 (OMe), 137.9 (C-1
(C-4 ).
Dehydration by I2 of 5d for 6 hr at 140 C and chromatography as reported
gave 6d (198 mg, 0.8 mmol, 73%): 1H NMR d 6.94 (1H, dd, J 2.6 and 8.4 Hz,
H-5), 7.22–7.35 (6H, m, H-3, H-6, H-2 –H-6 ), 6.78 (1H, dd, J 11.0 and 17.5
′ ′ ′ ′ ′
) 128.7 (C-2 and C-6 ), 129.8 (C-3 and C-5 ), 136.5
′
′
′
Hz, H-7), 5.76 (1H, dd, J 1.3 and 17.5 Hz, H-8), 5.25 (1H, dd, J 1.3 and
11.0 Hz, H-8), 2.45 (3H, s, Me), 3.91 (3H, s, OMe); 13C NMR d 133.8 (C-1),
136.9 (C-2), 110.6 (C-3), 158.9 (C-4), 113.6 (C-5), 131.2 (C-6), 136.1 (C-7),
114.6 (C-8), 55.3 (OMe), 137.7 (C-1
C-5 ), 136.3 (C-4 ), 21.1 (Me).
Photocyclization of 6d (99 mg, 0.4 mmol) in the absence and in pres-
′ ′ ′ ′
), 128.7 (C-2 and C-6 ), 129.8 (C-3 and
′
′
ence of atmospheric oxygen, as reported above, gave 7-methyl-2-methoxy-
9,10-dihydrophenathrene (7g) (74 mg, 0.3 mmol, 75%) and 7-methyl-2-
1
methoxyphenanthrene (8g) (50 mg, 0.2 mmol, 50%). 7g had: H NMR d 6.79
(1H, d, J 2.1 Hz, H-1), 6.85 (1H, dd, J 2.1 and 8.2 Hz, H-3), 7.65 (1H, d, J
8.2 Hz, H-4), 7.58 (1H, d, J 7.9 Hz, H-5), 7.10 (1H, dd, J 2.0 and 7.9 Hz,
H-6), 7.04 (1H, d, J 2.0 Hz, H-8), 2.84 (4H, brs, H-9 and H-10), 2.36 (3H,
s, Me), 3.85 (3H, s, OMe); 13C NMR d 112.2 (C-1), 158.7 (C-2), 113.4 (C-3),
124.9 (C-4), 123.2 (C-5), 127.7 (C-6), 136.5 (C-7), 129.0 (C-8), 29.5 (C-9), 29.7
(C-10), 139.1 (C-1a), 128.2 (C-4a), 131.7 (C-5a), 136.5 (C-8a), 21.3 (Me), 55.2
1
(OMe). 8g had: H NMR d 7.25 (1H, d, J 1.4 Hz, H-1), 7.28 (1H, dd, J 1.4
and 8.4 Hz, H-3), 8.55 (1H, d, J 8.4 Hz, H-4), 8.48 (1H, d, J 8.4 Hz, H-5),
7.47 (1H, dd, J 1.4 and 8.4 Hz, H-6), 7.64 (1H, d, J 1.4 Hz, H-8), 7.66 (2H,
d, J 9.4 Hz, H-9 and H-10), 2.53 (3H, s, Me), 3.94 (3H, s, OMe); 13C NMR
d 117.0 (C-1), 158.0 (C-2), 108.6 (C-3), 124.1 (C-4), 122.1 (C-5), 127.3 (C-6),

592
DELLAGRECA ET AL.
135.2 (C-7), 128.5 (C-8), 127.3 (C-9), 126.5 (C-10), 133.1 (C-1a), 124.8 (C-4a),
128.8 (C-5a), 131.2 (C-8a), 21.4 (Me), 55.4 (OMe).
1
BBr3 demethylation of 7g gave 7h (60 mg, 35%): H NMR d 6.71 (1H, d,
J
2.1 Hz, H-1), 6.77 (1H, dd, J 2.1 and 8.2 Hz, H-3), 7.61 (1H, d, J 8.2 Hz,
H-4), 7.57 (1H, d, J 7.9 Hz, H-5), 7.10 (1H, dd, J 2.0 and 7.9 Hz, H-6), 7.05
(1H, d, J 2.0 Hz, H-8), 2.82 (4H, brs, H-9 and H-10), 2.36 (3H, s, Me); 13C
NMR d 114.0 (C-1), 154.9 (C-2), 115.2 (C-3), 125.1 (C-4), 123.2 (C-5), 127.9
(C-6), 136.7 (C-7), 129.1 (C-8), 29.3 (C-9), 29.6 (C-10), 139.4 (C-1a), 128.0
(C-4a), 131.9 (C-5a), 136.6 (C-8a), and 21.4 (Me). Demethylation by BBr3 of
1
8g gave 8h (43 mg, 90%): H NMR d 7.23 (1H, d, J 1.4 Hz, H-1), 7.21 (1H,
dd, J 1.4 and 8.3 Hz, H-3), 8.54 (1H, d, J 8.3 Hz, H-4), 8.46 (1H, d, J
8.3 Hz, H-5), 7.47 (1H, dd, J 1.6 and 8.5 Hz, H-6), 7.64 (1H, d, J 1.6 Hz,
H-8), 7.64 (1H, d, J 9.6 Hz, H-9), 7.58 (1H, d, J 9.6 Hz, H-10), 2.56 (3H,
s, Me); 13C NMR d 116.6 (C-1), 153.9 (C-2), 111.7 (C-3), 124.3 (C-4), 122.0
(C-5), 127.5 (C-6), 135.3 (C-7), 128.5 (C-8), 127.5 (C-9), 126.0 (C-10), 133.1
(C-1a), 125.0 (C-4a), 128.3 (C-5a), 131.1 (C-8a), 21.4 (Me).
Synthesis of 2-Hydroxy-5-methyl-9,10-dihydrophenanthrene (7d) and 2-
Hydroxy-5-methylphenanthrene (8d). 2-Iodo-5-methoxyacetophenone, obtained
by reaction of equimolar amounts of 3-methoxyacetophenone (3), I2, and
CF3COOAg, was cross-coupled with 2-iodotoluene for 70 hr at 40 C as reported
1
above to give the corresponding biaryl: H NMR d 6.93 (1H, dd, J 2.1 and
′ ′
8.4 Hz, H-5), 7.10–7.32 (6H, m, H-3, H-6, H-3 –H-6 ), 2.15 (3H, s, H-8), 1.95
(3H, s, Me), 3.90 (3H, s, OMe); 13C NMR d 136.0 (C-1), 136.0 (C-2), 112.3 (C-
3), 158.8 (C-4), 117.3 (C-5), 130.3 (C-6), 203.1 (C-7), 29.8 (C-8), 55.6 (OMe),
141.2 (C-1
20.2 (Me).
′ ′ ′ ′ ′ ′
), 140.5 (C-2 ), 130.0 (C-3 ), 127.9 (C-4 ), 125.9 (C-5 ), 130.3 (C-6 ),
NaBH4 reduction of biaryl gave a crude product that was directly dehy-
1
drated by I2 in xylene to the vinyl intermediate 6b: H NMR d 6.90 (1H, dd, J
′ ′
2.6 and 8.4 Hz, H-5), 7.07–7.29 (6H, m, H-3, H-6, H-3 –H-6 ), 6.41 (1H, dd,
J
10.8 and 17.0 Hz, H-7), 5.66 (1H, dd, J 1.3 and 17.0 Hz, H-8), 5.13 (1H,
dd, J 1.3 and 10.8 Hz, H-8), 2.08 (3H, s, Me), 3.91 (3H, s, OMe); 13C NMR
d 133.6 (C-1), 137.0 (C-2), 109.7 (C-3), 158.8 (C-4), 113.5 (C-5), 131.0 (C-6),
135.2 (C-7), 114.5 (C-8), 55.4 (OMe), 140.4 (C-1
′ ′ ′
), 140.0 (C-2 ), 129.8 (C-3 ),
127.3 (C-4 ), 125.5 (C-5 ), 130.3 (C-6 ), 20.1 (Me).
′
′
′
Photocyclization of 6b in both the reported conditions gave 2-methoxy-
5-methyl-9,10-dihydrophenanthrene (7c) and 2-methoxy-5-methylphenanthrene
(8c). 7c had: 1H NMR d 6.87 (1H, d, J 2.2 Hz, H-1), 6.85 (1H, dd, J 2.2 and
8.4 Hz, H-3), 7.63 (1H, d, J 8.4 Hz, H-4), 7.13–7.15 (3H, m, H-6, H-7, and
H-8), 2.76 (4H, brs, H-9 and H-10), 2.62 (3H, s, Me), 3.87 (3H, s, OMe); 13C
NMR d 110.9 (C-1), 158.3 (C-2), 113.3 (C-3), 130.6 (C-4), 133.9 (C-5), 129.4
(C-6), 125.5 (C-7), 126.1 (C-8), 30.8 (C-9), 30.5 (C-10), 139.2 (C-1a), 127.7
1
(C-4a), 140.8 (C-5a), 134.1 (C-8a), 23.1 (Me), 55.3 (OMe). 8c had: H NMR d

SYNTHESIS OF ANTIALGAL COMPOUNDS
593
7.29 (1H, d, J 1.4 Hz, H-1), 7.28 (1H, dd, J 1.4 and 8.4 Hz, H-3), 8.59 (1H,
d, J 8.4 Hz, H-4), 7.47 (1H, dd, J 1.4 and 8.3 Hz, H-6), 7.32 (1H, ddd, J
1.4, 8.3 and 8.4 Hz, H-7), 7.76 (1H, dd, J 1.4 and 8.4 Hz, H-8), 7.69 (2H,
d, J 9.4 Hz, H-9 and H-10), 3.12 (3H, s, Me), 4.00 (3H, s, OMe); 13C NMR
d 115.5 (C-1), 159.7 (C-2), 109.1 (C-3), 131.3 (C-4), 135.0 (C-5), 129.0 (C-6),
128.7 (C-7), 125.0 (C-8), 127.6 (C-9), 126.7 (C-10), 133.0 (C-1a), 124.2 (C-4a),
134.3 (C-5a), 131.3 (C-8a), 27.4 (Me), 55.4 (OMe).
BBr3 demethylation of 7c and 8c gave 7d and 8d, respectively. 7d had: 1H
NMR d 6.79 (1H, d, J 2.3 Hz, H-1), 6.78 (1H, dd, J 2.3 and 8.4 Hz, H-3),
7.48 (1H, d, J 8.4 Hz, H-4), 7.13–7.15 (3H, m, H-6, H-7, and H-8), 2.73 (4H,
brs, H-9 and H-10), 2.61 (3H, s, Me); 13C NMR d 112.4 (C-1), 154.0 (C-2),
114.4 (C-3), 130.4 (C-4), 133.8 (C-5), 129.5 (C-6), 125.4 (C-7), 125.9 (C-8),
30.6 (C-9), 29.7 (C-10), 139.0 (C-1a), 127.7 (C-4a), 141.9 (C-5a), 134.0 (C-8a),
1
23.0 (Me). 8d had: H NMR d 7.28 (1H, d, J 1.5 Hz, H-1), 7.24 (1H, dd, J
1.5 and 8.4 Hz, H-3), 8.59 (1H, d, J 8.4 Hz, H-4), 7.47 (1H, dd, J 1.4 and
8.3 Hz, H-6), 7.30 (1H, ddd, J 1.4, 8.3 and 8.4 Hz, H-7), 7.74 (1H, dd, J 1.4
and 8.4 Hz, H-8), 7.69 (1H, d, J 9.4 Hz, H-9), 7.56 (1H, d, J 9.4 Hz, H-10),
3.11 (3H, s, Me); 13C NMR d 115.2 (C-1), 153.3 (C-2), 112.1 (C-3), 131.3 (C-4),
135.8 (C-5), 129.3 (C-6), 128.6 (C-7), 125.1 (C-8), 127.6 (C-9), 125.2 (C-10),
132.8 (C-1a), 122.1 (C-4a), 134.6 (C-5a), 131.8 (C-8a), 27.8 (Me).
Synthesis of 2-Hydroxy-6-methyl-9,10-dihydrophenanthrene (7f), 2-Hy-
droxy-8-methyl-9,10-dihydrophenanthrene (7l), 2-Hydroxy-6-methylphenan-
threne (8f), and 2-Hydroxy-8-methylphenanthrene (8l). Equimolar amounts of
1 (6 mmol) and 3-iodotoluene were cross-coupled as described for 7h at 40 C
to give biaryl 5c: 1H NMR d 7.38 (1H, d, J 2.7 Hz, H-3), 7.03 (1H, dd, J 2.7
′ ′
and 8.4 Hz, H-5), 7.30 (1H, d, J 8.4 Hz, H-6), 7.24–7.50 (4H, m, H-2 –H-6 ),
5.15 (1H, q, J 6.4 Hz, H-7), 1.58 (3H, d, J 6.4 Hz, H-8), 2.57 (3H, s, Me),
4.04 (3H, s, OMe); 13C NMR d 133.0 (C-1), 144.6 (C-2), 110.3 (C-3), 159.4 (C-
4), 112.9 (C-5), 131.1 (C-6), 66.4 (C-7), 25.1 (C-8), 55.3 (OMe), 140.7 (C-1
128.0 (C-2 ), 137.6 (C-3 ), 127.6 (C-4 ), 130.3 (C-5 ), 126.6 (C-6 ), 21.4 (Me).
Dehydration of 5c gave biaryl 6c: H NMR d 6.90 (1H, dd, J 2.3 and
8.3 Hz, H-5), 7.08–7.29 (6H, m, H-3, H-6, H-2 –H-6 ), 6.42 (1H, dd, J 11.0
′
),
′
′
′
′
′
1
′
′
and 17.1 Hz, H-7), 5.13 (1H, dd, J 2.0 and 11.0 Hz, H-8), 5.61 (1H, dd, J
2.0 and 17.1 Hz, H-8), 2.08 (3H, s, Me), 3.91 (3H, s, OMe); 13C NMR d 133.9
(C-1), 136.8 (C-2), 109.7 (C-3), 158.8 (C-4), 113.5 (C-5), 131.0 (C-6), 135.2
(C-7), 114.5 (C-8), 55.4 (OMe), 140.4 (C-1
(C-4 ), 130.6 (C-5 ), 127.0 (C-6 ), 20.1 (Me).
Photocyclization of 6c under argon gave a mixture of 2-methoxy-6-methyl-
′ ′ ′
), 127.8 (C-2 ), 137.5 (C-3 ), 127.3
′
′
′
9,10-dihydrophenanthrene (7e) and 2-methoxy-8-methyl-9,10-dihydrophenan-
threne (7i) which was separated by HPLC-NH2 (isopropyl ether–hexane 1 : 49).
1
7e had: H NMR d 6.79 (1H, d, J 2.3 Hz, H-1), 6.84 (1H, dd, J 2.3 and
8.3 Hz, H-3), 7.68 (1H, d, J 8.3 Hz, H-4), 7.51 (1H, d, J 2.1 Hz, H-5), 7.00

594
DELLAGRECA ET AL.
(1H, dd, J 2.1 and 7.7 Hz, H-7), 7.12 (1H, d, J 7.7 Hz, H-8), 2.84 (4H, brs,
H-9 and H-10), 2.40 (3H, s, Me), 3.85 (3H, s, OMe); 13C NMR d 112.3 (C-1),
158.9 (C-2), 113.5 (C-3), 124.9 (C-4), 124.9 (C-5), 134.2 (C-6), 127.9 (C-7),
127.3 (C-8), 29.7 (C-9), 28.7 (C-10), 139.2 (C-1a), 128.6 (C-4a), 136.2 (C-5a),
1
133.3 (C-8a), 21.4 (Me), 55.3 (OMe). 7i had: H NMR d 6.83 (1H, d, J 2.2
Hz, H-1), 6.88 (1H, dd, J 2.2 and 8.2 Hz, H-3), 7.74 (1H, d, J 8.2 Hz, H-4),
7.61 (1H, d, J 7.8 Hz, H-5), 7.23 (1H, dd, J 7.8 and 7.8 Hz, H-6), 7.12 (1H,
d, J 7.8 Hz, H-7), 2.87 (4H, brs, H-9 and H-10), 2.39 (3H, s, Me), 3.85 (3H, s,
OMe); 13C NMR d 112.3 (C-1), 158.4 (C-2), 113.2 (C-3), 125.3 (C-4), 121.1 (C-
5), 126.3 (C-6), 128.5 (C-7), 135.1 (C-8), 24.7 (C-9), 29.1 (C-10), 138.7 (C-1a),
127.8 (C-4a), 135.2 (C-5a), 134.8 (C-8a), 19.9 (Me), 55.3 (OMe).
1
BBr3 demethylation of 7e and 7i gave 7f and 7l. 7f had: H NMR d 6.73
(1H, d, J 2.3 Hz, H-1), 6.78 (1H, dd, J 2.3 and 8.3 Hz, H-3), 7.65 (1H, d, J
8.3 Hz, H-4), 7.51 (1H, d, J 2.1 Hz, H-5), 7.00 (1H, dd, J 2.1 and 7.7 Hz,
H-7), 7.13 (1H, d, J 7.7 Hz, H-8), 2.82 (4H, brs, H-9 and H-10), 2.40 (3H, s,
Me); 13C NMR d 113.7 (C-1), 154.8 (C-2), 114.9 (C-3), 125.0 (C-4), 125.5 (C-
5), 134.1 (C-6), 127.9 (C-7), 127.2 (C-8), 29.8 (C-9), 28.9 (C-10), 139.5 (C-1a),
128.5 (C-4a), 136.3 (C-5a), 133.4 (C-8a), 21.7 (Me). 2-Hydroxy-8-methyl-9,10-
1
dihydrophenanthrene (7l) had: H NMR d 6.73 (1H, d, J 2.2 Hz, H-1), 6.79
(1H, dd, J 2.2 and 8.2 Hz, H-3), 7.63 (1H, d, J 8.2 Hz, H-4), 7.57 (1H, d, J
7.6 Hz, H-5), 7.21 (1H, dd, J 7.6 and 7.9 Hz, H-6), 7.10 (1H, d, J 7.9 Hz,
H-7), 2.80 (4H, brs, H-9 and H-10), 2.35 (3H, s, Me); 13C NMR d 114.1 (C-1),
155.1 (C-2), 114.9 (C-3), 125.9 (C-4), 121.3 (C-5), 126.6 (C-6), 128.9 (C-7),
135.3 (C-8), 24.9 (C-9), 29.2 (C-10), 139.4 (C-1a), 128.3 (C-4a), 135.6 (C-5a),
134.6 (C-8a), 20.2 (Me).
Photocyclization in the presence of oxygen atmosphere followed by
HPLC-NH2 gave 2-methoxy-6-methylphenanthrene (8e) and 2-methoxy-8-
1
methylphenanthrene (8i). 8e had: H NMR d 7.29 (1H, d, J 1.4 Hz, H-1),
7.28 (1H, dd, J 1.4 and 8.4 Hz, H-3), 8.62 (1H, d, J 8.4 Hz, H-4), 8.41 (1H,
d, J 1.5 Hz, H-5), 7.43 (1H, dd, J 1.5 and 8.4 Hz, H-7), 7.68 (1H, d, J 8.4
Hz, H-8), 7.76 (2H, d, J 9.4 Hz, H-9 and H-10), 2.64 (3H, s, Me), 3.99 (3H,
s, OMe); 13C NMR d 117.3 (C-1), 158.3 (C-2), 108.6 (C-3), 124.3 (C-4), 123.5
(C-5), 134.9 (C-6), 126.9 (C-7), 128.5 (C-8), 126.4 (C-9), 125.6 (C-10), 133.8
(C-1a), 123.5 (C-4a), 130.5 (C-5a), 128.2 (C-8a), 22.2 (Me), 55.4 (OMe). 8i had:
1H NMR d 7.25 (1H, d, J 1.4 Hz, H-1), 7.27 (1H, dd, J 1.4 and 8.4 Hz, H-3),
8.62 (1H, d, J 8.4 Hz, H-4), 8.51 (1H, dd, J 1.5 and 8.4 Hz, H-5), 7.52 (1H,
ddd, J 1.5, 8.4 and 8.4 Hz, H-6), 7.37 (1H, dd, J 1.5 and 8.4 Hz, H-7), 7.95
(1H, d, J 9.4 Hz, H-9), 7.73 (1H, d, J 9.4 Hz, H-10), 2.76 (3H, s, Me), 3.98
(3H, s, OMe); 13C NMR d 116.9 (C-1), 158.3 (C-2), 108.4 (C-3), 124.7 (C-4),
120.5 (C-5), 126.3 (C-6), 127.7 (C-7), 136.3 (C-8), 122.0 (C-9), 125.6 (C-10),
133.8 (C-1a), 123.5 (C-4a), 129.8 (C-5a), 133.8 (C-8a), 20.0 (Me), 55.4 (OMe).
1
BBr3 demethylation of 8e and 8i afforded 8f and 8l. 8f had: H NMR d

SYNTHESIS OF ANTIALGAL COMPOUNDS
595
7.27 (1H, d, J 1.5 Hz, H-1), 7.24 (1H, dd, J 1.5 and 8.3 Hz, H-3), 8.61 (1H,
d, J 8.3 Hz, H-4), 8.38 (1H, d, J 1.6 Hz, H-5), 7.39 (1H, dd, J 1.6 and 8.3
Hz, H-7), 7.72 (1H, d, J 8.3 Hz, H-8), 7.68 (1H, d, J 9.6 Hz, H-9), 7.55 (1H,
d, J 9.6 Hz, H-10), 2.63 (3H, s, Me); 13C NMR d 117.7 (C-1), 156.1 (C-2),
111.2 (C-3), 124.2 (C-4), 123.0 (C-5), 134.7 (C-6), 126.9 (C-7), 128.3 (C-8),
126.3 (C-9), 125.2 (C-10), 133.7 (C-1a), 123.9 (C-4a), 130.9 (C-5a), 129.1 (C-
8a), 22.1 (Me). 8l had: 1H NMR d 7.23 (1H, d, J 1.4 Hz, H-1), 7.21 (1H, dd, J
1.4 and 8.3 Hz, H-3), 8.56 (1H, d, J 8.3 Hz, H-4), 8.47 (1H, dd, J 1.5 and
8.3 Hz, H-5), 7.50 (1H, ddd, J 1.5, 8.3, and 8.5 Hz, H-6), 7.34 (1H, dd, J 1.5
and 8.3 Hz, H-7), 7.90 (1H, d, J 9.5 Hz, H-9), 7.63 (1H, d, J 9.5 Hz, H-10),
2.75 (3H, s, Me); 13C NMR d 116.8 (C-1), 156.6 (C-2), 111.1 (C-3), 124.5 (C-4),
120.2 (C-5), 126.1 (C-6), 127.0 (C-7), 136.4 (C-8), 121.5 (C-9), 125.9 (C-10),
133.7 (C-1a), 123.9 (C-4a), 129.7 (C-5a), 134.2 (C-8a), 20.5 (Me).
Bioassay. The strain UTEX 1648 of Selenastrum capricornutum was main-
tained on Bold basal medium (BBM) (Nichols, 1973) solidified with 1.5% agar in
continuous light at 23 C. Fresh axenic cultures for the experiments were grown
in 100-ml cylinders on the same culture medium. For the growth tests, the com-
pounds were dissolved in acetone. Each solution (20 ml) was added to the test
4
tubes containing 6 ml of inoculated medium, giving final concentrations of 10
,
5
5
5 × 10 and 10 M. Blanks containing only acetone were also tested. The
test tubes were incubated at 23 C on a shaking apparatus previously described
(Aliotta et al., 1991). The total irradiation of 150 mE sec m2 was provided by
/
/
daylight fluorescent lamps (Philips TLD 30 w 55) from below the apparatus. The
/
photoperiod was 16 hr light–8 hr dark. Growth of cultures was followed daily
either by measuring the absorbance increase at 550 nm with a Bausch & Lomb
Spectronic 20 colorimeter or by counting the cell numbers with a Thoma blood-
counting chamber. The cell numbers of the initial inocula ranged from 106 to 1.5
× 106 ml, corresponding to 0.05–0.06 units of absorbance. Growth experiments
/
were carried out in triplicate. To test statistical significance of results, one-way
ANOVA was performed at P 0.05. For each compound, a comparison among
means was performed by using the Student-Newman-Keuls test (SNK), at P
0.05. The SPSS statistical package was used.
The index of inhibition for compounds was calculated as: [(1 Xa) Ya] ×
/
100 (Blankley, 1973), where Xa is the growth-rate of the alga in the presence of
the compound tested and Ya is the growth rate of the control.
RESULTS AND DISCUSSION
The building block 1-(2-iodo-5-methoxy)-phenylethanol (1) was obtained
with an overall 90% yield from 3-hydroxyacetophenone (2) (Scheme 1). Com-
mercially available (Sigma) 2 was converted into its O-methyl derivative 3 by

596
DELLAGRECA ET AL.
SCHEME 1. Synthesis of 1. i: Me2SO4, NaOH, EtOH; ii: NaBH4, MeOH; iii: I2,
CF3COOAg, CH2Cl2.
Me2SO4, and NaBH4 reduction of this latter gives 1-(3-methoxy)-phenylethanol
(4), which, by treatment with I2 and CF3COOAg, afforded the target.
In the first synthesis, 1-(2-iodo-5-methoxy)-phenylethanol (1) was cross-
coupled with iodobenzene. The nickel catalyzed homo- and hetero-
coupling of aryl halides has been extensively studied (Tiecco et al., 1984) and
has been found to be dependent on the selection of zero valent nickel complexes,
solvents, the nature of the halides, and additives such as PPh3 or Et4NI.
The coupling was investigated under the conditions reported. The best
results were obtained in DMF when equimolar amounts of 1-(2-iodo-5-
methoxy)-phenylethanol (1) and iodobenzene were added at once to a reac-
tion mixture containing the active nickel complex (Scheme 2). The complex
was formed by zinc reduction of NiCl2(PPh3)2, generated in situ from NiCl2
and PPh3 in a 1 : 4 ratio. Under such conditions, the asymmetric biaryl 1-(5-
methoxy-2-phenyl)-phenylethanol (5a) was obtained in 47% yield along with
minor amounts of the symmetric biaryls. Biaryl 5a was then dehydrated to 5-
methoxy-2-phenylstyrene (6a) in 86% yield by warming at 140 C in dry xylene
with I2 for 6 hr. The vinyl derivative 6a was then photocyclized to 2-methoxy-
9,10-dihydrophenanthrene (7a) by irradiation (Padwa et al., 1977) with a 450-W
Hanovia Lamp. The best yields of conversion of 6a to 7a were achieved when
irradiation was run in dry benzene at room temperature for 1 hr under argon. In
such cases about 50% of 6a was recovered from the reaction mixture, and the
only product obtained was 7a. At longer reaction times a series of byproducts
was formed. An overall 87% conversion yield of 6a to 7a was obtained after
two photocyclization reactions. When the reaction was run in the presence of
atmospheric oxygen under the same conditions, 2-methoxyphenanthrene (8a) in
overall 82% yield was formed along with small amounts of 7a (5%). Finally 7a
and 8a were demethylated by BBr3 in CH2Cl2 for 3 hr at 70 C to afford 2-
hydroxy-9,10-dihydrophenanthrene (7b) and 2-hydroxyphenanthrene (8b) in 70
and 73% yields, respectively.
2-Hydroxy-7-methylphenathrene (8h) and its 9,10-dihydro analog (7h)
were obtained in the same way starting from 4-iodotoluene: the biaryl 5d,
obtained in 37% yield in the coupling, was dehydrated to the vinyl derivative

SYNTHESIS OF ANTIALGAL COMPOUNDS
597
SCHEME 2. Synthesis of 2-hydroxy-9,10-dihydrophenanthrene (7b) and 2-hydrox-
yphenanthrene (8b). i: Zn, PPh3, NiCl2, DMF; ii: I2, xylene; iii: hn, benzene, Ar; iv:
hn, benzene, air; v: BBr3, CH2Cl2.
6d (78% yields); photocyclization in absence and in the presence of oxygen
gave 2-methoxy-7-methyl-9,10-dihydrophenathrene (7g) (75%) and 2-methoxy-
7-methylphenanthrene (8g) (50%), which were demethylated to furnish 7h and
8h in 85% and 90% yields, respectively.
2-Hydroxy-6-methyl-9,10-dihydrophenanthrene (7f) and 2-hydroxy-8-
methyl-9,10-dihydrophenanthrene (7l), as well as the corresponding 2-hydroxy-
6-methylphenathrene (8f) and 2-hydroxy-8-methylphenanthrene (8l), were
obtained in the cross-coupling of 3-iodotoluene with 1. The asymmetric biaryl
5c, obtained in 38% yield, was dehydrated to the vinyl intermediate 6c. The
photocyclization of the latter under argon gave a mixture of 2-methoxy-6-
methyl- (7e) and 2-methoxy-8-methyl-9,10-dihydrophenanthrene (7i). In con-
trast, 2-methoxy-6-methyl (8e) and 2-methoxy-8-methylphenanthrene (8i) were
formed in the presence of oxygen. The predominance in both cases of the 6-
methyl isomers 7e and 8e may be explained on steric grounds. The mixtures
were resolved by HPLC. Demethylation of the pure methoxyderivatives by BBr3

598
DELLAGRECA ET AL.
afforded the targets 7f, 7l, 8f, and 8l in overall 11%, 8%, 13%, and 9% yields,
respectively.
When 1 was coupled with 2-iodotoluene in the synthesis of 2-hydroxy-
5-methyl-9,10-dihydrophenanthrene (7d) and the corresponding phenanthrene
8d, the only products formed were toluene and 3. As reported by Semmel-
hack et al. (1981), the coupling of sterically hindered 2-halotoluenes requires
long times, and, under the present conditions, the primary process was the
replacement of iodide by the alcoholic hydrogen of 1. Compounds 7d and 8d
were obtained starting from 2-iodo-5-methoxyacetophenone, which was coupled
with 2-iodotoluene. The reaction was run at 40 C for 70 hr to give the cor-
responding asymmetric biaryl in 26% yield. Reduction by NaBH4 and dehy-
dration afforded the vinyl intermediate 6b. Photocyclization in both condi-
tions afforded 2-methoxy-5-methyl-9,10-dihydrophenanthrene (7c) and the cor-
responding phenanthrene 8c, which, by demethylation, were converted to the
targets 7d and 8d.
The 2-hydroxy-9,10-dihydrophenanthrenes, the 2-hydroxyphenathrenes,
and the corresponding O-methyl derivatives were assayed in broth against Sele-
nastrum capricornutum at concentrations of 10 4–10 5 M, the range usually used
with commercial algicides. All compounds were purified by HPLC before the
tests and were found to be stable under the conditions of the assay. The statistical
significance of results and the index of inhibition were calculated.
All compounds, except 2-methoxy-7-methylphenanthrene (8g), had strong
4
activity at 10 M, with inhibition higher than 70% (Tables 1 and 2). The most
active were dihydrophenathrenes 7a, 7b, 7c, 7e, and 7i and the phenathrenes 8c
and 8d, which caused full inhibition of algal growth. At the lowest concentra-
tion, all compounds, except the dihydrophenathrenes 7d, 7g, 7h, and 7l and the
phenathrenes 8a, 8b, 8c, and 8g, retained strong activity. Dihydrophenanthrenes
7b, 7c, 7e, and 7i and phenanthrene 8d fully inhibited the algal growth.
TABLE 1. INHIBITION OF S. capricornutum GROWTH BY SYNTHETIC 9,10-DIHYDRO-
a
PHENANTHRENES
Inhibition (%)
7b
7a
7d
7c
7f
7e
7h
7g
7l
7i
4
10
M
96b
96b
96b
0a
98c
93b
93b
0a
86b
86b
0a
95b
95b
95b
0a
91b
91b
91b
0a
100b
100b
100b
0a
80d
75c
48b
0a
92c
92c
20b
0a
77b
77b
0a
98b
98b
98b
0a
5
5 × 10
M
5
10
M
Control
0a
0a
a
In each column values followed by different letters are statistically significant. Student-Newman-
Keuls test; P 0.05.

SYNTHESIS OF ANTIALGAL COMPOUNDS
599
TABLE 2. INHIBITION OF S. capricornutum GROWTH BY SYNTHETIC PHENANTHRENES
Inhibition (%)
8b
8a
8d
8c
8f
8e
8h
8g
8l
8i
4
10
M
72c
72c
47b
0a
80d
76c
69b
0a
95b
95b
95b
0a
97c
97c
20b
0a
85c
80b
80b
0a
90b
90b
90b
0a
80b
80b
80b
0a
10b
10b
0a
85c
80b
80b
0a
90b
90b
90b
0a
5
5 × 10
M
5
10
M
Control
0a
a
In each column values followed by different letters are statistically significant. Student-Newman-
Keuls test; P 0.05.
The methoxyderivatives are more active than hydroxyderivatives in the
dihydrophenanthrene series, while in the phenanthrene series their activities
are comparable. The introduction of a methyl in the C ring of methoxydi-
hydrophenanthrenes did not change the activity, while a reduction was observed
in the hydroxydihydrophenanthrenes. The activity increased in all the hydrox-
yphenathrenes and in the substituted methoxyphenanthrenes, except for 2-
methoxy-7-methylphenanthrene, which was inactive for all concentrations.
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