A modified thermodynamically controlled deracemization of 2-allylcyclohexanone and its application to asymmetric synthesis of (R)-(-)-epilachnene

Article abstract of DOI:10.1246/cl.2004.516

The efficiency of thermodynamically controlled deracemization was influenced considerably by the solvent used. Based on this finding, an improved method was developed, by which 2-allylcyclohexanone was converted to the R-isomer of 93% ee in 72% yield. As an application of the method, (R)-(-)-epilachnene, an antipode of the defensive droplets from the Mexican bean beetle, Epilachna varivestis, was synthesized in short steps.

Full text of DOI:10.1246/cl.2004.516

516
Chemistry Letters Vol.33, No.5 (2004)
A Modified Thermodynamically Controlled Deracemization of 2-Allylcyclohexanone
and Its Application to Asymmetric Synthesis of (R)-(À)-Epilachnene
Hiroto Kaku, Natsuko Okamoto, Aya Nakamaru, and Tetsuto Tsunodaꢀ
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima 770-8514
(Received January 20, 2004; CL-040073)
The efficiency of thermodynamically controlled deracemi-
new findings, a new procedure of the deracemization of 2b, and its
application to an asymmetric synthesis of (R)-(ꢁ)-epilachnene
(3), which is the antipode of the natural epilachnene isolated as
a component of the defensive droplets from glandular hairs of
the pupa of the Mexican bean beetle, Epilachna varivestis.6
In the previous method (Scheme 1), the reaction mixture was
treated with a saturated NH4Cl aq and extracted with ether to re-
cover satisfactorily all of the guest molecules (ketone). As a re-
sult, the recovered guest molecules were contaminated with the
free guest molecules, which were not included by the host mole-
cules and were a 1:1 mixture of racemic isomers (See Figure 1).
When the amount of guest molecules remaining in the liquid
phase increases, the optical purity of the recovered ketone lowers
to some extent. That is, the enantiomeric excess of the ketone is
presumed to lower considerably when the solubility of the ketone
into the solvent (into the liquid phase) increases according as the
decrease of the proportion of water in aqueous MeOH used as a
solvent.
zation was influenced considerably by the solvent used. Based
on this finding, an improved method was developed, by which
2-allylcyclohexanone was converted to the R-isomer of 93%
ee in 72% yield. As an application of the method, (R)-(ꢁ)-epi-
lachnene, an antipode of the defensive droplets from the Mexi-
can bean beetle, Epilachna varivestis, was synthesized in short
steps.
Thermodynamically controlled deracemization which is con-
ceptually summarized in Figure 11 was developed as a new meth-
od to prepare optically active ꢀ-monosubstituted cyclohexanones.
The method was substantiated in basic suspension media based on
inclusion complexation.2,3
< liquid phase >
in MeOH-H2O
O
O
–OH
R
R
In the present study, therefore, the solid phase was separated
from the liquid phase by filtration after the deracemization in or-
der to evaluate exactly the efficiency of the molecular recognition
process (Scheme 2). Optical and chemical yields of the guest com-
pound recovered from the solid phase were examined and were
plotted against the proportion (in %) of water in aqueous MeOH.
First, the results of the combination of 2b and 1a are shown in
Figure 2a.
stage C
< solid phase >
O
O
R
R
(R)
+
+
host
host
host
(S)
stage B
stage A
less stable inclusion complex
more stable inclusion complex
Figure 1. Concept of thermodynamically controlled deracemization.
host (1 equiv.)
NaOH (4 equiv.)
For example, use of (R,R)-(ꢁ)-trans-2,3-bis(hydroxydiphen-
ylmethyl)-1,4-dioxaspiro[5.4]decane (1a)4 (1.0 equiv.) with alka-
line in aqueous MeOH converted racemic 2-benzylcyclohexanone
(2a) to the R-isomer of 74% ee in quantitative yield. Further, (R)-
2-allylcyclohexanone (2b) of 62% ee was obtained in 96% yield,
when 1b was used in place of 1a (Scheme 1). Resolution efficien-
cy (E)5 of the deracemization for 2a and 2b reached 148 and
119%, respectively. Thus, the deracemization provided a conven-
ient and excellent method for the preparation of optically active
ꢀ-substituted cyclohexanones.
O
O
solid
filt.
H2O / MeOH
rt, 2 days
< GLC analysis >
( )-2b
filtrate
Scheme 2.
When the proportion of water was 40%, none of 2b was ob-
tained from the solid phase because of the high solubility of 2b
into the solvent. In 60% water, 55% ee of 2b was recovered in
about 60–80% yield. Thus, as the proportion of water became
higher, 2b was recovered more effectively. However, optical pu-
rity of 2b decreased gradually down to 40% ee. A more or less
similar phenomenon was observed in the combination of 2bꢂ1b.
The results are shown in Figure 2.
By comparison between Figures 2a and 2b, it was clear that
1b was superior to 1a to recognize 2b. This fact corresponded
to the finding reported in the previous paper,2 in which 2b was
converted more effectively to the R-isomer (62% ee) in the pres-
ence of 1b than 1a (34% ee) in H2O–MeOH (50:50). However, as
mentioned above, the optical purity was unsatisfactory owing to
the procedure by which all of the guest molecules 2b were recov-
ered.
OH OH
Ph
Ph
Ph
Ph
1 (1 equiv.)
NaOH (4 equiv.)
O
O
R
R
( )-
O
O
H2O / MeOH (1 / 1)
rt, 2 days
R
R1
1a: R1, R2= -(CH2)5-
b: R1= Ph, R2= H
2a 100%, 74% ee
2b 96%, 62% ee
2a : R = -Bn
2b : R = -Allyl
Scheme 1.
However, the ketone recovered was not optically pure enough
for use as a starting material for asymmetric syntheses. In prelimi-
nary studies, we recognized the importance of the solubility of
guest molecules into aqueous MeOH used as the solvent. Actual-
ly, the proportion of water in aqueous MeOH influenced the opti-
cal purity of the ketones. In this paper, we would like to describe
Based on the fact shown in Figure 2b, an improved procedure
for deracemization was developed according to the following con-
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.5 (2004)
517
60% yield along with 6% of a dimer and 30% of recovered se-
co-acid 8. Although deprotection of the tosyl group of 10 with so-
dium naphtalenide at ꢁ40 ꢃC in DME took place smoothly, the
product of the reaction was unfortunately, undesired lactam 11
generated by intramolecular acyl migration. So, trans-lactoniza-
tion10 of 11 was carried out by treatment with p-toluenesulfonic
(b)
(a)
(%, %ee)
100
(%, %ee)
100
OH OH
OH OH
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
80
60
40
20
0
80
60
40
20
O
O
O
O
1a
1b
20
: recovery of guest (%)
: optical yield (%ee)
: recovery of guest (%)
: optical yield (%ee)
acid to yield 3 as a pale yellow oil, ½ꢀꢄ D ꢁ44:0 (c 0.47, MeOH),
whose physical properties compared well with those in the litera-
25
ture ½ꢀꢄ
þ50:8 (c 1.36, MeOH)].11c
D
0
0
0
20
40
60
80
100
20
40
60
80
100
H2O (%)
H2O (%)
O
O
CN
a, b
c, d
OH
Figure 2. Solvent dependence of chemical and optical yields of 2b recov-
ered from the solid phase. (a): 2bꢂ1a (b): 2bꢂ1b.
O
Z
5
4
91% ee, by GLC
93% ee
e
Z / E = 94 / 6
siderations: 1) In order to ensure high optical purity, the recovery
of guest molecules is sacrificed to some extent by filtration. 2) In
order to increase the optical purity further, the solid phase ob-
tained by the filtration, a mixture of the host and the optically en-
riched guest molecules, is suspended again into fresh solvent
without a base. That is, the mixture is subjected to optical resolu-
tion by inclusion recomplexation. 3) It is important that the choice
of the H2O–MeOH ratio influences considerably the efficiency of
the new procedure.
TBDMSO
CN
HO
g
f
CO2H
N
N
Ts
Ts
7
8
O
O
OH
h
O
O
O
N
N
N
Ts
H
11
10
(R)-epilachnene (3)
Actually, a 7:3 mixture of H2O–MeOH (shown as a vertical
line in Figure 2b) was chosen as a solvent for improved deracem-
ization of 2b with 1b. The suspension of 2b (50 mg, 0.36 mmol),
host compound 1b (186 mg, 0.36 mmol), and sodium hydroxide
(1.4 mmol) in H2O–MeOH (5 mL) was stirred at room tempera-
ture for 2 days. The mixture was filtered and the residue was
washed with H2O–MeOH (7:3, 1 mL 3 times). The resulting res-
idue, the solid phase, was suspended again into a fresh mixture of
H2O–MeOH (7:3, 5 mL) at ambient temperature for 1 day. After
filtration followed by washing with H2O–MeOH (7:3, 1 mL 3
times), the residue was dissolved in ether and subjected to gas
chromatography (GC) to afford 93% ee of (R)-2b in 70% yield
(Scheme 3).7 Thus, the value of E increased to 130%.
total 15% yield (10 steps)
Scheme 4.a
a
Reagent and Conditions: (a) H2, Pd/C, NaHCO3, ether; (b) m-CPBA,
NaH2PO4, CH2Cl2, rt, quant. (2 steps); (c) DIBAL, CH2Cl2; (d)
Ph3Pþ(CH2)4CN Brꢁ, sodium dimsylate, DMSO, rt, 30 min, 70% (2 steps);
(e) 6 (1.5 equiv.), CMMP (1.5 equiv.), tol., rt, 24 h, 91%; (f) KOH, EtOH,
95 ꢃC, 18 h, quant.; (g) 9, NEt3, MeCN, reflux, 30 min, 60%; (h) i) Na,
C10H8, DME, ꢁ40 ꢃC, 0.5 h, ii) p-TsOH, tol., 80 ꢃC, 4 h, 56%.
Thus, since the solubility of the guest molecule into a media
has a significant impact upon the efficiency of the deracemization,
we are continuing further investigation to obtain highly optically
active ꢀ-substituted cycloalkanones and to reveal the detailed na-
ture of the molecular recognition process affected by the media.
host (1 equiv.)
filt. solid
filt. solid
filtrate
NaOH (4 equiv.)
References and Notes
( ) - 2b
(R) - 2b
H2O / MeOH
rt, 2 days
H2O / MeOH
rt, 1 day
1
2
H. Kaku, S. Takaoka, and T. Tsunoda, Tetrahedron, 58, 3401 (2002).
T. Tsunoda, H. Kaku, M. Nagaku, and E. Okuyama, Tetrahedron Lett., 38,
7759 (1997), and references cited therein.
filtrate
3
4
5
H. Kaku, S. Ozako, S. Kawamura, S. Takatsu, M. Ishii, and T. Tsunoda,
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D. Seebach, A. K. Beck, R. Imwikelried, S. Roggo, and A. Wonnacott,
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2/100. In the case of optical resolution, the value of E never exceed the
100%. See, K. Sakai, R. Sakurai, A. Yuzawa, and N. Hirayama, Tetrahe-
dron: Asymmetry, 14, 3713 (2003).
Scheme 3.
A 2-g-scale reaction of racemic 2b was successfully achieved
in a 67:33 mixture of H2O–MeOH (200 mL) to give 93% ee of
(R)-2b in 72% yield. When a 70:30 mixture was used, the optical
yield of (R)-2b decreased down to 80% ee. This finding proved
that solvent composition has a significant impact upon the effi-
ciency of the deracemization.
In order to demonstrate the usefulness of the improved dera-
cemization, 3 was synthesized using (R)-2b (93% ee) as the start-
ing material (Scheme 4). First, (R)-2b was converted to lactone 4
by hydrogenation — Baeyer–Villiger oxidation sequence. DIBAL
reduction of 4 followed by Wittig reaction gave hydroxy nitrile 5,
which was subjected to Mitsunobu-type reaction with N-[2-(t-bu-
tyldimethylsilyloxy)ethyl]tosylamide (6) in the presence of cya-
nomethylenetrimethylphosphorane (CMMP)8 to yield sulfona-
mide 7 with Walden inversion at the carbinol stereocenter of 5.
Hydrolysis of the nitrile 7 provided seco-acid 8, which was suc-
cessfully cyclized by the reaction of 2-chloro-1-methylpyridinium
iodide (9)9 under high dilution conditions to afford lactone 10 in
6
7
A. B. Attygalle, K. D. McCormick, C. L. Blankespoor, T. Eisner, and
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GC on a Shimadzu GC-15A instrument using a J&W Scientific DB-1 capil-
lary column. Dodecane was employed as an internal standard. The enantio-
meric excess of the ketone was determined by GC using a chiral column
(SUPELCO, ꢀ-DEX120).
ˆ
T. Tsunoda, C. Nagino, M. Oguri, and S. Ito, Tetrahedron Lett., 37, 2459
8
9
ˆ
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ˆ
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Published on the web (Advance View) March 30, 2004; DOI 10.1246/cl.2004.516