Enantioselective tandem Michael reaction to nitroalkene catalyzed by bifunctional thiourea: Total synthesis of (-)-epibatidine

Article abstract of DOI:10.1016/j.tet.2005.08.109

Successive treatment of γ,δ-unsaturated β-ketoesters and nitroalkenes with a bifunctional thiourea and TMG promoted the tandem Michael addition, giving rise to highly functionalized cyclohexanones in good yields. The three contiguous stereogenic centers o

Full text of DOI:10.1016/j.tet.2005.08.109

Tetrahedron 62 (2006) 365–374
Enantioselective tandem Michael reaction to nitroalkene
catalyzed by bifunctional thiourea:
total synthesis of (K)-epibatidine
*
Yasutaka Hoashi, Takaya Yabuta, Pei Yuan, Hideto Miyabe and Yoshiji Takemoto
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Received 1 March 2005; revised 18 July 2005; accepted 31 August 2005
Available online 21 September 2005
Abstract—Successive treatment of g,d-unsaturated b-ketoesters and nitroalkenes with a bifunctional thiourea and TMG promoted the
tandem Michael addition, giving rise to highly functionalized cyclohexanones in good yields. The three contiguous stereogenic centers of the
obtained products were constructed with high diastereo- and enantioselectivity (up to O99% de and 92% ee). The reaction was successfully
applied to the asymmetric synthesis of (K)-epibatidine, which was synthesized from the cyclohexanone derivative in seven steps in 30%
overall yield.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
providing the chiral 4-nitrocyclohexanone derivatives
bearing three contiguous stereogenic centers with high
diastereo- and enantioselectivity10 (Scheme 1). In this
article, we describe the details of the thiourea-catalyzed
tandem Michael reaction and the asymmetric synthesis of
(K)-epibatidine.
In the past decade, urea and thiourea derivatives1 have been
intensively investigated as organocatalysts in asymmetric
reactions because of their strong hydrogen bonding
activity.2 These catalysts can be used as an acidic promoter
in a variety of reactions such as Diels–Alder cycloaddition,
Strecker reaction, Mannich reaction, Michael addition, and
so on.1a–f We reported that novel bifunctional thioureas,
which had both a thiourea moiety and an amino group on a
chiral scaffold, significantly promoted the Michael reaction
of 1,3-dicarbonyl compounds to nitroalkenes to give the
Michael adducts with high enantioselectivity.1c On the other
hand, the enantioselective construction of multiple stereo-
genic centers in a single operation has been the subject of
recent research.3 In particular, such methods have been
developed to synthesize highly functionalized chiral
cyclohexanes4–7 due to their versatility as synthetic
intermediates for natural products such as epibatidine and
pancratistatin. Although substantial progress has been
achieved in the development of asymmetric Michael
additions,8 few of these reactions succeeded in the
enantioselective construction of contiguous stereogenic
centers.9 Recently, we have already reported the
bifunctional thiourea 1 could be applied to tandem Michael
addition of g,d-unsaturated b-ketoesters 2 to nitroalkens 3,
Scheme 1. Tandem Michael reaction of 2 and 3 with thiourea 1.
2. Results and discussion
2.1. Thiourea-catalyzed tandem Michael reaction
We first investigated the tandem Michael addition of g,d-
unsaturated-b-ketoesters 2a–c11 to nitrostyrene 3a in the
presence of bifunctional thiourea 1 (Scheme 2). According
to the previous report,1c 2a and 3a were combined in toluene
Keywords: Thiourea; Organocatalyst; Michael addition; Asymmetric
synthesis; Tandem reaction; Nitroalkenes; (K)-Epibatidine.
*
Corresponding author. Tel.: C81 75 753 4528; fax: C81 75 753 4569;
e-mail: takemoto@pharm.kyoto-u.ac.jp
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.08.109

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Y. Hoashi et al. / Tetrahedron 62 (2006) 365–374
bulky iso-propyl group as that of 2b provided only Michael
adduct 6c but not 4c. After several experiments, we found
that the subsequent treatment (method A) of the obtained
adduct 6c with 0.1 equiv of 1,1,3,3-tetramethylguanidine
(TMG) did give rise to the desired product 4c stereo-
selectively (71% yield, O99% de, 88% ee). Based on these
results, it was revealed that the high diastereoselectivity of
the intramolecular Michael addition would be attributed to
the reaction substrates, but not to the catalysts employed.
Therefore, we next investigated the two-step cyclization of
2b–e11 using catalytic amounts of thiourea 1 and TMG
(Table 1, method A). Reexamination of the reaction of 2b
and 3a using method A revealed that 4b could be prepared
as a single product with higher enantioselectivity than that
obtained by the one-pot method (entry 1). We next
employed (Z)-2c as a Michael acceptor with the aim of
synthesizing another diastereomer as a major product.
Although the first thiourea-catalyzed conjugate addition of
(Z)-2c with 3a proceeded smoothly, an unexpected product
6c was produced along with the desired product (Z)-6c due
to the isomerization of (Z)-6c into 6c (Scheme 2).
Furthermore, subsequent treatment of diastereomerically
pure (Z)-6c by method A led to the exclusive formation of
4c, which was derived from (E)-6c, with no desired 4,5-anti-
5,6-anti adduct (entries 2 and 3). These results suggest that
the intramolecular cyclization of (Z)-6c into an all-anti
adduct would be an energetically unfavorable process. In
contrast to 2b and 2c, the tandem Michael reaction of phenyl
substituted derivative 2d gave a mixture of diastereoisomers
4d and 5d in a ratio of 95/5. Similarly, the methoxy
substituted derivative 2e afforded an 82/18 mixture of 4e
and 5e. In both cases, the same 3,4-anti-4,5-syn adducts 4d
and 4e were obtained as major products with high
enantioselectivity (entries 4 and 5). Since the diastereomers
5d and 5e seemed to be generated by a base-catalyzed
epimerization of the major products 4d and 4e, we screened
a variety of bases other than TMG for the intramolecular
Michael reaction. Consequently, replacement of TMG with
KOH in ethanol was revealed to suppress the epimerization
of 4 into 5, affording 4d and 4e in good yield as a single
isomer, respectively, (entries 6 and 7). It is worthy to note
that this is the first report of successful asymmetric synthesis
Scheme 2. Tandem Michael addition of ketoesters 2a–c and nitroalkene 3a
in the presence of 1.
together with 10 mol% of the catalyst 1 at room
temperature. However, the reaction gave a complex mixture
due to instability of 2a and we could obtain neither Michael
adducts nor the desired cyclized product 4a. In contrast to
2a, the same reaction with 2b bearing a methyl group at the
d-position proceeded cleanly to provide the tandem Michael
adduct 4b as a single product in 65% yield with 86% ee. The
result demonstrates that, according to expectation, the
bifunctional thiourea 1 catalyzed both the inter- and
intramolecular Michael additions of
Unfortunately, the same treatment of 2c bearing a more
2
and 3a.
Table 1. Tandem Michael reaction of 2b–e and 3a catalyzed by thiourea 1 and TMG/KOH
Entry
2 (R)
Temperature (8C)
Methoda
Yield (%)b
de (%)c
ee (%)d
1
2
3
4
5
6
7
2b (Me)
2c (i-Pr)
(Z)-2c (i-Pr)
2d (Ph)
2e (OMe)
2d (Ph)
2e (OMe)
K20
A
A
Ae
A
A
B
87
71
66
79
63
62
79
O99
O99
O99
90
64
O99
O99
92
88
86
89
85
92
84
Room temperature
Room temperature
K40
Room temperature
K40
Room temperature
B
a Method A: TMG (0.1 equiv), CH3CN, 0 8C, method B: KOH (0.1 equiv), EtOH, 0 8C.
b Isolated yield.
c The ratio of 4/5 was determined by isolated yields.
d Determined by HPLC analysis.
e The reaction was conducted at room temperature.

Y. Hoashi et al. / Tetrahedron 62 (2006) 365–374
367
of three contiguous stereogenic centers by the tandem
Michael reaction with nitroalkenes.
group, the corresponding cyclic adduct 9 would be
stereoselectively transformed into trans-nitroalcohol 10a,
which is a key intermediate for the synthesis of (K)-
epibatidine (Scheme 3).
1
The relative configuration of 4b–e was determined by H
NMR analysis. For an example, coupling constants (H1–H5)
and NOE experiment of 4d unambiguously demonstrated
that 4d possessed the conformation as shown in Figure 1.
Furthermore, the absolute configuration of C-6 of 4b–e was
assumed to be S from the previous results.1c Based on these
results, we determined the absolute configuration of 4d to be
(4R,5S,6S). Therefore, the stereoselective formation of 4b–e
would be rationally explained by considering the transition
state A shown in Figure 2. The transition state A, giving the
major adducts 4, would be energetically more stable than
the other transition state B, giving the minor adducts 5, due
to the steric hindrance between the phenyl ring and the
nitronate anion.
Scheme 3. Retrosynthetic analysis of (K)-epibatidine.
The asymmetric synthesis of (K)-epibatidine commenced
from the base-catalyzed condensation of trans-4-methoxy-
3-buten-2-one with allyl cyanoformate to obtain 711
(Scheme 4). Treatment of 7 and a known compound 816
under the standard conditions (10 mol% of 1, toluene, 0 8C)
afforded the Michael adduct 11 in 90% yield, but the ee of
11 was revealed to be only 75% ee. (Table 2, entry 1). To
improve the ee of 11, the Michael reaction was examined
under several reaction conditions, but all attempts proved
fruitless (entries 2–4). It is not clear why the conjugate
reaction of 7 with 8 proceeded with lower enantioselectivity
compared to the previous results of 4b–e. We therefore
decided to improve the enantiomeric excess by recrystal-
lization of 14 at a late stage of the synthetic route
(Scheme 5). The second cyclization of 11 (75% ee)
successfully occurred by the reaction with KOH in ethanol
at 0 8C to provide cyclic ketoester 12 in 85% yield as a
single isomer. Subsequent decarboxylation of 12 using the
Tsuji conditions [Pd(OAc)2, PPh3, HCO2H, Et3N, THF,
room temperature]17 gave rise to the desired ketone 9 in
quantitative yield.
Figure 1. Determination of relative configuraion of 4d.
Figure 2. Diastereoselective formation of 4b–e.
2.2. Asymmetric synthesis of (K)-epibatidine
Having established the two-step procedure to synthesize
chiral 4-nitrocyclohexanones, we next applied this manipu-
lation to the total synthesis of (K)-epibatidine, an alkaloid
isolated from the skin of the Ecuadorian frog Epibatidores
tricolor in 1992 by Daly et al.12 From biological
investigations, it has been found that epibatidine possesses
extremely interesting pharmacological properties such as a
nonopiate analgesic approximately 200 times more potent
than morphine.13 Epibatidine is a potent nicotinic acetyl-
choline receptor agonist, and these receptors are involved in
the mediation of several human disorders such as
Alzheimer’s and Parkinson’s diseases. In addition, a unique
feature of this alkaloid is the presence of a strained
nitrogen-bridged six-membered carbon ring system with
an exo-oriented aryl group. Because of the unprecedented
biological activity and the unique structural feature,
widespread efforts have culminated in numerous total and
formal syntheses. Although a variety of synthetic studies on
the natural product have been reported,14 enantioselective
total syntheses are few.15 In particular, the catalytic version
was only achieved by Trost et al.15f Our synthetic approach
to (K)-epibatidine relies on the thiourea-catalyzed tandem
Michael addition of g,d-unsaturated-b-ketoester 7 to
nitroalkene 8. By taking advantage of the axial methoxy
Scheme 4. Enantioselective Michael addition of 7 and 8 with 1.
The remaining key task for the total synthesis of (K)-
epibatidine was the conversion of 3,4-trans-adduct 9 to 3,4-
cis adduct 10a. For this purpose, we planned to employ the
axial methoxy group of 9 for the stereoselective reduction of
the ketone 9 and formation of the requisite nitroalkene 14.
We initially investigated the former reaction (Table 3).
Treatment of 9 with smaller hydride reagents such as
NaBH4 and DIBAL-H gave a mixture of diastereoisomers
13a and 13b in good yield (entries 1 and 2). The axial

368
Y. Hoashi et al. / Tetrahedron 62 (2006) 365–374
Table 2. Thiourea-catalyzed Michael reaction of 7 and 8a
Entry
Solvent
Temperature (8C)
Time (h)
Yield (%)b
ee (%)c
1
2
3
4
Toluene
Toluene
CH2Cl2
THF
0
5
90
82
90
88
75
75
71
57
K40 to K20
K20
K20
56
16
78
a The reaction was carried out with 10 mol% of 1.
b Isolated yield.
c Determined by HPLC analysis, after 11 was converted into 9.
alcohol 13a was predominantly produced in both cases.
However, the reduction of 9 with L-Selectride afforded the
desired alcohol 13a in 71% yield as a single isomer (entry
3).6d Subsequently, the elimination of methanol from 13a
was examined under several conditions as shown in Table 4.
The initial attempt for the reaction of 13a with methane-
sulfonic acid resulted in recovery of the starting material
(entry 1). Similarly, no desired product was obtained by the
reaction of 13a with a catalytic amount of TMG in
acetonitrile (entry 2). On the other hand, switching the
base from TMG to KOH promoted the elimination of
methanol to yield the aimed compound 14 in moderate
yield, regardless of the solvent employed (entries 3 and 4).
We finally found that the reaction of 13a with 1.5 equiv of
NaOMe in tert-BuOH gave the best result to yield 14 in 71%
yield (81% yield based on the recovered starting material) as
colorless crystals (entries 5 and 6). At this stage, the ee of 14
could be improved to 99% ee by recrystallization from
CHCl3.
We finally undertook the 1,4-hydride reduction of nitro-
cycloalkene 14 to obtain 1,4-cis-nitroalcohol 10a (Table 5).
The initial attempt to reduce 14 utilizing a sterically
demanding hydride reagent, 3,5-bis(ethoxycarbonyl)-2,6-
dimethyl-1,4-dihydropyridine (Hantzsch ester, HEH),18a led
to recovery of the starting material (entry 1). However,
reduction of 14 with relatively smaller reducing agents such
as NaBH4 and NaBH3CN18b afforded the axial nitroalkane
10a as a major product (entries 2–4).7c–d,19 The best result
(87% yield, 10a/10bZ9:1) was obtained by reduction with
Scheme 5. Enantioselective total sysnthesis of (K)-epibatidine. (i) KOH,
EtOH, 0 8C; (ii) Pd(OAc)2, PPh3, HCO2H, Et3N, THF, rt; (iii) MsCl, Et3N,
DMAP, CH2Cl2, 0 8C; (iv) Zn, AcOH, THF, rt; (v) CHCl3, 60 8C.
Table 3. Hydride reduction of ketone 9
Entry
Reagent
Solvent
Temperature (8C)
Yield (%)a
13a
13b
1
2
3
NaBH4
i-Bu2AlH
L-selectrideb
MeOH
Toluene
THF
K78
K78
K78
65
63
71
25
18
0
a Isolated yield.
b Lithium tri-sec-butylborohydride.
NaBH3CN in AcOH and MeOH at K20 8C. The structural
assignment of 10a and 10b was confirmed from the coupling
constants of their 1H NMR spectra (Scheme 5). To complete
the total synthesis of (K)-epibatidine, alcohols 10a/10b
were converted into the corresponding mesylates (MsCl,
Et3N, DMAP), from which diastereomerically pure product
15 was isolated in 91% yield by column chromatography.
Successive treatment of 15 with zinc dust in a mixture of
AcOH and THF and refluxing in CHCl3 gave the final
compound (K)-epibatidine ([a]2D5 K6.0 (c 0.58, CHCl3)) in
85% yield. The structure of the synthetic sample was
Table 4. Transformation of 13a into nitroalkene 14 with several reagentsa
Entry
Reagent (equiv) Solvent
Yield (%)b
1
2
3
4
5
6
MeSO3H (1.0)
TMG (0.1)
KOH (0.1)
KOH (0.1)
NaOMe (1.5)
NaOMe (3.0)
CH2Cl2
MeCN
EtOH
t-BuOH
t-BuOH
t-BuOH
0
0
29c
22
71
41
a The reaction was carried out at room temperature.
b Isolated yield.
c Michael adduct of ethanol to 14 was produced.

Y. Hoashi et al. / Tetrahedron 62 (2006) 365–374
Table 5. Diastereoselective 1,4-reduction of nitroalkene 14
369
Entry
Reagent
Temperature (8C)
Time (h)
Yield (%)a
Ratio (10a/10b)b
1
2
3
4
HEH
NaBH4
NaBH3CN
NaBH3CN
80
12
0
K78
0
K20
0.25
1.0
6.5
45
78
87
2.5/1
9/1
9/1
a Isolated yield.
1
b Determined by H NMR analysis.
confirmed by comparison with reported literature data (1H,
13C NMR, IR, Mass).15c
residue was purified by preparative TLC (hexane/AcOEtZ
10:1 as eluent) to afford desired product 4b (19.8 mg, 65%
yield) as a single diastereomer.
3. Conclusion
4.2.2. Typical procedure for tandem Michael addition
catalyzed by thiourea 1 and TMG (Method A). To a
stirred solution of 2b (23.4 mg, 0.15 mmol) and thiourea 1
(4.1 mg, 0.010 mmol) in dry toluene (0.20 mL) was added
trans-b-nitrostyrene 3a (14.9 mg, 0.10 mmol) at K20 8C.
After being stirred for 17 h, thiourea 1 was removed by
silica gel column chromatography, and the obtained residue
was treated with 1,1,3,3-tetramethylguanidine (0.1 equiv,
1.2 mg) in acetonitrile (1 mL) at 0 8C for 0.5 h. The reaction
mixture was diluted with AcOEt and quenched with 1 N
HCl. The separated aqueous phase was extracted with
AcOEt twice, and then the combined organic fractions were
washed with brine, dried over MgSO4, filtered, and
concentrated in vacuo. The residue was purified by
preparative TLC (hexane/AcOEtZ10:1 as eluent) to afford
desired product 4b (26.5 mg, 87% yield) as a single
diastereomer.
We have developed thiourea/TMG-catalyzed tandem
Michael reaction of g,d-unsaturated-b-ketoesters and
nitroalkenes to synthesize chiral 4-nitrocyclohexanone
derivatives bearing three contiguous stereogenic centers.
In some cases, the diastereoselectivity of the tandem
Michael adducts could be improved by using a thiourea/
KOH combination (method B). Furthermore, we have
revealed that the tandem reaction of (Z)-g,d-unsaturated
b-ketoesters 2c with 3a provided the same product 4c
regardless of the (E)/(Z) stereochemistry of the starting
material 2c due to the isomerization of the intermediates 6.
The synthetic utility of these products has been demon-
strated by the asymmetric synthesis of (K)-epibatidine.
4. Experimental
4.1. General information
4.2.3. Typical procedure for tandem Michael addition
catalyzed by thiourea 1 and KOH (Method B). To a
stirred solution of 2d (48.0 mg, 0.22 mmol) and thiourea 1
(8.2 mg, 0.020 mmol) in dry toluene (0.40 mL) was added
trans-b-nitrostyrene 3a (29.8 mg, 0.20 mmol) at K40 8C.
After being stirred for 17 h, thiourea 1 was removed by
silica gel column chromatography, and the obtained residue
was treated with KOH (1.1 mg, 0.020 mmol) in EtOH
(2 mL) at 0 8C for 1.5 h. The reaction mixture was diluted
with AcOEt and quenched with a saturated NH4Cl solution.
The separated aqueous phase was extracted with AcOEt
twice, and then the combined organic fractions were washed
with brine, dried over MgSO4, filtered, and concentrated in
vacuo. The residue was purified by preparative TLC
(hexane/AcOEtZ10:1 as eluent) to afford desired product
4d (45.6 mg, 62% yield) as a single diastereomer.
Nominal (LR-MS) and exact mass (HR-MS) spectra were
recorded on a JEOL JMS-01SG-2 or JMS-HX/HX 110A
mass spectrometer. 1H and 13C NMR spectra were
registered on JEOL JNM-LA500 using TMS as an internal
standard. (sZsinglet, dZdoublet, ddZdouble doublet,
dddZdoublet of double doublets, tZtriplet, qZquartet,
mZmultiplet, brZbroad). Optical rotations were measured
in CHCl3 unless otherwise noted with a JASCO DIP-360
digital polarimeter. For column chromatography, Kanto
Silica gel 60 (spherical, 63–210 mm) was employed and
preparative thin-layer chromatography (PTLC) was carried
out using Silica gel 60 (Merck). Enantiomer ratios were
determined by chiral HPLC using a Shimadzu SPD-10A
with Daicel Chemical Industries, LTD. Chiralpak AD-H
(0.46 cm!25 cm) or Chiralpak OD-H (0.46 cm!25 cm) or
Chiralpak AS-H (0.46 cm!25 cm). Unless otherwise
noted, materials were purchased from Tokyo Kasei Co.,
Aldrich Inc., and other commercial suppliers and were used
without purification. The ketoesters 2a–e and nitroolefin 8
were synthesized according to the literature procedures.20
4.2.4. (4S,5S,6S)-2-Hydroxy-4-methyl-5-nitro-6-phenyl-
cyclohex-1-enecarboxylic acid ethyl ester 4b. Yellow
oil; [a]2D7 C83.6 (c 0.57, CHCl3, 87% ee); 1H NMR
(500 MHz, CDCl3) d 12.6 (s, 1H), 7.38–7.17 (m, 5H), 4.65
(s, 1H), 4.46 (s, 1H), 4.07–3.93 (m, 2H), 2.56 (dd, JZ18.6,
6.7 Hz, 1H), 2.48 (dd, JZ18.6, 10.3 Hz, 1H), 2.39–2.24 (m,
1H), 1.06 (d, JZ6.7 Hz, 3H), 0.9 (t, JZ7.0 Hz, 3H) ppm;
13C NMR (126 MHz, CDCl3) d 171.8, 171.5, 141.6, 128.8,
127.8, 127.4, 96.1, 91.2, 60.5, 43.6, 32.6, 26.2, 16.9,
13.6 ppm; IR (CHCl3) n 3029, 1656, 1622, 1549 cmK1; MS
(FABC) 306 (MHC, 88), 213 (100); HRMS (FABC) Calcd
for [C16H20NO5]C: 306.1341. Found: 306.1339; HPLC
[Chiralcel AS-H, hexane/2-propanolZ95:5, 0.5 mL/min,
4.2. Tandem Michael reaction
4.2.1. Tandem Michael addition catalyzed by thiourea 1.
To a stirred solution of 2b (23.4 mg, 0.150 mmol) and
thiourea-catalyst 1 (0.010 mmol, 4.1 mg) in dry toluene
(0.20 mL) was added trans-b-nitrostyrene 3a (14.9 mg,
0.10 mmol) at room temperature. After being stirred for
44 h, the reaction mixture was concentrated in vacuo. The

370
Y. Hoashi et al. / Tetrahedron 62 (2006) 365–374
lZ210 nm, retention times: (major) 12.5 min, (minor)
14.9 min].
(MHC, 91), 275 (100); HRMS (FABC) Calcd for
[C21H22NO5]C: 368.1498. Found: 368.1507.
4.2.8. (4S,5R,6S)-2-Hydroxy-4-methoxy-5-nitro-6-
phenylcyclohex-1-enecarboxylic acid ethyl ester 4e
4.2.5. (4R,5S,6S)-2-Hydroxy-4-iso-propyl-5-nitro-6-
diphenylcyclohex-1-enecarboxylic acid ethyl ester 4c.
Colorless solid; mp 195–196 8C (Hexane/AcOEt); [a]D24
C63.6 (c 1.00); 1H NMR (500 MHz, CDCl3) d 12.6 (s, 1H),
7.21–7.36 (m, 5H), 4.91 (s, 1H), 4.49 (s, 1H), 4.00–4.04 (m,
2H), 2.64 (dd, JZ18.9, 6.4 Hz, 1H), 2.52 (dd, JZ18.9,
10.4 Hz, 1H), 1.58–1.63 (m, 2H), 0.96 (t, JZ6.2 Hz, 3H),
0.93 (d, JZ6.1 Hz, 3H), 0.82 (d, JZ6.1 Hz, 3H) ppm; 13C
NMR (126 MHz, CDCl3) d 172.6, 171.5, 141.3, 128.8,
127.7, 127.4, 95.6, 87.6, 60.5, 44.4, 37.6, 29.9, 29.5, 20.5,
(mixture of keto and enol form). Yellow oil; [a]D24
C52.4 (c 1.12); H NMR (500 MHz, CDCl3) d 12.5 (s,
1
0.68H), 7.20–7.30 (m, 5H), 5.20 (dd, JZ11.9, 2.8 Hz,
0.32H), 4.91 (t, JZ4.0 Hz, 0.68H), 4.50–4.56 (m, 1.32H),
3.91–4.09 (m, 2.68H), 3.62 (d, JZ12.5 Hz, 0.32H), 3.39 (s,
0.96H), 3.33 (s, 2.04H), 3.07 (dd, JZ15.0, 3.7 Hz, 1H),
2.76–2.89 (m, 1.68H), 1.08 (t, JZ7.0 Hz, 0.96H), 0.90 (t,
JZ7.3 Hz, 2.04H) ppm; 13C NMR (126 MHz, CDCl3) d
199.4, 171.2, 169.1, 166.6, 141.5, 137.0, 128.9, 128.8,
128.2, 128.1, 127.7, 127.4, 97.2, 88.6, 88.4, 78.7, 72.2, 61.5,
61.4, 60.6, 57.6, 57.0, 42.8, 42.7, 42.0, 31.6, 13.8, 13.5 ppm;
IR (CHCl3) n 1747, 1626, 1658, 1625, 1556 cmK1; MS
(FABC) 322 (MHC, 85), 197 (100); HRMS (FABC) Calcd
for [C16H20NO6]C: 322.1291. Found: 322.1299; HPLC
[Chiralcel OJ-H, hexane/2-propanolZ90:10, 0.5 mL/min,
lZ210 nm, retention times: (major) 20.3 min, (minor)
25.1 min].
20.2, 13.7 ppm; IR (CHCl3) n 2971, 1658, 1626, 1548 cmK1
;
MS (FABC) 334 (MHC, 100). Anal. Calcd for C18H23NO5:
C, 64.85; H, 6.95; N, 4.20. Found: C, 64.56; H, 6.87; N,
3.90. Determination of ee was accomplished by reduction
with zinc followed by di-benzoylation. Benzoic acid
(3S,4S,5R)-4-benzoylamino-2-ethoxycarbonyl-5-iso-pro-
pyl-3-phenylcyclohex-1-enyl ester. Colorless amorphous;
[a]2D5 C83.6 (c 0.82); H NMR (500 MHz, CDCl3) d 8.21
1
(d, JZ7.9 Hz, 2H), 7.98 (d, JZ7.6 Hz, 2H), 7.64–7.67 (m,
1H), 7.50–7.55 (m, 5H), 7.36–7.43 (m, 4H), 7.25–7.28 (m,
1H), 6.81 (d, JZ9.5 Hz, 1H), 4.89 (d, JZ9.5 Hz, 1H), 4.37
(s, 1H), 3.88–3.97 (m, 2H), 2.72 (dd, JZ6.7, 6.7 Hz, 1H),
2.27 (dd, JZ11.0, 11.3 Hz, 1H), 1.57–1.63 (m, 1H), 1.45–
1.52 (m, 1H), 0.82–0.85 (m, 9H) ppm; 13C NMR (126 MHz,
CDCl3) d 167.1, 165.3, 164.6, 157.2, 140.6, 134.3, 133.9,
131.6, 130.3, 129.1, 128.6, 127.3, 126.9, 118.4, 60.7, 50.7,
48.6, 38.1, 31.1, 29.6, 20.6, 20.2, 13.6 ppm; IR (CHCl3) n
1724, 1661, 1602, 1517 cmK1; MS (FABC) 512 (MHC,
18), 105 (100); HRMS (FABC) Calcd for [C32H34NO5]C:
512.2437. Found: 512.2435; HPLC [Chiralcel OD-H,
hexane/2-propanolZ90:10, 0.5 mL/min, lZ254 nm,
retention times: (major) 12.5 min, (minor) 10.8 min].
4.2.9. (4S,5S,6S)-2-Hydroxy-4-methoxy-5-nitro-6-
phenylcyclohex-1-enecarboxylic acid ethyl ester 5e.
[a]2D4 C217 (c 1.06); H NMR (500 MHz, CDCl3) d 12.4
1
(s, 1H), 7.26–7.29 (m, 3H), 6.99–7.01 (m, 2H), 4.81 (dd, JZ
11.0, 6.4 Hz, 1H), 4.51 (d, JZ6.4 Hz, 1H), 3.99–4.10 (m,
3H), 3.35 (s, 3H), 3.23 (dd, JZ18.6, 7.3 Hz, 1H), 2.51 (dd,
JZ18.6, 8.6 Hz, 1H), 1.00 (t, JZ7.2 Hz, 3H) ppm; 13C
NMR (126 MHz, CDCl3) d 170.7, 168.6, 137.5, 128.5,
128.1, 128.0, 98.3, 88.8, 70.6, 60.9, 57.8, 42.7, 34.2,
13.6 ppm; IR (CHCl3) n 1658, 1624, 1558 cmK1; MS
(FABC) 322 (MHC, 100). Anal. Calcd for C16H19NO6: C,
59.81; H, 5.96; N, 4.36. Found: C, 60.04; H, 5.94; N 4.28.
4.2.6. (4R,5S,6S)-2-Hydroxy-5-nitro-4,6-diphenyl-cyclo-
hex-1-enecarboxylic acid ethyl ester 4d. Colorless solid;
mp 106–108 8C (hexane); [a]2D6 C32.8 (c 1.00, CHCl3, 89%
ee); 1H NMR (500 MHz, CDCl3) d 12.7 (s, 1H), 7.39 (t, JZ
7.5 Hz, 2H), 7.35–7.19 (m, 6H), 7.05 (d, JZ7.0 Hz, 2H),
4.91–4.96 (m, 1H), 4.55 (s, 1H), 4.11–3.97 (m, 2H), 3.43
(ddd, JZ11.7, 6.5, 3.5 Hz, 1H), 3.32 (dd, JZ18.3, 11.7 Hz,
1H), 2.78 (dd, JZ18.3, 6.4 Hz, 1H), 0.97 (t, JZ7.2 Hz,
3H) ppm; 13C NMR (126 MHz, CDCl3) d 172.2, 171.6,
141.4, 137.7, 129.1, 129.0, 128.0, 127.8, 127.7, 127.3, 96.0,
91.5, 60.8, 44.4, 36.3, 29.8, 13.8 ppm; IR (CHCl3) n 3029,
1675, 1624, 1550 cmK1; MS (FABC) 368 (MHC, 78), 154
(100). Anal. Calcd for C21H21NO5: C, 68.65; H, 5.76; N,
3.81. Found: C, 68.50; H, 3.79; N, 5.08; HPLC [Chiralcel OD-
H, hexane/2-propanolZ70:30, 0.5 mL/min, lZ210 nm,
retention times: (major) 14.0 min, (minor) 10.4 min].
4.3. Total synthesis of (K)-epibatidine
4.3.1. 5-Methoxy-3-oxo-4-pentenoic acid allyl ester 7. To
a stirred solution of 1,1,1,3,3,3-hexamethyldisilazane
(4.84 g, 30.0 mmol) in THF (75 mL) at K78 8C was
added n-BuLi (19.0 mL of a 1.58 M solution, 30.0 mmol).
The reaction mixture was stirred for 15 min and then a
solution of trans-3-methoxy-2-butenone (90% purity,
1.67 g, 15.0 mmol) in THF (75 mL) was added dropwise
over 20 min via canula. After 30 min, a solution of
hexamethylphosphoramide (4.52 g, 25.2 mmol) and allyl
cyanoformate20 in THF (15 mL) were added. Quenching
with a saturated NH4Cl solution, extraction with AcOEt,
washing with brine, drying over MgSO4, evaporation of the
solvent and flash chromatography (hexane/AcOEtZ2:1)
1
afforded 7 (2.02 g, 73%). Yellow oil; H NMR (500 MHz,
CDCl3) d 7.66 (d, JZ12.8 Hz, 1H), 6.00–5.83 (m, 1H), 5.68
(d, JZ12.5 Hz, 1H), 5.35 (dd, JZ17.1, 1.5 Hz, 1H), 5.25
(dd, JZ10.7, 1.2 Hz, 1H), 4.64 (d, JZ5.8 Hz, 2H), 3.75 (s,
3H), 3.51 (s, 2H); 13C NMR (126 MHz, CDCl3) d 190.7,
167.3, 164.3, 131.7, 118.7, 104.8, 65.9, 57.8, 48.0 ppm; IR
(CHCl3) n 3027, 1739, 1685, 1656, 1621, 1594 cmK1; MS
(EIC) 184 (MC), 85 (100). Anal. Calcd for C9H12O4: C,
58.69; H, 6.57. Found: C, 58.69; H, 6.48.
4.2.7. (4R,5R,6S)-2-Hydroxy-5-nitro-4,6-diphenyl-cyclo-
hex-1-enecarboxylic acid ethyl ester 5d. Colorless oil; 1H
NMR (500 MHz, CDCl3) d 12.5 (s, 1H), 7.36–7.07 (m,
10H), 5.30 (dd, JZ12.5, 5.8 Hz, 1H), 4.64 (d, JZ5.8 Hz,
1H), 4.12–3.99 (m, 2H), 3.68–3.58 (m, 1H), 2.98 (dd, JZ
19.4, 6.9 Hz, 1H), 2.64 (dd, JZ19.2, 11.3 Hz, 1H), 1.01 (t,
JZ7.2 Hz, 3H) ppm; 13C NMR (126 MHz, CDCl3) d 170.9,
170.1, 139.6, 137.6, 129.0, 128.5, 128.4, 128.1, 127.7,
127.2, 98.3, 89.1, 60.9, 43.4, 37.0, 36.9, 13.7 ppm; IR
(CHCl3) n 3031, 1658, 1623, 1554 cmK1; MS (FABC) 368
4.3.2. Allyl (4E)-2-[(1R)-1-(6-chloropyridin-3-yl)-2-
nitroethyl]-5-methoxy-3-oxo-4-pentenoate 11 (Table 2,

Y. Hoashi et al. / Tetrahedron 62 (2006) 365–374
371
entry 1). To a solution of 7 (235 mg, 1.28 mmol) and
thiourea (35.1 mg, 0.0850 mmol) in toluene (1.7 mL) was
added 8 (157 mg, 0.850 mmol) at 0 8C. After 5 h, flash
chromatography (hexane/AcOEtZ3:2) of the obtained
residue afforded 11 (282 mg, 90%). (Table 2, entry 2). To
a solution of 7 (55.2 mg, 0.300 mmol) and thiourea (8.2 mg,
0.020 mmol) in toluene (0.4 mL) was added 8 (36.9 mg,
0.200 mmol) at K40 8C, and the mixture was stirred for
46 h. The reaction mixture was warmed up to K20 8C and
stirred for additional 10 h. Flash chromatography of the
crude residue (hexane/AcOEtZ3:2) afforded 11 (60.4 mg,
82%). (Table 2, entry 3). To a solution of 7 (55.2 mg,
0.300 mmol) and thiourea (8.2 mg, 0.020 mmol) in toluene
(0.4 mL) was added 8 (36.9 mg, 0.200 mmol) at K20 8C.
After being stirred for 16 h, flash chromatography of the
obtained residue (hexane/AcOEtZ3:2) afforded 11
(66.4 mg, 90%). (Table 2, entry 4). To a solution of 7
(27.6 mg, 0.150 mmol) and thiourea (4.1 mg, 0.010 mmol)
in toluene (0.2 mL) was added 8 (18.5 mg, 0.100 mmol) at
K20 8C. After 78 h, flash chromatography of the obtained
residue (hexane/AcOEtZ3:2) afforded 11 (32.5 mg, 88%).
The diastereomers could not be separated. Colorless oil; 1H
NMR (500 MHz, CDCl3) d 8.32 (d, JZ2.4 Hz, 0.59H), 8.30
(d, JZ2.8 Hz, 0.41H), 7.79 (d, JZ12.5 Hz, 0.59H), 7.62–
7.55 (m, 1.41H), 7.32–7.26 (m, 1H), 5.93–5.84 (m, 0.41H),
5.77 (d, JZ12.2 Hz, 0.59H), 5.70–5.61 (m, 0.59H), 5.60 (d,
JZ12.2 Hz, 0.41H), 5.38–5.27 (m, 0.82H), 5.23–5.14 (m,
1.18H), 4.91–4.62 (m, 2.82H), 4.43 (d, JZ6.1 Hz, 1.18H),
4.37–4.28 (m, 1H), 4.10 (d, JZ10.4 Hz, 0.59H), 4.05 (d,
JZ9.5 Hz, 0.41H), 3.78 (s, 1.77H), 3.72 (s, 1.23H); 13C
NMR (126 MHz, CDCl3) d 189.9, 189.4, 167.3, 166.6,
166.0, 165.8, 151.4, 151.3, 149.7, 149.4, 138.6, 138.5,
131.8, 131.6, 130.8, 130.6, 124.5, 124.4, 119.8, 103.6,
103.5, 77.1, 66.7, 66.6, 59.8, 59.7, 58.4, 39.6, 39.4 ppm; IR
(CHCl3) n 3030, 3003, 1738, 1684, 1590, 1559 cmK1; MS
(EIC) 368 (MHC), 85 (100). Anal. Calcd for
C16H17ClN2O6: C, 52.11; H, 4.65; N, 7.60. Found: C,
52.29; H, 4.62; N, 7.34.
138.3, 136.5, 130.8, 124.2, 119.2, 96.7, 88.6, 73.3, 65.6,
57.4, 38.1, 32.0 ppm; IR (CHCl3) n 3029, 3000, 2935, 1731,
1662, 1621, 1559, 1460 cmK1; MS (FABC) 369 (MHC,
100). Anal. Calcd for C16H17ClN2O6: C, 52.11; H, 4.65; N,
7.60. Found: C, 51.98; H, 4.67; N, 7.50.
4.3.4. (3R,4R,5S)-3-(6-Chloropyridin-3-yl)-5-methoxy-4-
nitrocyclohexanone 9. To a stirred solution of palladium
acetate (0.0461 mmol, 10.3 mg) and PPh3 (0.0922 mmol,
24.2 mg) in THF (3 mL) was added in one portion a mixture
of formic acid (0.922 mmol, 42.4 mg) and Et3N (1.15 mmol,
160 mL) in THF (2 mL) at room temperature under an argon
atmosphere. The mixture was vigorously stirred and a
solution of 12 (0.461 mmol, 170 mg) in THF (1 mL) was
added, and then the resulting mixture was stirred for
additional 1 h. The reaction mixture was passed through a
short SiO2 column, followed by AcOEt washing. Evapor-
ation of the organic solvent afforded 9 (130 mg, 99%).
Yellow amorphous; [a]D29 C43.1 (c 1.00, CHCl3, 75% ee);
1H NMR (500 MHz, CDCl3) d 8.39 (d, JZ2.4 Hz, 1H), 7.59
(dd, JZ8.1, 2.6 Hz, 1H), 7.33 (d, JZ8.2 Hz, 1H), 5.10 (dd,
JZ11.8, 2.6 Hz, 1H), 4.52 (ddd, JZ2.6, 2.5, 2.5 Hz, 1H),
4.19 (ddd, JZ12.5, 11.8, 5.2 Hz, 1H), 3.38 (s, 3H), 3.00 (dt,
JZ15.4, 2.7 Hz, 1H), 2.75–2.66 (m, 1H), 2.55–2.47 (m,
1H) ppm; 13C NMR (126 MHz, CDCl3) d 202.7, 151.1,
148.8, 137.6, 134.1, 124.7, 88.2, 78.8, 57.7, 45.8, 42.7,
37.4 ppm; IR (CHCl3) n 3030, 3002, 1730, 1561 cmK1; MS
(FABC) 285 (MHC, 100); HRMS (FABC) Calcd for
[C12H14ClN2O4]C: 285.0642. Found: 285.0639; HPLC
[Chiralcel AD-H, hexane/2-propanolZ70:30, 0.5 mL/min,
lZ210 nm, retention times: (major) 23.8 min, (minor)
20.2].
4.3.5. (1S,3R,4R,5S)-3-(6-Chloropyridin-3-yl)-5-meth-
oxy-4-nitrocyclohexanol 13a and (1R,3R,4R,5S)-3-(6-
chloropyridin-3-yl)-5-methoxy-4-nitrocyclohexanol 13b
(Table 3, entry 1). To a stirred solution of 9 (14.5 mg,
0.0508 mmol) in MeOH (0.5 mL) was added NaBH4
(2.3 mg, 0.0609 mmol) at K78 8C. After 20 min, the
reaction mixture was diluted with AcOEt, quenched with
a saturated NH4Cl solution, and separated. The aqueous
phase was extracted with AcOEt twice, and the combined
organic phases were washed with brine, dried over MgSO4.
Evaporation of the solvent and preparative TLC (CHCl3/
MeOHZ20:1) afforded 13a (9.4 mg, 65%) and 13b
(3.6 mg, 25%). (Table 3, entry 2) To a stirred solution of
9 (18.4 mg, 0.0647 mmol) in toluene (0.7 mL) was added a
solution of i-Bu2AlH in toluene (1 M, 97.1 mL,
0.0971 mmol) dropwise at K78 8C. After 40 min, the
reaction mixture was quenched with 1 N HCl, and extracted
with AcOEt twice. The combined organic phases were
washed with brine, dried over MgSO4. Evaporation of the
solvent and preparative TLC (CHCl3/MeOHZ20:1)
afforded 13a (11.6 mg, 63%) and 13b (3.3 mg, 18%).
(Table 3, entry 3) To a stirred solution of 9 (0.223 mmol,
63.5 mg) in dry THF (2.5 mL) was added a solution of
L-Selectride in THF (1 M, 223 mL, 0.223 mmol) dropwise at
K78 8C. The reaction mixture was allowed to warm up to
0 8C after addition of 0.2 mL of 30% hydrogen peroxide,
and 5% HCl was added until the solution was slightly acidic.
Extraction with AcOEt three times, washing with brine,
drying over Na2SO4, evaporation of the solvent and flash
chromatography (Et2O/MeOHZ20:1) afforded 13a
4.3.3. (4S,5R,6S)-6-(6-Chloropyridin-3-yl)-2-hydroxy-4-
methoxy-5-nitrocyclohex-1-enecarboxylic acid allyl
ester 12. To a solution of 7 (235 mg, 1.28 mmol) and
thiourea (35.1 mg, 0.085 mmol) in toluene (1.7 mL) was
added 8 (157 mg, 0.85 mmol) at 0 8C. After 5 h, purification
of the obtained crude product by flash chromatography
(hexane/AcOEtZ3:2) afforded 11 (282 mg, 90%). A
solution of KOH (0.422 mmol, 23.6 mg) in 42 mL EtOH
was poured onto 11 (1.56 g, 4.22 mmol) at 0 8C. After 10 h,
the reaction mixture was diluted with AcOEt, quenched
with a saturated NH4Cl solution, and separated. The
aqueous phase was extracted with AcOEt twice, and the
combined organic phases were washed with brine, dried
over MgSO4. Evaporation of the solvent and flash
chromatography (hexane/AcOEtZ3:2) afforded 12
(1.33 g, 85%). Colorless solid; mp 114–116 8C (Et2O);
[a]2D8 C61.8 (c 1.00, CHCl3, 75% ee); 1H NMR (500 MHz,
CDCl3) d 12.5 (s, 1H), 8.31 (d, JZ2.8 Hz, 1H), 7.52 (dd,
JZ8.4, 2.6 Hz, 1H), 7.28 (d, JZ8.2 Hz, 1H), 5.61–5.49 (m,
1H), 5.12 (d, JZ10.4 Hz, 1H), 5.01 (d, JZ17.1 Hz, 1H),
4.70 (dd, JZ6.7, 3.1 Hz, 1H), 4.66 (d, JZ6.7 Hz, 1H), 4.46
(d, JZ13.1, 5.8 Hz, 1H), 4.41 (dd, JZ13.0, 6.0 Hz, 1H),
4.11–4.07 (m, 1H), 3.37 (s, 3H), 2.85 (d, JZ5.2 Hz, 2H);
13C NMR (126 MHz, CDCl3) d 170.3, 169.6, 150.5, 149.7,

372
Y. Hoashi et al. / Tetrahedron 62 (2006) 365–374
(45.7 mg, 71%). Compound 13a. Colorless solid; mp 123–
126 8C (Hexane/AcOEt); [a]2D7 K13.7 (c 0.97, CHCl3, 75%
ee); 1H NMR (500 MHz, CDCl3) d 8.35 (d, JZ2.4 Hz, 1H),
7.56 (dd, JZ8.2, 2.8 Hz, 1H), 7.31 (d, JZ8.2 Hz, 1H), 4.72
(dd, JZ12.1, 3.2 Hz, 1H), 4.39 (q, JZ2.4 Hz, 1H), 4.12 (dt,
JZ9.8, 2.7 Hz, 1H), 4.01 (td, JZ12.7, 4.1 Hz, 1H), 3.72 (d,
JZ10.1 Hz, 1H), 3.45 (s, 3H), 2.58–2.50 (m, 1H), 2.27–2.20
(m, 1H), 1.76 (dt, JZ15.4, 2.8 Hz, 1H), 1.68 (td, JZ13.7,
2.8 Hz, 1H) ppm; 13C NMR (126 MHz, CDCl3) d 150.3,
148.9, 137.7, 135.6, 124.4, 89.0, 79.3, 65.4, 59.0, 40.1, 32.4,
32.3 ppm; IR (CHCl3) n 3519, 3006, 2942, 1556 cmK1; MS
(EIC) 286 (MC), 221 (100). Anal. Calcd for C12H15ClN2O4:
C, 50.27; H, 5.27; N, 9.77. Found: C, 50.13; H, 5.24; N,
9.67. Compound 13b. Yellow oil; 1H NMR (500 MHz,
CDCl3) d 8.34 (s, 1H), 7.55 (dd, JZ8.2, 2.1 Hz, 1H), 7.29
(d, JZ8.2 Hz, 1H), 4.67 (dd, JZ11.8, 2.9 Hz, 1H), 4.28 (s,
1H), 4.19–4.10 (m, 1H), 3.77 (td, JZ12.5, 3.7 Hz, 1H), 3.37
(s, 3H), 2.56 (d, JZ14.0 Hz, 1H), 2.20 (d, JZ11.3 Hz, 1H),
1.60–1.46 (m, 2H) ppm; 13C NMR (126 MHz, CDCl3) d
150.5, 149.1, 137.5, 135.4, 124.4, 89.4, 78.3, 64.3, 57.8,
solution of 14 (2.0 mg, 0.0079 mmol) in MeOH (0.1 mL)
was added NaBH4 (0.60 mg, 0.016 mmol) at K78 8C. After
20 min, the reaction mixture was diluted with AcOEt,
quenched with a saturated NH4Cl solution, and separated.
The aqueous phase was extracted with AcOEt twice, and the
combined organic phases were washed with brine, dried
over MgSO4. Evaporation of the solvent and short
chromatography (Et2O) afforded 10a and 10b (0.9 mg,
45%, drZ2.5/1). (Table 5, entry 3) To a solution of 14
(0.038 mmol, 9.6 mg) in MeOH (0.4 mL) were added acetic
acid (20 mL) and NaBH3CN (0.045 mmol, 2.8 mg) at 0 8C.
After 1 h, the reaction mixture was diluted with AcOEt,
washed with a saturated Na2CO3 solution, and separated.
The aqueous phase was extracted with AcOEt twice, and the
combined organic phases were washed with brine, dried
over Na2SO4. Evaporation of the solvent and short
chromatography (Et2O) afforded 10a and 10b (7.5 mg,
87%, drZ9/1). (Table 5, entry 4) To a solution of 14
(0.161 mmol, 41.1 mg) in MeOH (1.6 mL) were added
acetic acid (70 mL) and NaBH3CN (0.242 mmol, 15.2 mg)
at K20 8C. After 6.5 h, the reaction mixture was diluted
with AcOEt, washed with a saturated Na2CO3 solution, and
separated. The aqueous phase was extracted with AcOEt
twice, and the combined organic phases were washed with
brine, dried over Na2SO4. Evaporation of the solvent and
short chromatography (Et2O) afforded 10a and 10b
41.4, 36.5, 36.2 ppm; IR (CHCl3) n 3611, 2932, 1556 cmK1
;
MS (FABC) 287 (MHC, 100); HRMS (FABC) Calcd for
[C12H16ClN2O4]C: 287.0798. Found: 287.0804.
4.3.6. (1S,5R)-5-(6-Chloropyridin-3-yl)-4-nitrocyclohex-
3-enol 14 (Table 4, entry 3). To a stirred solution of 13a
(0.024 mmol, 7.0 mg) in EtOH (0.24 mL) was added KOH
(0.0024 mmol, 0.14 mg). After 1 h, the reaction mixture was
diluted with AcOEt, quenched with a saturated NH4Cl
solution, and separated. The aqueous phase was extracted
with AcOEt twice, and the combined organic phases were
washed with brine, dried over MgSO4. Evaporation of the
solvent and flash chromatography (CHCl3/MeOHZ20:1)
afforded 14 (1.8 mg, 29%). (Table 4, entry 4) To a stirred
solution of 13a (0.027 mmol, 7.7 mg) in t-BuOH (0.27 mL)
was added KOH (0.0027 mmol, 0.15 mg). The same
treatment of the mixture as described above afforded 14
(1.5 mg, 22%). (Table 4, entry 5). To a stirred solution of
13a (1.28 mmol, 366 mg) in t-BuOH (64 mL) was added
NaOMe (1.92 mmol, 104 mg). The same treatment of the
mixture as described above afforded 14 (231 mg, 71%).
(Table 4, entry 6). To a stirred solution of 13a (0.017 mmol,
5.0 mg) in t-BuOH (0.87 mL) was added NaOMe
(0.052 mmol, 2.8 mg). The same treatment of the mixture
as described above afforded 14 (1.8 mg, 41%). Colorless
solid; mp 165–158 8C (CHCl3); [a]2D8 K152.1 (c 0.48,
CHCl3, O99% ee); 1H NMR (500 MHz, CDCl3) d 8.24 (d,
JZ2.4 Hz, 1H), 7.49 (t, JZ4.1 Hz, 1H), 7.42 (dd, JZ8.2,
2.8 Hz, 1H), 7.29 (d, JZ7.9 Hz, 1H), 4.42 (t, JZ5.2 Hz,
1H), 4.12–4.04 (m, 1H), 2.85 (dt, JZ19.6, 4.7 Hz, 1H),
2.51–2.41 (m, 1H) 2.23 (ddd, JZ13.3, 9.3, 6.1 Hz, 1H),
2.00–1.92 (m, 1H) ppm; 13C NMR (126 MHz, CDCl3) d
150.3, 149.2, 148.5, 137.3, 136.2, 134.6, 124.4, 62.0, 39.4,
1
(36.0 mg, 87%, drZ9/1). Colorless amorphous; H NMR
(500 MHz, CDCl3) d 8.30 (d, JZ2.1 Hz, 1H), 7.51 (dd, JZ
8.2, 2.4 Hz, 1H), 7.29 (d, JZ8.2 Hz, 1H), 4.89 (m, 0.9H),
4.66 (dt, JZ11.7, 4.1 Hz, 0.1H), 4.44 (br s, 0.9H), 4.27 (s,
0.1H), 3.65 (td, JZ12.1, 3.7 Hz, 0.1H), 3.65 (td, JZ13.1,
4.0 Hz, 0.9H), 2.69 (t, JZ13.6 Hz, 1H), 2.53–2.43 (m, 1H),
2.27–2.18 (m, 1H), 2.15–2.04 (m, 1H), 1.92 (d, JZ14.0 Hz,
1H), 1.80 (d, JZ14.3 Hz, 1H) ppm; 13C NMR (126 MHz,
CDCl3) for major diastereomer d 150.5, 149.2, 137.9, 137.4,
124.3, 86.3, 64.6, 35.4, 31.3, 26.5, 24.1 ppm; IR (CHCl3) n
3614, 2932, 2863, 1549 cmK1; MS (EIC) 256 (MC), 192
(100); HRMS (EIC) Calcd for [C11H13Cl3N2O3]C:
256.0615. Found: 256.0615.
4.3.8. Methanesulfonic acid (1R,3R,4R)-3-(6-chloro-
pyridin-3-yl)-4-nitrocyclohexyl ester 15. To a stirred
solution of 10a. (0.172 mmol, 44.1 mg), 10b (0.019 mmol,
4.9 mg), and 4-(N,N-dimethylamino)pyridine (0.019 mmol,
2.3 mg) in CH2Cl2 (2 mL) were added MsCl (0.382 mmol,
29.6 mL) and Et3N (0.573 mmol, 79.7 mL) at 0 8C. After
10 min, quenching with a saturated NH4Cl solution,
extraction with AcOEt three times, washing with brine,
drying over Na2SO4, evaporation of the solvent and flash
chromatography (hexane/AcOEtZ1:2) afforded 15
(52.4 mg, 91%) in pure form. Colorless solid; mp 113–
116 8C (hexane/AcOEt); [a]3D0 K102.3 (c 0.89, CHCl3); 1H
NMR (500 MHz, CDCl3) d 8.30 (d, JZ1.5 Hz, 1H), 7.49
(dd, JZ8.7, 1.7 Hz, 1H), 7.31 (d, JZ8.2 Hz, 1H), 5.31 (s,
1H), 4.95 (s, 1H), 3.54 (dt, JZ14.0, 4.0 Hz, 1H), 3.08 (s,
3H), 2.84 (t, JZ13.1 Hz, 1H), 2.46–2.31 (m, 2H), 2.29–2.11
(m, 3H) ppm; 13C NMR (126 MHz, CDCl3) d 151.1, 149.1,
137.4, 133.2, 124.4, 85.3, 76.7, 38.5, 35.6, 29.5, 24.8,
24.1 ppm; IR (CHCl3) n 2940, 1550, 1462 cmK1; MS (EIC)
335 (MHC, 100). Anal. Calcd for C12H15ClN2O5S: C,
43.05; H, 4.52; N, 8.37. Found: C, 42.95; H, 4.51; N, 8.15.
36.6, 33.5 ppm; IR (CHCl3) n 3610, 2930, 1564, 1524 cmK1
;
MS (FABC) 255 (MHC, 90), 154 (100). Anal. Calcd for
C11H11ClN2O3: C, 51.88; H, 4.35; N, 11.00. Found: C,
51.61; H, 4.12; N, 11.00; HPLC [Chiralcel AD-H, hexane/
2-propanolZ70:30, 0.5 mL/min, lZ254 nm, retention
times: (major) 14.6 min, (minor) 12.8 min].
4.3.7. (1R,3R,4R)-3-(6-Chloropyridin-3-yl)-4-nitro-cyclo-
hexanol 10a and (1R,3R,4S)-3-(6-chloropyridin-3-yl)-4-
nitrocyclohexanol 10b (Table 5, entry 2). To a stirred
4.3.9. (K)-Epibatidine. To a stirred solution of 15

Y. Hoashi et al. / Tetrahedron 62 (2006) 365–374
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(0.0651 mmol, 21.8 mg) in THF (0.4 mL) were added
AcOH (0.4 mL) and Zn (2.41 mmol, 158 mg) at room
temperature. After 2 h, the mixture was filtrated through a
pad of Celite (AcOEt as eluent). Washing with a saturated
Na2CO3 solution and brine, drying over K2CO3, evaporation
of the solvent afforded amine product. A solution of the
amine product in CHCl3 (3 mL) was heated at 60 8C. After
3 days, the reaction mixture was diluted with additional
CHCl3, then 10% aqueous K2CO3 was added. The mixture
was extracted with CHCl3. The combined extracts were
dried over K2CO3, filtrated and evaporated. The residue was
purified by preparative TLC (CHCl3/MeOH/30% aqueous
NH3Z20:1:0.1 as eluent) to afford (K)-epibatidine
(11.5 mg, 85%). Colorless solid; mp 62–63 8C (hexane);
[a]2D9 K6.00 (c 0.58, CHCl3); 1H NMR (500 MHz, CDCl3) d
8.27 (d, JZ2.4 Hz, 1H), 7.72 (dd, JZ8.2, 2.4 Hz, 1H), 7.23
(d, JZ8.2 Hz, 1H), 3.80 (t, JZ4.0 Hz, 1H), 3.56 (d, JZ
2.4 Hz, 1H), 2.77 (dd, JZ9.0, 4.7 Hz, 1H), 1.91 (dd, JZ
12.2, 8.9 Hz, 1H), 1.67–1.46 (m, 2H) ppm; 13C NMR
(126 MHz, CDCl3) d 149.0, 148.8, 141.1, 137.7, 123.9,
62.7, 56.4, 44.5, 40.3, 31.3, 30.1 ppm; IR (CHCl3) n 2969,
2876, 1584, 1565, 1459 cmK1; MS (EIC) 208 (MC, 33), 69
(100); HRMS (EIC) Calcd for [C11H13ClN2]C: 208.0768.
Found: 208.0777.
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This work was supported by grants from 21st Century COE
Program ‘Knowledge Information Infrastructure for
Genome Science’ and Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science
and Technology (KAKENHI/16390006).
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