Enantiodivergent synthesis of the quinolizidine poison frog alkaloid 195C

Article abstract of DOI:10.1016/j.tet.2013.10.009

Herein, we describe the enantiodivergent synthesis of the 1,4-cis-disubstituted quinolizidine alkaloid 195C. Although the stereoselectivity of the final hydrogenation reaction was low, we have proposed the first chiral total synthesis of both (-)- and (+)-195C as an enantiodivergent process.

Full text of DOI:10.1016/j.tet.2013.10.009

Tetrahedron 69 (2013) 10311e10315
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Tetrahedron
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Enantiodivergent synthesis of the quinolizidine poison frog alkaloid
195C
,b,
Xu Wang a, Jie Li b, Ralph A. Saporito c, Naoki Toyooka a
*
a Graduate School of Innovative Life Science, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan
b Graduate School of Science and Technology for Research, University of Toyama, 3190 Gofuku, 930-8555, Japan
c Department of Biology, John Carroll University, University Heights, OH 44118, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein, we describe the enantiodivergent synthesis of the 1,4-cis-disubstituted quinolizidine alkaloid
195C. Although the stereoselectivity of the final hydrogenation reaction was low, we have proposed the
first chiral total synthesis of both (ꢀ)- and (þ)-195C as an enantiodivergent process.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 9 September 2013
Received in revised form 1 October 2013
Accepted 4 October 2013
Available online 18 October 2013
Keywords:
Enantiodivergent synthesis
Poison-frog alkaloid
195C
Quinolizidine
Brazilian myrmicine ant
1. Introduction
The poison frog alkaloid quinolizidine 195C has been detected in
numerous skin extracts from certain dendrobatid, bufonid, man-
tellid, and myobatrachid anurans,1 and an extract of a Brazilian
myrmicine ant.2 The presence of alkaloids in poison frogs is a direct
result of dietary uptake from certain alkaloid-containing arthro-
pods, including ants, mites, millipedes, and beetles.3 The quinoli-
zidine alkaloids are relatively rare in nature, but have a 4,6-cis-
disubstitution and exhibit intriguing biological activities. There
have been some synthetic studies of 195C,2,4 however the enan-
tioselective synthesis of this alkaloid has not been reported to date.
As part of our program directed at studying the synthesis of poison
frog alkaloids,5 we report here the enantiodivergent synthesis of
195C (Fig. 1).
Fig. 1. Structure of 195C.
known allyl derivative 1,6 which was prepared from
D-pipecolic
acid as shown in Scheme 1. Reduction of D-pipecolic acid with
LiAlH4 followed by protection of the resulting aminoalcohol with
ClCO2Me afforded alcohol 2 in good overall yield. After conversion
of 2 to the acetate 3,7 the anodic oxidation of 3 provided the
methoxy derivative 4. Treatment of 4 with base yielded the corre-
sponding oxazolizinone, which was transformed into the allyl de-
rivative 1 via the acyliminium ion8 as the single isomer in 75% yield.
2. Results and discussion
From the pseudo symmetric property of 195C, we planned the
enantiodivergent synthesis of 195C. The synthesis began with
* Corresponding author. Tel.: þ81 76 445 6859; fax: þ81 76 445 6697; e-mail
Scheme 1. Synthesis of key intermediate 1.
address: toyooka@eng.u-toyama.ac.jp (N. Toyooka).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.10.009

10312
X. Wang et al. / Tetrahedron 69 (2013) 10311e10315
Next we examined the synthesis of (ꢀ)-195C starting from the
common precursor 1. Hydrolysis of 1 followed by protection of the
resulting amine with CbzCl gave rise to the alcohol 5.9 Swern oxi-
dation of 5, and then the Wittig reaction of the resulting aldehyde
afforded the olefin 6 as the E, Z mixture. The cross-metathesis re-
action of the olefin 6 with methyl vinyl ketone proceeded smoothly
to yield the desired unsaturated ketone 7. Finally, the hydrogena-
tion reaction of 7 furnished the (ꢀ)-195C (½a D26
ꢀ14.1) along with
ꢁ
the epimer 8 on the 4-position as a 1.4:1 mixture. The structure of
(ꢀ)-195C was determined by the 1H, 13C NMR, MS, and HRMS
spectra. The spectral data of the epimer 8 were completely identical
with those of the reported values4b (Scheme 2).
Scheme 5. Synthesis of (þ)-195C.
In the favorable conformation on A and B, the n-propyl or
methyl substituent on the 4-position would occupy in the pseudo-
axial orientation due to the A1,3 strain between the substituent on
the iminium moiety. In the conformer A, hydrogenation would
occur from the less hindered
b
-face to give rise to (ꢀ)-195C as
a major product. On the other hand, in the confomer B, the propenyl
or n-propyl substituent on the iminium moiety would occupy the
upper face due to the steric repulsion with methyl group at the 4-
position, and hydrogenation would occur from the a-face to afford
14 as the major product (Fig. 2).12
Scheme 2. Synthesis of (ꢀ)-195C.
For the synthesis of (þ)-195C, we first tried to synthesize the
unsaturated ketone 10 from 5. However, all attempts to convert 5 to
the corresponding mesylate or iodide, which could have then been
converted to the corresponding methyl derivative 9, resulted in the
formation of 1 (Scheme 3).
Fig. 2. Stereoselectivity of the final hydrogenation step for 7 and 10.
3. Conclusions
This study represents the first chiral synthesis of the quinolizi-
dine alkaloid 195C. We have achieved the enantiodivergent syn-
thesis of both (ꢀ)- and (þ)-195C starting from the common
precursor of oxazolizinone 1. The antagonist activities of both en-
antiomers of this alkaloid against nicotinic acetylcholine receptors
are now in progress.
Scheme 3. Attempt to synthesize of 10 via mesylation of iodination of 5.
To avoid the formation of 1 as shown in Scheme 3, we next in-
vestigated the use of benzyl derivative 11, which was synthesized
from 1 in two steps as shown in Scheme 3. Treatment of 11 with
methyl vinyl ketone in the presence of Grubbs’ second-generation
catalyst or GrubbseHoveyda catalyst did not proceed, and the re-
sults were recovery of only 1110 (Scheme 4).
4. Experimental section
4.1. General
Flash chromatography was performed with Kanto Kagaku silica
gel 60N (63e210 mm). NMR spectra were recorded on a JEOL JNM-
A400 or JEOL JNM-ECX500 spectrometer in the solvent indicated.
Scheme 4. Attempt to synthesize of homologated ketone via cross metathesis.
Chemical shifts (d) are given in parts per million downfield from
TMS and referenced with CHCl3 (7.26 ppm) as an internal standard.
Peak multiplicities are designated by the following abbreviations: s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet; and br, broad.
Coupling constants are given in (J) Hertz. High resolution mass
spectral data was obtained on a JEOL JMS-GC MATE II or JEOL JMS-
AX505HAD. All commercial reagents were used as received unless
otherwise noted.
In an alternative attempt to synthesize (þ)-195C, we tried to
convert 11 to the methyl derivative 13 via iodide 12. Treatment of 11
with iodine and Ph3P afforded the iodide 12, which was reduced
with LiAlH4 to give rise to the desired reduction product 13.11 The
benzyl group in 13 was then transformed into the Cbz group by
thermal conditions to provide 9. The olefin cross-metathesis re-
action of 9 with 1-hexen-3-one in the presence of Grubbs’ second-
generation catalyst yielded the unsaturated ketone 10. Finally, hy-
drogenation reaction of 10 provided the two quinolizidines as
a 1:4.6 mixture. The structure of the minor product was de-
4.2. (R)-Methyl 2-(hydroxymethyl)piperidine-1-carboxylate (2)
termined to be (þ)-195C (½a D26
ꢁ
þ14.6) by comparing it to the 1H and
LiAlH4 (3.42 g, 30.00 mmol) was added to a stirred solution of
13C NMR spectra of (ꢀ)-195C (Scheme 5).
D
-pipecolic acid (3.87 g, 30.00 mmol) in THF (40 mL) at 0 ꢂC, and the

X. Wang et al. / Tetrahedron 69 (2013) 10311e10315
10313
resulting suspension was refluxed for 2 h. After cooling, the re-
action was quenched with 10% NaOH (aq), and the aqueous mixture
was extracted with hot ethyl acetate (10 mLꢃ5). The organic ex-
tracts were combined, dried over Na2SO4, and evaporated to give
a colorless oil, which was used directly in the next step. Saturated
NaHCO3 (aq) (40 mL) and ClCO2Me (2.5 mL, 33.00 mmol) were
added to a stirred solution of the above alcohol in THF (40 mL) at
room temperature, and the resulting mixture was stirred overnight.
The reaction mixture was diluted with CH2Cl2, the organic layer
was separated, and the aqueous layer was extracted with CH2Cl2
(20 mLꢃ3). The organic layer and extracts were combined, dried
over Na2SO4, and evaporated to give a pale yellow oil, which was
chromatographed on silica gel (30 g, hexane/acetone¼8:1) to afford
2 (5.1 g, 98%) as a colorless oil.
1H NMR (500 MHz)
d
1.24e1.36 (1H, m), 1.58e1.86 (5H, m),
2.24e2.30 (1H, m), 2.39e2.45 (1H, m), 3.73e3.79 (1H, m),
3.85e3.88 (1H, m), 4.01e4.05 (1H, m), 4.38 (1H, t, J¼8.1 Hz),
5.06e5.14 (2H, m), 5.73e5.80 (1H, m); 13C NMR (125 MHz)
d 17.37,
26.11, 30.10, 34.08, 48.42, 50.05, 67.91, 116.85, 134.14, 156.50; ½a D26
ꢁ
þ27.0 (c 1.00, MeOH), Ref. 6: ½a D25
ꢀ28.8 (c 1.02, MeOH).
ꢁ
4.6. (2R, 6R)-Benzyl 2-allyl-6-(hydroxymethyl)piperidine-1-
carboxylate (5)8
Oxazolidinone 1 (195 mg, 1.10 mmol) was added to a solution of
KOH (1M in iPrOH) (10.8 mL,10.80 mmol) at room temperature, and
the resulting solution was refluxed for 24 h. After cooling, the sol-
vent was evaporated, and then H2O (2 mL) was added to the resi-
due. After saturation with NaCl, the aqueous layer was extracted
with CH2Cl2 (10 mLꢃ5). The organic extracts were combined, dried
over NaSO4, and evaporated to give a pale yellow oil, which was
used directly in next step.
IR (neat) 3414, 2939, 1695, 1450, 1271, 770 cmꢀ1
;
1H NMR
(400 MHz) 1.25e1.53 (2H, m), 1.56e1.71 (4H, m), 2.92 (1H, t-like,
d
J¼10.9 Hz), 3.61e3.67 (1H, m), 3.70 (3H, s), 3.83 (1H, td-like, J¼10.9,
4.0 Hz), 3.96 (1H, br), 4.30e4.33 (1H, m); 13C NMR (125 MHz)
d
19.40, 25.07, 25.26, 40.00, 52.65 (two carbons), 60.81, 157.14; MS
Saturated NaHCO3 (aq) (3 mL) and ClCO2Bn (0.15 mL, 1.10 mmol)
were added to a stirred solution of the above oil in THF (3 mL) at
room temperature, and the resulting mixture was stirred overnight.
The reaction mixture was diluted with CH2Cl2, the organic layer
was separated, and the aqueous layer was extracted with CH2Cl2
(5 mLꢃ3). The organic layer and extracts were combined, dried
over Na2SO4, and evaporated to give a pale yellow oil, which was
chromatographed on silica gel (15 g, hexane/ethyl acetate¼10:1) to
afford 5 (260 mg, 84%) as a colorless oil.
(EI): m/z 173 [M]þ; HRMS: Calcd for C8H15NO3 [M]þ 173.1052; found
173.1051; ½a 2D6
þ40.2 (c 2.90, CHCl3).
ꢁ
4.3. (R)-Methyl 2-(acetoxymethyl)piperidine-1-carboxylate (3)7
Et3N (1.8 mL, 12.60 mmol) and Ac2O (0.95 mL, 10.10 mmol) were
added to a stirred solution of alcohol 2 (1.46 g, 8.40 mmol) in CH2Cl2
at 0 ꢂC, and the resulting mixture was stirred at room temperature
overnight. The solvent was evaporated and the residue was chro-
matographed on silica gel (30 g, hexane/acetone¼30:1) to afford 3
(1.8 g, 99%) as a pale yellow oil.
1H NMR (400 MHz)
d 2.20e2.27 (1H, m), 2.24e2.50 (1H, m), 3.54
(1H, br), 3.77e3.84 (2H, m), 4.30 (1H, br), 5.00e5.17 (4H, m),
5.63e5.72 (1H, m), 7.30e7.39 (5H, m); ½a D26
þ30.7 (c 1.00, MeOH),
ꢁ
1H NMR (400 MHz)
d
1.39e1.54 (2H, m), 1.56e1.68 (4H, m), 2.04
Ref. 3: ½a 2D3
ꢀ32.0 (c 0.99, MeOH).
ꢁ
(3H, s), 2.87 (1H, t-like, J¼13.2 Hz), 3.69 (3H, s), 4.04 (1H, br), 4.14
(1H, dd, J¼11.0, 6.6 Hz), 4.24 (1H, dd, J¼11.0, 8.4 Hz), 4.51 (1H, br s);
4.7. (2R, 6R)-Benzyl 2-allyl-6-(prop-1-en-1-yl)piperidine-1-
carboxylate (6)
½
a 2D6
ꢁ
þ41.0 (c 1.00, CHCl3), Ref. 7: ½a D28
ꢁ
ꢀ45.6 (c 1.10, CHCl3).
4.4. (R)-Methyl 2-(acetoxymethyl)-6-methoxypiperidine-1-
carboxylate (4)
DMSO (0.18 mL, 2.60 mmol) was added to a stirred solution of
(COCl)2 (0.11 mL, 1.30 mmol) in CH2Cl2 (5 mL) at ꢀ78 ꢂC, and the
reaction mixture was stirred at ꢀ78 ꢂC for 5 min. To the resulting
mixture, a solution of the alcohol 5 (250 mg, 0.86 mmol) in CH2Cl2
(5 mL) was added dropwise via a double-tripped stainless steel
needle at ꢀ78 ꢂC, and the reaction mixture was stirred at the same
temperature for 30 min. Triethylamine (0.54 mL, 3.89 mmol) was
added to the reaction mixture, and the reaction mixture was
warmed to 0 ꢂC for 1 h. The reaction was quenched with water, and
the organic layer was separated. The aqueous mixture was extrac-
ted with CH2Cl2 (10 mLꢃ2), and the organic layer and extracts were
combined, dried over Na2SO4, and evaporated to give a pale yellow
oil, which was used directly in the next step.
Et4NBF4 (540 mg, 1.82 mmol) was added to a solution of 3
(800 mg, 3.70 mmol) in MeOH (9 mL) and MeCN (36 mL) at room
temperature. The resulting mixture was stirred at ꢀ15 ꢂC for 2 h,
with 100 mA of electricity passing through it. The solvent was
evaporated and the residue was chromatographed on silica gel
(30 g, hexane/acetone¼40:1) to afford 4 (802 mg, 88%) as a pale
yellow oil.
1H NMR (400 MHz)
d 1.40e1.66 (3H, m), 1.74e1.91 (3H, m), 2.05
(3H, s), 3.27 & 3.32 (3H, br s), 3.73 (3H, s), 4.02e4.18 (1H, m), 4.37 &
4.51 (2H, br s), 5.30 & 5.48 (1H, br s).
n-BuLi (1.58 M in THF, 1.59 mL, 2.51 mmol) was added to a stir-
red suspension of ethyltriphenylphosphonium bromide (962 mg,
2.59 mmol) in THF (5 mL) and to the resulting orange solution was
added the above aldehyde in THF (5 mL) via a double-tripped
stainless steel needle at 0 ꢂC. After stirring the reaction mixture
for 1 h, the reaction was quenched with water. The aqueous mix-
ture was extracted with Ethyl acetate (10 mLꢃ3), and the organic
extracts were combined, dried over Na2SO4, and evaporated to give
a colorless oil, which was chromatographed on silica gel (15 g,
hexane/ethyl acetate¼50:1e30:1) to afford 6 (190 mg, 73%) as
a colorless oil.
4.5. (5R, 8aR)-5-Allyltetrahydro-1H-oxazolo[3,4-a]pyridin-
3(5H)-one (1)6
K2CO3 (360 mg, 2.60 mmol) was added to a stirred solution of 4
(640 mg, 2.60 mmol) in MeOH (12 mL) at room temperature, and
the resulting mixture was stirred for 1 h. The solvent was evapo-
rated, and the residue was dissolved in CH2Cl2, filtered by Celite,
and evaporated to give a pale yellow oil.
Allyltrimethylsilane (1.85 mL, 11.70 mmol) and TiCl4 (0.28 mL,
2.60 mmol) was added to a stirred solution of the above oil in
CH2Cl2 (15 mL) at ꢀ78 ꢂC, and the resulting mixture was stirred and
allowed to warm to room temperature over 1 h. The reaction was
quenched with saturated NaHCO3, and the aqueous mixture was
extracted with CH2Cl2 (10 mLꢃ3). The organic extracts were com-
bined, dried over NaSO4, and evaporated to give a residue, which
was chromatographed on silica gel (25 g, hexane/acetone¼10:1) to
give 1 (356 mg, 75%) as a colorless oil.
IR (neat) 2941, 1693, 1404, 1267, 1065 cmꢀ1; 1H NMR (500 MHz)
d
1.14e1.77 (7H, m), 1.81e1.94 (1H, m), 2.19e2.31 (1H, m),
2.33e2.43 (1H, m), 2.50e2.54 (1H, m), 3.95e4.02 (1H, m),
4.69e4.71 (1H, m), 5.00e5.09 (2H, m), 5.13e5.18 (2H, m),
5.44e5.57 (2H, m), 5.66e5.79 (1H, m), 7.22e7.50 (5H, m); 13C NMR
(125 MHz)
d 12.66 & 12.74, 14.19 & 14.32, 22.41 & 26.47, 27.23 &
30.21, 38.67 & 39.07, 47.30 & 48.91, 50.39 & 51.69, 66.51 & 66.82,

10314
X. Wang et al. / Tetrahedron 69 (2013) 10311e10315
116.67 & 116.77, 124.24 & 125.46, 127.69, 128.20, 131.01, 132.22,
135.61 & 135.97, 136.80 & 136.83, 155.63 & 155.70; MS (EI): m/z 299
[M]þ; HRMS: Calcd for C19H25NO2 [M]þ 299.1885; found 299.1883;
K2CO3 (250 mg, 1.81 mmol) was added to a stirred solution of
the above oil in MeCN (10 mL) and stirred for 15 min at room
temperature. BnCl (0.15 mL, 1.33 mmol) was then added to the
resulting mixture and refluxed overnight. The reaction solution
was diluted with CH2Cl2, and the insoluble materials were fil-
tered off by Celite and the filtrate was evaporated to give a pale
yellow oil, which was chromatographed on silica gel (15 g,
hexane/ethyl acetate¼10:1) to afford 11 (280 mg, 92%) as a col-
orless oil.
½
a 2D6
ꢁ
ꢀ45.4 (c 1.00, CHCl3).
4.8. (2R, 6R)-Benzyl 2-((E)-4-oxopent-2-en-1-yl)-6-(prop-1-
en-1-yl)piperidine-1-carboxylate (7)
Methyl vinyl ketone (0.22 mL, 2.67 mmol) and Grubbs’ second
catalyst (45 mg, 0.05 mmol) were added to a stirred solution of 6
(160 mg, 0.53 mmol) in CH2Cl2 (15 mL), and the resulting mixture
was refluxed for 12 h. After cooling, the solvent was evaporated,
and the residue was chromatographed on silica gel (10 g, hexane/
ethyl acetate¼10:1) to give 7 (140 mg, 77%) as a pale yellow oil.
IR (neat) 2947, 1682, 1404, 1254, 1099 cmꢀ1; 1H NMR (500 MHz)
IR (neat) 2931, 2854, 1444, 1450, 1179, 910, 732 cmꢀ1
;
1H NMR
(500 MHz) 1.14e1.22 (1H, m), 1.45e1.50 (2H, m), 1.57e1.80 (3H,
d
m), 2.19e2.25 (1H, m), 2.34e2.42 (1H, m), 2.87e2.94 (1H, m),
2.95e3.00 (1H, m), 3.25e3.28 (1H, m), 3.65 & 3.90 (2H, ABq,
J¼13.5 Hz), 3.71 (1H, t, J¼10.3 Hz), 5.05e5.09 (2H, m), 5.76e5.85
(1H, m), 7.16e7.47 (5H, m); 13C NMR (125 MHz)
d 20.43, 20.55,
d
1.61 (3H, d, J¼8.6 Hz), 1.63e1.73 (4H, m), 1.80e1.92 (2H, m), 2.18
24.35, 36.81, 48.88, 53.48, 54.52, 59.66, 116.27, 126.89, 128.29,
(3H, s), 2.42e2.48 (1H, m), 2.69e2.74 (1H, m), 4.06e4.10 (1H, m),
4.73e4.76 (1H, m), 5.10 & 5.13 (2H, ABq, J¼11.8 Hz), 5.46e5.54 (2H,
m), 6.04e6.07 (1H, d, J¼15.9 Hz), 6.74 (1H, td, J¼7.7, 15.9 Hz),
128.55, 136.11, 139.75; MS (EI): m/z 246 [MþH]þ; HRMS: Calcd for
C
16H24NO [MþH]þ 246.1858; found 246.1857; ½a 2D6
ꢀ22.6 (c 1.70,
ꢁ
CHCl3).
7.28e7.47 (5H, m); 13C NMR (125 MHz)
d 12.82, 14.47, 24.72, 26.73,
27.22, 37.77, 49.24, 51.39, 66.90, 125.17, 127.84, 128.41, 131.65,
4.12. (2R, 6R)-2-Allyl-1-benzyl-6-(iodomethyl)piperidine (12)
132.90, 136.73,137.84, 145.08, 155.80, 198.56; MS (EI): m/z 341[M]þ;
HRMS: Calcd for C21H27NO3 [M]þ 341.1991; found 341.1994; ½a 2D6
ꢁ
Imidazole (34 mg, 0.50 mmol), PPh3 (132 mg, 0.51 mmol), and
I2 (103 mg, 0.40 mmol) were added to a stirred solution of 11
(50 mg, 0.20 mmol) in benzene (3 mL), and the resulting mixture
was stirred at room temperature for 30 min. The reaction was
quenched with 10% Na2S2O3 in satd NaHCO3 (aq), and the aque-
ous layer was extracted with CH2Cl2 (5 mLꢃ3). The organic ex-
tracts were combined, dried over K2CO3, and evaporated to give
a pale yellow oil, which was chromatographed on silica gel (10 g,
hexane/ethyl acetate¼100:1) to give 12 (52 mg, 72%) as a color-
less oil.
ꢀ31.8 (c 0.75, CHCl3).
4.9. (4R, 6S, 9aS)-4-Methyl-6-propyloctahydro-1H-quinolizine
((L)-195C)
20% Pd(OH)2/C (5 mg) was added to a stirred solution of 7
(60 mg, 0.15 mmol) in MeOH (5 mL), and the resulting suspension
was stirred for 12 h under H2 atmosphere. The catalyst was filtered
off by Celite and the filtrate was evaporated to afford a 1.6:1 mix-
ture of the crude product, which was chromatographed on silica gel
(5 g, CH2Cl2/MeOH¼6:1 (in the presence of Et3N)) to give (ꢀ)-195C
(17 mg, 50%) and 8 (11 mg, 32%), whose spectral data were identical
with those reported for the racemic compound.4b
IR (neat) 2931, 2854, 1444, 1450, 1179, 910, 732 cmꢀ1
;
1H NMR
(500 MHz) 1.33e1.35 (1H, m), 1.58e1.70 (3H, m), 2.12e2.18 (1H,
d
m), 2.33e2.38 (1H, m), 2.75e2.82 (2H, m), 3.31e3.38 (2H, m), 3.61
& 3.81(2H, ABq, J¼12.5 Hz), 4.96e5.00 (2H, m), 5.70e5.77 (1H, m),
7.23 (1H, t, J¼6.9 Hz), 7.30 (2H, t, J¼7.5 Hz), 7.41 (2H, d, J¼7.5 Hz);
IR (neat) 2932, 2864, 2793, 1450, 1366, 1030 cmꢀ1
(500 MHz)
;
1H NMR
d
0.90 (3H, t, J¼7.5 Hz), 1.06 (3H, d, J¼6.3 Hz), 1.08e1.14
13C NMR (125 MHz)
d 10.76, 19.19, 26.16, 26.96, 34.54, 51.21, 53.90,
(2H, m), 1.23e1.40 (2H, m), 1.43e1.72 (11H, m), 1.75e1.86 (1H, m),
55.41,115.99,126.75,128.13,128.55,136.40,139.92; MS (EI): m/z 314
2.94e3.09 (1H, m), 3.10e3.15 (1H, m), 3.16e3.25 (1H, m); 13C NMR
[MꢀC3H5]þ; HRMS: Calcd for C13H17IN [MꢀC3H5]þ 314.0406; found
(125 MHz)
d
14.32, 19.79, 20.04, 20.24, 20.61, 22.27, 24.45, 29.88,
314.0407; ½a 2D6
ꢀ12.0 (c 2.50, CHCl3).
ꢁ
33.39, 34.03, 47.14, 49.40, 52.50; MS (EI): m/z 195 [M]þ; HRMS:
Calcd for C13H25N [M]þ 195.1987; found 195.1989; ½a 2D6
ꢁ
ꢀ14.1 (c
4.13. (2R, 6S)-2-Allyl-1-benzyl-6-methylpiperidine (13)10
1.00, CHCl3).
LiAlH4 (27 mg, 0.72 mmol) was added to a stirred solution of 12
(85 mg, 0.24 mmol) in THF (8 mL) at 0 ꢂC, and the resulting sus-
pension was refluxed for 13 h. After cooling, the reaction was
quenched with 10% NaOH (aq), and the aqueous mixture was
extracted with hot ethyl acetate (3 mLꢃ6). The organic extracts
were combined, dried over K2CO3, and evaporated to give a color-
less oil, which was chromatographed on silica gel (10 g, hexane/
ethyl acetate¼30:1) to give 13 (41 mg, 75%) as a colorless oil.
4.10. (4S, 6S, 9aS)-4-Methyl-6-propyloctahydro-1H-quinoli-
zine (8)4b
IR (neat) 2930, 2862, 2792, 1457, 1374, 1104 cmꢀ1
;
1H NMR
(500 MHz)
d
0.94 (3H, t, J¼7.3 Hz), 1.06 (3H, d, J¼6.3 Hz), 1.09e1.38
(5H, m), 1.44e1.63 (9H, m), 1.65e1.82 (2H, m), 2.31 (1H, t-like,
J¼10.8 Hz), 2.46e2.52 (1H, m), 3.12e3.19 (1H, m); 13C NMR
(125 MHz)
d
14.50, 18.56, 20.04, 20.40, 22.42, 24.51, 27.92, 34.59,
1H NMR (500 MHz)
d
1.03 (3H, t, J¼6.6 Hz), 1.25e1.31 (2H, m),
35.29, 35.61, 52.94, 53.04, 54.03; MS (EI): m/z 195 [M]þ; HRMS:
1.40e1.50 (1H, m), 1.54e1.59 (3H, m), 2.21e2.27 (1H, m), 2.32e2.37
(1H, m), 2.76e2.84 (1H, m), 2.85e2.90 (1H, m), 3.55 & 3.90 (2H,
ABq, J¼14.2 Hz), 4.95e5.00 (2H, m), 5.67e5.76 (1H, m), 7.21 (1H, t,
Calcd for C13H25N [M]þ 195.1987; found 195.1989; ½a 2D6
þ13.8 (c
ꢁ
0.25, CHCl3).
J¼7.5 Hz), 7.29 (2H, t, J¼7.5 Hz), 7.37 (2H, d, J¼7.5 Hz); ½a D26
þ33.0 (c
ꢁ
4.11. (2R, 6R)-6-Allyl-1-(benzylpiperidin-2-yl)methanol (11)
1.30, CHCl3), Ref. 10: ½a D26
ꢀ35.8 (c 1.30, CHCl3).
ꢁ
Oxazolidinone 1 (237 mg, 1.31 mmol) was added to a solution of
KOH (1 M in iPrOH) (13.1 mL,13.10 mmol) at room temperature, and
the resulting solution was refluxed for 24 h. After cooling, the al-
cohol was evaporated, and the residue was added to H2O (4 mL)
saturated with NaCl, and extracted with CH2Cl2 (10 mLꢃ5). The
organic layer and extracts were combined, dried and evaporated to
give a pale yellow oil, which was used directly in next step.
4.14. (2R, 6S)-Benzyl 2-allyl-6-methylpiperidine-1-carboxylate
(9)
K2CO3 (72 mg, 0.52 mmol) and CbzCl (0.15 mL, 1.05 mmol) was
added to a stirred solution of 13 (24 mg, 0.11 mmol) in 1,2-
dichloroethane (10 mL) at room temperature, and the resulting
suspension was refluxed for 24 h. Additional K2CO3 (72 mg,

X. Wang et al. / Tetrahedron 69 (2013) 10311e10315
10315
0.52 mmol) and CbzCl (0.15 mL, 1.05 mmol) were added to the re-
4.17. (4S, 6S, 9aR)-4-Methyl-6-propyloctahydro-1H-quinoli-
action mixture, and the resulting mixture was refluxed an addi-
tional 48 h. After cooling, the insoluble materials were filtered off
by Celite and the filtrate was evaporated to give a colorless oil,
which was chromatographed on silica gel (10 g, hexane/ethyl
acetate¼40:1) to give 9 (11 mg, 38%) as a colorless oil, and the
starting material 13 (13 mg, 54%) was recovered.
zine (14)
IR (neat) 2930, 2868, 2793, 1456, 1383, 1096 cmꢀ1
(500 MHz)
;
1H NMR
d
0.90 (3H, t, J¼7.3 Hz), 0.95 (3H, d, J¼5.9 Hz), 1.09e1.72
(15H, m), 1.72e1.85 (1H, m), 2.21e2.26 (1H, m), 2.36e2.39 (1H, m),
3.41e3.47 (1H, m); 13C NMR (125 MHz)
d
8.47, 14.59, 18.55, 18.75,
IR (neat) 2945, 2360,1695, 1405 cmꢀ1; 1H NMR (500 MHz)
d
1.26
24.40, 31.29, 32.48, 34.29, 34.57, 47.49, 53.73, 58.10; MS (EI): m/z
(3H, d, J¼6.9 Hz), 1.55e1.75 (4H, m), 1.78e1.85 (1H, m), 2.17e2.23
(1H, m), 2.47e2.53 (1H, m), 3.93e3.96 (1H, m), 4.04e4.08 (1H, m),
4.99e5.05 (2H, m), 5.11 & 5.16 (2H, ABq, J¼11.9 Hz), 5.71e5.79 (1H,
195 [M]þ; HRMS: Calcd for C13H25N [M]þ 195.1987; found 195.1989;
½
a 2D6
ꢁ
þ13.8 (c 0.25, CHCl3).
m), 7.21e7.47 (5H, m); 13C NMR (125 MHz)
d 13.08, 20.85, 22.36,
Supplementary data
26.58, 38.92, 47.27, 51.36, 66.56, 116.67, 127.73, 128.26, 128.37,
135.78, 137.07, 155.59; MS (EI): m/z 232 [MꢀC3H5]þ; HRMS: Calcd
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.10.009.
for C14H18NO [MꢀC3H5]þ 232.1338; found 232.1339; ½a 2D6
þ24.7 (c
ꢁ
1.60, CHCl3).
References and notes
4.15. (2S, 6R)-Benzyl 2-methyl-6-((E)-4-oxohept-2-en-1-yl)pi-
1. Daly, J. W.; Spande, T. F.; Garraffo, H. M. J. Nat. Prod. 2005, 68, 1556e1575.
2. Jones, T. H.; Gorman, J. S. T.; Snelling, R. R.; Delabie, J. H. C.; Blum, M. S.; Gar-
raffo, H. M.; Jain, P.; Daly, J. W.; Spande, T. F. J. Chem. Ecol. 1999, 25, 1179e1193.
3. (a) Saporito, R. A.; Spande, T. F.; Garraffo, H. M.; Donnelly, M. A. Heterocycles
2009, 79, 277e297; (b) Saporito, R. A.; Donnelly, M. A.; Spande, T. F.; Garraffo,
H. M. Chemoecology 2012, 22, 159e168.
4. (a) Airiau, E.; Girard, N.; Pizzeti, M.; Salvadori, J.; Taddei, M.; Mann, A. J. Org.
Chem. 2010, 75, 8670e8673; (b) Chou, S.; Zhang, J.; Chen, K. Tetrahedron 2013,
69, 1499e1508.
5. (a) Toyooka, N.; Tanaka, K.; Momose, T.; Daly, J. W.; Garraffo, H. M. Tetrahedron
1997, 53, 9553e9574; (b) Toyooka, N.; Fukutome, A.; Nemoto, H.; Daly, J. W.;
Spande, T. F.; Garraffo, H. M.; Kaneko, T. Org. Lett. 2002, 4, 1715e1718; (c)
Toyooka, N.; Nemoto, H. Tetrahedron Lett. 2003, 44, 569e570; (d) Toyooka, N.;
Fukutome, A.; Shinoda, H.; Nemoto, H. Angew. Chem., Int. Ed. 2003, 42,
3808e3810; (e) Tsuneki, H.; You, Y.; Toyooka, N.; Kagawa, S.; Kobayashi, S.;
Sasaoka, T.; Nemoto, H.; Kimura, I.; Dani, J. A. Mol. Pharmacol. 2004, 66,
1061e1069; (f) Toyooka, N.; Nemoto, H.; Kawasaki, M.; Garraffo, H. M.; Spande,
T. F.; Daly, J. W. Tetrahedron 2005, 61, 1187e1198; (g) Toyooka, N.; Dejun, Z.;
Nemoto, H.; Garraffo, H. M.; Spande, T. F.; Daly, J. W. Tetrahedron Lett. 2006, 47,
577e580; (h) Toyooka, N.; Dejun, Z.; Nemoto, H.; Garraffo, H. M.; Spande, T. F.;
Daly, J. W. Tetrahedron Lett. 2006, 47, 581e582; (i) Toyooka, N.; Kobayashi, S.;
Zhou, D.; Tsuneki, H.; Wada, T.; Sakai, H.; Nemoto, H.; Sasaoka, T.; Garraffo, H.
M.; Spande, T. F.; Daly, J. W. Bioorg. Med. Chem. Lett. 2007, 17, 5872e5875; (j)
Toyooka, N.; Zhou, D.; Kobayashi, S.; Tsuneki, H.; Wada, T.; Sakai, H.; Nemoto,
H.; Sasaoka, T.; Tezuka, Y.; Subehan; Kadota, S.; Garraffo, H. M.; Spande, T. F.;
Daly, J. W. Synlett 2008, 61e64; (k) Toyooka, N.; Zhou, D.; Nemoto, H.; Tezuka,
Y.; Kadota, S.; Andriamaharavo, N. R.; Garraffo, H. M.; Spande, T. F.; Daly, J. W. J.
Org. Chem. 2009, 74, 6784e6791; (l) Wang, X.; Tsuneki, H.; Urata, N.; Tezuka, Y.;
Wada, T.; Sasaoka, T.; Sakai, H.; Saporito, R. A.; Toyooka, N. Eur. J. Org. Chem.
2012, 7082e7092.
peridine-1-carboxylate (10)
1-Hexen-3-one (0.13 mL, 1.12 mmol) and Grubbs’ second cata-
lyst (19 mg, 0.02 mmol) was added to a stirred solution of 9 (61 mg,
0.22 mmol) in CH2Cl2 (7 mL), and the resulting mixture was
refluxed for 12 h. After cooling, the solvent was evaporated and the
residue was chromatographed on silica gel (10 g, hexane/ethyl
acetate¼10:1) to give 10 (53 mg, 69%) as a pale yellow oil.
R (neat) 2936, 1694, 1404, 1088 cmꢀ1 1H NMR (500 MHz)
;
d
0.92 (3H, t, J¼7.5 Hz), 1.26 (3H, d, J¼6.6 Hz), 1.55e1.76 (7H, m),
1.85e1.93 (1H, m), 2.35e2.42 (1H, m), 2.47 (2H, t, J¼7.3 Hz),
2.61e2.67 (1H, m), 4.02e4.09 (2H, m), 5.11 & 5.15 (2H, ABq,
J¼12.5 Hz), 6.08 (1H, d, J¼15.7 Hz), 6.72e6.80 (1H, m), 7.29e7.47
(5H, m); 13C NMR (125 MHz)
d 13.10, 13.77, 17.63, 20.74, 23.26,
26.49, 37.75, 41.80, 47.38, 50.91, 66.78, 127.80, 127.90, 128.46,
132.08, 136.84, 143.67, 155.58, 200.65; MS (EI): m/z 343 [M]þ;
HRMS: Calcd for C13H25NO [M]þ 343.2147; found 343.2148; ½a 2D6
ꢁ
þ21.5 (c 1.00, CHCl3).
4.16. (4S, 6R, 9aR)-4-Methyl-6-propyloctahydro-1H-quinoli-
zine ((D)-195C)
20% Pd(OH)2/C (5 mg) was added to a stirred solution of 10
(49 mg, 0.14 mmol) in MeOH (5 mL), and the resulting suspension
was stirred for 12 h under H2 atmosphere. The catalyst was filtered
off by Celite and the filtrate was evaporated to afford a 1:4.6 mix-
ture of crude product, which was chromatographed on silica gel
(5 g, CH2Cl2/MeOH¼6:1 (Et3N drops)) to give (þ)-195C (4 mg, 14%)
and 14 (18 mg, 65%).
6. David, M.; Dhimane, H.; Canucci-Bacque, C.; Lhommet, G. Synlett 1998,
206e208.
7. Moriyama, N.; Matsumura, Y.; Kuriyama, M.; Onomura, O. Tetrahedron: Asym-
metry 2009, 20, 2677e2687.
8. (a) Reviews see: Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56,
ꢀ
3817e3856 Martínez-Estibalez, U.; Gomez-SanJuan, A.; García-Calvo, O.; Ara-
nzamendi, E.; Lete, E.; Sotomayor, N. Eur. J. Org. Chem. 2011, 3610e3633 (b) For
the application to the pyrrolidine homologues see: Dhimanea, H.; Vanucci-
(þ)-195C: 1H NMR (500 MHz)
0.90 (3H, t, J¼7.4 Hz),1.04 (3H, d,
d
ꢀ
Bacque, C.; Hamon, L.; Lhommet, G. Eur. J. Org. Chem. 1998, 1955e1963.
9. David, M.; Dhimane, H.; Canucci-Bacque, C.; Lhommet, G. J. Org. Chem. 1999, 64,
8402e8405.
J¼6.3 Hz), 1.04e1.32 (4H, m), 1.48e1.72 (11H, m), 1.76e1.86 (1H, m),
2.95e3.05 (1H, m), 3.06e3.12 (1H, m), 3.16e3.23 (1H, m); 13C NMR
10. Sancibrao, P.; Karila, D.; Vincent, G. J. Org. Chem. 2010, 75, 4333e4336.
11. Takahata, H.; Yotsui, Y.; Momose, T. Tetrahedron 1998, 54, 13505e13516.
12. The reduction of the iminium ion to give an indolizidine nuclei provided good
diastereoselectivity, see: Toyooka, N.; Zhou, D.; Nemoto, H. J. Org. Chem. 2008,
73, 4575e4577 and references cited therein. However in the case of quinoli-
zidinium ion, the diastereoselectivity is not so high, see; Ref. 4b.
(125 MHz)
d 14.33, 19.87, 20.15, 20.24, 20.68, 22.30, 24.52, 29.96,
33.46, 34.10, 47.15, 49.38, 52.49; MS (EI): m/z 195 [M]þ; HRMS:
Calcd for C13H25N [M]þ 195.1987; found 195.1985; ½a 2D6
þ14.6 (c
ꢁ
0.10, CHCl3).