4244 J . Org. Chem., Vol. 64, No. 12, 1999
Goekjian et al.
(1H, dddd, J ) 7.6, 7.4, 3.1, 3.1 Hz); 3.51 (1H, dddd, J ) 12.5,
6.1, 3.2, 3.1 Hz); 3.12 (3H, s). 13C NMR {H} (75 MHz, CDCl3):
δ 89.1 ppm (d, J ) 175.5 Hz); 78.9 (d, J ) 25.9 Hz); 66.8; 59.0
(d, J ) 5.5 Hz); 48.6 (d, J ) 27.0 Hz). 19F NMR (376 MHz,
CDCl3): δ -185.9 ppm (dddd, J ) 41, 34, 9, 7 Hz). [R]25D +34°
(c 0.172 CHCl3). UV-vis λmax: 282, 370, 452 nm.
The (2R) diastereomer 11b (60.3 mg, 0.103 mmol) was
converted to the corresponding diol (39.6 mg, 37.0 mg carried
on) then to the primary alcohol 12b (21.5 mg, 0.0455 mmol,
47% yield for three steps) in the same manner. 12b (19R):
HRMS (FAB): calculated for C27H24FN3O4+Na: 496.1649,
observed: 496.1661. FTIR (neat film): 3453 cm-1, 1703. 1H
NMR (300 MHz, CDCl3): δ 8.05-7.95 ppm (2H); 7.40-7.20
(6H); 7.20 (1H, s); 7.17 (1H, s); 4.95 (1H, dddd, J ) 42.9, 8.5,
3.3, 3.3 Hz); 4.52 (1H, ddd, J ) 14.8; 8.5, 5.7 Hz); 4.40-4.20
(2H); 4.10 (1H, m); 4.00 (1H, ddd, J ) 10.3, 9.1, 1.5 Hz); 3.86
(1H, m); 3.80-3.60 (3H); 3.20 (3H, s). 13C NMR {H} (75 MHz,
CDCl3): δ 90.2 ppm (d, J ) 176.4 Hz); 78.6 (d, J ) 25.3 Hz);
67.6; 60.0 (d, J ) 2.5 Hz); 46.1 (d, J ) 33.0 Hz). 19F NMR (376
MHz, CDCl3): δ -187.2 ppm (dddd, J ) 43, 15, 12, 6 Hz). UV-
vis λmax: 282, 374, 498 nm.
(18R,19S)- an d (18R,19R)-19-Flu or o-18-(h ydr oxym eth yl)-
17-oxa -4,14,21-tr ia za h exa cyclo[19.6.1.17,14.0.2,6.08,13.022,27]-
n on a cosa -1(28),2(6),7(29),8,10,12,22(27),23,25-n on a en e-
3,5-d ion e (3 a n d 4). A solution of 12a (50 mg, 0.106 mmol)
in C2H5OH (3 mL) and 5 N KOH (3 mL) was stirred at 70 °C
for 20 h. The solution was cooled to 0 °C and acidified with 5
N HCl. A red precipitate appeared. After 10 min of stirring,
the mixture was extracted with methylene chloride and
washed with water. Drying over Na2SO4, evaporation, and
silica gel chromatography in 5% ethyl acetate-hexane yields
the anhydride (33 mg, 0.0717 mmol, 68% yield) and recovered
starting material (2.5 mg, 5%).
(18R,19S)- a n d (18R,19R)-19-F lu or o-18-[(d im eth yl-
am in o)m eth yl]-17-oxa-4,14,21-tr iazah exacyclo[19.6.1.17,14
.
0.2,6.08,13.022,27]n on acosa-1(28),2(6),7(29),8,10,12,22(27),23,25-
n on a en e-3,5-d ion e (1 a n d 2). A solution of the primary
alcohol 3 (31 mg, 0.067 mmol) in THF (15 mL) was treated
with triethylamine (210 µL, 1.56 mmol), and methanesulfonyl
chloride (85 µL, 1.02 mmol) was added. The reaction mixture
was stirred at room temperature under N2 for 3 h. The mixture
was concentrated under reduced pressure, taken up in meth-
ylene chloride, and washed with 1 N HCl and brine. Drying
over Na2SO4 and evaporation yielded the crude mesylate. A
solution of the crude mesylate in THF (6 mL) was treated with
dimethylamine (40% aqueous, 1 mL), and the flask was sealed
with a Teflon stopper and stirred at 50 °C for 24 h. The flask
was cooled to 0 °C and opened, and the volatiles were removed
under reduced pressure. Silica gel chromatography in 0-10%
triethylamine in ethyl acetate yields the dimethylamine 1 (13.2
mg, 0.027 mmol, 40% yield) as a purple-red solid. 1 (19S):
HRMS (FAB): calculated for C28H27FN4O3 + Na 509.1965,
observed 509.1971. FTIR (neat film): 3053 cm-1, 1715. 1H
NMR (300 MHz, CDCl3-C6D6, 2:1): δ 8.12-7.95 (2H); 7.30-
7.05 (9H); 4.67 (1H, dddd, J ) 43.9, 7.4, 4.0, 3.2 Hz); 4.14 (1H,
ddd, J ) 20.4, 14.9, 3.2 Hz); 4.02 (1H, ddd, J ) 14.9, 14.9, 7.4
Hz); 3.94 (1H, ddd, J ) 15.0, 4.0, 4.0 Hz); 3.81 (1H, ddd, J )
150, 4.2, 5.6 Hz); 3.58 (2H, dd, J ) 4.2, 4.8 Hz); 3.47 (1H, dddd,
J ) 14.0, 4.5, 4.3, 4.2 Hz); 1.79 (6H, s); 1.73 (1H, ddd, J )
13.4, 4.5, 2.8 Hz); 1.64 (1H, dd, J ) 13.4, 4.3 Hz). 13C NMR
{H} (75 MHz, CDCl3): δ 172.7 ppm; 172.6; 137.6; 136.8; 134.1;
133.7; 128.6; 128.0; 123,0; 122.7; 122.6; 121.3; 121.1; 111.1;
110.7; 105.5; 104.6; 90.9 (d, J ) 175.1 Hz); 79.6 (d, J ) 21.3
Hz); 69.3; 59.3 (d, J ) 8.8 Hz); 47.7; 46.6 (d, J ) 31.6 Hz);
45.9. 19F NMR (376 MHz, acetone-d6): δ -187.3 ppm (ddddd,
J ) 43, 15, 15, 15, 3 Hz). UV-vis λmax: 282, 372, 494 nm.
The anhydride (54 mg, 0.117 mmol) in DMF (5 mL) was
treated with 1,1,1,3,3,3-hexamethyldisilazane (500 µL, 2.36
mmol) and CH3OH (48 µL, 0.62 mmol). The resulting mixture
was stirred at room temperature under N2 for 36 h. The
volatiles were removed under reduced pressure. The residue
was dissolved in 6 mL of CH3CN-1 N HCl (2:1) and stirred
at room temperature for 1 h. The organic solvent was removed,
and the suspension was extracted with methylene chloride and
washed with water and brine. The residue was dried over
Na2SO4, concentrated, and separated on silica gel column
eluted with 9:1 CH3CN-CH2Cl2 to yield the imide 3 (31 mg)
and recovered anhydride (20 mg). The recovered anhydride
was resubmitted to the same reaction conditions to yield an
additional 18 mg of 3 (combined 49 mg, 0.107 mmol, 91% yield;
66% for two steps) as a purple solid. 3 (19S): HRMS (FAB):
calculated for C26H22FN3O4 + H 460.1672, observed 460.1655.
FTIR (neat film): 3450 cm-1, 1697. 1H NMR (300 MHz,
acetone-d6): δ 9.72 ppm (1H, s); 8.04 (1H, dd, J ) 7.6, 1.0 Hz);
7.89 (1H, dd, J ) 7.7, 1.1 Hz); 7.56 (1H, s); 7.51 (1H, d, J )
8.1 Hz); 7.49 (1H, d, J ) 8.0 Hz); 7.40 (1H, s); 7.30-7.10 (4H),
4.95 (1H, dddd, J ) 43.8, 7.2, 5.3; 2.1 Hz); 4.62 (1H, ddd, J )
15.4, 9.8, 5.4 Hz); 4.56-4.35 (3H); 4.02 (2H, m); 3.86 (1H, m);
3.68 (1H, dddd, J ) 7.6, 7.4, 3.1, 3.1 Hz); 3.51 (1H, dddd, J )
12.5, 6.1, 3.2, 3.1 Hz). 13C NMR {H} (125 MHz, CD2Cl2): _
89.8 ppm (d, J ) 175.5 Hz); 79.1 (d, J ) 25.9 Hz); 58.8 (d, J )
5.7 Hz); 48.5 (d, J ) 27.0 Hz). 19F NMR (376 MHz, CDCl3): δ
-183.8 ppm (dddd, J ) 44, 35, 10, 7 Hz). UV-vis λmax: 282,
374, 498 nm.
The fluorine diastereomer 4 (3.4 mg, 7.4 µmol) was con-
verted to the dimethylamine 2 (1.9 mg, 3.9 µmol, 53% yield
after recrystallization from methylene chloride-hexane) by the
same procedure. 2 (19R): FTIR (neat film): 3051 cm-1, 1703.
1H NMR (300 MHz, CDCl3): δ 8.05-7.95 ppm (2H); 7.40-7.20
(8H); 4.86 (1H, dddd, J ) 43.2, 7.9, 3.2, 3.0 Hz); 4.50-4.30
(3H); 4.20-4.00 (2H); 3.80-3.60 (3H); 2.50-2.30 (2H, m); 2.09
(6H, s). 19F NMR (376 MHz, CDCl3): δ -180.9 ppm (m). UV-
vis λmax: 282, 384, 498 nm.
(2S,3R)-3-[(2R)-1,4-Dioxa sp ir o[4.5]d eca n yl]-2-flu or o-3-
(2-h yd r oxyp r op oxy)-p r op a n -1-ol (14). A solution of 9-BBN
(0.5 M in THF, 1.0 mL, 0.50 mmol) at 0 °C under N2 was
treated with a solution of 9a (69 mg, 0.250 mmol) in THF (2
mL). The solution was stirred at room temperature for 3 h.
The mixture was treated with NaOH (3 N, 1 mL) and 30%
H2O2 (2 mL). The solution was adjusted to pH 8 and stirred
at 50 °C for 1 h.28 The reaction was cooled to room temperature,
diluted with ethyl acetate, and washed with saturated K2CO3,
water, and brine. The organic layer was dried over Na2SO4
and evaporated at reduced pressure. The residue was chro-
matographed on silica gel column using 1:1 ethyl acetate-
hexane and then ethyl acetate as eluent, yielding the diol 14
(48 mg, 0.164 mmol, 66% yield) as a clear colorless oil, along
with recovered starting material (13 mg, 19%). HRMS (EI):
calculated for C14H25FO5 292.1686, observed 292.1685. FTIR
(neat film): 3450 cm-1 1H NMR (300 MHz, CDCl3): δ 4.67
.
ppm (1H, dddd, J ) 47.2, 5.0, 4.1, 3.6 Hz); 4.18 (1H, ddd, J )
6.1, 6.1, 6.0 Hz); 4.07 (1H, ddd, J ) 7.1, 7.1, 1.0 Hz); 4.00-
3.65 (8H); 2.88 (1H, br. s); 2.45 (1H, br. s); 1.80 (2H, tt, J )
6.0, 6.0 Hz). 13C NMR {H} (75 MHz, CDCl3): δ 93.4 ppm (d, J
) 173.8 Hz); 79.3 (d, J ) 20.7 Hz); 74.2 (d, J ) 6.6 Hz); 70.2;
65.7; 61.6 (d, J ) 21.9 Hz); 60.1. 19F NMR (376 MHz, CDCl3):
The fluorine diastereomer 12b (11.9 mg, 25.1 µmol) was
converted to the imide 4 (6.0 mg, 13.1 µmol, 52% yield) by the
same procedure, except that 250 µL of HMDS and 15 µL of
methanol were used. 4 (19R): HRMS (FAB): calculated for
C
26H22FN3O4 + Na 482.1492, observed 482.1485. FTIR (neat
δ -197.6 ppm (dddd, J ) 47.3, 24.5, 24.5, 14.5 Hz). [R]25
4.1° (c 0.93 CHCl3).
+
D
film): 3273 cm-1, 1719. H NMR (300 MHz, CDCl3): δ 8.03-
7.95 ppm (2H); 7.43-7.21 (9H); 4.94 (1H, dddd, J ) 42.9, 8.5,
3.3, 3.3 Hz); 4.55 (1H, ddd, J ) 14.8; 8.5, 5.7 Hz); 4.40-4.20
(2H); 4.15 (1H, ddd, J ) 14.5, 8.8, 1.9 Hz); 4.02 (1H, ddd, J )
10.2, 8.8, 1.0 Hz); 3.83 (1H, m); 3.77 (1H, ddd, J ) 10.8, 4.4,
1.9 Hz); 3.75-3.64 (2H). 13C NMR {H} (151 MHz, CDCl3): 90.1
ppm (d, J ) 176.4 Hz); 78.6 (d, J ) 25.3 Hz); 46.1 (d, J ) 33.0
Hz). 19F NMR (376 MHz, CDCl3): δ -186.8 ppm (ddddd, J )
43, 15, 12, 6, 3 Hz). UV-vis λmax: 290, 372, 496 nm.
1
(19R ,20S )-19-[(2R )-1,4-Dioxa sp ir o[4.5]d e ca n yl]-20-
flu or o-4-m e t h yl-18-oxa -4,14,21-t r ia za h e xa cyclo[20.6.
1.17,14.0.2,6.08,13.022,28]t r ia con t a -1(29),2(6),7(30),8,10,12,
23(28),24,26-n on a en e-3,5-d ion e (15). A solution of the diol
(28) Brown, H. C.; Knights, E. F.; Scouten, G. J . Am. Chem. Soc.
1974, 96, 7765.