A novel approach to the enantioselective synthesis of Nuphar alkaloids: First total synthesis of (-)-(5S,8R,9S)-5(3-furyl)-8- methyloctahydroindolizidine and total synthesis of (-)-nupharamine

Full text of DOI:10.1021/jo9823240

3736
J . Org. Chem. 1999, 64, 3736-3740
Canadian beaver (Castor fiber L.).3 The structural for-
A Novel Ap p r oa ch to th e En a n tioselective
mula of 1 was determined exclusively by the fragmenta-
tion pattern displayed in the mass spectrum, as there
was insufficient material for further characterization.
Interestingly, indolizidine 1 belongs to the class of
5-substituted octahydroindolizines, compounds with
marked biological activity;4 in particular, 5-arylindoliz-
idines have been identified recently as new antinoci-
ceptive agents with analgesic activity.5 Three of the
possible stereoisomers of 1 have been synthesized in
racemic form,6 and to the best of our knowledge, no
asymmetric synthesis has been reported.
Syn th esis of Nu p h a r Alk a loid s: F ir st Tota l
Syn th esis of (-)-(5S,8R,9S)-5-
(3-F u r yl)-8-m eth ylocta h yd r oin d olizid in e
a n d Tota l Syn th esis of (-)-Nu p h a r a m in e
J ose´ Barluenga,* Fernando Aznar, Cristina Ribas, and
Carlos Valde´s
Instituto Universitario de Quı´mica Organometa´lica
“Enrique Moles” (Unidad asociada al CSIC),
Universidad de Oviedo, J ulia´n Claverı´a s/ n Oviedo,
33071 Asturias, Spain
On the other hand, in the recent years, we have been
interested in exploring the synthetic applications of chiral
2-amino-1,3-butadienes in asymmetric Diels-Alder cy-
cloadditions. We have previously shown that chiral
2-aminodiene 3 reacts with aromatic N-trimethylsilyla-
ldimines 4 in the presence of ZnCl2 to afford, after mild
hydrolysis of the [4 + 2] cycloadduct, 4-piperidones 5 with
high to very high enantiomeric excesses (Scheme 1).7
Piperidones 5 are versatile synthetic intermediates that
have been used as precursors of different types of
substituted pipecolic acids and that could be employed
as a starting point for the preparation of enantiomerically
pure piperidine alkaloids. In this paper, we wish to report
our initial efforts in this direction; a novel approach to
the enantioselective synthesis of nuphar alkaloids. Thus,
we describe herein the first enantioselective total syn-
thesis of nuphar indolizidine (-)-(5S,8R,9S)-1. Moreover,
the generality of our methodology is illustrated by the
total synthesis of (-)-nupharamine (2).8
Received November 24, 1998
In tr od u ction
The asymmetric synthesis of piperidine and indolizi-
dine alkaloids remains a field of great interest, as these
types of alkaloids display a very wide range of biological
activity and in many cases are scarcely available from
natural sources.1 In particular, sesquiterpenoid and
triterpenoid alkaloids incorporating piperidine, indolizi-
dine, and quinolizidine rings, isolated from aquatic plants
of the genus Nuphar, are known as nuphar alkaloids.
Representative members of this family are 5-(3-furyl)-8-
methyloctahydroindolizine (1) and (-)-nupharamine (2).
Resu lts a n d Discu ssion
For our study, we chose 4-piperidone 5a , which can be
obtained from the cycloaddition of 2-amino diene 3 with
N-trimethylsilyl-3-furaldimine with 51% yield and ee
>99% (HPLC). Piperidone 5a is a very convenient start-
ing material for the total synthesis of Nuphar alkaloids,
since it already incorporates the methyl and 3-furyl
substituents characteristic of nuphar alkaloids and a
hydroxymethyl group attached at C2 that can be elabo-
The structural motif common to nuphar alkaloids is the
presence of a trisubstituted piperidine ring with a methyl
group attached at C-3 and a 3-furyl substituent at C-6.
Some members of this family of alkaloids have shown
antibiotic and antifungal activity.2 Aquatic plants are not
the only source of nuphar alkaloids; for example, 5-(3-
furyl)-8-methyloctahydroindolizine (1) is a minor com-
pound (0.0002%) detected in castoreum, a perfume
extract derived from the dried scent glands of the
(3) Maurer, B.; Ohloff, G. Helv. Chim. Acta 1976, 59, 1169-1185.
(4) Daly, J . W.; Garrafo, H. M.; Spande, T. F. In The Alkaloids;
Cordell, G. A., Ed.; Academic Press: New York, 1993; Vol. 43, pp 185-
288.
(5) (a) Carson, J . R.; Carmosin, R. J .; Vaught, J . L.; Gardocki, J . F.;
Costanzo, M. J .; Raffa, R. B.; Almond, H. R., J r. J . Med. Chem. 1992,
35, 2855-2863. (b) Pearson, W. H.; Gallagher, B. M. Tetrahedron 1996,
12039-12048.
(6) For (()-(5S,8R,9S)-1, see: (a) LaLonde, R. T.; Muhammad, N.;
Wong, C. F.; Sturiale, E. R. J . Org. Chem. 1980, 45, 3664-3671. (b)
Tufariello, J . J .; Dyszlewski, A. D. J . Chem. Soc., Chem. Commun.
1987, 1138-1140. For (()-(5R,8R,9S)-1, see: (c) Ohnuma, T.; Tabe,
M.; Shiiya, K.; Ban, Y.; Date, T. Tetrahedron Lett. 1983, 24, 4249-
4252. (d) Kurihara, T.; Matsubara, Y.; Osaki, H.; Harusawa, S.;
Yoneda, R. Heterocycles 1990, 30, 885-896. (e) Clive, D. L. J .; Bergstra,
R. J . J . Org. Chem. 1991, 56, 4976-4977. For (()-(5R,8R,9R)-1, see:
ref 3c.
(7) (a) Barluenga, J .; Aznar, F.; Valde´s, C.; Mart´ın, A.; Garc´ıa-
Granda, S.; Mart´ın, E. J . Am. Chem. Soc. 1993, 115, 4403-4404. (b)
Barluenga, J .; Aznar, F.; Ribas, C.; Valde´s, C.; Ferna´ndez, M.; Cabal,
M. P.; Trujillo, J . Chem. Eur. J . 1996, 2, 805-811.
* To whom correspondence should be addressed. E-mail:
barluenga@sauron.quimica.uniovi.es.
(1) Some leading references regarding the enantioselective synthesis
of piperidine and indolizidine alkaloids: (a) Holmes, A. B.; Smith, L.
B.; Williams, S. F. J . Org. Chem. 1991, 56, 1393-1405. (b) Comins, D.
L.; Hong, H. J . Am. Chem. Soc., 1991, 113, 6672-6673. (c) Shishido,
Y.; Kibayashi, C. J . Chem. Soc., Chem. Commun. 1991, 1237-1239.
(d) Lin, N.-H.; Overman, L. E.; Rabinowitz, M. H.; Robinson, L. A.;
Sharp, M. J .; Zablocki, J . J . Am. Chem. Soc. 1996, 118, 9062-9072.
(e) Cheˆnevert, R.; Dickman, M. J . Org. Chem. 1996, 61, 3332-3341.
(f) Solladie´, G.; Chu, G.-H. Tetrahedron Lett. 1996, 37, 111-114. (g)
Cossy, J .; Cases, M.; Go´mez Pardo, D. Bull Soc. Chim. Fr. 1997, 134,
141-144. (h) Angle, S. R.; Henry, R. M. J . Org. Chem. 1997, 62, 8549-
8552. (i) Kadota, I.; Kawada, M.; Muramatsu, Y.; Yamamoto, Y.
Tetrahedron Lett. 1997, 38, 7469-7470. (j) Comins, D. L.; LaMunyon,
D. H.; Chen, X. J . Org. Chem. 1997, 62, 8182-8187. (k) Bailey, P. D.;
Millwood, P. A.; Smith, P. D. Chem. Commun. 1998, 633-640. (l)
Bardou, A.; Ce´le´rier, J .-P.; Llhommet, G. Tetrahedron Lett. 1998, 39,
5189-5192.
(8) Several asymmetric total syntheses of (-)-nupharamine have
been reported: (a) Shimizu, I.; Yamazaki, H. Chem. Lett. 1990, 777-
778. (b) Aoyagi, S.; Shishido, Y.; Kibayashi, C. Tetrahedron Lett. 1991,
32, 4325-4328. (c) Honda, T.; Ishikawa, F.; Yamane, S. J . Chem. Soc.,
Chem. Commun. 1994, 499-500.
(2) (a) Wro´bel, J . T. In The Alkaloids; Manske, R. H. F., Ed.;
Academic Press: New York, 1967; Vol. 9, pp 441-465. (b) Cybulski,
J .; Wro´bel, J . T. In The Alkaloids; Brossi, A. Ed.; Academic Press: New
York, 1989; Vol. 35, pp 215-257.
10.1021/jo9823240 CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/28/1999

Notes
J . Org. Chem., Vol. 64, No. 10, 1999 3737
Sch em e 1
Sch em e 2
(c 1.3, CH2Cl2). Synthetic (-)-1 showed an MS spectrum
identical to the natural material3 and IR and 13C NMR
spectra identical to those of previously reported synthetic
(()-1.6a
Chiral piperidine 8 can be regarded as a key inter-
mediate in the total synthesis of other nuphar alkaloids.
The synthetic sequence developed to elaborate the C2
side chain of (-)-nupharamine is summarized in Scheme
3. First, N-Cbz-protected hydroxymethylpiperidine 12
was obtained from 8 in 59% yield after a three-step
sequence that involves protection of the hydroxy group
as a TBDMS ether, formation of the carbamate by
treatment with benzyl chloroformate, and deprotection
of the silyl ether in acidic media. Then, the same one-
pot procedure of Swern oxidation followed by Wittig
olefination described above, led to protected conjugated
ester 13 with excellent yield. Careful hydrogenation of
the double bond of 13 (H2 (1 atm), Pd/C, EtOH, rt, 3.5 h)
gave ester 14,12 which was then treated with an excess
of MeLi to give tertiary alcohol 15. Finally, (-)-n-
upharamine 2 was obtained after deprotection of the
benzyl carbamate. Spectroscopic data (IR, MS, and 13C
NMR) and optical rotation of synthetic (-)-nupharamine
2 were in accordance with those previously reported.8
In summary, we have described a new approach to the
enantioselective synthesis of nuphar alkaloids, exempli-
fied by the first enantioselective synthesis of (-)-
(5S,8R,9S)-5-(3-furyl)-8-methyloctahydroindolizine alka-
loid and the total synthesis of (-)-nupharamine. Our
approach demonstrates that 4-piperidones derived from
chiral 2-aminodienes are useful precursors of piperidine
alkaloids. It is worth pointing out that the enantiomers
of these alkaloids are equally approachable in optically
pure form by this synthetic approach by employing the
chiral 2-aminodiene derived from (R)-2-methoxymeth-
ylpyrrolidine. Additionally, derivatives with other aro-
matic rings instead of the 3-furyl group would also be
accessible, and furthermore, the keto group of the start-
ing 4-piperidone will allow for the synthesis 4-substituted
derivatives.
rated to build each particular compound. Moreover, 5a
features the same absolute and relative stereochemistry
of the substituents on the piperidine ring as most of the
alkaloids of this family (Scheme 1). Therefore, the
transformation of 4-piperidone 5a into nuphar alkaloids
would require two synthetic operations: the transforma-
tion of the chain at C2 and the deoxygenation of the
ketone functionality.
We decided to carry out the deoxygenation step first,
to avoid undesired side reactions due to the ketone, such
as epimerization of the C3 atom during the synthesis.
First, both the amino and hydroxy functionalities were
simultaneously protected as the bicyclic carbamate 69
(Scheme 2) by treatment of 4-piperidone 5a with tri-
phosgene in the presence of NEt3. The deoxygenation was
then achieved in one step by NaBH3CN reduction of the
in situ generated tosylhydrazone of 6 to obtain compound
7 with a poor 33% yield.10 Nevertheless, better results
were obtained in a two-step procedure by formation of
an enoltriflate followed by catalytic hydrogenation in the
presence of PtO2,11 which afforded bicyclic carbamate 7
in 85% yield (based on 70% conversion of 6). At this point,
hydrolysis of the carbamate moiety of compound 7
employing anhydrous t-BuOK in THF afforded the de-
sired piperidine 8.
The indolizidine structure was built as depicted in
Scheme 3; a one-pot process of Swern oxidation followed
by a Wittig olefination reaction over compound 8 led to
conjugated ester 9. Catalytic hydrogenation of the double
bond in the presence of Pd/C gave aminoester 10, which
was cyclized to indolizidone 11 in refluxing toluene.
Finally, reduction of the lactam with excess of LiAlH4
Exp er im en ta l Section
Gen er a l Meth od s. The same experimental techniques were
used as reported previously; see ref 5b. Compounds 4a and 6
were prepared as described in refs 5b and 7, respectively.
Syn th esis of (-)-(2S,5R,6R)-2-(3-F u r yl)-5-m eth yl-1-a za -
8-oxa b icyclo[4,3,0]n on a n -9-on e (7). (a ) Th e H yd r a zon e
Meth od . To a solution of carbamate 6 (3.40 mmol, 800 mg) in
DMF (8.5 mL) were successively added sulfolane (8.5 mL),
p-toluensulfonylhydrazide (3.97 mmol, 740 mg), and p-toluen-
led to nuphar alkaloid (-)-(5S,8R,9S)-1, [R]20 ) -99.0
D
(9) Barluenga, J .; Aznar, F.; Valde´s, C.; Ribas, C. J . Org. Chem.
1998, 63, 3918-3924.
(10) Hutchins, R. O.; Milewski, C. A.; Maryanoff, B. E. J . Am. Chem.
Soc. 1973, 95, 3662-3668.
(11) (a) Comins, D. L.; LaMunyon, D. H.; Chen, X. J . Org. Chem.
1997, 62, 8182-8187. (b) J igajinni, V. B.; Wightman, R. H. Tetrahedron
Lett. 1982, 23, 117-120.
(12) Longer reaction times and/or larger quantities of Pd/C led to
deprotection of the Cbz group and, ultimately, to the reduction of the
furan ring.

3738 J . Org. Chem., Vol. 64, No. 10, 1999
Notes
Sch em e 3
sulfonic acid (0.45 mmol, 86 mg). The resulting solution was
heated at 110 °C, and NaBH4 was added in three portions at 1
h intervals. Then, 1 h after the last addition, the reaction
mixture was cooled, and H2O (10 mL) was carefully added,
followed by EtOAc (10 mL). The aqueous layer was extracted
with EtOAc, and the combined organic layers were washed with
brine, dried over anhydrous Na2SO4, and evaporated under
vacuum. Sulfolane and DMF were eliminated by Kugelro¨hr
distillation (0.01 mmHg, 90 °C, 6 h). Column chromatography
(SiO2, hexane/EtOAc 2:1) of the residue afforded bicyclic com-
pound 7 (33% yield, 248 mg).
CH2Cl2); 1H NMR (200 MHz, CDCl3) δ 7.40-7.39 (m; 2H), 6.44-
6.43 (m; 1H), 4.38 (dd, J ) 8.6, 7.6 Hz; 1H), 4.12 (dd, J ) 10.9,
3.6 Hz; 1H), 3.87 (t, J ) 8.6 Hz; 1H), 3.26 (td, J ) 9.2, 7.6 Hz;
1H), 1.98-1.47 (m; 4H), 1.35-1.14 (m; 1H), 0.94 (d, J ) 6.4 Hz;
3H) ppm; 13C NMR (75 MHz, CDCl3) δ 156.1, 142.3, 139.2, 123.8,
109.6, 66.2, 62.4, 50.1, 34.5, 33.2, 31.6, 16.6 ppm. Anal. Calcd
for C12H15NO3 (221.26): C, 65.14; H, 6.83; N, 6.33. Found: C,
64.76; H, 6.69; N, 6.22.
Dep r otection of th e Bicyclic Ca r ba m a te. Syn th esis of
(-)-(2R,3R,6S)-6-(3-F u r yl)-2-h yd r oxym eth yl-3-m eth ylp ip -
er id in e (8). To a solution of carbamate 7 (1.10 mmol, 240 mg)
in dry THF (15 mL) cooled at 0 °C was added t-BuOK (4.40
mmol, 495 mg). After 30 min of stirring at this temperature,
the reaction mixture was poured over an aqueous HCl solution
(1 N, 5 mL), and the resulting mixture was made basic by
addition of Na2CO3. The organics were extracted with EtOAc (5
× 10 mL), and the combined organic layers were washed with
brine, dried over anhydrous Na2SO4, and evaporated under
vacuum. Flash column chromatography (Al2O3) of the residue
afforded piperidine 8 (95% yield, 205 mg): colorless oil; Rf )
0.33 (Al2O3, EtOAc); [R]20D ) -22.9 (c 0.5, CH2Cl2); 1H NMR (200
MHz, CDCl3) δ 7.38-7.37 (m; 2H), 6.43-6.41 (m; 1H), 3.79 (dd,
J ) 11.0, 3.1 Hz; 1H), 3.64 (dd, J ) 10.7, 2.6 Hz; 1H), 3.51 (dd,
J ) 11.0, 7.6 Hz; 1H), 2.47 (ddd, J ) 9.5, 7.6, 3.1 Hz; 1H), 1.93-
1.79 (m; 2H), 1.61-1.13 (m; 3H), 0.91 (d, J ) 6.1 Hz; 3H) ppm;
13C NMR (50 MHz, CDCl3) δ 142.6, 138.5, 128.4, 108.9, 63.8,
(b) Th e En oltr ifla te Meth od . To a solution of ketone 6 (200
mg, 0.82 mmol) in 15 mL of dry THF, under nitrogen atmosphere
and cooled to -80 °C, was added dropwise 1 mL (1 mmol) of 1
M solution lithium hexamethyldisilylamide in THF. After the
reaction was stirred for 90 min at -80 °C, a solution of 500 mg
(1.4 mmol) of freshly prepared N-(2-pyridyl)triflimide13 in 2 mL
of THF was added, and the stirring was continued at -80 °C
for 90 min. The cold bath was removed, and the reaction was
quenched with 2 mL of H2O. The reaction mixture was diluted
with 40 mL of Et2O, dried over Na2SO4, and concentrated in
vacuo. The reaction crude contained a mixture of the enoltriflate
and the starting material 6, which were separated by column
chromatography (SiO2, hexane/EtOAc 3:1-1:1). The first fraction
(Rf ) 0.34, SiO2, hexane/EtOAc 1:1) consisted in the desired
enoltriflate (202 mg, 0.55 mmol), and the second fraction (Rf )
0.24, SiO2, hexane/EtOAc 1:1) afforded the unreacted ketone
(0.24 mmol, 60 mg): yield 96% (based on 70% conversion of 6);
1H NMR (300 MHz, CDCl3) δ 7.55 (m; 1H), 7.41 (m; 1H), 6.42-
6.40 (m; 1H), 5.79 (m; 1H), 5.16 (m; 1H), 4.51 (dd, J ) 8.2, 7.4
Hz; 1H), 3.99 (dd, J ) 10.6, 8.2 Hz; 1H), 3.77 (ddd, J ) 10.6,
9.0, 7.4 Hz; 1H), 2.96-2.80 (m; 1H), 1.20 (d, J ) 7.1 Hz; 3H)
ppm; 13C NMR (75 MHz, CDCl3) δ 156.0, 148.0, 142.2, 141.2,
121.5, 120.1, 109.1, 66.6, 59.9, 47.1, 37.5, 11.9 ppm. The
enoltriflate was hydrogenated according with the following
procedure: A flask containing the enoltriflate (90 mg, 0.24 mmol)
and 6.8 mg of PtO2 was capped with a rubber septum, evacuated
with a needle, and filled with hydrogen with a balloon. Then, 8
mL of EtOH was added to the flask with a syringe, and the
mixture was stirred at room temperature. The reaction was
monitored by TLC (SiO2, hexane/EtOAc/methylene chloride
1:1:1), and the septum was removed when the spot of the starting
material disappeared (Rf ) 0.37), typically 6-8 h (longer reaction
times will result in hydrogenation of the furan ring). The
reaction was diluted with diethyl ether, filtered through Celite,
and concentrated under reduced pressure to obtain a pale yellow
oil. The crude was purified by flash chromatography (SiO2,
hexane/EtOAc 2:1), affording 47 mg of carbamate 7 (yield 89%).
Overall yield of the two steps (based on 70% conversion of 6)
63.1, 52.5, 33.7, 32.8, 32.2, 17.8 ppm; HRMS (EI) calcd for C11H16
-
NO2 (M+ - H) 194.1181, found 194.1183.
(-)-(2R,3R,6S)-(E)-2-(2-Eth oxyca r bon yl-1-eth en yl)-6-(3-
fu r yl)-3-m eth ylp ip er id in e (9). Dry DMSO (1.31 mmol, 93 mL)
was added dropwise to a cooled (-65 °C) solution of (COCl)2 (0.66
mmol, 58 mL) in dry CH2Cl2 (10 mL), and stirring was continued
at this temperature for 20 min. Then, a solution of alcohol 8
(0.50 mmol, 98 mg) in dry CH2Cl2 (7 mL) was added dropwise,
and the reaction mixture was stirred at -65 °C for 90 min.
Thereafter, NEt3 (1.97 mmol, 275 mL) was added and the
temperature was permitted to reach -15 °C during 90 min.
Afterward, Ph3PdCHCO2Et (0.75 mmol, 260 mg) was added in
one portion, and the reaction mixture was warmed to room
temperature over 90 additional min. The reaction mixture was
poured over brine (10 mL), and the aqueous layer was extracted
with CH2Cl2; the combined organic layers were dried over
anhydrous Na2SO4 and evaporated under vacuum. Column
chromatography (SiO2) of the residue afforded conjugated ester
9 (44% yield, 58 mg): yellow oil; Rf ) 0.57 (SiO2, CH2Cl2/EtOAc
2:1); [R]18 ) -31.0 (c 0.9, CH2Cl2); 1H NMR (200 MHz, CDCl3)
D
δ 7.38-7.35 (m; 2H); 6.95 (dd, J ) 15.7, 7.9 Hz; 1H), 6.41-6.39
(m; 1H), 5.98 (dd, J ) 15.7, 0.9 Hz; 1H), 4.24-4.13 (m; 1H), 4.19
(q, J ) 7.0 Hz; 2H), 3.67 (dd, J ) 11.0, 2.8 Hz; 1H), 2.99 (ddd,
J ) 9.1, 7.9, 0.9 Hz; 1H), 1.94-1.18 (m; 4H), 1.28 (t, J ) 7.0 Hz;
3H), 0.88 (d, J ) 6.4 Hz; 3H) ppm; 13C NMR (50 MHz, CDCl3) δ
166.3, 149.3, 142.8, 138.4, 128.8, 122.1, 108.9, 65.2, 60.3, 52.6,
35.4, 33.6, 33.3, 18.5, 14.1 ppm.
85%: Rf ) 0.27 (SiO2, hexane/EtOAc 1:1); [R]20 ) -69.3 (c 1.4,
D
(13) Comins, D. L.; Dehghani, A.; Foti, C. J .; J oseph, S. P. Org.
Synth. 1996, 74, 77-81.

Notes
(-)-(2S,3R,6S)-2-(2-E t h oxyca r b on ylet h yl)-6-(3-fu r yl)-3-
J . Org. Chem., Vol. 64, No. 10, 1999 3739
separated. The aqueous layer was extracted with EtOAc, and
the combined organic layers were washed with brine, dried over
anhydrous Na2SO4, and evaporated under vacuum. Column
chromatography (SiO2) of the residue afforded (-)-(2R,3R,6S)-
N-benzyloxycarbonyl-2-(tert-butyldimethylsilyloxymethyl)-6-(3-
furyl)-3-methylpiperidine (310 mg, 99% yield) as a colorless oil:
m eth ylp ip er id in e (10). A suspension of conjugated ester 9
(0.19 mmol, 50 mg), EtOH (8 mL), and Pd/C (50 mg) was
degassed through a freezing-vacuum-melting sequence (three
turnovers); the flask was finally filled with H2 with the aid of a
balloon (1 atm), and a vigorous stirring was kept for 6 h at room
temperature. Then, the reaction mixture was filtered through
a Celite pad, the retained solid was washed with EtOH (3 × 3
mL), and the organic solvent was eliminated under vacuum.
Flash column chromatography (SiO2) of the residue afforded
ester 10 (91% yield, 46 mg): colorless oil; Rf ) 0.40 (SiO2, CH2-
Rf ) 0.45 (SiO2, hexane/Et2O 4:1); [R]20 ) -66.6 (c 2.2, CH2-
D
Cl2); 1H NMR (200 MHz, CDCl3) δ 7.44-7.25 (m; 7H), 6.26 (s;
1H), 5.36-5.30 (m; 1H), 5.27 (d, J ) 12.5 Hz; 1H), 5.19 (d, J )
12.5 Hz; 1H), 4.11-4.00 (m; 1H), 3.83-3.19 (m; 2H), 2.22-1.79
(m; 4H), 1.40-1.25 (m; 1H), 1.11 (d, J ) 7.0 Hz; 3H), 0.83 (s;
9H), -0.06 (s; 6H) ppm. The O,N-diprotected piperidine obtained
was then dissolved in THF (15 mL), and aqueous HCl (3N, 10
mL) was added. After 30 min of stirring, H2O (10 mL) and EtOAc
(10 mL) were added; the aqueous layer was extracted with
EtOAc, and the combined organic layers were washed with brine,
dried over anhydrous Na2SO4, and evaporated under vacuum.
Column chromatography (SiO2) of the residue afforded hydroxy-
piperidine 12 (88% yield, 203 mg): colorless oil; Rf ) 0.23 (SiO2,
hexane/EtOAc 2:1); [R]22D ) -75.6 (c 0.8, CH2Cl2); 1H NMR (200
MHz, CDCl3) δ 7.46-7.28 (m; 7H), 6.33 (s; 1H), 5.41-5.32 (m;
1H), 5.27 (d, J ) 12.2 Hz; 1H), 5.18 (d, J ) 12.2 Hz; 1H), 4.22-
4.10 (m; 1H), 3.42 (dd, J ) 11.3, 7.3 Hz; 1H), 3.36 (dd, J ) 11.3,
7.9 Hz; 1H), 2.20-1.78 (m; 4H), 1.43-1.23 (m; 1H), 1.12 (d, J )
7.0 Hz; 3H), ppm; 13C NMR (75 MHz, CDCl3) δ 157.5, 143.2,
138.7, 136.5, 128.4, 127.9, 127.7, 127.6, 109.7, 67.4, 64.2, 58.8,
45.8, 27.2, 22.2, 22.1, 18.9 ppm. Anal. Calcd for C19H23NO4
(329.40): C, 69.28; H, 7.04; N, 4.25. Found: C, 69.04; H, 7.03;
N, 4.25.
Cl2/EtOAc 1:1); [R]23 ) -39.3 (c 1.8, CH2Cl2); 1H NMR (300
D
MHz, CDCl3) δ 7.35-7.33 (m; 2H), 6.39 (s; 1H), 4.12 (q, J ) 7.3
Hz; 2H), 3.58 (dd, J ) 11.2, 2.2 Hz; 1H), 2.43 (dd, J ) 8.8, 6.7
Hz; 1H), 2.42 (t, J ) 7.7 Hz; 1H), 2.31 (td, J ) 8.4, 3.0 Hz; 1H),
2.07-1.95 (m; 1H), 1.88-1.77 (m; 2H), 1.69-1.62 (m; 4H), 1.25
(t, J ) 7.3 Hz; 3H), 0.90 (d, J ) 6.0 Hz; 3H) ppm; 13C NMR (50
MHz, CDCl3) δ 174.1, 142.7, 138.3, 129.4, 109.1, 62.3, 60.2, 53.2,
35.4, 34.1, 33.8, 30.5, 28.5, 18.3, 14.2 ppm.
(-)-(2S,5R,6S)-2-(3-F u r yl)-5-m eth yl-1-a za bicyclo[4.3.0]-
n on a n -9-on e (11). A solution of amino ester 10 (0.15 mmol, 42
mg) in dry toluene (6 mL) was refluxed for 48 h. Then, the
reaction mixture was allowed to cool to room temperature, and
the solvent was evaporated under vacuum. The resulting yellow
oil was purified by column chromatography (SiO2) to afford
lactam 11 (78% yield, 28 mg): colorless oil; Rf ) 0.40 (SiO2, CH2-
Cl2/EtOAc 3:1); [R]20 ) -74.4 (c 1.0, CH2Cl2); 1H NMR (200
D
MHz, CDCl3) δ 7.36-7.33 (m; 1H), 7.33 (s; 1H), 6.38-6.37 (m;
1H), 4.41 (dd, J ) 7.6, 4.0 Hz; 1H), 3.12 (td, J ) 10.1, 6.1 Hz;
1H), 2.39-2.14 (m; 3H), 1.95-1.16 (m; 6H), 0.96 (d, J ) 6.4 Hz;
3H) ppm; 13C NMR (50 MHz, CDCl3) δ 175.0, 142.6, 138.7, 126.2,
109.8, 63.4, 49.0, 36.4, 31.4, 31.2, 29.9, 25.1, 17.5 ppm; HRMS
(CI) calcd for C13H18NO2 (M + H) 220.1338, found 220.1330.
(-)-(5S,8R,9S)-5-(3-F u r yl)-8-m et h yloct a h yd r oin d oliz-
in e [(5S,8R,9S)-1]. To a solution of lactam 11 (0.13 mmol, 28
mg) in dry THF (8 mL) cooled to 0 °C was added LiAlH4 (0.52
mmol, 20 mg), and the reaction mixture was then refluxed for
2.5 h. The reaction was allowed to cool to room temperature,
and an aqueous saturated solution of Na2SO4 was added
dropwise until the reaction mixture became clear, with a solid
stuck to the walls of the flask. The liquid was decanted, the solid
was washed with THF (5 × 2 mL), and the resulting organic
solution was concentrated under vacuum. Flash column chro-
matography (Al2O3) of the residue afforded indolizidine
(5S,8R,9S)-1 (71% yield, 19 mg): colorless oil; Rf ) 0.48 (Al2O3,
hexane/EtOAc 10:1); [R]20D ) -99.0 (c 1.3, CH2Cl2); 1H NMR (400
MHz, CDCl3) δ 7.33-7.26 (m; 2H), 6.44 (s; 1H), 2.91 (dd, J )
8.4, 5.7 Hz; 1H), 2.88 (td, J ) 8.8, 2.2 Hz; 1H), 1.98-1.87 (m;
2H), 1.82-1.39 (m; 8H), 1.13-1.02 (m; 1H), 0.90 (d, J ) 6.6 Hz;
3H) ppm; 13C NMR (50 MHz, CDCl3) δ 142.6, 139.3, 128.0, 109.6,
71.4, 59.7, 53.1, 36.2, 34.0, 33.8, 28.9, 20.0, 18.8 ppm; MS (EI)
m/z 205 (79), 190 (24), 176 (11), 162 (16) 136 (51), 94 (100);
HRMS (EI) calcd for C13H20NO (M+) 205.1466, found 205.1461;
HRMS (FAB) calcd for C13H20NO (M + H) 206.1545, found
206.1536.
(-)-(2R,3R,6S)-(E)-N-Ben zyloxyca r bon yl-2-(2-eth oxyca r -
bon yl-1-eth en yl)-6-(3-fu r yl)-3-m eth ylp ip er id in e (13). The
same experimental procedure described for compound 9 was
applied to alcohol 12 (0.50 mmol, 200 mg). Column chromatog-
raphy (SiO2) of the resulting residue afforded conjugated ester
13 (96% yield, 165 mg): yellow oil; Rf ) 0.38 (SiO2, hexane/
1
EtOAc 3:1); [R]22 ) -46.0 (c 1.0, CH2Cl2); H NMR (200 MHz,
D
CDCl3) δ 7.47-7.24 (m; 7H), 6.66 (dd, J ) 15.9, 7.3 Hz; 1H),
6.26-6.24 (m; 1H), 5.75 (dd, J ) 15.9, 1.4 Hz; 1H), 5.46-5.38
(m; 1H), 5.25 (d, J ) 12.4 Hz; 1H), 5.19 (d, J ) 12.4 Hz; 1H),
4.68-4.59 (m; 1H); 4.12 (q, J ) 7.0 Hz; 2H), 2.21-1.87 (m; 4H),
1.44-1.36 (m; 1H), 1.25 (t, J ) 7.0 Hz; 3H), 1.12 (d, J ) 7.0 Hz;
3H), ppm; 13C NMR (75 MHz, CDCl3) δ 166.0, 156.3, 147.6, 142.9,
139.2, 136.3, 128.3, 127.9, 127.7, 126.9, 121.4, 110.2, 67.4, 60.0,
57.5, 45.7, 30.4, 22.2, 21.9, 18.1, 14.0 ppm; HRMS (EI) calcd for
C23H27NO5 397.1889, found 397.1907.
(-)-(2S ,3R ,6S )-N -B e n z y lo x y c a r b o n y l-2-(2-e t h o x y -
ca r bon yleth yl)-6-(3-fu r yl)-3-m eth ylp ip er id in e (14). An ad-
aptation of the experimental procedure described for compound
10 was applied to alcohol 13 (0.32 mmol, 127 mg), carrying out
the hydrogenation for 3.5 h with a smaller ammount of Pd/C
(10 mg). Flash column chromatography (SiO2) of the resulting
residue afforded ester 14 (85% yield, 110 mg): colorless oil; Rf
) 0.39 (SiO2, hexane/EtOAc 4:1); [R]23D ) -79.1 (c 2.7, CH2Cl2);
1H NMR (300 MHz, CDCl3) δ 7.39-7.26 (m; 7H), 6.33 (s, br; 1H),
5.39 (s, br; 1H), 5.26 (d, J ) 12.5 Hz; 1H), 5.11 (d, J ) 12.5 Hz;
1H), 4.08-3.98 (m; 1H), 3.99 (q, J ) 7.3 Hz; 2H), 2.22-1.99 (m;
4H), 1.91-1.64 (m; 2H), 1.55 (quint, J ) 7.1 Hz; 1H), 1.37-1.18
(m; 2H), 1.16 (t, J ) 7.3 Hz; 3H), 1.05 (d, J ) 7.1 Hz; 3H) ppm;
13C NMR (75 MHz, CDCl3) δ 172.9, 156.8, 142.8, 138.6, 136.5,
128.3, 127.8, 127.6, 127.5, 110.1, 67.1, 59.9, 56.4, 45.1, 31.3, 31.0,
(-)-(2R,3R,6S)-N-Ben zyloxyca r b on yl-6-(3-fu r yl)-2-h y-
d r oxym eth yl-3-m eth ylp ip er id in e (12). To a solution of pip-
eridine 8 (1.05 mmol, 205 mg) in MeCN (15 mL) were succes-
sively added imidazole (2.63 mmol, 179 mg) and tert-butyl-
dimethylsilylchlorosilane (2.63 mmol, 397 mg); the mixture was
stirred at room temperature for 4 h. The reaction was quenched
by addition of H2O (10 mL) and EtOAc (15 mL), and the aqueous
layer was extracted with EtOAc; the combined organic layers
were washed with brine, dried over anhydrous Na2SO4, and
evaporated under vacuum. Column chromatography (SiO2) of
the residue afforded (-)-(2R,3R,6S)-2-(tert-butyldimethylsily-
loxymethyl)-6-(3-furyl)-3-methylpiperidine (220 mg, 67% yield)
29.3, 21.9, 21.4, 18.5, 14.0 ppm; HRMS (EI) calcd for C23H29
NO5 399.2046, found 399.2057.
-
(-)-(2S,3R,6S)-N-Ben zyloxyca r bon yln u p h a r a m in e (15).
To a solution of ester 14 (0.24 mmol, 96 mg) in dry THF (15
mL) cooled to -70 °C was added dropwise MeLi (1.6M in Et2O,
1.15 mmol, 720 mL), and the mixture was stirred at this
temperature for 15 min. Then, the reaction was quenched by
the slow addition of H2O (5 mL), and the cooling bath was
removed. The reaction was allowed to reach rt and then
extracted with EtOAc; the combined organic layers were dried
over anhydrous Na2SO4, and the solvent was eliminated under
vacuum. Column chromatography (SiO2) of the residue afforded
compound 15 (77% yield, 72 mg): colorless oil; Rf ) 0.25 (SiO2,
hexane/EtOAc 2:1); [R]24D ) -82.5 (c 2.0, CH2Cl2); 1H NMR (200
MHz, CDCl3) δ 7.35-7.31 (m; 7H), 6.37 (s; 1H), 5.39 (s, br; 1H),
5.22 (s; 2H), 4.08-3.94 (m; 1H), 2.17-1.23 (m; 9H), 1.07 (d, J )
7.0 Hz; 3H), 0.99 (s; 3H), 0.96 (s; 3H) ppm; 13C NMR (50 MHz,
as a colorless oil: Rf ) 0.30 (SiO2, hexane/Et2O 3:1); [R]25
)
D
1
-47.5 (c 0.8, CH2Cl2); H NMR (200 MHz, CDCl3) δ 7.38-7.37
(m; 2H), 6.40-6.39 (m; 1H), 3.88 (dd, J ) 9.8, 3.1 Hz; 1H), 3.62
(dd, J ) 11.0, 2.6 Hz; 1H), 3.49 (dd, J ) 9.8, 8.9 Hz; 1H), 2.43
(td, J ) 8.9, 3.1 Hz; 1H), 1.92-1.75 (m; 2H), 1.61-1.10 (m; 3H),
0.92-0.84 (m; 12H), 0.07 (s, 6H) ppm. The silylated derivative
obtained was dissolved in MeCN (10 mL). To the stirred solution
were successively added aqueous saturated K2CO3 (10 mL), and
benzylchloroformate (2.10 mmol, 300 µL). The biphasic mixture
was vigorously stirred for 4 h, and then the layers were

3740 J . Org. Chem., Vol. 64, No. 10, 1999
Notes
CDCl3) δ 157.0, 142.5, 138.9, 136.7, 128.4, 128.1, 127.9 (×2),
110.7, 70.4, 67.1, 57.5, 45.1, 40.5, 31.3, 29.3, 29.0, 28.6, 22.0,
21.6, 18.7 ppm; HRMS (EI) calcd for C23H31NO4 385.2253, found
385.2249.
Hz; 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 142.9, 138.3, 128.7,
109.1, 68.7, 62.8, 52.9, 39.5, 34.0, 33.7, 33.4, 30.1, 29.1, 28.3,
18.4 ppm; MS (EI) m/z 251 (2), 236 (8), 164 (100), 107 (33) 94
(36). HRMS (EI) calcd for C15H25NO2 251.1885, found 251.1879.
(-)-Nu p h a r a m in e (2). To a solution of piperidine 15 (0.16
mmol, 62 mg) in MeOH (10 mL) were added black Pd (10 mg)
and HCO2NH4 (0.80 mmol, 50 mg), and the mixture was
vigorously stirred at room temperature for 14 h. Afterward, the
solvent was removed under vacuum, and the residue obtained
was dissolved in EtOAc (6 mL), aqueous saturated NaHCO3 (3
mL), and brine (3 mL). The aqueous layer was extracted with
EtOAc; the combined organic layers were dried over anhydrous
Na2SO4, and the solvent was eliminated under vacuum. Flash
column chromatography (Al2O3) of the residue afforded alkaloid
2 (99% yield, 40 mg): colorless oil; Rf ) 0.37 (Al2O3, CH2Cl2/
Ack n ow led gm en t. We acknowledge financial sup-
port of this work by the Comisio´n Asesora de Investi-
gacio´n Cient´ıfica y Te´cnica DGICYT of Spain (PB-92
1005). A FICYT predoctoral fellowship to C.R. from the
Regional Government of the Principado de Asturias is
gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Copies of 13C NMR
and DEPT 3 NMR spectra of all the compounds described. This
material is available free of charge via the Internet at
http://pubs.acs.org.
EtOAc 3:1); [R]20 ) -29.5 (c 2.2, CHCl3); H NMR (300 MHz,
1
D
CDCl3) δ 7.33 (s; 2H), 6.41 (s; 1H), 3.61 (dd, J ) 11.2, 2.1 Hz;
1H), 2.43-2.33 (m; 1H), 1.90-1.64 (m; 4H); 1.61-1.39 (m; 4H),
1.28-1.12 (m; 2H); 1.19 (s; 3H), 1.17 (s; 3H), 0.89 (d, J ) 6.4
J O9823240