Notes
J . Org. Chem., Vol. 67, No. 3, 2002 1035
a
dichloromethane (10 mL) at 0 °C was added 2,6-lutidine (0.5
mL, 4.1 mmol) followed by bromoacetyl bromide (0.3 mL, 3.2
mmol), and the reaction mixture was stirred at 0 °C for 2 h.
After the consumption of 5 (monitored by TLC), the reaction
mixture was neutralized to pH 7 using 0.5 N HCl and the organic
layer was separated. The aqueous phase was extracted with
EtOAc (2 × 10 mL). The combined organic extracts were dried
(Na2SO4) and concentrated, and the residue was purified by flash
Sch em e 2
column chromatography (EtOAc/hexanes, 1:10). Bromoacetoxy-
24
pentene 6 (0.554 g, 89%) was obtained as a colorless oil: [R]D
-
1.25 (c 10.0, toluene); 1H NMR 7.24-7.35 (m, 5H), 5.67-5.55
(m, 1H), 5.05-5.16 (m, 3H), 4.54 (d, 1H, J ) 12.0 Hz), 4.49 (d,
1H, J ) 12.0 Hz), 3.79 (s, 2H), 3.55 (s, 1H), 3.53 (s, 1H), 2.23-
2.48 (m, 2H); 13C NMR 166.5 (C), 137.7 (C), 132.5 (CH), 128.2
(CH), 127.5 (CH), 127.4 (CH), 118.3 (CH2), 73.7 (CH), 73.0 (CH2),
70.0 (CH2), 35.0 (CH2), 25.9 (CH2); IR (neat) 3030, 2896, 1741,
1642, 1495, 1433, 1363, 1277 cm-1; MS (EI, 70 eV) m/z (%) 314
(M + 2, 63), 312 (M+, 62), 260 (19), 258 (34), 233 (61), 206 (39);
HRMS (EI, 70 eV) C14H17O3Br calcd 312.0361 and 314.0341,
found 312.0370 and 314.0357.
(4R,6S)-6-Ben zyloxym eth yl-4-h yd r oxy-tetr a h yd r o-2-p y-
r on e (2). A solution of dichloromethane (10 mL) containing
bromoacetoxypentene 6 (0.308 g, 0.99 mmol) and methanol (0.5
mL) was bubbled with ozone gas at -78 °C until a blue color
persisted (about 3-4 min), and then DMS (1 mL) was added.
The reaction mixture was warmed to 0 °C and stirred for an
additional 10 h and then concentrated under reduced pressure.
The residue was dissolved in ether (20 mL). The ethereal solution
was washed with distilled water (5 mL) followed by brine (5 mL),
dried (Na2SO4), and concentrated in vacuo. The resulting (3S)-
4-benzyloxy-3-bromoacetoxybutanal7 (3) was used in the next
step without further purification.
a
Reagents and conditions: (i) CH2dCH-MgBr, CuCN, -10 °C;
(ii) BrCOCH2Br, 2,6-lutidine, 0 °C; (iii) O3, CH2Cl2-MeOH; DMS;
(iv) SmI2, THF, 0 °C, 2 h.
enforced by chelation, was proposed6 as the rationale for
the stereoselectivity observed in samarium(II) iodide
mediated intramolecular Reformatsky reactions. In the
present case, exclusive formation of the (+)-lactone 2
(>95:5; vide H and 13C NMR) presumably proceeded via
1
a low-energy transition structure (Scheme 2) assuming
a chair-like conformation with the benzyloxymethyl
group in the favorable equatorial position.
A round-bottom flask was charged with samarium (40 mesh,
0.500 g, 3.33 mmol), connected to a vacuum system, heated on
a flame (2-3 min), and cooled under a slow flow of argon. A
solution of 1,2-diiodoethane (0.562 g, 2 mmol) in THF (12 mL)
was added to the samarium under argon, and the mixture was
stirred at room temperature until the solution turned deep blue
in color (2 h). The reagent was cooled to 0 °C, and a solution of
aldehyde 3 in THF (0.5 mL) was added to it; the mixture was
stirred at 0 °C for 2 h. The reaction mixture was added to a
saturated aqueous solution of NH4Cl (15 mL) and extracted with
EtOAc (3 × 10 mL). The organic layer was separated, and the
aqueous layer was extracted with EtOAc (2 × 10 mL). The
combined organic layers were washed with brine (10 mL), dried
(Na2SO4), and concentrated. The residue was purified by flash
column chromatography (EtOAc/hexanes, 4:1) to give (+)-
In conclusion, we have provided a new, concise, and
stereocontrolled approach to the (+)-compactin lactone
2. A shorter reaction sequence and high overall yield of
the optically pure lactone rendered our protocol an
alternative to the known methods.
Exp er im en ta l Section
All experiments were carried out under argon in flame- or
oven-dried glassware using syringe-septum cap techniques.
THF was freshly distilled from sodium benzophenone ketyl
under argon prior to use. Dichloromethane was distilled from
calcium hydride. Flash column chromatography was performed
1
using Merck silicagel 60 (Art. No. 7734). H (400 MHz) and 13C
compactin lactone 2 (0.212 g, 91% from 6): [R]30 +6.82 (c 0.85,
D
(100 MHz) NMR spectra were recorded in CDCl3 solution, and
chemical shifts (δ) were given in parts per million relative to
TMS. Carbon multiplicities were assigned by DEPT experiments.
(4S)-5-Ben zyloxy-4-h yd r oxy-1-p en ten e (5). A round-bot-
tom flask was charged with copper(I) cyanide (0.030 g, 0.55
mmol), gently heated under vacuum, and slowly cooled with a
flow of argon, and THF (5 mL) was added. This suspension was
cooled to -10 °C and vigorously stirred, and vinylmagnesium
bromide (1 M in THF, 2.6 mL, 2.6 mmol) was injected into it. A
solution of glycidyl ether 4 (0.41 g, 2.5 mmol) in THF (5 mL)
was added slowly to the above reagent, and the mixture was
stirred at -10 °C for 16 h. The reaction mixture was neutralized
to pH 7 using 0.5 N HCl and extracted with EtOAc (3 × 10 mL).
The combined organic extracts were dried (Na2SO4) and con-
centrated, and the residue was purified by flash column chro-
matography (EtOAc/hexanes, 1:6) to furnish alcohol 5 (0.451 g,
1
CHCl3) (lit.5e [R]29 +6.59 (c 1.03, CHCl3)); H NMR 7.26-7.37
D
(m, 5H), 4.83-4.88 (m, 1H), 4.58 (d, 1H, J ) 12.0 Hz), 4.55 (d,
1H, J ) 12.0 Hz), 4.36-4.40 (m, 1H), 3.68 (dd, 1H, J ) 10.4, 3.6
Hz), 3.60 (dd, 1H, J ) 10.4, 4.4 Hz), 2.67 (dd, 1H, J ) 18.0, 4.8
Hz), 2.59 (dd, 1H, J ) 18.0, 1.2 Hz), 1.92-1.99 (m, 2H); 13C NMR
170.5 (C), 137.6 (C), 128.4 (CH), 127.8 (CH), 127.7 (CH), 75.0
(CH), 73.5 (CH2), 71.5 (CH2), 62.4 (CH), 38.5 (CH2), 32.0 (CH2);
IR (neat) 3416, 3031, 2906, 1720, 1249, 1087, 744 cm-1; MS
(FAB) m/z (%) 237 (M + 1, 8), 238 (M + 2, 2), 91 (100).
Ack n ow led gm en t. We thank the National Science
Council and Ministry of Education (Grant 89-B-FA04-
1-4) of the Republic of China for the financial support.
J O016216G
94%) as a colorless oil: [R]D +2.21 (c 2.8, CHCl3); 1H NMR
23
(7) To characterize (3S)-4-benzyloxy-3-bromoacetoxybutanal (3), it
was prepared from 6 (0.10 g) following the procedure described in
Experimental Section and purified by HPLC (E. Merck Catal. 51469
LiChrosorb CN-7µm column) eluting with EtOAc/hexanes (1:4). Pure
aldehyde 3 was obtained as a colorless oil: [R]D24 -12.8 (c 1.02, CHCl3);
1H NMR 9.71 (dd, 1H, J ) 1.6, 1.2 Hz), 7.24-7.36 (m, 5H), 5.45-5.50
(m, 1H), 4.55 (d, 1H, J ) 12.0 Hz), 4.51 (d, 1H, J ) 12.0 Hz), 3.80 (s,
2H), 3.63 (dd, 1H, J ) 10.8, 3.2 Hz), 3.6 (dd, 1H, J ) 10.8, 4.4 Hz),
2.81 (d, 1H, J ) 1.6 Hz), 2.80 (d, 1H, J ) 1.2 Hz); 13C NMR 198.3
(CH), 166.4 (C), 137.3 (C), 128.3 (CH), 127.8 (CH), 127.6 (CH), 73.2
(CH2), 69.8 (CH2), 69.7 (CH), 44.4 (CH2), 25.5 (CH2); IR (neat) 3030,
2896, 1741, 1720, 1433, 1363 cm-1; MS (FAB) m/z (%) 313 (M + 1,
100), 251 (M - 61, 39) 249 (M - 59, 39) 225 (M - 87, 39).
7.28-7.37 (m, 5H), 5.75-5.88 (m, 1H), 5.07-5.13 (m, 2H), 4.55
(s, 2H), 3.84-3.90 (m, 1H), 3.51 (dd, 1H, J ) 9.6, 3.2 Hz), 3.37
(dd, 1H, J ) 9.6, 7.2 Hz), 2.46 (s, 1H), 2.24-2.46 (m, 2H); 13C
NMR 137.90 (C), 134.18 (CH), 128.38 (CH), 127.71 (CH), 127.67
(CH), 117.58 (CH2), 73.84 (CH2), 73.31 (CH2), 69.66 (CH), 37.85
(CH2); IR (neat) 3416, 3070, 3030, 2893, 1641, 1450, 1273, 1094
cm-1; MS (EI, 70 eV) m/z (%) 193 (M + 1, 41), 192 (M+, 92), 174
(M - 18, 98), 132 (M - 60, 100); HRMS (EI, 70 eV) C12H16O2
calcd 192.1138, found 192.1147.
(4S)-5-Ben zyloxy-4-br om oa cetoxy-1-p en ten e (6). To a
solution of homoallyl alcohol 5 (0.383 g, 1.99 mmol) in dry