Total synthesis of (+)-epilupinine via an intramolecular nitrile oxide-alkene cycloaddition

Article abstract of DOI:10.1021/jo101910r

Total synthesis of (+)-epilupinine was accomplished in nine steps and in 48% overall yield, in which INOC was used as the key step for the construction of the quinolizidine skeleton. We found that it was an extremely difficult task to prepare the key intermediates (R)-N-(3-nitropropyl)-2-vinylpiperidine or (R)-(2-vinylpiperid-1-yl)propanal by routine methods. Thus, by using Fukuyama's oxime synthesis, a general method was developed for highly efficient conversion of 3-(N,N-dialkylamino)propanols into 3-(N,N-dialkylamino)propanal oximes without using the corresponding aldehydes.

Full text of DOI:10.1021/jo101910r

pubs.acs.org/joc
Total Synthesis of (þ)-Epilupinine via An Intramolecular Nitrile
Oxide-Alkene Cycloaddition
Deyong Su, Xinyan Wang,* Changwei Shao, Jimin Xu, Rui Zhu, and Yuefei Hu*
Department of Chemistry, Tsinghua University, Beijing 100084, People’s Republic of China
wangxinyan@mail.tsinghua.edu.cn; yfh@mail.tsinghua.edu.cn
Received September 27, 2010
Total synthesis of (þ)-epilupinine was accomplished in nine steps and in 48% overall yield, in which INOC
was used as the key step for the construction of the quinolizidine skeleton. We found that it was an extremely
difficult task to prepare the key intermediates (R)-N-(3-nitropropyl)-2-vinylpiperidine or (R)-(2-vinylpiper-
id-1-yl)propanal by routine methods. Thus, by using Fukuyama’s oxime synthesis, a general method was
developed for highly efficient conversion of 3-(N,N-dialkylamino)propanols into 3-(N,N-dialkylamino)-
propanal oximes without using the corresponding aldehydes.
Introduction
drug discovery. Many molecules bearing epilupinyl unit are
potential ligands for 5-HT3, 5-HT4 or Sigma receptors5 as well
as antiviral, antiarrhythmic, antimalarial or platelet antiaggre-
gating agents.6 Since its typical structure and biologically im-
portant properties, especially the fact that it often served as an
excellent vehicle for the validation of new synthetic methodology
and strategy, (þ)-epilupinine (2) has attracted great interest as a
challenging target for total synthesis.
Many novel routes have been developed for the total
synthesis of (þ)-epilupinine (2) based on the different cycli-
zation methods in literature.4,7 Surprisingly, the well-known
intramolecular nitrile oxide-alkene cycloaddition (INOC)8
Quinolizidine alkaloid is one of three major types of chiral
nitrogen-bridged bicyclic alkaloids found in nature, along
with indolizidine and pyrrolizidine alkaloids.1 The diaster-
eoisomers of (-)-lupinine (1) and (þ)-epilupinine (2) are the
simplest members of quinolizidine alkaloids isolated from
lupine seeds or as derivatives isolated from seedlings of L.
luteus.2 They are characterized by a hydroxymethyl group
substituted on C1 position of quinolizidine ring with oppo-
site configurations (Chart 1). When (-)-lupinine (1) is heated
under basic conditions, it can be isomerized to the thermo-
dynamically stable (þ)-epilupinine (2).3
Almost two decades ago, (þ)-epilupinine (2) was reported to
show in vitro inhibitory activity against P-388 (LD50=28 μg/mL)
and L1210 (LD50 = 20 μg/mL) cell lines.4 In recent years, it has
been widely employed as intermediates or pharmacophores in
(6) (a) Tonelli, M.; Vazzana, I.; Tasso, B.; Boido, V.; Sparatore, F.;
Fermeglia, M.; Paneni, M. S.; Posocco, P.; Pricl, S.; La Colla, P.; Ibba, C.; Secci,
B.; Collu, G.; Loddo, R. Bioorg. Med. Chem. 2009, 17, 4425–4440. (b) Tonellia,
M.; Pagliettib, G.; Boidoa, V.; Sparatore, F.; Marongiuc, F.; Marongiuc, E.; La
Collac, P.; Loddoc, R. Chem. Biodiv. 2008, 5, 2386–2481. (c) Casagrande, M.;
Basilico, N.; Parapini, S.; Romeo, S.; Taramelli, D.; Sparatore, A. Bioorg. Med.
Chem. 2008, 16, 6813–6823. (d) Vazzana, I.; Budriesi, R.; Terranova, E.; Ioan, P.;
Ugenti, M. P.; Tasso, B.; Chiarini, A.; Sparatore, F. J. Med. Chem. 2007, 50, 334–
343. (e) Sparatore, A.; Basilico, N.; Parapini, S.; Romeo, S.; Novelli, F.;
Sparatorec, F.; Taramelli, D. Bioorg. Med. Chem. 2005, 13, 5338–5345. (f) Ercoli,
M.; Mina, L.; Boido, C. C.; Boido, V.; Sparatore, F.; Armani, U.; Piana, A. IL
Farmaco 2004, 59, 101–109.
(7) For asymmetric syntheses of optical epilupinine, see: (a) Ahari, M.;
Perez, A.; Menant, C.; Vasse, J.-L.; Szymoniak, J. Org. Lett. 2008, 10, 2473–
2476. (b) Ma, S.; Ni, B. Chem.;Eur. J. 2004, 10, 3286–3300. (c) Mangeney,
P.; Hamon, L.; Raussou, S.; Urbain, N.; Alexakis, A. Tetrahedron 1998, 54,
10349–10362. (d) Naidu, B. N.; West, F. G. Tetrahedron 1997, 53, 16565–
16574. (e) West, F. G.; Naidu, B. N. J. Am. Chem. Soc. 1994, 116, 8420–8421.
(f) Morley, C.; Knight, D. W.; Share, A. C. J. Chem. Soc. Perkin Trans I 1994,
2903–2907. (g) Nagao, Y.; Dai, W.-M.; Ochiai, M.; Tsukagoshi, S.; Fujita, E.
J. Am. Chem. Soc. 1988, 110, 289–291.
(1) For reviews, see: (a) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139–165.
(b) Michael, J. P. Nat. Prod. Rep. 2007, 24, 191–222. (c) Daly, J. W.; Spande,
T. F.; Garraffo, H. M. J. Nat. Prod. 2005, 68, 1556–1575.
(2) For reviews, see: (a) Takamatsu, S.; Saito, K.; Murakoshi, I.; Ohmiya,
S. J. Nat. Prod. 1991, 54, 477–482. (b) Beck, A. B.; Goldspink, B. H.; Knox,
J. R. J. Nat. Prod. 1979, 42, 385–398. (c) Aslanov, K. A.; Kushmuradow,
Y. K.; Sadykov, A. S. in The alkaloids; Brossi, A., Ed.; Academic Press, Inc.:
New York, 1987; Vol. 31, pp 140-146.
(3) Sparatore, A.; Tasso, B.; Boido, V.; Sparatore, F. Helv. Chim. Acta
2005, 88, 245–251.
(4) Hua, D. H.; Miao, S. W.; Bravo, A. A.; Takemoto, D. J. Synthesis
1991, 970–974.
(5) (a) Sparatore, A.; Novelli, F.; Sparatore, F. Helv. Chim. Acta 2004, 87,
580–591. (b) Sparatore, A.; Cagnotto, A.; Sparatore, F. IL Farmaco 1999, 54,
248–254.
188 J. Org. Chem. 2011, 76, 188–194
Published on Web 12/01/2010
DOI: 10.1021/jo101910r
r
2010 American Chemical Society

Su et al.
JOCArticle
CHART 1
SCHEME 2a
SCHEME 1
aConditions: i. H2CdCHMgBr, THF, 0 °C, 1 h, 92%; ii. (a) LiAlH4,
THF, 0 °C, 0.5 h; (b) aq. NaOH, MeOH, THF, 60 °C, 6 h; (c) sat. HCl in
MeOH, 93% yield for three steps.
SCHEME 3
has never been employed for such purpose, even though it
was often used for the construction of substituted piperidine
rings.9 However, when a retro-synthetic route was proposed
for (þ)-epilupinine (2) by using INOC as a key step (Scheme 1),
we realized that it may be hampered by three obstacles: (a)
efficient preparation of chiral (R)-2-vinylpiperidine [(R)-5)]; (b)
efficient preparation of (R)-(2-vinylpiperid-1-yl)propanal oxime
(13a); (c) efficient preparation of 14a by a oxidative INOC of
tertiary amine 13a.
Herein, we report a novel route for the total synthesis of
enantiopure (þ)-epilupinine (2) by using INOC as a key step, in
which all three obstacles in Scheme 1 are overcome efficiently.
This practical and scalable route is characterized by easy perfor-
mance, short steps and high overall yield.
syntheses of alkaloids.10 But its application is far from that
expected, most possibly because its preparation is still a
challenging subject to date.10,11
Recently, we reported a general method for the preparation of
enantiopure 2-alkene substituted piperidines from Betti base deri-
vative 3.10a,b Its high efficiency owes to a novel base-catalyzed
N-debenzylation. As shown in Scheme 2, when 3was treated with
H2CdCHMgBr in THF, its Bt-group (1,2,3-benzotriazol-1-yl)
was substituted by a vinyl group to give a single diastereomer 4 in
92% yield. When 4was subjected to a reductive cleavage of C-O
bond followed by a N-debenzylation in one-pot, (R)-2-vinylpi-
Results and Discussion
Efficient Preparation of (R)-2-Vinylpiperidine Hydrochlo-
ride [(R)-5 HCl]. The investigation shows that nonracemic
2-vinylpiperidine (5) is a versatile precursor in the total
3
peridine hydrochloride [(R)-5 HCl] was obtained in 93% yield.
3
This method is so practical that (R)-5 HCl can be prepared in
gram scale within a few hours.
3
(8) Recent reviews for intramolecular nitrile oxide-alkene cycloaddition
(INOC), see: (a) Rai, K. M. L. Top. Heterocycl. Chem. 2008, 13, 1–69. (b)
Namboothiri, I. N. N.; Rastogi, N. Top. Heterocycl. Chem. 2008, 12, 1–44.
(c) Jager, V.; Colinas, P. A. Nitrile Oxides. In The Chemistry of Heterocyclic
Compounds; Padwa, A., Pearson, W. H., Eds.; John Wiley & Sons Inc.: New
York, 2002; Vol. 59. (d) Namboothiri, I. N. N.; Hassner, A. Top. Curr. Chem.
2001, 216, 1–49.
(9) Recent references for the construction of substituted piperidine rings
by INOC, see: (a) Noguchi, M.; Tsukimoto, A.; Kadowaki, A.; Hikata, J.;
Kakehi, A. Tetrahedron Lett. 2007, 48, 3539–3542. (b) Kadowaki, A.;
Nagata, Y.; Uno, H.; Kaminura, A. Tetrahedron Lett. 2007, 48, 1823–
1825. (c) Nath, M.; Mukhopadhyay, R.; Bhattacharjya, A. Org. Lett.
2006, 8, 317–320. (d) Andres, J. I.; Alcazar, J.; Alonso, J. M.; Alvarez,
R. M.; Bakker, M. H.; Biesmans, I.; Cid, J. M.; De Lucas, A. I.; Fernandez,
J.; Font, L. M.; Hens, K. A.; Iturrino, L.; Lenaerts, I.; Martinez, S.; Megens,
A. A.; Pastor, J.; Vermote, P. C. M.; Steckler, T. J. Med. Chem. 2005, 48,
2054–2071. (e) Akritopoulou-Zanze, I.; Gracias, V.; Moore, J. D.; Djuric,
S. W. Tetrahedron Lett. 2004, 45, 3421–3423. (f) Falb, E.; Nudelman, A.;
Gottlieb, H. E.; Hassner, A. Eur. J. Org. Chem. 2000, 645–655.
Efficient Preparation of (R)-(2-Vinylpiperid-1yl)propanal
Oxime (13a). INOC has been proved to be a powerful tool for
the preparation of bicyclic derivatives of 4,5-dihydroisoxazole.8
By using the substrates that two functional groups are linked by
a nitrogen atom, the nitrogen-containing heterocyclic products
are expected. As shown in Scheme 3, when the derivatives of N-
allyl-3-nitropropylamine (6)9e or 3-(allylamino)propanal oxime
(7)9a were treated under INOC conditions, 4,5-dihydroisoxa-
zolo[4,3-c]piperidines (8) can be prepared stereoselectively with
satisfactory yields.
Thus, we tried to convert (R)-5 HCl into the correspond-
3
ing (R)-N-(3-nitropropyl)-2-vinylpiperidine (9) or (R)-(2-vinyl-
piperid-1-yl)propanal (10) (Scheme 4). Unfortunately, when
(10) (a) Cheng, G.; Wang, X.; Su, D.; Liu, H.; Liu, F.; Hu, Y. J. Org.
Chem. 2010, 75, 1911–1916. (b) Liu, H.; Su, D.; Cheng, G.; Xu, J.; Wang, X.;
Hu, Y. Org. Biomol. Chem. 2010, 1899–1904. (c) Friestad, G. K.; Korapala,
C. S.; Ding, H. J. Org. Chem. 2006, 71, 281–289. (d) Zheng, J.-F.; Jin, L.-R.;
Huang, P.-Q. Org. Lett. 2004, 6, 1139–1142. (e) Lim, S. H.; Ma, S.; Beak, P.
J. Org. Chem. 2001, 66, 9056–9062. (f) Brosius, A. D.; Overman, L. E.;
Schwink, L. J. Am. Chem. Soc. 1999, 121, 700–709.
(11) (a) Spiess, S.; Welter, C.; Franck, G.; Taquet, J.-P.; Helmchen,
G. Angew. Chem., Int. Ed. 2008, 47, 7652–7655. (b) Yamauchi, S.; Omi,
Y. Biosci., Biotechnol., Biochem. 2005, 69, 1589–1594. (c) Welter, C.;
Koch, O.; Lipowsky, G.; Helmchen, G. Chem. Commun. 2004, 896–
897.
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SCHEME 4
SCHEME 6
In the further investigation, a novel two-step conversion of
alcohols into oximes reported by Fukuyama14 drew our atten-
tion, by which the aldehyde oxime can be prepared without
using the corresponding aldehyde. This method has a wide
range of substrates,14,15 but no 3-(N,N-dialkylamino)propanol
(11) was determined as a substrate. Thus, we tried to use this
method for the preparation of the required oxime 13a from
alcohol 11a.
SCHEME 5a
As shown in Scheme 6, 11a was prepared in 95% yield by a
normal alkylation of (R)-5a HCl and ClCH2CH2CH2OH.
aA retro-Micheal addition by an intramolecular E1cB elimination
3
Following Fukuyama’s step, when 11a was treated with
TsNHOTBS under Mitsunobu conditions at 0 °C for 1 h,
its hydroxyl group was substituted by N-Ts-N-OTBS-amino
group to give the intermediate 12a in 98% yield. As was
expected, the desired product 13a was produced in 94% yield
by treatment of 12a with CsF in MeCN.
To generalize this method, different 3-(N,N-dialkylamino)-
propanols 11b-11k were tested under the similar conditions. As
shown in Table 1, all of them were converted into the corre-
sponding tosylamides 12b-12k in excellent yields under
Mitsunobu conditions. In N-detosylation, the acyclic amines
12b-12f gave the corresponding 3-(N,N-dialkylamino)propanal
oximes 13b-13f in high yields. The double bonds in those sub-
strates stayed intact in both steps. When cyclic amines 11g-11k
were used as substrates, desired products 13g-13k were ob-
tained in moderate to high yields. Since numerous biologically
important alkaloids are polycycles with different types and
sizes, therefore, the successful syntheses of 13g-13k provides
a new pathway to build their skeletons.
INOC of (R)-(2-Vinylpiperid-1yl)propanal Oxime (13a).
Oxidative INOC usually proceeds in the presence of an
oxidant, by which the oxime is oxidized to the corresponding
nitrile oxide. Although many oxidants8 have been reported for
this purpose, there is no general rule to follow. Thus, different
oxidants were tested by using oxime 13a as a model substrate.
We found that 13a was almost inert to chloramine-T under the
reference conditions,9d but it was completely decomposed by
PhI(OAc)2/TFAA16 within 30 min. When 13a was treated with
NCS for 72 h, the expected product 14a was obtained in only
28% yield.9c To our delight, the simplest oxidant NaOCl9a,f
gave the best result. As shown in Scheme 7, after the mixture of
(R)-5 HCl was subjected to an alkylation with BrCH2CH2-
3
CH2NO2, the expected product 9 was obtained in poor yield
(17-23%). It was worse that a complex mixture was produced
in Michael addition between (R)-5 HCl and CH2dCHCHO at
3
room temperature. We observed a major product on TLC plate
when Michael addition proceeded at 0 °C, but a similar mixture
was obtained after a routine workup. Although the alkylation of
(R)-5 HCl with ClCH2CH2CH2OH gave 11a in excellent yield,
3
the conversion of 11a to 10 failed too by oxidation with PCC,
DMSO-(COCl)2 or Dess-Martin periodinane. In fact, Marko’s
early works have demonstrated that the preparation, isolation,
storage and application of 3-(N,N-dialkylamino)propionals
were extremely difficult tasks.12
These results strongly indicate that the problems may be
from the structural natures of 9 and 10 rather than from the
synthetic methods used. We hypothesized that the instability of
9 and 10 may be caused by their intramolecular E1cB elimina-
tion, in which the amine group may play dual roles as shown in
Scheme 5 (by using 10 as a model). (a) Initially, amine is used as
a base to remove the R-proton to generate an ammonium inter-
mediate. (b) After amine is converted into ammonium, it is used
as a good leaving group to lead to a retro-Michael addition.
Thus, the amide-protected9 (as a weak base) or R,R-disubsti-
tuted13 (without R-protons) aldehydes were successfully pre-
pared in literature because they could not carry out an intra-
molecular E1cB elimination. That may be the reason that INOC
was rarely used as a key step to construct the piperidine ring in
the syntheses of polycyclic alkaloids. Therefore, both N,N-
dialkyl-3-nitropropylamines and 3-(N,N-dialkylamino)propio-
nals are not suitable intermediates in INOC and there is a great
need to develop new methods to avoid using them.
(14) Kitahara, K.; Toma, T.; Shimokawa, J.; Fukuyama, T. Org. Lett.
2008, 10, 2259–2261.
(12) (a) Chesney, A.; Marko, I. E. Synth. Commun. 1990, 20, 3167–3180.
(b) Marko, I. E.; Chesney, A. Synlett 1992, 275–278. (c) Marko, I. E.;
Southern, J. K.; Adams, H. Tetrahedron Lett. 1992, 33, 4657–4660.
(13) Noguchi, M.; Okada, H.; Tanaka, M.; Matsumoto, S.; Kakehi, A.;
Yamamoto, H. Bull. Chem. Soc. Jpn. 2001, 74, 917–925.
(15) (a) Rai, G.; Thomas, C. J.; Leister, W.; Maloney, D. J. Tetrahedron
Lett. 2009, 50, 1710–1713. (b) Singh, M. K.; Lakshman, M. K. J. Org. Chem.
2009, 74, 3079–3084.
(16) Mendelsohn, B. A.; Lee, S.; Kim, S.; Teyssier, F.; Aulakh, V. S.;
Ciufolini, M. A. Org. Lett. 2009, 11, 1539–1542.
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JOCArticle
TABLE 1. Preparation of 3-(N,N-Dialkylamino)propanal Oximes 13a-13ka
aIsolated yields were obtained.
13a and NaOCl (10% aqueous solution) in CH2Cl2 was stirred
at room temperature for 2 h, a single product 14a was obtained
in 88% yield. Since its two chiral carbons were formed in
separated steps, 14a was easily confirmed to be an enantiopure
product by its 1H and 13C NMR spectra. The favored transition
state 17 was proposed because the new formed chiral carbon has
R-configuration [it was deducted from the final product (þ)-
epilupinine (2)].
J. Org. Chem. Vol. 76, No. 1, 2011 191

Su et al.
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SCHEME 7
SCHEME 8
TABLE 2. Chemo- and Stereoselective INOC of 13a-13fa
give desired product 15 in 84% yield. Then, 15 was smoothly
converted into S,S-ketal 16 by reaction with ethane-1,2-
dithiol. Finally, 16 was subjected to a highly efficient Raney
nickel promoted desulfurization to give the target product
(þ)-epilupinine (2) in 95% yield. Since the stereochemistry of
(þ)-epilupinine (2) has been well established in literature,7,17
its structure was confirmed easily by its optical rotation data
and NMR spectra. Thus, the total synthesis of enantiopure 2
was accomplished in nine steps [starting from (R)-3] and in
48% overall yield.
Conclusion
Total synthesis of enantiopure (þ)-epilupinine was accom-
plished in nine steps and in 48% overall yield by using INOC
as the key step for the construction of the quinolizidine
skeleton. Three obstacles to hamper this total synthesis were
overcome efficiently. Prominent among them is the prepara-
tion of (R)-(2-vinylpiperid-1-yl)propanal oxime (13a) from
(R)-(2-vinylpiperid-1-yl)propanol (11a), by which (R)-(2-
vinylpiperid-1-yl)propanal (10) was avoided to using as an
essential intermediate because it is a highly unstable Michael
adduct and its preparation is an extremely difficult task.
Finally, a general method was developed for highly efficient
conversion of 3-(N,N-dialkylamino)propanols into the cor-
responding 3-(N,N-dialkylamino)propanal oximes without
using the corresponding aldehydes. Since numerous natural
alkaloids are nitrogen-bridged polycycles, it is expected that
the method will promote the application of INOC in total
syntheses of alkaloids in future.
aIsolated yields were obtained.
Experimental Section
The starting material 318 and the intermediate 410b were
prepared by the reference methods.
Preparation of (R)-2-Vinylpiperidine Hydrochloride [(R)-
Thus, the oximes 13b-13f were treated with aqueous
NaOCl by the similar procedure. As shown in Table 2, the
desired cyclic product 14b was obtained in 90% yield from
13b (entry 2). When N,N-diallyl 13c was used as a substrate,
one allyl group involved in INOC reaction and another one
stay intact (entry 3). In entry 4, the N-allyl group in 13d took
a highly chemoselective INOC to give 14d in 85% yield, while
the N-butene group stayed intact. It was not surprise that
13e-13f could not give desired seven-membered ring prod-
ucts (entries 5 and 6).
5 HCl]. To a cold solution (ice-water bath) of compound 4
3
(1.02 g, 3 mmol) in dry THF (20 mL) was added LiAlH4 (170 mg,
4.5 mmol) under N2. After the reaction was stirred at 0 °C for 30
min (monitored by TLC), a saturated aqueous solution of
NH4Cl (30 mL) was added to quench the reaction. Then the
resultant mixture was extracted with Et2O (3 ꢀ 10 mL). The
combined organic layers were washed with H2O and brine and
dried over Na2SO4.
Total Synthesis of Natural Alkaloid (þ)-Epilupinine (2). So
far, we have successfully overcome all three obstacles in the
total synthesis of (þ)-epilupinine (2). As shown in Scheme 8,
when 14a was routinely treated by Raney nickel in the
presence of HOAc, its 4,5-dihydroisoxazole was cleaved to
(17) Koziol, A. E.; Gdaniec, M.; Kosturkiewicz, Z. Acta Crystallogr.
1980, B36, 982–983.
(18) (a) Dong, Y.; Li, R.; Lu, J.; Xu, X.; Wang, X.; Hu, Y. J. Org. Chem.
2005, 70, 8617–8620. (b) Wang, X.; Dong, Y.; Sun, J.; Li, R.; Xu, X.; Hu, Y.
J. Org. Chem. 2005, 70, 1897–1900.
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Su et al.
After removal of the solvent, the residue was diluted by a
solution of THF (4 mL), CH3OH (4 mL) and aq NaOH (6.0 M,
2 mL). The resultant mixture was stirred at 60 °C for 6 h and then
was cooled to room temperature. It was extracted with CH2Cl2 (3ꢀ
10 mL) and the combined organic layers were washed with brine
and dried over Na2SO4. After the solid was filtered off, the filtrate
was immediately treated with saturated solution of HCl in MeOH
(6 mL) at 0 °C for 30 min. Then, the solvent was removed in
vacuum and the residue was recrystallized from MeOH-Et2O to
JOCArticle
5H), 1.37-1.25 (m, 1H). 13C NMR: δ 149.8, 149.1, 140.7, 115.9,
66.2, 66.0, 51.9, 51.7, 51.5, 51.2, 32.8, 25.8, 25.2, 23.5, 21.4. MS m/z
(%): 182 (Mþ, 0.42), 124 (100). Anal. calcd for C10H18N2O: C,
65.90; H, 9.95; N, 15.37; Found: C, 65.95; H, 9.92; N, 15.26.
By similar procedure, 4-methyl-benzenesulfonamides 12b-12k
were converted into 13b-13k (see Supporting Information).
Preparation of (10aR,9bR)-Octahydro-1H-isoxazolo[4,3-a]qui-
nolizine (14a), A Typical Procedure of INOC. To a stirred solution
of compound 13a (91 mg, 0.5 mmol) in CH2Cl2 (5 mL) was added
an aqueous solution of NaOCl (10%, 0.9 mL) at 0 °C within 30 min.
Then the reaction was stirred at room temperature for 2 h (moni-
tored by TLC). After the reaction was quenched by H2O (20 mL),
the resultant mixture was extracted by CH2Cl2 (2 ꢀ 20 mL). The
combined organic layers were washed with brine (20 mL) and dried
over Na2SO4. Removal of the solvent gave a residue, which was
purified by chromatography (silica gel, 50% EtOAc in PE) to give
79 mg (88%) of product 14a as a yellowish oil, [R]D20 =-30.4 (c 0.9,
CHCl3). IR: v 2929, 2856, 2800, 2763 cm-1. 1H NMR: δ 4.50-4.43
(m, 1H), 3.83-3.77 (m, 1H), 3.08-2.93 (m, 3H), 2.76-2.70 (m,
1H), 2.55-2.45 (m, 1H), 2.20-2.03 (m, 2H), 1.80-1.54 (m, 5H),
1.38-1.16 (m, 2H). 13C NMR: δ 157.7, 70.5, 67.3, 55.2, 55.1, 54.0,
32.3, 25.2, 24.7, 23.4. MS m/z(%):180(Mþ, 42.12), 179 (100). Anal.
calcd for C10H16N2O: C, 66.63; H, 8.95; N, 15.54. Found: C, 66.81;
H, 8.89; N, 15.42.
give product (R)-5 HCl as a white crystal (410 mg, 93%). It had mp
199-200 °C (MeOH-Et2O). [R]D20 = þ5.5 (c 0.2, CHCl3); IR: v
3
1
3440, 2983, 1252, 1013 cm-1. H NMR: δ 9.53-9.40 (m, 2H),
6.13-6.02 (m, 1H), 5.56-5.37 (m, 2H), 3.60-3.43 (m, 2H),
2.95-2.88 (m, 1H), 2.04-1.82 (m, 5H), 1.55-1.52 (m, 1H). 13C
NMR: δ 133.3, 120.5, 58.1, 44.2, 28.1, 21.8, 21.5. MS m/z (%): 111
(Mþ - HCl, 1.71), 84(100). Anal. calcdforC7H14ClN: C, 56.94; H,
9.56; N, 9.49. Found: C, 56.67; H, 9.43; N, 9.66.
Preparation of (R)-3-(2-Vinylpiperidin-1-yl)propan-1-ol (11a).
The mixture of compound (R)-5 HCl (2.00 g, 13.5 mmol),
3
ClCH2CH2CH2OH (1.42 g, 15 mmol), dry K2CO3 (4.14 g, 30
mmol) and KI (2.49 g, 15 mmol) in acetone (50 mL) was refluxed
for 2 h. Then the solid was filtrated off and the solvent was
evaporated. The residue was purified by chromatography (silica
gel, EtOAc) to give 2.18 g (95%) of product 11a as a colorless oil,
20
By similar procedure, 3-aminopropanal oximes 13b-13d
were converted into 14b-14d (see Supporting Information).
(1S,9aR)-Octahydro-1-hydroxymethyl-2H-quinolizin-2-one (15).
At room temperature, a suspension of compound 14a (400 mg,
2.22 mmol), Raney nickel (13 mg, 0.22 mmol) and HOAc (1.33 g,
22.2 mmol) in aqueous MeOH (75%, 20 mL) under H2 (balloon)
was vigorously stirred for 1.5 h. Then the reaction was quenched by
saturated aqueous Na2CO3 (20 mL) and the catalyst was filtrated
off. The filtration was extracted with EtOAc (3 ꢀ 20 mL) and
combined organic layers were washed with brine (20 mL) and dried
over Na2SO4. Removal of the solvent gave a residue, which was
purified by chromatography (silica gel, EtOAc) to give 342 mg
(84%) of product 15 as a white solid. It had mp 69-71 °C (EtOAc),
[R]D20 =þ8.8 (c 0.04, CHCl3). IR:v3440, 1714, 1092, 647 cm-1. 1H
NMR: δ 3.97-3.93 (m, 1H), 3.74-3.68 (m, 1H), 3.14-3.05 (m,
1H), 3.00-2.96 (m, 1H), 2.83-2.70 (m, 2H), 2.46-2.33 (m, 3H),
2.17-2.07 (m, 2H), 1.98-1.95 (m, 1H), 1.83-1.56 (m, 3H),
1.40-1.20 (m, 2H). 13C NMR: δ 211.9, 63.0, 58.3, 56.6, 55.69,
55.67, 41.7, 31.1, 25.3, 23.3. MS m/z (%): 183 (Mþ, 28.76), 28 (100).
Anal. calcd for C10H17NO2: C, 65.54; H, 9.35; N, 7.64. Found: C,
65.81; H, 9.42; N, 7.56.
[R]D = þ76.4 (c 0.2, CHCl3). IR: v 3387, 2933, 2857, 1053
cm-1. 1H NMR: δ 5.78-5.67 (m, 1H), 5.49 (s, 1H), 5.10-4.99
(m, 2H), 3.70-3.63 (m, 2H), 3.10-2.87 (m, 2H), 2.53-2.48 (m,
1H), 2.23-2.14 (m, 1H), 1.86-1.25 (m, 9H). 13C NMR: δ 141.0,
116.0, 66.9, 64.2, 54.9, 51.7, 33.5, 27.1, 25.5, 23.3. MS m/z (%):
169 (Mþ, 1.87), 124 (100). Anal. calcd for C10H19NO: C, 70.96;
H, 11.31; N, 8.28. Found: C, 71.21; H, 11.24; N, 8.32.
Preparation of N-[(2R)-2-Vinyl-1-piperidine-propyl]-N-[(tert-
butyl-dimethylsilyl)oxy]-4-methyl-benzenesulfonamide (12a), a
Typical Procedure of Mutsunobu Reaction. To a stirred solution
of 11a (508 mg, 3 mmol), TsNHOTBS (915 mg, 3.15 mmol), PPh3
(1.58 g, 6 mmol) and THF (3 mL) in toluene (9 mL) was added a
solution of DEAD (784 mg, 4.5 mmol) in toluene (3 mL) at 0 °C
under N2. One hour later, the solvent was removed to give a residue,
which was purified by chromatography (silica gel, 10% EtOAc in
20
PE) to give 1.33 g (98%) of product 12a as a colorless oil, [R]D
=
þ21.0 (c 0.2, CHCl3).IR:v2932, 2856, 1465 cm-1. 1HNMR:δ7.73
(d, J = 8.2, 2H), 7.33 (d, J = 7.9, 2H), 5.71-5.62 (m, 1H), 5.12-
4.98 (m, 2H), 3.02-2.83 (m, 3H), 2.71-2.51 (m, 2H), 2.44 (s, 3H),
2.16-2.06 (m, 1H), 1.97-1.91 (m, 1H), 1.74-1.23 (m, 8H), 0.93 (s,
9H), 0.30 (s, 6H). 13CNMR:δ144.3, 141.8, 129.9, 129.7 (2C), 129.1
(2C), 115.3, 66.4, 54.3, 52.4, 51.9, 33.5, 25.9 (3C), 25.8, 23.7, 23.5,
21.5, 18.0. -4.4 (2C). MS m/z (%): 452 (Mþ, 1.08), 44 (100). Anal.
calcd for C23H40N2O3SSi: C, 61.02; H, 8.91; N, 6.19. Found: C,
61.25; H, 8.99; N, 6.06.
(1S,9aR)-Octahydro-1-hydroxymethyl-spiro[1,3-dithiolane-2,
20-[2H]quinolizine] (16). To a solution of compound 15 (293 mg,
1.60 mmol) in dry CH2Cl2 was added a mixture of ethane-1,2-
dithiol (1.23 mL, 14.7 mmol) in BF3 Et2O (0.46 mL, 3.68 mmol).
3
Two hours later, the reaction was quenched by aqueous NaOH
(2.0 M, 3 mL). The resultant mixture was extracted by CH2Cl2 (3 ꢀ
20 mL) and combined organic layers were washed with H2O
(20 mL) and brine (20 mL) and dried over Na2SO4. Removal of
the solvent gave a residue, which was purified by chromatography
(silica gel, EtOAc) to give 344 mg (83%) of product 16 as a white
By similar procedure, 3-aminopropanols 11b-11k were con-
verted into the corresponding 4-methyl-benzenesulfonamides
12b-12k (see Supporting Information).
Preparation of (R)-2-Vinyl-1-piperidinepropanal Oxime (13a),
a Typical Procedure of Oximation. A stirred mixture of com-
pound 12a (453 mg, 1.0 mmol) and CsF (301 mg, 2 mmol) in
MeCN (10 mL) was heated at 60 °C under N2 for 2 h. After it was
cooled to room temperature, saturated aqueous NH4Cl was added
to quench the reaction. The resultant mixture was extracted by
EtOAc (3 ꢀ 30 mL) and combined organic layers were washed with
brine (20 mL) and dried over Na2SO4. Removal of the solvent gave
a residue, which was purified by chromatography (silica gel, 30%
EtOAc in PE) to give 171 mg (94%, E:Z=72:28) ofproduct13a as
a white crystal. It had mp 43-45 °C (PE/EtOAc), [R]D20 = þ11.2
20
solid. It had mp 128-130 °C (EtOAc), [R]D = -13.0 (c 0.1,
CHCl3). IR: v 3452, 1641, 1048, 1025 cm-1. 1H NMR: δ 4.21-4.17
(m, 1H), 3.90-3.86 (m, 1H), 3.39-3.23 (m, 4H), 2.94-2.77 (m,
3H), 2.47-2.24 (m, 2H), 2.16-1.95 (m, 4H), 1.82-1.73 (m, 2H),
1.65-1.52 (m, 2H), 1.38-1.14 (m, 2H). 13C NMR: δ 71.8, 63.7,
61.3, 56.3, 55.2, 52.7, 44.9, 39.3, 38.7, 29.9, 25.3, 24.2. MS m/z (%):
259 (Mþ, 28.33), 97 (100). Anal. calcd for C12H21NOS2: C, 55.56;
H, 8.16; N, 5.40. Found: C, 55.51; H, 8.17; N, 5.44.
(c 0.2, CHCl3). IR:v 3305, 3179, 3073, 2931, 2854, 2789, 2726 cm-1
.
Preparation of (þ)-Epilupinine (2). A suspension of compound 16
(260 mg, 1.00 mmol), Raney nickel (secondary grad, 900 mg, 15.3
mmol) in anhydrous EtOH (20 mL) was refluxed for 1.5 h. After the
reaction was cooled to room temperature, the catalyst was filtrated
off. Removal of the solvent gave a residue, which was purified by
1H NMR (as a mixture of E:Z isomers): δ 11.06 (s, br, 1H),
7.37-7.32 (m, 0.28H, minor), 6.70-6.67 (m, 0.72H, major), 5.88-
5.74 (m, 1H), 5.18-5.04 (m, 2H), 3.02-2.87 (m, 2H), 2.75-2.63
(m, 1H), 2.62-2.33 (m, 3H), 2.17-2.08 (m, 1H), 1.74-1.45 (m,
J. Org. Chem. Vol. 76, No. 1, 2011 193

Su et al.
JOCArticle
chromatography (silica gel, 25% MeOH in EtOAc) to give 161 mg
(95%) of product 2 as a white solid. It had mp 77-79 °C (lit.7b,g
78-79 °C), [R]D20 = þ31.8 (c 0.60, EtOH) [lit.[7b] [R]D20= þ32.6 (c
0.72, EtOH), lit.7g [R]D22= þ31.2 (c 0.86, EtOH)]. IR: v 3183, 2929,
2860, 1064 cm-1. 1H NMR: δ 3.62-3.56 (m, 1H), 3.50-3.45 (m,
1H), 2.77-2.69 (m, 2H), 2.33 (s, br, 1H), 2.00-1.50 (m, 9H),
1.38-1.28 (m, 1H), 1.26-1.11 (m, 4H). 13C NMR: δ 64.4, 64.3,
56.8, 56.6, 43.9, 29.7, 28.2, 25.5, 24.9, 24.5. MS m/z (%): 169 (Mþ,
42.96), 83 (100). Anal. calcd for C10H19NO: C, 70.96; H, 11.31; N,
8.28. Found: C, 70.91; H, 11.34; N, 8.23.
Acknowledgment. This work was supported by NNSFC
(30600779, 20672066) and the CFKSTIP from Ministry of
Education of China (706003).
Supporting Information Available: Experiments, character-
ization, 1H and 13C NMR spectra for products (R)-5 HCl,
3
11a-11k, 12a-12k, 13a-13k, 14a-14d, 15, 16, and (þ)-epilu-
pinine (2). This material is available free of charge via the
Internet at http://pubs.acs.org.
194 J. Org. Chem. Vol. 76, No. 1, 2011