Preparation of enantiopure substituted piperidines containing 2-alkene or 2-alkyne Chains: Application to total syntheses of natural quinolizidine- alkaloids

Article abstract of DOI:10.1021/jo902615u

"Chemical Equation Presented" A general method, for the preparation of enantiopure 2-alkene- or 2-alkyne-containing chain substituted piperidines was established by using nonracemic Betti base as a chiral auxiliary. The key step is that the auxiliary residue was removed by a novel base-catalyzed N-debenzylation via a formation of o-quinone methide mechanism in stead, of the traditional hydrogenolysis, by which the alkene or alkyne groups survived. By this method, ten 2-alkene- or 2-alkyne-containing chain substituted piperidines were prepared on the gram scale within a few hours. To demonstrate the efficiency of the method and the versatility of the product, total, syntheses of natural alkaloids (+)-pelletierine((-)-lasubine II, and (-)-cermizine C were achieved by using (S)-2-allyl-N-Bocpiperidine as a versatile building block.

Full text of DOI:10.1021/jo902615u

pubs.acs.org/joc
Preparation of Enantiopure Substituted Piperidines Containing 2-Alkene
or 2-Alkyne Chains: Application to Total Syntheses of Natural
Quinolizidine-Alkaloids
Guolin Cheng, Xinyan Wang,* Deyong Su, Hui Liu, Fei Liu, and Yuefei Hu*
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education),
Department of Chemistry, Tsinghua University, Beijing 100084, People’s Republic of China
wangxinyan@mail.tsinghua.edu.cn; yfh@mail.tsinghua.edu.cn
Received December 13, 2009
A general method for the preparation of enantiopure 2-alkene- or 2-alkyne-containing chain
substituted piperidines was established by using nonracemic Betti base as a chiral auxiliary. The
key step is that the auxiliary residue was removed by a novel base-catalyzed N-debenzylation via a
formation of o-quinone methide mechanism in stead of the traditional hydrogenolysis, by which the
alkene or alkyne groups survived. By this method, ten 2-alkene- or 2-alkyne-containing chain
substituted piperidines were prepared on the gram scale within a few hours. To demonstrate the
efficiency of the method and the versatility of the product, total syntheses of natural alkaloids
(þ)-pelletierine, (-)-lasubine II, and (þ)-cermizine C were achieved by using (S)-2-allyl-N-Boc-
piperidine as a versatile building block.
Introduction
rearrangement,2 hydroxylation,3 catalytic hydrogenation,4
iodine-catalyzed lactonization,5 RCM reaction,6 Wacker
oxidation,5 etc. (Scheme 1).
Investigation proved that the preparation of chiral
2-alkene-containing chain substituted piperidines is still a
challenging subject. Although asymmetric catalytic methods
are very attractive,4a,7 the chiral pool3,5,8 and chiral auxiliary
A number of natural alkaloids contain the unit of chiral
2-substituted piperidine.1 For their biological importance
and novel structures, they have continuously been the chal-
lenging targets of total synthesis. Various building blocks
have been applied to this purpose, prominent among them
are chiral 2-alkene-containing chain substituted piperidines,
because the alkene group can be easily transformed into
other groups by using different reactions, such as aza-Claisen
(5) (a) Takahata, H.; Saito, Y.; Ichinose, M. Org. Biomol. Chem. 2006, 4,
1587–1595. (b) Takahata, H.; Ouchi, H.; Ichinose, M.; Nemoto, H. Org. Lett.
2002, 4, 3459–3462.
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281–289. (b) Scheiper, B.; Glorius, F.; Leitner, A.; Furstner, A. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 11960–11965.
*To whom correspondence should be addressed. Phone: þ86-10-
62795380. Fax: þ86-10-62771149.
(7) (a) Spiess, S.; Welter, C.; Franck, G.; Taquet, J.-P.; Helmchen, G.
Angew. Chem., Int. Ed. 2008, 47, 7652–7655. (b) Coldham, I.; Raimbault, S.;
Chovatia, P. T.; Patel, J. J.; Leonori, D.; Sheikha, N. S.; Whittakerb, D. T. E.
Chem. Commun. 2008, 4174–4176. (c) Wu, T. R.; Chong, J. M. J. Am. Chem.
Soc. 2006, 128, 9646–9647. (d) Welter, C.; Dahnz, A.; Brunner, B.; Streiff, S.;
Du1bon, P.; Helmchen, G. Org. Lett. 2005, 7, 1239–1242. (e) Welter, C.;
Koch, O.; Lipowsky, G.; Helmchen, G. Chem. Commun. 2004, 896–897. (f)
Braun, M.; Kotter, W. Angew. Chem., Int. Ed. 2004, 43, 514–517. (g)
Fernandes, R. A.; Stimac, A.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125,
14133–14139.
(1) For reviews, see: (a) Michael, J. P. Nat. Prod. Rep. 2007, 24, 191–222.
(b) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139–165.
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1142. (b) Suh, Y. G.; Kim, S. A.; Jung, J. K.; Shin, D. Y.; Min, K. A.; Koo,
B. A.; Kim, H. S. Angew. Chem., Int. Ed. 1999, 38, 3545–3547.
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Tetrahedron 2008, 64, 2951–2961. (b) Takahata, H.; Kubota, M.; Ikota, N.
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DOI: 10.1021/jo902615u
r
Published on Web 02/15/2010
J. Org. Chem. 2010, 75, 1911–1916 1911
2010 American Chemical Society

Cheng et al.
JOCArticle
SCHEME 1
SCHEME 2
SCHEME 3
CHART 1
excellent chiral auxiliary in total syntheses of natural alkaloids
(2S,6R)-dihydropinidine and (2S,6R)-isosolenopsins.14b As
shown in Scheme 2, one of the key steps is removal of the
auxiliary residue via an N-debenzylation under hydrogenolysis.
But, this original procedure has the same limitation as that of
nonracemic 2-phenylglycinol, because no alkene group could
be survived under hydrogenolysis conditions.
synthesis2,4b,6a,9,10 are the major methods for this purpose
because of their satisfied enantioselectivity and ease in scale
up. Interestingly, nonracemic 2-phenylglycinol as an auxi-
liary has been well-known in the preparation of chiral
piperidines,11 but it was rarely used for the preparation of
such compounds.2a,10,12 This phenomenon may result from
the fact that the removal of its N-benzylated auxiliary residue
seriously suffered from low efficiency under non-hydrogeno-
lysis conditions.13 In fact, a general, efficient, and scalable
method for the preparation of such compounds is still not
available.
Herein, we would like to report such a method, by which
the reported chiral 2-alkene- or 2-alkyne-containing chain
substituted N-Boc-piperidines (1) were prepared in the gram
scale within a few hours. The total syntheses of natural
alkaloids (þ)-pelletierine (2), (-)-lasubine II (3), and (þ)-
cermizine C (4) were achieved by using (S)-2-allyl-N-Boc-
piperidine (1h) as a versatile building block (Chart 1).
However, we realized that intermediate 5 can also be
considered as a Mannich derivative of o-phenol, which often
served as a good precursor to generate o-quinone methides.15
Investigation showed that this generation could be influ-
enced by thermal initiation,16 photoirradiation,17 or bases18
(Scheme 3). Deductively, when 5 is treated by one of those
conditions, the corresponding o-quinone methide may be
formed accompanied by an N-debenzylation.
Thus, (R)-Betti base was condensed with 1,5-pentanedial
in the presence of 1,2,3-benzotriazole (BtH) to give a diaster-
eopure pyrido[2,1-b][1,3]oxazine (6) in 93% yield by a known
procedure.14b As shown in Scheme 4, when 6 was treated
with Grignard reagents (7a-g) in THF, highly diastereo-
and regioselective alkylations occurred on its C11 to give the
corresponding 8a-g in excellent yields. However, the alkyla-
tion occurred on both C7a and C11 when Et2O was used as
solvent. All those alkylations may go through an SN2
mechanism because the Bt-group was replaced with com-
plete inversion of configuration. Many attempts proved that
H2CdCHCH2MgBr was not a suitable reagent for this
alkylation. But, this problem was easily resolved by using
H2CdCHCH2TMS as an alternative19 in the presence of
Results and Discussion
Enantiopure Syntheses of 2-Alkene- or 2-Alkyne-Contain-
ing Chain Substituted Piperidines. In our recent works, Betti
base was resolved to its nonracemic isomers in kilogram scale
by a kinetic resolution.14a (S)-Betti base has proved to be an
BF3 Et2O and the diastereoselectivity was controlled by
3
temperature. At room temperature, a mixture with 11R-
isomer as the major product (11R:11S=9:1) was obtained.
(9) (a) Turcaud, S.; Sierecki, E.; Martens, T.; Royer, J. J. Org. Chem. 2007,
72, 4882–4885. (b) Pandey, G.; Das, P. Tetrahedron Lett. 1997, 38, 9073–9076.
(c) Wanner, K. T.; Wadenstorfer, E.; Kaertner, A. Synlett 1991, 797–799.
(15) For a review, see: Van De Water, R. W.; Pettus, T. R. R. Tetrahedron
2002, 58, 5367–5405.
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(16) (a) Bew, S. P.; Hughes, D. L.; Sharma, S. V. J. Org. Chem. 2006, 71,
7881–7884. (b) Yaacov Herzig, Y.; Lena Lerman, L.; Goldenberg, W.;
Lerner, D.; Gottlieb, H. E.; Nudelman, A. J. Org. Chem. 2006, 71, 4130–
4140.
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K. N.; Mitchell, C. H.; Freccero, M.; Rokita, S. E. J. Am. Chem. Soc.
2006, 128, 11940–11947. (b) Colloredo-Mels, S.; Doria, F.; Verga, D.;
Freccero, M. J. Org. Chem. 2006, 71, 3889–3895. (c) Richter, S.; Maggi, S.;
Colloredo-Mels, S.; Palumbo, M.; Freccero, M. J. Am. Chem. Soc. 2004, 126,
13973–13979.
(18) (a) Antonio, M. D.; Doria, F.; Mella, M.; Merli, M.; Profumo, A.;
Freccero, M. J. Org. Chem. 2007, 72, 8354–8360. (b) Modica, E.; Zanaletti,
R.; Freccero, M.; Mella, M. J. Org. Chem. 2001, 66, 41–52. (c) Katritzky,
A. R.; Zhang, Z.; Lan, X.; Lang, H. J. Org. Chem. 1994, 59, 1900–1903.
(19) Veerman, J. J. N.; Klein, J.; Aben, R. W. M.; Scheeren, H. W.; Kruse,
C. G.; Maarseveen, J. H.; Rutjes, F. P. J. T.; Hiemstra, H. Eur. J. Org. Chem.
2002, 3133–3139.
Tetrahedron: Asymmetry 2008, 19, 2406–2410. (b) Amat, M.; Lozano, O.;
Escolano, C.; Molins, E.; Bosch, J. J. Org. Chem. 2007, 72, 4431–4439. (c)
Amat, M.; Escolano, C.; Gomez-Esque, A.; Lozano, O.; Llor, N.; Griera, R.;
Molins, E.; Bosch, J. Tetrahedron: Asymmetry 2006, 17, 1581–1588.
(11) For selected reviews, see: (a) Groaning., M. D.; Meyers, A. I.
Tetrahedron 2000, 56, 9843–9873. (b) Husson, H.-P.; Royer, J. Chem. Soc.
Rev. 1999, 28, 383–394.
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(13) (a) Fains, O.; Vernon, J. M. Tetrahedron Lett. 1997, 38, 8265–8266.
(b) Nyzam, V.; Belaud, C.; Zammattio, F.; Villieras, J. Tetrahedron: Asym-
metry 1996, 7, 1835–1843. (c) Burgess, L. E.; Meyers, A. I. J. Org. Chem.
1992, 57, 1656–1662. (d) Mehmandoust, M.; Marazano, C.; Das, B. C.
J. Chem. Soc., Chem. Commun. 1989, 1185–1187.
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J. Org. Chem. 2005, 70, 1897–1900.
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SCHEME 4
SCHEME 6
SCHEME 7
SCHEME 5
However, the ratio of 11S-isomer increased fast by decreas-
ing the reaction temperature. At -20 °C, desired 8h was
obtained in 90% yield as a single product. When 8f and 8g
were hydrogenated over Lindlar catalyst, 8f gave an unse-
parated mixture, while 8g was selectively converted into cis-
alkene 8i in almost quantitative yield.
As shown in Scheme 5, when 8h was treated with LiAlH4 in
THF, its C-O bond was cleaved smoothly at 0 °C within 30
min. After the reduction was quenched by aq NaOH, we
interestingly found that, besides the expected 9h, 2-allylpi-
peridine (10) was also isolated in 23% yield. However, the
same reaction quenched by saturated aq NH4Cl gave only
8% yield of 10. Those results clearly indicated that a base-
catalyzed N-debenzylation of 9h occurred during the workup
performance.
Further experiments showed slight improvement on the
yield of 10 even by heating 9h in aq NaOH at 60 °C.
Considering the base-catalyzed N-debenzylation of 9h may
go through an o-quinone methide mechanism, MeOH was
added as a nucleophilic reagent. As was expected, the yield of
10 was increased up to 59% by using MeOH as a cosolvent.
Finally, when a solution of 9h in aq NaOH (6.0 M)-
MeOH-THF (1:2:2 by v/v) was heated at 60 °C for 1 h
followed by treatment with Boc2O, 2-allyl-N-Boc-piperidine
(1h) was obtained in 85% yield. Control experiments proved
that each component in this combined reagent was neces-
sary. As shown in Scheme 6, we hypothesized that (a) aq
NaOH was a real catalyst for the formation of 11, (b) MeOH
was used as a nucleophilic reagent to capture 11, and (c) the
use of THF may increase the solubility of the reaction
system. This hypothesis was strongly supported by the fact
that the racemic 12 was obtained as a byproduct in 89%
yield.
As shown in Scheme 7, the reductive cleavage of the C-O
bond in 9a-i was accomplished smoothly by a similar
procedure. However, when 8f was treated with LiAlH4 in
refluxed THF for 1 h, a cleavage of the C-O bond and a
selective reduction of alkyne occurred simultaneously to give
trans-alkene 9j as a single product. Since the rotation of the 2-
substituted piperidine moiety was restricted by a strong
hydrogen bond, the structural assignments of 9a-j suffered
1
from ambiguous H and 13C NMR spectra14b (coalescence
phenomenon). Therefore, they were directly used in the
next step without further purification and characterization.
Under standard conditions (aq NaOH-MeOH-THF, at
60 °C), the alkene substrates (9a-e,h-j) were N-debenzylated
within 1 h and the alkyne substrates (9f-g) needed longer time.
Since we have proved that the procedure for removal of the
auxiliary does not lead to racemization of the product (see
the Supporting Information), therefore, enantiopure 1a-j were
obtained in 75-86% overall yields from 8a-i.
Total Syntheses of (þ)-Pelletierine (2) and (-)-Lasubine II
(3). Alkaloid 3 was isolated from the leaves of Lagerstroemia
subcostata Koehne in 1978.20 Due to its representative
(20) Fuii, K.; Yamada, T.; Fuiita, E.; Murata, H. Chem. Pharm. Bull.
1978, 26, 2515–2521.
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SCHEME 8
SCHEME 9
quinolizidine-alkaloid structure, it often served as a good
vehicle for the validation of new synthetic methodology. A
variety of precursors have been used in asymmetrical total
syntheses of 3.21 However, the most efficient one appeared in a
racemic route, in which (()-3 was constructed in a single step
from (()-2.22 This method has never been employed in asym-
metrical synthesis of 3, possibly because the preparation of
nonracemic 2 is not a trivial task up to now.23 On the basis of
our method, 1h was synthesized in the gram scale within a few
hours in three steps. As shown in Scheme 8, 1h carried out a
Wacker oxidation to give (S)-N-Boc-pelletierine (13) in 91%
yield. Then 13 was treated with TFA to give 2 in 99% yield.
In 1984, Kibayashi22 reported that a base-catalyzed (1%
aq NaOH) condensation between (()-2 and 3,4-dimethoxy-
benzaldehyde gave a mixture of (()-14a and (()-14b. Later,
Pilli24 found that (()-14a could be isomerized completely
into the thermodynamically more stable (()-14b in the
presence of 2.0 M aq NaOH. When we heated the mixture
of 2 and 3,4-dimethoxybenzaldehyde in 2.0 M aq NaOH at
60 °C for 70 h, 14b was obtained in 70% yield as a single
isomer, by which the condensation and isomerization were
achieved in one pot. Finally, 14b was reduced with K-
Selectride to give desired 3 in 90% yield. Thus, the total
synthesis of 3 was accomplished in seven steps [starting from
(R)-Base base] and in 40.4% overall yield.
We proposed that 16 may be prepared within two highly
efficient steps from 1h. As shown in Scheme 9, 1h was treated
with TFA to give a crude deprotected product. Without
purification, it was directly converted into R,β-unsaturated
amide 15 in 96% yield. When the mixture of 15 and Grubbs
catalyst (2st generation, 3% mol) was refluxed in CH2Cl2 for
15 min, an extremely efficient RCM reaction was achieved to
give 16 in 98% yield.
Following the procedure of Snider, 16 was stereoselec-
tively methylated by Me2CuLi to give 17 in 82% yield in the
presence of BF3 Et2O. We observed that this methylation
3
was so sensitive to solvent that no reaction occurred in THF.
(þ)-Cermizine C (4) was obtained in a methylation of 17 with
MeMgBr followed by a stereoselective reduction with
NaBH3CN. Finally, it was converted into the corresponding
hydrochloride 4 HCl in 95% yield for a convenient separa-
3
tion. Thus, the total synthesis of 4 HCl was accomplished in
3
seven steps [starting from (R)-Base base] and in 52.1%
overall yield.
Conclusion
In conclusion, a general and efficient method for the
preparation of 2-alkene- or 2-alkyne-containing chain sub-
stituted piperidines was established by using nonracemic
Betti base as a chiral auxiliary. The key step is that the
removal of the auxiliary residue went through a novel base-
catalyzed generation of o-quinone methide mechanism. By
using 1h as a versatile building block, total syntheses of
natural alkaloids (þ)-pelletierine, (-)-lasubine II, and (þ)-
cermizine C were achieved in the shortest steps and highest
overall yields.
Total Syntheses of (þ)-Cermizine C (4). Alkaloid 4 was
isolated in 2004 from the club moss Lycopodium cernuum25
and it structurally belongs to a quinolizidine-alkaloid. The
only total synthesis of 4 was reported by Snider,26a in which
R,β-unsaturated lactam 16 was used as a key intermediate.
Recently, an alternative preparation of 16 was reported, but
the protocol is still tedious.26b
Experimental Section
(21) (a) Lim, J.; Kim, G. Tetrahedron Lett. 2008, 49, 88–89. (b) Yu, R. T.;
Ravis, T. J. Am. Chem. Soc. 2006, 128, 12370–12371. (c) Back,
T. G.; Hamilton, M. D.; Lim, V. J. J.; Pavez, M. J. Org. Chem. 2005, 70,
967–972. (d) Zaja, M.; Blechert, S. Tetrahedron 2004, 60, 9629–9634. (e)
Gracias, V.; Zeng, Y.; Desai, P.; Aube, J. Org. Lett. 2003, 5, 4999–5001. (f)
Back, T. G.; Hamilton, M. D. Org. Lett. 2002, 4, 1779–1781. (g) Ma, D.; Zhu,
W. Org. Lett. 2001, 3, 3927–3929. (h) Davis, F. A.; Chao, B. Org. Lett. 2000,
2, 2623–2625.
(22) Iida, H.; Tanaka, M.; Kibayashi, C. J. Org. Chem. 1984, 49, 1909–
1912.
(23) Carlson, E. C.; Rathbone, L. K.; Yang, H.; Collett, N. D.; Carter,
R. G. J. Org. Chem. 2008, 73, 5155–5158.
(24) Pilli, R. A.; Dias, L. C.; Maldaner, A. O. J. Org. Chem. 1995, 60, 717–
722.
(25) Morita, H.; Hirasawa, Y.; Shinzato, T.; Kobayashi, J. Tetrahedron
2004, 60, 7015–7023.
(26) (a) Snider, B. B.; Grabowski, J. F. J. Org. Chem. 2007, 72, 1039–1042.
(b) Amat, M.; Griera, R.; Fabregat, R.; Bosch, J. Tetrahedron: Asymmetry
2008, 19, 1233–1236.
A Typical Procedure for Preparation of (7aS,11S,13R)-
11-Isopropenyl-13-phenyl-7a,8,10,11-tetrahydro-9H,13H-naphtho-
[1,2-e]pyrido[2,1-b][1,3]oxazine (8a). To a cold solution (ice-
water bath) of 6 (4.32 g, 10 mmol) in dry THF (70 mL) was
added isopropenyl magnesium bromide (0.5 M in THF, 6 mL,
30 mmol) dropwise under nitrogen. After the reaction was
stirred at 0 °C for 1.0 h (monitored by TLC), a saturated
aqueous solution of NH4Cl (30 mL) was added to quench the
reaction. Then the resulting mixture was extracted with CH2Cl2
(3 ꢀ 30 mL). The combined organic layers were washed with
H2O and brine and dried over anhydrous Na2SO4. After re-
moval of the solvent, the residue was purified by chromatography
(silica gel, EtOAc:PE=1:15) to give desired product 8a (3.26 g,
92%) as a colorless crystal, mp 130-131 °C, [R]25 -212.3
D
1914 J. Org. Chem. Vol. 75, No. 6, 2010

Cheng et al.
JOCArticle
(c 0.3, CHCl3). IRν 3069, 2943, 1625 cm-1; 1H NMR δ7.61-7.58
(m, 2H), 7.29-7.11 (m, 9H), 5.48 (s, 1H), 5.14 (s, 1H), 5.07-5.04
(m, 2H), 3.03-2.99 (m, 1H), 2.15-2.12 (m, 1H), 1.76 (s, 3H),
1.68-1.54 (m, 4H), 1.08-1.04 (m, 1H); 13C NMR δ 150.3, 147.0,
138.0, 130.9, 130.5 (2C), 128.7 (2C), 128.4, 127.6 (2C), 127.3,
126.2, 122.7, 121.9, 118.0, 115.0, 113.6, 81.8, 62.2, 56.9, 32.2, 31.8,
20.3, 18.1; MS m/z (%) 355 (Mþ, 5.09), 231 (100). Anal. Calcd for
C25H25NO: C, 84.47; H, 7.09; N, 3.94. Found: C, 84.30; H, 7.11;
N, 4.01.
with aq HCl (1.0 M, 3 ꢀ 10 mL), and the combined aqueous
layers were neutralized by aq NaOH (6.0 M) and extracted with
CH2Cl2 (3 ꢀ 10 mL). The combined organic layers were washed
with brine, dried with Na2SO4, and filtered.
To the filtrate of the free amine were immediately added
Boc2O (650 mg, 3 mmol) and K2CO3 (830 mg, 6 mmol). After
the mixture was stirred for 1 h at room temperature, it was
concentrated under vacuum. Then the residue was diluted with
THF (10 mL) and aq NaOH (6.0 M, 5 mL). After the unreacted
Boc2O was destroyed (ca. 1 h), the reaction mixture was
neutralized by aq HCl (1.0 M) and extracted with CH2Cl2
(3 ꢀ 10 mL). The combined organic layers were washed with
brine and dried with anhydrous Na2SO4. After removal of the
solvent, the residue was purified by chromatography (silica gel,
EtOAc:PE=1:15) to give desired product 1a (560 mg, 83%) as a
colorless oil, [R]25D -56.3 (c 0.22, CHCl3). IR ν 2939, 1693, 1411
cm-1; 1H NMR δ 4.97 (d, J=1.4 Hz, 1H), 4.74 (s, 1H), 4.65 (br,
s, 1H), 3.96 (d, J=13.7 Hz, 1H), 2.74-2.69 (m, 1H), 2.01-1.97
(m, 1H), 1.68 (s, 3H), 1.64-1.51 (m, 5H), 1.45 (s, 9H); 13C NMR
δ 155.3, 142.8, 111.5, 79.1, 54.7, 39.9, 28.3 (3C), 26.2, 25.4, 20.7,
19.4; MS m/z (%) 154 (22), 128 (62), 84 (50), 57 (100). Anal.
Calcd for C13H23NO2: C, 69.29; H, 10.29; N, 6.22. Found: C,
69.19; H, 10.10; N, 6.45.
By using a similar procedure, the intermediates 8b-g were
1
prepared (the experiments, characterization, and H and 13C
NMR spectra for products 8b-g are given in the Supporting
Information).
Preparation of (7aS,11S,13R)-11-(2-Propenyl)-13-phenyl-7a,
8,10,11-tetrahydro-9H,13H-naphtho[1,2-e]pyrido[2,1-b][1,3]-
oxazine (8h). Allyltrimethylsilane (11.4 g, 100 mmol) and BF3
3
OEt2 (14.2 g, 100 mmol) were added to a solution of 6 (4.32 g, 10
mmol) in dry CH2Cl2 (200 mL) at -20 °C. After stirring for 12 h
at -20 °C, the reaction mixture was then poured into saturated
aqueous K2CO3 (100 mL), the organic layer was separated, and
the aqueous layer was extracted with CH2Cl2 (3 ꢀ 50 mL). The
combined organic layers were washed with H2O and brine and
dried over anhydrous Na2SO4. After removal of the solvent, the
residue was purified by chromatography (silica gel, EtOAc:PE=
1:15) to give desired product 8h (3.20 g, 90%) as a white crystal,
mp 123-124 °C, [R]25D -162.8 (c 0.18, CHCl3). IR ν 3059, 2937,
1621 cm-1; 1H NMR δ 7.70-7.60 (m, 2H), 7.29-7.01 (m, 9H),
5.52-5.39 (m, 1H), 5.12 (s, 1H), 4.894.86 (m, 1H), 4.79-4.70 (m,
2H), 3.32-3.29 (m, 1H), 2.28-2.17 (m, 1H), 2.15-1.17 (m, 7H);
13C NMR δ 154.5, 143.9, 136.9, 131.7, 128.9 (2C), 128.8, 128.7,
128.5, 128.0 (2C), 126.9, 126.3, 123.2, 122.9, 119.1, 116.3, 114.3,
81.4, 60.7, 59.1, 35.2, 29.4, 27.2, 13.6; MS m/z (%) 355 (Mþ,
2.37), 231 (100). Anal. Calcd for C25H25NO: C, 84.47; H, 7.09;
N, 3.94. Found: C, 84.79; H, 7.20; N, 3.90.
By using a similar procedure, the compounds 1b-j were
1
prepared. (The experiments, characterization, and H and 13C
NMR spectra for products 1b-j are given in the Supporting
Information.)
(S)-2-(2-Oxo-propyl)piperidine-1-carboxylic Acid tert-Butyl
Ester (13). A suspension of PdCl2 (39 mg, 0.22 mmol) and CuCl
(220 mg, 2.2 mmol) in a solution of DMF and H2O (10:1) (3 mL)
was stirred under oxygen atmosphere at room temperature for
1 h. A solution of 1h (500 mg, 2.2 mmol) in DMF and H2O (10:1)
(2 mL) was added to the reaction mixture. After 10 h at room
temperature, the mixture was quenched with 20% KHSO4 and
extracted with Et2O (3 ꢀ 10 mL). The extracts were washed with
saturated NaHCO3 and brine and dried with anhydrous
Na2SO4 After removal of the solvent, the residue was purified
with chromatography (silica gel, EtOAc:PE=1:5) to yield 13
(487 mg, 91%), [R]25D -12.7 (c 0.22, CHCl3). IR ν 2934, 1686,
1412 cm-1; 1H NMR δ 4.73 (br, d, J=3.4 Hz, 1H), 3.97 (br, d,
J=12.0 Hz, 1H), 2.78 (t, J=12.7 Hz, 1H), 2.66 (d, J=7.2 Hz,
2H), 2.19 (s, 3H), 1.71-1.50 (m, 6H), 1.45 (s, 9H); 13C NMR δ
206.8, 154.5, 79.4, 47.0, 44.1, 39.2, 29.9, 28.2, 28.1 (3C), 25.1,
18.7; MS m/z (%) 241 (Mþ, 0.12), 84 (100). Anal. Calcd for
C13H23NO3: C, 64.70; H, 9.61; N, 5.80. Found: C, 64.82; H, 9.75;
N, 5.67.
(7aS,11S,13R)-11-[(1Z)-1-Propenyl]-13-phenyl-7a,8,10,11-
tetrahydro-9H,13H-naphtho[1,2-e] pyrido[2,1-b][1,3]oxazine (8i).
A mixture of compound 8g (3.53 g, 10 mmol) and Lindlar cata-
lyst (5% Pd/CaCO3 poisoned with lead, 353 mg) in THF (80
mL) under H2 was stirred at room temperature and atmospheric
pressure until the absorption of hydrogen ceased. After the
catalyst was filtered out and the filtrate was evaporated, the
residue was purified by chromatography (silica gel, EtOAc:PE=
1:15) to give desired product 8i (3.52 g, 99%) as a white crystal,
mp 113-114 °C, [R]25D -174.5 (c 0.16, CHCl3). IR ν 3054, 2934,
1621 cm-1; 1H NMR δ 7.68-7.60 (m, 2H), 7.23-7.18 (m, 9H),
5.65-5.62 (m, 1H), 5.29 (s, 1H), 5.22-5.12 (m, 1H), 4.98-4.95
(m, 1H), 3.92-3.89 (m, 1H), 1.98-1.79 (m, 4H), 1.65-1.53 (m,
4H), 1.51-1.30 (m, 1H); 13C NMR δ 152.4, 141.9, 132.8, 131.8,
129.5 (2C), 128.7, 128.6, 128.4, 127.9 (2C), 127.1, 126.1, 124.6,
122.7 (2C), 118.5, 114.6, 81.5, 59.7, 54.9, 31.4, 30.4, 16.5, 13.0;
MS m/z (%) 355 (Mþ, 10.83), 231 (100). Anal. Calcd for
C25H25NO: C, 84.47; H, 7.09; N, 3.94. Found: C, 84.52; H,
7.12; N, 4.18.
A Typical Procedure for the Preparation of (S)-2-Isopropenyl-
piperidine-1-carboxylic Acid tert-Butyl Ester (1a). To a cold
solution (ice-water bath) of 8a (1.07 g, 3 mmol) in dry THF
(20 mL) was added LiAlH4 (170 mg, 4.5 mmol) under nitrogen.
After the mixture 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 resulting mixture was
extracted with Et2O (3 ꢀ 10 mL). The combined organic layers
were washed with H2O and brine and dried over anhydrous
Na2SO4.
Preparation of (S)-(þ)-Pelletierine (2). To a stirred solution of
13 (434 mg, 1.8 mmol) in CH2Cl2 (5 mL) was added TFA (4 mL)
dropwise at 0 °C under N2. The resulting solution was stirred at
0 °C for 2 h. Then, aq NaOH (6.0 M) was added until pH 10. The
aqueous layer was extracted with CH2Cl2 (5 ꢀ 20 mL). The
combined organic layers were washed with brine and dried with
MgSO4. Removal of the solvent under vacuum gave teh product
(S)-(þ)-pelletierine (2) as a yellowish oil (253 mg, 99%), which
was pure enough to use in the next step without purification. The
analytical data were obtained from a purified sample by chro-
25
matography (silica gel, EtOAc:PE=3:7). [R]D þ19.4 (c 0.47,
EtOH) [lit.27 for (R)-(-)-pelletierine, [R]25D -22.1 (c 4.1, EtOH)].
IR ν 3326, 2930, 1709, 1356 cm-1; 1H NMR δ 3.04-2.89 (m, 2H),
2.71-2.61 (m, 1H), 2.56-2.49 (m, 2H), 2.36 (s, 1H), 2.14 (s, 3H),
1.77-1.70 (m, 1H), 1.62-1.54 (m, 2H), 1.52-1.30 (m, 2H),
1.22-1.08 (m, 1H); 13C NMR δ 208.0, 52.1, 50.4, 46.5, 32.2,
30.3, 25.7, 24.3; MS m/z (%) 141 (Mþ, 3.6), 84 (100). Anal. Calcd
for C8H15NO: C, 68.04; H, 10.71; N, 9.92. Found: C, 68.36; H,
10.75; N, 9.87.
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). After the reaction mixture was stirred at 60 °C for 1 h, it
was cooled to 0 °C, then diluted with CH2Cl2 (30 mL) and stirred
with aq HCl (1.0 M, 10 mL) for 0.5 h. The mixture was extracted
(27) Takahata, H.; Kubota, M.; Takahashi, S.; Momose, T. Tetrahedron:
Asymmetry 1996, 7, 3047–3054.
J. Org. Chem. Vol. 75, No. 6, 2010 1915

Cheng et al.
JOCArticle
Preparation of (4S,9aS)-4-(3,4-dimethoxyphenyl)octahydro-
2H-quinolizin-2-one (14b). To a stirring solution of (S)-(þ)-
pelletierine (2) (141 mg, 1.0 mmol) and 3,4-dimethoxylbenzal-
dehyde (166 mg, 1.0 mmol) in CH3OH (10 mL) was added aq
NaOH (2.0 M, 5 mL) under N2. After the resulting mixture was
stirred at 60 °C for 70 h, it was neutralized by addition of aq HCl
(10%) and extracted with CH2Cl2 (3 ꢀ 10 mL), then the
combined organic layers were washed with brine and dried over
MgSO4. After removal of the solvent, the residue was purified by
chromatography (silica gel, EtOAc:PE=1:1) to give the desired
product 14b (202 mg, 70%) as a yellow oil, [R]25D -70.6 (c 0.22,
CHCl3) [lit.21f [R]25D -86 (c 0.3, CHCl3), lit.28 for (4R,10R)-14b,
Preparation of (9aS)-1,6,7,8,9,9a-Hexahydro-4H-quinolizin-
4-one (16). To a stirred solution of 15 (270 mg, 1.5 mmol) in
CH2Cl2 (10 mL) was added Grubbs 2st generation catalyst (38
mg, 0.045 mmol) in one portion at room temperature under N2.
After the resulting solution was refluxed for 15 min, the solution
was allowed to cool to room temperature. Removal of the
solvent under vacuum gave a crude product, which was purified
by chromatography (silica, EtOAc:PE=1:1) to give product 16
(227 mg, 98%) as a colorless oil, [R]25D þ45.7 (c 0.42, CHCl3);
[lit.26a [R]22 þ47 (c 1.0, CHCl3); lit.26b [R]22 þ45.1 (c 1.0,
D
D
CHCl3)]. IR ν 2933, 1668, 1613 cm-1; 1H NMR δ 6.51-6.45 (m,
1H), 5.89-5.84 (m, 1H), 4.49 (d, J=13.4 Hz, 1H), 3.57-3.40 (m,
1H), 2.60-2.45 (m, 2H), 2.25-2.13 (m, 1H), 1.86-1.68 (m, 3H),
1.56-1.38 (m, 3H); 13C NMR δ 165.2, 137.9, 124.3, 54.5, 42.7,
33.1, 30.8, 24.6, 23.7; MS m/z (%) 151 (Mþ, 7.05), 18 (100).
Anal. Calcd for C9H13NO: C, 71.49; H, 8.67; N, 9.26. Found: C,
71.55; H, 8.77; N, 9.08.
[R]25D þ71 (c 0.25, CHCl3)]. IR ν 2944, 1715, 1510, 1261 cm-1
;
1H NMR δ 6.91 (s, 1H), 6.82 (m, 2H), 3.90 (s, 3H), 3.87 (s, 3H),
3.20 (dd, J=12.0, 3.1 Hz, 1H), 2.80-2.60 (m, 2H), 2.55-2.20 (m,
4H), 1.78-1.20 (m, 7 H); 13C NMR δ 207.6, 149.2, 148.2, 135.0,
119.3, 110.9, 109.6, 69.8, 62.2, 55.8, 55.7, 52.6, 50.7, 48.6, 34.2,
25.7, 24.0; MS m/z (%) 289 (Mþ, 25.07), 191 (100). Anal. Calcd
for C17H23NO3: C, 70.56; H, 8.01; N, 4.84. Found: C, 70.62; H,
8.07; N, 4.68.
Preparation of (2S,9aS)-2-Methyloctahydro-4H-quinolizin-4-
one (17). To a suspension of CuI (383 mg, 2.0 mmol) in dry Et2O
(20 mL) was added dropwise a solution of MeLi in Et2O (1.6 M,
2.5 mL, 4 mmol) at 0 °C. After the resulting solutionwas stirred at
Preparation of (-)-Lasubine II (3). To a solution of 14b (145
mg, 0.5 mmol) in dry THF (10 mL) was added a solution of K-
Selectride in THF (1.0 M, 0.6 mL, 0.6 mmol) at -78 °C under
N2. After the resulting mixture was stirred at -78 °C for 1 h, it
was quenched by aq NaOH (1.0 M, 5 mL). After the mixture was
stirred for 1 h at room temperature, it was extracted with
CH2Cl2 (3 ꢀ 10 mL). The combined organic layers were washed
with brine and dried over MgSO4. After removal of the solvent,
the residue was purified by chromatography (silica gel, EtOAc:
PE=1:1) to give the desired product (-)-lasubine II (3) (131 mg,
0 °C for 30 min, it was cooled to -78 °C and BF3 OEt2 (0.26 mL,
3
2.0 mmol) was added dropwise. Five minutes later, a solution of
16 (151 mg, 1.0 mmol) in dry Et2O (10 mL) was added dropwise
and the resulting solution was stirred for 1 h. Then a saturated
NH4Cl solution (30 mL) was added and the organic layer
was separated. The aqueous layer was extracted with Et2O (3 ꢀ
10 mL) and the combined organic layers were washed with brine
and dried over MgSO4. After the solvent was evaporated under
vacuum, the residue was purified by chromatography (silica gel,
EtOAc:PE=1:1) to give product 17 (137 mg, 82%) as a colorless
oil, [R]25D -20.2 (c 0.4, CHCl3) [lit.26a [R]25D -21 (c 1.0, CHCl3)].
90%) as a yellow oil, [R]25D -51.0 (c 0.12, MeOH) [lit.21f [R]25
D
-53 (c 0.13, MeOH), lit.28 for (2R,4R,10R)-(þ)-lasubine II,
1
1
[R]25 þ50 (c 0.3, MeOH)]. IR ν 3563, 2932, 1515 cm-1; H
IR ν 2931, 1637, 1442 cm-1; H NMR δ 4.78-4.74 (m, 1H),
D
NMR δ 6.90-6.77 (m, 3H), 4.15 (s, 1H), 3.88 (s, 3H), 3.86 (s,
3H), 3.21 (dd, J=11.3, 3.5 Hz, 1H), 2.69 (d, J=11.7 Hz, 1H),
2.40-2.38 (m, 1H), 1.95-1.20 (m, 12H); 13C NMR δ 148.8,
147.6, 137.1, 119.6, 110.7, 110.3, 64.6, 63.3, 56.3, 55.8, 55.6, 53.0,
42.6, 40.2, 33.4, 26.0, 24.7; MS m/z (%) 291 (Mþ, 100), 164 (95).
Anal. Calcd for C17H25NO3: 70.07; H, 8.65; N, 4.81. Found:
70.11; H, 8.69; N, 4.70.
3.35-3.32 (m, 1H), 2.46-2.38 (m, 2H), 2.08-1.86 (m, 3H),
1.71-1.20 (m, 7H), 0.98 (d, J=6.2 Hz, 3H); 13C NMR δ 168.2,
55.3, 42.8, 40.4, 36.6, 33.4, 25.2, 24.8, 24.3, 20.2; MS m/z (%) 167
(Mþ, 25.69), 18 (100). Anal. Calcd for C10H17NO: C, 71.81; H,
10.25; N, 8.37. Found: C, 71.93; H, 10.29; N, 8.20.
Preparation of (þ)-Cermizine C Hydrochloride (4 HCl). To a
3
stirring solution of lactam 17 (250 mg, 1.5 mmoL) in dry THF
(15 mL) was added dropwise a solution of MeMgBr in THF
(1.0 M, 6 mL, 6 mmoL). After the mixture was allowed to heat
at 60 °C for 3 h, it was then cooled to 0 °C. Then NaBH3CN
(570 mg, 9 mmoL) was added followed by addition of glacial
acetic acid (0.75 mL). The resulting mixture was stirred for 1 h, a
saturated solution HCl in MeOH (15 mL) was added, then the
mixture was stirred for another 10 min. After the solvent was
evaporated under vacuum, the residue was purified by chromato-
Preparation of (2S)-N-Acryloyl-2-allylpiperidine (15). To a
stirred solution of 1h (450 mg, 2.0 mmol) in CH2Cl2 (5 mL) was
added TFA (4 mL) dropwise at 0 °C under N2. After the
resulting mixture was stirred at 0 °C for 2 h, aq NaOH (6.0 M)
was added until pH 10. The aqueous layer was extracted with
CH2Cl2 (3 ꢀ 20 mL) and the combined organic layers were
washed with brine.
To a stirred solution of the crude amine and aq NaOH (10%, 2
mL) was added a solution of acryloyl chloride (272 mg, 3 mmol) in
CH2Cl2 (5 mL) dropwise at room temperature under N2. After the
resulting mixture was stirred for 4 h, H2O (5 mL) were added and
the organic layer was separated. The aqueous layer was extracted
with CH2Cl2 (3 ꢀ 20 mL). The combined organic layers were
washed with brine and dried over MgSO4. Removal of the solvent
under vacuum gave a crude product, which was purified by
chromatography (silica, EtOAc:PE = 1:1) to give product 15
graphy (silica gel, CHCl3:MeOH=10:1) to give product 4 HCl
3
(288 mg, 95%) as a yellow wax, [R]25D þ8.4 (c 0.3, MeOH) [lit.26a
[R]23D -2.0 (c 0.4, MeOH); lit.25 [R]25D þ4.0 (c 0.8, MeOH)]. IR
ν 2931, 1637, 1442 cm-1; 1H NMR (CD3OD) δ 3.90-3.80 (m,
1H), 3.66-3.56 (m, 2H), 3.08 (ddd, J=13.1, 13.1, 3.3 Hz, 1H),
2.26-2.10 (m, 1H), 2.08-1.56 (m, 9H), 1.41-1.20 (m, 4H), 0.95
(d, J = 6.2 Hz, 3H); 13C NMR (CD3OD) δ 61.3, 51.2, 49.9,
41.7, 38.3, 25.5, 24.7, 23.8, 21.6, 18.5, 17.7; MS m/z (%) 167
(Mþ, 5.04), 152 (100). Anal. Calcd for C11H22ClN: C, 64.84; H,
10.88; N, 6.87. Found: C, 64.94; H, 10.91; N, 6.62.
(344 mg, 96%) as a colorless oil, [R]25 -70.6 (c 0.42, CHCl3).
D
IR ν 2937, 1643, 1609, 1432 cm-1; 1H NMR δ 6.60-6.52 (m, 1H),
6.21 (d, J=16.8 Hz, 1H), 5.65-5.60 (m, 2H), 5.04-5.10 (br, 2H),
4.11 and 4.91 (br, 1H), 3.75 and 4.55 (br, 1H), 2.70 and 3.11 (br,
1H), 2.46-2.27 (m, 2H), 1.71-1.58 (m, 5H), 1.52-1.30 (br, 1H);
13C NMR δ 165.5, 134.8, 133.9, 128.3, 126.4, 117.5, 116.4, 52.6,
47.3, 41.1, 36.5, 34.5, 33.9, 28.3, 26.9, 25.8, 24.9, 18.5; MS m/z (%)
179 (Mþ, 0.37), 84 (100). Anal. Calcd for C11H17NO: C, 73.70; H,
9.56; N, 7.81. Found: C, 73.78; H, 9.62; N, 7.60.
Acknowledgment. This work was supported by NNSFC
(20672066, 30600779) and CFKSTIP from Education Min-
istry of China (706003).
Supporting Information Available: Experiments, characteri-
1
zation, and H and 13C NMR spectra for 1a-j, 2, 3, 4 HCl,
3
8a-i, 12, 13, 14b, and 15-17. This material is available free of
charge via the Internet at http://pubs.acs.org.
(28) Mancheno, O. G.; Arrayas, R. G.; Adrio, J.; Carretero, J. C. J. Org.
Chem. 2007, 72, 10294–10297.
1916 J. Org. Chem. Vol. 75, No. 6, 2010