6-s-cis- and 6-s-trans-Locked 9Z-Retinoids
J . Org. Chem., Vol. 65, No. 19, 2000 5923
aqueous Na2S2O3 solution and the solvent was evaporated in
vacuo, affording 0.020 g of a yellow solid (mp 62 °C, hexane/
EtOAc) which by NMR showed a 7:1 E/ Z (E-13:Z-13) isomer
Hz, 3H), 1.9-2.1 (m, 2H), 2.3-2.4 (m, 1H), 4.0-4.2 (m, 2H),
5.3-5.4 (m, 1H), 5.4-5.5 (m, 1H); 13C NMR (100.63 MHz,
CDCl3) δ 19.5, 20.1, 23.3, 25.4, 30.2, 31.1, 60.4, 124.4, 125.0,
142.1, 142.5; HRMS (EI+) calcd for C11H18O 166.1358, found
166.1352.
ratio (91%). FTIR (NaCl) ν 1662 (s) cm-1 1H NMR (400.13
;
MHz, CDCl3) δ 0.93 (s, 3H), 1.3-2.4 (m, 10H), 1.82 (s, 3H),
1.91 (s, 3H), 6.24 (d, J ) 7.6 Hz, 1H), 6.88 (s, 1H), 10.18 (d, J
) 7.6 Hz); 13C NMR (100.63 MHz, CDCl3) δ 13.8, 18.3, 19.0,
22.8, 23.2, 31.9, 33.4, 36.9, 37.4, 124.6, 128.2, 134.0, 134.1,
135.8, 156.8, 191.8; HRMS (EI+): calcd for C16H22O 230.1671,
found 230.1670.
(Z)-3-(6,6-Dim eth ylcycloh ex-1-en -1-yl)bu t-2-en -1-ol (29).
According to the general procedure described above, a mixture
of Pd2(dba)3 (0.01 g, 0.011 mmol), AsPh3 (0.027 g, 0.087 mmol),
triflate 2229a (0.1 g, 0.387 mmol), and stannane 7 (0.17 g, 0.477
mmol) in NMP (1.2 mL) was stirred at 25 °C for 5 h. The
residue was purified by chromatography (SiO2, 85:15 hexane/
EtOAc) to afford 0.058 g (84%) of 29 as a yellow oil. FTIR
(NaCl) ν 3600-3100 (br) cm-1; 1H NMR (400.13 MHz, CDCl3)
δ 1.02 (s, 6H), 1.5-1.8 (m, 4H), 1.85 (d, J ) 0.7 Hz, 3H), 2.02
(td, J ) 6.3, 3.7 Hz, 2H), 4.02 (d, J ) 6.9 Hz, 2H), 5.23 (t, J )
3.7 Hz, 1H), 5.45 (t, J ) 6.9 Hz, 1H); 13C NMR (100.62 MHz,
CDCl3) δ 19.4, 25.9, 26.8, 29.5, 34.1, 40.2, 61.4, 124.6, 126.6,
142.8, 145.9; HRMS (EI+) calcd for C12H20O 180.1514, found
180.1521.
Eth yl
r a c-(2E,4E,6Z)-7-(4a ,8-Dim eth yl-3,4,4a ,5,6,7-
h exa h yd r on a p h t h a len -2-yl)-3-m et h yloct a -2,4,6-t r ien o-
a te (16). A solution of diethyl 3-(ethoxycarbonyl)-2-methyl-
prop-2-enylphosphonate 15 (0.122 g, 0.462 mmol) in THF (1.0
mL) was cooled to 0 °C and treated with DMPU (0.11 mL, 0.91
mmol) and n-BuLi (2.35 M in hexanes, 0.19 mL, 0.447 mmol).
The mixture was stirred at this temperature for 20 min and
then cooled to -78 °C. A solution of the aldehyde 13 (0.071 g,
0.308 mmol) in THF (1.0 mL) was slowly added, and the
reaction mixture was stirred at -78 °C for 30 min. The mixture
was allowed to warm to -40 °C to complete the reaction.
Saturated aqueous NH4Cl was added, and the reaction mixture
was extracted with Et2O. The combined organic layers were
washed with H2O and brine, dried (MgSO4), and concentrated.
The residue was purified by chromatography on silica gel (95:5
hexane/EtOAc) to afford 0.073 g of 16 (70%) as a yellow oil.
FTIR (NaCl) ν 1708 (s) cm-1; 1H NMR (400.13 MHz, CDCl3) δ
1.02 (s, 3H), 1.0-2.5 (m, 10H), 1.28 (t, J ) 7.1 Hz, 3H), 1.69
(s, 3H), 1.95 (s, 3H), 2.27 (d, J ) 1.0 Hz, 3H), 4.16 (c, J ) 7.1
Hz, 2H), 5.74 (s, 1H), 6.02 (d, J ) 11.1 Hz, 1H), 6.21 (d, J )
15.3 Hz, 1H), 6.29 (s, 1H), 6.96 (dd, J ) 15.3, 11.1 Hz, 1H);
13C NMR (100.63 MHz, CDCl3) δ 13.8, 14.3, 18.5, 18.6, 23.2,
23.4, 25.0, 31.8, 33.0, 37.3, 37.8, 59.5, 117.8, 124.6, 126.0, 129.7,
132.8, 132.9, 133.2, 135.6, 146.2, 153.3, 167.3; HRMS (EI+)
calcd for C23H32O2 340.2402, found 340.2399.
(Z)-3-(2,6-Dim eth ylcycloh ex-1-en -1-yl)bu t-2-en -1-ol (30).
According to the general procedure described above, a mixture
of Pd2(dba)3 (0.01 g, 0.011 mmol), AsPh3 (0.027 g, 0.087 mmol),
triflate 2319a (0.1 g, 0.387 mmol), and stannane 7 (0.17 g, 0.477
mmol) in NMP (1.2 mL) was stirred at 25 °C for 24 h. The
residue was purified by chromatography (SiO2, 85:15 hexane/
EtOAc) to afford 48 mg (70%) of 30 as a yellow oil. FTIR (NaCl)
1
ν 3600-3100 (br) cm-1; H NMR (400.13 MHz, CDCl3) δ 0.88
(d, J ) 6.9 Hz, 3H), 1.3-1.8 (m, 4H), 1.50 (s, 3H), 1.73 (s, 3H),
1.9-2.0 (m, 2H), 2.2-2.3 (m, 2H), 3.96 (d, J ) 7.2 Hz, 2H),
5.49 (t, J ) 6.2 Hz, 1H); 13C NMR (100.62 MHz, CDCl3) δ 20.2,
20.4, 20.8, 23.0, 30.1, 31.5, 31.7, 61.5, 125.8, 128.2, 135.8, 139.4;
HRMS (EI+): calcd for C12H18 [M - H2O]+ 162.1409, found
162.1403.
(Z)-3-[(3R,6S)-6-Isop r op yl-3-m eth ylcycloh ex-1-en -1-yl]-
bu t-2-en -1-ol (31). According to the general procedure de-
scribed above, a mixture of Pd2(dba)3 (0.01 g, 0.011 mmol),
AsPh3 (0.027 g, 0.087 mmol), triflate 2419d (0.1 g, 0.349 mmol),
and stannane 7 (0.17 g, 0.477 mmol) in NMP (1.2 mL) was
stirred at 25 °C for 24 h. The residue was purified by
chromatography (SiO2, 85:15 hexane/EtOAc) to afford 0.062 g
(85%) of 31 as a yellow oil. The NMR of the purified sample
revealed the presence of an inseparable mixture of diaster-
omers in a 90:10 ratio, due to contamination of the starting
ketone with its C-2 epimer. The major diastereomer showed
the following spectroscopic data: 1H NMR (400.13 MHz,
CDCl3) δ 0.67 (d, J ) 6.8 Hz, 3H), 0.91 (d, J ) 7.0 Hz, 3H),
0.95 (d, J ) 7.0 Hz, 3H), 1.4-2.0 (m, 5H), 1.79 (s, 3H), 2.1-
2.4 (m, 2H), 4.0-4.4 (m, 2H), 5.26 (d, J ) 1.0 Hz, 1H), 5.3-
5.5 (m, 1H); 13C NMR (100.63 MHz, CDCl3) δ 16.9, 21.6, 21.7,
22.4, 23.8, 29.0, 31.1, 31.6, 42.0, 60.7, 125.4, 134.1, 140.7, 142.8.
Selected spectroscopic data for the minor diastereomer: (Z)-
3-[(3R, 6R)-6-Isop r op yl-3-m eth ylcycloh ex-1-en -1-yl]bu t-
2-en -1-ol. 1H NMR (400.13 MHz, CDCl3) δ 0.74 (d, J ) 6.9
Hz, 3H), 0.91 (d, J ) 7.0 Hz, 3H), 0.95 (d, J ) 7.0 Hz, 3H),
1.4-2.0 (m, 5H), 1.79 (s, 3H), 2.1-2.4 (m, 2H), 4.0-4.4 (m,
2H), 5.26 (d, J ) 1.0 Hz, 1H), 5.3-5.5 (m, 1H); 13C NMR
(100.62 MHz, CDCl3) δ 15.6, 16.9, 18.1, 19.8, 22.0, 29.2, 29.7,
30.3, 40.8, 66.2, 125.7, 133.6, 140.3, 142.8.
r a c-(2E,4E,6Z)-7-(4a ,8-Dim et h yl-3,4,4a ,5,6,7-h exa h y-
d r on a p h th a len -2-yl)-3-m eth ylocta -2,4,6-tr ien oic Acid (3).
A solution of ester 16 (0.015 g, 0.044 mmol) in ethanol (0.1
mL) was treated with 0.08 mL of 5 M aqueous KOH and
refluxed for 30 min. The solution was cooled to room temper-
ature, acidified with 10% HCl, and then extracted with a 70:
30 Et2O/CH2Cl2 mixture. The combined organic layers were
washed with brine, dried (Na2SO4), and concentrated. The
residue was purified on silica gel (95:5 CH2Cl2/MeOH) to afford
0.01 g of 3 (77%) as a yellow solid (mp 198 °C, hexane/EtOAc).
FTIR (NaCl): ν 3200-2900 (br), 1674 (s) cm-1 1H NMR
;
(400.13 MHz, CD2Cl2) δ 1.01 (s, 3H), 1.2-2.3 (m, 10H), 1.70
(s, 3H), 1.97 (s, 3H), 2.27 (d, J ) 1.0 Hz, 3H), 5.77 (s, 1H),
6.04 (d, J ) 10.6 Hz, 1H), 6.23 (d, J ) 15.2 Hz, 1H), 6.29 (s,
1H), 7.02 (dd, J ) 15.2, 10.6 Hz, 1H); 13C NMR (100.63 MHz,
CD2Cl2) δ 14.4, 18.8, 18.9, 23.3, 23.6, 25.4, 32.1, 33.3, 37.7,
38.2, 125.1, 126.2, 130.2, 133.1, 133.1, 133.3, 134.7, 136.0,
147.7, 156.3, 172.3; HMRS (EI+) calcd for C21H28O2 312.2089,
found 312.2082.
(Z)-3-(Cycloh ex-1-en -1-yl)bu t-2-en -1-ol (27). According to
the general procedure described above, a mixture of Pd2(dba)3
(0.01 g, 0.011 mmol), AsPh3 (0.027 mg, 0.087 mmol), triflate
2019c (0.1 g, 0.434 mmol), and stannane 7 (0.17 g, 0.477 mmol)
in NMP (1.2 mL) was stirred at 25 °C for 0.25 h. The residue
was purified by chromatography (SiO2, 85:15 hexane/EtOAc)
to afford 0.053 g (80%) of 27 as a yellow oil. FTIR (NaCl) ν
(Z)-3-(2,6,6-Tr im eth ylcycloh ex-1-en -1-yl)bu t-2-en -1-ol
(32). According to the general procedure described above, a
mixture of Pd2(dba)3 (0.01 g, 0.011 mmol), AsPh3 (0.027 g, 0.087
mmol), triflate 2519a (0.1 g, 0.368 mmol), and stannane 7 (0.17
g, 0.477 mmol) in NMP (1.2 mL) was stirred at 25 °C for 72 h.
The residue was purified by chromatography (SiO2, 85:15
hexane/EtOAc) to afford 0.04 g (56%) of 32 as a yellow oil. FTIR
(NaCl) ν 3600-3100 (br) cm-1; 1H NMR (400.13 MHz, CDCl3)
δ 0.92 (s, 3H), 1.04 (s, 3H), 1.3-1.5 (m, 2H), 1.50 (s, 3H), 1.5-
1.7 (m, 2H), 1.82 (d, J ) 1.2 Hz, 3H), 1.97 (t, J ) 6.4 Hz, 2H),
3.94 (d, J ) 6.7 Hz, 2H), 5.5-5.6 (m, 1H); 13C NMR (100.63
MHz, CDCl3) δ 19.5, 21.1, 26.1, 29.0, 30.6, 31.8, 34.5, 40.1,
1
3600-3100 (br) cm-1; H NMR (400.13 MHz, CDCl3) δ 1.4-
1.7 (m, 4H), 1.79 (s, 3H), 1.9-2.2 (m, 4H), 4.13 (d, J ) 6.4 Hz,
2H), 5.3-5.4 (m, 2H); 13C NMR (100.62 MHz, CDCl3) δ 22.1,
22.7, 22.9, 25.0, 29.7, 60.3, 124.0, 124.5, 137.4, 143.0; HRMS
(EI+) calcd for C10H16O 152.1201, found 152.1197.
(Z)-3-(6-Meth ylcycloh ex-1-en -1-yl)bu t-2-en -1-ol (28). Ac-
cording to the general procedure described above, a mixture
of Pd2(dba)3 (0.01 g, 0.011 mmol), AsPh3 (0.027 g, 0.087 mmol),
triflate 2119a (0.1 g, 0.410 mmol), and stannane 7 (0.17 g, 0.477
mmol) in NMP (1.2 mL) was stirred at 25 °C for 1 h. The
residue was purified by chromatography (SiO2, 85:15 hexane/
EtOAc) to afford 0.052 mg (76%) of 28 as a yellow oil. FTIR
(NaCl) ν 3600-3100 (br) cm-1; 1H NMR (400.13 MHz, CDCl3)
δ 0.89 (d, J ) 7.0 Hz, 3H), 1.4-1.8 (m, 4H), 1.79 (d, J ) 1.0
61.9, 126.8, 127.7, 138.8, 139.6; HRMS (EI+) calcd for C13H22
194.1671, found 194.1674.
O
6,6-Dim eth yl-2-eth yl-1-[((tr iflu or om eth yl)su lfon yl)oxy]-
cycloh ex-1-en e (26). A solution of diisopropylamine (0.20 mL,
1.426 mmol) in THF (2.0 mL) was cooled to 0 °C and treated