Formal synthesis of (+)- and (-)-ferruginine

Article abstract of DOI:10.1002/ejoc.200700427

A formal synthesis of the naturally occurring (+)-ferrugine and of its enantiomer starting from the commercially available tropinone is reported. The desymmetrization of tropinone was achieved through formation of diastereomeric unsaturated sulfoxides usi

Full text of DOI:10.1002/ejoc.200700427

FULL PAPER
DOI: 10.1002/ejoc.200700427
Formal Synthesis of (+)- and (–)-Ferruginine
Riccardo Piccardi[a] and Philippe Renaud*[a]
Keywords: Alkaloids / Tropanes / Sulfoxides / Desymmetrization / α,β-Unsaturated sulfones / Conjugate addition
A formal synthesis of the naturally occurring (+)-ferrugine
and of its enantiomer starting from the commercially avail-
able tropinone is reported. The desymmetrization of trop-
inone was achieved through formation of diastereomeric un-
saturated sulfoxides using the Andersen procedure. Intro-
duction of the acetyl C(2) side chain was achieved by conju-
gate addition of lithiated ethyl vinyl ether to an unsaturated
sulfone. N-Boc-Norferruginine, an advanced intermediate
for the synthesis of ferruginine, was prepared in six steps and
19% overall yield.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Due to their biological activity and their interesting
structural features, 8-azabicyclo[3.2.1]octane derivatives
(tropanes) are privileged target molecules for the develop-
ment of new synthetic methods and strategies.[6] Ferrugin-
ine itself has been synthesized in racemic[7–9] and enantio-
merically pure forms.[10–16] We present here a concise formal
synthesis of both enantiomers of ferruginine using an easy
resolution procedure based on the formation of dia-
stereomeric alkenyl sulfoxides. The retrosynthetic analysis is
depicted in Scheme 1. Late introduction of the acetyl side
chain as in Bäckvall’s synthesis[9] was planned in order to
maximize the flexibility of our approach. The synthesis was
to start with the commercially available N-Boc-nortrop-
inone (2), and the vinyl bromide 3 was to be resolved by
conversion into the two diastereomeric sulfoxides 4. The
acetyl C(2) side chain was to be introduced by conjugate
addition close to the end of the synthesis.
Introduction
The tropane alkaloid (+)-ferruginine [(+)-1] was isolated
from the extracts of two arboreal species, Darlingia Dar-
lingiana and Darlingia Ferruginea, in 1979.[1,2] It is a potent
neurotoxin of potential interest for the treatment of neurod-
egenerative disorders such as Alzheimer’s disease.[3,4] Its un-
natural isomer (–)-1 has shown interesting activities as a
nicotine acetylcholine receptor (nAChR) agonist.[5]
Scheme 1. Retrosynthesis of (+)- and (–)-ferruginine.
Results and Discussion
[a] Universität Bern, Departement für Chemie und Biochemie,
Freiestrasse 3, 3012 Bern, Switzerland
Fax: +41-31-631-34-26
The racemic vinyl bromide (Ϯ)-3 was prepared from the
commercially available N-Boc-nortropinone (2)[17] by the
E-mail: philippe.renaud@ioc.unibe.ch
4752
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4752–4757

Formal Synthesis of (+)- and (–)-Ferruginine
procedure of Marchand and Takeda,[18,19] and the hydraz- (SS,1S,5R)-4 and (SS,1R,5S)-4 were attributed by conver-
one derived from 2 was treated with CuBr2 and triethyl- sion into the known enantiomers of N-Boc-norferruginine
amine in methanol. The reaction afforded a mixture of the (8; vide infra).
expected gem-dibromide and bromoalkene 3. This mixture
All attempts to introduce the C(2) side chain by conju-
of products was treated with 1,8-diazabicyclo[5.4.0]un- gate additions to the alkenyl sulfoxides 4 were unsatisfac-
decene (DBU) in benzene at reflux to give the desired racemic tory, so we decided to convert the sulfoxides into the sul-
bromide (Ϯ)-3 in 73% yield from 2 (Scheme 2). The racemic fones, which are known to be more reactive. Both dia-
bromide (Ϯ)-3 was converted into the corresponding organ- stereomers of 4 were separately treated with Oxone® to af-
omagnesium derivative and allowed to react with (–)-(1R)- ford the enantiomeric sulfones (–)-5 and (+)-5 in 90% yields
menthyl (S)-para-toluenesulfinate according to Andersen’s (Scheme 3).
procedure[20–22] to afford a 1:1 mixture of diastereomeric
unsaturated sulfoxides (SS,1S,5R)-4 and (SS,1R,5S)-4. Inter-
estingly, the two diastereoisomers are very easily separated
by flash chromatography [Rf(SS,1S,5R)-4
=
0.48;
Rf(SS,1R,5S)-4 = 0.57 (hexane/EtOAc, 1:3)]. This difference
in Rf values is remarkable and may be attributed to a shield-
ing of the nitrogen atom by the para-tolyl group in the less
polar (SS,1R,5S)-4, indicating that this diastereomer exists
preferentially in a conformation in which the C=C bond is
coplanar with the S–O bond of the sulfoxide.[23] No crystal
suitable for an X-ray analysis was obtained and it was there-
fore not possible to confirm this hypothesis experimentally.
The relative configurations of both diastereomers of
Scheme 3. Preparation of the unsaturated sulfones (–)-5 and (+)-5.
In order to introduce the acetyl side chain, Bäckvall’s
approach using conjugated addition of nitroethane followed
by a Nef reaction was attempted first.[9] However, the con-
jugate addition of nitroethane to 5 gave unsatisfactory re-
sults. A more satisfactory outcome was obtained through
conjugate addition of lithium trimethylsilylacetylide to (–)-
(1R,5S)-5, followed by desilylation with K2CO3 to afford
the terminal alkyne (1S,5R)-6 in 74% yield (Scheme 4). The
mercury(II)-catalyzed hydrolysis of the terminal alkyne pro-
ceeded in moderate yield (44%) and delivered the sulfo-
nylated ketone (+)-(1S,2S,3R,5R)-7 as
a single dia-
stereomer. A third approach involving conjugate addition
of lithiated ethyl vinyl ether to (–)-(1R,5S)-5 afforded the
methyl ketone (+)-(1S,2R,3R,5R)-7 in 70% overall yield as
a single diastereomer (after treatment of the intermediate
enol ether with HCl/MeOH). Surprisingly, the two methyl
Scheme 2. Preparation of the diastereomeric unsaturated sulfoxides
4.
Scheme 4. Synthesis of (+)-N-Boc-norferruginine [(+)-8] from unsaturated sulfone (–)-5.
Eur. J. Org. Chem. 2007, 4752–4757
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4753

R. Piccardi, P. Renaud
FULL PAPER
(3 g), K2CO3 (20 g), 5% NaOH (3 mL) in H2O (300 mL) and sub-
sequent heating. Melting points are not corrected. NMR spec-
ketones obtained by conjugate addition either of lithiated
TMS-acetylene or of lithiated ethyl vinyl ketones are epi-
meric at C(2). Their relative configurations have been at-
tributed from coupling constants and NOE difference spec-
tra (Figure 1). Treatment of either diastereomer of 7 with
KOtBu gave (+)-N-Boc-norferruginine [(+)-(1S,5R)-8] in
77% yield; physical and spectroscopic data are in agreement
with literature data.[11] The conversion of (+)-Boc-norferru-
ginine [(+)-8] into (+)-norferruginine [(+)-9] and (+)-ferrug-
inine [(+)-1] by removal of the N-Boc group (CF3CO2H)
and N-methylation (CH2O, NaBH3CN) has been reported
1
troscopy: chemical shifts (δ) in ppm relative to CHCl3 for H (δ =
7.26 ppm) and CDCl3 for 13C (δ = 77.0 ppm) for room-temperature
spectra, or relative to DMSO for 1H (δ = 2.50 ppm) and (CD3)2SO
for 13C (δ = 39.52 ppm) for high-temperature spectra.
Part a. Synthesis of Optically Pure Sulfones (–)-5 and (+)-5
tert-Butyl (؎)-3-Bromo-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate
[(؎)-3]:[18,19]
A solution of hydrazine monohydrate (46 mL,
946 mmol) in MeOH (125 mL) and powdered molecular sieves
(4 Å) (25 g) was stirred for 30 min. Then, a solution of 2 (10.6 g,
by Davies with the racemic mixture[7] and by Rapoport with 47.0 mmol) in MeOH (63 mL) was added under N2. The mixture
the optically pure material.[11] Therefore, our synthesis of
was stirred at room temperature for 3 h and filtered through Celite,
and the solvent was evaporated. Excess hydrazine was removed un-
norferruginine can also be considered a formal synthesis of
der high vacuum. The crude hydrazone (partially solid) was used
ferruginine.
without further purification for the preparation of the gem-dibro-
mide. A suspension of CuBr2 (63.1 g, 283 mmol) in MeOH
(130 mL) and NEt3 (19 mL, 136 mmol) was stirred for 15 min.
Then, a solution of the crude hydrazone in MeOH (65 mL) was
added dropwise at 0 °C. At the end of the addition, the ice bath
was removed and the reaction mixture was stirred for 2 h. The mix-
ture was then poured into CH2Cl2 and a solution of NH4OH (3%)
was added until dissolution of all the copper salts. The aqueous
phase was extracted with CH2Cl2. The combined organic layers
were washed with NH4OH (3% solution), H2O, and brine. After
drying with MgSO4 and evaporation of the solvent, an orange oil
was obtained. Filtration through silica gel (hexane/EtOAc, 9:1)
gave a mixture of the gem-dibromide and the bromoalkene 3 (color-
less oil). Benzene (110 mL) and DBU (11 mL, 73.6 mmol) were
added and the solution was heated under reflux overnight. The
mixture was cooled to room temperature and a saturated aqueous
solution of NH4Cl was added. The aqueous phase was extracted
Figure 1. Relative configurations of diastereomers 7 from 1H NMR
coupling constants and NOE difference spectra.
Starting from the unsaturated sulfone (+)-(1R,5S)-5, (–)-
Boc-norferruginine [(–)-8] was prepared by both routes pre-
sented for (+)-8 in similar yields. Details for these transfor- twice with Et2O and the combined organic layers were washed with
brine and dried (MgSO4). Evaporation of the solvent gave a yellow-
ish oil that was purified by FC (hexane/EtOAc 9:1) to afford (Ϯ)-
3 (10.1 g, 74% from 2). White solid. M.p. 53–55 °C. 1H NMR
(500 MHz, [D6]DMSO, T = 338 K): δ = 6.42 (dt, J = 5.45, 1.49 Hz,
1 H), 4.27 (t, J = 5.7 Hz, 1 H), 4.22–4.18 (m, 1 H), 3.00–2.93 (m,
1 H), 2.26–2.20 (d, J = 17.3 Hz, 1 H), 2.13 (q, J = 10.6 Hz, 1 H),
1.93–1.80 (m, 2 H), 1.74–1.66 (m, 1 H), 1.40 (s, 9 H) ppm. 13C
NMR (125 MHz, [D6]DMSO, T = 338 K): δ = 152.7, 134.1, 119.1,
mations are given in the Experimental Section.
Conclusions
A short synthesis of both enantiomers of N-Boc-norfer-
ruginine (8) in six steps and 19% yield from N-Boc-tropi-
none (2) has been developed. The desymmetrization of tro-
pinone has been achieved through the formation of dia-
stereomeric unsaturated sulfoxides by Andersen’s pro-
cedure. Introduction of the acetyl side chain is best achieved
by conjugate addition of lithiated ethyl vinyl ether to an
α,β-unsaturated sulfone. It is expected that this strategy will
be efficient for the synthesis of a range of optically pure 2,3-
disubstituted 8-azabicyclo[3.2.1]octane (tropane) alkaloids.
78.7, 54.3, 52.8, 43.1, 33.3, 28.7, 27.7 ppm. IR (KBr): ν = 2978,
˜
2926, 2876, 2833, 1686, 1628, 1412, 1364, 1353, 1321, 1314, 1162,
1105, 1006, 972, 886, 751, 709 cm–1. MS (EI): m/z (%) = 289 (1),
287 (1), 233 (25), 231 (25), 189 (5), 187 (5), 160 (11), 158 (11), 108
(38), 91 (10), 57 (100). HRMS: calcd. for C12H18BrNO2 287.0521;
found 287.0521.
tert-Butyl (+)-(SS,1R,5S)- and (–)-(SS,1S,5R)-3-[(4-Methylphenyl)-
sulfinyl]bicyclo[3.2.1]oct-2-ene-8-carboxylate [(+)-(SS,1R,5S)-4 and
(–)-(SS,1S,5R)-4]: The organomagnesium reagent was prepared
from a solution of (Ϯ)-3 (7.6 g, 26.3 mmol) in THF (40 mL), Mg
(960 mg, 39.5 mmol) and MeI (0.2 mL) to activate the Mg. On
cooling to room temperature, a suspension was formed and then
transferred by cannula at 0 °C to a solution of (–)-(1R,2S,5R)-men-
thyl (S)-para-toluenesulfinate (11.6 g, 39.4 mmol) in benzene
(100 mL). The flask containing the organomagnesium reagent was
rinsed with THF (2ϫ10 mL) to transfer the remaining reagent.
When the addition was finished, the ice bath was removed and the
reaction mixture was stirred at room temperature for 20 h. Then
Et2O and a saturated solution of NH4Cl were added to the reaction
mixture. The H2O phase was separated and extracted three times
with Et2O. The combined organic layers were washed with brine
Experimental Section
General Techniques: C6H6, CH2Cl2, and THF were dried and puri-
fied by passing these solvents through activated alumina columns
prior to use. MeOH was used without previous distillation; elimi-
nation of excess H2O was performed by adding activated molecular
sieves (4 Å). Other reagents were obtained from commercial
sources and used as received. Filtration and flash column
chromatography (FC): SdS silica gel (40–63 µm); EtOAc, hexane
as eluents. Thin-layer chromatography (TLC): Macherey–Nagel
SIL G-25 UV254, or Merck silica gel 60 F254 precoated TLC plates;
detection either with UV or by dipping in a solution of KMnO4
4754
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4752–4757

Formal Synthesis of (+)- and (–)-Ferruginine
and dried (MgSO4). Evaporation of the solvent afforded a yellow-
ish solid containing a 1:1 mixture of the two diastereoisomers,
which was purified by FC (hexane/EtOAc, 1:2) to remove impuri-
ties. Further FC (hexane/EtOAc, 1:1.7) allowed the separation of
the two diastereomeric sulfoxides (+)-(SS,1R,5S)-4 (Rf = 0.57; hex-
ane/EtOAc, 1:3; 2.46 g, 27%) and (–)-(SS,1S,5R)-4 (Rf = 0.48; hex-
ane/EtOAc, 1:3; 2.44 g, 27%).
(SS,1R,5S)-4 (920 mg, 2.65 mmol). Compound (+)-(1R,5S)-5
(870 mg, 90%) was obtained. White solid. M.p. 110–112 °C. [α]2D0
= +42.9 (CHCl3, c = 1.0). HRMS: calcd. for C19H25NO4 363.1504;
found 363.1509. Spectral data identical to those for (–)-(1S,5R)-5.
Part b. Synthesis of (+)-N-Boc-Norferruginine [(+)-8]
tert-Butyl (1S,5R)-2-Ethynyl-3-[(4-methylphenyl)sulfonyl]-8-azabi-
cyclo[3.2.1]octane-8-carboxylate [(1S,5R)-6]: nBuLi (4.6 mL,
6.4 mmol) was added at 0 °C to a solution of ethynyltrimethylsilane
(930 µL, 6.7 mmol) in THF (19 mL). The reaction mixture was
stirred for 30 min and was then added by cannula at 0 °C to a
solution of (–)-(1S,5R)-5 (780 mg, 2.14 mmol) in toluene (45 mL).
When the addition was finished, the bath was removed and the
reaction was allowed to proceed for 5 h at room temperature. A
saturated solution of NH4Cl and Et2O were added. The aqueous
phase was extracted with Et2O, and the combined organic layers
were washed with brine and dried (MgSO4). After the evaporation
of the solvent, the residue was dissolved in MeOH (11 mL), and
K2CO3 (300 mg, 2.17 mmol) was added. The reaction mixture was
stirred for 16 h, and H2O and Et2O were added. The aqueous phase
was extracted with Et2O, and the combined organic layers were
washed with brine and dried (MgSO4). Evaporation of the solvent
and purification by FC (cyclohexane/EtOAc, 2:1) afforded (1S,5R)-
6 (600 mg, 1.55 mmol, 73% yield). White solid. M.p. 148–150 °C.
1H NMR (400 MHz, [D6]DMSO, T = 343 K): δ = 7.83–7.79 (m, 2
H), 7.46–7.41 (m, 2 H), 4.40–4.35 (m, 1 H), 4.35–4.30 (m, 1 H),
3.58 (dt, J = 12.7, 4.8 Hz, 1 H), 2.84–2.80 (m, 1 H), 2.77–2.73 (m,
1 H), 2.43 (s, 3 H), 1.98 (td, J = 12.7, 2.8 Hz, 1 H), 1.86–1.65 (m,
3 H), 1.51–1.40 (m, 1 H), 1.40 (s, 9 H) ppm. 13C NMR (100 MHz,
[D6]DMSO, T = 343 K): δ = 151.6, 143.9, 134.9, 129.0, 128.4, 79.5,
78.1, 74.9, 57.1, 56.9, 51.2, 32.5, 27.8, 27.6, 26.7, 26.5, 20.5 ppm.
Compound (+)-(SS,1R,5S)-4: Rf = 0.57. White solid. M.p. 122–
124 °C. [α]2D0 = +127.6 (CHCl3, c = 1.1). 1H NMR (400 MHz, [D6]-
DMSO, T = 333 K): δ = 7.45–7.43 (m, 2 H), 7.36–7.35 (m, 2 H),
6.89–6.86 (dm, J = 5.2 Hz, 1 H), 2.40–2.33 (m + s, 1 + 3 H), 2.10–
2.00 (m, 1 H), 1.99–1.85 (m, 2 H), 1.63 (d, J = 17 Hz, 1 H), 1.41–
1.29, (m, 1 H), 1.32 (s, 9 H) ppm. 13C NMR (125 MHz, [D6]-
DMSO, T = 333 K): δ = 152.8, 141.1, 140.9, 139.4, 134.6, 129.5,
124.3, 78.7, 69.0, 53.2, 51.2, 33.2, 29.3, 29.2, 28.5, 27.6, 20.5 ppm.
IR (KBr): ν = 3048, 2973, 2915, 2841, 1697, 1594, 1379, 1325, 1176,
˜
1102, 1043, 1012, 807, 625, 527, 507, 436 cm–1. MS (EI): m/z (%)
= 347 (8), 291 (29), 274 (9), 246 (16), 230 (40), 208 (52), 202 (33),
152 (88), 140 (39), 124 (20), 123 (22), 108 (100), 106 (22), 92 (22),
91 (51), 81 (24), 79 (20), 57 (94), 41 (46). HRMS: calcd. for
C19H25NO3S 347.1555; found 347.1554.
Compound (–)-(SS,1S,5R)-4: Rf = 0.48. M.p. 114–115 °C. [α]2D0
=
–65.5 (CHCl3, c = 1.1). 1H NMR (400 MHz, [D6]DMSO, T =
343 K): δ = 7.42–7.40 (m, 2 H), 7.35–7.30 (m, 2 H), 6.96 (dt, J =
5.1, 1.7 Hz, 1 H), 4.51–4.40 (m, 1 H), 4.25–4.19 (m, 1 H), 2.36 (s,
3 H), 2.23 (dm, J = 17 Hz, 1 H), 2.16–2.05 (m, 1 H), 1.99–1.85 (m,
3 H), 1.49–1.37 (m, 1 H), 1.28 (s, 9 H) ppm. 13C NMR (125 MHz,
[D6]DMSO, T = 343 K): δ = 152.6, 141.4, 140.4, 139.2, 136.8,
129.2, 123.8, 78.5, 52.8, 51.3, 32.9, 28.4, 27.4, 27.3, 20.2 ppm. IR
(KBr): ν = 3047, 2971, 2927, 1686, 1591, 1415, 1365, 1326, 1172,
˜
1113, 1081, 1047, 1008, 890, 813, 624, 511 cm–1. MS (EI): m/z (%)
= 347 (6), 291 (16), 274 (6), 246 (12), 230 (24), 208 (34), 202 (19),
152 (80), 140 (21), 124 (9), 123 (9), 109 (90), 91 (19), 80 (17), 57
(100), 41 (14). HRMS: calcd. for C19H25NO3S 347.1555; found
347.1554.
IR (KBr): ν = 3272, 2985, 2932, 2874, 1684, 1421, 1318, 1288, 1147,
˜
1110, 1086, 875, 817, 679 cm–1. MS (EI): m/z (%) = 316 (40), 235
(7), 234 (40), 179 (20), 178 (72), 135 (27), 134 (84), 132 (19), 117
(15), 106 (17), 91 (50), 68 (23), 65 (12), 57 (100). C21H27NO4S
(389.17): calcd. C 64.75, H 6.99, N 3.60; found C 64.75, H 6.98, N
3.68.
tert-Butyl (–)-(1S,5R)-3-[(4-Methylphenyl)sulfonyl]bicyclo[3.2.1]oct-
2-ene-8-carboxylate [(–)-(1S,5R)-5]:[24] A buffered H2O solution
(20 mL, pH = 5) of Oxone® (1.98 g, 3.22 mmol) was added at 0 °C
to a solution of (SS,1S,5R)-4 (1.12 g, 3.22 mmol) in MeOH
(40 mL). The cooling bath was removed and the reaction mixture
was stirred for 3 h. H2O and CH2Cl2 were added to the reaction
mixture. The aqueous phase was extracted with CH2Cl2 and the
combined organic layers were washed with brine and dried
(MgSO4). FC (hexane/AcOEt, 2:1) afforded (–)-(1S,5R)-5 (1.09 g,
3.0 mmol, 93% yield). White solid. M.p. 113–114 °C. [α]2D0 = –51.9
tert-Butyl 2-Acetyl-3-(phenylsulfonyl)-8-azabicyclo[3.2.1]octane-8-
carboxylate [(+)-(1S,2S,3R,5R)-7]:[25]
A solution of (1S,5R)-6
(890 mg, 2.28 mmol), Hg(OAc)2 (220 mg, 0.68 mmol), and para-
toluenesulfonic acid (440 mg, 2.3 mmol) in THF (70 mL) was
heated under reflux for 1.5 h. After cooling to room temperature,
the solution was concentrated to 10 mL and filtered through a
short pad of silica gel (Et2O). After evaporation, the yellow residue
was dissolved in Et2O (5 mL) and (+)-(1S,2S,3R,5R)-7 (418 mg,
45%) was obtained by two successive crystallizations at 4 °C. White
1
(CHCl3, c = 1.0). H NMR (400 MHz, [D6]DMSO, T = 343 K): δ
1
solid. M.p. 142–143 °C. [α]2D0 = +78.0 (CHCl3, c = 1.00). H NMR
= 7.69–7.63 (m, 2 H), 7.46–7.40 (m, 2 H), 7.20 (dt, J = 5.3, 1.7 Hz,
1 H), 4.49 (t, J = 5.2 Hz, 1 H), 4.25 (dd, J = 7.2, 4.9 Hz, 1 H), 2.57
(dm, J = 17.2 Hz, 1 H), 2.41 (s, 3 H), 2.16–2.04 (m, 1 H), 1.99 (d,
J = 17.2 Hz, 1 H), 1.99–1.85 (m, 2 H), 1.48–1.38 (m, 1 H), 1.28 (s,
9 H) ppm. 13C NMR (125 MHz, [D6]DMSO, T = 343 K): δ =
152.8, 143.8, 141.6, 137.2, 135.5, 129.4, 127.0, 78.8, 52.6, 51.0, 32.6,
(400 MHz, [D6]DMSO, T = 343 K): δ = 7.69–7.64 (m, 2 H), 7.48–
7.43 (m, 2 H), 4.23 (dd, J = 6.8, 3.3 Hz, 1 H), 4.15–4.09 (m, 1 H),
4.03 (td, J = 11.6, 6.44Hz, 1 H), 3.25 (dd, J = 11.3, 3.24 Hz, 1 H),
2.42 (s, 3 H), 2.22 (s, 3 H), 1.92–1.54 (m, 6 H), 1.39 (s, 9 H) ppm.
13C NMR (100 MHz, [D6]DMSO, T = 343 K): δ = 203.9, 151.8,
144.3, 133.9, 129.4, 128.1, 79.1, 55.9, 53.3, 52.1, 48.9, 29.2, 28.5,
27.6, 26.3, 22.4, 20.5 ppm. NOE difference spectra (400 MHz, T =
343 K): δ = 3.29–3.22 (CHCOCH3) Ǟ 7.69–7.64 (3.41%), 4.26–
4.21 (8.93%), 4.08–3.99 (1.72%), 2.24–2.19 (6.19%), 1.90–1.79
(1.23%); 4.09–3.99 (CHSO2Ar) Ǟ 7.69–7.64 (3.78%), 3.31–3.23
(1.77%), 1.91–1.80 (0.57%), 1.80–1.71 (2.80%), 1.71–1.63 (3.13%),
31.0, 28.6, 27.4, 20.5 ppm. IR: ν = 3091, 3056, 3004, 2970, 2952,
˜
2877, 1932, 1698, 1627, 1595, 1463, 1393, 1371, 1354, 1325, 1312,
1165, 1147, 1106, 1093, 1028, 946, 817, 665, 611 cm–1. MS (EI):
m/z (%) = 363 (3), 308 (12), 307 (50), 263 (36), 247 (14), 234 (12),
199 (13), 198 (13), 139 (24), 108 (100), 91 (50), 80 (25), 79 (50), 57
(95), 52 (12), 41 (43). HRMS: calcd. for C19H25NO4 363.1504;
found 363.1507.
1.63–1.54 (2.10%). IR (KBr): ν = 2966, 2932, 2890, 1711, 1688,
˜
1595, 1457, 1388, 1368, 1331, 1314, 1302, 1172, 1130, 1106, 1083,
827, 820, 770, 743, 647 cm–1. MS (EI): m/z (%) = 407 (0.2), 389
(0.3), 253 (20), 252 (56), 195 (51), 180 (17), 153 (64), 152 (100), 139
(55), 136 (36), 135 (32), 122 (28), 108 (46), 91 (35), 68 (81), 57 (89).
tert-Butyl (+)-(1R,5S)-3-[(4-Methylphenyl)sulfonyl]bicyclo[3.2.1]oct-
2-ene-8-carboxylate [(+)-(1R,5S)-5]:[24] This compound was pro-
duced as described in the procedure for (–)-(1S,5R)-5 starting from
Eur. J. Org. Chem. 2007, 4752–4757
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4755

R. Piccardi, P. Renaud
FULL PAPER
HRMS (ESI-POS, [M + Na+], sample dissolved in MeOH/H2O/
Hfo, 74:25:1): calcd. for C21H29NNaO5S 430.1664; found 430.1669.
178 (92), 135 (59), 134 (100), 132 (51), 117 (51), 106 (46), 91 (90),
67 (54), 65 (54), 57 (90). C21H27NO4S (389.17): calcd. C 64.75, H
6.99, N 3.60; found: C 64.72, H 6.94, N 3.61.
tert-Butyl (+)-(1S,2R,3R,5R)-2-Acetyl-3-(phenylsulfonyl)-8-azabicy-
clo[3.2.1]octane-8-carboxylate [(+)-(1S,2R,3R,5R)-7]:[26–28] tBuLi
(1.1 mL, 1.5  in hexane) was added dropwise at –78 °C to a solu-
tion of ethyl vinyl ether (425 µL, 4.42 mmol) in THF (1.5 mL). The
reaction mixture turned yellow and it decolored at 0 °C. A solution
of (–)-(1S,5R)-5 (300 mg, 0.83 mmol) in THF (1.3 mL) was added
at –20 °C. After 4 h, a solution of NH4Cl was added and the mix-
ture was allowed to warm to room temperature. H2O and Et2O
were added, and the aqueous phase was separated and extracted
with Et2O. The combined organic layers were washed with brine
and dried (Mg2SO4). Evaporation of the solvent and FC (cyclohex-
ane/EtOAc, 7:3) afforded a colorless oil, which was dissolved in
MeOH (3.6 mL) and treated with HCl (0.5 ). After 10 min, a
white precipitate had formed and the reaction mixture was stirred
for an additional 20 min. H2O and EtOAc were added and the
aqueous phase was extracted twice with EtOAc. The combined or-
ganic layers were washed with brine and dried (MgSO4). Evapora-
tion of the solvent afforded (1S,2R,3R,5R)-7 (236 mg, 70% yield).
tert-Butyl (–)-(1R,2R,3S,5S)-2-Acetyl-3-(phenylsulfonyl)-8-azabicy-
clo[3.2.1]octane-8-carboxylate [(–)-(1R,2R,3S,5S)-7]:[25] This com-
pound was produced according to the procedure for the synthesis
of (+)-(1S,2S,3R,5R)-7 starting from (1R,5S)-6 (530 mg,
1.36 mmol); (–)-(1R,2R,3S,5S)-7 (244 mg, 44% yield) was ob-
tained. White solid. M.p. 141–142 °C. [α]2D0 = –74.2 (CHCl3, c =
1.01). Spectral data are identical to those for (+)-(1S,2S,3R,5R)-7.
HRMS (ESI-POS, [M + Na]+, sample dissolved in MeOH/H2O/
Hfo, 74:25:1): calcd. for C21H29NNaO5S 430.1664; found 430.1646.
tert-Butyl (–)-(1R,2S,3S,5S)-2-Acetyl-3-(phenylsulfonyl)-8-azabicy-
clo[3.2.1]octane-8-carboxylate [(–)-(1R,2S,3S,5S)-7]:[26–28] This
compound was produced according to the procedure for the syn-
thesis of (+)-(1S,2R,3R,5R)-7 starting from (+)-(1R,5S)-5 (325 mg,
0.89 mmol); (–)-(1R,2S,3S,5S)-7 (253 mg, 70% yield) was obtained.
White solid. M.p. 184–185 °C. [α]2D0 = –40.0 (c = 1.0, CHCl3). Spec-
tral data are identical to those for (+)-(1S,2R,3R,5R)-7. HRMS
(ESI-POS, [M + Na]+, sample dissolved in H2O/CH3CN, 1:1):
calcd. for C21H29NNaO5S 430.1664; found 430.1669.
White solid. M.p. 187–188 °C. [α]2D0 = +47.3 (c = 1.0, CHCl3). H
1
NMR (400 MHz, [D6]DMSO, T = 343 K): δ = 7.71–7.65 (m, 2 H),
7.46–7.39 (m, 2 H), 4.51 (d, J = 6.72 Hz, 1 H), 4.31–4.25 (m, 1 H),
3.59 (dt, J = 12.6, 5.26 Hz, 1 H), 3.23 (dd, J = 4.82, 1.77 Hz, 1 H),
2.43 (s, 3 H), 2.36 (td, J = 12.5, 2.57 Hz), 2.18 (s, 3 H), 2.05–1.89
(m, 1 H), 1.87–1.72 (m, 2 H), 1.66–1.58 (m, 1 H), 1.51–1.39 (m, 1
H), 1.34 (s, 9 H) ppm. 13C NMR (100 MHz, [D6]DMSO, T =
343 K): δ = 203.5, 150.8, 143.6, 136.6, 129.1, 127.8, 78.3, 59.4, 53.5,
(–)-(1R,5S)-N-Boc-Norferruginine [(–)-(1R,5S)-8]:[9] This com-
pound was produced according to the procedure for the synthesis
of (+)-(1S,5R)-8. Starting from (1R,2S,3S,5S)-7 (194 mg,
0.48 mmol) afforded (–)-(1R,5S)-8 (92 mg, 77% yield). White solid.
M.p. 63–64 °C (ref.[11] m.p. 63–64 °C). [α]2D0 = –125.2 (CHCl3, c =
1.0) {ref.[11] [α]2D4 = –126.8 (CHCl3, c = 1.0)}. Spectral data are in
agreement with literature data.[11]
51.3, 29.2, 27.6, 27.4, 26.5, 20.6 ppm. IR (KBr): ν = 2975, 2928,
˜
2984, 1709, 1685, 1410, 1174, 1105, 677 cm–1. MS (EI): m/z (%) =
334 (9), 252 (10), 195 (18), 152 (100), 139 (29), 108 (63), 91 (61),
68 (48), 57 (94), 43 (19), 41 (55). HRMS (ESI-POS, [M + Na]+,
sample dissolved in H2O/CH3CN, 1:1): calcd. for C21H29NNaO5S
430.1664; found: 430.1651.
Acknowledgments
We thank the Swiss National Science Foundation (Project 200020-
112250) and the State Secretariat for Education and Research (Pro-
ject C03.0047, COST D28) for funding.
(+)-(1S,5R)-N-Boc-Norferruginine [(+)-(1S,5R)-8]:[9] A mixture of
(+)-(1S,2R,3R,5R)-7 (205 mg, 0.50 mmol) and tBuOK (57 mg,
0.50 mmol) in THF (7 mL) was stirred under N2 for 1 h. The solu-
tion became yellow and a white salt precipitated. H2O and Et2O
were added, and the two phases were separated. The aqueous phase
was extracted with Et2O, and the combined organic layers were
washed with brine and dried (MgSO4). Evaporation of the solvent
gave a yellow oil that was purified by FC (cyclohexane/EtOAc, 7:3)
to afford (+)-(1S,5R)-8 (100 mg, 80% yield). White solid. M.p. 65–
66 °C (ref.[11] m.p. 64–65 °C). [α]2D0 = +113.7 (CHCl3, c = 1.0)
{ref.[11] [α]2D4 = +129.1 (CHCl3, c = 1.0)}. Spectral data were in
agreement with literature data.[11]
[1] H. M. Leow, I. R. C. Bick, J. W. Gillard, Aust. J. Chem. 1979,
32, 2523.
[2] I. R. C. Bick, J. W. Gillard, M. Woodruff, Chem. Ind. 1975,
794.
[3] K. L. Swanson, E. X. Albuquerque, in Handbook of Experi-
mental Pharmacology, Springer-Verlag, Berlin, Heidelberg,
1992, vol. 102, p. 620.
[4] W. S. Caldwell, H. M. L. Davies, P. M. Lippiello, Wake Forest
University, USA, R. J. Reynolds, Tobacco Co., USA, 1993, p.
6.
[5] S. Schwarz, T. Kampchen, M. C. Tilotta, D. Gundisch, G. Se-
itz, Pharmazie 2003, 58, 295.
Part c. Synthesis of (–)-N-Boc-Norferruginine [(–)-8]
[6] G. P. Pollini, S. Benetti, C. De Risi, V. Zanirato, Chem. Rev.
2006, 106, 2434.
tert-Butyl (1R,5S)-2-Ethynyl-3-[(4-methylphenyl)sulfonyl]-8-azabi-
cyclo[3.2.1]octane-8-carboxylate [(1R,5S)-6]: This compound was
produced by the procedure for the synthesis of (1S,5R)-6, starting
from (+)-(1R,5S)-5 (840 mg, 2.3 mmol); (1R,5S)-6 (650 mg, 7%)
was obtained. White solid. M.p. 148–149 °C. Spectral data are
[7] H. M. L. Davies, E. Saikali, W. B. Young, J. Org. Chem. 1991,
56, 5696.
[8] W. H. Ham, Y. H. Jung, K. Lee, C. Y. Oh, K. Y. Lee, Tetrahe-
dron Lett. 1997, 38, 3247.
[9] S. Y. Jonsson, C. M. G. Löfström, J.-E. Bäckvall, J. Org. Chem.
2000, 65, 8454.
[10] J. H. Rigby, F. C. Pigge, J. Org. Chem. 1995, 60, 7392.
[11] A. S. Hernandez, A. Thaler, J. Castells, H. Rapoport, J. Org.
Chem. 1996, 61, 314.
[12] I. Gauthier, J. Royer, H.-P. Husson, J. Org. Chem. 1997, 62,
6704.
[13] I. Gillaizeau-Gauthier, J. Royer, H.-P. Husson, Eur. J. Org.
Chem. 2002, 1484.
[14] T. Katoh, K. Kakiya, T. Nakai, S. Nakamura, K. Nishide, M.
Node, Tetrahedron: Asymmetry 2002, 13, 2351.
1
identical to those for (1S,5R)-6. H NMR (400 MHz, [D6]DMSO,
T = 343 K): δ = 7.83–7.79 (m, 2 H), 7.46–7.41 (m, 2 H), 4.40–4.35
(m, 1 H), 4.35–4.30 (m, 1 H), 3.58 (dt, J = 12.7, 4.8 Hz, 1 H), 2.84–
2.80 (m, 1 H), 2.77–2.73 (m, 1 H), 2.43 (s, 3 H), 1.98 (td, J = 12.7,
2.8 Hz, 1 H), 1.86–1.65 (m, 3 H), 1.51–1.40 (m, 1 H), 1.40 (s, 9 H)
ppm. 13C NMR (100 MHz, [D6]DMSO, T = 343 K): δ = 151.6,
143.9, 134.9, 129.0, 128.4, 79.5, 78.1, 74.9, 57.1, 56.9, 51.2, 32.5,
27.8, 27.6, 26.7, 26.5, 20.5 ppm. IR (KBr): ν = 3271, 2985, 2932,
˜
2874, 1681, 1419, 1317, 1288, 1146, 1109, 1086, 875, 817, 678 cm–1.
MS (EI): m/z (%) = 389 (2), 316 (10), 235 (20), 234 (75), 179 (43),
4756
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4752–4757

Formal Synthesis of (+)- and (–)-Ferruginine
[15] T. Wegge, S. Schwarz, G. Seitz, Pharmazie 2000, 55, 779.
[16] V. K. Aggarwal, C. J. Astle, M. Rogers-Evans, Org. Lett. 2004,
6, 1469.
[17] V. Berdini, M. C. Cesta, R. Curti, G. D’Anniballe, N. Di Bello,
G. Nano, L. Nicolini, A. Topai, M. Allegretti, Tetrahedron
2002, 58, 5669.
[18] A. P. Marchand, B. R. Aavula, S. G. Bott, Tetrahedron 1998,
54, 5105.
[19] T. Takeda, R. Sasaki, S. Yamauchi, T. Fujiwara, Tetrahedron
1997, 53, 557.
[20] K. K. Andersen, Tetrahedron Lett. 1962, 3, 93.
[21] G. Solladié, M. C. Carreno, in Organosulfur Chemistry: Syn-
thetic Aspects, vol. 1 (Ed.: P. Page), Academic Press, London,
1995, p. 1.
[22] S. M. Allin, in Organosulfur Chemistry: Synthetic and Stereo-
chemical Aspects, vol. 2 (Ed.: P. Page), Academic Press, Lon-
don, 1998, p. 41.
[23] S. D. Kahn, W. J. Hehre, J. Am. Chem. Soc. 1986, 108, 7399.
[24] B. M. Trost, D. P. Curran, Tetrahedron Lett. 1981, 22, 1287.
[25] B. Witulski, U. Bergstrasser, M. Gossmann, Tetrahedron 2000,
56, 4747.
[26] J. E. Baldwin, G. A. Höfle, O. W. Lever Jr, J. Am. Chem. Soc.
1974, 96, 7125.
[27] R. W. Friesen, J. Chem. Soc., Perkin Trans. 1 2001, 1969.
[28] G. Courtemanche, A. Alexakis, J. Vaissermann, J.-F. Normant,
J. Organomet. Chem. 1992, 423, 281.
Received: May 14, 2007
Published Online: July 25, 2007
Eur. J. Org. Chem. 2007, 4752–4757
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4757