Catalytic kinetic resolution reaction of (±)-5- methylbicyclo[3.3.0]oct-1-ene-3,6-dione

Full text of DOI:10.1021/jo9904922

5318
J . Org. Chem. 1999, 64, 5318-5320
Sch em e 1. Str a tegy for Ca ta lytic Kin etic
Resolu tion of
(()-5-Meth ylbicyclo[3.3.0]oct-1-en e-3,6-d ion e
Ca ta lytic Kin etic Resolu tion Rea ction of
(()-5-Meth ylbicyclo[3.3.0]oct-1-en e-3,6-d ion e
Eita Emori, Takehiko Iida, and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The University
of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, J apan
Received March 22, 1999
We have recently developed an efficient catalytic
asymmetric Michael addition of thiols to R,â-unsaturated
carbonyl compounds1 using heterobimetallic asymmetric
complexes,2 in particular, LaNa3tris(binaphthoxide) (LSB)
and SmNa3tris(binaphthoxide) complexes.3 As an exten-
sion of this catalytic asymmetric reaction, we became
very interested in catalytic kinetic resolutions using
Michael addition of thiols as a key step. In this paper,
we describe a catalytic kinetic resolution of (()-5-
methylbicyclo[3.3.0]oct-1-ene-3,6-dione (1), in which in-
teresting additive effects and nonlinear effects are also
discussed.
LSB (5 mol %) (toluene/THF 40:1, -40 °C, 0.5 h), giving
2′ as a single stereoisomer (see 13C NMR) (47%) (Rf )
0.70, hexanes-ethyl acetate 1:1 (v/v), silica gel plate) in
only 9% ee and (R)-1 (49%) (Rf ) 0.31, hexanes-ethyl
acetate 1:1 (v/v), silica gel plate) in 8% ee. The enantio-
meric excesses of 2′ and (R)-1 were determined by HPLC
analysis using a chiral stationary phase column (DAICEL
CHIRALCEL OJ , i-PrOH/hexane 1:9 for 2′ and 2:98 for
(R)-1), and the absolute configuration of (R)-1 was
determined by optical rotation.4 On the other hand, the
relative stereochemistry of 2′ was tentatively assigned
on the basis of the precedent.5 Changing the solvent to
CH2Cl2 allowed the enantiomeric excesses of both com-
pounds to be improved, although ee’s were still modest
(37% for 2′ and 36% ee for (R)-1). We then turned our
attention to the use of other heterobimetallic asymmetric
complexes. It was first observed that treatment of race-
mic 1 with 0.5 equiv of 4-tert-butyl(thiophenol) in the
presence of a AlLibis((R)-binaphthoxide) ((R)-ALB) com-
plex (15 mol %) (THF, 0 °C, 2 h) afforded 2′ (48%, 19%
ee) and (R)-1 (49%, 20% ee). After several attempts, we
were pleased to find that the use of toluene as a solvent,
instead of THF, gave rise to 2′ (47%, 63% ee) and (R)-1
(48%, 60% ee) even at room temperature8 (entry 4, Table
1).
To further improve this result, we paid attention to
the structure of the ALB complex in toluene. It was found
that the 13C NMR spectrum of ALB in THF clearly
showed 10 peaks corresponding to the binaphthyl moiety,
while that of ALB in benzene9 did not show any signifi-
cant peaks. These results appeared to indicate that the
ALB complex exists as an oligomeric form in toluene.
Consequently, we were interested to see the result
obtained by the disaggregation of ALB in the reaction
mixture. To do this, we decided to add 9 mol % (1.2 equiv
of OH moiety to ALB)10 of (R)-BINOL to ALB (15 mol %)
in toluene and then carry out a catalytic kinetic resolu-
tion (rt, 6 h). Under these conditions, a better result was
obtained (entry 5, Table 1), giving 2′ (46%, 76% ee) and
(R)-1 (49%, 73% ee). Furthermore, as shown in entry 6
(Table 1), we observed an interesting result by the
addition of an achiral alcohol, such as tert-butyl alcohol11
5-Methylbicyclo[3.3.0]oct-1-ene-3,6-dione (1)4 is a ver-
satile intermediate for the synthesis of several natural
products such as coriolin.5 Opically active 1 was initially
synthesized by Trost and Curran using an intramolecular
asymmtric Wittig reaction, giving 1 in 40% ee.4 This
enantioselectivity was soon greatly improved to 77% ee
by the same group.6 In 1987, Brooks and Woods suc-
ceeded in synthesizing 1 in greater than 98% ee by
bakers’ yeast.7 To the best of our knowledge, however,
there have been no reports concerning an asymmetric
synthesis of 1 using a molecular catalyst.
We envisioned that (()-5-methylbicyclo[3.3.0]oct-1-ene-
3,6-dione (1) would be a suitable Michael acceptor for the
catalytic asymmetric Michael addition of thiols, hopefully
resulting in the formation of optically active 1 and the
Michael adduct 2, with the opposite absolute configura-
tion on the bridgehead carbon atom (Scheme 1). Further-
more, optically active 2 was expected to be transformed
into the other enantiomer of 1. Thus, both enantiomers
of 1 could be readily obtained using a catalytic amount
of a heterobimetallic asymmetric complex. To examine
the feasibility of the above-mentioned strategy, a large
amount of racemic 1 was synthesized according to the
procedure developed by Trost and Curran.4 On the basis
of our precedent,1 racemic 1 was first treated with 0.5
equiv of 4-tert-butyl(thiophenol), in the presence of (R)-
(1) Emori, E.; Arai, T.; Sasai, H.; Shibasaki, M. J . Am. Chem. Soc.
1998, 120, 4043-4044.
(2) Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem., Int. Ed. Engl.
1997, 36, 1236-1256.
(3) For other catalytic asymmetric Michael additions of thiols, see:
(a) Suzuki, K.; Ikegawa, A.; Mukaiyama, T. Bull. Chem. Soc. J pn. 1982,
55, 3277-3282. (b) Nishimura, K.; Ono, M.; Nagaoka, Y.; Tomioka, K.
J . Am. Chem. Soc. 1997, 119, 12974-12975. (c) Tomioka, K.; Okuda,
M.; Nishimura, K.; Manabe, S.; Kanai, M.; Nagaoka, Y.; Koga, K.
Tetrahedron Lett. 1998, 39, 2141-2144.
(4) Trost, B. M.; Curran, D. P. J . Am. Chem. Soc. 1980, 102, 5699-
5700.
(5) Trost, B. M.; Curran, D. P. J . Am. Chem. Soc. 1981, 103, 7380-
7381.
(8) The reaction at 0 °C gave 2′ in 62% ee.
(9) Benzene was used instead of toluene for simplifing the 13C NMR
spectrum.
(6) Trost, B. M.; Curran, D. P. Tetrahedron Lett. 1981, 22, 4929-
4932.
(10) The addition of 18 mol % of (R)-BINOL gave similar results.
(11) For the effects of tert-butyl alcohol on
a heterobimetallic
(7) Brooks, D. W.; Woods, K. W. J . Org. Chem. 1987, 52, 2036-
2039.
catalysis, see: Funabashi, K.; Saida, Y.; Kanai, M.; Arai. T.; Sasai,
H.; Shibasaki, M. Tetrahedron Lett. 1998, 39, 7557-7558.
10.1021/jo9904922 CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/09/1999

Notes
J . Org. Chem., Vol. 64, No. 14, 1999 5319
Ta ble 1. Ca ta lytic Kin etic Resolu tion of 5-Meth ylbicyclo[3.3.0]oct-1-en e-3,6-d ion e
(R)-1
T (°C) time (h) yield (%)
2′
entry
catalyst (mol %)
additive (mol %)
none
none
none
solvent
ee (%)
8
yield (%) ee (%)
1
2
3
4
5
6
7
8a
(R)-LSB (5)
(R)-LSB (5)
(R)-ALB (15)
(R)-ALB (15)
(R)-ALB (15)
(R)-ALB (15)
(R)-ALB (15)
(R)-ALB (8)
toluene-THF (40:1)
CH2Cl2
-40
-40
0
0.5
0.5
2
49
48
49
48
49
48
49
47
47
47
48
47
46
47
48
48
9
37
19
63
76
73
78
78
36
20
THF
none
toluene
toluene
toluene
toluene
rt
6
60
(R)-BINOL (9)
t-BuOH (18)
4-MeOC6H4OH (18)
rt
6
73
rt
6
72
rt
rt
6
6
77
4-MeOC6H4OH (9.6) toluene
79 (91)b
a
b
1.80 g of (()-1 (12 mmol) was used. (()-1 was separated by selective crystallization.
Sch em e 2. P r op osed Ca ta lytic Cycle of th e
Kin etic Resolu tion Usin g Mich a el Ad d ition of
Th iols
F igu r e 1. Influence of the amount of 4-methoxyphenol on ee.
(18 mol %), which gave rise to 2′ (47%, 73% ee) and (R)-1
(48%, 72% ee). After several attempts, the addition of
4-methoxyphenol (18 mol %: 1.2 equiv to ALB) was found
to give the best result, providing 2′ (48%, 78% ee) and
(R)-1 (49%, 77% ee) (entry 7, Table 1). As shown in Figure
1, the enantiomeric excess of 2′ was highest with the
addition of 1.2 equiv of 4-methoxyphenol, while no
improvement was obtained by adding more than 1.2
equiv. In a larger scale experiment (1.8 g of 1), we were
able to decrease the catalyst amount of ALB to 8 mol %,
affording 2′ (48%, 78% ee) and (R)-1 (47%, 79% ee) (entry
8, Table 1). The Michael adduct 2′ was readily converted
to (S)-1 through the sulfoxide (91% yield). Based on the
fact that such additive effects were not observed when
THF was used as a solvent, the above-mentioned im-
proved result can be attributed to the disaggregation of
the oligomeric ALB in toluene. To clarify the role of
It was also found that interesting nonlinear effects
(asymmetric amplification)12 were observed in the ab-
sence and presence of 4-methoxyphenol, as shown in
Figure 2. These phenomena suggest that the oligomeric
complex, formed from (R)-ALB and (S)-ALB, shows lower
reactivity than ALB itself and also suggest that the
oligomeric complex is not readily disaggregated even in
the presence of 4-methoxyphenol.13
We finally attempted to increase the optical purity of
(R)-1 (79% ee) by the separation of racemic 1 as a
crystalline solid [hexanes-ethyl acetate 2:1 (v/v), -30
°C], affording (R)-1 in 91% ee and 85% yield.
7
4-methoxyphenol, Li NMR and 27Al NMR observations
were performed. The 7Li NMR spectrum of ALB in
toluene showed two signals at δ ) -0.33 and -1.07 ppm
with similar intensities. After the addition of 4-methoxy-
phenol (1.6 equiv to ALB), one major peak (δ ) -0.08
ppm) was obtained together with a small peak (δ ) -1.02
ppm). On the other hand, the 27Al NMR spectrum of ALB
in toluene did not give rise to the obvious change after
the addition of 4-methoxyphenol. Thus, 4-methoxyphenol
appears to coordinate to the lithium atom of ALB, and
the resulting monomeric ALB should catalyze the kinetic
resolution as shown in Scheme 2.
In conclusion, we have developed a catalytic kinetic
resolution of (()-5-methylbicyclo[3.3.0]oct-1-ene-3,6-dione
(1) by the Michael addition of 4-tert-butyl (thiophenol)
promoted by ALB and 4-methoxyphenol. Moreover, we
(12) For a recent review, see: Girard, C.; Kagan, H. B. Angew.
Chem., Int. Ed. Engl. 1998, 37, 2922-2959.
(13) The ALB complex consisting of a (R)-BINOL and a (S)-BINOL
cannot be formed due to steric hindrance.

5320 J . Org. Chem., Vol. 64, No. 14, 1999
Notes
and (R)-5-methylbicyclo[3.3.0]oct-1-ene-3,6-dione ((R)-1) (840 mg,
47%) as a colorless oil.
The spectral data of (R)-1 were identical to those previously
reported.7 The enantiomeric excess of (R)-1 was determined by
chiral stationary-phase HPLC analysis (DAICEL CHIRALCEL
OJ , i-PrOH-hexane 2:98; flow rate, 1.1 mL/min; retention time,
46.8 min (minor), 50.7 min (major)). The absolute configuration
of (R)-1 was determined by the optical rotation: [R]20 -104° (c
D
0.80, CHCl3) (79% ee).
1
Compound 2′: IR (neat) 1746 cm-1; H NMR (CDCl3) δ 1.32
(s, 9H), 1.34 (s, 3H), 2.05-2.09 (m, 1H), 2.25-2.31 (m, 2H), 2.35-
2.46 (m, 2H), 2.62-2.75 (m, 3H) 7.37-7.43 (m, 4H); 13C NMR
(CDCl3) δ 17.2, 31.2, 31.3, 34.5, 34.7, 46.4, 50.3, 57.4, 60.7, 126.4,
126.7, 136.4, 152.9, 212.7, 217.8; MS m/z 316 (M+); [R]20D +66.3°
(c 0.66, CHCl3) (78% ee). Anal. Calcd for C19H24O2S: C, 72.11;
H, 7.64. Found: C, 71.79; H, 7.51. The enantiomeric excess of
2′ was determined by chiral stationary-phase HPLC analysis
(DAICEL CHIRALCEL OJ , i-PrOH-hexane 1:9; flow rate, 1.0
mL/min; retention time, 12.4 min (major), 21.1 min (minor)). The
absolute configuration of 2′ was determined by the optical
rotation after its conversion into (S)-1.
F igu r e 2. Nonlinear effects in catalytic kinetic resolution.
Con ver sion of 2′ to (S)-5-Meth ylbicyclo[3.3.0]oct-1-en e-
3,6-d ion e ((S)-1). To a solution of 2′ (1.4 g, 4.4 mmol) in CH2Cl2
(10 mL) was added m-chloroperbenzoic acid (5.3 mmol) at 0 °C.
After being stirred for 0.5 h at the same temperature, the
reaction mixture was quenched with saturated aqueous Na2S2O3.
The resulting mixture was extracted with CH2Cl2 (3 × 50 mL).
The combined organic layers were vigorously stirred with
saturated aqueous NaHCO3 (150 mL). Then the organic layer
was washed with brine, dried (Na2SO4), and concentrated. The
residue was purified by flash column chromatography (SiO2,
ethyl acetate-hexane 1:1) to give (S)-5-methylbicyclo[3.3.0]oct-
have found interesting additive effects and asymmetric
amplification in the ALB-catalyzed reaction. Although
the ee’s of both enantiomers are not excellent (91% ee),
the method described herein offers a simple method to
obtain both enantiomers of 1, which are synthetically
very versatile intermediates.
Exp er im en ta l Section
1-ene-3,6-dione ((S)-1) (601 mg, 91%) as a colorless oil: [R]20
D
+102° (c 0.82, CHCl3) (77% ee). The spectral data of (S)-1 were
Gen er a l Meth od s. In general, reactions were carried out in
dry solvents under an argon atmosphere, unless otherwise
stated. Tetrahydrofuran (THF) was distilled from sodium benzo-
phenone ketyl. Toluene was distilled from sodium.
identical to those previously reported.7
In cr ea se in th e Op tica l P u r ity of (R)-5-Meth ylbicyclo-
[3.3.0]oct-1-en e-3,6-d ion e ((R)-1) by Selective Cr ysta lliza -
tion of (()-5-Meth ylbicyclo[3.3.0]oct-1-en e-3,6-d ion e ((()-
1). (R)-5-Methylbicyclo[3.3.0]oct-1-ene-3,6-dione ((R)-1) (79% ee)
(420 mg, 2.8 mmol) was dissolved in hexanes-ethyl acetate (2:
1, v/v) (4 mL). To this solution was added a seed of (()-5-
methylbicyclo[3.3.0]oct-1-ene-3,6-dione ((()-1) (0.5 mg), at 0 °C,
and then the mixture was kept at -30 °C for 40 h. (()-1 was
obtained as a crystalline solid. The supernatant solution was
separated by decantation and then concentrated to give (R)-5-
methylbicyclo[3.3.0]oct-1-ene-3,6-dione ((R)-1) (357 mg, 85%) as
a colorless oil in 91% ee.
Ca t a lyt ic Kin et ic R esolu t ion R ea ct ion of (()-5-Met h -
ylbicyclo[3.3.0]oct-1-en e-3,6-d ion e (1). A solution of (R)-ALB
(0.96 mmol) in THF (9.6 mL)14 was concentrated under reduced
pressure for 30 min at room temperature. To the residual (R)-
ALB was added a solution of 4-methoxyphenol (143 mg, 1.2
mmol) in toluene (13 mL) at 0 °C, and the mixture was stirred
for 30 min at 0 °C. To this mixture (0 °C) was successively added
a solution of (()-5-methylbicyclo[3.3.0]oct-1-ene-3,6-dione (1)
(1.80 g, 12 mmol) in toluene (12 mL) and then 4-tert-butyl-
(thiophenol) (1.00 mL, 6.0 mmol). After being stirred for 6 h at
room temperature, the reaction mixture was quenched with 1
N HCl (20 mL), and the organic layer was separated. The
aqueous layer was extracted with ethyl acetate (3 × 50 mL).
The combined organic layers were washed with brine, dried
(Na2SO4), and concentrated. The residue was purified by flash
column chromatography (SiO2, ethyl acetate-hexane 1:5 then
1:1) to give the Michael adduct 2′ (1.81 g, 48%) as a colorless oil
Ack n ow led gm en t. This study was financially sup-
ported by CREST, The J apan Science and Technology
Corporation (J ST).
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra of the Michael adduct 2′. This material is
available free of charge via the Internet at http://pubs.acs.org.
(14) Shimizu, S.; Ohori, K.; Arai, T.; Sasai, H.; Shibasaki, M. J . Org.
Chem. 1998, 63, 7547-7551.
J O9904922