Flexible syntheses of 5,8-disubstituted indolizidine poisonous-frog alkaloids via a Michael-type conjugate addition

Article abstract of DOI:10.3184/174751917X14858862342223

The efficient and flexible syntheses of 5,8-disubstituted indolizidine poisonous-frog alkaloids is described using a highly stereoselective Michael-type conjugate addition reaction as the key step. In this work, syntheses of the 5,8-disubstituted indolizidine poisonous-frog alkaloids (-)-231C, (-)-221I and the proposed structure for (-)-193E are reported.

Full text of DOI:10.3184/174751917X14858862342223

98 RESEARCH PAPER
VOL. 41 FEBRUARY, 98–105
JOURNAL OF CHEMICAL RESEARCH 2017
Flexible syntheses of 5,8-disubstituted indolizidine poisonous-frog alkaloids
via a Michael-type conjugate addition
De-Jun Zhoua*, Zhen-Hui Wanga, Yan-Ru Zhanga and Zheng-Guo Cuia,b*
aMedical School, Henan Polytechnic University, Jiaozuo, 454000 Henan Province, P.R. China.
bGraduate School of Medicine and Pharmaceutical Science, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
The efficient and flexible syntheses of 5,8-disubstituted indolizidine poisonous-frog alkaloids is described using a highly stereoselective
Michael-type conjugate addition reaction as the key step. In this work, syntheses of the 5,8-disubstituted indolizidine poisonous-frog
alkaloids (−)-231C, (−)-221I and the proposed structure for (−)-193E are reported.
Keywords: efficient and flexible synthesis, 5,8-disubstituted indolizidine, poisonous-frog alkaloids, Michael-type conjugate addition
Various biologically active alkaloids have been found in
amphibian skin. These include over 20 structural classes and
more than 800 alkaloids.1,2 A great number of these alkaloids
show interesting biological activities, such as pharmacological
effects at neuronal nicotinic acetylcholine receptors.3,4 A great
need for the development of efficient synthetic routes to these
poisonous-frog alkaloids has arisen in order to determine
the structures of these natural products and investigate their
biological activities. However, these alkaloids have been
isolated in only micro amounts from the skin of poisonous
frogs. Consequently, we report here synthetic efforts directed
at these alkaloids.
5,8-Disubstituted indolizidines constitute the largest subclass
of these alkaloids, and over 80 alkaloids have been detected to
date.1,2 In our previous work, we found that (−)-235B', one of
this class of alkaloids, acts as a selective and noncompetitive
antagonist for α4β2 nicotinic acetylcholine receptors.5 These
interesting results suggest that the alkaloid (−)-235B' is a
promising lead compound for drugs designed to treat cholinergic
disorders such as autosomal dominant nocturnal frontal lobe
epilepsy. In this study, we synthesised the 5,8-disubstituted
indolizidines (−)-231C, (−)-221I and the proposed structure
(−)-193E.6,7
This synthetic strategy began with the enantiomerically pure
piperidone 1,8 which was converted to the Cbz-urethane 2.
Treatment of 2 with LiHMDS followed by addition of 2-[N,N-
bis(trifluoromethylsulfonyl)amino]-5-chloropyridine (Comins’
reagent)9 to the resulting lithium enolate gave the enol triflate
3, which was subjected to a palladium-catalysed carbonylation
to provide the enaminoester 4. The key Michael-type conjugate
addition reaction10 at the 3-position of 4 proceeded smoothly
to obtain the desired trisubstituted piperidine 5 in a highly
stereoselective manner. Reduction of the ester moiety with
lithium triethylborohydride (Super-Hydride®) afforded
the corresponding alcohol 6, which was converted to α,β-
unsaturatedester7usingaSwernoxidationfollowedbyaHorner-
Emmons reaction of the resulting aldehyde. Hydrogenation of 7
over palladium hydroxide followed by treatment of amino ester
with trimethylaluminum under Weinreb’s reaction conditions11
provided the key lactam 8. Removal of the silyl group with
TBAF yielded the corresponding alcohol 9, which was
subjected to a Swern oxidation followed by a Wittig reaction
to provide the olefin 10. Hydrogenation and cleavage of the
silylether with TBAF afforded the corresponding alcohol 11,
which was treated with Swern oxidation and a Wittig reaction
to give the (Z)-iodoolefin 12 under Stork’s reaction conditions.12
A Sonogashira coupling reaction13 of 12 with TMS-acetylene
followed by removal of the trimethylsilyl group with K2CO3
obtained the desired (−)-231C. In the FTIR spectra, there was
a strong, sharp Bohlmann band14 at about 2787 cm−1, which
established the 5,9-Z configuration and is same as the natural
(−)-231C obtained from extracts of the dendrobatid frog. The
relative stereochemistry was determined to be 5,8-E and 5,9-
Z configurations based on the GC-FTIR and GC-MS data1
(Scheme 1).
The stereoselectivity of the key Michael-type conjugate
addition reaction was rationalised as follows. The conformation
of 4 will be restricted to A due to A(1,3) strain15 between the
side chain on the α-position and the N-Cbz group. The anion
attacks from the α-axial face owing to stereoelectronic
effects,16 bringing about the protonation of the enolate to obtain
trisubstituted piperidine as a single isomer. This remarkable
stereoselectivity can be also explained by Cieplak’s hypothesis.17
In the preferred conformation A, the developing σ* of the
transition state is stabilised by the antiperiplanar donor σC–H of
the C4 position (Fig. 1).
The reaction conditions for the synthesis of the trisubstituted
piperidine 5werestudiedandtheresultsaregiveninTable1.THF
was used as the solvent for the reaction in the initial experiment,
either at −78 °C for 2 h or at −78 °C to room temperature over
0.8 h. The yields were 71% and 75%, respectively (Table 1,
entries 1 and 4). After several experiments, it was determined
that ether was the best solvent for these conjugate addition
reactions, and at −78 °C to −10 °C over 1 h gave the desired
compound 5 quantitatively (Table 1, entry 5).
In a similar manner, the Michael-type conjugate addition
reaction of 4 with lithium divinylcuprate gave the trisubstituted
piperidine 13. The carbon-chain extension at the 2-position of 13
was performed via the alcohol 14, which was converted to the α,β-
Table 1 Optimisation of the reaction conditions for the synthesis of the
trisubstituted piperidine 5 from compound 4
Entry Me2CuLi/equiv. Solvent Temperature/°C Time/h Yield/%
1
2
3
4
5
6
2
2
5
5
5
5
THF
Et2O
Et2O
THF
Et2O
Et2O
−78
−78
−78 to r.t.
−78 to r.t.
−78 to −10
−78 to −30
2.0
2.0
0.8
0.8
1.0
1.5
71
70
93
75
99
91
All the reactions were performed with 100 mg of the substrate 4, and the reactions were
stopped when the substrate disappeared.
* Correspondent. E-mail: 704573403@qq.com

JOURNAL OF CHEMICAL RESEARCH 2016 99
H
H
d
H
c
b
OTBDPS
OTBDPS
OTBDPS
N
R
O
TfO
N
MeO2C
N
Cbz
Cbz
3
:
1
R=H
4
a
:
2
R=Cbz
H
H
H
Me
Me
H
Me
H
H
f
e
g
H
H
H
OTBDPS
HO
OTBDPS
OTBDPS
EtO2C
N
N
MeO2C
N
Cbz
7
Cbz
Cbz
5
6
H
H
H
Me
Me
Me
H
OTBDPS
H
H
i
h
H
H
j
H
OH
OTBDPS
N
N
N
O
O
9
10
8
H
H
H
Me
Me
H
Me
k
l
H
H
H
H
H
N
N
N
OH
I
12
11
(-)-231C
Reagents and conditions: (a) n-BuLi, CbzCl, THF, (86%); (b) LiHMDS, 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloro-pyridine (Comins’ reagent),
THF, −78 to −50 °C (91%); (c) Pd(PPh3) , Et3N, MeOH, DMF, CO balloon, 75 °C (78%); (d) Me CuLi, Et2O, −78 to −10 °C (99%); (e) Super-Hydride®, THF,
0 °C (92%); (f) (1) Swern oxidation, (2)4NaH, (EtO)2P(O)CH2CO2Et, 0 °C to r.t. (97%); (g) 20% 2Pd(OH)2/C, MeOH, 4 atm then Me3Al, CH2Cl2, reflux (71%);
(h) TBAF, THF, r.t. (99%); (i) (1) LiAlH4, THF, reflux; (2) Swern oxidation; (3) TBDPSO(CH2)3P+Ph3Br−, n-BuLi, THF, 0 °C to r.t. (83%); (j) (1) 10% Pd/C, H2,
EtOAc, 1 atm; (2) TBAF, THF, r.t. (79%); (k) (1) Swern oxidation; (2) ICH2P+Ph3I−, NaHMDS, HMPA, THF, −78 °C to r.t. (61%); (l) (1) CuI, TMS-acetylene,
Pd(Ph3P)4, i-Pr2NH, THF, r.t. (90%); (2) K2CO3, MeOH, r.t. (89%).
Scheme 1 Synthesis of (–)-231C.
[Me-]
OTBDPS
CO2Me
N
CO2Bn
N
CO2Bn
OTBDPS
CO2Me
B
[R'']-
A
Stereoelectronicallty
favoured axial attack
X
A(1,3) strain
CO2Me
N
OBn
O
Me
OR
N
OTBDPS
OTBDPS
CO2R'
N
CO2Bn
OMe
-O
-O
OMe
Me
OTBDPS
H3O+
H
CO2Bn
CO2Me
N
4
H
OTBDPS
Me
H
Nu
MeO2C
R''
H
OTBDPS
N
CO2Bn
Cieplak's hypothesis
MeO2C
N
CO2Bn
Fig. 1 Stereoselectivity of the key Michael-type conjugate addition reaction.

100 JOURNAL OF CHEMICAL RESEARCH 2016
unsaturated ester 15 using Swern oxidation followed by a Horner-
Emmons reaction of the corresponding aldehyde. Hydrogenation
of 15 followed by treatment of the resulting amino ester under
Weinreb’s reaction conditions11 yielded the key intermediate
16. Cleavage of the silyl group provided compound 17, which
was subjected to a two-step oxidation followed by Arndt-Eistert
reaction15 of the resulting carboxylic acid to give the homologated
ester 18. The ester moiety of 18 was reduced with LAH. Swern
oxidation and Wittig olefination afforded the desired alkaloid (−)-
221I. The relative stereochemistry of natural (−)-221I was shown
to be the same as that of synthetic (−)-221I by GC-MS and GC-
FTIR. In addition, the ester 18 was transformed to the proposed
structure for (−)-193E in a similar three-step sequence to that used
in the synthesis of alkaloid (−)-221I. However, comparison of the
synthetic material with natural (−)-193E on GC analysis showed
that the synthetic material had a slightly longer GC retention time
than the natural product. The GC-mass spectra of the synthetic
compound and natural material were almost identical and the
GC-FTIR spectra were very similar in the Bohlmann band region
(indicating 5,9-Z configurations).14 Consequently, it is most likely
that the natural alkaloid 193E is the 8-epimer of the synthetic
product.4 The synthesis of the 8-epimer of 193E would confirm
this interesting result (Scheme 2).
relative stereochemistry of (−)-231C and (−)-221I was also
determined. The present asymmetric synthesis of the proposed
structure for 193E revealed that the C8 configuration of natural
193E should be revised.
Experimental
All chemical reagents were obtained from commercial suppliers
(Aldrich, Kanto Chemical, Tokyo Chemical Industry, Aladdin, Wako
Pure Chemical Industries) and used without further purification.
Anhydrous solvents were obtained by commercial protocols. All non-
aqueous reactions were carried out under an Ar atmosphere. Thin-
layer chromatography (TLC) was performed on silica gel 60 F254 glass
plates pre-coated with 0.25-mm-thick silica gel (Merck). Column
chromatography was carried out on Cica silica gel 60N (spherical,
neutral, 40–50 μm or 63–210 μm). 1H NMR and 13C NMR spectra were
1
obtained on a Varian UNITY plus 300 (300 MHz for H NMR and
75 MHz for 13C NMR) instrument, with CDCl3, CD3OD or DMSO-d6
as an internal reference. IR spectra were measured on a JNM FT/IR-
460Plus spectrometer. Mass spectra were recorded on a JEOL D-200,
JEOL JMS-GCmate II, Shimadzu GC-MS-QP 500 or JEOL AX 505
spectrometer. Melting points were taken with a Yanagimoto micro-
melting point apparatus and are uncorrected.
Phenylmethyl 2-(tert-butyldiphenylsilyloxymethyl)-6-oxopiperidine-
1-carboxylate (2)
Conclusion
A stirred solution of 1 (5.2 g, 14.2 mmol) in THF (30 mL) was treated
with a solution of n-BuLi (1.6 M in hexane, 9.74 mL, 15.6 mmol) at
–78 °C, and the resulting mixture was stirred at –78 °C for 30 min.
We have achieved the total synthesis of (−)-231C, (−)-221I and
an epimer of 193E starting from common chiral lactams. The
H
H
H
H
b
a
H
H
H
c
HO
OTBDPS
OTBDPS
OTBDPS
N
MeO2C
N
MeO2C
N
Cbz
Cbz
13
Cbz
4
14
H
H
H
Et
Et
f
H
H
H
H
e
d
H
H
OH
H
OTBDPS
OTBDPS
N
EtO2C
N
N
Cbz
O
15
O
17
16
H
Et
Et
H
8
8
H
H
5
H
9
9
5
N
N
g
H
Et
H
(-)-193E(proposed)
193E(revised)
H
CO2Me
N
h
H
O
Et
18
H
H
N
(-)-221I
Reagents and conditions: (a) (vinyl)2CuLi, Et2O, −78 to −10 °C (99%); (b) Super-Hydride®, THF, 0 °C (92%); (c) (1) Swern oxidation; (2) NaH, (EtO)2P(O)
CH2CO Et, 0 °C to r.t. (97%); (d) 20% Pd(OH)2/C, MeOH, 4 atm then Me3Al, CH2Cl , reflux (68%); (e) TBAF, THF, r.t. (91%); (f) (1) Swern oxidation; (2)
NaClO22, NaH2PO4, t-BuOH/H2O, 0 °C to r.t.; (3) ClCO2Et, Et3N, THF, 0 °C; (4) CH2N22, Et2O, r.t.; (5) PhCO2Ag, Et3N, MeOH, r.t. (81%); (g) (1) LiAlH4, THF
reflux; (2) Swern oxidation; (3) MeP+Ph3I−, n-BuLi, THF, 0 °C to r.t. (63%); (h) (1) LiAlH4, THF reflux; (2) Swern oxidation; (3) n-Pr3P+Ph3I−, NaHMDS, THF,
−78 °C to r.t. (62%).
Scheme 2 Syntheses of (–)-221C and the proposed structure of (–)-193E.

JOURNAL OF CHEMICAL RESEARCH 2016 101
ClCO2Bn (2.23 mL, 15.6 mmol) was added to the reaction mixture at
the same temperature. The reaction mixture was stirred at ~–78 to 0 °C
for 3 h, and quenched with saturated aqueous NaHCO3. The aqueous
mixture was extracted with CH2Cl2 (3 × 50 mL). The organic extracts
were combined, dried and evaporated to give a pale yellow oil, which
1-Phenylmethyl 2-methyl 6-(tert-butyldiphenylsilyloxymethyl)-3-
methylpiper- idine-1,2-dicarboxylate (5)
A stirred suspension of CuI (8.2 g, 43.1 mmol) in Et2O (50 mL) was
treated with a solution of MeLi (0.98 M in Et2O, 88 mL, 87 mmol) at
–78 °C, and the resulting suspension was stirred at –78 to –35 °C for 20
min. The resulting solution was cooled to –78 °C, and a solution of 4
(4.7 g, 8.7 mmol) in Et2O (15 mL) was added dropwise via a double-
tipped stainless steel needle to the above reaction mixture at –78 °C.
The temperature was gradually raised to –10 °C, and then the reaction
was quenched with saturated aqueous NH4Cl. The aqueous mixture
was diluted with CH2Cl2, and the insoluble material was removed
through a Celite pad. The filtrate was separated and the aqueous layer
was extracted with CH2Cl2. The filtrate and organic layers were
combined, dried and evaporated to give a pale yellow oil, which was
chromatographed on silica gel (70 g, hexane:acetone = ~50:1–30:1) to
afford compound 5 as: Colourless oil; yield 4.8 g (99%); IR (neat)
was chromatographed on silica gel (100 g, hexane:acetone
=
~20:1–15:1) to afford compound 2 as colourless oil; yield 6.1 g (86%);
IR (neat) (cm−1): 3069, 2956, 1772, 1716, 1255; 1H NMR (500 MHz): δ
1.09 (9H, s), 1.73–1.78 (1H, m), 1.90–2.00 (2H, m), 2.15–2.19 (1H, m),
2.55 (2H, t, J = 7.0 Hz), 3.77 (2H, d-like, J = 5.5 Hz), 4.45–4.49 (1H,
m), 5.24 (2H, ABq, J = 12.0 Hz), 7.35–7.48 (11H, br m), 7.66–7.70 (4H,
m); 13C NMR (75 MHz): δ 17.61 (t), 19.13 (s), 24.42 (t), 26.78 (q), 34.87
(t), 56.26 (d), 64.22 (t), 68.25 (t), 127.56 (d), 127.72 and 127.95 (each d),
128.31 (d), 129.60 (d), 129.63 (s), 132.54 and 132.76 (each s), 135.18 (s),
135.31 and 135.38 (each d), 153.80 (s), 171.60 (s); MS m/z: 444 (M+ −
57); [α]2D6 –52.3 (c 1.25, CHCl3). HRMS calcd for C26H26NO4Si:
444.1629; found: 444.1643.
1
(cm−1): 3070, 2954, 1746, 1703; H NMR (500 MHz) δ 1.09 (9H, s),
1.10 (3H, d, J = 7.4 Hz), 1.22–1.28 (1H, m), 1.57–1.62 (1H, m),
1.88–1.92 (2H, m), 2.49 (1H, br), 3.42 (3H, s), 3.52 (1H, t-like,
J = 10.4 Hz), 3.79 (1H, dd, J = 10.4, 4.6 Hz), 4.43 (1H, br), 4.52 (1H, br),
5.14 and 5.21 (2H, ABq, J = 12.6 Hz), 7.26–7.47 (11H, br m), 7.66–7.70
(4H, m); 13C NMR (75 MHz): δ 18.16 (q), 18.25 (t), 19.30 (s), 21.97 (t),
26.88 (q), 28.06 (d), 51.74 (q), 52.18 (d), 58.62 (d), 62.41 (t), 67.24 (t),
127.38 and 127.45 (each d), 127.67 (d), 128.24 (d), 129.41 and 129.44
(each d), 130.12 (d), 133.37 and 133.47 (each s), 135.33 and 135.36
(each d), 136.46 (s), 156.47 (s), 172.49 (s); MS m/z: 502 (M+ − 57);
[α]2D6 −0.43 (c 2.73, CHCl3). HRMS calcd for C29H32NO5Si: 502.2048;
found: 502.2039.
Phenylmethyl 2-(tert-butyldiphenylsilyloxymethyl)-6-trifluoromethane-
sulfonyl- oxy-3,4-dihydro-2H-pyridine-1-carboxylate (3)
A stirred solution of 2 (6.1 g, 12.2 mmol) in THF (15 mL) was treated
with a solution of LiHMDS (prepared from 1,1,1,3,3,3-hexamethyl-
disilazane (3.1 mL, 14.6 mmol) and n-BuLi (1.6 M in hexane, 9.2 mL,
14.6 mmol) in THF (12 mL) at 0 °C for 30 min) at –78 °C, and the
reaction mixture was stirred at the same temperature for 30 min. A
solution of 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloro-
pyridine (Comins’ reagent) (5.25 g, 13.4 mmol) in THF (6 mL) was
added dropwise to the reaction mixture via a double-tipped stainless
steel needle at –78 °C, and the resulting mixture was stirred at ~–78 to
−40 °C for 30 min. The reaction was quenched with saturated aqueous
NH4Cl, and the aqueous mixture was extracted with Et2O (3 × 50 mL).
The ethereal layers were combined, dried and evaporated to give a pale
yellow oil, which was chromatographed on silica gel (100 g,
hexane:acetone = ~60:1–50:1) to afford compound 3 as: Colourless oil;
yield 7.0 g (91%); IR (neat) (cm−1): 3071, 2958, 1730, 1683, 1215;
1H NMR (500 MHz): δ 1.12 (9H, s), 1.73–1.80 (1H, m), 1.96–2.08 (2H,
br m), 2.17–2.23 (1H, br m), 3.62–3.67 (1H, m), 3.85–3.92 (1H, m),
4.75–4.80 (1H, m), 5.22–5.42 (3H, m), 7.38–7.49 (11H, br m), 7.67–7.74
(4H, m); 13C NMR (75 MHz): δ 19.03 (s), 19.24 (t), 22.22 (t), 26.76 (q),
55.77 (d), 60.80 (t), 68.47 (t), 106.41 (d), 126.06 (d), 127.58 and 128.16
(each d), 128.22 and 128.35 (each d), 129.63 (d), 133.03 and 133.08
(each s), 135.15 (s), 135.34 and 135.38 (each d), 135.64 (s), 138.00 and
139.16 (each s), 149.13 (d), 153.17 (s); MS m/z: 576 (M+ − 57); [α]2D6
–57.2° (c 1.26, CHCl3). HRMS calcd for C27H25F3NO6SSi: 576.1122;
found: 576.1127.
Phenylmethyl 6-(tert-butyldiphenylsilyloxymethyl)-2-hydroxymethyl-
3-methyl- piperidine-1-carboxylate (6)
A stirred solution of 5 (4.8 g, 8.6 mmol) in THF (30 mL) was treated
with a solution of lithium triethylborrohydride (Super-Hydride®, 1 M in
THF, 18.9 mL, 18.9 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. The organic layer was dried and
evaporated to give a colourless oil, which was chromatographed on
silica gel (80 g, hexane:acetone = ~10:1–8:1) to afford compound 6 as:
Colourless oil; yield 4.2 g (92%); IR (neat) (cm−1): 3445, 3070, 2957,
1697, 1112; 1H NMR (500 MHz): δ 1.06–1.07 (12H, br s-like),
1.15–1.22 (1H, m), 1.46 (1H, br), 1.65 (1H, br), 1.85 (2H, br), 2.92 (1H,
br), 3.54–3.75 (4H, br m), 4.10 (1H, br), 4.50 (1H, br), 5.10 (1H, br), 5.21
(1H, d-like, J = 12.4 Hz), 7.34–7.47 (11H, br m), 7.69 (4H, br); 13C NMR
(75 MHz): δ 19.17 (q), 19.37 (s), 19.82 (t), 22.73 (t), 26.80 (q), 27.52 (d),
51.03 (d), 59.07 (d), 65.03 (t), 67.29 (t), 126.75 (d), 127.58 and 127.61
(each d), 127.71 (d), 128.31 (d), 129.62 (d), 132.85 (s), 135.33 and
135.39 (each d), 136.53 (s), 157.57 (s); MS m/z: 474 (M+ − 57); [α]2D6
+8.80 (c 1.59, CHCl3). HRMS calcd for C28H32NO4Si: 474.2099; found:
474.2093.
1-Phenylmethyl 2-methyl 6-(tert-butyldiphenylsilyloxymethyl)-5,6-
dihydro-4H- pyridine-1,2-dicarboxylate (4)
A stirred solution of 3 (7 g, 11.1 mmol) in DMF (45 mL) was treated
with Pd(Ph3P)4 (640 mg, 0.55 mmol), and the resulting mixture was
stirred at room temperature under a CO balloon pressure for 30 min.
Et3N (6.3 mL, 45.3 mmol) and MeOH (18 mL, 445.3 mmol) was added
to the reaction mixture, and then the mixture was stirred at 75 °C under
a CO balloon pressure for 15 h. After cooling, the reaction mixture was
diluted with H2O (100 mL) and brine (25 mL), and the aqueous
mixture was extracted with Et2O (4 × 50 mL). The organic layers were
combined, dried and evaporated to give a pale yellow oil, which was
chromatographed on silica gel (80 g, hexane:acetone = ~50:1–30:1) to
afford compound 4 as: Pale yellow oil; yield 4.7 g (78%); IR (neat)
(cm−1): 3069, 2955, 1737, 1714, 1269; 1H NMR (500 MHz): δ 1.09 (9H,
s), 1.82–1.89 (1H, m), 1.95–2.03 (1H, m), 2.06–2.15 (1H, m), 2.17–2.19
(1H, m), 3.48 (3H, br), 3.57 (1H, t-like, J = 6.5 Hz), 3.81–3.84 (1H, m),
4.68 (1H, br), 5.08 and 5.26 (2H, ABq, J = 11.9 Hz), 6.01 (1H, t-like, J =
3.8 Hz), 7.33–7.49 (11H, br m), 7.65–7.73 (4H, m); 13C NMR (75 MHz):
δ 19.24 (t), 19.48 (s), 22.44 (t), 26.76 (q), 51.73 (q), 52.60 (d), 61.24 (t),
67.89 (t), 126.75 (d), 127.51 (d), 128.00 (d), 128.29 (d), 129.54 (d),
130.39 (s), 133.11 and 133.26 (each s), 135.38 (d), 135.64 (s), 153.79 (s),
165.21 (s); MS m/z: 543 (M+); [α]2D6 –37.4 (c 1.30, CHCl3). HRMS calcd
for C32H37NO5Si: 543.2442; found: 543.2465.
Phenylmethyl
6-(tert-butyldiphenylsilyloxymethyl)-2-(2-ethoxy-
carbonylvinyl)- 3-methylpiperidine-1-carboxylate (7)
A stirred solution of (COCl)2 (1.04 mL, 11.86 mmol) in CH2Cl2 (15
mL) was treated with DMSO (1.68 mL, 23.73 mmol) at –78 °C, and
the resulting mixture was stirred at the same temperature for 5 min. A
solution of 6 (4.2 g, 7.91 mmol) in CH2Cl2 (6 mL) was added dropwise
to the reaction mixture via a double-tipped stainless steel needle at
–78 °C. The resulting solution was stirred at –78 °C for 30 min, and then
triethylamine (4.92 mL, 35.59 mmol) was added to the reaction mixture.
The reaction mixture was warmed to 0 °C for 1 h, and quenched with
H2O. The aqueous mixture was extracted with Et2O (3 × 50 mL), and
the organic extracts were combined, dried and evaporated to give a pale
yellow oil, which was used directly in the next step.
A stirred suspension of NaH (60%, 350 mg, 8.7 mmol) in THF
(15 mL) was treated with (EtO)2P(O)CH2CO2Et (1.74 mL, 8.7 mmol)
at 0 °C, and the reaction mixture was stirred at 0 °C for 30 min. A
solution of the above aldehyde in THF (6 mL) was added dropwise
to the resulting mixture via a double-tipped stainless steel needle

102 JOURNAL OF CHEMICAL RESEARCH 2016
at 0 °C. The reaction mixture was stirred at room temperature for
20 h. The reaction was quenched with H2O, and the aqueous mixture
was extracted with CH2Cl2 (4 × 40 mL). The organic extracts were
combined, dried and evaporated to give a pale yellow oil, which was
chromatographed on silica gel (80 g, hexane:acetone = ~20:1–10:1) to
afford compound 7 as a 2:1 mixture of the E- and Z-isomers as: Pale
yellow oil; yield 4.6 g (97%); 1H NMR (500 MHz): δ 1.03–1.07 (12H,
br s-like), 1.21 (3H, t, J = 7.1 Hz), 1.50–1.66 (3H, br m), 1.80–1.94 (2H,
br m), 3.44–3.68 (2H, br m), 4.05–4.18 (2H, m), 4.48–4.54 (2H, br
m), 5.01–5.20 (2H, m), 5.62 and 5.87 (1H, m), 6.22 and 6.89 (1H, m),
7.28–7.43 (11H, br m), 7.64 (4H, t-like, J = 7.4 Hz).
quenched with saturated aqueous NaHCO3, and the organic layer
was separated. The aqueous mixture was extracted with CH2Cl2
(2 × 15 mL), and the organic layer and extracts were combined, dried
over K2CO3 and evaporated to give a pale yellow oil, which was used
directly in the next step.
A stirred suspension of TBDPSO(CH2)3P+Ph3Br− (5.4 g, 8.45 mmol)
in THF (30 mL) was treated with a solution of n-BuLi (1.6 M in hexane,
5 mL, 7.97 mmol) at 0 °C, and the resulting orange solution was stirred
at 0 °C for 10 min. A solution of the above aldehyde in THF (9 mL)
was added dropwise to this mixture via a double-tipped stainless
steel needle at 0 °C. After stirring the reaction mixture for 18 h, the
reaction was quenched with H2O. The aqueous mixture was extracted
with Et2O (3 × 30 mL), and the organic extracts were combined,
dried over K2CO3 and evaporated to give a pale yellow oil, which was
chromatographed on silica gel (50 g, hexane:acetone = ~100:1–20:1) to
afford compound 10 as: Pale yellow oil; yield 949 mg (83%); 1H NMR
(500 MHz): δ 0.90 (3H, d, J = 6.4 Hz), 0.99–1.04 (1H, m), 1.07 (9H, s),
1.36–1.61 (6H, br m), 1.70–1.74 (2H, m), 1.84 (1H, q-like, J = 8.9 Hz),
1.93–1.97 (1H, m), 2.36–2.41 (2H, m), 2.70–2.74 (1H, m), 3.10 (1H,
t-like, J = 8.5 Hz), 3.68 (2H, t, J = 6.9 Hz), 5.41–5.48 (2H, m), 7.38–7.46
(6H, m), 7.69–7.71 (4H, m).
5-(tert-Butyldiphenylsilyloxymethyl)-8-methylhexahydroindolizin-3-
one (8)
A stirred solution of 7 (4.6 g, 7.68 mmol) in MeOH (20 mL) was treated
with 20% Pd(OH)2/C (500 mg), and the resulting suspension was
hydrogenated at 4 atm under a hydrogen atmosphere for 44 h. The
catalyst was filtered off and the filtrate was evaporated to give a pale
yellow oil. The solution of this oil in CH2Cl2 (50 mL) was treated with a
solution of Me3Al (1 M in hexane, 9.2 mL, 9.2 mmol) at 0 °C, and then
refluxed for 15 h. After cooling, the reaction mixture was quenched with
10% aqueous HCl, and the organic layer was separated. The aqueous
layer was extracted with CH2Cl2 (3 × 30 mL), and the organic layer and
extracts were combined, dried and evaporated to give a pale yellow oil,
which was chromatographed on silica gel (60 g, hexane:acetone =
~20:1–10:1) to afford compound 8 as: Colourless solid; m.p. ~78–80 °C;
yield 2.3 g (71%); IR (KBr) (cm−1): 3066, 2958, 1752, 1688, 1109, 1088;
1H NMR (500 MHz): δ 0.91 (3H, d, J = 6.4 Hz), 1.12 (9H, s), 1.13–1.21
(1H, m), 1.29–1.35 (1H, m), 1.52–1.59 (2H, m), 1.85–1.89 (1H, m),
2.11–2.16 (2H, m), 2.25–2.28 (2H, m), 2.95 (1H, m), 3.34–3.38 (1H, m),
4.17–4.21 (1H, m), 4.60–4.64 (1H, m), 7.38–7.45 (6H, m), 7.72–7.74 (4H,
br); 13C NMR (75 MHz): δ 17.61 (q), 19.27 (s), 24.09 (t), 26.89 (q), 27.59
(t), 31.20 (t), 31.34 (t), 37.26 (d), 57.55 (d), 63.67 (t), 64.36 (d), 127.35 and
129.29 (each d), 133.53 and 133.58 (each d), 135.31 (s), 135.36 (d), 174.37
(s); MS m/z: 364 (M+ − 57); [α]2D6 –62.5 (c 1.74, CHCl3). HRMS calcd for
C22H26NO2Si: 364.1731; found: 364.1755.
4-(8-Methyloctahydroindolizin-5-yl)butan-1-ol (11)
A stirred solution of 10 (121 mg, 0.27 mmol) in EtOAc (5 mL) was
treated with 10% Pd/C (50 mg), and the resulting suspension was
hydrogenated at 1 atm under a hydrogen atmosphere for 37 h. The
catalyst was filtered off and the filtrate was evaporated to give a pale
yellow oil. A solution of this oil in THF (8 mL) was mixed with a
solution of TBAF (1 M in THF, 0.7 mL, 0.68 mmol), and the reaction
mixture was stirred at room temperature for 14 h. The solvent was
evaporated and the residue was chromatographed on silica gel (10 g,
hexane:acetone = ~30:1–1:1) to afford compound 11 as: Pale yellow
oil; yield 45 mg (79%); IR (neat) (cm−1): 3309, 2928, 2870, 2785;
1H NMR (500 MHz): δ 0.87 (3H, d, J = 6.8 Hz), 0.95 (1H, qd, J = 12.8,
4.3 Hz), 1.26–1.77 (15H, br m), 1.91–1.97 (2H, br), 2.00 (1H, q-like,
J = 9.0 Hz), 3.28 (1H, t-like, J = 8.6 Hz), 3.65 (2H, t-like, J = 6.8 Hz);
13C NMR (75 MHz): δ 18.95 (q), 20.39 (t), 22.09 (t), 29.01 (t), 31.07 (t),
33.17 (t), 33.64 (t), 34.30 (t), 36.39 (d), 51.79 (t), 62.78 (t), 63.49 (d),
71.39 (d); MS m/z: 211 (M+); [α]2D6 –112.2 (c 1.98, CHCl3). HRMS
calcd for C13H25NO: 211.1935; found: 211.1944.
5-Hydroxymethyl-8-methylhexahydroindolizin-3-one (9)
A stirred solution of 8 (300 mg, 0.71 mmol) in THF (5 mL) was treated
with a solution of TBAF (1M in THF, 0.78 mL, 0.78 mmol) at 0 °C, and
the resulting mixture was stirred at room temperature for 13 h. The
solvent was evaporated, and the residue was chromatographed on silica
gel (10 g, hexane:acetone = ~20:1–2:1) to afford compound 9 as:
Colourless oil; yield 129 mg (99%); IR (neat) (cm−1): 3342, 2929, 1663;
1H NMR (500 MHz): δ 0.86 (3H, d, J = 6.5 Hz), 1.09–1.25 (2H, br m),
1.28–1.37 (1H, m), 1.53–1.63 (2H, m), 1.76–1.80 (1H, m), 2.15–2.21 (1H,
m), 2.30–2.37 (2H, m), 2.92–2.97 (1H, m), 3.06 (1H, br), 3.72 (1H, d-like,
J = 12.9 Hz), 3.81–3.86 (1H, m), 4.77 (1H, br); 13C NMR (75 MHz): δ
17.28 (q), 23.90 (t), 28.12 (t), 31.44 (t), 32.30 (t), 38.10 (d), 60.48 (d),
63.70 (t), 65.84 (d), 175.39 (s); MS m/z: 183 (M+); [α]2D6 –53.6 (c 1.25,
CHCl3). HRMS calcd for C10H17NO2: 183.1258; found: 183.1269.
5-(5-Iodopent-4-enyl)-8-methyloctahydroindolizine (12)
A stirred solution of (COCl)2 (0.35 mL, 4 mmol) in CH2Cl2 (10
mL) was treated with DMSO (0.58 mL, 8 mmol) at –78 °C, and the
resulting mixture was stirred at the same temperature for 5 min.
A solution of 11 (210 mg, 1.00 mmol) in CH2Cl2 (3 mL) was added
dropwise to this mixture via a double-tipped stainless steel needle
at –78 °C, and the reaction mixture was stirred at –78 °C for 30 min.
Triethylamine (1.66 mL, 12 mmol) was added to the reaction mixture,
and the reaction mixture was warmed to 0 °C for 1 h. The reaction was
quenched with saturated aqueous NaHCO3, and the aqueous mixture
was extracted with CH2Cl2 (3 × 20 mL). The organic layers were
combined, dried over K2CO3 and evaporated to give a pale yellow oil,
which was used directly in the next step.
5- [4- (tert-But yldiphenylsilyloxy) but-1-enyl] - 8-methyl-
octahydroindolizine (10)
A stirred suspension of ICH2P+Ph3I− (1.33 g, 2.5 mmol) in THF
(15 mL) was treated with a solution of NaHMDS (1M in THF, 2.5 mL,
2.5 mmol) at room temperature, and the reaction mixture was stirred
at room temperature for 1 min. HMPA (0.6 mL) was added to the
mixture followed by dropwise a solution of the above aldehyde in
THF (6 mL) via a double-tipped stainless steel needle at –78 °C. The
reaction mixture was stirred at ~–78 °C to room temperature for 2 h
and quenched with saturated aqueous NaHCO3. The aqueous mixture
was extracted with Et2O (4 × 25 mL), and the organic extracts were
combined, dried over K2CO3 and evaporated to give a pale yellow oil,
which was chromatographed on silica gel (30 g, hexane:acetone =
~80:1–20:1) to afford compound 12 as: Pale yellow oil; yield 203 mg
(61%); IR (neat) (cm−1): 2926, 2869, 2778, 2457; 1H NMR (500 MHz):
δ 0.88 (3H, d, J = 6.8 Hz), 0.96 (1H, qd-like, J = 12.0, 4.2 Hz), 1.22–1.41
(5H, br m), 1.42–1.58 (2H, m), 1.61–1.78 (5H, m), 1.89–1.95 (2H, m),
A stirred solution of 9 (470 mg, 2.57 mmol) in THF (30 mL) was
treated with LiAlH4 (292 mg, 7.70 mmol) at 0 °C, and the resulting
suspension was refluxed for 15 h. After cooling, the reaction was
quenched with 10% aqueous NaOH, and the aqueous mixture was
extracted with hot CHCl3 (10 × 15 mL). The organic extracts were
combined, dried over K2CO3, and evaporated to give a colourless oil,
which was used directly in the next step.
A stirred solution of (COCl)2 (0.34 mL, 3.86 mmol) in CH2Cl2
(6 mL) was treated with DMSO (0.55 mL, 7.71 mmol) at –78 °C, and
the reaction mixture was stirred at –78 °C for 5 min. A solution of the
above alcohol in CH2Cl2 (9 mL) was added dropwise to this mixture
via a double-tipped stainless steel needle at –78 °C, and the mixture
was then stirred at the same temperature for 30 min. Triethylamine
(1.6 mL, 11.57 mmol) was added to the reaction mixture, and the
reaction mixture was warmed to 0 °C for 1 h. The reaction was

JOURNAL OF CHEMICAL RESEARCH 2016 103
1.97 (1H, q-like, J = 8.9 Hz), 2.12–2.17 (2H, m), 3.26 (1H, t-like, J =
8.6 Hz), 6.15–6.21 (2H, m); 13C NMR (75 MHz): δ 18.96 (q), 20.42
(t), 24.22 (t), 29.09 (t), 31.18 (t), 33.67 (t), 34.04 (t), 35.00 (t), 36.57 (d),
51.86 (t), 63.17 (d), 71.31 (d), 82.50 (d), 140.96 (d); MS m/z: 333 (M+);
[α]D –67.4 (c 1.67, CHCl3). HRMS calcd for C14H24IN: 333.0953;
found: 333.0973.
(1H, m), 7.28–7.45 (11H, br m), 7.64 (4H, d-like, J = 6.4 Hz); 13C NMR
(75 MHz): δ 18.43 (t), 19.26 (s), 20.70 (t), 26.84 (q), 36.66 (d), 51.84 (q),
52.13 (d), 55.81 (d), 61.97 (t), 67.26 (t), 115.28 (t), 127.37 and 127.45
(each d), 127.67 (d), 128.06 (d), 128.21 (d), 129.41 and 129.44 (each d),
133.26 and 133.37 (each s), 135.30 and 135.33 (each d), 136.38 (s),
138.55 (d), 156.10 (s), 172.17 (s); MS m/z: 514 (M+ − 57); [α]2D6 –8.80 (c
1.69, CHCl3). HRMS calcd for C30H32NO5Si: 514.2048; found:
514.2067.
26
8-Methyl-5-[7-(trimethylsilyl)hept-4-en-6-ynyl]octahydroindolizine
(12*)
Ph enylm ethyl 6 - (ter t- bu t yl diph enylsilylox y m ethyl) -2-
hydroxymethyl-3- vinylpiperidine-1- carboxylate (14)
A stirred suspension of CuI (11 mg, 0.057 mmol) and Pd(Ph3P)4 (23
mg, 0.02 mmol) in THF (2 mL) was treated with i-Pr2NH (0.2 mL, 1.44
mmol) at room temperature. A solution of 12 (65 mg, 0.2 mmol) and
TMS-acetylene (0.1 mL, 0.93 mmol) in THF (3 mL) was added
dropwise to this solution via a double-tipped stainless steel needle. The
reaction mixture was stirred at room temperature for 17 h, and then
quenched with saturated aqueous NaHCO3. The aqueous mixture was
extracted with Et2O (4 × 10 mL), and the organic extracts were
combined, dried over K2CO3 and evaporated to give a pale yellow oil,
which was chromatographed on silica gel (10 g, hexane:acetone =
~100:1–20:1) to afford compound 12* as: Pale yellow oil; yield 41 mg
A stirred solution of 13 (6.04 g, 10.58 mmol) in THF (80 mL) was
treated with a solution of Super-Hydride® (1 M in THF, 23 mL,
23.0 mmol) at 0 °C, and the resulting solution was stirred at 0 °C for
2 h. The reaction was quenched with small pieces of ice, and the
mixture was diluted with CH2Cl2. The organic layer was dried and
evaporated to give a colourless oil, which was chromatographed on
silica gel (70 g, hexane:acetone = ~20:1–8:1) to afford compound 14 as:
Colourless oil; yield 5.3 g (92%); IR (neat) (cm−1): 3445, 3070, 2932,
2858, 1695, 1112; 1H NMR (500 MHz): δ 1.09 (9H, s), 1.30–1.43 (1H,
m), 1.47 (1H, br), 1.67–1.72 (1H, m), 1.84–1.90 (1H, m), 2.43 (1H, br),
3.14 (1H, br), 3.58–3.75 (4H, br m), 4.36 (1H, br m), 4.51 (1H, br),
5.09–5.24 (4H, m), 5.89 (1H, m), 7.33–7.48 (11H, m), 7.70–7.71 (4H,
br); 13C NMR (75 MHz): δ 19.14 (s), 20.15 (t), 22.67 (t), 26.78 (q), 36.79
(d), 50.98 (d), 56.36 (d), 64.41 (t), 67.33 (t), 115.04 (t), 127.58 (d),
127.72 (d), 128.29 (d), 129.62 (d), 132.79 (s), 135.31 (d), 135.36 (d),
136.41 (s), 140.02 (d), 157.15 (s); MS m/z: 486 (M+ − 57); [α]2D6 +14.2 (c
1.11, CHCl3). HRMS calcd for C29H32NO4Si: 486.2099; found:
486.2107.
1
(90%); IR (neat) (cm−1): 3017, 2958, 2778, 2148, 843; H NMR (500
MHz): δ 0.21 (9H, s), 0.88 (3H, d, J = 6.4 Hz), 0.97 (1H, qd-like, J =
12.0, 3.9 Hz), 1.27–1.53 (8H, br m), 1.67–1.78 (4H, m), 1.94–2.18 (3H,
m), 2.33 (2H, q-like, J = 6.9 Hz), 3.29 (1H, br), 5.49 (1H, d-like, J = 11.1
Hz), 5.95 (1H, dt-like, J = 11.1, 7.7 Hz); 13C NMR (75 MHz): δ 12.33
(q), 18.96 (q), 20.37 (t), 22.73 (t), 24.93 (t), 29.04 (t), 30.57 (t), 31.07 (t),
33.66 (t), 36.42 (d), 51.81 (t), 63.23 (d), 71.42 (d), 98.57 (s), 102.01 (s),
109.34 (d), 144.99 (d); MS m/z: 303 (M+); [α]2D6 –57.9 (c 1.11, CHCl3).
HRMS calcd for C19H33NSi; 303.2380; found: 303.2372.
5-Hept-4-en-6-ynyl-8-methyloctahydroindolizine (231C)
Phenylmethyl
6-(tert-butyldiphenylsilyloxymethyl)-2-(2-ethoxy-
carbonylvinyl)-3-vinyl-piperidine-1-carboxylate (15)
A stirred solution of 12* (20 mg, 0.066 mmol) in MeOH (0.6 mL) was
treated with K2CO3 (20 mg, 0.15 mmol), and the reaction mixture was
stirred at room temperature for 1 h. The reaction mixture was diluted
with Et2O, and the insoluble material was filtered off. The filtrate was
evaporated to give indolizidine 231C as: Colourless oil; yield 14 mg
A stirred solution of (COCl)2 (1.28 mL, 14.64 mmol) in CH2Cl2
(20 mL) was treated with DMSO (2.1 mL, 29.28 mmol) at –78 °C,
and the resulting mixture was stirred at the same temperature for
5 min. A solution of 14 (5.3 g, 9.76 mmol) in CH2Cl2 (9 mL) was added
dropwise to this mixture via a double-tipped stainless steel needle at
–78 °C. The resulting solution was stirred at –78 °C for 30 min and then
triethylamine (6.1 mL, 43.92 mmol) was added to the reaction mixture,
which was then warmed to 0 °C for 1 h, and quenched with H2O. The
aqueous mixture was extracted with Et2O (3 × 50 mL), and the organic
extracts were combined, dried and evaporated to give a pale yellow oil,
which was used directly in the next step.
1
(89%); IR (neat) (cm−1): 3328, 3034, 2787, 1457, 1249, 851; H NMR
(500 MHz): δ 0.87 (3H, d, J = 6.8 Hz), 0.95 (1H, qd, J = 12.0, 4.3 Hz),
1.20–1.56 (3H, br m), 1.51–1.57 (7H, br m), 1.60–1.78 (5H, br m),
1.86–1.91 (2H, m), 1.92 (1H, q-like, J = 9.0 Hz), 2.28–2.40 (2H, m),
3.08 (1H, br s), 3.26 (1H, t-like, J = 8.6 Hz), 5.45 (1H, d-like,
J = 9.9 Hz), 6.01 (1H, dt-like, J = 9.9, 6.7 Hz); 13C NMR (75 MHz): δ
18.98 (q), 20.44 (t), 25.02 (t), 29.13 (t), 30.58 (t), 31.26 (t), 33.70 (t),
34.16 (t), 36.63 (d), 51.87 (t), 63.18 (d), 71.29 (d), 80.48 (s), 81.27 (d),
108.15 (d), 145.68 (d); MS m/z: 231 (M+); [α]2D6 –107.67 (c 0.68,
CHCl3). HRMS calcd for C16H25N: 231.1986; found: 231.1999.
A stirred suspension of NaH (60%, 430 mg, 10.74 mmol) in THF
(30 mL) was treated with (EtO)2P(O)CH2CO2Et (2.2 mL, 10.74 mmol)
at 0 °C, and the reaction mixture was stirred at 0 °C for 30 min. A
solution of the above aldehyde in THF (9 mL) was added dropwise
to this mixture via a double-tipped stainless steel needle at 0 °C. The
reaction mixture was stirred at room temperature for 22 h. The reaction
was quenched with H2O, and the aqueous mixture was extracted with
CH2Cl2 (4 × 50 mL). The organic extracts were combined, dried and
evaporated to give a pale yellow oil, which was chromatographed on
silica gel (80 g, hexane:acetone = ~20:1–10:1) to afford compound 15
as a 2:1 mixture of the E- and Z-isomers as: Pale yellow oil; yield 5.78 g
1-Phenylmethyl2-methyl6-(tert-butyldiphenylsilyloxymethyl)-3-
vinylpiperidine-1,2- dicarboxylate (13)
A stirred solution of tetravinyltin (4 mL, 24.5 mmol) in Et2O (10 mL)
was treated with a solution of MeLi (0.98 M in Et2O, 100 mL, 98 mmol)
at 0 °C, and the reaction mixture was stirred at 0 °C for 30 min. A
stirred suspension of CuI (9.33 g, 49.0 mmol) in Et2O (20 mL) was
treated with a solution of vinyllithium (prepared as above) at –78 °C,
and the resulting mixture was stirred at ~–78 to −35°C for 30 min. A
solution of 4 (6.1 g, 11.2 mmol) in Et2O (20 mL) was added dropwise to
the reaction mixture via a double-tipped stainless steel needle at –78
°C. The reaction mixture was stirred at ~–78 to −10 °C for 1 h, and then
the reaction was quenched with saturated aqueous NH4Cl. The aqueous
mixture was diluted with CH2Cl2, and the insoluble material was
filtered off. The organic layer was separated and the aqueous layer was
extracted with CH2Cl2 (2 × 30 mL). The organic layer and extracts
were combined, dried and evaporated to give a pale yellow oil, which
1
(97%); H NMR (500 MHz): δ 1.03 (9H, s), 1.22 (3H, t, J = 7.1 Hz),
1.51–1.85 (4H, br m), 2.51 (1H, br), 3.44–3.68 (2H, br m), 4.03–4.18
(2H, m), 4.48 (1H, br m), 4.84 (1H, br), 5.01–5.22 (4H, br m), 5.62 and
5.87 (1H, m), 5.71–5.86 (1H, m), 6.22 and 6.89 (1H, m), 7.28–7.43 (11H,
br m), 7.64 (4H, t-like, J = 7.4 Hz).
5-(tert-Butyldiphenylsilyloxymethyl)-8-ethylhexahydroindolizin-3-
one (16)
A stirred solution of 15 (1.6 g, 2.61 mmol) in MeOH (10 mL) was
treated with 20% Pd(OH)2/C (100 mg), and the resulting suspension
was hydrogenated at 4 atm under a hydrogen atmosphere for 44 h. The
catalyst was filtered off and the filtrate was evaporated to give a pale
yellow oil. A solution of this oil in CH2Cl2 (30 mL) was treated with a
solution of Me3Al (1 M in hexane, 3.1 mL, 3.1 mmol) at 0 °C, and the
resulting solution was refluxed for 17 h. After cooling, the reaction was
was chromatographed on silica gel (100 g, hexane:acetone
=
~25:1–20:1) to afford compound 13 as: Pale yellow oil; yield 6.3 g
(99%); IR (neat) (cm−1): 3074, 2953, 1744, 1698, 1269, 1113; 1H NMR
(500 MHz): δ 1.05 (9H, s), 1.21 (1H, br), 1.44 (1H, br), 1.80 (1H, m),
1.87 (1H, br), 3.02 (1H, br), 3.40 (3H, s), 3.47 (1H, t-like, J = 9.9 Hz),
3.74 (1H, m), 4.40 (1H, br), 4.82 (1H, br), 5.11–5.19 (4H, m), 5.82–5.89

104 JOURNAL OF CHEMICAL RESEARCH 2016
quenched with 10% aqueous HCl, and the organic layer was separated.
The aqueous layer was extracted with CH2Cl2 (3 × 30 mL), and the
organic layer and extracts were combined, dried and evaporated to give
a pale yellow oil, which was chromatographed on silica gel (50 g,
hexane:acetone = ~20:1–10:1) to afford compound 16 as: Colourless
solid; m.p. ~84–87 °C; yield 771 mg (68%); IR (KBr) (cm−1): 3070,
as: Pale yellow oil; yield 335 mg (81%); IR (neat) (cm−1): 2964, 1739,
1688, 1173; 1H NMR (500 MHz): δ 0.86 (3H, t, J = 7.2 Hz), 0.97–1.15
(3H, m), 1.34–1.66 (4H, br m), 1.88–1.94 (1H, m), 2.06–2.21 (1H, m),
2.22–2.27 (2H, m), 2.41 (1H, dd, J = 16.5, 4.7 Hz), 3.03 (1H, q-like,
J = 7.4 Hz), 3.41 (1H, dd, J = 16.5, 8.8 Hz), 3.52–3.61 (1H, m), 3.66
(3H, s); 13C NMR (75 MHz): δ 10.73 (q), 24.03 (t), 24.19 (t), 28.41 (t),
31.46 (t), 31.84 (t), 37.89 (t), 44.24 (d), 51.39 (q), 52.57 (d), 63.62 (d),
171.97 (s), 175.05 (s); MS m/z: 239 (M+). HRMS calcd for C13H21NO3:
239.1520; found: 239.1544.
1
2931, 1690, 1112; H NMR (500 MHz): δ 0.88 (3H, t, J = 7.3 Hz),
0.90–1.18 (3H, m), 1.11 (9H, s), 1.44–1.60 (3H, br m), 1.87–1.91 (1H,
m), 2.04–2.11 (2H, m), 2.19–2.22 (2H, m), 3.00 (1H, q-like, J = 7.7 Hz),
3.40–3.43 (1H, m), 4.11 (1H, t-like, J = 9.0 Hz), 4.56 (1H, dd, J = 9.0,
4.2 Hz), 7.35–7.40 (6H, m), 7.71–7.74 (4H, m); 13C NMR (75 MHz): δ
10.44 (q), 18.92 (s), 24.22 (t), 24.26 (t), 26.31 (t), 26.59 (q), 30.89 (t),
43.10 (d), 56.36 (d), 61.94 (d), 63.22 (t), 127.04 (d), 128.99 (d), 133.13
(d), 134.96 and 135.00 (each s), 173.96 (s); MS m/z: 378 (M+ − 57);
[α]2D6 –63.1 (c 1.71, CHCl3). HRMS calcd for C23H28NO2Si: 378.1888;
found: 378.1897.
5-Allyl-8-ethyloctahydroindolizine [193E (proposed)]
A stirred solution of 18 (167 mg, 0.71 mmol) in THF (8 mL) was treated
with LiAlH4 (80 mg, 2.1 mmol) at 0 °C, and the resulting suspension was
refluxed for 13 h. After cooling, the reaction was quenched with 10%
aqueous NaOH, and the aqueous mixture was extracted with CHCl3 (10
× 10 mL). The organic extracts were combined, dried over K2CO3 and
evaporated to give a colourless oil, which was used directly in the next step.
A stirred solution of (COCl)2 (0.1 mL, 1.14 mmol) in CH2Cl2 (1 mL)
was treated with DMSO (0.17 mL, 2.40 mmol) at –78 °C, and the reaction
mixture was stirred at –78 °C for 5 min. A solution of the alcohol obtained
above in CH2Cl2 (2 mL) was added dropwise to this mixture via a double-
tipped stainless steel needle at –78 °C, and the reaction mixture was stirred
at –78 °C for 30 min. Triethylamine (0.5 mL, 3.61 mmol) was added to the
reaction mixture, which was then warmed to 0 °C for 1 h. The reaction was
quenched with saturated aqueous NaHCO3, and the aqueous mixture was
extracted with CH2Cl2 (3 × 10 mL). The organic layers were combined,
dried over K2CO3 and evaporated to give a pale yellow oil, which was used
directly in the next step.
A stirred suspension of MeP+Ph3I− (1.27 g, 3.15 mmol) in THF (15 mL)
was treated with a solution of n-BuLi (1.6 M in hexane, 1.84 mL, 2.94
mmol) at 0 °C, and the resulting mixture was stirred at the same
temperature for 5 min. A solution of the aldehyde obtained above in THF
(3 mL) was added dropwise to this mixture via a double-tipped stainless
steel needle at 0 °C. The reaction mixture was stirred at room temperature
for 17 h, and the reaction was quenched with saturated aqueous NaHCO3.
The aqueous mixture was extracted with Et2O (4 × 15 mL), and the organic
extracts were combined, dried over K2CO3 and evaporated to give pale
yellow oil, which was chromatographed on silica gel (20 g, hexane:acetone
= ~100:1–20:1) to afford a product with the proposed structure of 193E as:
Pale yellow oil; yield 85 mg (63%); IR (neat) (cm−1): 3083, 2963, 2933,
2788, 910; 1H NMR (500 MHz): δ 0.83–0.92 (1H, m), 0.88 (3H, t, J = 7.7
Hz), 1.03–1.09 (1H, m), 1.13–1.28 (2H, m), 1.41–1.52 (2H, m), 1.57–1.69
(2H, m), 1.74–1.78 (2H, m), 1.85–2.02 (4H, m), 2.08–2.12 (1H, m), 2.44
(1H, m), 3.29 (1H, t, J = 9.0 Hz), 5.00–5.07 (2H, m), 5.77–5.85 (1H, m);
13C NMR (75 MHz): δ 11.17 (q), 20.53 (t), 25.99 (t), 29.08 (t), 29.79 (t),
31.21 (t), 39.53 (t), 42.99 (d), 51.95 (t), 63.05 (d), 70.01 (d), 116.37 (t), 135.76
(d); MS m/z: 193 (M+); [α]2D6 –68.7 (c 3.30, CHCl3). HRMS calcd for
C13H23N: 193.1829; found: 193.1833.
8-Ethyl-5-hydroxymethylhexahydroindolizin-3-one (17)
A stirred solution of 16 (783 mg, 1.8 mmol) in THF (12 mL) was
treated with a solution of TBAF (1M in THF, 2.7 mL, 2.7 mmol)
at 0 °C, and the resulting mixture was stirred at room temperature
for 16 h. The reaction mixture was evaporated, and the residue was
chromatographed on silica gel (20 g, hexane:acetone = ~20:1–2:1)
to afford compound 17 as: Colourless solid; m.p. ~54–57 °C; yield
1
340 mg (91%); IR (KBr) (cm−1): 3298, 2941, 1656; H NMR (500
MHz): δ 0.92 (3H, t, J = 7.7 Hz), 1.02–1.13 (3H, m), 1.30–1.38 (1H, m),
1.50–1.57 (1H, m), 1.61–1.69 (2H, m), 1.96–2.01 (1H, m), 2.21–2.28
(1H, m), 2.34–2.46 (2H, m), 3.06–3.11 (2H, m), 3.76 (1H, dd, J = 12.8,
2.1 Hz), 3.90 (1H, dd, J = 12.8, 7.2 Hz), 4.57 (1H, br); 13C NMR (75
MHz): δ 10.53 (q), 23.93 (t), 23.98 (t), 27.85 (t), 28.30 (t), 31.33 (t),
44.24 (d), 60.34 (d), 63.62 (t), 64.25 (d), 175.26 (s); MS m/z: 197 (M+).
HRMS calcd for C11H19NO2: 197.1415; found: 197.1401.
Methyl (8-ethyl-3-oxooctahydroindolizin-5-yl)acetate (18)
A stirred solution of (COCl)2 (0.25 mL, 2.82 mmol) in CH2Cl2
(10 mL) was treated with DMSO (0.40 mL, 5.63 mmol) at –78 °C, and
the resulting mixture was stirred at the same temperature for 5 min.
A solution of 17 (340 mg, 1.73 mmol) in CH2Cl2 (3 mL) was added
dropwise to this mixture via a double-tipped stainless steel needle
at –78 °C, and the reaction mixture was stirred at –78 °C for 30 min.
Triethylamine (1.17 mL, 8.45 mmol) was added to the reaction mixture,
and the reaction mixture was warmed to 0 °C for 1 h. The reaction was
quenched with H2O, and the aqueous mixture was extracted with Et2O
(3 × 25 mL). The organic layers were combined, dried and evaporated
to give a pale yellow oil, which was used directly in the next step.
A stirred solution of the above aldehyde in t-BuOH (9 mL) were
treated with 2-methyl-2-butene (7.9 mL, 75.13 mmol), NaH2PO4•2H2O
(2.93 g, 18.78 mmol), and then a solution of NaClO2 (80%, 1.27 mg,
11.27 mmol) in H2O (3 mL) at 0 °C. The reaction mixture was stirred
at room temperature for 1 h and then quenched with saturated aqueous
NaHSO3 at 0 °C. The aqueous mixture was acidified with 10% aqueous
HCl, saturated with solid NaCl and extracted with EtOAc (10 × 10 mL).
The organic extracts were combined, dried and evaporated to give a
pale yellow oil, which was used directly in the next step.
A stirred solution of the above carboxylix acid in THF (15 mL)
was treated with Et3N (0.29 mL, 2.07 mmol) and ClCO2Et (0.2 mL,
2.07 mmol) at 0 °C, and the resulting suspension was stirred at the
same temperature for 1 h. The insoluble material was filtered off, and
the filtrate was evaporated to give a pale yellow oil, which was used
directly in the next step.
A stirred solution of the above oil in Et2O (30 mL) was treated with a
solution of CH2N2 in Et2O at 0 °C, and the yellow mixture was stirred at
room temperature for 16 h. The solvent was removed in vacuo and the
residue was dissolved in MeOH (12 mL). PhCO2Ag (43 mg, 0.19 mmol)
and Et3N (0.52 mL, 3.76 mmol) were added to the MeOH solution, and
the resulting suspension was stirred at room temperature in the dark
for 15 h. The insoluble material was filtered off, and the filtrate was
evaporated to give a pale brown oil, which was chromatographed on
silica gel (25 g, hexane:acetone = ~30:1–10:1) to afford compound 18
8-Ethyl-5-pent-2-enyloctahydroindolizine (221I)
A stirred solution of 18 (167 mg, 0.71 mmol) in THF (8 mL) was treated
with LiAlH4 (80 mg, 2.1 mmol) at 0 °C, and the resulting suspension was
refluxed for 13 h. After cooling, the reaction was quenched with 10%
aqueous NaOH, and the aqueous mixture was extracted with CHCl3 (10
× 10 mL). The organic extracts were combined, dried over K2CO3 and
evaporated to give a colourless oil, which was used directly in the next step.
A stirred solution of (COCl)2 (0.1 mL, 1.14 mmol) in CH2Cl2 (1 mL)
was treated with DMSO (0.17 mL, 2.40 mmol) at –78 °C, and the reaction
mixture was stirred at –78 °C for 5 min. A solution of the alcohol obtained
above in CH2Cl2 (2 mL) was added dropwise to this mixture via a double-
tipped stainless steel needle at –78 °C, and the reaction mixture was stirred
at –78 °C for 30 min. Triethylamine (0.5 mL, 3.61 mmol) was added to the
reaction mixture, and the reaction mixture was warmed to 0 °C for 1 h. The
reaction was quenched with saturated aqueous NaHCO3, and the aqueous
mixture was extracted with CH2Cl2 (3 × 10 mL). The organic layers were
combined, dried over K2CO3 and evaporated to give a pale yellow oil,
which was used directly in the next step.
A stirred suspension of n-PrP+Ph3Br− (1.21 g, 3.15 mmol) in THF (15 mL)
was treated with a solution of NaHMDS (1 M in THF, 2.8 mL, 2.8 mmol)

JOURNAL OF CHEMICAL RESEARCH 2016 105
References
at room temperature, and the resulting mixture was stirred at the same
temperature for 1 min. HMPA (0.8 mL) was added to the mixture followed
by dropwise a solution of the aldehyde obtained above in THF (3 mL) via a
double-tipped stainless steel needle at −78 °C. The reaction mixture was
stirred at ~–78 °C to room temperature for 22 h, and the reaction was
quenched with saturated aqueous NaHCO3. The aqueous mixture was
extracted with Et2O (4 × 15 mL), and the organic extracts were combined,
dried over K2CO3 and evaporated to give a pale yellow oil, which was
chromatographed on silica gel (20 g, hexane:acetone = ~100:1–20:1) to
afford compound 221I as: Pale yellow oil; yield 96 mg (62%); IR (neat)
(cm−1): 3015, 2963, 2932, 2787, 1459; 1H NMR (500 MHz): δ 0.86–0.91
(1H, m), 0.89 (3H, t, J = 7.2 Hz), 0.96 (3H, t, J = 7.6 Hz), 1.03–1.09 (1H, m),
1.11–1.27 (2H, m), 1.42–1.52 (2H, m), 1.58–1.70 (2H, m), 1.74–1.82 (2H,
m), 1.84–1.97 (3H, m), 2.00–2.15 (4H, m), 2.40 (1H, br), 3.32 (1H, t, J = 8.9
Hz), 5.32–5.47 (2H, m); 13C NMR (75 MHz): δ 11.17 (q), 14.30 (q), 20.53
(t), 20.78 (t), 26.00 (t), 29.09 (t), 29.82 (t), 31.26 (t), 32.60 (t), 42.96 (d),
51.98 (t), 63.64 (d), 70.06 (d), 125.70 (d), 133.00 (d); MS m/z: 221 (M+);
[α]2D6 –77.8 (c 3.75, CHCl3). HRMS calcd for C15H27N: 221.2142; found:
221.2165.
1
2
3
J.W. Daly, T.F. Spande and H.M. Garraffo, J. Nat. Prod., 2005, 68, 1556.
J.W. Daly, J. Med. Chem., 2003, 46, 445.
J.W. Daly, T. Kaneko, J. Wilham, H.M. Garraffo, T.F. Spande, A. Espinosa
and M. Donelly, Proc. Natl Acad. Sci. USA, 2002, 99, 13996.
V.C. Clark, C.J. Raxworthy, V. Rakotomalala, P. Sierwald and B.L. Fisher,
Proc. Natl Acad. Sci. USA, 2005, 102, 11617.
H. Tsneki, Y. You, N. Toyooka, S. Kagawa, S. Kobayashi, T. Sasaoka, H.
Nemoto, I. Kimura and J.A. Dani, Mol. Pharmacol., 2004, 66, 1061.
N. Toyooka, D.J. Zhou, H. Nemoto, H.M. Garraffo, T.F. Spande and J.W.
Daly, Tetrahedron Lett., 2006, 47, 577.
N. Toyooka, D.J. Zhou, H. Nemoto, H.M. Garraffo, T.F. Spande and J.W.
Daly, Tetrahedron Lett., 2006, 47, 581.
4
5
6
7
8
9
T.J. Hodgkinson and M. Shipman, Synthesis, 1998, 1141.
D.L. Comins and A. Dehghani, Tetrahedron Lett., 1992, 33, 6299.
10 N. Toyooka and H. Nemoto, Recent Res. Dev. Org. Chem., 2002, 6, 611.
11 A. Basha, M. Lipton and S.M. Weinreb, Tetrahedron Lett., 1977, 18, 4171.
12 G. Stork and K. Zhao, Tetrahedron Lett., 1989, 30, 2173
13 S. Takahashi, Y. Kuroyama, K. Sonogashira and N. Hagihara, Synthesis,
1980, 627.
14 S. Wolff, H. Schlegel, M.H. Whangbo and F. Bernardi, Can. J. Chem. 1974,
52, 3787.
15 R.W. Hoffmann, Chem. Rev., 1989, 89, 1841.
Received 24 October 2016; accepted 5 January 2017
Paper 1604393 DOI: 10.3184/174751917X14858862342223
Published online: 17 February 2017
16 P. Deslongchamps, Stereoelectronic effects in organic chemistry,
Pergamon, New York, 1983, pp. 203–290.
17 A.S. Cieplak, J. Am. Chem. Soc., 1981, 103, 4540.