Bifunctional thiourea-catalyzed enantioselective double Michael reaction of γ,δ-unsaturated β-ketoester to nitroalkene: Asymmetric synthesis of (-)-epibatidine

Article abstract of DOI:10.1016/j.tetlet.2004.10.082

The asymmetric synthesis of 4-nitrocyclohexanone derivatives has been accomplished by enantioselective double Michael additions of γ,δ-unsaturated β-ketoesters to nitroalkenes using a catalytic amount of bifunctional thiourea and TMG. The three contiguous

Full text of DOI:10.1016/j.tetlet.2004.10.082

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9185–9188
Bifunctional thiourea-catalyzed enantioselective double
Michael reaction of c,d-unsaturated b-ketoester to
nitroalkene: asymmetric synthesis of (ꢀ)-epibatidine
Yasutaka Hoashi, Takaya Yabuta and Yoshiji Takemoto*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Received 17 September 2004; revised 15 October 2004; accepted 18 October 2004
Abstract—The asymmetric synthesis of 4-nitrocyclohexanone derivatives has been accomplished by enantioselective double Michael
additions of c,d-unsaturated b-ketoesters to nitroalkenes using a catalytic amount of bifunctional thiourea and TMG. The three
contiguous stereogenic centers of the obtained products were constructed with good to high diastereoselectivity and up to 92%
ee. The biologically active natural product, (ꢀ)-epibatidine, has been synthesized from the intermediate 11a in seven steps in
30% overall yield.
Ó 2004 Elsevier Ltd. All rights reserved.
The catalytic asymmetric formation of a carbon–carbon
bond represents one of the most challenging fields in or-
ganic chemistry. In particular, the enantioselective con-
struction of multiple stereogenic centers in a single
reaction has been the subject of intensive research over
the past several years.1 Among the various reactions,
the direct Michael addition of 1,3-dicarbonyl com-
pounds to electron-deficient alkenes may be an ideal
reaction in terms of operational simplicity, atom econ-
omy, and versatile utility of the products.2 Thus far, var-
ious types of enantioselective reactions have been
reported by employing chiral catalysts such as a Lewis
acid, a Lewis base, or a bimetallic complex.3,4 Although
substantial progress has been realized in the develop-
ment of asymmetric Michael addition reactions, few of
these reactions succeeded in the enantioselective con-
struction of contiguous stereogenic centers.4a,5 On the
other hand, due to their versatility as synthetic interme-
diates for natural products,6–9 various methods such as
Diels–Alder reaction,6,7 intramolecular and intermo-
lecular Michael reactions,8,9 have been developed to syn-
thesize chiral nitrocyclohexanes. However, there are few
successful reports using catalytic asymmetric reaction.9
Recently, we reported that the bifunctional thiourea 1-
catalyzed Michael reaction of malonates to nitroalkenes
proceeded with high enantioselectivity up to 93% ee.10
We then planed to apply this method to a domino reac-
tion,1 that is, double Michael reactions to synthesize
optically active 4-nitrocyclohexanones C (Scheme 1).
Herein we present a thiourea/TMG-catalyzed double
Michael reactions of c,d-unsaturated-b-ketoesters A to
nitroalkenes B and also an asymmetric synthesis of
(ꢀ)-epibatidine from the resultant intermediate bearing
three stereogenic centers.
We first investigated the double Michael reactions
of c,d-unsaturated-b-ketoesters3a–d to nitrostyrene 2a
(Table 1).
O
O
OR3
O
double Michael addition
OR3
*
*
R2
R1
R1
R2
O
B
*
O2N
NO2
C
A
NMe2
H
H
F3C
N
N
S
Keywords: Thiourea; Organocatalyst; Michael reaction; Asymmetric
synthesis; c,d-Unsaturated b-ketoester; (ꢀ)-Epibatidine.
1
CF3
Scheme 1. Double Michael reaction of A and B with thiourea 1.
*
Corresponding author. Tel.: +81 75 753 4528; fax: +81 75 753
4569; e-mail: takemoto@pharm.kyoto-u.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.082

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Y. Hoashi et al. / Tetrahedron Letters 45 (2004) 9185–9188
Table 1. Thiourea 1 and TMG-catalyzed enantio- and diastereoselec-
tive double Michael reaction of 2a and 3a–d
minor products in the cases of 3c and 3d bearing phenyl
and methoxy groups at the d-position. The stereoselec-
tive formation of 5a–d would be rationally explained
by considering the plausible reaction mechanism shown
in Figure 2. Namely, the transition state D, giving the
major isomer 5, would be energetically more stable than
the transition state E, due to the steric hindrance be-
tween the phenyl ring and the nitronate anion in E. This
is the first report that succeeds in asymmetric synthesis
of three contiguous stereogenic centers by the double
Michael reactions with nitroalkenes.
O
O
O
O
2a
R
OEt
R
OEt
1 (0.1 eq)
3a: R = Me
3b: R = i-Pr
3c: R = Ph
Ph
toluene, rt
NO2
4a-d
MeCN, 0 o
3d: R = OMe
TMGa
C
OH
O
OH
O
OEt
OEt
+
3
5
Having established the asymmetric synthesis of 4-nitro-
cyclohexanones, we next applied this method to the total
synthesis of (ꢀ)-epibatidine 6, an alkaloid isolated from
the skin of the Ecuadorian frog Epibatidores tricolor11
Although many syntheses of 6 have been reported,12
only a few full syntheses are enantioselective.13 In partic-
ular, the only catalytic version by Trost and Cook is
known.13f Our synthetic approach to 6 relies on the dou-
ble Michael reactions of c,d-unsaturated-b-ketoester 7
to nitroalkene 8. By taking advantage of the axial meth-
oxy group, the corresponding cyclic adduct 9 would be
stereoselectively converted into trans-nitroalcohol 10a,
which is a key intermediate for the synthesis of (ꢀ)-epi-
batidine (Scheme 2).
R
Ph
R
Ph
4
NO2
NO2
5a-d
Entry 3 (R)
6a-d
Temp (°C) Yield (%)b de (%)c ee (%)d
1e
2
3a (Me)
rt
65
87
71
79
63
>99
>99
>99
90
86
92
88
89
85
3a (Me)
3b (i-Pr)
3c (Ph)
ꢀ20
rt
3
4
ꢀ40
5
3d (OMe) rt
64
a 1,1,3,3,-Tetramethylguanidine.
b Isolated yield.
c The ratio of 5/6 was determined by 1H NMR.
d Determined by HPLC analysis.
e The reaction was carried out without TMG.
The synthesis of 9 began with a condensation of trans-4-
methoxy-3-buten-2-one and allyl cyanoformate using
LHMDS as a base, giving the desired product 7 in
73% yield (Scheme 3). Successive treatment of 7 and a
known compound 814 with thiourea 1 and TMG at
0°C provide the cyclic product 11a in 67% yield along
with diastereomer 11b (20% yield). The diastereomer
11b seemed to be generated by a base-catalyzed epimeri-
zation of the major product 11a. Fortunately, replace-
ment of TMG with KOH in EtOH suppressed the
When 2a and 3a were combined in toluene in the pres-
ence of 10mol% of bifunctional thiourea 1, the domino
reaction proceeded at room temperature, giving the cyc-
lic adduct 5a in 65% yield as the single isomer (entry 1).
The enantioselectivity of 5a was revealed to be 86% ee
by chiral HPLC analysis. In contrast to 3a, no domino
reaction of 3b–d with 2a occurred, providing acyclic ad-
ducts 4b–d in good yields (entries 3–5). Although we
could not succeed in the domino reaction with 1, subse-
quent treatment of the obtained products 4b–d with
0.1equiv of 1,1,3,3-tetramethylguanidine (TMG) at
0°C furnished the desired cyclic adducts 5b–d with good
enantioselectivity (85–89% ee). Similarly, the reaction of
3a under the same two-step conditions provided 5a in
better yield with 92% ee (entry 2). The relative configu-
O−
−O
H
O
O
N+
H
H
H
1
R
CO2Et
N+
R
Ph
rations of 5a–d were determined by H NMR analysis
CO2Et
Ph
H
−O
O−
H
(Fig. 1). All the major products 5a–d possess the same
configuration (3,4-trans-4,5-cis), whereas the 3,4-cis-
4,5-trans-diastereoisomers 6c and 6d were produced as
H
D
E
Figure 2. Diastereoselective formation of 5a-d.
NO2
OH
O2N
Cl
N
Cl
H2
H1
Ph
H
H4
Ph
N
H3
OH
H5
N
H1
H2
Ar
NO2
OH
CO2Et
H
10a
(−)-epibatidine 6
H3
5c
10a
NO2
coupling constant (Hz) NOE (%)
H
H1: 18.3, 11.7
H3 - H4: 7.8
H4 - H5: 7.8
H3 - H5: 0.0
Cl
coupling constant (Hz)
H1: br s (W1/2 = 9.9)
H2: 13.1, 4.0
N
8
NO2
H2: 18.3, 6.5
+
H3: 11.7, 6.5, 3.5
H4: br s (W1/2 = 6.6)
H5: br s (W1/2 = 5.2)
O
MeO
H
O
O
N
Cl
H3: br s (W1/2 = 9.8)
MeO
O
9
7
Figure 1. Relative configurations of 5c and 10a.
Scheme 2. Retrosynthetic analysis of (ꢀ)-epibatidine 6.

Y. Hoashi et al. / Tetrahedron Letters 45 (2004) 9185–9188
9187
H
resulting in recovery of the starting material (entry 1).
Although the hindered reagent did not give the prod-
ucts, relatively smaller reducing agents such as NaBH4
and NaBH3CN16b did afford the axial nitroalkane 10a
as a major product (entries 2–4).9c,d,17 The best result
(87% yield, 10a/10b = 9:1) was obtained by reduction
with NaBH3CN in AcOH and MeOH at ꢀ20°C. The
structural assignment of 10a was confirmed by 1H
NMR analysis (Fig. 1).
O allyl
O
NO2
N
i
ii, iii
O
7
MeO
HO
MeO
73%
85%
(75% ee)
H
Cl
11a: α-NO2, 11b: β-NO2
H
NO2
iv
v
H
HO
9
11a
99%
71%
MeO
H
N
Cl
12
To complete the total synthesis of 6, alcohols 10a/10b
were converted into the corresponding mesylates (MsCl,
Et3N, DMAP), from which 14 was isolated in 91% yield.
Successive treatment of 14 with zinc/AcOH in THF and
O2N
Cl
NO2
N
vi
71%
vii
H
N
87%
OH
H
Cl
(9/1)
OH
13
10a: β-NO2
10b: α-NO2
refluxing in CHCl3 gave enantiomerically pure (ꢀ)-epi-
25
D
O2N
Cl
batidine [6, ½aꢁ ꢀ6.0 (c 0.58, CHCl3)] in 85% yield.
viii
91%
ix, x
The structure of synthetic 6 was confirmed by compari-
son to reported literature data (1H, 13C NMR, IR,
Mass).11
(−)-epibatidine 6
N
85%
OMs
14
Scheme 3. Enantioselective total syntheis of (ꢀ)-epibatidine 6.
Reagents and conditions: (i) LHMDS, THF; allyl cyanoformate,
ꢀ78°C; (ii) 8, 1 (10mol%), toluene, 0°C; (iii) KOH, EtOH, 0°C; (iv)
Pd(OAC)2, PPh3, HCO2H, Et3N, THF, rt; (v) L-Selectride, THF,
ꢀ78°C; (vi) NaOMe, t-BuOH, rt; (vii) NaBH3CN, AcOH, MeOH,
ꢀ20°C; (viii) MsCl, Et3N, DMAP, CH2Cl2, 0°C; (ix) Zn, AcOH,
THF, rt; (x) CHCl3, 60°C.
In summary, we have developed a catalytic enantioselec-
tive synthesis of 4-nitrocyclohexanone derivatives bear-
ing three contiguous stereogenic centers by using
thiourea/TMG-catalyzed double Michael reactions of
c,d-unsaturated-b-ketoesters to nitroalkenes, and the
synthetic utility of these products has been demon-
strated by the asymmetric synthesis of (ꢀ)-epibatidine.
epimerization of 11a into 11b, affording 11a in 85% yield
as a single isomer. Subsequent decarboxylation of 11a
using Tsuji conditions [Pd(OAc)2, PPh3, HCO2H,
Et3N, THF, rt]15 gave rise to the desired adduct 9 in
good yield, but the ee of 9 was revealed to be only
75% ee. In spite of various screenings of the reaction
conditions for the thiourea-catalyzed Michael reaction
of 7 and 8, we could not improve the ee of 9. The
remaining key task for the total synthesis of 6 is conver-
sion of 3,4-trans-adduct 9 to 3,4-cis adduct 10a. For this
purpose, we planed to employ the axial methoxy group
of 9 for the stereoselective reduction of the ketone of 9
and formation of the requisite nitroalkene 13. Initial
treatment of 9 with L-Selectride gave the aimed axial
alcohol 12 as a single isomer.8d The subsequent elimina-
tion of methanol from 12 with NaOMe (1.5equiv) in
tert-BuOH afforded nitrocycloalkene 13 in 71% yield
(80% yield based on the consumed starting material)
as colorless crystals. At this stage, the ee of 13 could
be improved to 99% ee by recrystallization from CHCl3.
We finally investigated the 1,4-hydride reduction of
nitrocycloalkene 13 to obtain 1,4-cis-nitroalcohol 10a
(Table 2). Initial attempt to reduce 13 utilized sterically
demanding hydride reagent 3,5-bis(ethoxycarbonyl)-2,6-
dimethyl-1,4-dihydropyridine (Hantzsch ester, HEH),16a
Acknowledgements
This work was supported by grants from 21st Century
COE Program ÔKnowledge Information Infrastructure
for Genome ScienceÕ and Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture,
Sports, Science, and Technology.
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Temp
(°C)
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(h)
Yield
(%)a
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