6296 J . Org. Chem., Vol. 62, No. 18, 1997
Hom and Katzenellenbogen
allowed to warm to rt and stir for 12 h. Concentration and
flash chromatography (20-30% EtOAc/hexanes) yielded a
colorless oil as product (1.04 g, 91%): Rf 0.69 (50% EtOAc/
6-H yd r oxy-1-((((2-t h ioet h yl)t h io)a cet a m id o)m et h yl)-
1,2,3,4-tetr a h yd r oisoqu in olin e Hyd r och lor id e (21‚HCl).
The thiol 20 (524 mg, 1.05 mmol) was taken up in a minimal
amount (0.5 mL) of THF at rt; then 4 N HCl in dioxane (10
mL) was introduced by syringe. After 15 min an off-white
precipitate was deposited onto the sides of the reaction vessel.
Concentration and repeated cycles of addition of dry Et2O and
evaporation to remove excess acid gave a white to off-white
solid (365 mg, 100%) after concentration under vacuum. This
was taken to the next step (metal complexation) without
further purification. An analytical sample was purified by
dissolution in 20% MeOH/CH2Cl2 and passage through a silica
plug with elution with 20% MeOH/CH2Cl2. Collection of
appropriate fractions allowed for the isolation of a colorless
oil 16: 1H NMR (DMSO-d6, 400 MHz, 100 °C) δ 2.76-3.00
(m, 5), 3.14-3.23 (m, 1), 3.20 (s, 2), 3.25 (s, 2), 3.37 (dt, J )
12.5, 6.3, 1), 3.54-3.68 (m, 2), 4.37 (dd, J ) 7.6, 4.4, 1), 6.60
(d, J ) 2.0, 1), 6.68 (dd, J ) 8.4, 2.3, 1), 7.07 (d, J ) 8.5, 1),
8.30 (s, 1), 9.20 (b s, 2); MS (CI, CH4) m/z 313 (M + H+, 0.5),
1
hexanes); IR (CDCl3, cm-1) 2103 (NdNdN), 1682 (CdO); H
NMR (DMSO-d6, 400 MHz, 100 °C) δ 1.43 (s, 9), 2.68-2.83
(m, 2), 3.25 (s, 3), 3.26-3.36 (m, 1), 3.55 (ABX, J AB ) 12.7, ∆ν
) 0.092, J AX ) 7.8, J BX ) 4.9, 2), 3.6045 (AB q, J AB ) 5.4, ∆ν
) 0.23, 2), 3.6050 (AB q, J AB ) 4.5, ∆ν ) 0.25, 2), 3.90 (dt, J
) 13.2, 4.9, 1), 5.16 (dd, J ) 7.6, 5.1, 1), 5.20 (s, 2), 6.83 (d, J
) 2.4, 1), 6.86 (dd, J ) 8.3, 2.4, 1), 7.20 (d, J ) 8.3, 1); MS (CI,
CH4) m/z 393 (M + H+, 5), 337 (22), 336 (37), 294 (24), 293
(95), 291 (18), 281 (20), 280 (100), 250 (30), 236 (38), 218 (13),
+
217 (40), 192 (45), 148 (49); HRMS calcd for C19H28N4O5
393.2138, found 393.2132.
1-(Am in om et h yl)-2-(ter t-b u t oxyca r b on yl)-6-((2-m et h -
oxyeth oxy)m eth oxy)-1,2,3,4-tetr a h yd r oisoqu in olin e (18).
To a solution of azide 17 (1.01 g, 2.58 mmol) in ethanol (15
mL) was added 10% palladium on carbon (400 mg). The
reaction mixture was then placed under a hydrogen atmo-
sphere for 21 h. Palladium-carbon was then removed by
filtering through Celite and rinsing with 10% MeOH/CH2Cl2.
Concentration and flash chromatography (10% MeOH/CH2Cl2)
gave the title compound as a somewhat air- and moisture-
sensitive red oil (797 mg, 84%): Rf 0.018 (50% EtOAc/hexanes);
IR (CDCl3, cm-1) 1682 (CdO); 1H NMR (DMSO-d6, 400 MHz,
100 °C) δ 1.44 (s, 9), 2.37 (b s, 2), 2.66-2.81 (m, 2), 3.25 (s, 3),
3.29 (tt, J ) 8.4, 5.0, 1), 3.6065 (AB q, J AB ) 5.2, ∆ν ) 0.23,
2), 3.6070 (AB q, J AB ) 4.6, ∆ν ) 0.25, 2), 3.87 (dt, J ) 13.2,
5.0, 1), 4.88 (t, J ) 6.3, 1), 5.19 (s, 2), 6.80 (d, J ) 2.0, 1), 6.84
(dd, J ) 8.3, 2.4, 1), 7.14 (d, J ) 8.3, 1); 13C NMR (DMSO-d6,
100 MHz, 100 °C) δ 27.7, 37.5, 46.3, 56.0, 57.46, 57.52, 66.9,
70.6, 78.4, 93.0, 113.9, 115.8, 127.6, 128.6, 135.4, 154.2, 155.2;
MS (FAB) m/z 367 (M + H+, 100), 336 (15), 311 (56), 280 (77),
267 (85), 250(24), 236 (26), 192 (16), 148 (22); HRMS calcd for
293 (10), 231 (21), 203 (100), 89 (12); HRMS calcd for
+
C
14H21N2O2S2 313.1045, found 313.1040.
Syn th esis of Rh en iu m (V) Com p lexes. [6-Hyd r oxy-1-
((((2-m er ca p toeth yl)th io)a ceta m id o)m eth yl)-1,2,3,4-tet-
r a h yd r oisoq u in olin a t o-S,N,N′]oxor h en iu m (V) (5a a n d
5b). A sample of 21‚HCl (366 mg, 1.05 mmol) was dissolved
in degassed MeOH (10 mL), and 1 N NaOAc in MeOH (10 mL)
was added at rt. Benzyltriethylammonium tetrachloroox-
orhenate(V)49 (675 mg, 1.26 mmol) in degassed MeOH (30 mL)
was added to this solution slowly with stirring at rt. The
resulting red solution was then heated to reflux for 4 h. The
reaction mixture was then cooled and concentrated, and the
residue was taken up in CH2Cl2/H2O. The layers were
separated, and the aqueous layer was back-extracted with
CH2Cl2. The organic extracts were combined, washed (satu-
rated NaCl), dried (MgSO4), and concentrated to leave a deep
red residue. Flash chromatography (50% EtOAc/benzene) gave
two closely eluting bands, one orange and one red, of which a
small portion was separated for analytical characterization.
Combined fractions of oxorhenium(V) products afforded 45 mg
(8%) of a 1:1 diastereomeric mixture of 5a and 5b.
+
C19H31N2O5 367.2233, found 367.2233.
1-((Br om oa ceta m id o)m eth yl)-2-(ter t-bu toxyca r bon yl)-
6-((2-m eth oxyeth oxy)m eth oxy)-1,2,3,4-tetr ah ydr oisoqu in -
olin e (19). Acylation of the amine was performed according
to a literature method.37 A solution of bromoacetyl bromide
(24 µL, 0.275 mmol) in CH2Cl2 (1 mL) was cooled to -20 °C. A
mixture of amine 18 (99 mg, 0.27 mmol) and triethylamine
(40 µL, 0.287 mmol) was then added dropwise with stirring.
The reaction mixture was allowed to warm to rt. After 10 min,
the reaction mixture was concentrated, and flash chromatog-
raphy (50-60% EtOAc/hexanes) gave a clear, colorless oil as
product (114 mg, 87%): 1H NMR (DMSO-d6, 400 MHz, 100
°C) δ 1.43 (s, 9), 2.74 (dd, J ) 9.8, 5.5, 2), 3.23-3.34 (m, 1),
3.25 (s, 3), 3.34-3.45 (m, 2), 3.49 (t, J ) 5.0, 2), 3.73 (t, J )
5.0, 2), 3.83 (d, J ) 2.0, 2), 3.84-3.94 (m, 1), 5.11 (dd, J ) 8.2,
5.8, 1), 5.20 (s, 2), 6.81 (d, J ) 2.4, 1), 6.85 (dd, J ) 8.3, 2.4, 1),
7.11 (d, J ) 8.3, 1), 7.99 (b s, 1); MS (FAB) m/z 489 (M + H+,
15), 487 (M + H+, 16), 390 (16), 389 (89), 388 (17), 387 (93),
336 (33), 309 (41), 281 (16), 280 (100), 236 (18), 192 (16), 155
(22), 119 (56); HRMS calcd for C21H32N2O681Br+ 489.1423,
found 489.1414. Anal. Calcd for C21H31BrN2O5: C, 53.51; H,
6.63; N, 5.94. Found: C, 53.79; H, 6.59; N, 6.15.
a n ti isom er (5a ): 1H NMR (acetone-d6, 500 MHz) δ 1.92-
2.02 (m, 1), 2.78 (td, J ) 16.1, 2.6, 1), 2.85 (td, J ) 13.8, 3.6,
1), 3.08 (ddd, J ) 17.0, 11.1, 5.8, 1), 3.27 (t, J ) 10.9, 1), 3.78
(d, J ) 16.9, 1), 3.86 (ddd, J ) 8.8, 3.6, 1.3, 1), 4.01 (dd, J )
13.5, 3.8, 1), 4.36 (td, J ) 12.1, 3.8, 1), 4.66 (d, J ) 16.9, 1),
4.71 (t, J ) 8.7, 1), 4.87 (dd, J ) 11.6, 7.1, 1), 4.94 (dd, J )
11.8, 5.3, 1), 6.62 (d, J ) 2.1, 1), 6.68 (dd, J ) 8.3, 2.6, 1), 7.04
(d, J ) 8.3, 1), 8.13 (s, 1); MS (FAB) m/z 513 (M + H+ for 187Re,
8), 511 (M + H+ for 185Re, 8), 307 (47), 289 (32), 273 (21), 165
(18), 155 (65), 154 (100), 152 (36), 138 (78), 137 (90), 136 (97);
+
HRMS calcd for C14H18N2O2ReS2 513.0317, found 513.0304.
syn isom er (5b): 1H NMR (DMSO-d6, 500 MHz) δ 1.94
(ddd, J ) 14.6, 10.5, 4.5, 1), 2.63 (dt, J ) 15.8, 2.7, 1), 2.75
(td, J ) 13.7, 3.4, 1), 2.81 (ddd, J ) 15.4, 11.9, 3.9, 1), 3.24-
3.33 (m, 1), 3.66-3.70 (m, 1), 3.94 (d, J ) 17.1, 1), 3.92-3.99
(m, 1), 4.01 (t, J ) 11.2, 1), 4.44 (dd, J ) 12.6, 7.2, 1), 4.66 (d,
J ) 17.1, 1), 4.83-4.89 (m, 1), 5.52 (t, J ) 8.0, 1), 6.49 (d, J )
2.3, 1), 6.59 (dd, J ) 8.3, 2.5, 1), 7.04 (d, J ) 8.5, 1), 9.20 (s, 1);
1H NMR (acetone-d6, 500 MHz) δ 1.89-1.97 (m, 1), 2.01-2.08
(m, 1), 2.63-2.72 (m, 1), 2.77-2.90 (m, 1), 3.28 (dd, J ) 12.2,
9.9, 1), 3.82 (d, J ) 17.5, 1), 3.84 (ddd, J ) 10.5, 3.7, 1.5, 1),
3.92-3.97 (m, 1), 3.97-4.03 (m, 1), 4.51 (dd, J ) 12.6, 7.2, 1),
4.60 (d, J ) 17.9, 1), 4.94 (ddd, J ) 13.5, 4.6, 2.5, 1) , 5.56 (t,
J ) 8.3, 1), 6.60 (d, J ) 2.5, 1), 6.70 (dd, J ) 8.3, 2.6, 1), 7.08
(d, J ) 8.5, 1), 8.14 (s, 1); MS (FAB) m/z 513 (M + H+ for 187Re,
7), 511 (M + H+ for 185Re, 7), 307 (41), 289 (25), 165 (13), 154
(100), 139 (30), 138 (63), 137 (86), 136 (95), 135 (15), 124 (19),
2-(ter t-Bu toxycar bon yl)-6-((2-m eth oxyeth oxy)m eth oxy)-
1-((((2-th ioeth yl)th io)a ceta m id o)m eth yl)-1,2,3,4-tetr a h y-
d r oisoqu in olin e (20). To a solution of 1,2-ethanedithiol (1.0
mL, 8.4 equiv) and bromide 19 (662 mg, 1 equiv, 1.36 mmol)
in THF (30 mL), NaH (60% dispersion in mineral oil, 110 mg,
2 equiv) at 0 °C. After 45 min, the suspension was allowed to
warm to rt and was stirred for an additional 1.5 h. The
reaction mixture was subsequently quenched with MeOH and
then concentrated. Flash chromatography (60% EtOAc/hex-
anes) gave a colorless oil as product (524 mg, 77%): Rf 0.52
(50% EtOAc/hexanes); 1H NMR (DMSO-d6, 400 MHz, 100 °C)
δ 1.43 (s, 9), 2.29 (t, J ) 7.7, 1), 2.66-2.80 (m, 5), 3.14 (d, J )
2.0, 2), 3.24-3.32 (m, 1), 3.25 (s, 3), 3.32-3.43 (m, 2), 3.49 (t,
J ) 4.9, 2), 3.73 (t, J ) 4.8, 2), 5.09 (dd, J ) 7.3, 5.6, 1), 5.20
(s, 2), 6.81 (d, J ) 2.4, 1), 6.85 (dd, J ) 8.5, 2.4, 1), 7.12 (d, J
) 8.1, 1), 7.74 (b s, 1); MS (CI, CH4) m/z 501 (M + H+, 2), 429
(13), 403 (17), 402 (29), 401 (100), 369 (11), 341 (20), 309 (22),
123 (15), 121 (17), 120 (26), 107 (55); HRMS calcd for
+
C
14H18N2O2ReS2 513.0317, found 513.0323.
Estr ogen Recep tor Bin d in g Affin ity. Receptor binding
affinity (RBA) values were determined by a competitive
+
280 (14), 61 (27); HRMS calcd for C23H37N2O6S2 501.2093,
(49) Fietz, T.; Spies, H.; Pietzsch, H.-J .; Leibnitz, P. Inorg. Chim.
Acta 1995, 231, 233.
found 501.2084.