Chiral Cyclopentenone Building Blocks
continued for 90 min while the temperature was kept between
-5 to 0 °C. Then, the mixture was recooled to -10 °C and a
solution of 36 (3.25 g, 7.5 mmol) in dry THF (25 mL) was added
dropwise. After stirring at this temperature for 1 h, the
reaction mixture was allowed to warm to RT, was left for 1 h,
and warmed to reflux for 2 h. The reaction after cooling was
quenched by the addition of saturated aqueous NH4Cl (5 mL).
CH2Cl2 (50 mL) was added, and the mixture was washed with
water (100 mL). The aqueous phase was extracted with
dichloromethane (3 × 100 mL), the combined organic phases
were dried, and the solvent was evaporated. The residue was
purified by column chromatography (EtOAc/hexanes ) 1/12)
to give alcohol 37 (2.98 g, 93%) as a white solid: mp 78-80
Thus, synthesis of the parent ones, (+)-1 and (-)-1, two
widely used key intermediates in organic synthesis, was
accomplished in a straightforward manner. Moreover,
branched analogues such as pentenomycin I (2) and the
pseudo-sugar moiety of neplanocin A (3) are easily
approached according to the same methodology.
Experimental Section
General Procedure (A): Preparation of Nitrones in the
Presence of Na2CO3. The crude aldehyde obtained as de-
scribed in each case was dissolved in EtOH 95% (10 mL/mmol),
and RNHOH‚HCl (1.2-2.4 equiv) along with Na2CO3 (2-3
equiv) was added. The mixture was stirred at RT for 1-4 h,
while the reaction progress was monitored with TLC. Then,
the solids were removed by filtration, and the filtrate was
concentrated. The resulting nitrone was used in the cycload-
dition reaction as it was unless otherwise mentioned.
General Procedure (B): Cycloaddition Reactions. The
residue, which contained the intermediate nitrone, was dis-
solved in chlorobenzene (10 mL/mmol), and the solution was
heated at reflux for 1-2 h, while the reaction progress was
monitored with TLC. Then, the solvent was evaporated and
the residue was purified by column chromatography.
General Procedure (C): Reductive Cleavage of Isox-
azolidines with Zn. To a solution of isoxazolidine in Et2O
(20 mL/mmol) kept in an icebath were added glacial acetic acid
(2.2 mL/mmol) and activated39 Zn dust (15 equiv). The suspen-
sion was allowed to reach RT and was stirred vigorously for
24 h. Then, the solids were filtered off and the filtrate was
neutralized with 2 M NaOH under cooling. The organic layer
was washed with H2O (150 mL), and the aqueous one was
extracted with CH2Cl2 (3 × 150 mL). The combined organic
phases were dried and concentrated in a vacuum and the
residue was purified by column chromatography.40
General Procedure (D): Preparation of Ammonium
Iodides. Amino alcohol was dissolved in dry THF (20 mL/
mmol), and K2CO3 (2.5 equiv) was added. Subsequently, MeI
(20 equiv) was added portionly under an inert atmosphere.
The mixture was stirred at RT for 20 h and after evaporating
off the volatiles the resulting solid (ammonium iodide deriva-
tive) was used in the next reaction without any further
purification.
General Procedure (E): Preparation of Ammonium
Hydroxides. Crude iodide was dissolved in water (20 mL/
mmol). Ag2O (1.5 equiv) was added under vigorous stirring
and the mixture was allowed to react for 48 h at RT. After
filtration, the solvent was evaporated giving a crude solid,
which was used in the next reaction without any further
purification.
°C (lit.26 78.2-79.5 °C); [R]D25 -5.2° (c 2.3, CHCl3) [lit.26 [R]D
25
-5.0° (c 2.2, CHCl3)]; FTIR (neat film) 3468, 3058, 2986, 2933,
2878, 1595, 1491, 1449, 1381, 1217, 1059, 1032, 874 cm-1; 1H
NMR and 13C NMR spectra are identical with those reported
in the literature;26 HRMS m/e calcd for C28H30O4Na: [(M +
Na)+]: 453.2036; found: 453.2036.
1-[(4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl]-2-tri-
tyloxy1-ethanone (38). To a solution of pyridine (1.2 mL, 7.0
mmol) in dry benzene (25 mL), TFA (0.6 mL, 7.0 mmol) and
DMSO (2 mL, 28 mmol) were added. This was added to a
solution of 37 (2.96 g, 6.9 mmol) in dry benzene (30 mL), and
the mixture was cooled to 0 °C. Then, DCC (3.6 g, 17.5 mmol)
was added under an inert atmosphere and the resulting
solution was allowed to warm to RT. After 20 h of stirring,
ether (30 mL) was added, and dicyclohexylurea precipitated
as a white solid. The clear solution obtained by filtration was
washed with water (50 mL) and the aqueous phase was
extracted with dicloromethane (2 × 100 mL). The combined
organic phases were dried and the solvent was evaporated off.
The residue was purified by column chromatography (EtOAc/
hexanes ) 1/15) to give ketone 38 (2.47 g, 84%) as a white
solid: mp 105-107 °C (lit.26 mp 106.8-107.6 °C); [R]D25 -18.9°
(c 1.6, CHCl3) [lit.26 [R]D25 -19.1° (c 1.73, CHCl3)]; FTIR (neat
film) 3059, 3031, 2988, 2927, 2915, 2861, 1733, 1597, 1490,
1
1450, 1378, 1260, 1213, 1158, 1108, 1001, 938, 871 cm-1; H
NMR and 13C NMR spectra are identical with those reported
in the literature;26 HRMS m/e calcd for C28H28O4Na: [(M +
Na)+]: 451.1880, found: 451.1881.
(3aS,4S,7R,7aS)-2,2,4,5-Tetramethyl-7-trityloxymethyl-
hexahydro[1,3]dioxolo[4,5-c]pyridin-7-ol (39). Prepared
from 38 (925 mg, 2.2 mmol) following successively general
procedures A and B. Elution with EtOAc/hexanes ) 1:7 to
25
obtain 39 (880 mg, 84%, overall from 38) as a foam: [R]D
+29.7° (c 1.1, CHCl3); FTIR (neat film) 3445, 3088, 3061, 3023,
2979, 2934, 2878, 1598, 1489, 1463, 1447, 1417, 1372, 1219,
1073, 941, 780, 747, 702, 633 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.49 (d, J ) 7.9 Hz, 6H), 7-32-7.20 (m, 9H), 4.27 (bs, 1H),
4.16 (d, J ) 5.5 Hz, 1H), 3.94 (dd, J ) 9.2, 5.5 Hz, 1H), 3.26
(s, 2H), 2.60 (s, 3H), 2.56-2.48 (m, 1H), 1.41 (s, 3H), 1.33 (s,
3H), 1.10 (d, J ) 6.1 Hz, 3H);13C NMR (75 MHz, CDCl3) δ
143.6, 128.8, 127.7, 127.0, 109.4, 97.4, 86.7, 77.1, 74.3, 65.2,
62.6, 42.4, 28.0, 26.2, 14.9; HRMS m/e calcd for C29H33NO5-
Na: [(M + Na)+]: 498.2251, found: 498.2251.
General Procedure (F): Oxidative Elimination with
PDC. Crude iodide or tosylate or hydroxide prepared as
described in each case was suspended in dry CH2Cl2 (20 mL/
mmol) in the presence of PDC (1.3 equiv) at RT. After 4 h, the
solution was washed with water (20 mL) and dried, and the
organic solvent was removed in a vacuum at RT. The residue
was purified by column chromatography.
(1R)-1-[(4R,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl]-
2-trityloxy-1-ethanol (37). NaH (95%) (593 mg, 23.5 mmol)
was suspended in dry THF (15 mL), and DMSO (3.35 mL, 47.0
mmol) was added at 0 °C. The mixture was stirred under an
argon atmosphere for 30 min, and then it was transferred to
a suspension of methyl triphenylphosphonium bromide (8.45
g, 23.7 mmol) in dry THF (25 mL) at -5 °C. Stirring was
(1R,2R,6R,7S)-4,4,9-Trimethyl-1-trityloxymethyl-3,5,8-
trioxa-9-aza-tricyclo [5.2.1.02,6]decane (40). Ketone 38 (2.4
g, 5.6 mmol) was dissolved in dry pyridine (60 mL) and
MeNHOH‚HCl (1.64 g, 19.6 mmol) was added at RT. The
resulting solution was stirred under an inert atmosphere for
24 h until complete consumption of the starting material.
Then, the solvent was evaporated and the crude nitrone was
dissolved in chlorobenzene (50 mL). The resulting solution was
heated to reflux for 1 h. Evaporation of the solvent afforded a
residue which was purified by (EtOAc/hexanes ) 1/10) to give
adduct 40 (1.92 g, 75%) as an amorphous solid: [R]D25 -33.7°
(c 0.8, CHCl3); FTIR (neat film) 3058, 2986, 2929, 2885, 1634,
(39) Casey, M.; Leonard, J.; Lygo, B.; Procter, G. Advanced Practical
Organic Chemistry; Blackie and Son: Glasgow, U.K., 1991; p 49.
(40) Optical rotation value for 27 was mistakenly assigned in our
original comunication paper. The correct value is given here and it is
in accordance with the one given in the literature, see: Marco-
Contelles, J.; Rodr´ıguez-Ferna´ndez, M. M. Tetrahedron: Asymmetry
1997, 8, 2249-2256.
1491, 1449, 1375, 1208, 1072, 864, 768, 701 cm-1 1H NMR
;
(300 MHz, CDCl3) δ 7.50-7.47 (m, 6H), 7.33-7.21 (m, 9H),
4.39-4.29 (m, 3H), 3.60 (d, J ) 10.4 Hz, 1H), 3.34 (d, J ) 10.4
Hz, 1H), 2.41 (s, 3H), 1.91-1.81 (m, 2H), 1.42 (s, 3H), 1.33 (s,
J. Org. Chem, Vol. 70, No. 17, 2005 6889