Notes
J . Org. Chem., Vol. 62, No. 20, 1997 7067
filtered through silica gel (4.5 × 3 cm pad), followed by elution
with diethyl ether (200 mL). The initial toluene filtrate was
discarded. The combined ether washings containing the prod-
ucts was stripped of solvent to give a brownish, viscous syrup
(3.51 g). This was subjected to MPLC on silica, gradient elution
of CH2Cl2 to 15:85 ethyl acetate/CH2Cl2, with rechromatography
of mixed fractions to provide 6a (0.79 g, 23%) and 6b (0.92 g,
27%), both as colorless foams, recovered starting ketone 3a (0.18
g, 9%), and a final mixed 6a and 6b fraction (0.12 g, 3.5%).
Separation of 6a and 6b could also be performed by gradient
elution with 2:98 to 5:95 ethyl acetate/hexanes.
for
C
20H28O3 316.2038, found 316.2032. Anal. Calcd for
C20H28O3: C, 75.91; H, 8.92. Found: C, 75.96; H, 8.81.
In another run with 0.23 g of 6a in 10 mL of THF and 10 mL
of 3 N HClO4 for 2.4 h at 70 °C followed by workup and
chromatography (PLC) on silica (3:7 ethyl acetate/hexanes) there
was obtained 0.102 g, 74%, of (-)-3a .
The alternate use of 8:2 glacial acetic acid/water gave, after
workup and PLC, 64% of (-)-3a , [R]25 ) -93 (c 0.12, CHCl3).
D
(6a S ,10a S )-6,6a ,7,8,10,10a -H e xa h yd r o-1-h yd r oxy-6,6-
dim eth yl-3-pen tyl-9H-diben zo[b,d]pyr an -9-on e; (6a S,10aS)-
3a . The (6aS,10aS)-ketal 6b (0.60 g, 1.13 mmol) was heated at
70 °C in THF (10 mL) and 3 N HClO4 (10 mL) for 3 h. Workup
as before followed by PLC on silica (3:7 ethyl acetate/hexanes)
then gave (6aS,10aS)-3a (0.22 g, 62%) as a pale yellow crystal-
lizing gum, elongated prisms from hexanes (at -20 °C): mp
The (6aS,10aS)-ketal 6b: TLC Rf ) 0.39 (silica, 15:85 ethyl
acetate/hexanes, three elutions); TLC Rf ) 0.33 (silica, CH2Cl2);
[R]25 ) -52.9 (c 0.22, CHCl3); IR (CHCl3) 1625 (m), 1732 (s),
D
3300-3650 (br) cm-1; 1H NMR (400 MHz) d 0.87 (t, 3H, J ) 7.1
Hz), 1.10 (s, 3H), 1.25-1.37 (m, 16H), 1.39 (s, 3H), 1.37-1.50
(m, 2H), 1.52-1.63 (m, 3H), 1.85-1.94 (m, 2H), 2.04 (br d, 1H,
J ∼ 13 Hz), 2.38-2.50 (m, 2H), 2.91 (ddd, 1H, J ) 2.0, 13.5,
13.5 Hz), 2.95 (ddd, 1H, J ) 2.4, 2.4, 13.5 Hz), 4.73 (d, 1H , J )
5.4 Hz), 4.74 (d, 1H, J ) 5.4 Hz), 5.15 (qq, 1H, J ) 6.3, 6.3 Hz),
5.21 (qq, 1H, J ) 6.3, 6.3 Hz), 6.20 (s, 1H, OH), 6.24 (d, 1H, J )
1.8 Hz), 6.28 (d, 1H, J ) 1.8 Hz); 13C NMR δ 14.01 (q), 18.94 (q),
21.73 (q × 4), 22.56 (t), 25.26 (t), 27.76 (q), 30.54 (t), 31.59 (t),
32.02 (d), 35.53 (t), 36.51 (t), 38.95 (t), 48.77 (d), 69.90 (d), 70.71
(d), 76.44 (s), 77.45 (d × 2), 108.33 (s), 108.93 (d), 109.65 (d),
114.48 (s), 143.32 (s), 154.47 (s), 154.98 (s), 168.72 (s), 171.67
(s); MS m/z 532 [M+], 490, 489, 476, 445, 403, 315, 299, 298,
283, 273, 260, 245, 233, 231; HRMS calcd for C30H44O8 532.3036,
found 532.3013.
115-117 °C; [R]25 ) +92 (c 0.09, CHCl3); UV (MeOH) 207 (ꢀ
D
44000), 230 (sh, 9300), 275 (1280), 282 (1370) nm; IR (KBr) 1620
(s), 1690 (s), 3000-3600 (br) cm-1 1H NMR (400 MHz) δ 0.88
;
(t, 3H, J ) 6.8 Hz), 1.12 (s, 3H), 1.25-1.38 (m, 4H), 1.47 (s, 3H),
1.48-1.53 (m, 3H), 1.96 (ddd, 1H, J ) 3.2, 11.2, 11.2 Hz), 2.14
(dd, 1H, J ) 12.8, 14.7 Hz), 2.17 (m, 1H), 2.44 (t, 2H, J ) 7.7
Hz), ca. 2.48 (m, 1H), 2.62 (dddd, 1H, J ) 2.9, 2.9, 5.8, 15.4 Hz),
2.89 (ddd, 1H, J ) 3.5, 12.2, 13.4 Hz), 4.05 (ddd, 1H, J ) 2.2,
3.5, 15.0 Hz), 6.20 (d, 1H, J ) 1.1 Hz), 6.26 (s, 1H), 6.59 (s, 1H,
OH); 13C NMR δ 1405 (q), 18.88 (q), 22.55 (t), 26.92 (t), 27.86
(q), 30.69 (t), 31.62 (t), 34.81 (d), 35.54 (t), 40.88 (t), 45.09 (t),
47.43 (d), ca. 77 (s), 107.79 (d), 108.06 (s), 109.38 (d), 143.59 (s),
154.61 (s), 155.10 (s), 213.88 (s); MS m/z 316 [M+], 301, 283,
273, 260, 245, 233, 231, 206, 193, 150; HRMS calcd for C20H28O3
316.2038, found 316.2034. Anal. Calcd for C20H28O3: C, 75.91;
H, 8.92. Found: C, 75.70; H, 9.09.
The (6aR,10aR)-ketal 6a : TLC Rf ) 0.32 (silica, 15:85 ethyl
acetate/hexanes, 3 elutions); TLC Rf ) 0.18 (silica, CH2Cl2); [R]25
D
) -55.9 (c 0.23, CHCl3); IR (CHCl3) 1624 (m), 1740 (s), 3300-
3650 (br), 3590 (m, free OH) cm-1 1H NMR (400 MHz) δ 0.88
;
In some runs, especially on a larger scale, incomplete hy-
drolysis of the tartrate ketals accounted for lower yields of the
ketones. A run with 6aS,10aS-6b (0.89 g) provided after workup
and silica gel filtration 0.17 g of 6aS,10aS-3a (33%) from ethyl
acetate extraction of the basic aqueous. Acidification (concd HCl)
of the aqueous and ethyl acetate extraction then gave, after
(t, 3H, J ) 7.0 Hz), 1.08 (s, 3H), 1.24-1.37 (m, 16H), 1.38 (s,
3H), 1.39-1.59 (m, 5H), 1.72 (ddd, 1H, J ) 4.8, 13.7, 13.7 Hz),
1.83 (m, 1H), 2.07 (dddd, 1H, J ) 2.5, 2.5, 2.5, 13.3 Hz), 2.35-
2.48 (m, 2H), 2.81 (ddd, 1H, J ) 2.5, 10.5, 11.6 Hz), 3.36 (ddd,
1H, J ) 2.5, 2.5, 13.3 Hz), 4.73 (d, 1H, J ) 5.7 Hz), 4.83 (d, 1H,
J ) 5.7 Hz), 5.04 (s, 1H, OH), 5.13 (qq, 1H, J ) 6.3, 6.3 Hz),
5.14 (qq, 1H, J ) 6.3, 6.3 Hz), 6.07 (d, 1H, J ) 1.5 Hz), 6.23 (d,
1H, J ) 1.5 Hz); 13C NMR δ 14.01 (q), 19.14 (q), 21.73 (q × 4),
22.54 (t), 25.06 (t), 27.80 (q), 30.56 (t), 31.58 (t), 32.60 (d), 35.43
(t), 35.72 (t), 39.16 (t), 48.02 (d), 69.62 (d), 69.73 (d), 76.80 (s),
77.18 (d × 2), 107.72 (d), 109.02 (s), 109.83 (d), 114.35 (s), 142.79
(s), 154.62 (s), 154.92 (s), 169.44 (s), 169.59 (s); MS m/z 532 [M+],
490, 489, 445, 403, 315, 299, 298, 283, 273, 271, 260, 258, 245,
removal of solvent, a brownish foam (0.44 g, 58% crude).
A
sample was purified on florisil, eluting with 1:1 CHCl3/MeOH,
to give pale yellow flakes of the corresponding tartaric diacid
ketal (4′R,5′R,6aS)-6,6a,7,8,10,10a-hexahydro-1-hydroxy-6,6-
dimethyl-3-pentylspiro-9H-dibenzo[b,d]pyran-9,2′-[1,3]dioxolane-
4′,5′-dicarboxylic acid: 1H NMR δ 0.85 (t, 3H, J ) 6.4 Hz), 1.00
(s, 3H), 1.10-1.60 (m, 12H; s at δ 1.35), 1.85 (m, 2H), 1.99 (m,
1H), 2.37 (t, 2H, J ) 7.5 Hz), 2.82 (dd, 1H, J ∼ 11,11 Hz), 3.10
(d, 1H, J ∼ 12.5 Hz), 4.96 (d, 1H, J ) 4.0 Hz), 5.04 (d, 1H, J )
4.0 Hz), 6.15 (s, 1H), 6.23 (s, 1H), 6.89 (br, ca 3H, OH + 2 ×
CO2H); δ (CD3OD) 0.89 (t, 3H, J ) 6.4 Hz), 1.06 (s, 3H), 1.20-
1.65 (m, 12H; s at δ 1.34), 1.79 (m, 2H), 2.10 (m, 1H), 3.02 (dd,
1H, J ∼ 11, 11 Hz), 3.14 (d, 1H, J ∼ 12.5 Hz), 4.41 (m, 2H), 6.08
(s, 1H), 6.15 (s, 1H); HRMS (+)-FAB m/z 449.2137 [M‚H]+, calcd
for C24H33O8 449.2175.
Other methods24 that were tried for the deprotection of the
tartrate ketals, and the yields of ketone obtained, included the
following: (i) wet MgSO4, benzene, rt; no reaction; (ii) silica gel,
cat. 15% H2SO4, CH2Cl2, rt; no reaction; (iii) wet acetone, cat.
PPTS or TsOH, reflux; no reaction or decomposition; (iv) 10%
aqueous HCl, THF, reflux, 15 h, 24% ketone.
242, 233, 231; HRMS calcd for
532.3004.
C30H44O8 532.3036, found
(6a R ,10a R )-6,6a ,7,8,10,10a -H e xa h yd r o-1-h yd r oxy-6,6-
dim eth yl-3-pen tyl-9H-diben zo[b,d]pyr an -9-on e; (6aR,10aR)-
3a . To a solution of the (6aR,10aR)-ketal 6a (0.69 g, 1.30 mmol)
in THF (20 mL) under argon was added 3 N HClO4 (10 mL)
and the clear solution heated at 70 °C for 4 h. The clear, light
yellow solution was cooled to rt, diluted with water (20 mL),
cautiously treated with solid sodium bicarbonate to saturation,
and extracted with four portions of ethyl acetate. The combined
extracts were washed with water and saturated NaCl, dried
(Na2SO4), and evaporated in vacuo to provide the crude product
(0.232 g, 57%) as a slightly discolored foam. This material was
dissolved in 35:65 THF/hexanes and passed through a short
column of silica gel, eluting with the same solvent mixture.
Evaporation in vacuo of the filtrates then provided pure
(6aR,10aR)-3a (0.184 g, 45%) as a white crystalline foam: mp
(6aR,10aR)-6a,7,8,10a-Tetr ah ydr o-1-h ydr oxy-6,6-dim eth yl-
3-p en t yl-6H -d ib en zo[b,d ]p yr a n -9-ca r b oxylic Acid , (6a R,
10a R)-2c. In an analogous manner to that described above for
the racemic ketone, the (6aR,10aR)-ketone (-)-3a (30 mg, 0.096
mmol) was converted to the trisyl hydrazone and then treated
with n-butyllithium (4.2 mol equiv) at -78 °C to -10 °C to 0 °C
(9:1 hexanes/TMEDA) followed by CO2 gas (3 min). Workup up
then gave a light yellow oil which was subjected to MPLC on
silica (CHCl3 gradient to 95:5 CHCl3/MeOH) to give the crude
acid (17 mg, 50%) as a light yellow oil. Rechromatography
(silica, 98:2 CHCl3/MeOH) provided (6aR,10aR)-2c as a white
crystalline solid: mp 206-209 °C (subl ∼170 °C) (lit.19 205-
114-117 °C; [R]25 ) -91 (c 0.12, CHCl3); UV (MeOH) 207 (e
D
49750), 230 (sh, 10500), 275 (1420), 282 (1510) nm; IR (KBr)
1
1623 (s), 1691 (s), 3000-3650 (br) cm-1; H NMR (400 MHz) δ
0.88 (t, 3H, J ) 7.0 Hz), 1.12 (s, 3), 1.25-1.38 (m, 4H), 1.47 (s,
3H), 1.48-1.52 (m, 3H), 1.97 (ddd, 1H, J ) 3.2, 11.2, 12.2 Hz),
2.14 (dd, 1H, J ) 12.8, 15.0 Hz), 2.18 (m, 1H), 2.44 (t, 2H, J )
7.7 Hz), ca. 2.48 (m, 1H), 2.62 (dddd, 1H, J ) 2.6, 2.6, 5.2, 15.2
Hz), 2.89 (ddd, 1H, J ) 3.2, 12.5, 13.4 Hz), 4.04 (ddd, 1H, J )
2.1, 3.5, 15.1 Hz), 6.20 (d, 1H, J ) 1.5 Hz), 6.26 (d, 1H, J ) 1.5
Hz), 6.50 (s, 1H, OH); 13C NMR d 14.04 (q), 18.88 (q), 22.55 (t),
26.89 (t), 27.85 (q), 30.68 (t), 31.60 (t), 34.77 (d), 35.52 (t), 40.86
(t), 45.15 (t), 47.42 (d), 77.22 (s), 107.78 (d), 108.11 (s), 109.48
(d), 143.58 (s), 154.62 (s), 154.98 (s), 213.50 (s); MS m/z 316 [M+],
301, 283, 273, 260, 245, 233, 231, 206, 193, 150; HRMS calcd
207 °C); [R]25 ) -169 (c 0.15, CHCl3)25 (authentic material,18a
D
(24) For leading references, see: Greene, T. W. Protective Groups
in Organic Synthesis; Wiley: New York, 1981; pp 124-128.