5584 J . Org. Chem., Vol. 63, No. 16, 1998
Wasserman and Wang
118.0, 113.1, 112.1, 56.7, 40.3, 28.7, 27.7. (Both 1H NMR and
13C NMR spectra were identical to the corresponding spectra
of the natural material1a). HRMS FAB (m-NBA) Calcd for
extracted with CH2Cl2 (3 × 100 mL) and dried over NaOH.
Evaporation of solvent gave the product (0.8 g, 84% as a
colorless oil. IR (CHCl3): 3000; 2960; 2840; 1600; 1500; 1460;
1420; 1280; 1250; 1050; 1020. 1H NMR (CDCl3): 7.38 (d J )
1.6, 1H), 7.09 (dd, J ) 8.4, 1.6, 1H); 6.83 (d, J ) 8.4, 1H); 3.87
(s, 3H, OCH3); 2.92 (m, 2H); 2.66 (t, J ) 6.8, 2H); 1.02 (s, 2H,
NH2). 13C NMR (CDCl3): 154.3, 133.6, 133.4, 129.7, 111.9,
111.5, 56.2, 43.5, 38.8. HRMS EI Calcd for C9H1279BrNO: M+
229.0102; found 229.0100.
Cou p lin g P r od u ct 12 of 3-Br om o-4-m eth oxyp h en eth yl-
a m in e (11) w ith 10. Ozone was added to a solution of ylide
10 (500 mg, 0.82 mmol) in CH2Cl2 (30 mL) for 5 min at -78
°C, and the resulting greenish solution was purged with N2
for 5 min. To this yellowish solution was added a solution of
amine 11 (150 mg, 0.66 mmol) in CH2Cl2 (5 mL) via cannula,
and the mixture was stirred at -78 °C for 5 min and room
temperature for 1 h. The solvent was evaporated in vacuo,
and the residue was purified by column chromatography on
silica gel. The fraction eluted with EtOAc/n-hexane (1:3) was
collected. Removal of the solvents gave 12 (281 mg, 76%) as
a pale yellow oil. IR (CHCl3): 3400; 3000; 2920; 1680; 1520;
1500; 1480; 1420; 1250; 1110; 1060; 990. 1H NMR (CDCl3):
7.38 (s, 2H); 7.36 (d, J ) 2.0, 1H); 7.05 (dd, J ) 8.3, 2.0, 1H);
7.01 (t, J ) 6.7, 1H, NH); 6.82 (d, J ) 8.3, 1H); 4.12 (s, 2H,
CH2); 3.87 (s, 3H, OCH3); 3.86 (s, 3H, OCH3); 3.53 (q, J ) 6.7,
2H); 2.77 (t, J ) 6.7, 2H). 13C NMR (CDCl3): 162.9; 154.6;
152.6; 151.9; 134.8; 133.4 (2C); 133.3; 132.1, 128. 6; 117.8 (2C);
112.1; 111.7; 60.5; 56.2; 40.7; 34.2; 27.9. HRMS FAB (m-NBA)
Calcd for C19H1979Br281BrNO4: (M + H)+ 563.8844; found
563.8847.
C
15H1879BrN4O3: (M + H)+ 381.0562; found 381.0558.
Syn th esis of Hem iba sta d in -2 (14). Meth yl (3,5-Di-
br om o-4-h yd r oxylp h en yl)a ceta te (7). To a solution of tert-
butylamine (1.5 g, 20.0 mmol) in toluene (20 mL) was added
bromine (3.2 g, 20.0 mmol) at -78 °C followed by addition of
the solution of methyl (4-hydroxyphenyl)acetate (6) in CH2Cl2
(20 mL). The resulting reaction mixture was allowed to warm
to room temperature and stirring continued. After 3 h, CH2Cl2
(100 mL) was added, and the resulting solution was washed
with aqueous HCl (0.1 N, 120 mL) and brine (100 mL). The
organic solution was separated and dried over anhydrous
Na2SO4. Evaporation of the solvents gave the product 7 (3.1
g, 95%) as a white solid, mp 115-117 °C (from AcOEt/n-
hexane). IR (CHCl3): 3500; 3000; 2960; 1730; 1560; 1460;
1420; 1320; 1280; 1160; 1010. 1H NMR (CDCl3): 7.38 (s, 2H);
5.93 (s, 1H, OH); 3.71 (s, 3H, OCH3); 3.51 (s, 2H, CH2). 13C
NMR (CDCl3): 171.2 (COO); 148.6; 132.7(2C); 128.3; 109.7(2C);
52.3; 39.3. HRMS EI Calcd for C9H879Br81BrO3: M+ 323.8820;
found 323.8816.
Meth yl (3,5-Dibr om o-4-m eth oxyp h en yl)a ceta te (8). A
mixture of 7 (10 g, 30.8 mmol), K2CO3 (7.0 g, 50.7 mmol), and
Me2SO4 (5 g, 39.7 mmol) in acetone (200 mL) was stirred at
room temperature for 4 h. After most of the acetone was
removed in vacuo, the residue was dissolved in CH2Cl2 (200
mL) and H2O (200 mL). The organic solution was separated
and washed with H2O (200 mL) and brine (200 mL) and dried
over anhydrous Na2SO4. Evaporation of the solvents gave the
product 8 (9.7 g, 93%) as a colorless oil. IR (CHCl3): 3000;
2960; 1730; 1550; 1460; 1420; 1250; 1160; 1000. 1H NMR
(CDCl3): 7.43 (s, 2H); 3.87 (s, 3H, OCH3); 3.72 (s, 3H, OCH3);
3.54 (s, 2H, CH2). 13C NMR (CDCl3): 170.9 (COO); 153.2; 133.4
(2C), 131.1; 118.0 (2C); 60.5; 52.3; 39.5. HRMS EI Calcd for
Com p ou n d 13 (E-Oxim e of 12). A mixture of 12 (200 mg,
0.345 mmol), NH2OH‚HCl (200 mg, 2.89 mmol) and NaOAc
(300 mg, 3.66 mmol) in EtOH (20 mL) was stirred at room
temperature for 24 h and then partitioned between CH2Cl2
(200 mL) and water (100 mL). The CH2Cl2 fraction was
washed with brine (200 mL) and dried over anhydrous Na2SO4.
Evaporation of the solvents gave a residue which was purified
by column chromatography on silica gel. The fraction eluted
with EtOAc/n-hexane (1:3) was collected. Removal of the
solvents afforded the product 13 (174 mg, 85%) as a yellowish
oil. IR (CHCl3): 3550; 3400; 3000; 2920; 1670; 1600; 1530;
1500; 1480; 1420; 1250; 1000. 1H NMR (CDCl3): 7.49 (s, 2H);
7.33 (d, J ) 2.1, 1H); 7.01 (dd, J ) 8.4, 2.1, 1H); 7.01 (t, J )
7.2, 1H, NH); 6.77 (d, J ) 8.4, 1H); 4.12 (s, 2H, CH2); 3.84 (s,
3H, OCH3); 3.83 (s, 3H, OCH3); 3.49 (q, J ) 7.2, 2H); 2.72 (t,
J ) 7.2, 2H). 13C NMR (CDCl3): 194.8; 159.5; 154.8; 153.3;
133.9 (2C); 133.3; 131.5; 131.2; 128.5; 118.1 (2C); 112.1; 118.8;
60.5; 56.2; 41.5; 40.6; 34.0. HRMS FAB (m-NBA) Calcd for
C
10H1079Br2O3: M+ 335.8997; found 335.8994.
3,5-Dibr om o-4-m eth oxyp h en yla cetic Acid (9). To a
solution of 8 (10 g, 29.6 mmol) in CH3OH (200 mL) was added
NaOH (2 N, 20 mL) at room temperature. The resulting
reaction mixture was stirred for 1.5 h. After most of the
CH3OH was removed in vacuo, H2O (200 mL) was added. The
resulting solution was adjusted to pH 2.0 by the addition of
HCl (2 N). The solid was filtered and washed with H2O (10
mL) to afford the product 9 (9.1 g, 95%) as a white solid, mp
143-145 °C (from AcOEt/n-hexane). IR (CHCl3): 3000; 2920;
1710; 1550; 1470; 1410; 1260; 1000. 1H NMR (CDCl3): 7.45
(s, 2H); 3.89 (s, 3H, OCH3); 3.58 (s, 2H, CH2). 13C NMR
(CDCl3): 176.7 (COO); 153.5; 133.6 (2C), 131.5; 118.2 (2C);
60.6; 39.4. HRMS EI Calcd for C9H879Br81BrO3: M+ 323.8820;
found 323.8820.
C
19H2079Br3N2O4: (M + H)+ 576.8973; found 576.8955.
Hem iba sta d in -2 (14). A mixture of 13 (150 mg, 0.26
(Tr ip h en ylp h osp h or a n ylid en e)(3,5-d ib r om o-4-m et h -
oxyp h en yla cetyl)a ceton itr ile (10). A solution of carboxylic
acid 10 (6.5 g, 20.0 mmol), Ph3PCHCN (6.0 g, 20.0 mmol), and
EDCI (4.5 g, 23.5 mmol) in CH2Cl2 (150 mL) was stirred at
room temperature for 4 h. The reaction mixture was then
diluted by addition of CH2Cl2 (150 mL), washed with water
(200 mL) and brine (200 mL), and dried over anhydrous
Na2SO4. The solvent was evaporated, and the residue was
purified by column chromatography on silica gel. The fraction
eluted with AcOEt/hexane/CH2Cl2 (1:1:1) was collected. Re-
moval of the solvents gave the product 10 (11.0 g, 90%) as a
white crystal, mp 215-217 °C (from AcOEt). IR (CHCl3):
3000; 2180; 1580; 1470; 1430; 1340; 1250; 1100; 1000. 1H NMR
(CDCl3): 7.67-7.50 (m, 17H); 3.88 (s, 3H, OCH3); 3.86 (s, 2H,
CH2). 13C NMR (CDCl3): 192.6 (CO); 152.6; 135.1; 133.5 (d J
) 10, 6C); 133.3 (3C); 133.2 (2C); 129.2 (d, J ) 13, 6C); 122.7
(d, J ) 93, 3C); 122.4 (d, J ) 16, CN); 117.7 (2C); 60.5; 49.3
(d, J ) 125); 44.6 (d, J ) 7). HRMS FAB (m-NBA) Calcd for
mmol), Me2SO4 (200 mg, 1.58 mmol), and Na2CO3 (250 mg,
2.34 mmol) in acetone (15 mL) was stirred at room tempera-
ture for 18 h. To this reaction mixture was added CH2Cl2 (150
mL). The resulting solution was washed with water (2 × 50
mL) and brine (100 mL). Removal of the solvents gave a
residue which was purified by column chromagraphy on silica
gel. The fraction eluted with EtOAc/n-hexane (1:3) was
collected. Evaporation of the solvents afforded the product
hemibastadin-2 (14) (132 mg, 86%) as a yellowish oil. The
spectroscopic properties (IR, 1H NMR, and 13C NMR were
identical to the corresponding values for the natural hemibas-
tadin-2. IR (CHCl3): 3400; 3000; 1940; 1670; 1600; 1520; 1500;
1470; 1420; 1250; 1050; 990. 1H NMR (CDCl3): 7.43 (s, 2H);
7.38 (d, J ) 2.1, 1H); 7.08 (dd, J ) 8.4, 2.1, 1H); 6.83 (d, J )
8.4, 1H); 6.78 (t, J ) 7.1, 1H, NH); 4.00 (s, 3H, OCH3); 3.88 (s,
3H, OCH3); 3.85 (s 3H, OCH3); 3.82 (s, 2H, CH2); 3.52 (q, J )
7.2, 2H); 2.77 (t, J ) 7.2, 2H). 13C NMR (CDCl3): 162.1; 154.6;
152.7; 150.7; 134.8; 133.5; 133.3 (2C); 132.3; 128.7; 117.8 (2C);
112.1; 111.7; 63.2; 60.5; 56.3; 40.7; 34.4; 28.5. (Both 1H NMR
and 13C NMR spectra were identical to the corresponding
spectra of the natural material1b). HRMS FAB (m-NBA) Calcd
for C20H2279Br3NO4: (M + H)+ 590.9129; found 590.9119.
Syn th esis of Aer oth ion in (28). 2-(Ben zyloxy)-4-m eth -
oxya cetop h en on e (16). A mixture of 2′-hydroxy-4′-meth-
oxyacetophenone (15) (3.5 g, 21.1 mmol), benzyl bromide (4.5
C
29H2379Br2NO2P: (M + H)+ 605.9833; found 605.9832.
3-Br om o-4-m eth oxyp h en eth yla m in e (11). A mixture of
N-benzoyl-3-bromo-4-methoxyphenethylamine (1.4 g, 4.2 mmol),
AcOH (5 mL), and HCl (6 N, 20 mL) was refluxed for 48 h
under N2. After the benzoic acid was removed by extraction
with CH2Cl2 (2 × 50 mL), the aqueous solution was adjusted
to pH 0-1 by the addition of solid NaOH. The product was