Weitz-Scheffer Epoxidation of Isoflavones
J . Org. Chem., Vol. 67, No. 1, 2002 263
P r ep a r a tion of th e Sta r tin g Ma ter ia ls. P TC 1c.23 To a
solution of 500 mg (0.937 mmol) of PTC 1b in 5 mL of CH2Cl2
at 0 °C were added 0.274 mL (5.00 mmol) of bromomethane
(precooled to -78 °C) and 0.5 mL of a saturated aqueous NaOH
solution. The flask was stoppered and stirred for 5 h at 25 °C.
Water (5 mL) was added and the mixture extracted with CH2-
Cl2 (3 × 5 mL). The combined organic phases were dried
(MgSO4) and evaporated on a rotary evaporator (20 °C, 20
mbar). The residual orange oil was stirred in 20 mL of Et2O
for 16 h, and the resulting yellow solid was collected and
recrystallized from EtOH/Et2O to yield 436 mg (85%) of a pale
Sch em e 5. Ep oxid a tion of th e s-tr a n s-F ixed
En on e 6 u n d er P TC-Med ia ted Con d ition s.
1
yellow powder. H NMR (400 MHz, CDCl3): δ 0.99-1.10 (m,
fer reaction because coordination to the carbonyl group
for the oxygen transfer is difficult.11 Since the isoflavones
3 also possess a fixed s-trans configuration, one would
expect the same difficulties here for the aggregate B.
However, the endocyclic ether oxygen atom in the isofla-
vones 3 offers the required coordination site for the
hydrogen bonding in structure A (Scheme 4). Thus,
aggregate A accounts adequately for the high ee values
observed in the epoxidation of the isoflavones 3, but low
ones with the enone 6 (Scheme 5),18 since the latter
provides no accessible coordination site for hydrogen
bonding.
The comparison of the PTCs 1a and 1d , which possess
opposite configurations at the pertinent catalyst site,
further corroborate this mechanistic rationale. The ep-
oxidation with PTC 1d yields the opposite isoflavone
epoxide enantiomer 4c (1aS,7aR, 64% ee) versus PTC 1a
(1aR,7aS, 83% ee), whereas in the epoxidation of enone
6 both PTCs 1a ,d deliver the same enantiomer of the
epoxide 7 in the low ee values of 18% (PTC 1a ) and 8%
ee (PTC 1d ). The essential ether-oxygen coordination site
for hydrogen bonding with the hydroxy group of the PTC,
as is the case for the isoflavone 3 in aggregate A, is absent
in enone 6 and only little enantiofacial control may be
expected.
In summary, the asymmetric Weitz-Scheffer epoxi-
dation of isoflavones 3 with the cinchonine- and cinchoni-
dine-derived phase-transfer catalysts 1 and cumyl hy-
droperoxide2b asoxidant constitutesa highlyenantioselective
method that provides at will both enantiomers of epoxides
4 nearly quantitatively. The efficacious enantiocontrol is
rationalized in terms of the hydrogen-bonded aggregate
A between PTC 1 and isoflavone 3 during the asymmetric
oxygen transfer. This expedient asymmetric method
should be of synthetic value for the preparation of a wide
range of optically active enone epoxides related to the
isoflavone structure.
1 H), 1.61-2.01 (m, 4 H), 2.26-2.33 (m, 1 H), 2.45-2.51 (m, 1
H), 2.72-2.79 (m, 1 H), 3.36-3.62 (m, 2 H), 3.54 (s, 3 H), 4.13-
4.18 (m, 1 H), 4.44-4.45 (m, 1 H), 4.79 (s br, 1 H), 5.20 (d, J
) 17.2 Hz, 1 H), 5.28 (d, J ) 10.4 Hz, 1 H), 5.40 (s br, 1 H),
5.86 (ddd, J ) 17.2, 10.4, 7.1 Hz, 1 H), 5.98-6.01 (m, 1 H),
6.68-6.75 (m, 1 H), 7.61 (s br, 1 H), 7.69-7.76 (m, 3 H), 7.86-
7.90 (m, 1 H), 8.09-8.16 (m, 3 H), 8.94-8.95 (m, 2 H). 13C NMR
(100 MHz, CDCl3): δ 22.1 (t), 23.4 (t), 27.0 (d), 37.8 (d), 54.9
(t), 55.8 (t), 57.2 (q), 60.6 (t), 66.3 (d), 77.2 (d), 118.4 (t) 119.4
(d), 122.1 (s), 125.0 (d), 126.0 (d), 128.9 (d), 129.9 (d), 130.2
(d), 131.1 (s), 132.6 (s), 134.7 (2xd), 134.9 (d), 139.0 (s), 148.5
(s), 149.4 (d). C28H30BrF3N2O (547.5) HRMS (FAB, glycerine/
PEG400 100:5 matrix): [M - Br]+ calcd 467.2310, found
467.2310.
3-Isop r op yl-7-h yd r oxyisofla von e. A 500-mL, round-bot-
tom flask was charged with 2,4-dihydroxybenzoin (10.0 g, 45.6
mmol), isobutyric anhydride (55 mL), and isobutyryl chloride
(30 mL) in 100 mL of toluene. Triethylamine (50 mL) was
added, and the mixture was kept at reflux for 9 h. The hot
solution was poured onto ice (200 g) and acidified with 7 M
aqueous HCl (pH 1-2). The resulting colorless oil was collected
by means of a pipet, and the aqueous phase was extracted with
CH2Cl2 (2 × 40 mL). The combined organic phases were
washed with saturated aqueous NaHCO3 (2 × 70 mL), dried
(MgSO4), and evaporated on a rotary evaporator (40 °C, 20
mbar). The residue was dissolved in methanol (200 mL) and
heated with 20% NaOH solution (40 mL) for 15 min at reflux.
After the reaction mixture was cooled in an ice bath, the
precipitate was collected by filtration, washed with water (2
× 50 mL), and dried (MgSO4). Recrystallization from methanol
gave 10.0 g (70%) of 3-isopropyl-7-hydroxyisoflavone as a white
powder, mp 273-275 °C. IR (KBr): ν (cm -1) 3191, 2972, 1625,
1569, 1493, 1455, 1401, 1375, 1266, 1164, 1115, 988. 1H NMR
(200 MHz, DMSO): δ 1.29 (d, J ) 6.8 Hz, 6 H), 2.98 (septet,
J ) 6.8 Hz, 1 H), 6.85-6.90 (m, 2 H), 7.29-7.34 (m, 2 H), 7.40-
7.48 (m, 3 H), 8.05 (d, J ) 9.2 Hz, 1 H). 13C NMR (63 MHz,
DMSO): δ 20.6 (q), 31.5 (d), 103.2 (d), 115.9 (d), 117.1 (s), 122.3
(s), 128.3 (d), 128.6 (d), 129.4 (d), 131.4 (d), 134.7 (s), 159.0
(s), 164.0 (s), 170.6 (s), 178.0 (s). C18H15O (280.1) HRMS (CI):
[M - H]+ calcd 279.1021, found 279.1024.
3-Isop r op yl-7-m eth oxyisofla von e (3d ). To a solution of
4.07 g (14.9 mmol) of 3-isopropyl-7-hydroxyisoflavone and 4.47
mL (72.1 mmol) of methyl iodide in acetone was added 14.9 g
(107 mmol) solid K2CO3 with magnetic stirring, and the
mixture was heated for 5 h at reflux. The solid K2CO3 was
removed by filtration, the solvent was evaporated (20 °C, 20
mbar), and the crude product was recrystallized from methanol
to yield 2.76 g (63%) of 3-isopropyl-7-methoxyisoflavone (3d )
as a white powder, mp 164-166 °C. IR (KBr): ν (cm -1) 3054,
3015, 2981, 2932, 1636, 1608, 1440, 1258, 1168, 1017. 1H NMR
(400 MHz, CDCl3): δ 1.18 (d, J ) 6.8 Hz, 6 H), 2.88 (septet, J
) 6.8 Hz, 1 H), 3.84 (s, 3 H), 6.79 (d, J ) 2.4 Hz, 1 H), 6.87
(dd, J ) 8.8, 2.4 Hz, 1 H), 7.17-7.19 (m, 2 H), 7.28-7.37 (m,
3 H), 8.05 (d, J ) 8.8 Hz, 1 H). 13C NMR (100 MHz, CDCl3):
δ 20.2 (q), 31.0 (d), 55.8 (q), 99.8 (d), 114.1 (d), 117.4 (s), 121.8
(s), 127.6 (d), 128.4 (d), 128.4 (d), 130.3 (d), 133.3 (s), 157.7
(s), 163.9 (s), 169.4 (s), 176.7 (s). C19H18O3 (294.1): calcd C
77.53 H 6.16, found C 77.44, H 6.31.
Exp er im en ta l Section
Gen er a l Asp ects. The 1H and 13C NMR spectra were
recorded on a Bruker AC 200 (1H: 200 MHz, 13C: 50 MHz), a
Bruker AC 250 (1H: 250 MHz, 13C: 63 MHz), or a Bruker
Avance 400 (1H: 400 MHz, 13C: 100 MHz) spectrometer, and
the IR spectra were measured on a Perkin-Elmer 1600 FT-IR
spectrophotometer. The HPLC analyses were carried out on
chiral columns (Daicel CHIRALCEL OD) with a Kontron
instrument, furnished with a spectrophotometer UVIKON 720
micro and a CHIRALYSER 1.6 from IBZ Messtechnik (Han-
nover, Germany). The optical rotations were determined on a
Perkin-Elmer Polarimeter 241 MC. Mass spectra were carried
out on a Finigan MAT8200; the exact mass was determined
on a Finigan MAT90.
Solvents and commercially available chemicals were purified
by standard procedures. PTCs 1a ,b and 1d and hydroperoxides
2a ,b are commercially available. Cumyl hydroperoxide (2b)
was used as technical grade (80%). Hydroperoxides 2c,d 20 and
isoflavones 3a -c,e, as well as the correponding epoxides 4a -
c,e, were prepared according to the literature procedures.16,17
P r ep a r a tion of th e Ep oxid es. Rep r esen ta tive P r oce-
d u r e for th e P h a se-Tr a n sfer -Ca ta lyzed Ep oxid a tion of
(23) Hughes, D. L.; Dolling, U. H.; Ryan, K. M.; Schoenewaldt, E.
F.; Grabowski, E. J . J . J . Org. Chem. 1987, 52, 4745-4752.