Synthesis of dehydroindolizidine-type poison-frog alkaloids via Michael-type conjugate addition

Article abstract of DOI:10.3184/174751917X14967701766987

A concise stereoselective synthesis of proposed dehydroindolizidine-alkaloids of types 179 and 207E¹ was accomplished via Michael-type conjugate addition. A comparison of natural 207E and synthesised compound 207E on GC–FTIR revealed the double bond of natural 207E is most likely at the 7,8-position.

Full text of DOI:10.3184/174751917X14967701766987

398 RESEARCH PAPER
VOL. 41 JULY, 398–402
JOURNAL OF CHEMICAL RESEARCH 2017
Synthesis of dehydroindolizidine-type poison-frog alkaloids via Michael-type
conjugate addition
De-Jun Zhoua*, Xue-Yan Lia, Dong Lia, Zhong-Shuai Guoa, Qin-Ling Zhanga, Hong-yan Bieb and
Zheng-Guo Cuia,c*
aMedical School, Henan polytechnic University, Jiaozuo, 454000, Henan Province, P.R. China
bSchool of Chemistry & Chemical Engineering, Henan polytechnic University, Jiaozuo, 454000, Henan Province, P.R. China
cGraduate School of Medicine and Pharmaceutical Science, University of Toyama, 2630 Sugitani, Toyama 930-0194 Japan
A concise stereoselective synthesis of proposed dehydroindolizidine-alkaloids of types 179 and 207E1 was accomplished via Michael-type
conjugate addition. A comparison of natural 207E and synthesised compound 207E on GC–FTIR revealed the double bond of natural 207E
is most likely at the 7,8-position.
Keywords: dehydroindolizidine, Michael-type conjugate addition
GC–MS and GC–FTIR spectral data showed more than 800
alkaloids in the amphibian skin, among them, a subclass of
dehydro-5,8-disubstituted indolizidine. Most alkaloids appeared
as minor or trace alkaloids typical of dendrobatid, mantellid
and bufonid anurans. Dietary source was unknown, but ants
were the likely food source.1,2 Several methods for the synthesis
of dehydroindolizidine alkaloids have been established.3–5 We
have reported previously6 the flexible synthesis of poison frog
alkaloids of the 5,8-disubstituted indolizidine class. In the
present study, the efficient chiral syntheses of the compounds
207E and 179 are addressed.
Dimethylcuprate and dipropylcuprate were used for the
Michael-type conjugate additions to 2 in order to transform
compounds 3 and 4 each into single stereoisomers. The ester
moieties of 3 and 4 were treated with superhydride reduction,
Swern oxidation and Horner–Emmons reaction to obtain the
α,β-unsaturated esters 5 and 6. The esters were hydrogenated to
obtain an amino ester under Weinreb’s reaction conditions,9 as
well as to form lactams 7 and 8. Next, by eliminating mesylates,
the lactams were converted into dehydropiperidines 9 and 10.
Reducing the lactam moiety with LAH (lithium aluminum
hydride) produced the compounds 11 and 12 with 91% and
70% yields, respectively. The compounds 11 and 12 are
alkaloids 179 and 207E1 respectively. The stereochemistry of
the compound 11 was determined by conducting an NOE NMR
experiment. The GC–FTIR spectrum and GC retention time
of the compound 12 differed from those of the natural 207E.1
Results and discussion
Chiral piperidinol 17 was gradually converted to the
MOM (methoxymethyl) ether. Next, the MOM ether was
transformed into enaminoester 2 following Rubio’s procedure.8
H
H
H
H
R
MOMO
H
HO
H
MOMO
H
H
c
H
a
b
N
Me
CO2
N
Me
CO2
N
Me
CO2
Cbz
Cbz
Cbz
:
3 R=Me
2
1
4
: R=n-Pr
H
H
H
H
H
R
H
MOMO
H
R
H
R
H
MOMO
H
d
e
H
f
N
:
N
N
Et
CO2
Cbz
O
7
O
:
5
6
R=Me
: R=n-Pr
:
R=Me
9 R=Me
10
8
: R=n-Pr
: R=n-Pr
NOE (R=Me)
7
H
9
R
H
6
8
H
H
H
N
N
5
NOE (R=Me)
13
:
11
12
R=Me
: R=n-Pr
Scheme 1 Syntheses of the proposed 179 and 207E. Reagents and conditions: (a) i) MOMCl, (i-Pr) EtN, CH2Cl2 (98%); ii) LiHMDS, PhSeCl (2 equiv.),
THF, –78 °C to r.t. (79%); (b) 3: Et O, 4: THF, R CuX [3: R = Me, X = Li, (78%); 4: R = n-Pr, X = MgBr2(83%)]; (c) i) Super-Hydride, THF, 0 °C; ii) Swern
oxidation; iii) (EtO)2P(O)CH CO2Et,2NaH, THF, 02°C to r.t. (5: 73%; 6: 76%); (d) i) 20% Pd(OH)2, H2, MeOH, 1 atm; ii) Et3Al, DCE, reflux (7: 86%); 8: 98%); (e)
i) conc. HCl MeOH, reflux;2ii) MsCl, Et3N, CH2Cl2, 0 °C; iii) DBU, toluene, reflux (9: 62% in 3 steps; 10: 64% in 3 steps); (f) LAH, THF (11: 91%; 12: 70%).
* Correspondent. E-mail: renjm@ecust.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2017 399
[R-]
Me
CO2
BnO
N
CO2
N
2C
MOMO
Bn
MeO2C
MOMO
[R-]
B
A
Me
(1,3) strain
CO2
N
A
OBn
O
X
R
N
BnO
2C
BnO
N
2C
MeO
R
O
MeO
OMOM
OMOM
O
H
Protonation
BnO
N
2C
Me
R
4
CO2
MeO2C
Nu
BnO
N
2C
MOMO
OMOM
R = Me or n-pr
Scheme 2 Stereoselectivity of the key Michael-type conjugate addition.
Cieplak's hypothesis
Table 1 Study the conditions for synthesis of the compound 3 from the
compound 2a
Table 2 Study the conditions for synthesis of the compound 4 from the
compound 2a
Entry Me2CuX (equiv.)
Solvent
Time (h)
Yield (%)
Entry n-Pr2CuX (equiv.)
Solvent
Et2O
Et2O
Et2O
THF
Time (h)
1
1.5
2.0
1
Yield (%)
60
75
63
61
1
2
3
4
5
6
n-Pr2CuLi (5)
1
2
3
4
5
6
Me2CuLi (5)
Et2O
Et2O
Et2O
THF
THF
THF
1
78
70
61
75
69
59
n-Pr2Cu MgBr (5)
n-Pr2Cu MgCl (5)
n-Pr2CuLi (5)
n-Pr2Cu MgBr (5)
n-Pr2Cu MgCl (5)
Me2Cu MgBr (5)
Me2Cu MgCl (5)
Me2CuLi (5)
Me2Cu MgBr (5)
Me2Cu MgCl (5)
1.5
2.0
1
1.5
2.0
THF
THF
1.5
2.0
83
71
aAll the reactions were performed with 100 mg of the substrate 2 and the reactions
stopped once the substrate disappeared.
aAll the reactions were performed with 100 mg of the substrate 2 and the reactions
stopped once the substrate disappeared.
In the GC–FTIR spectra, both compound 12 and natural 207E
were sharp and intense Bohlmann band appeared near 2790
cm−1, which suggest 5,8a-cis in both compounds. Compound 12
developed an absorption band at 3030 cm−1, which is typical
of vinyl C–H stretching. In contrast, the natural 207E showed
only weak vinyl C–H stretching and no enamine absorption was
observed.1 Results suggest that the natural alkaloid 207E might
have developed a 7,8-double bond similar to that of compound
13. (Scheme 1) In order to prove this hypothesis the synthesis of
compound 13 is now in progress.
The stereoselectivity of the main Michael-type conjugate
addition is shown in Scheme 2. An A(1,3) strain10 was observed
between the N-Cbz group and the allyl substituent at the α
position. The anion attacks from the α-axial orientation were
caused by stereoelectronic effects,11 after which the enolate
protonation produced a single isomer from the trisubstituted
piperidine. The remarkable stereoselectivity can also be
explained by Cieplak’s hypothesis.12 The desired conformation
of A was obtained. The σ* at the transition state developed and
stabilised because of the antiperiplanar donor σC–H at the C-4
position.
The reaction conditions required to synthesise compound 3 from
compound 2 are shown in Table 1. Et2O was used as the reaction
solvent in the experiment (entries 1–3). The nucleophilic reagents
Me2CuLi, Me2CuMgBr and Me2CuMgCl obtained 78%, 70% and
61% yields, respectively. When THF was used as the reaction solvent,
the corresponding yields were 75%, 69% and 59% yields (entries 4–6).
The reaction conditions for synthesis of the compound 4 from the
compound 2 are shown in Table 2. Et2O was used as the reaction
solvent in the initial experiment (entries 1–3) The nucleophilic
reagents n-Pr2CuLi, n-Pr2Cu MgBr and n-Pr2Cu MgCl obtained
60%, 75% and 63% yields, respectively. When THF was used as
a reaction solvent, results compared with the Et2O at 61%, 83%
and 71% yields for n-Pr2CuLi, n-Pr2Cu MgBr and n-Pr2Cu MgCl,
respectively (entries 4–6).
Conclusion
The proposed dehydroindolizidine frog alkaloids 179 and 207E
were synthesised. A comparison of natural 207E with synthesised
compound 207E on GC and FTIR showed they were different and
suggests that the double bond of natural 207E is at the 7,8-position
(compound 13).

400 JOURNAL OF CHEMICAL RESEARCH 2017
Experimental
NH4Cl solution. The aqueous mixture was diluted with CHCl3 (50 mL)
and the insoluble material was removed through a celite pad. The
filtrate was separated and the aqueous layer was extracted with CHCl3
(3 × 30 mL). The organic layers were combined, dried and evaporated
to give pale yellow oil, which was purified by column chromatography
to afford 3: Colourless oil; yield 0.83 g, 78%; IR (νmax, cm–1) neat: 2950,
1747, 1700, 1408, 1294, 1039; 1H NMR (300 MHz) δ 1.15 (3H, d, J =
6.41 Hz), 1.35–1.41 (1H, m), 1.58 (1H, br. s), 2.00–2.05 (1H, m),
2.13–2.19 (2H, m), 2.51 (1H, br. d, J = 13.70 Hz), 3.31 (3H, s),
3.63–3.76 (4H, br. m), 4.26–4.58 (1H, br. m), 4.60 (2H, s), 5.05–5.21
(4H, m), 5.80–5.82 (1H, br. d, J = 8.54 Hz), 7.28–7.40 (5H, m);
13C NMR (75 MHz) δ 20.18 (q), 27.59 (d), 32.09 (t), 39.12 (t), 51.92 (q),
55.40 (q), 56.39 (d), 60.69 (d), 67.44 (t), 73.38 (d), 94.59 (t), 117.38 (t),
127.61 (d), 127.79 (d), 128.24 (d), 134.83 (d), 136.30 (s), 156.23 (s),
172.95 (s); HRMS calcd for C21H29NO6:391.1995; found: 391.1997; [α]
All chemical reagents were obtained from commercial suppliers
(Aldrich, Kanto Chemical, Tokyo Chemical Industry (TCI), Aladdin,
Wako Pure Chemical Industries) and used without further purification.
Anhydrous solvents were obtained from commercial protocols. All
non-aqueous reactions were carried out under Ar atmosphere. Thin
layer chromatography (TCL) was performed on silica gel 60 F254
glass plates precoated with a 0.25 mm thickness of silica gel (Merck).
Column chromatography was carried out on Cica Silica Gel 60N
(spherical, neutral, 40–50 μm or 63–210 μm). 1H and 13C NMR spectra
1
were obtained on a Varian UNITY plus 300 (300 MHz for H and 75
MHz for 13C) instrument in CDCl3, CD3OD or DMSO-d6. IR spectra
were measured on a JNM FT/IR-460Plus spectrometer. Mass spectra
were recorded on a JEOL D-200, JEOL JMS-GCmate II, SHIMAZU
GC-MS-QP 500, or JEOL AX 505 spectrometer.
2ꢁꢀ –48.11 (c 2.65, CHCl ).
3
Synthesis of 1-benzyl 2-methyl (5R,6S)-6-allyl-5-(methoxymethoxy)
piperidine-1,2-dicarboxylate (2A)
Synthesis of 1-benzyl 2-methyl (2S,3S,5R,6S)-6-allyl-5-(methoxy-
methoxy)-3-propylpiperidine-1,2- dicarboxylate (4)
To a stirred solution of 1 (5.1 g, 9.4 mmol) in CHCl3 (50 mL), was
added MOMCl (1.42 mL, 18.8 mmol) and (i-Pr)2EtN (3.56 mL,
20.6 mmol) at 0 °C and the reaction mixture was stirred at room
temperature for 15 h. Then the reaction was quenched with saturated
NaHCO3 solution, extracted with CH2Cl2 (3 × 30 mL) and the organic
extracts were combined, dried (MgSO4) and evaporated to give pale
yellow oil, which was purified by column chromatography (silica gel,
hexane/acetone, 10:1) to afford 2A: Pale yellow oil; yield 5.4 g, 98%;
IR (νmax, cm–1) neat: 2930, 1735, 1698, 1413, 1295, 1211, 1036; 1H NMR
(300 MHz) δ 1.71-1.73 (2H, m), 2.06-2.11 (3H, m), 2.16-2.47 (1H, br.
m), 3.28 (3H), 3.34 (3H), 3.65-3.80 (4H, m), 4.29-4.32 (1H, br. m),
4.60-4.64 (2H, m), 4.85-5.25 (5H, m), 5.74-5.79 (1H,br. m), 7.30-7.36
(5H, m); 13C NMR (75 MHz) δ19.03 (t), 20.70 (t), 35.79 (t), 36.36 (t),
51.97 (q), 52.16 (d), 55.22 (q), 55.58 (d), 67.28 (t), 69.35 (d), 70.08 (d),
94.38 (t), 94.55 (t), 117.17 (t), 127.42 (d), 127.63 (d), 128.10 (d), 134.65
(d), 136.27 (s), 155.71 (s), 156.33 (s), 172.65 (s); MS: 377; HRMS calcd
for C H NO : 377.1838; found: 377.1839; [α]2ꢁꢀ –64.27 (c 1.28,
To a stirred suspension of CuI (4.2 g) in THF (10 mL) was added a
solution of n-PrMgBr (44.3 mL, 44.4 mmol) at –78°C and the resulting
suspension was stirred at –78 °C to –35 °C for 20 min. The resulting
solution was cooled to –78°C and a solution of 2 (1.66g, 4.43 mmol) in
THF (9 mL) was added dropwise via a double-tipped stainless steel
needle at –78°C. The temperature was gradually raised to 0 °C and then
the reaction mixture was quenched with saturated NH4Cl solution. The
aqueous mixture was diluted with CHCl3 (50 mL), stirring continued at
room temperature for 20 min. The insoluble material was removed by
filtration through a celite pad. The filtrate was separated and the
aqueous layer was extracted with CHCl3 (3 × 30 mL). The organic
layers were combined, dried and evaporated to give pale yellow oil,
which was purified by column chromatography (silica gel, hexane/
acetone, 20:1–15:1) to afford 4: Colourless oil; yield 1.54 g, 83%; IR
(νmax, cm–1) neat: 2954, 1737, 1701, 1639, 1438, 1411, 1295, 1208, 1150,
1097, 1040, 917, 739, 698; 1H NMR (300 MHz) δ 0.91 (3H, t,
J = 7.26 Hz), 1.30 (1H, br. s), 1.33–1.46 (4H, m), 1.59 (1H, sep-like,
J = 2.09), 2.01 (1H, dt-like, J = 14.01, 5.13), 2.09–2.17 (1H, m), 2.45
(1H, br. d-like J = 14.10 Hz), 3.31 (3H, s), 3.59–3.75 (4H, m), 4.33 (1H,
br. s), 4.57 (1H, br. s), 4.59 (2H, t-like, J = 6.84 Hz), 5.06 (2H, br.
d-like, J = 17.09 Hz), 5.18 (2H, br. d-like, J = 2.99 Hz), 5.78 (1H, br. s),
7.29–7.38 (5H, m); 13C NMR (75 MHz) δ 13.73 (q), 19.88 (t), 27.65 (t),
31.83 (d), 35.49 (t), 37.78 (t), 51.54 (q), 54.96 (q), 56.13 (d), 57.45 (d),
67.07 (t), 72.80 (d), 94.31 (t), 116.96 (t), 127.36 (d), 127.56 (d), 128.02
(d), 128.10 (d), 134.76 (d), 136.23 (s), 156.25 (s), 172.86 (s); HRMS
calcd for C H NO : 419.2308; found: 419.2340; [α]2ꢁꢀ –42.52 (c 1.06,
20 27
6
CHCl3).
Synthesis of 1-benzyl 2-methyl (5R,6S)-6-allyl-5-(methoxymethoxy)-
5,6-dihydropyridine-1,2(4H)-dicarboxylate (2)
To a stirred solution of 2A (3.2 g, 8.49 mmol) in THF at –78 °C was
added
a
solution
of
LiHMDS
[prepared
from
1,1,1,3,3,3-hexamethyldisilazane (2.37 mL, 10.3 mmol) and BuLi
(1.6M in hexane, 6.4 mL, 10.3 mmol) in THF (20 mL) at 0 °C for
30 min] and the reaction stirred for 30 min. To the reaction mixture
was added dropwise a solution of PhSeCl (3.25g, 17 mmol) in THF
(9 mL) via a double-tipped stainless steel needle at –78 °C and the
resulting mixture was stirred at –78 °C – 0 °C for 1h. The reaction
mixture was evaporated to give pale yellow oil, which was purified by
column chromatography (silica gel, hexane/acetone, 20:1–6:1) to
afford 2: Pale yellow oil; yield 2.52 g, 79%; IR (νmax, cm–1) neat: 3075,
3026, 2950, 2353, 1715, 1652, 1437, 1396, 1270, 1033, 752, 697;
1H NMR (300 MHz) δ 1.92–2.03 (1H, m), 2,16–2.23 (1H, m), 2.33 (2H,
br. s), 3.15–3.91 (7H, br. m), 4.34–4.71 (3H, br. m), 5.02–5.17 (2H, m),
5.26 (2H, br. s), 5.82–5.90 (1H, m), 6.07 (1H, br. s), 7.27–7.47 (5H, m);
13C NMR (75 MHz) δ 26.67 (t), 33.14 (t), 51.78 (q), 54.61 (d), 55.43 (q),
67.91 (t), 69.30 (d), 93.96 (t), 117.61 (t), 119.55 (d), 127.90 (d), 127.98
(d), 128.18 (d), 129.08 (d), 132.95 (d), 133.21 (d), 135.64 (s), 144.29 (s),
154.84 (s), 164.73 (s); HRMS calcd for C20H25NO6: 375.1682; found:
23 33
6
CHCl3).
Synthesis of benzyl (2S,3R,5S,6S)-2-allyl-6-(hydroxymethyl)-3-
(methoxymethoxy)-5-methylpiperidine-1-carboxylate (5A)
To a stirred solution of 3 (367 mg, 0.94 mmol) in THF (10 mL) was
added a solution of lithium triethylborohydride (Super-Hydride®, 1 M
in THF, 2.06 mL, 2.06 mmol) at 0 °C and the reaction mixture was
stirred at 0 °C for 2h. The reaction was quenched with small pieces of
ice and the mixture was diluted with CH2Cl2 (30 mL). The organic
layer was dried and evaporated to give colourless oil, which was
purified by column chromatography (silica gel, hexane/acetone,
10:1–5:1) to afford 5A: Colourless oil; yield 300 mg, 88%; IR (νmax
,
cm–1) neat: 3444, 2932, 1683, 1417, 1313, 1095, 1038, 916, 769, 698;
1H NMR (300 MHz) δ 1.13 (3H, d, J = 8.84 Hz), 1.29–1.36 (1H, m),
1.60 (1H, br. s), 1.91–1.96 (1H, m), 2.33 (2H, t-like, J = 7.26 Hz), 3.32
(3H, s), 3.60 (2H, d-like, J = 7.69 Hz), 3.74 (1H, br. d, J = 8.97 Hz), 3.91
(1H, sxt-like, J = 3.73 Hz), 4.39 (1H, br. s), 4.63 (2H, q-like, J = 6.74
Hz), 5.04–5.21 (4H, m), 5.78 (1H, br. d, J = 7.69 Hz), 7.28–7.39 (5H,
m); 13C NMR (75 MHz) δ 20.97 (q), 27.02 (d), 31.84 (t) 40.40 (t), 55.16
(q), 56.48 (d), 58.49 (d), 60.58 (d), 66.89 (t), 67.21 (t), 94.65 (t), 116.79
(t), 117.22 (t), 127.29 (d), 127.38 (d), 127.46 (d), 127.59 (d), 128.01 (d),
128.08 (d), 134.73 (d), 134.84 (d), 136.17 (s),136.40 (s), 157.36 (s);
HRMS calcd for C H NO : 363.2046; found: 363.2048; [α]2ꢁꢀ –61.67
375.1680; [α]2ꢁꢀ +74.76 (c 0.70, CHCl ).
3
Synthesis
of
1-benzyl
2-methyl
(2S,3S,5R,6S)-6-allyl-5-
(methoxymethoxy)-3-methylpiperidine-1,2-dicarboxylate (3)
To a stirred suspension of CuI (2.6 g, 13.6 mmol) in Et2O (5 mL) was
added a solution of MeLi (26.2 mL, 27.2 mmol) at –78 °C and the
resulting suspension was stirred at –78 °C to –35 °C for 20 min. The
resulting solution was cooled to –78 °C and a solution of 2 (1.02 g,
2.72 mmol) in Et2O (9 mL) was added dropwise via a double-tipped
stainless steel needle to at –78°C. The temperature was gradually raised
to 0 °C and then the reaction mixture was quenched with saturated
20 29
5
(c 1.51, CHCl3)

JOURNAL OF CHEMICAL RESEARCH 2017 401
Synthesis of benzyl (2S,3R,5S,6S)-2-allyl-6-(hydroxymethyl)-3-
(methoxymethoxy)-5-propylpiperidine-1-carboxylate (6A)
To a stirred suspension of NaH (60%, 66 mg, 1.64 mmol) in THF
(10 mL) was added (EtO)2P(O)CH2CO2Et (0.35 mL, 1.64 mmol) at
0 °C and the reaction mixture was stirred for 30 min. To the resulting
mixture was added dropwise a solution of the above aldehyde in THF
(6 mL) via a double-tipped stainless steel needle at 0 °C. The reaction
mixture was stirred at room temperature for 20 h. The reaction was
quenched with H2O (10 mL) and the aqueous mixture was extracted
with CH2Cl2 (4 × 30 mL). The organic extracts were combined, dried
and evaporated to give pale yellow oil, which was purified by column
chromatography (silica gel, hexane/acetone, 20:1–10:1) to afford 6 as
a 2:1 mixture of the E- and Z-isomers: Pale yellow oil; yield 565 mg,
90%.
To a stirred solution of 4 (650 mg, 1.55 mmol) in THF (20 mL) was
added a solution of lithium triethylborohydride (Super-Hydride®, 1 M
in THF, 3.41 mL, 3.41 mmol) at 0 °C and the reaction mixture was
stirred at 0 °C for 2h. The reaction was quenched with small pieces of
ice and the mixture was diluted with CH2Cl2 (30 mL). The organic
layer was dried and evaporated to give colourless oil, which was
purified by column chromatography (silica gel, hexane/acetone,
10:1–8:1) to afford 6A: Colourless oil; yield 507 mg, 84%; IR (νmax
,
cm–1) neat: 3467, 3100, 2954, 1688, 1417, 1313, 1217, 1038, 919, 744,
1
691; H NMR (300 MHz) δ 0.90 (3H, t, J = 6.84 Hz), 1.28–1.41 (5H,
m), 1.52 (1H, br. s), 1.96 (1H, dt, J = 12.82 Hz, 4.27 Hz), 2.34 (2H, t, J
= 7.26 Hz), 3.32 (3H, s), 3.58 (2H, t-like, J = 8.54 Hz), 3.67 (1H, br. s),
4.08 (2H, dt-like, J = 8.12 Hz, 5.55 Hz), 4.32 (1H, br. s), 4.61 (2H, dd-
like, J = 19.65 Hz, 6.84 Hz), 5.02–5.23 (4H, m), 5.79 (1H, br. s),
7.30–7.37 (5H, m); 13C NMR (75 MHz) δ 13.94 (q), 20.15 (t), 28.72 (t),
32.35 (d), 36.98 (t), 40.00 (t), 55.32 (q), 56.68 (d), 58.27 (d), 65.54 (t),
67.27 (t), 75.02 (d), 94.80 (t), 117.20 (t), 127.57 (d), 127.75 (d), 128.17
(d), 128.22 (d), 134.91 (d), 136.32 (s), 156.72 (s); MS: 391; HRMS
calcd for C H NO : 391.2359; found: 391.2361; [α]2ꢁꢀ 0.64 (c 1.395,
Synthesis of (5S,6R,8S,8aR)-6-(methoxymethoxy)-8-methyl-5-propyl-
hexahydroindolizin-3(2H)-one (7)
To a stirred solution of 5 (300 mg, 0.7 mmol) in MeOH (15 mL) was
added 20% Pd(OH)2/C (50 mg) and the resulting suspension was
hydrogenated at 1 atm under hydrogen atmosphere for 44 h. The
catalyst was filtered off and the filtrate was evaporated to give pale
yellow oil. The oil was dissolved in ClCH2CH2Cl (10 mL) and Et3Al
(0.92M in hexane, 2.3 mL, 2.1 mmol) was added at 0 °C and the
resulting solution was refluxed for 15 h. After cooling, the reaction was
quenched with 10% HCl (aq) and the organic layer was separated. The
aqueous layer was extracted with CH2Cl2 (3 × 30 mL) and the organic
portions were combined, dried and evaporated to give pale yellow oil,
which was purified by column chromatography (silica gel, hexane/
acetone, 20:1–5:1) to afford 7: Colourless oil; yield 153 mg, 86%; IR
(νmax, cm–1) neat: 2958, 2886, 1691, 1418, 1150, 1103, 1039, 917;
1H NMR (300 MHz) δ 0.91 (3H, t, J = 7.26 Hz), 0.94 (3H, d,
J = 6.41 Hz), 1.23–1.30 (1H, m), 1.31–1.38 (1H, m), 1.44–1.62 (4H, m),
2.06–2.15 (2H, m), 2.16–2.22 (1H, m), 2.34 (2H, t-like, J = 6.41 Hz),
3.20 (1H, q-like, J = 6.84 Hz), 3.35 (3H, s), 3.42 (1H, q-like, J = 6.92
Hz), 3.71 (1H, q-like, J = 5.54 Hz), 4.66 (2H, dd-like, J = 16.66 Hz,
6.84 Hz); 13C NMR (75 MHz) δ 14.02 (q), 17.79 (q), 19.89 (t), 24.28 (t),
31.65 (t), 31.73 (t), 34.66 (d), 36.32 (t), 55.39 (q), 57.98 (d), 62.62 (d),
73.33 (d), 94.88 (t), 174.45 (s); HRMS calcd for C14H25NO3: 255.1834;
22 33
5
CHCl3).
Synthesis of benzyl (2S,3R,5S,6S)-2-allyl-6-(3-ethoxy-3-oxoprop-1-
en-1-yl)-3-(methoxymethoxy)-5-methylpiperidine-1-carboxylate (5)
To a stirred solution of (COCl)2 (0.17 mL, 1.9 mmol) in CH2Cl2 (10
mL) was added DMSO (0.27 mL, 3.8 mmol) at –78 °C and the resulting
mixture was stirred for 5 min. To the reaction mixture was added
dropwise a solution of 5A (345 mg, 0.95 mmol) in CH2Cl2 (6 mL)
via a double-tipped stainless steel needle at –78 °C. The resulting
solution was stirred at –78 °C for 30 min followed by the addition of
triethylamine (0.79 mL, 5.7 mmol) to the reaction mixture. The
reaction mixture was warmed to 0 °C for 1 h and quenched with H2O
(15 mL). The aqueous mixture was extracted with Et2O (3 × 30 mL)
and the organic extracts were combined, dried and evaporated to give
pale yellow oil, which was used directly in the next step.
found: 255.1836; [α]2ꢁꢀ +146.90 (c 0.62, CHCl ).
3
To a stirred suspension of NaH (60%, 46 mg, 1.14 mmol) in THF
(15 mL) was added (EtO)2P(O)CH2CO2Et (0.24 mL, 1.14 mmol) at
0 °C and the reaction mixture was stirred at 0 °C for 30 min. To the
resulting mixture was added dropwise a solution of the above aldehyde
in THF (6 mL) via a double-tipped stainless steel needle at 0 °C.
The reaction mixture was stirred at room temperature for 20 h. The
reaction was quenched with H2O (15 mL) and the aqueous mixture
was extracted with CH2Cl2 (4 × 40 mL). The organic extracts were
combined, dried and evaporated to give pale yellow oil, which was
purified by column chromatography (silica gel, hexane/acetone,
20:1–10:1) to afford 5 as a 2:1 mixture of the E- and Z-isomers: Pale
Synthesis of (5S,6R,8S,8aR)-6-(methoxymethoxy)-5,8-dipropylhexa-
hydroindolizin-3(2H)-one (8)
To a stirred solution of 6 (500 mg, 1.09 mmol) in MeOH (20 mL) was
added 20% Pd(OH)2/C (100 mg) and the resulting suspension was
hydrogenated at 1 atm under hydrogen atmosphere for 44 h. The
catalyst was filtered off and the filtrate was evaporated to give pale
yellow oil. The oil was dissolved in ClCH2CH2Cl (15 mL) and Et3Al
(0.92M in hexane, 3.55 mL, 3.27 mmol) was added at 0 °C and the
resulting solution was refluxed for 15 h. After cooling, the reaction was
quenched with 10% HCl (aq) and the organic layer was separated. The
aqueous layer was extracted with CH2Cl2 (3 × 30 mL) and the organic
portions were combined, dried and evaporated to give pale yellow oil,
which was purified by column chromatography (silica gel, hexane/
acetone, 10:1–5:1) to afford 8: Colourless oil; yield 302 mg, 98%; IR
(νmax, cm–1) neat: 2957, 2360, 1688, 1458, 1415, 1377, 1278, 1215, 1149,
1
yellow oil; yield 339 mg, 83%; H NMR (300 MHz) δ 1.05 (3H, d,
J = 8.84 Hz), 1.29 (3H, t, J = 7.10 Hz), 1.70–1.75 (2H, br. m), 1.98–2.05
(1H, m), 2.24–2.42 (2H, m), 3.32 (3H, s), 3.69 (1H, t–like J = 7.26 Hz),
4.16–4.20 (2H, d, J = 7.10 Hz), 4.22 (1H, br. s), 4.47 (1H, t-like, J = 6.91
Hz), 4.60–4.64 (2H, m), 5.07–5.16 (4H, m), 5.71–5.98 (3H, m), 6.78
(1H, q, J = 7.26 Hz), 7.28–7.37 (5H, m).
1
1097, 1039, 917, 861, 740; H NMR (300 MHz) δ 0.87–0.93 (6H, m),
1.04–1.11 (1H, m), 1.21–1.40 (3H, m), 1.40–1.55 (6H, m), 1.98–2.05
(1H, m), 2.09–2.21 (2H, m), 2.30–2.33 (2H, m), 3.33–3.35 (1H, m),
3.34 (3H, s), 3.53 (1H, q-like, J = 5.98 Hz), 3.78 (1H, q-like,
J = 4.13 Hz), 4.60–4.65 (2H, m); 13C NMR (75 MHz) δ 13.85 (q), 14.06
(q), 19.07 (t), 19.72 (t), 24.99 (t), 31.43 (t), 32.29 (t), 32.57 (t), 34.51 (t),
39.13 (d), 55.16 (q), 56.68 (d), 60.41 (d), 72.78 (d), 94.50 (t), 174.29 (s);
HRMS calcd for C H NO :283.2147; found: 283.2145; [α]2ꢁꢀ +21.41 (c
Synthesis of benzyl (2S,3R,5S,6S)-2-allyl-6-(3-ethoxy-3-oxoprop-1-
en-1-yl)-3-(methoxymethoxy)-5-propylpiperidine-1-carboxylate (6)
To a stirred solution of (COCl)2 ( 0.24 mL, 2.74 mmol) in CH2Cl2
(15 mL) was added DMSO (0.39 mL, 5.48 mmol) at –78 °C and the
resulting mixture was stirred for 5 min. To the reaction mixture was
added dropwise a solution of 6A (536 mg, 1.37 mmol) in CH2Cl2
(3 × 3 mL) via a double-tipped stainless steel needle at –78 °C.
The resulting solution was stirred at –78 °C for 30 min and then
triethylamine (1.37 mL, 8.22 mmol) was added to the reaction
mixture. The reaction mixture was warmed to 0 °C for 1 h. and
quenched with H2O (10 mL). The aqueous mixture was extracted with
Et2O (3 × 30 mL) and the organic extracts were combined, dried and
evaporated to give pale yellow oil, which was used directly in the next
step.
16 29
3
1.67, CHCl3).
Synthesis of (5S,6R,8S,8aR)-8-methyl-3-oxo-5-propyloctahydro-
indolizin-6-yl methanesulfonate (9A)
To a stirred solution of 7 (185 mg, 0.725 mmol) in MeOH (10 mL),
was added dropwise 6 drops HCl (36%). The reaction mixture was
reflux for 15 h, allowed to cool and the reaction mixture evaporated
to give colourless oil. To a stirred solution of the oil in CH2Cl2, was

402 JOURNAL OF CHEMICAL RESEARCH 2017
added MsCl (0.09 mL, 1.1 mmol) and Et3N (0.18 mL, 1.3 mmol) at 0
°C and the reaction mixture was stirred at the temperature for 1h. the
resulting mixture was quenched with NaHCO3, extracted with CH2Cl2
(3 × 20 mL), the extracts was combined, dried over MgSO4, evaporated
to give 9A pale yellow oil, which was used directly in the next step.
Synthesis of (5S,8S,8aR)-8-methyl-5-propyl-1,2,3,5,8,8a-hexahydro-
indolizine (11)
To a stirred solution of 9 (64.9 mg, 0.336 mmol) in THF (7 mL) was added
LiAlH4 (25.5 mg, 0.67 mmol) at 0 °C and the resulting suspension was
refluxed for 15 h. After cooling, the reaction was quenched with 10%
NaOH (aq) and the aqueous mixture was extracted with hot CHCl3
(10 × 15 mL). The organic extracts were combined, dried over K2CO3 and
evaporated to give the compound 11: Colourless oil; yield 54.7 mg, 91%; IR
(νmax, cm–1) neat: 3025, 2957, 2871, 2781, 1456, 1377, 1326, 1287, 1179, 913,
798, 715; 1H NMR (300 MHz, CDCl3) δ 0.93 (3H, t, J = 7.5 Hz), 0.94 (3H,
d, J = 6.8 Hz), 1.25–1.34 (1H, m), 1.35–1.41 (1H, m), 1.42–1.52 (2H, m),
1.61–1.67 (1H, m), 1.68–1.75 (1H, m), 1.76–1.83 (1H, m), 1.84 (1H, td,
J = 9.1, 6.9 Hz), 1.99–2.07 (2H, m), 2.08–2.14 (1H, m), 2.64 (1H, dtd,
J = 11.0, 3.6, 1.9 Hz), 3.35 (1H, td, J = 8.4, 1.9 Hz), 5.50 (1H, dt, J = 10.2, 1.9
Hz), 5.57 (1H, dt, J = 10.2, 1.9 Hz); 13C NMR (75 MHz, CDCl3) d 14.39
(q), 18.14 (q), 18.64 (t), 20.77 (t), 29.38 (t), 36.04 (t), 37.61 (d), 52.79 (t), 63.00
(d), 67.83 (d), 128.55 (d), 131.53 (d); MS; HRMS calcd for C12H21N:
Synthesis of (5S,8S,8aR)-8-methyl-5-propyl-1,5,8,8a-tetrahydro-
indolizin-3(2H)-one (9)
To a stirred solution of the above 9A in toluene, was added DBU
(0.4 mL, 2.9 mmol) at room temperature, then was reflux for 15 h, the
reaction mixture was diluted with AcOEt (100 mL), then washed with
water (2 × 2 mL), 10% HCl (aq) (2 × 2 mL) and saturated NaCl (5 mL),
dried over MgSO4, evaporated to give pale yellow oil which was
purified by column chromatography (silica gel, hexane/acetone,
30:1–20:1) to afford 9: Colourless oil; yield 69.4 mg, 62% for three
steps; IR (νmax, cm–1) neat: 3038, 2959, 2930, 2871, 1695, 1456, 1406,
1315, 1274, 800, 753; 1H NMR (300 MHz) δ 0.86 (3H, t, J = 7.69 Hz),
1.01 (3H, d, J = 7.26 Hz), 1.22 (2H, sxt-like, J = 7.26 Hz), 1.51 (1H,
quint-like, J = 9.82 Hz), 1.79–1.84 (1H, m), 2.04–2.11 (2H, m),
2.20–2.27 (2H, m), 2.29–2.40 (3H, m), 3.01 (1H, q-like, J = 5.55 Hz),
4.10 (1H, br. d, J = 3.42 Hz), 5.60 (1H, d-like, J = 9.82 Hz), 5.66 (1H,
dt-like, J = 10.25 Hz, 2.89 Hz); 13C NMR (75 MHz) δ 14.03 (q), 16.56
(q), 16.82 (t), 25.3 (t), 31.20 (t), 34.62 (t), 36.77 (d), 52.32 (d), 62.20 (d),
128.11 (d), 131.15 (d), 175.54 (s); HRMS calcd for C12H19NO: 193.1467;
179.1674; found: 179.1686; [α]2ꢁꢀ +129.3 (c 2.74, CHCl ).
3
Synthesis of (5S,8S,8aR)-5,8-dipropyl-1,2,3,5,8,8a-hexahydro-indolizine
(12)
To a stirred solution of 10 (50 mg, 0.23 mmol) in THF (5 mL) was added
LiAlH4 (20 mg, 0.46 mmol) at 0 °C and the resulting suspension was
refluxed for 15 h. After cooling, the reaction was quenched with 10%
NaOH (aq) and the aqueous mixture was extracted with hot CHCl3 (10 × 10
mL). The organic extracts were combined, dried (K2CO3) and evaporated to
give compound 12: Colourless oil; IR (νmax, cm–1) neat: 3030, 2957, 2929,
found: 193.1468; [α]2ꢁꢀ +114.63 (c 0.79, CHCl ).
3
Synthesis of (5S,6R,8S,8aR)-3-oxo-5,8-dipropyloctahydroindolizin-
6-yl methanesulfonate (10A)
1
2871, 2790, 1458, 1378, 1329, 1260, 1177, 1105, 929, 803, 713; H NMR
To a stirred solution of 8 (165 mg, 0.58 mmol) in MeOH (10 mL), was
added dropwise 10 drops HCl (aq., 36%). The reaction mixture was
reflux for 15h, allowed to cool and the reaction mixture evaporated
to give a pale yellow residue, which was diluted with CHCl3, dried
(K2CO3) and evaporated to give a colourless oil. To a stirred solution
of the oil in CH2Cl2 (10 mL), was added MsCl (0.067 mL, 0.87 mmol)
and Et3N (0.15 mL, 1.04 mmol) at 0 °C and the reaction mixture was
stirred for 1 h, the resulting mixture was quenched with NaHCO3,
extracted with CH2Cl2, the extracts was combined, dried (MgSO4) and
evaporated to give 10A as pale yellow oil, which was used directly in
the next step.
(300 MHz, CDCl3) δ 0.89 (3H, t, J = 6.8 Hz), 0.91 (3H, t, J = 7.3 Hz),
1.12–1.21 (1H, m), 1.23–1.34 (2H, m), 1.35–1.40 (2H, m), 1.43–1.53 (3H,
m), 1.59–1.68 (1H, m), 1.69–1.74 (1H, m), 1.76–1.82 (1H, m), 1.93 (1H, td, J
= 9.4, 6.8 Hz), 1.99–2.06 (3H, m), 2.63 (1H, dtd, J = 11.0, 3.4, 1.7 Hz), 3.34
(1H, td, J = 8.5, 2.1 Hz), 5.60 (1H, dt, J = 9.8, 1.7 Hz), 5.63 (1H, dt, J= 9.8, 1.7
Hz); 13C NMR (75 MHz, CDCl3) d 14.43 (q x 2), 18.64 (t), 19.67 (t), 20.92
(t), 29.69 (t), 34.91 (t), 36.11 (t), 42.54 (d), 52.76 (t), 62.97 (d), 66.13 (d),
129.01 (d), 129.44 (d); HRMS calcd for C14H25N: 207.1986; found:
207.1973; [α]2ꢁꢀ +109.1 (c0.32, CHCl ).
3
Received 19 March 2017; accepted 29 May 2017
Paper 1704661
https://doi.org/10.3184/174751917X14967701766987
Published online: 30 June 2017
Synthesis of (5S,8S,8aR)-5,8-dipropyl-1,5,8,8a-tetrahydroindolizin-
3(2H)-one (10)
To a stirred solution of 10A in toluene (7 mL), was added DBU
(0.43 mL, 2.9 mmol) at room temperature, the reaction was then stirred
at reflux for 15 h, the reaction mixture was diluted with EtOAc
(100 mL), then washed with water (2 × 2 mL), 10% HCl (aq., 2 × 2 mL)
and saturated NaCl (5 mL), dried (MgSO4) and evaporated to give pale
yellow oil. The product was then purified by column chromatography
(silica gel, hexane/acetone, 30:1–20:1) to afford 10: Colourless oil;
yield 82.8 mg, 64% for three steps; IR (νmax, cm–1) neat: 3035, 2958,
2871, 2369, 1697, 1646, 1512, 1406, 1319, 1271, 1190, 1125, 875;
1H NMR (300 MHz) δ 0.89 (3H, t, J = 7.26 Hz), 0.94 (3H, t,
J = 7.26 Hz), 1.17–1.27 (2H, m), 1.32–1.38 (1H, m), 1.40–1.47 (1H, m),
1.49–1.59 (2H, m), 1.64 (1H, s), 1.79–1.85 (1H, m), 1.96 (1H, t-like,
J = 9.40 Hz), 2.02–2.09 (1H, m), 2.19–2.40 (3H, m), 3.12 (1H, sxt-like,
J = 5.55 Hz), 4.10 (1H, br. d, J = 3.85 Hz), 5.68 (1H, t-like, J = 3.41 Hz),
5.71 (1H, dd-like, J = 18.37 Hz, 3.41 Hz); 13C NMR (75 MHz) δ 14.04
(q), 14.29 (q), 16.91 (t), 19.23 (t), 25.55 (t), 31.25 (t), 32.84 (t), 34.77 (t),
41.71 (d), 52.39 (d), 60.68 (d), 128.44 (d), 129.05 (d), 175.54 (s); HRMS
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14 23
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