BF3-induced rearrangement of aziridino cyclopropanes derived from 2-phenylsulfonyl 1,3-dienes. Application to the total synthesis of (±)-ferruginine

Article abstract of DOI:10.1021/jo001147b

Total synthesis of the alkaloid (±)-ferruginine (1) has been developed via the 2-phenylsulfonyl 1,3-diene approach. BF₃-induced rearrangement of the N-protected cyclohexane aziridino cyclopropane 8, derived from its corresponding epoxy cyclopropane, afforded the desired tropane alkaloid skeleton 9 in good yield. Michael addition of nitroethane (as an acyl anion equivalent) and transformation of the nitro group of the adduct 10 to a keto function gave 11. Elimination of benzenesulfinic acid and subsequent replacement of the tosyl group by a methyl group afforded the title compound 1.

Full text of DOI:10.1021/jo001147b

8454
J . Org. Chem. 2000, 65, 8454-8457
BF 3-In d u ced Rea r r a n gem en t of Azir id in o Cyclop r op a n es Der ived
fr om 2-P h en ylsu lfon yl 1,3-Dien es. Ap p lica tion to th e Tota l
Syn th esis of (()-F er r u gin in e
Sandra Y. J onsson,† Claes M. G. Lo¨fstro¨m,‡,§ and J an-E. Ba¨ckvall*,†
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University,
SE-106 91 Stockholm, Sweden, and Department of Organic Chemistry,
University of Uppsala, Box 531, SE-751 21 Uppsala, Sweden
jeb@organ.su.se
Received J uly 28, 2000
Total synthesis of the alkaloid (()-ferruginine (1) has been developed via the 2-phenylsulfonyl 1,3-
diene approach. BF3-induced rearrangement of the N-protected cyclohexane aziridino cyclopropane
8, derived from its corresponding epoxy cyclopropane, afforded the desired tropane alkaloid skeleton
9 in good yield. Michael addition of nitroethane (as an acyl anion equivalent) and transformation
of the nitro group of the adduct 10 to a keto function gave 11. Elimination of benzenesulfinic acid
and subsequent replacement of the tosyl group by a methyl group afforded the title compound 1.
In tr od u ction
some 3,4-epoxy-1,2-methylene-2-(phenylsulfonyl)cycloal-
kanes9 and their analogous 3,4-aziridines10 to bicylic
compounds. When the aziridine analogues are used, the
rearrangement leads to a tropane alkaloid skeleton. In
the present paper we have demonstrated the utility of
the latter rearrangement and applied it to the total
synthesis of the alkaloid (()-ferruginine (Figure 1).
Ferruginine is a potent neurotoxin and has been
isolated from the arboreal species Darlingiana ferru-
ginea11 and D. darlingiana.12 Ferruginine (1) was found
to be a good agonist for the nicotinic acetylcholine
receptor (nAChR),13 and its synthesis has attracted
considerable attention.14
Our retrosynthetic analysis (Scheme 1) denotes the
usefulness of 3 as starting material in the synthesis of
ferruginine. Sequential cyclopropanation-epoxidation9
would provide epoxy cyclopropane 6. Compound 6 could
subsequently be converted to the requisite syn aziridino
cyclopropane, which on derivatization would give access
to N-tosylamide 8. Formation of the tropane alkaloid ring
system (9) could be accomplished via a Lewis acid
catalyzed rearrangement, which would serve as a key
step in this synthesis. Michael addition of an acyl anion
The organic chemistry of sulfones has undergone
remarkable expansion over the last two decades, and a
number of synthetic transformations involving the sul-
fone functional group have been developed.1 A variety of
versatile sulfone-containing synthons are known today,
and among those, 2-arylsulfonyl 1,3-dienes have recently
attracted attention.1d,2-7 Such 2-sulfonyl 1,3-dienes are
useful Diels-Alder dienes,1d and furthermore, they can
be transformed into versatile synthetic intermediates via
regioselective functionalization at either double bond by
taking advantage of their different electron density.1d,2b,f
In our group we have previously developed regioselective
cyclopropanations2f and epoxidations.2b,8 Recently, we
reported on the Lewis acid catalyzed rearrangement of
† Stockholm University.
‡ University of Uppsala.
§ Present address: Dr. Claes Lo¨fstro¨m, Pharmacia & Upjohn, 112
87 Stockholm, Sweden.
(1) (a)Tanaka, K.; Kaji, A. In The Chemistry of Sulphones and
Sulphoxides; Rappoport, Z., Patai, S., Eds.; Wiley: New York, 1988; p
759. (b) Oae, S.; Uchida, Y. In The Chemistry of Sulphones and
Sulphoxides; Rappoport, Z., Patai, S., Eds.; Wiley: New York, 1988; p
583. (c) Simpkins, N. S. Sulphones in Organic Synthesis; Pergamon
Press: Oxford, 1993. (d) Ba¨ckvall, J . E.; Chinchilla, R.; Na´jera, C.; Yus,
M. Chem. Rev. 1998, 98, 2291.
(2) (a) Ba¨ckvall, J . E.; J untunen, S. K. J . Am. Chem. Soc. 1987, 109,
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Ba¨ckvall, J . E.; J untunen, S. K.; Andell, O. S. Org. Synth. 1989, 68,
148. (e) Ba¨ckvall, J . E.; Na´jera, C.; Yus, M. Tetrahedron Lett. 1988,
29, 1445. (f) Ba¨ckvall, J . E.; Lo¨fstro¨m, C. M. G.; J untunen, S K.;
Mattson, M. Tetrahedron Lett. 1993, 34, 2007.
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K; Ba¨ckvall, J . E. J . Org. Chem. 1995, 60, 3586.
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Hentemann, M.; Fuchs, P. L. Tetrahedron. Lett. 1997, 38, 5615.
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M. J . Org. Chem. 1993, 58, 5221.
(13) Swanson, K. L.; Albuquerque, E. X. Handbook of Exp. Phar-
macology, Vol. 102. Selective Neurotoxicity; Herken, H., Hucho, F., Eds.;
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10.1021/jo001147b CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/14/2000

Total Synthesis of (()-Ferruginine
J . Org. Chem., Vol. 65, No. 25, 2000 8455
Sch em e 2a
F igu r e 1. Ferruginine (1), isolated from D. ferruginea and
D. darlingiana.
Sch em e 1
a
Reagents: (a) HgCl2, NaSO2Ph, 97%; (b) Na2CO3, 2 M NaOH,
86%; (c) Me3SOI, NaH, 95%; (d) NBS, H2O, 98% crude yield; (e) 2
M NaOH, 75% from 4.
Sch em e 3a
a
equivalent and transformation of the nitro group of the
adduct to a keto function, followed by an elimination of
benzenesulfinic acid, would lead to the N-derivatized
intermediate. Subsequent N-deprotection of the nitrogen
and reductive methylation would provide ferruginine 1.
Reagents: (a) NaN3, NH4Cl; (b) PPh3; (c) TsCl, NEt3, 51% from
6; (d) BF3, 76%.
Sch em e 4a
Resu lts a n d Discu ssion
The requisite 2-(phenylsulfonyl)-1,3-cyclohexadiene 3
is readily available from 1,3-cyclohexadiene 2 in 83%
overall yield according to known procedures developed
in our laboratory.1d,2c-e Vinylcyclopropane 4 was synthe-
sized in 95% yield by performing a regioselective cyclo-
propanation of the electron-deficient double bond of 3
using a nucleophilic cyclopropanation reagent, according
to an earlier published procedure.2g,9 The remaining
olefinic double bond in 4 was then subjected to epoxida-
tion via the bromohydrin 5 to afford the anti epoxy
cyclopropane 6 in 75% yield from 4 with complete
stereoselectivity.9 Apparently, the phenylsulfonyl group
exerts a more powerful blocking effect toward the incom-
ing electrophilic reagent (NBS) than the cyclopropane
moiety. Direct epoxidation with m-CPBA gives exclu-
sively the epoxide syn to the cyclopropane.2f,9 The regio-
selectivity exhibited by these transformations appears to
stem from the electron-withdrawing nature of the sulfo-
nyl group, which is dictating the course of these reactions
by forcing the cyclopropanation to occur at the electron
deficient alkene of the diene system.
Anti epoxy cyclopropane 6 was converted to syn aziri-
dino cyclopropane 7 via ring opening with sodium azide15
and subsequent cyclization with triphenylphosphine.15b
Aziridine 7 was then easily derivatized into tosylamide
8 (Scheme 3).16 Compound 8 was isolated in 51% yield
from 6. The electron-deficient aziridine 8 was reacted
with BF3‚Et2O in dichloromethane/nitroethane 9:1 for 40
h at -78 °C, which resulted in rearrangement to the
tropane alkaloid skeleton 9.9,10 The long reaction time,
the low temperature, and the polar solvent system
strongly favored the formation of 9, and to our delight
we were able to isolate 9 in a yield of 76%. We have
previously suggested that the rearrangement reaction
a
Reagents: (a) EtNO2, DBU, 91%; (b) H2O2, K2CO3, 98%; (c)
t-BuOK, THF, 87%.
proceeds via a cyclopropyl carbinyl cation.9,10 It was found
that for the six-membered ring it is necessary to have a
syn relationship between the cyclopropane and aziridine10
(or epoxide9) functionalities. An anti relationship gave
no bicyclic compound in the Lewis acid-induced reaction
of the six-membered ring analogues.9,10
The transformation of a vinyl sulfone to an R,â-
unsaturated ketone via addition of an acyl anion equiva-
lent followed by elimination of phenylsulfinic acid has
previously been demonstrated in our group.17 A nitroal-
kane was employed as acyl anion equivalent in this
transformation. This methodology was employed to in-
troduce an acetyl group in the 2-position of 9. Michael-
type addition of nitroethane to the tropane alkaloid
skeleton 9 in the presence of 1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU) produced the nitrosulfone 10 as a 2:1
diastereomeric mixture in 91% yield (Scheme 4). It was
not possible to separate the isomers by column chroma-
tography, but this is not a problem since the stereogenic
centers causing the diastereomeric mixture are removed
later in the synthesis (vide infra). Attempts to use a
catalytic amount of DBU were unsuccessful. However,
in the presence of an equimolar amount of DBU the
reaction proceeded smoothly.
The Nef-type transformation of the nitrosulfone to the
ketone 11 was accomplished by using 30% aqueous H2O2
and potassium carbonate in a methanol solution, which
produced exclusively ketone 11 in 98% yield.17,18 Subse-
(15) (a) Saito, S.; Bunya, N; Inaba, M.; Morikawe, T.; Torii, S.
Tetrahedron Lett. 1985, 26, 5309. (b) Tanner, D.; Birgersson, C.; Gogoll,
A.; Luthman, K. Tetrahedron 1994, 50, 9797.
(16) Dure´ault, A.; Greck, C.; Depezay, J . C. Tetrahedron Lett, 1986,
27, 4157.
(17) Ba¨ckvall, J . E.; Ericsson, A. M.; Plobeck, N. A.; J untunen, S.
K. Tetrahedron Lett. 1992, 33, 131.
(18) Olah, G. A.; Arvanaghi, M.; Vankar, Y. D.; Prakash, G. K. S.
Synthesis 1980, 662.

8456 J . Org. Chem., Vol. 65, No. 25, 2000
J onsson et al.
Sch em e 5a
were performed at room temperature unless otherwise noted.
Tetrahydrofuran (THF) and diethyl ether (Et2O) were freshly
distilled from sodium benzophenone ketyl prior to use. Meth-
ylene chloride (CH2Cl2) was distilled from calcium hydride. In
the Mg-in-methanol reduction under ultrasonic conditions,
magnesium powder (Aldrich, -50 mesh 99+%), anhydrous
methanol (Aldrich, 99.8%), and a NEY 19H ULTRAsonic
ultrasonic bath were used. The sulfonyl diene 3 was synthe-
sized according to previously published procedures.2a,c-e
1,2-Meth ylen e-2-(ph en ylsu lfon yl)-3-cycloh exen e (3) was
prepared according to a previously reported procedure.9
c-3,4-Ep oxy-t-1,2-m eth ylen e-r -2-(p h en ylsu lfon yl)cyclo-
h exa n e (6), was synthesized according to a previously pub-
lished procedure.9
a
Reagents: (a) Me3SiOTf, BTSE, 63%; (b) Mg, MeOH, ultra-
sound; (c) CH2O, Na(CN)BH3, 75% from 13.
quent elimination of benzenesulfinic acid by treatment
of 11 with potassium tert-butoxide in tetrahydrofuran
(THF) proceeded smoothly to give 12 as the only product
in 87% yield.
t-3,4-NH-Azir idin o-t-1,2-m eth ylen e-r -2-(ph en ylsu lfon yl)-
cycloh exa n e (7). Compound 6 (2.05 g, 10.0 mmol) was
dissolved in 36 mL of 2-methoxyethanol and 4.5 mL of water.
Sodium azide (2.11 g, 10.0 mmol), ammonium chloride (720
mg, 14.2 mmol) was added, and the reaction mixture was
refluxed for 3 h. After cooling down the mixture, water (100
mL) was added, and the resulting mixture was extracted with
ether (4 × 50 mL). The combined organic phases were washed
with brine (2 × 30 mL) and dried (Na2SO4). After evaporation
of the solvent, 2.08 g of the crude azido alcohol remained. This
material was without further purification dissolved in benzene
(50 mL). Triphenylphosphine (2.28 g, 8.69 mmol) was added,
and the resulting solution heated at reflux for 4 h. After the
mixture had been cooled down the solvent was evaporated. The
oily residue was subjected to flash chromatography (EtOAc).
Removal of the solvent gave a residue of 2.85 g. However, this
material still contained ∼35 mol % of triphenylphosphine oxide
(determined by NMR). As a result, no thorough spectral
characterization of 7 was made and the material was used
without further purification for the next transformation. 1H
NMR (300 MHz, CDCl3): δ 7.97-7.87 (m, 2H, ArH), 7.70-
7.40 (m, containing PPh3O and ArH signals), 2.63 (br d, J )
5.5 Hz, 1H), 2.13 (br d, J ) 5.5 Hz, 1H), 1.88-1.56 (m, 5H),
1.52-1,37 (m, 1H), 1.11 (dd, J ) 5.6 Hz, 1H, cyclopropyl).
t-3,4-N-Tosyla zir id in o-t-1,2-m eth ylen e-r -2-(p h en ylsu l-
fon yl)cycloh exa n e (8). Compound 7 containing ∼35 mol %
triphenylphospine (1.38 g, ∼3.5 mmol) was dissolved in CH2-
Cl2 (25 mL). TsCl (1.53 g, 8.0 mmol) and Et3N (1 mL, 7.2 mmol)
were added, and the reaction mixture stirred at room tem-
perature for 18 h. The reaction mixture was washed with
saturated NaHCO3 (3 × 20 mL) and dried (Na2SO4). After
evaporation of the solvent the oily residue (2.86 g) was purified
by flash chromatography (gradient EtOAc/pentane 30:70 to 50:
50) giving 1.29 g of pure 8 as white crystals. The yield was
51% in three steps from 6. Mp: 171-172 °C (EtOAc/hexane).
1H NMR (400 MHz, CDCl3): δ 7.85-7.78 (m, 4H, ArH), 7.65-
7.60 (m, 1H, ArH), 7.56-7.49 (m, 2H, ArH), 7.31 (br d, J ) 8
Hz, 2H, ArH), 3.32 (dd, J ) 7.7, 1.4 Hz, 1H, H-3), 2.92 (br d,
J ) 7.4 Hz, 1H, H-4), 2.43 (s, 3H, MeAr), 2.05-2.00 (m, 1H),
1.94-1.80 (m, 2H), 1.76-1.61 (m, 2H), 1.55-1.43 (m, 1H), 1.10
(dd, J ) 6.9, 5.8 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 144.4,
138.2, 134.7, 133.4, 129.4, 129.0, 128.5, 128.0, 39.3, 38.9, 38.6,
21.7, 19.4, 17.7, 16.1, 15.3. IR (CDCl3): 3426, 2943, 1654, 1597,
1447, 1306, 1184, 1156, 1091, 983 cm-1. Anal. Calcd: C, 59.53;
H, 5.25; N, 3.47; Found: C, 59.68; H, 5.35; N, 3.54.
Attempts to detosylate 12 using sodium naphthalen-
ide19 proved to be unsuccessful. A milder method using
magnesium in dry methanol under ultrasonic conditions
was therefore tried.20 Using this cleaving agent, the
N-sulfonyl group was removed, but unfortunately the
presence of the enone function affected the selectivity and
thereby precluded this method on 12. We therefore
decided to protect the keto group of 12 (63%) using 1,2-
bis((trimethylsilyl)oxy)ethene (BTSE) in the presence of
trimethylsilyl trifluoromethanesulfonate (Me3SiOTf) as
catalyst-Noyori’s reagent (Scheme 5).21 This protocol
made it possible to remove the tosyl group employing the
magnesium-in-methanol method on 13 to afford the free
amine 14 (NMR analysis), not isolated but immediately
subjected to reductive methylation in the presence of
aqueous formaldehyde and sodium cyanoborohydride
(Na(CN)BH3).22 In the subsequent workup, including
acid-base extraction, the protecting group on the ketone
was cleaved off to give (()-ferruginine 1 in good yield
(75% from 13). Spectral data were in accordance with
those previously reported.14c,e
In conclusion, we have developed a new and efficient
synthesis of (()-ferruginine from 1,3-cyclohexadiene in
10% overall yield, via 2-(phenylsulfonyl)-1,3-cyclohexa-
diene 3 and involving a BF3-induced rearrangement of a
tosyl-protected aziridino cyclopropane. The rearrange-
ment of the aziridine cyclopropane constitutes a novel
route for constructing tropane alkaloids. This rearrange-
ment should allow easy access to a range of analogues.
Exp er im en ta l Section
Gen er a l Meth od s. 1H (400 or 300 MHz) and 13C (100 or
75 MHz) spectra were recorded on a Varian Mercury spec-
trometer. Chemical shifts (δ) are reported in ppm, using
residual solvent as internal standard, and coupling constants
(J ) are given in hertz. IR spectra were obtained using a Perkin-
Elmer 1600 FT-IR instrument, and the samples were exam-
ined as CDCl3 solutions on NaBr plates. Only the strongest/
structurally most important peaks (cm-1) are listed. Merck
silica gel 60 (240-400 mesh) was used for flash chromatog-
raphy, and analytical thin-layer chromatography was per-
formed on Merck precoated silica gel 60-F254 plates. Melting
points (mp) are uncorrected. Elemental analyses were per-
formed by Analytische Laboratorien, Lindlar, Germany. Un-
less otherwise noted, all material was otained from commercial
suppliers and used without further purification. All reactions
3-(P h en ylsu lfon yl)-8-[(4-m eth ylp h en yl)su lfon yl]-8-a za -
bicyclo[3.2.1]-2-octen e (9). Compound 8 (1.0 g, 2.48 mmol)
was dissolved in a mixture of 90% v/v CH2Cl2 and 10% v/v of
MeNO2 (44 mL). An argon atmosphere was established, and
the solution was cooled to -78 °C. BF3‚OEt2 (997 µL, 7.94
mmol) was introduced dropwise via a syringe. When the
addition was complete, the stirring continued at -78 °C for
40 h, and then the reaction mixture was allowed to rise to room
temperature over 5 h. Water (40 mL) was added, and the
phases separated. The aqueous phase was extracted with CH2-
Cl2 (3 × 50 mL), and the combined organic phases were dried
(MgSO4). Evaporation followed by flash chromatography using
pentane/Et2O (gradient 80:20 to 50:50) as eluent afforded 9
(0.76 g, 76%) as white crystals. Mp: 128.5-129.5 °C (EtOAc/
hexane). 1H NMR (400 MHz, CDCl3): δ 7.80-7.78 (m, 2H,
ArH), 7.69-7.62 (m, 3H, ArH), 7.56-7.52 (m, 2H, ArH), 7.32-
(19) Heathcock, C. H.; Blumenkopf, T. A.; Smith, K. M. J . Org.
Chem. 1989, 54, 1548.
(20) (a) Alonso, D. A.; Andersson, P. G. J . Org. Chem. 1998, 63, 9455.
(b) Lee, G. H.; Choi, E. B.; Lee, E.; Pak, C. S. Tetrahedron Lett. 1993,
34, 4541. (c) Na´jera, C.; Yus, M. Tetrahedron 1999, 55, 10547.
(21) Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron. Lett. 1980,
21, 1357.
(22) Borch, R. F.; Hassid, A. I. J . Org. Chem. 1972, 37, 1673.

Total Synthesis of (()-Ferruginine
J . Org. Chem., Vol. 65, No. 25, 2000 8457
7.28 (m, 2H, ArH), 7.13 (d, J ) 5.5 Hz, 1H, H-2), 4.57 (br t, J
) 5.9 Hz, 1H, H-1), 4.41 (m, 1H, H-5), 2.59 (br d, J ) 16.5 Hz,
1H, H-4), 2.42 (s, 3H, Me Ar), 2.18 (d, J ) 17.2 Hz, 1H, H-4′),
(m, 2H), 1.50-1.43 (m, 1H). 13C NMR (75 MHz, CDCl3): δ
195.5, 144.3, 143.3, 139.9, 139.3, 129.4, 127.3, 54.8, 54.0, 36.4,
35.4, 30.1, 24.9, 21.6. IR (CDCl3): 2954, 2923, 1664, 1447, 1340,
1246, 1160, 1095, 1056 cm-1. Anal. Calcd: C, 62.93; H, 6.27;
N, 4.59; Found: C, 62.78; H, 6.39; N, 4.54.
1.95-1.87 (m, 2H), 1.75-1.71 (m, 1H), 1.53-1.46 (m, 1H). 13
C
NMR (75 MHz, CDCl3): δ 143.9, 139.3, 138.1, 137.8, 136.5,
133.6, 129.7, 129.2, 127.9, 127.2, 55.4, 54.6, 34.5, 33.8, 29.5,
21.7. IR (CDCl3): 3172, 2978, 2955, 2919, 2872, 1596, 1449,
1343, 1314, 1308, 1161, 1091, 1149, 1020, 967, 949 cm-1. Anal.
Calcd: C, 59.53; H, 5.25; N, 3.47; Found: C, 59.51; H, 5.45;
N, 3.38.
2-(2-Meth yl-1,3-d ioxola n -2-yl)-8-[(4-m eth ylp h en yl)su l-
fon yl]-8-a za bicyclo[3.2.1]oct-2-en e (13). Me3SiOTf (5.0 µL,
0.03 mmol) was added into a reaction flask containing dry
dichloromethane (0.5 mL) under argon. The mixture was
cooled to -78 °C. 1,2-Bis((trimethylsilyl)oxy)ethane (115 µL,
0.56 mmol) was then added into the reaction flask, followed
by injection of 12 (85 mg, 0.28 mmol) in CH2Cl2 (1 mL). Stirring
continued at -78 °C for 5 h, then at room temperature for 14
h. The reaction was quenched by adding dry pyridine (6.0 µL,
0.07 mmol). The reaction mixture was poured into a saturated
NaHCO3 aqueous solution and extracted several times with
CH2Cl2. The combined organic layers were washed with
saturated NaCl aqueous solution and dried over a 1:1 mixture
of K2CO3 and Na2SO4. After the solution was concentrated,
the residue was purified by flash chromatography to give 61.7
mg (63%) of 13 as white crystals. Mp: 121-122 °C (EtOAc/
3-(P h en ylsu lfon yl)-8-[(4-m et h ylp h en yl)su lfon yl]-2-(1-
n itr oeth yl)-8-a za biyclo[3.2.1]octa n e (10). To a solution of
9 (0.88 g, 2.18 mmol) in nitroethane (22 mL) was added DBU
(326 µL, 2.18 mmol). The reaction mixture was stirred at room
temperature for 3.5 h. Ether and water were added to the
reaction mixture, and the layers were separated. The aqueous
phase was extracted three times with ether, and the combined
organic phases were washed with 2 M HCl, H2O (twice), and
brine. The resulting organic phase was dried over Na2SO4, and
the solvent was removed under reduced pressure. Purification
of the crude product by silica gel column chromatography using
pentane/EtOAc (gradient 8:1 to 8:3) gave 0.95 g (91%) of 10
as white crystals in a 2:1 diastereomeric mixture. Mp: 172-
174 °C (EtOAc/hexane). 1H NMR (300 MHz, CDCl3) for the
combined diastereoisomers: δ 7.85-7.76 (m, 2H, ArH), 7.72-
7.65 (m, 3H, ArH), 7.62-7.54 (m, 2H, ArH), 7.32-7.28 (m, 2H,
ArH), 4.92-4.83 (m, 1/3H), 4.83-4.73 (m, 2/3H), 4,28-4.09 (m,
2H), 3.32 (dt, J ) 9.9, 2.1 Hz, 1/3H), 3.18 (dt, J ) 9.3, 2.7 Hz,
2/3H), 3.08 (dm, J ) 6 Hz, 1/3H), 2.93 (dt, J ) 8.7, 2.4, 2/3H),
2.44 (s, 3H), 2.33-1.91 (m, 4H), 1.76 (d, J ) 6.6 Hz, 2H), 1.67-
1.53 (m, 1H), 1.48 (d, J ) 6.9 Hz, 1H), 1.41-1.33 (m, 1H). 13C
NMR (75 MHz, CDCl3) δ Dia ster eoisom er A (major): 144.4,
138.2, 136.0, 134.2, 130.0, 129.5, 128.4, 127.4 (A + B), 86.0,
57.7, 55.7, 55.2, 45.1, 30.3, 28.4, 27.1, 21.6 (A + B), 16.6.
Dia ster eoisom er B (minor): 144.3, 137.8, 136.1, 134.3, 129.9,
129.6, 128.8, 127.4 (A + B), 85.4, 57.6, 55.8, 55.1, 43.7, 30.7,
28.7, 27.5, 21.6 (A + B), 16.2. IR (CDCl3): 3064, 2955, 1596,
1
hexane). H NMR (300 MHz, CDCl3): δ 7.77-7.46 (2H, ArH),
7.26-7.24 (2H, ArH), 5.56 (t, J ) 2.9 Hz, 1H), 4.36 (d, J ) 5.5
Hz, 1H), 4.32 (t, J ) 7.7 Hz, 1H), 3.97-3.91 (m, 2H), 3.85-
3.79 (m, 2H), 2.63 (dt, J ) 15.4, 2.2, 1H), 2.41 (s, 3H), 1.95-
1.74 (m, 4H) 1.56-1.48 (m, 1H), 1.25 (s, 3H). 13C NMR (75
MHz, CDCl3): δ 143.2, 143.1, 137.6, 129.4, 127.4, 118.7, 107.8,
64.7, 64.5, 55.4, 54.9, 35.8, 35.2, 30.3, 24.3, 21.5. IR (CDCl3):
2983, 2954, 2919, 1597, 1339, 1160, 1094, 1039 cm-1
.
2-(2-Meth yl-1,3-d ioxola n -2-yl)-8-a za bicyclo[3.2.1]oct-2-
en e (14). To a suspension of Mg (23 mg, 0.94 mmol) in
anhydrous methanol (2 mL) was added a solution of 13 (62
mg, 0.18 mmol) in anhydrous methanol (2 mL). The resulting
suspension was sonicated for 40 min. The reaction was then
diluted with brine (5 mL) and extracted with dichloromethane
(3 × 5 mL). The combined organic layers were dried over Na2-
SO4 and concentrated in vacuo (83%). No thorough spectral
characterization of the free amine 14 was made, and the
material was used without further purification in the next
step. 1H NMR (300 MHz, CDCl3): 5.59 (t, J ) 2.7 Hz, 1H),
3.99-3.89 (m, 2H), 3.88-3.79 (m, 2H), 3.70 (t, J ) 3.3 Hz, 1H),
3.65 (br t, J ) 5.2 Hz, 1H), 2.48 (dm, 1H), 2.05-1.89 (m, 4H),
1.86 (dd, J ) 17.9, 3.8 Hz, 1H), 1.60-1.44 (m, 1H), 1.47 (s,
3H).13C NMR (75 MHz, CDCl3): δ 129.3, 127.4, 117.8, 108.4,
64.8, 64.5, 52.6, 36.2, 35.4, 30.6, 24.4.
8-Meth yl-2-(m eth ylca r bon yl)-8-a za bicyclo[3.2.1]oct-2-
en e (1). To a stirred solution of 14 (42 mg, 0.22 mmol) and 87
µL (1.17 mmol) of 37% aqueous formaldehyde in 700 µL
acetonitrile was added sodium cyanoborohydride (23.4 mg, 0.37
mmol). The reaction mixture was stirred for 15 min, and then
glacial acetic acid was added dropwise until the solution tested
neutral on wet pH paper. Stirring was continued for an
additional 45 min, glacial acetic acid being added occasionally
to maintain the pH near neutrality. The solvent was evapo-
rated at reduced pressure, and 1 mL of 2 N KOH was added
to the residue. The resulting mixture was extracted with ether
(3 × 5 mL). The combined ether extracts were washed with 5
mL of 0.5 N KOH and then extracted with three 5 mL portions
of 1 N HCl. The acid extracts were combined and neutralized
with solid KOH and then extracted with three 10 mL portions
of ether. The combined ether extracts were dried (K2CO3) and
evaporated in vacuo to afford 32 mg (90%) of (()-ferruginine
1. Spectral data were in accordance with those previously
reported.14c,e
1550, 1447, 1341, 1306, 1150, 1093, 1024, 948 cm-1
.
2-Acetyl-8-[(4-m eth ylp h en yl)su lfon yl]-3-(p h en ylsu lfo-
n yl)-8-a za bicyclo[3.2.1]octa n e (11). To a stirred solution of
10 (0.1 g, 0.21 mmol) in methanol (7 mL), cooled to 0 °C was
added 30% aqueous hydrogen peroxide (418 µL, 4.06 mmol),
followed by a solution of potassium carbonate (0.17 g, 1.21
mmol) in water (0.5 mL). Stirring continued for 23 h at room
temperature. The solution was then acidified with dilute
hydrochloric acid (7 mL) and extracted with CH2Cl2 (3 × 10
mL). The combined organic layers were dried over anhydrous
Na2SO4, and the solvent was removed under reduced pressure
to give almost pure carbonyl compound 11. The product was
further subjected to flash chromatography using pentane/Et2O
(gradient 8:1 to 8:3) to provide ketone 11 in 98% yield (92.1
mg). Mp: 202-203 °C (EtOAc/hexane). 1H NMR (300 MHz,
CDCl3): δ 7.85-7.81 (m, 2H), 7.70-7.62 (m, 3H), 7.58-7.52
(m, 2H), 7.30-7.27 (m, 2H), 4.72 (br d, 8.1 Hz, 1H), 4.21 (dt,
J ) 9.6, 2.7, 1H), 4.11 (br t, J ) 6.2 Hz, 1H), 3.36 (t, J ) 2.0
Hz, 1H), 2.42 (s, 3H), 2.30 (s, 3H), 2.24-1.87 (m, 5H), 1.68-
1.58 (m, 1H). 13C NMR (75 MHz, CDCl3): δ 203.3, 144.1, 138.4,
136.2, 133.9, 129.8, 129.4, 128.4, 127.6, 55.8, 55.3, 54.5, 53.7,
29.6, 29.0, 28.3, 27.4, 21.6. IR (CDCl3): 3427, 1642, 1447, 1340,
1304, 1169, 1148, 1093, 1034 cm-1
.
1-Acetyl-8-[(4-m eth ylph en yl)su lfon yl]-8-azabicyclo[3.2.1]-
oct-2-en e (12). Potassium tert-butoxide (42.4 mg, 0.38 mmol)
was added to a stirred solution of 11 (169 mg, 0.38 mmol) in
THF (4.8 mL) at room temperature. A precipitate formed
immediately, and stirring was continued for 55 min. Water (5
mL) was added, and the mixture was extracted with ether.
The organic phase was washed with water and brine, dried
(Na2SO4), and concentrated in vacuo. The crude product was
purified by flash chromatography using pentane/Et2O (gradi-
ent 8:2 to 1:1) to give 100 mg (87%) of 12 as white crystals.
Mp: 202-203 °C (EtOAc/hexane). 1H NMR (300 MHz,
CDCl3): δ 7.74-7.72 (m, 2H), 7.27-7.25 (m, 2H), 6.52 (t, J )
3.3 Hz, 1H), 4.90 (d, J ) 5.5 Hz, 1H), 4.42-4.40 (t, J ) 5.1
Hz, 1H), 2.88 (dm, J ) 19.4 Hz, 1H), 2.41 (s, 3H), 2.20 (s, 3H),
2.10 (dd, J ) 19.4, 4.4 Hz, 1H), 1.94-1.85 (m, 1H), 1.76-1.65
Ackn owledgm en t. Financial support from the Swed-
ish Natural Science Research Council and the Swedish
Research Council for Engineering Sciences is gratefully
acknowledged. The authors would like to thank Prof.
J . H Rigby for copies of the NMR spectra of ferruginine.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra for compounds 7, 10-11, 13-14. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O001147B