A new divergent synthesis of (+)- and (-)-ferruginine utilizing PLE-catalyzed asymmetric dealkoxycarbonylation

Article abstract of DOI:10.1016/S0957-4166(02)00657-2

A new divergent synthesis of (+)- and (-)-ferruginine 4, via the optically active 8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylates 6 is described. The β-keto ester intermediates 6 were prepared by a novel PLE-catalyzed asymmetric dealkoxycarbonylation of the symmetric tropinone-type diesters 5. The key problem in the synthesis is controlling the regioselectivity of the reaction at the 2- and 4-positions in the tropane framework of the β-keto ester 6 for introduction of the acetyl group.

Full text of DOI:10.1016/S0957-4166(02)00657-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 2351–2358
A new divergent synthesis of (+)- and (−)-ferruginine utilizing
PLE-catalyzed asymmetric dealkoxycarbonylation
Takahiro Katoh, Kiyoshi Kakiya, Takashi Nakai, Soichi Nakamura, Kiyoharu Nishide and
Manabu Node*
Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan
Received 4 September 2002; accepted 27 September 2002
Abstract—A new divergent synthesis of (+)- and (−)-ferruginine 4, via the optically active 8-benzyl-3-oxo-8-azabicy-
clo[3.2.1]octane-2-carboxylates 6 is described. The b-keto ester intermediates 6 were prepared by a novel PLE-catalyzed
asymmetric dealkoxycarbonylation of the symmetric tropinone-type diesters 5. The key problem in the synthesis is controlling the
regioselectivity of the reaction at the 2- and 4-positions in the tropane framework of the b-keto ester 6 for introduction of the
acetyl group. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
Several asymmetric syntheses of ferruginine 4 have been
reported as a result of its on its nicotinic agonist
activity: These include the tandem rhodium(II)-cata-
lyzed cyclopropanation/Cope rearrangement for the
asymmetric synthesis of (−)-4 by Davies et al.11 and the
8-Azabicyclo[3.2.1]octane (tropane) skeletons are found
in numerous naturally occurring alkaloids. Among the
tropane-type compounds, the optically active 2b-substi-
tuted-3b-aryltropanes 1, such as 2b-carbomethoxy-3b-
(4-iodophenyl)tropane (b-CIT)1 and 2b-carbomethoxy-
3b-(4-fluorophenyl)tropane (b-CFT),1 have attracted
considerable attention as radiopharmaceuticals in the
diagnosis of Parkinson’s disease.2 Traditionally these
compounds have been synthesized from the important
intermediate (−)-anhydroecgonine methyl ester 23
derived4 from (−)-cocaine, 3 (Fig. 1). However, since
(−)-cocaine is difficult to obtain commercially, many
groups have attempted to synthesize the intermediate
using other more readily available starting materials.
Recently, we published a new synthesis of (−)-2 using a
novel porcine liver esterase (PLE)-catalyzed asymmetric
dealkoxycarbonylation5,6 (asymmetric desymmetriza-
tion) which should be useful in the synthesis of opti-
cally active tropane alkaloids.
enantiospecific synthesis of (+)- and (−)-4 from L-glu-
tamic acid, presented by Rapoport et al.12 Aside from
these asymmetric syntheses, the practical synthesis of
(−)-4 and its analogues for evaluation as nAChR lig-
ands still depends on (−)-cocaine 3 as the optically
active starting material.10 For the asymmetric synthesis
of natural (+)-4, the CN(R,S) method and a metal-pro-
moted [6p+2p] cycloaddition were reported by Royer et
al.,13 and Rigby and Pigge,14 respectively. We report
herein a new divergent synthesis of (+)- and (−)-fer-
ruginine 4 utilizing a novel PLE-catalyzed asymmetric
dealkoxycarbonylation method.
2. Results and discussion
Our synthetic strategy towards (+)- and (−)-ferruginine
4 is outlined in Scheme 1. The tropinone-type diesters 5
prepared by Robinson’s tropinone synthesis15 from 1,3-
acetonedicarboxylates, succindialdehyde and a primary
amine in one step, could be converted to the
monoesters 6 having excellent enantiomeric excesses by
the use of our PLE-catalyzed asymmetric dealkoxycar-
bonylation. The optically active monoesters 6 are suit-
able divergent intermediates, which can lead to both
(+)- and (−)-ferruginine 4 by the introduction of a
The tropane-type alkaloid (+)-ferruginine (+)-4 was iso-
lated from the arboreal species Darlingia ferruginea7
and D. darlingiana.8 Its unnatural enantiomer (−)-4
prepared7 from (−)-cocaine 3 was found to be an ago-
nist for the nicotine acetylcholine receptor (nAchR).9,10
* Corresponding author. Tel.: +81-75-595-4639; fax: +81-75-595-4775;
e-mail: node@mb.kyoto-phu.ac.jp
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00657-2

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T. Katoh et al. / Tetrahedron: Asymmetry 13 (2002) 2351–2358
Figure 1.
Scheme 1. A new divergent synthetic strategy for (+)- and (−)-ferruginine 4.
C2-unit at the 4-position (reaction site B) or by conver-
sion of the ester moiety at the 2-position to an acetyl
group (reaction site A), respectively.
was obtained in 38% yield with high enantiomeric
excess (96% ee). The exact reaction conditions were as
follows: PLE (5000 units) in 1.0 M phosphate buffer
(pH 8.0)–DMSO (9:1) for 24 h at room temperature.
Addition of DMSO greatly improved the reaction.
Although the n-butyl diester 5a was the most effective
compound for this enzymatic reaction, the preparation
of 5a required ester interchange with commercially
available dimethyl or diethyl 1,3-acetonedicarboxylate
before Robinson’s tropinone synthesis. The ethyl
diester 5b is more stable to autohydrolysis with buffer
and subsequent decarboxylation during the enzymatic
reaction than the methyl diester 5c.5 Thus, we selected
the ethyl diester 5b as our starting material. We reopti-
mized the reaction conditions for the PLE-catalyzed
asymmetric dealkoxycarbonylation of the readily acces-
sible tropinone-type diethyl ester 5b. Since the yield of
the monoethyl ester product 6b16 was reduced on pro-
longed reaction time probably due to over dealkoxycar-
bonylation of the product 6b to tropinone by PLE, we
added dimethyl sulfoxide (DMSO) to the phosphate
buffer to reduce the activity of PLE. As a result, (−)-6b
Since Davies et al.11 and Rapoport et al.12 reported
asymmetric syntheses of (−)-ferruginine 4 via the a,b-
unsaturated methyl ester (−)-8, we tried to convert
(−)-6b into (−)-8. A formal asymmetric synthesis of
(−)-ferruginine 4 is illustrated in Scheme 2. Ester
exchange of the monoethyl ester (−)-6b (96% ee) with
methoxide gave the methyl ester 6c in high yield.
Hydrogenolysis of the N-benzyl group of 6c followed
by tert-butoxycarbonylation afforded the b-keto ester
(−)-7c in excellent yield (95%, two steps). Reduction of
(−)-7c with tetrabutylammonium borohydride and sub-
sequent b-elimination by trifluoroacetylation afforded
(−)-8 in 80% yield (two steps). The spectroscopic data
and specific rotation of (−)-8 were identical with those
reported.11,12

T. Katoh et al. / Tetrahedron: Asymmetry 13 (2002) 2351–2358
2353
Scheme 2. A formal asymmetric synthesis of (−)-ferruginine 4. Reagents and conditions: (a) Na, MeOH, 95%; (b) (1) 10%
Pd–C/H2, (2) (Boc)2O, Et3N, 95% (two steps); (c) (1) Bu4NBH4, 85%, (2) (CF3CO)2O, Et3N, DMAP, CHCl3, 94%.
A new total asymmetric synthesis of natural (+)-fer-
ruginine 4 was carried out, as shown in Scheme 3. The
N-benzyl group of (−)-6b (96% ee) was exchanged for
an N-Boc group in 7b by hydrogenolysis/carbamoyla-
tion. In preliminary experiments, decarboxylation
using alkaline hydrolysis of the b-keto ester after
introduction of the 1-hydroxyethyl substituent at the
4-position was unsuccessful because of the steric bulki-
ness of the axial substituent at the 4-position.16 In
order to use hydrogenolysis to remove the ester moiety
in the b-keto ester 7b, the ester exchange of 7b with
benzyl alcohol and 4-dimethylaminopyridine (DMAP)
gave the benzyl ester 7d in excellent yield. At this
stage, the 1-hydroxyethyl group was introduced at the
4-position of the tropane framework of the b-keto
ester 7d by reacting the dianion formed with sodium
hydride and lithium diisopropylamide (LDA) with
acetaldehyde to give the alcohol 9. Before oxidation of
the alcohol moiety, the b-keto ester 9 was subjected to
hydrogenolysis in the presence of Pd/C and decar-
boxylation with the assistance of catalytic hydrochloric
acid to give the b-hydroxy ketone (+)-10 as a single
diastereomer17 in high yield, even in the presence of
the N-Boc group. The keto alcohol (+)-10 was pro-
tected by the TBS ether and the ketone moiety of 11
was transformed to the enol triflate 12 with N-phenyl-
trifluoromethanesulfonimide in the presence of potas-
sium
tert-butoxide.
The
palladium(0)-catalyzed
reduction of the triflate 12 with formic acid18 followed
by deprotection of the OTBS group with tetra-
butylammonium fluoride (TBAF) gave the homoallylic
alcohol 13 in moderate yield. Oxidation of the alcohol
13 and subsequent isomerization of the olefin with
DBU afforded the conjugated enone (+)-14 in good
yield. The specific rotation of (+)-14 (96% ee) showed
the same value {[h]D25=+123.3 (0.81, CHCl3)} as
reported by Rapoport {[h]2D4=+129.1 (1.0, CHCl3)}.12
Conversion of the N-Boc group of (+)-14 into the
N-Me by the usual method12 completed the asymmet-
ric total synthesis of (+)-ferruginine 4. Physical data
of the synthesized (+)-4 was identical with those
reported for the natural (+)-ferruginine 4, {the synthe-
sized (+)-4: [h]D25=+41.3 (0.21, CHCl3)}; lit.7{[h]D19=
+37 (CHCl3)}.
Scheme 3. Total asymmetric synthesis of (+)-ferruginine 4. Reagents and conditions: (a) (1) Pd–C/H2, (2) (Boc)2O, 83% (two steps);
(b) BnOH, DMAP, toluene/reflux, 98%; (c) NaH, LDA, CH3CHO, THF, 56%; (d) (1) Pd–C/H2, (2) HCl (cat.), D, 85% (two
steps); (e) TBSCl, imidazole, DMF, 95%; (f) KO-t-Bu, PhNTf2, THF, 73%; (g) (1) Pd(OAc)2, PPh3, Et3N, HCO2H, (2) TBAF,
66% (two steps); (h) (1) PCC, (2) DBU, 83% (two steps); (i) (1) TFA, (2) HCHO, NaBH3CN, 94% (two steps).

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T. Katoh et al. / Tetrahedron: Asymmetry 13 (2002) 2351–2358
3. Conclusion
atmosphere. The reaction mixture was concentrated in
vacuo. The residue was purified by silica gel column
chromatography (eluent: hexane:acetone=5:1) to give
5b (14.7 g, 82%). Compound 5b: pale yellow oil (a
mixture of keto–enol tautomers); 1H NMR (CDCl3, 300
MHz): l 12.0 (s, 0.25H), 11.9 (s, 0.25H), 7.36–7.24 (m,
5H), 4.32–3.57 (m, 8H), 3.36 (s, 0.33H), 3.31 (s, 0.33H),
3.16 (d, J=2.5 Hz, 0.33H), 2.93 (d, J=1.2 Hz, 0.5H),
2.25–1.77 (m, 4H), 1.34–1.03 (m, 6H); IR (CHCl3):
1732, 1654, 1622, 1321, 1301, 1261, 1230, 1182, 1029
cm−1; MS (FAB) m/z 360 (M++H, 100); HRMS calcd
for C20H26NO5 (FAB): 360.1811 (M++H), found:
360.1821.
In conclusion, we were able to develop divergent syn-
thetic routes to (+)- and (−)-ferruginine 4 via the opti-
cally active ethyl 8-benzyl-3-oxo-8-azabicyclo[3.2.1]-
octane-2-carboxylate (−)-6b by controlling the regiose-
lectivity of the reaction at the 2- and 4-positions of the
tropane framework for introduction of the acetyl
group.
4. Experimental
4.1. General
4.4. Ethyl (1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]-
octan-2-carboxylate, (−)-6b
Melting points were taken with a micro hot-stage
apparatus (Yanagimoto) and are uncorrected. IR spec-
tra were recorded with a Shimadzu FT-IR 8300. 1H
NMR spectra were obtained with a JEOL JNM-AL
300, Varian XL 300 and Varian Unity INOVA 400
NMR spectrometer. Signals are given in ppm using
tetramethylsilane as an internal standard. MS spectra
were determined on a JEOL JMS SX-102A QQ and
JEOL JMS-GCmate mass spectrometer. Combustion
analyses were performed by a Yanaco CHN-corder
MT-3. Silica Gel 60N (Kanto Chemical Co., Inc.) was
used for flash column chromatography. Kieselgel 60
To a 0.1 M phosphate buffer (pH 8.0, 9 ml)–dimethyl
sulfoxide (1 ml) solution of diethyl 8-benzyl-3-oxo-8-
azabicyclo[3.2.1]octan-2,4-dicarboxylate 5b (276 mg,
0.77 mmol) was added PLE (202 mg, 5000 units/mmol).
The reaction mixture was stirred at room temperature
for 24 h. The reaction mixture was filtered with Hyflo
Super-Cel® (eluent: chloroform), then the filtrate was
concentrated in vacuo. The residue was purified by
silica gel column chromatography (eluent: hexane:ethyl
acetate=4:1) to give (−)-6b (83 mg, 38%). (−)-6b; pale
yellow oil (mixture of keto–enol tautomers); [h]2D4=
F254 plates (Merck) were used for thin-layer chromatog-
1
raphy (TLC). If necessary, the compounds were
purified by a recycle HPLC (LC-908, Japan Analytical
Industry Co., Ltd.) on GPC columns (JAIGEL 1H and
2H) after purification on silica gel.
−20.5 (c 1.19, CHCl3); H NMR (CDCl3, 300 MHz): l
11.9 (s, 0.3H), 7.44–7.22 (m, 5H), 4.29–3.97 (m, 2H),
3.88–3.43 (m, 4H), 3.39–3.36 (m, 0.4H), 3.11 (t, J=2.0
Hz, 0.3H), 2.96–2.89 (m, 0.5H), 2.80–2.68 (m, 1H),
2.31–2.03 (m, 2.5H), 1.92–1.75 (m, 1H), 1.69–1.49 (m,
1H), 1.38–1.04 (m, 3H); IR (CHCl3): 1732, 1714, 1647,
1604, 1301, 1236, 1224 cm−1; MS (FAB) m/z 288 (M++
H, 100); HRMS (FAB) calcd for C17H22NO3 (M++H):
288.1599, found: 288.1590. The enantiomeric excess of
(−)-6b was determined by chiral HPLC analysis after
conversion into the enol triflate, according to the fol-
lowing procedure.
4.2. Materials
THF and toluene were distilled from sodium benzophe-
none ketyl under a nitrogen atmosphere before use.
N,N-Dimethylformamide, dichloromethane, diiso-
propylamine and triethylamine were distilled from cal-
cium hydride under a nitrogen atmosphere before use.
Chloroform was distilled from calcium chloride under a
nitrogen atmosphere before use. Methanol was distilled
from magnesium under a nitrogen atmosphere before
use.
4.5. Ethyl (1R,5S)-3-trifluoromethanesulfonyloxy-8-aza-
bicyclo[3.2.1]oct-2-en-2-carboxylate
To a suspension of sodium hydride (60% in mineral oil,
17 mg, 0.43 mmol) in THF (1 ml) was added a solution
of (−)-6b (83 mg, 0.29 mmol) in THF (2 ml) at 0°C. The
mixture was stirred at 0°C for 30 min under a nitrogen
4.3. Diethyl 8-benzyl-3-oxo-8-azabicyclo[3.2.1]octan-2,4-
dicarboxylate, 5b
To an solution of 2,5-dimethoxyTHF (6.48 ml, 50.0
mmol) in water (30 ml) was added concd hydrochloric
acid (4 ml). The reaction mixture was stirred at room
temperature for 2.5 h. The reaction mixture was neu-
tralized with potassium carbonate, then concentrated in
vacuo. The residue was applied to an Extrelut® column
(eluent: chloroform). The extract was dried over anhy-
drous magnesium sulfate, filtered, and concentrated in
vacuo. A methanol (15 ml) solution of benzylamine
(9.08 ml, 50 mmol) was added to a methanol (15 ml)
solution of the residue, and the reaction mixture was
stirred at 0°C for 2 h under a nitrogen atmosphere. A
methanol (15 ml) solution of diethyl 1,3-acetonedicar-
boxylate (5.46 ml, 50 mmol) was added, and the result-
ing mixture was stirred at 0°C for 16 h under a nitrogen
atmosphere.
1,1,1-Trifluoro-N-phenyl-N-[(trifluoro-
methyl)sulfonyl]methanesulfonamide (162 mg, 0.43
mmol) was added at 0°C, and the reaction mixture was
stirred at room temperature for 2 h. The reaction
mixture was poured into brine (20 ml), then extracted
with chloroform (5×20 ml). The combined organic layer
was dried over anhydrous sodium sulfate, filtered, and
concentrated in vacuo. The residue was purified by
silica gel column chromatography (eluent: chloroform)
to give ethyl (1R,5S)-3-trifluoromethanesulfonyloxy-8-
azabicyclo[3.2.1]oct-2-en-2-carboxylate as a pale yellow
oil (91 mg, 75%); [h]2D5=+14.6 (c 0.742, CHCl3); 1H
NMR (CDCl3, 300 MHz): l 7.34–7.26 (m, 5H), 4.28 (q,
J=7.5 Hz, 2H), 3.93 (d, J=5.1 Hz, 1H), 3.68 (s, 2H),
3.46–3.44 (m, 1H), 2.84 (dd, J=18.3 and 4.5 Hz, 1H),

T. Katoh et al. / Tetrahedron: Asymmetry 13 (2002) 2351–2358
2355
2.17–1.94 (m, 4H), 1.61–1.56 (m, 1H), 1.32 (t, J=7.5
Hz, 3H); IR (CHCl3): 3028, 1713, 1423, 1223, 1142
cm−1; MS (FAB) m/z 420 (M++H, 83); HRMS (FAB)
calcd for C18H21F3NO5S (M++H): 420.1093, found:
420.1096; a HPLC analysis [DAICEL CHIRALCEL
OD (25×0.46), eluent: hexane:2-propanol=99:1, flow
rate: 0.2 ml/min, temp.: 23°C, detector: 254 nm, (−)-:
34.0 min, (+)-: 36.4 min], 96% ee.
3.26 (s, 0.33H), 3.09–3.01 (m, 0.67H), 2.42–1.81 (m,
3.67H), 1.70–1.56 (m, 2H), 1.51 (s, 2H), 1.47 (s, 3.5H),
1.45 (s, 3.5H); IR (CHCl3): 1811, 1755, 1691, 1396,
1373, 1340, 1315, 1286, 1261, 1226, 1203, 1164, 1120,
1074 cm−1; MS (FAB) m/z 283 (M++H, 18); HRMS
(FAB) calcd for C14H22NO5 (M++H): 284.1498, found:
284.1493.
4.8. Methyl (1R,5S)-8-tert-butoxycarbonyl-8-azabicyclo-
[3.2.1]oct-2-en-2-carboxylate, (−)-8
4.6. Methyl (1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]-
octan-2-carboxylate, 6c
To a solution of 7c (126 mg, 0.44 mmol) in methanol (5
ml) was added tetrabutylammonium borohydride (230
mg, 0.89 mmol) at 0°C. The reaction mixture was
stirred at 0°C for 1 h. The reaction mixture was concen-
trated in vacuo. The residue was added a saturated
ammonium chloride solution (20 ml), then extracted
with chloroform (5×30 ml). The combined organic layer
was dried over anhydrous sodium sulfate, filtered, and
concentrated in vacuo. The residue was purified by
silica gel column chromatography (eluent: hexane:ethyl
acetate=5:1) to give methyl (1R,5S)-3-hydroxy-8-tert-
butoxycarbonyl-8-azabicyclo[3.2.1]octan-2-carboxylate
(107 mg, 85%).
To a solution of (−)-6b (1.22 g, 4.26 mmol) in methanol
(20 ml) was added sodium methoxide (28% in
methanol, 4.8 ml, 85.2 mmol). The reaction mixture
was heated under refluxed for 48 h under a nitrogen
atmosphere. The reaction mixture was poured into a
saturated ammonium chloride solution (20 ml), and
concentrated in vacuo. The residue was extracted with
chloroform (3×30 ml). The combined organic layer was
dried over anhydrous sodium sulfate, filtered, and con-
centrated in vacuo. The residue was purified by silica
gel column chromatography (eluent: chloroform) to
give 6c as a pale yellow oil (1.10 g, 95%—mixture of
1
keto–enol tautomers); H NMR (CDCl3, 300 MHz): l
11.8 (s, 0.4H), 7.42–7.23 (m, 5H), 3.85–3.76 (m, 1H),
3.74 (s, 2H), 3.72 (s, 1H), 3.64 (s, 1.33H), 3.62 (s,
0.67H), 3.61–3.47 (m, 1H), 3.37 (t, J=5.7 Hz, 1H), 3.12
(t, J=2.0 Hz, 0.3H), 2.97–2.90 (m, 0.3H), 2.80–2.69 (m,
1H), 2.32–2.03 (m, 2H), 1.92–1.49 (m, 2H); IR (CHCl3):
1736, 1713, 1655, 1445, 1350, 1221, 1217 cm−1; MS
(FAB) m/z 274 (M++H, 100); HRMS (FAB) calcd for
C16H20NO3: 274.1443 (M++H), found: 274.1433.
To a solution of methyl (1R,5S)-3-hydroxy-8-tert-
butoxycarbonyl-8-azabicyclo[3.2.1]octan-2-carboxylate
(288 mg, 1.01 mmol) in chloroform (10 ml) was added
trifluoroacetic anhydride (430 ml, 3.03 mmol), triethyl-
amine (1.2 ml, 6.06 mmol) and a catalytic amount of
4-dimethylaminopyridine. The reaction mixture was
refluxed for 22.5 h under a nitrogen atmosphere. The
reaction mixture was poured into brine (30 ml), then
neutralized with a saturated sodium hydrogen carbon-
ate solution. The aqueous layer was extracted with
chloroform (5×20 ml). The combined organic layer was
dried over anhydrous sodium sulfate, filtered, and con-
centrated in vacuo. The residue was purified by silica
gel column chromatography (eluent: hexane:ethyl acet-
ate=5:1) to give (−)-8 as a colorless oil; (254 mg, 94%);
[h]D25=−70.6 (c 1.55, CHCl3), {lit.11 [h]2D5=−47.2 (c 2.45,
CHCl3) (66% ee), lit.12 [h]D21=−52.4 (c 1.00, CHCl3)};
1H NMR (CDCl3, 300 MHz): l 6.78–6.75 (m, 1H),
4.85–4.78 (m, 1H), 4.37–4.28 (m, 1H), 3.78 (s, 3H),
2.89–2.81 (m, 1H), 2.20–1.87 (m, 4H), 1.65–1.53 (m,
1H), 1.44 (s, 9H); IR (KBr): 1716, 1701, 1641, 1442,
1419, 1380, 1369, 1340, 1323, 1259, 1224, 1164, 1105,
1089 cm−1; MS (FAB) m/z 268 (M++H, 19); HRMS
(FAB) calcd for C14H22NO4: 268.1548 (M++H), found:
268.1552. Anal. Calcd for C14H21NO4: C, 62.90; H,
7.92; N, 5.24. Found: C, 62.69; H, 7.90; N, 5.53; a
HPLC analysis [DAICEL CHIRALCEL OD (25×0.46);
eluent: hexane:2-propanol=100:1; flow rate: 0.5 ml/
min; temperature: 25°C; detector: 254 nm; (−)-8; 20.5
min, (+)-8; 24.9 min], 96% ee.
4.7. Methyl (1R,5S)-8-tert-butoxycarbonyl-3-oxo-8-
azabicyclo[3.2.1]octan-2-carboxylate, (−)-7c
To a solution of 6c (424 mg, 1.55 mmol) in methanol (5
ml)–acetic acid (5 ml) was added a catalytic amount of
10% palladium on activated carbon, and the reaction
mixture was stirred at room temperature for 16 h under
a hydrogen atmosphere. The palladium on activated
carbon was filtered off with Celite® (eluent: methanol),
and the filtrate was concentrated in vacuo. A saturated
sodium hydrogen carbonate solution (20 ml) was added
to the residue, and the mixture was extracted with
chloroform (3×20 ml). The combined organic layer was
dried over anhydrous sodium sulfate, filtered, and con-
centrated in vacuo. The residue was dissolved in a
chloroform (20 ml), and di-tert-butyl dicarbonate (428
ml, 1.86 mmol) and triethylamine (260 ml, 1.86 mmol)
were added, and finally the resulting mixture was
stirred at room temperature for 4 h under a nitrogen
atmosphere. The reaction mixture was poured into
brine (10 ml), and extracted with chloroform (3×20 ml).
The combined organic layer dried over anhydrous
sodium sulfate, filtered, and concentrated in vacuo. The
residue was purified by silica gel column chromatogra-
phy (eluent: hexane:ethyl acetate=5:1) to give (−)-7c as
a pale yellow oil (416 mg, 95%—mixture of keto–enol
tautomers); [h]D27=−30.9 (c 0.78, CHCl3); 1H NMR
(CDCl3, 300 MHz): l 11.8 (s, 0.33H), 4.85 (br s, 1H),
4.36 (br m, 1H), 3.78 (s, 1H), 3.77 (s, 1H), 3.71 (s, 1H),
4.9. Ethyl (1R,5S)-8-tert-butoxycarbonyl-3-oxo-8-azabi-
cyclo[3.2.1]octan-2-carboxylate, 7b
To a solution of (−)-6b (253 mg, 0.88 mmol) in
methanol (5 ml)–acetic acid (5 ml) was added a cata-
lytic amount of 10% palladium on activated carbon,
and the reaction mixture was stirred at room tempera-

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T. Katoh et al. / Tetrahedron: Asymmetry 13 (2002) 2351–2358
ture for 20 h under a hydrogen atmosphere. The pal-
ladium on activated carbon was filtered off with
Celite® (eluent: methanol), and the filtrate was con-
centrated in vacuo. A saturated sodium hydrogen car-
bonate solution (20 ml) was added to the residue, and
the mixture was extracted with chloroform (3×20 ml).
The combined organic layer was dried over anhy-
drous sodium sulfate, filtered, and concentrated in
vacuo. The residue was dissolved in chloroform (15
ml), and di-tert-butyl dicarbonate (240 ml, 1.05 mmol)
and triethylamine (140 ml, 1.05 mmol) were added,
and finally the resulting mixture was stirred at room
temperature for 30 min under a nitrogen atmosphere.
The reaction mixture was poured into brine (10 ml),
and extracted with chloroform (3×20 ml). The com-
bined organic layer dried over anhydrous sodium sul-
fate, filtered, and concentrated in vacuo. The residue
was purified by silica gel column chromatography
(eluent: hexane:ethyl acetate=5:1) to give 7b as a col-
orless oil (218 mg, 83%—mixture of keto–enol tau-
tomers); 1H NMR (CDCl3, 300 MHz): l 11.9 (s,
0.25H), 4.68–4.10 (m, 4H), 3.10–2.80 (m, 0.75H),
2.41–1.53 (m, 6H), 1.47 (s, 2.25H), 1.45 (s, 6.75H),
1.32 (t, J=7.2 Hz, 2.25H), 1.28 (t, J=6.9 Hz, 0.75H);
IR (CHCl3): 2982, 1736, 1690, 1612, 1408, 1169, 1111
cm−1; MS (FAB) m/z 298 (M++H, 21); HRMS (FAB)
calcd for C15H24NO5 (M++H): 298.1654, found:
298.1647.
−78°C, and the reaction mixture was stirred for 20
min. The reaction mixture was poured into 2N
hydrochloric acid (20 ml), and neutralized with a sat-
urated sodium hydrogen carbonate solution. The
aqueous layer was extracted with chloroform (5×20
ml). The combined organic layer was dried over
anhydrous sodium sulfate, filtered, and concentrated
in vacuo. The residue was purified by silica gel
column chromatography (eluent: hexane:ethyl ace-
tate=5:1) to give 9 as a pale yellow oil (244 mg,
56%, mixture of keto–enol tautomers); 1H NMR
(CDCl3, 300 MHz): l 12.2 (s, 0.4H), 7.36–7.33 (m,
5H), 5.25–5.00 (m, 2.6H), 4.69 (m, 0.4H), 4.49 (m,
1H), 4.09 (m, 1H), 3.82 (m, 0.3H), 3.08 (m, 0.3H),
2.31–2.05 (m, 4H), 1.89–1.81 (m, 1H), 1.69–1.50 (m,
1H), 1.49 (s, 2.25H), 1.46 (d, J=6.6 Hz, 1.5H), 1.45
(s, 6.75H), 1.39 (d, J=6.3 Hz, 1.5H); IR (CHCl3):
3020, 2982, 1690, 1612, 1416, 1269, 1204, 1165 cm−1;
MS (FAB) m/z 404 (M++H, 19); HRMS (FAB) calcd
for C22H30NO6 (M++H): 404.2073, found: 404.2079.
4.12. (1R,4S,5S)-8-tert-Butoxycarbonyl-4-(1%-hydroxy-
ethyl)-8-azabicyclo[3.2.1]octan-3-one, (+)-10
To a solution of 9 (224 mg, 0.56 mmol) in methanol
(7 ml) was added a catalytic amount of 10% palla-
dium on activated carbon, and the reaction mixture
was stirred at room temperature for 24 h under a
hydrogen atmosphere. The palladium/carbon was
removed by filtration through Celite® (eluent:
methanol), and the filtrate was concentrated in vacuo.
The residue was dissolved in methanol (7 ml), and
was added one drop of 1% hydrochloric acid. The
reaction mixture was refluxed for 2 h. The reaction
mixture was poured into a saturated sodium hydro-
gen carbonate solution (10 ml), and the mixture was
concentrated in vacuo. The residue was extracted with
chloroform (3×20 ml). The combined organic layer
was dried over anhydrous sodium sulfate, filtered,
and concentrated in vacuo. The residue was purified
by silica gel column chromatography (eluent: chloro-
form) to give (+)-10 (131 mg, 88%) as a single iso-
mer; colorless powder; mp 104–105°C (hexane:ethyl
4.10. Benzyl (1R,5S)-8-tert-butoxycarbonyl-3-oxo-8-
azabicyclo[3.2.1]octan-2-carboxylate, 7d
To a solution of 7b (326 mg, 1.10 mmol) in toluene
(50 ml) was added benzyl alcohol (2.84 ml, 2.74
mmol) and a catalytic amount of 4-dimethylaminopy-
ridine. The reaction mixture was heated under reflux
with a Dean–Stark trap for 16 h under a nitrogen
atmosphere. The reaction mixture was then concen-
trated in vacuo. The residue was purified by silica gel
column chromatography (eluent: hexane:ethyl ace-
tate=10:1) to give 7d as a colorless oil (385 mg,
98%—mixture of keto–enol tautomers); 1H NMR
(CDCl3, 300 MHz): l 11.8 (s, 0.25H), 7.40–7.29 (m,
5H), 5.22–5.06 (m, 2H), 4.89 (s, 1H), 4.37 (s, 1H),
3.03 (s, 0.75H), 2.41–1.82 (m, 5H), 1.70–1.60 (m, 1H),
1.57 (s, 2.25H), 1.49 (s, 6.75H); IR (CHCl3): 2982,
1736, 1690, 1655, 1394, 1285, 1229, 1167 cm−1; MS
(FAB) m/z 360 (M++H, 8); HRMS (FAB) calcd for
C20H26NO5 (M++H): 360.1811, found: 360.1807.
1
acetate=10:1); [h]D26=+81.1 (c 0.78, CHCl3); H NMR
(CDCl3, 300 MHz): l 4.59 (s, 1H), 4.50 (d, J=6.9
Hz, 1H), 4.05 (m, 1H), 2.74 (d, J=12.9 Hz, 1H),
2.39–2.02 (m, 4H), 1.64 (d, J=7.8 Hz, 2H), 1.51 (s,
9H), 1.36 (d, J=3.0 Hz, 3H); IR (CHCl3): 3009,
2978, 1686, 1420, 1369, 1346, 1161, 1111 cm−1; MS
(FAB) m/z 270 (M++H, 34); HRMS (FAB) calcd for
C14H24NO4 (M++H): 270.1705, found: 270.1711. Anal.
calcd for C14H23NO4: C, 62.43; H, 8.61; N, 5.20.
Found: C, 62.54; H, 8.82; N, 4.97%.
4.11. Benzyl(1R,5S)-8-tert-butoxycarbonyl-4-(1%-hydroxy-
ethyl)-3-oxo-8-azabicyclo[3.2.1]octan-2-carboxylate, 9
To a suspension of sodium hydride (60% in mineral
oil, 91 mg, 2.26 mmol) in THF (5 ml) was added a
THF (7 ml) solution of 7d (387 mg, 1.08 mmol) at
0°C. The reaction mixture was stirred at 0°C for 1.5
h under a nitrogen atmosphere. A THF (5 ml) solu-
tion of lithium diisopropylamide, which was prepared
from n-butyl lithium (2.6 M in hexane, 870 ml, 2.26
mmol) and diisopropylamine (317 ml, 2.26 mmol), was
added at −78°C. The reaction mixture was stirred for
6 h. Acetaldehyde (301 ml, 5.39 mmol) was added at
4.13. (1R,4S,5S)-8-tert-Butoxycarbonyl-4-{1%-(tert-butyl-
dimethylsilyloxy)ethyl}-8-azabicyclo[3.2.1]octan-3-one,
11
To a N,N-dimethylformamide (5 ml) solution of (+)-
10 (132 mg, 0.49 mmol) was added tert-
butyldimethylsilyl chloride (148 mg, 0.98 mmol) and
imidazole (134 mg, 1.96 mmol). The reaction mixture
was stirred at room temperature for 24 h under a

T. Katoh et al. / Tetrahedron: Asymmetry 13 (2002) 2351–2358
2357
nitrogen atmosphere. The reaction mixture was poured
into brine (20 ml), and extracted with chloroform (3×20
ml). The combined organic layer was dried over anhy-
drous sodium sulfate, filtered, and concentrated in
vacuo. The residue was purified by silica gel column
chromatography (eluent: hexane:ethyl acetate=15:1) to
give 11 (179 mg, 95%) as a single isomer; colorless oil;
1H NMR (CDCl3, 300 MHz): l 4.64 (br s, 1H), 4.44 (br
s, 1H), 4.08–4.03 (m, 1H), 2.65 (br s, 1H), 2.29–2.25 (m,
2H), 2.08–1.96 (m, 2H), 1.62 (d, J=8.4 Hz, 2H), 1.51
(s, 9H), 1.33 (d, J=5.4 Hz, 3H), 0.83 (s, 9H), 0.03 (s,
3H), 0.02 (s, 3H); IR (CHCl3): 3026, 3013, 2959, 2930,
1786, 1417, 1367, 1344, 1161, 1109 cm−1; MS (FAB)
m/z 384 (M++H, 20); HRMS (FAB) calcd for
C20H38NO4Si (M++H): 384.2570, found: 384.2566.
ml), and neutralized with a saturated sodium carbonate
solution. The aqueous layer was extracted with chloro-
form (3×30 ml). The combined organic layer was dried
over anhydrous sodium sulfate, filtered, and concen-
trated in vacuo. The residue was purified by silica gel
column chromatography (eluent: hexane:ethyl acetate=
1
5:1) to give 13 colorless oil (111 mg, 65%); H NMR
(CDCl3, 300 MHz): l 6.13 (ddd, J=9.6, 5.4 and 2.1 Hz,
1H), 5.67 (ddd, J=9.6, 3.9 and 1.5 Hz, 1H), 4.44 (s,
1H), 4.33 (d, J=7.8 Hz, 1H), 3.96 (m, 1H), 2.34–2.12
(m, 1H), 1.89–1.83 (m, 3H), 1.66–1.54 (m, 2H), 1.45 (s,
9H), 1.27 (d, J=6.3 Hz, 3H); IR (CHCl3): 3429, 3028,
3008, 2978, 2936, 1678, 1651, 1477, 1443, 1230, 1165
cm−1; MS (FAB) m/z 254 (M++H, 45); HRMS (FAB)
calcd for C14H24NO3 (M++H): 254.1756, found:
254.1761.
4.14. (1R,4S,5S)-8-tert-Butoxycarbonyl-4-{1%-(tert-butyl-
dimethylsilyloxy)ethyl}-8-azabicyclo[3.2.1]oct-2-enyl
3-trifluoromethanesulfonate, 12
4.16. (1R,5S)-4-Acetyl-8-tert-butoxycarbonyl-8-azabicy-
clo[3.2.1]oct-3-ene, (+)-14
To a solution of 11 (79 mg, 0.21 mmol) in THF (5 ml)
was added potassium tert-butoxide (35 mg, 0.31 mmol)
at 0°C. The reaction mixture was stirred at 0°C for 15
min under a nitrogen atmosphere. 1,1,1-Trifluoro-
N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfona-
mide (116 mg, 0.31 mmol) was added at 0°C, and the
reaction mixture was stirred at 0°C for additional 5 h.
The reaction mixture was poured into a solution of
brine (20 ml) and saturated ammonium chloride (10
ml), and extracted with chloroform (3×20 ml). The
combined organic layer was dried over anhydrous
sodium sulfate, filtered, and concentrated in vacuo. The
residue was purified by silica gel column chromatogra-
phy (eluent: hexane:ethyl acetate=50:1) to give 12 (78
To a solution of 13 (205 mg, 0.81 mmol) in
dichloromethane (15 ml) was added pyridinium
chlorochromate (PCC) (1.01 g, 4.03 mmol). The reac-
tion mixture was stirred at room temperature for 4.5 h
under a nitrogen atmosphere. PCC was removed by
filtration through silica gel (eluent: chloroform). The
residue was dissolved with a dichloromethane (8 ml),
and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (603 ml,
4.03 mmol) was added. The resulting mixture was
stirred at room temperature for 3 h under a nitrogen
atmosphere. The reaction mixture was concentrated in
vacuo. The residue was purified by silica gel column
chromatography (eluent: hexane:ethyl acetate=2:1) to
give (+)-14 as colorless needles (168 mg, 83%); mp
67–68°C (hexane:ethyl acetate=5:1); [h]2D5=+123.3 (c
1
mg, 73%) as a single isomer; colorless oil; H NMR
1
(CDCl3, 300 MHz): l 6.06 (m, 1H), 4.73 (d, J=7.8 Hz,
2H), 4.09–4.05 (m, 1H), 2.34 (d, J=6.0 Hz, 1H), 2.17–
2.09 (m, 1H), 2.02–1.95 (m, 1H), 1.86 (m, 1H), 1.67–
1.60 (m, 1H), 1.46 (s, 9H), 1.22 (d, J=7.2 Hz, 3H), 0.89
(s, 9H), 0.06 (s, 3H), 0.03 (s, 3H); IR (CHCl3): 2955,
2932, 1690, 1420, 1231, 1207, 1142, 1099 cm−1; MS
(FAB) m/z 516 (M++H, 7); HRMS (FAB) calcd for
C21H37F3NO6SSi (M++H): 516.2063, found: 516.2055.
0.81, CHCl3); H NMR (CDCl3, 300 MHz): l 6.65 (s,
1H), 4.92 (d, J=5.4 Hz, 1H), 4.36 (brs, 1H), 2.91 (m,
1H), 2.27 (s, 3H), 2.18–2.00 (m, 3H), 1.83–1.76 (m, 1H),
1.60–1.51 (m, 1H), 1.43 (s, 9H); IR (CHCl3): 3028,
3009, 2978, 2932, 1628, 1393, 1342, 1327, 1169, 1107
cm−1; MS (FAB) m/z 252 (M++H, 20); HRMS (FAB)
calcd for C14H22NO3 (M++H): 252.1600, found:
252.1603. Anal. calcd for C14H21NO3: C, 66.91; H, 8.42;
N, 5.57. Found: C, 66.99; H, 8.62; N, 5.60%.
4.15. (1R,4S,5S)-8-tert-Butoxycarbonyl-4-(1%-hydroxy-
ethyl)-8-azabicyclo[3.2.1]oct-2-ene, 13
4.17. (+)-Ferruginine, (+)-4
To a solution of (+)-14 (39 mg, 0.15 mmol) in
dichloromethane (3 ml) was added trifluoroacetic acid
(118 ml, 1.53 mmol). The reaction mixture was stirred at
room temperature for 4 h under a nitrogen atmosphere,
then poured into saturated aqueous sodium hydrogen
carbonate solution (5 ml), and extracted with chloro-
form (3×10 ml). The combined organic layer was dried
over anhydrous sodium sulfate, filtered, and concen-
trated in vacuo. Formaldehyde (37% in water, 57 ml,
0.77 mmol) and sodium cyanoborohydride (20 mg, 0.31
mmol) were added to an acetonitrile (3 ml) solution of
the residue. The resulting mixture was stirred at room
temperature for 40 min under a nitrogen atmosphere.
1N Hydrochloric acid (3 ml) was added, and reaction
mixture was stirred at room temperature for 2.5 h. The
reaction mixture was neutralized with a saturated
To a solution of 12 (348 mg, 0.67 mmol) in N,N-
dimethylformamide (12 mL) was added palladium(II)
acetate (3 mg, 0.013 mmol), triphenylphosphine (7 mg,
0.026 mmol), triethylamine (280 ml, 2.01 mmol) and
formic acid (51 ml, 1.34 mmol). The resulting mixture
was stirred at 60°C for 7 h. The reaction mixture was
poured into brine (10 ml), and extracted with chloro-
form (3×30 ml). The combined organic layer was
washed with brine (10 ml), dried over anhydrous
sodium sulfate, filtered, and concentrated in vacuo. The
residue was dissolved in THF (7 ml). Tetra-
butylammonium fluoride (1.0 M in THF, 1.35 ml, 1.35
mmol) was added, and the reaction mixture was stirred
at room temperature for 4 h under a nitrogen atmo-
sphere. The reaction mixture was poured into brine (10

2358
T. Katoh et al. / Tetrahedron: Asymmetry 13 (2002) 2351–2358
Keverline, K. I.; Abraham, P.; Lewin, A. H.; Carroll, F.
I. Tetrahedron Lett. 1995, 36, 3099–3102.
sodium hydrogen carbonate solution, and extracted
with chloroform (3×15 ml). The combined organic layer
was dried over anhydrous sodium sulfate, filtered, and
concentrated in vacuo. The residue was purified by
aluminum oxide column chromatography (eluent: chlo-
roform) to give (+)-4 as a pale yellow oil (24 mg, 94%);
[h]2D5=+41.3 (c 0.21, CHCl3); 1H NMR (CDCl3, 300
MHz): l 6.70 (br t, 1H), 3.91 (d, J=5.1 Hz, 1H), 3.25
(br t, 1H), 2.72 (br d, 1H), 2.32 (s, 3H), 2.26 (s, 3H),
2.18–2.12 (m, 2H), 1.92 (dd, J=19.8 and 4.5 Hz, 1H),
1.71 (t, J=9.3 Hz, 1H), 1.54–1.43 (m, 1H); 13C NMR
(CDCl3, 100 MHz): l 197.5, 143.6, 136.7, 57.6, 57.4,
37.2, 33.6, 33.1, 29.5, 24.9; IR (CHCl3): 2928, 2855,
1663, 1632, 1447, 1377, 1261 cm−1; MS (70 eV) m/z 165
(M+, 50), 150 (24), 136 (100), 122 (49); HRMS (70 eV)
calcd for C10H15NO (M+): 165.1154, found: 165.1150.
5. Node, M.; Nakamura, S.; Nakamura, D.; Katoh, T.;
Nishide, K. Tetrahedron Lett. 1999, 40, 5357–5360.
6. For lipase-catalyzed demethoxycarbonylation and appli-
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mura, D.; Nishide, K. Tetrahedron Lett. 1995, 36,
2255–2256; (b) Node, M.; Nakamura, D.; Nishide, K.;
Inoue, T. Heterocycles 1997, 46, 535–540; (c) Node, M.;
Inoue, T.; Araki, M.; Nakamura, D.; Nishide, K. Tetra-
hedron: Asymmetry 1998, 9, 157–167; (d) Node, M.;
Araki, M.; Tanaka, H.; Nakamura, D.; Inoue, T.;
Nishide, K. Chem. Pharm. Bull. 1998, 46, 736–738.
7. Bick, I. R. C.; Gillard, J. W.; Leow, H.-M. Aust. J.
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8. Bick, I. R. C.; Gillard, J. W.; Leow, H.-M. Aust. J.
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9. Swanson, K. L.; Albuquerque, E. X. Handbook of Exper-
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