Novel Fragmentation Reaction
2,4-carbolactone (18): mp 102-104 °C; [R]26 -95 (c 0.79); 1H
under reduced pressure to give a yellow oil. The crude product
was purified by flash column chromatography (hexanes/EtOAc,
1:1) to afford 32 (501 mg, 76%) as a colorless oil, which was
used without further purification for the next reaction (hy-
droxyketone/hemiketal, 10:1): [R]26D -125.2 (c 0.76); 1H NMR
δ 4.94 (s, 1H), 4.77 (d, J ) 5.4 Hz, 1H), 3.63 (m, 2H), 2.69-
2.60 (m, 2H), 2.58-2.53 (m, 1H), 2.44-2.37 (m, 1H), 1.99 (m,
1H), 1.81 (m, 1H), 1.58 (br s, 1H), 1.41 (m, 2H); 13C NMR δ
198.2, 170.1, 77.6, 62.7, 33.2, 27.6, 26.2, 23.7, 21.5; IR ν 3522,
1780, 1723 cm-1; CIMS 325 (M+ + 1).
(3E)-Tet r a h yd r o-3-[[(2R)-t et r a h yd r o-5-oxofu r a n yl]-
m eth ylen e]-2H-p yr a n -2-on e (34). To a solution of crude 32
(45 mg, 0.14 mmol) in CH2Cl2 (1 mL) was added 2 drops of
Et3N at room temperature. The reaction mixture was stirred
overnight. Water and CH2Cl2 were added, and the aqueous
phase was extracted with CH2Cl2. The combined organic layers
were dried over anhydrous Na2SO4, filtered, and concentrated
to give 34 (26 mg, 96%) as a white solid: [R]24D -41.4 (c 0.58);
1H NMR δ 6.93 (d, J ) 7.8 Hz, 1H), 5.16 (q, J ) 7.3 Hz, 1H),
4.32 (t, J ) 5.6 Hz, 2H), 2.70 (m, 1H), 2.56 (m, 4H), 2.46 (m,
1H), 2.05 (m, 1H), 1.94 (m, 1H); 13C NMR δ 176.3, 165.3, 140.3,
129.9, 128.6, 75.7, 69.0, 28.3, 28.2, 24.3, 22.6; IR ν 1763, 1719
cm-1; CIMS 197 (M+ + 1, 100). Anal. Calcd for C10H12O4: C,
61.22; H, 6.16. Found: C, 60.93; H, 6.17.
(2R,3R,4R)-2-(2′-Hyd r oxy)eth yl-3-iod o-4-m eth yl-1-oxo-
cycloh exa n -2,4-ca r bola cton e (33). To a solution of 1j (100
mg, 0.23 mmol) in CH2Cl2/H2O (21 mL, 20:1) was added DDQ
(61 mg, 0.27 mmol) at room temperature. The reaction mixture
was stirred for 3 h and quenched with water and extracted
with CH2Cl2. The combined organic layers were dried over
anhydrous Na2SO4 and concentrated to give 33. The crude
residue was directly used for the next reaction without further
purification: 1H NMR δ 4.66 (s, 1H), 3.48 (m, 1H), 3.33 (m,
1H), 2.27-1.53 (m, 6H), 1.00 (s, 3H); 13C NMR δ 198.4, 171.2,
84.5, 65.3, 58.6, 50.5, 33.6, 33.5, 33.3, 33.2, 28.1, 22.5, 22.4.
(5R)-5-[(E)-(Dih yd r o-2-oxo-3(2H)-fu r a n ylid en e)m eth yl]-
d ih yd r o-5-m eth yl-2(3H)-fu r a n on e (35). Crude 33, contami-
nated with 4-methoxybenzaldehyde, was dissolved in THF (10
mL), and Et3N (0.20 mL, 1.4 mmol) was added. The reaction
mixture was stirred for 3 h and extracted with CH2Cl2. The
combined organic layers were dried over anhydrous Na2SO4
and concentrated under reduced pressure. Flash column
chromatography (hexanes/EtOAc, 1:1) of the crude residue
D
NMR δ 5.02 (t, J ) 4.6 Hz, 1H), 4.82 (d, J ) 5.1 Hz, 1H), 2.62
(dd, J ) 8.8, 1.8 Hz, 1H), 2.54 (m, 2H), 2.42 (m, 1H), 1.62 (m,
1H), 1.53 (s, 3H), 1.51 (s, 3H), 1.49 (s, 3H), 1.40 (m, 5H), 1.15
(br s, 6H); 13C NMR δ 199.3, 172.2, 90.7, 75.3, 61.5, 40.5, 39.2,
34.3, 28.7, 26.2, 24.4, 16.8, 16.3, 16.0, 13.9, 13.2; IR ν 1790,
1725 cm-1; CIMS 310 (M+ + 1, 100). (2R,3S,4R)-1-Oxo-2-
methyl-3-(2′,2′,6′,6′-tetramethyl-1′-piperidinyloxy)cyclohexan-
2,4-carbolactone (19): mp 128-130 °C; [R]26 -126 (c 0.82);
D
1H NMR δ 5.40 (d, J ) 4.4 Hz, 1H), 4.25 (s, 1H), 2.56 (dd, J )
6.9, 2.2 Hz, 2H), 2.42 (m, 1H), 1.88 (m, 1H), 1.62-1.35 (m,
6H), 1.40 (s, 3H), 1.20 (s, 3H), 1.16 (s, 3H), 1.11 (s, 3H), 1.07
(s, 3H); 13C NMR δ 199.5, 174.7, 86.8, 76.9, 76.6, 62.5, 61.9,
60.0, 50.0, 40.4, 34.7, 34.0, 33.6, 5.0, 20.8, 20.6, 17.0, 8.80; IR
ν 1775, 1718 cm-1; CIMS 310 (M+ + 1, 100). Anal. Calcd for
C
17H27NO4: C, 65.99; H, 8.80. Found: C, 65.17; H, 8.59. The
foregoing combustion analysis of this sample indicates that
the sample was probably wet. A sample of compound 19,
sufficient for re-analysis, is no longer available.
F r a gm en ta tion of 18 w ith LiOH‚H2O. To a solution of
18 (175 mg, 0.57 mmol) in THF/H2O (4 mL, 5:1) was added
LiOH‚H2O (470 mg, 1.14 mmol). The resulting solution was
stirred overnight at room temperature. The reaction mixture
was neutralized with 10% HCl solution and extracted with
diethyl ether. The combined organic solution was dried over
anhydrous Na2SO4 and concentrated under reduced pressure
to give a colorless oil. Flash column chromatography (hexanes/
EtOAc, 3:1 to 2:1) of the crude residue gave 11a as a single
product (75 mg, 78%).
F r a gm en ta tion of 19 w ith LiOH‚H2O. To a solution of
19 (101 mg, 0.33 mmol) in THF/H2O (2.5 mL, 5:1) was added
LiOH‚H2O (140 mg, 0.65 mmol). The resulting solution was
stirred overnight at room temperature. The reaction mixture
was neutralized with 10% HCl solution and extracted with
diethyl ether. The combined organic solution was dried over
anhydrous Na2SO4 and concentrated under reduced pressure
to give a colorless oil. Flash column chromatography (hexanes/
EtOAc, 3:1 to 2:1) of the crude residue gave 11a (10 mg, 18%)
and 12a (21 mg, 51%).
Gen er a l P r oced u r e for th e F r a gm en ta tion of 1 w ith
Lith iu m Meth oxid e. Meth yl (2E)-2-Meth yl-3-[(2R)-3-tet-
r a h yd r o-5-oxofu r a n yl]-2-p r op en oa te (20). To a solution of
MeOH (30 µL, 0.8 mmol) in THF (5 mL) was added n-BuLi
(180 µL, 0.5 mmol, 2.5 M solution in hexanes) at -78 °C. The
resulting solution was stirred for 0.5 h. To this solution was
added dropwise a solution of 1a (106 mg, 0.4 mmol) in THF (5
mL) at -78 °C. The resulting solution was stirred overnight
at room temperature. The reaction mixture was diluted with
water and extracted with diethyl ether. The combined organic
layers were dried over Na2SO4 and concentrated under reduced
pressure. Flash column chromatography (hexanes/EtOAc, 3:1)
gave 35 (38 mg, 86%) as a white solid: mp 132-134 °C; [R]25
D
+30.0 (c 1.0); 1H NMR δ 6.66 (m, 1H), 4.34 (m, 2H), 3.15-
3.01 (m, 2H), 2.59 (m, 2H), 2.32-2.19 (m, 2H), 1.56 (s, 3H);
13C NMR δ 176.0, 171.6, 139.7, 126.0, 85.0, 66.1, 34.8, 28.7,
26.1, 25.7; IR ν 1766, 1744 cm-1; CIMS 197 (M+ + 1, 100).
Anal. Calcd for C10H12O4: C, 61.22; H, 6.16. Found: C, 60.95;
H, 6.24.
of the crude residue gave the desired product 20 (61 mg, 87%)
1
as a colorless oil: [R]27 -46.5 (c 0.71); H NMR δ 6.67 (dq, J
Ack n ow led gm en t. This work was supported by the
National Institutes of Health (GM 26568). We thank Dr.
Fook S. Tham for the X-ray structure determination.
D
) 8.1, 1.4 Hz, 1H), 5.25 (dd, J ) 15.1, 8.1 Hz, 1H), 3.75 (s,
3H), 2.60-2.53 (m, 2H), 2.50-2.44 (m, 1H), 2.04-1.96 (m, 1H),
1.91 (d, J ) 1.4 Hz, 3H); 13C NMR δ 176.4, 167.4, 137.6, 131.2,
76.3, 52.1, 28.3, 28.2, 13.0; IR ν 1780, 1718 cm-1; CIMS 185
(M+ + 1, 100), 153 (30). Anal. Calcd for C9H12O4: C, 58.69; H,
6.57. Found: C, 58.59; H, 6.61.
(2R,3R,4R)-2-(3′-Hydr oxy)p r opyl-3-iod o-1-oxocycloh ex-
a n -2,4-ca r bola cton e (32). 1e (840 mg, 2.03 mmol) and DDQ
(1.38 g, 6.09 mmol) were dissolved in CH2Cl2 (15 mL) at a
sealed tube. The reaction mixture was heated at 60 °C for 8 h
and then cooled to room temperature. The solid was removed
through a thin pad of Celite. The filtrate was concentrated
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for compounds discussed
in the text (but not described in the Experimental Section),
1H NMR spectra for 11e, 13, and 19, and ORTEP drawings
and crystal data and structure refinement for 23 and 35. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O0490853
J . Org. Chem, Vol. 69, No. 22, 2004 7733