Enantioselective synthesis of (R)- and (S)-4-benzyloxy-2-cyclohexen-1-one

Full text of DOI:10.1021/jo001413l

1
494
J . Org. Chem. 2001, 66, 1494-1496
En a n tioselective Syn th esis of (R)- a n d
S)-4-Ben zyloxy-2-cycloh exen -1-on e
Sch em e 1
(
Hidetaka Suzuki, Naoki Yamazaki, and
Chihiro Kibayashi*
School of Pharmacy, Tokyo University of Pharmacy & Life
Science, Horinouchi, Hachioji, Tokyo 192-0392, J apan
kibayasi@ps.toyaku.ac.jp
Received September 25, 2000
In connection with our work on natural product
synthesis, we required a general synthesis of both enan-
tiomers of 4-benzyloxy-2-cyclohexen-1-one (1). Inspection
of the literature revealed that the asymmetric synthesis
of the S enantiomer of 1 can be attained via diastereo-
Sch em e 2
1
selective reduction of a chiral ketosulfoxide. On the other
hand, the conversion of (-)-quinic acid into the S enan-
tiomer of [(4-methoxybenzyl)oxy]-2-cyclohexen-1-one (2)
has been reported in the context of the total synthesis of
2
the immunosuppressive FK-506. In this paper, we report
the development of a simple and efficient enantioselective
synthesis of both enantiomeric enones (R)-1 and (S)-1
based on a tandem asymmetric deprotonation-palla-
dium(II)-induced dehydrosilylation reaction sequence.
the reaction was rather sluggish and 1 was obtained in
moderate yield (55%) along with the recovered starting
material (34%), a stoichiometric amount of Pd(OAc) was
2
used, leading to a remarkable improvement in the yield
of 1 (98%).
A number of recent studies pointed out the utility of
asymmetric deprotonation with chiral bases for desym-
metrization of prochiral cyclic ketones. It is envisioned
that this asymmetric tactic could serve for a convenient
enantioselective access to both enantiomers of the enones,
For the purpose of the assignment of the absolute
configuration of the obtained chiral enone 1 and deter-
mination of its enantiomeric purity by chiral HPLC
analysis, the R enantiomer of the enone, (R)-1, was then
synthesized by an alternative route outlined in Scheme
3
(R)-1 and (S)-1, involving the formation of chiral enol
derivatives by σ symmetry-breaking deprotonation of the
cyclic ketone 4-(benzyloxy)cyclohexanone (3) under the
influence of both enantiomers of chiral lithium amide
2
. Thus, meso-1,4-(diacetyloxy)cyclohex-2-ene (5) was
subjected tohydrolase-catalyzed resolution with Pseudomo-
nas cepacia lipase (Amano) based on a reported proce-
4
bases. Thus, the Corey in situ quench technique was
dure,6 which delivered the enantiomerically enriched
applied to the cyclic ketone 3 for chiral base-mediated
enolization, followed by in situ conversion to the enol
silane 4 as shown in Scheme 1: In a typical experiment,
alcohol (1S,4R)-6 with 88% ee (by chiral HPLC analysis).
Oxidation of the latter with tetrapropylammonium per-
ruthenate (TPAP)/4-methylmorpholine N-oxide (NMO)
produced the enone (R)-7, which was converted via
acetate hydrolysis followed by O-benzylation to (R)-1.
the chiral lithium amide and Me
THF and the cyclic ketone 3 was added to this at -78
C. The resulting enantiomerically enriched enol silane
was subjected to palladium(II)-catalyzed dehydrosily-
lation (0.5 molar equiv of Pd(OAc) in the presence of 0.5
3
SiCl were premixed in
°
4
1
Comparison of the H NMR data of synthetic (R)-1 with
1
those for (S)-1 reported by Carre n˜ o et al. proved that
2
the chemical structures of these compounds are identical.
molar equiv of p-benzoquinone) according to the proce-
However, to our surprise, the sign of the optical rotation
5
dure developed by Saegusa et al. to yield the optically
24
of synthetic (R)-1 ([R]
D
+86 (c 1.2, CHCl
3
)) was found
+66
3
)). Furthermore, the sample of (S)-1 obtained
active cyclic enone 1. In this case, however, since
to be the same as that reported1 for (S)-1 ([R]
D
(c 0.4, CHCl
(
1) Carre n˜ o, M. C.; Rauno, J . L. G.; Garrido, M.; Ruiz, M. P.; Solladi e´ ,
G. Tetrtahedron Lett. 1990, 31, 6653-6656.
2) (a) Audia, J . E.; Boisvert, L.; Patten, A. D.; Villalobos, A.;
by following the exactly same reaction sequence reported
(
Danishefsky, S. J . J . Org. Chem. 1989, 54, 3738-3740. (b) J ones, A.
B.; Yamaguchi, M.; Patten, A.; Danishefsky, S. J .; Ragan, J . A.; Smith,
D. B.; Schreiber, S. L. J . Org. Chem. 1989, 54, 17-19.
(5) Ito, Y.; Hirao, T.; Saegusa, T. J . Org. Chem. 1978, 43, 1011-
1013.
(6) (a) Harris, K. J .; Shih, Y.-E.; Girdaukas, G.; Sih, C. J . Tetrahe-
dron Lett. 1991, 32, 3941-3944. (b) Kazlauskas, R. J .; Weissfloch, A.
N. E.; Rappaport, A. T.; Cuccia, L. A. J . Org. Chem. 1991, 56, 2656-
2665.
(
3) For a review, see: Cox, P. J .; Simpkins, N. S. Tetrahedron:
Asymmetry 1991, 2, 1-26.
(4) Corey, E. J .; Gross, A. W. Tetrahedron Lett. 1984, 25, 495-498.
1
0.1021/jo001413l CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/25/2001

Notes
J . Org. Chem., Vol. 66, No. 4, 2001 1495
has allowed the successful preparation of both enanti-
omers of cyclic enones 1. Additionally, our synthesis and
chiral HPLC analysis of 1 led to the conclusion that the
positive sign of the specific rotation reported for (S)-1
should be corrected to the negative sign.
Exp er im en ta l Section
F igu r e 1. Chiral lithium dialkylamides (represented by one
enantiomer in each case).
Gen er a l Meth od s. 1H NMR spectra were recorded at 400
1
3
MHz using residual CHCl
spectra were recorded at 100.6 MHz with CDCl
3
(7.26 ppm) as reference. C NMR
(77.05 ppm) as
Ta ble 1. En a n tioselective Syn th esis of Cyclic En on es
(
R)-1 a n d (S)-1 via En ol Sila n es (R)-4 a n d (S)-4 F or m ed
3
by Lith iu m Am id e-Med ia ted Dep r oton a tion a
reference. IR spectra were taken with an FTIR instrument. Mass
spectra were measured at an ionizing voltage of 70 eV. Organic
solvents used were dried by standard methods. Unless otherwise
noted, silica gel 60 (230-400 mesh, Merck) was used for column
chromatography, and precoated silica gel 60F254 plates (0.25 mm,
Merck) were used for TLC. All enantiomeric excesses were
determined by chiral HPLC on a solid stationary phase Chiral-
pak AD or Chiralcel OD column using hexane-2-propanol
mixtures as eluents.
enol silane (R)-4/(S)-4
entry lithium amide temp (°C) yield (%)b compoundd ee (%)e
cyclic enonec
1
2
3
4
5
6
7
(R)-9
(S)-9
-78
-78
-78
-95
-78
-78
-78
76
79
87
65
84
57
56
(S)-1
(R)-1
(S)-1
(S)-1
(R)-1
(S)-1
(R)-1
24
26
80
82
81
82
82
(R,R)-10
(R,R)-10
(S,S)-10
(R,R)-11
(S,S)-11
4-(Ben zyloxy)-1-tr im eth ylsilyloxycycloh ex-1-en e (4). In
a typical procedure, a solution of the chiral lithium amide (R,R)-
1
0 was prepared by treatment of a solution of the corresponding
a
Cf. Scheme 1. b Isolated yield of the enantiomeric mixture of
secondary amine (121 mg, 0.54 mmol) in THF (2 mL) at -78 °C
c
(
R)-4 and (S)-4 after silica gel chromatography. Converted from
the enantiomeric mixture of 4 by Pd(II)-induced dehydrosilylation
in 96-98% yield as the enantiomeric mixture. Major enantiomer
formed. Determined by chiral HPLC using a Chiralcel OD
under Ar with a solution (1.54 M) of BuLi (350 µL, 0.54 mmol)
d
3
in hexane. After 30 min, Me SiCl (310 µL, 2.45 mmol) was added
e
to it via a microsyringe with stirring. After being stirred for 2
7
min, a solution of 3 (100 mg, 0.49 mmol) in THF (0.5 mL) was
column.
added, and the mixture was stirred at -78 °C for 10 min. The
by the same authors1 was found to have the optical
mixture was quenched by addition of saturated NaHCO
3
solution
O (3 × 20 mL). The combined
organic extracts were washed with water (20 mL) and brine (20
mL), dried (MgSO ), and concentrated. Chromatography (hex-
ane-AcOEt, 50:1) of the crude residue gave an enantiomeric
mixture of 4 (118 mg, 87%) as a colorless oil: 1H NMR (CDCl
δ 0.20 (9H, s), 1.65-1.81 (1H, m), 1.95-2.01 (1H, m), 2.11-2.18
3H, m), 2.30-2.42 (1H, m), 3.61-3.68 (1H, m), 4.58 (2H, s),
.74-4.76 (1H, m), 7.26-7.38 (5H, m); 13C NMR (CDCl
) δ 0.3
(5 mL) and extracted with Et
2
rotation value ([R]23
D
3
-96 (c 1.2, CHCl )) being not only
significantly larger but also of the opposite sign from the
reported value. These facts led to the conclusion that the
4
positive sign of the optical rotation given for (S)-1 ([R]
66 (c 0.4, CHCl )) is erroneous and should be corrected
to the negative sign. Therefore, the correct value of [R]
98 (CHCl
S)-1, which was estimated from the observed value [R]
86 (c 1.2, CHCl
material of (R)-1).
D
3
)
+
3
(
4
D
D
3
-
(
+
3
) should be adopted for enantiomerically pure
(3 carbons), 28.1 (2 carbons), 29.8, 70.1, 73.5, 100.8, 127.3, 127.4
2
4
(2 carbons), 128.3 (2 carbons), 139.0, 149.9; IR (neat) 1670, 1372,
3
) for the above-described 88% ee
1
252, 1189, 1099, 888, 845 cm ; EIMS m/z (relative intensity)
-1
+
276 (M , 0.8), 204 (1.0), 170 (12), 155 (20), 104 (24), 91 (100).
Having established the absolute stereochemistry and
the optical rotation value of the enones (R)-1 and (S)-1,
we examined the effect of chiral lithium amide bases on
enantioselectivity in asymmetric synthesis of these enones
based on the asymmetric deprotection-dehydrosilylation
protocol described above. We chose a series of the chiral
arylethylamine-based lithium amides 9-11 for the rea-
son of their commercial availability in both enantiomeric
forms (Figure 1). The results from these experiments are
depicted in Table 1. Within the range of our experiments,
these results proved that the R (or S) chirality of the
arylethylamino moiety in the chiral lithium amides
induces the formation of the enone 1 having the S (or R)
absolute configuration. As can be seen in Table 1, the
use of the lithium amide 9 for the asymmetric deproto-
nation of the cyclic ketone 3 resulted in poor asymmetric
induction (24% and 26% ee) in the formation of the chiral
4-Ben zyloxy-2-cycloh exen -1-on e (1). Meth od A. To a
solution of Pd(OAc) (224 mg, 1 mmol) and p-benzoquinone (108
2
mg, 1 mmol) in acetonitrile (4 mL) was added the enantiomeric
mixture of 4 (552 mg, 2 mmol) with stirring under Ar at room
temperature. After being stirred at room temperature for 10 h,
the mixture was filtered through Celite and concentrated in
vacuo. Chromatography of the residue gave the unreacted
starting material 4 (188 mg, 45%) and an enantiomeric mixture
of 1 (222 mg, 55% or 83% based on recovered starting material)
as a colorless oil: 1H NMR (CDCl
.39 (2H, m), 2.58-2.65 (1H, m), 4.25-4.29 (1H, m), 4.66 (1H,
ABq, J ) 11.8 Hz), 5.55 (1H, ddd, J ) 10.3, 1.8, 0.9 Hz), 6.99
) δ 2.01-2.11 (1H, m), 2.30-
3
2
1
3
(
(
(
1H, ddd, J ) 10.3, 2.3, 1.5 Hz), 7.30-7.37 (5H, m); C NMR
CDCl ) δ 26.2, 35.3, 70.9, 72.5, 127.7 (2 carbons), 127.9, 128.6
2 carbons), 137.8, 150.5, 198.7; IR (neat) 1682, 1094 cm ; EIMS
3
-1
+
m/z (relative intensity) 202 (M , 0.2), 174 (0.5), 142 (0.6), 124
(1.1), 104 (1.7), 91 (100). Anal. Calcd for C13
6.98. Found: C, 76.9; H, 6.97.
14 2
H O : C, 77.20; H,
The enantiomeric excess of 1 (see Table 1) was determined
by chiral HPLC analysis using a Chiralcel OD column (hexane-
-propanol (90:10, v/v), 0.5 mL/min, detection at 254 nm, (S)-1:
7.04 min, (R)-1: 31.23 min).
cyclic enone 1 (entries 1, 2). However, the use of the C
symmetrical lithium amides 10 (entries 3, 5) and 11
entries 6, 7) led to good enantioselectivity (80-82% ee),
2
-
2
2
(
Meth od B. A solution of the enantiomeric mixture of 4 (118
though in the latter case the chemical yields of 4 were
rather low (57% and 56%). When the deprotonation of 3
using (R,R)-10 was carried out at lower temperature (-95
2
mg, 0.43 mmol) and Pd(OAc) (96 mg, 0.43 mmol) in acetonitrile
(
4 mL) was stirred at room temperature under Ar for 10 h. The
mixture was filtered through Celite and concentrated in vacuo.
Purification of the residue by chromatography (hexane-AcOEt,
9:1) afforded an enantiomeric mixture of 1 (85 mg, 98%).
°
C), the yield of the enol silane 4 decreased to 65% with
no change in the enantioselectivity (entry 4).
In conclusion, application of the tandem asymmetric
deprotonation-palladium(II)-induced dehydrosilylation
reaction sequence to the σ-symmetrical cyclic enone 3
(
7) Keck, G. E.; Dougherty, S. M.; Savin, K. A. J . Org. Chem. 1995,
60, 6210-6223.

1
496 J . Org. Chem., Vol. 66, No. 4, 2001
Notes
Lip a se-Ca ta lyzed Hyd r olysis of 5. To a stirred solution of
(1H, dt, J ) 16.8, 5.0 Hz), 5.53-5.58 (1H, m), 6.05 (1H, ddd, J
) 10.3, 1.9, 0.7 Hz), 6.84 (1H, ddd, J ) 10.3, 2.7, 1.4 Hz), 7.29-
8
the diacetate 5 (5.00 g, 25.2 mmol) in toluene (100 mL) were
added 0.1 M phosphate buffer solution (pH 7.5, 400 mL) and
then Pseudomonas cepacia lipase (Amano) (5.0 g) at room
temperature. The suspension was stirred at room temperature
7.59 (5H, m); 13C NMR (CDCl
) δ 21.0, 28.7, 34.9, 67.7, 130.8,
3
1
-
147.6, 170.3, 197.8; IR (neat) 1740, 1688, 1373, 1237, 1038 cm
;
+
EIMS m/z (relative intensity) 154 (M , 21), 126 (9), 112 (50), 94
+
for 2 days, extracted with Et
through Celite. The filtrate was dried (MgSO
2
O (3 × 200 mL), and filtered
(39), 84 (88), 43 (100); HRMS (EI) calcd for C
154.0630, found 154.0634.
8 10 3
H O (M )
4
) and concentrated.
The residue was chromatographed (hexane-AcOEt, 20:1) to give
the monoacetate (1S,4R)-6 (0.96 g, 25% or 64% based on
recovered starting material (3.50 g)) in 88% ee as determined
by HPLC using a Chiralpak AD column (hexane-2-propanol (95:
(R)-4-Hyd r oxy-2-cycloh exen -1-on e ((R)-8). To a solution
of above-described (R)-7 (200 mg, 1.29 mmol) in MeOH (4 mL)
was added K
room temperature for 10 min, the mixture was diluted with brine
(4 mL) and extracted with CHCl
(3 × 8 mL). The combined
organic layers were washed with brine (5 mL), dried (MgSO ),
2 3
CO (180 mg, 1.30 mmol). After being stirred at
5
6
1
, v/v), 0.5 mL/min, RI detection, (1S,4R)-6: 22.86 min, (1R,4S)-
3
1
: 23.86 min): H NMR (CDCl
3
) δ 1.51-1.62 (1H, br m), 1.70-
4
.95 (4H, m), 2.07 (3H, s), 4.15-4.23 (1H, br m), 5.17-5.20 (1H,
and concentrated in vacuo. The resulting residue was purified
by chromatography (hexane-AcOEt, 1:1) to give (R)-8 (129 mg,
89%) as a colorless oil, which had spectral data (NMR and IR)
in agreement with those previously reported2a for (S)-8.
P r ep a r a tion of (R)-1 by O-Ben zyla tion of (R)-8. To a
m), 5.80 (1H, ddd, J ) 10.1, 3.5, 0.8 Hz), 5.97 (1H, ddd, J )
1
1
0.1, 2.8, 0.9 Hz); 13C NMR (CDCl
28.0, 134.8, 170.7.
3
) δ 21.3, 25.0, 28.2, 65.4, 67.3,
(
R)-4-Acetoxy-2-cycloh exen -1-on e ((R)-7). To a stirred
solution of (1S,4R)-6 (88% ee, 2.0 g, 12.8 mmol) in CH Cl (120
2
2
solution of above-described (R)-8 (400 mg, 3.57 mmol) in CH
2
-
mL) were added powdered 4 Å molecular sieves (200 mg) and
NMO (2.59 g, 19.2 mmol). After the mixture was stirred at room
temperature for 30 min, TPAP (225 mg, 0.64 mmol) was added
and stirring was continued. After 10 min, the mixture was
Cl (7 mL) were added Ag O (993 mg, 4.28 mmol) and benzyl
2
2
bromide (855 mg, 5.00 mmol). The mixture was stirred at room
temperature for 24 h, filtered through Celite, and concentrated
in vacuo. After rapid chromatography of the residue on neutral
alumina (hexane-AcOEt, 4:1) to remove the resulting benzyl
alcohol, silica gel chromatography (hexane-AcOEt, 4:1) was
diluted with CHCl
solution (100 mL), 10% CuSO
mL). Drying (MgSO ) and concentration in vacuo left a residue
which was purified by chromatography (hexane-AcOEt, 5:1) to
3
(120 mL) and washed with 10% Na
2 3
CO
4
solution (100 mL), and brine (100
2
4
4
performed to give (R)-1 (390 mg, 54%) as a colorless oil: [R]
+86 (c 1.2, CHCl ).
D
3
2
6
give (R)-7 (1.24 g, 63%) as a colorless oil: [R]
D
+113 (c 1.48,
) δ 2.10 (3H, s), 2.04-12.13 (1H, m),
.31-2.38 (1H, m), 2.44 (1H, ddd, J ) 16.8, 11.6, 5.0 Hz), 2.61
Su p p or tin g In for m a tion Ava ila ble: Copies of H and 13C
NMR spectra for compounds (R)-4, (1S,4R)-6, and (R)-7. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1
1
3 3
CHCl ); H NMR (CDCl
2
(8) B a¨ ckvall, J .-E.; Bystr o¨ rn, S. E.; Nordberg, R. E. J . Org. Chem.
1
984, 49, 4619-4631.
J O001413L