Carba-Prostacyclin Analogues
A R T I C L E S
C20H27ClN2O4S (426.96): C, 56.26; H, 6.37; N, 6.56. Found: C, 55.92;
H, 6.31; N, 6.39.
128.36 (d), 129.11 (d), 137.91 (d), 140.76 (u), 142.82 (u), 144.02 (u),
167.29 (u); IR (KBr) ν 3448 (m, br), 3218 (m), 2955 (vs), 2931 (vs),
2858 (vs), 1741 (m) cm-1; MS (EI) m/z (relative intensity, %) 683
(M+, 3), 627 (15), 626 (35), 625 (78), 528 (20), 527 (49), 395 (24),
309 (42), 297 (40), 281 (45), 239 (32), 223 (16), 215 (25), 213 (33),
212 (22), 211 (100), 169 (25), 168 (11), 167 (16), 155 (14), 149 (39);
HRMS calcd for C34H49N2O5SSi (M+ - C4H9) 625.313 149, found
625.313 324.
(-)-(3′aS-cis)-[3′,3′a,4′,6′a-Tetrahydro-5,5′-dimethylspiro[1,3-di-
oxane-2,2′( 1′H)-pentalen-5′-yl]](p-toluenesulfonyl)diazene (Ts-9).
Saturated aqueous NaHCO3 (10 mL) was added at room temperature
to a suspension of tosylhydrazone 14 (1.63 g, 3.82 mmol) in Et2O (150
mL). After the mixture was shaken intensively for 3 min, the aqueous
phase was separated and the yellow organic phase was washed twice
with water, dried (MgSO4), and concentrated at room temperature in
vacuo. Drying of the residue at room temperature in vacuo gave azoene
Ts-9 (1.34 g, 90%) as a yellow solid containing 24 mg of Et2O, which
was stored at -70 °C: mp 70 °C (dec); [R]D -11.1 (c 1.00, THF); 1H
NMR (400 MHz, C6D6) δ 0.66 (s, 3 H, C(CH3)2), 0.79 (s, 3 H, C(CH3)2),
1.26 (dd, J ) 13.2, J ) 6.9 Hz, 1 H, 3-H), 1.46 (dd, J ) 13.7, J ) 6.6
Hz, 1 H, 1-H), 1.84 (s, 3 H, Tol), 1.86-2.20 (m, 3 H, 1-H, 3-H, 6-H),
2.35-2.45 (m, 2 H, 6-H, 6a-H), 2.79-2.88 (m, 1 H, 3a-H), 3.07 (m,
2 H, OCH2), 3.18 (s, 2 H, OCH2), 6.53 (m, 1 H, 4-H), 6.76 (m, 2 H,
Tol), 7.89 (m, 2 H, Tol); 13C NMR (100 MHz, C6D6) δ 21.23 (d),
22.29 (d), 22.52 (d), 29.85 (u), 34.21 (u), 37.09 (d), 38.63 (u), 39.97
(u), 47.32 (d), 71.65 (u), 72.25 (u), 108.46 (u), 129.84 (d), 130.66 (d),
131.82 (u), 145.19 (u), 156.41 (d), 156.66 (u); IR (KBr) ν 3431 (m),
2953 (s), 2866 (m), 2188 (w), 1598 (w, br) cm-1; MS (CI) m/z (relative
intensity, %) 365 (8), 364 (21), 363 (100), 207 (32); HRMS calcd for
C13H19O2 (M+ - C7H7N2O2S) 207.138 505, found 207.138 640.
(-)-N-{(3′aS,4′S,6′aR)-4′-[4-((S)-1′′-(tert-Butyldimethylsilanyl-
oxy)hexyl) phenyl]-1′,6′a,6′,3′a-tetrahydro-5,5-dimethylspiro[1,3-
dioxane-2,2′(1′H)-penta len-5′-ylidene]}-N′-(p-toluenesulfonyl)hy-
drazine (7d). t-BuLi (2.13 mmol, 1.44 mL of 1.48 M in pentanes)
was added at -78 °C to a solution of bromide 19 (793 mg, 2.17 mmol)
in Et2O (6 mL). After the mixture was stirred for 30 min at -78 °C,
the cold solution was added at -10 °C by means of a double-tipped
ended needle to a solution of [(n-Bu3P)CuI]4 (923 mg, 0.59 mmol) in
Et2O (6 mL). The resulting yellow solution of Cu-8d/P-n-Bu3 was stirred
at -10 °C for 40 min, and then THF (12 mL) was added and the
solution was cooled to -60 °C. Subsequently, a solution of azoene
Ts-7 (758 mg, 1.94 mmol) in THF (12 mL), which had been precooled
to -60 °C, was added at -60 °C under stirring to the solution of Cu-
9d/P-n-Bu3 by means of a double-tipped ended needle. After the
resulting mixture was stirred for 30 min at -60 °C, water (3 mL) was
added and the mixture was warmed to room temperature. Subsequently,
a mixture of saturated aqueous NH4Cl and concentrated aqueous NH3
(40 mL, 10:1) was added and the solution was stirred for 1 h. The
organic phase was then separated, and the aqueous phase was
successively extracted with THF (50 mL) and Et2O (50 mL). The
combined organic phases were concentrated in vacuo, and the residue
was dissolved in Et2O (80 mL). Then, the resulting solution was treated
with a mixture of saturated aqueous NH4Cl and concentrated aqueous
NH3 (10 mL, 10:1) and the mixture was stirred for 1 h. Subsequently,
the organic phase was separated, dried (MgSO4), and concentrated in
vacuo. Purification of the residue by chromatography (hexanes/EtOAc,
first 10:1 and then 1:1) gave hydrazone 7d (1.06 g, 80%) as a light-
yellow flaky solid: mp 57 °C (dec); Rf 0.42 (hexanes/EtOAc, 1:1):
[R]D -75.0 (c 1.00, THF); 1H NMR (400 MHz, [D8]THF) δ -0.14 (s,
3 H, Si(CH3)2), 0.06 (s, 3 H, Si(CH3)2), 0.86-0.92 (m, 18 H, SiC-
(CH3)3, C(CH3)2, CH3), 1.26-1.33 (m, 6 H, 3′-H, 4′-H, 5′-H), 1.41
(m, 1 H, 2’-H), 1.59 (m, 1 H, 2′-H), 1.67-1.71 (m, 1 H, 6-H), 1.84
(dd, J ) 13.7, J ) 4.9 Hz, 1 H, 3-H), 2.15 (dd, J ) 13.7, J ) 7.5 Hz,
1 H, 3-H), 2.25-2.30 (m, 2 H, 1-H, 6-H), 2.37 (s, 3 H, Tol), 2.52-
2.61 (m, 2 H, 1-H, 3a-H), 2.65-2.72 (m, 1 H, 6a-H), 3.36-3.43 (m,
4 H, OCH2), 3.59 (d, J ) 8.5 Hz, 1 H, 4-H), 4.66-4.69 (m, 1 H, 1′-
H), 6.98 (d, J ) 8.2 Hz, 2 H, o′-Ph), 7.14-7.19 (m, 4 H, m-, m′-Ar),
7.59-7.62 (m, 2 H, o-Ar), 8.78 (s, 1 H, NH); 13C NMR (100 MHz,
[D8]THF) δ -5.24 (d), -4.77 (d), 13.91 (d), 18.37 (u), 21.02 (d), 22.12
(d), 22.22 (d), 22.99 (u), 25.74 (u), 25.85 (d), 30.05 (u), 32.27 (u),
33.94 (u), 38.36 (d), 39.71 (u), 41.46 (u), 42.08 (u), 49.04 (d), 55.91
(d), 71.79, 72.32 (u), 75.32 (d), 110.14 (u), 125.86 (d), 128.11 (d),
(3′aS,4′S,6′aR)-[4′-[4-((S)-1′′-(tert-Butyldimethylsilanyloxy)hexyl)-
phenyl]-1′,6′a,6′,3′a-tetrahydro-5,5-dimethylspiro[1,3-dioxane-2,2′]]-
pentalen-5′-one (20) and (+)-(3′aS,4′S,5′R,6′aR)-[4′-[4-((S)-1′′-(tert-
butyldimethylsilanyloxy)hexyl)phenyl]-1′,6′a,6′,3′a-tetrahydro-5,5-
dimethylspiro[1,3-dioxane-2,2′]]pentalen-5′-ol (21). Benzeneseleninic
anhydride (0.55 g, 1.54 mmol) was added at room temperature
portionwise to a solution of tosylhydrazone 7d (1.00 g, 1.47 mmol) in
THF (50 mL), whereby gas evolution occurred. After the yellow
solution was stirred at room temperature for 1 h, saturated aqueous
NaHCO3 (2 mL) was added and the mixture was extracted with hexanes
(100 mL). Drying of the combined organic phases (MgSO4) and
evaporation of the solvent in vacuo gave crude ketone 20 as a brown
oil. This material was dissolved in ethanol (100 mL) and the solution
treated at -40 °C portionwise with NaBH4 (168 mg, 4.41 mmol). After
the mixture was stirred at -40 °C for 7 h, saturated aqueous NH4Cl (5
mL) was added and the solution was extracted with Et2O (200 mL).
The combined organic phases were dried (MgSO4) and concentrated
in vacuo. Purification of the residue by chromatography (hexanes/
EtOAc, 3:1) gave alcohol 21 (515 mg, 59% based on 7d) as a colorless
oil: Rf 0.27 (hexanes/EtOAc, 3:1); [R]D +46.4 (c 1.20, THF); 1H NMR
(500 MHz, CDCl3) δ 0.14 (s, 3 H, Si(CH3)2), 0.16 (s, 3 H, Si(CH3)2),
1.02 (m, 12 H, SiC(CH3)3, CH3), 1.07 (s, 3 H, C(CH3)2), 1.14 (s, 3 H,
C(CH3)2), 1.36-1.50 (m, 6 H, 3′-H, 4′-H, 5′-H), 1.68-1.76 (m, 2 H,
6-Hâ, 2′-H), 1.76-1.84 (m, 1 H, 2′-H), 1.85 (s, 1 H, OH), 2.02 (m, 2
H, 1-H, 3-H), 2.24 (m, 1 H, 3-H), 2.37 (dd, J ) 13.3, J ) 8.7 Hz, 1
H, 1-H), 2.50 (m, 1 H, 6-H), 2.64-2.78 (m, 2 H, 3a-H, 6a-H), 2.86 (t,
J ) 9.4 Hz, 1 H, 4-H), 3.60 (s, 2 H, OCH2), 3.66 (s, 2 H, OCH2), 4.26
(td, J ) 9.9, J ) 6.3 Hz, 1 H, 5-H), 4.75 (dd, J ) 7.5, J ) 5.0 Hz, 1
H, 1′-H), 7.31 (d, J ) 8.2 Hz, 2 H, o′-Ar), 7.38 (d, J ) 8.2 Hz, 2 H,
m′-Ar); 13C NMR (100 MHz, CDCl3) δ -4.90 (d), -4.54 (d), 14.04
(d), 18.21 (u), 22.46 (d), 22.58 (d), 25.24 (u), 25.84 (d), 30.06 (u),
31.73 (u), 35.44 (d), 38.25 (u), 40.85 (u), 41.15 (u), 40.92 (u), 46.00
(d), 60.28 (d), 71.92 (u), 71.99 (u), 74.66 (d), 79.68 (d), 110.05 (u),
125.92 (d), 126.98 (d), 140.02 (u), 144.20 (u); IR (KBr, CHCl3) ν 3420
(m), 2955 (vs), 2931 (vs), 2857 (vs), 1738 (m) cm-1; MS (EI) m/z
(relative intensity, %) 516 (M+, 1), 498 (12), 459 (26), 445 (43), 441
(11), 427 (29), 373 (26), 367 (18), 359 (13), 355 (21), 281 (100), 273
(14), 223 (13), 211 (17); HRMS calcd for C31H50O3Si (M+ - H2O)
498.352 924, found 498.352 833.
(3aS,4S,5R,6aR)-5-Hydroxy-4-[4-((S)-1′-hydroxyhexyl)phenyl]-
hexahydropentalen-2-one (22). p-Toluenesulfonic acid (80 mg) was
added at room temperature to a solution of acetal 21 (500 mg, 0.97
mmol) in acetone (40 mL) and water (4 mL). After the mixture was
stirred at room temperature for 12 h, saturated aqueous NaHCO3 was
added and the mixture was extracted with Et2O (150 mL). The combined
organic phases were dried (MgSO4) and concentrated in vacuo.
Purification of the residue by chromatography (Et2O) gave a mixture
(335 mg) of diol 22 and 2,2-dimethylpropane-1,3-diol in a molar ratio
of 61:39 as a white solid: Rf 0.21 (Et2O); 1H NMR (400 MHz, CDCl3)
δ 0.84 (s, 2,2-dimethypropane-1,3-diol), 0.87 (t, J ) 6.9 Hz, 3 H, CH3),
1.25-1.31 (m, 6 H, 5′-H, 4′-H, 3′-H), 1.51-1.58 (m, 1 H, 6-H), 1.60-
1.80 (m, 2 H, 2′-H), 2.12-2.22 (m, 2 H, 3-H, 1-H), 2.34-2.41 (m, 1
H, 3-H), 2.52-2.60 (m, 3 H, 1-H, 6-H, 4-H), 2.75-2.87 (m, 2 H, 3a-
H, 6a-H), 3.38 (s, 2,2-dimethylpropane-1,3-diol), 4.23 (td, J ) 8.9, J
) 7.2 Hz, 5-H), 4.58 (dd, J ) 7.7, J ) 5.8 Hz, 1 H, 1-H), 7.18 (d, J
) 8.2 Hz, 2 H, o′-Ar, 7.27 (d, J ) 8.2 Hz, 2 H, m′-Ar); 13C NMR (100
MHz, CDCl3) δ 14.04 (d), 21.72 (2,2-dimethylpropane-1,3-diol, d),
22.55 (u), 25.52 (u), 31.67 (u), 35.02 (d), 36.28 (2,2-dimethyl-propane-
9
J. AM. CHEM. SOC. VOL. 124, NO. 16, 2002 4327