A one-pot formal [4 + 2] cycloaddition approach to substituted piperidines, indolizidines, and quinolizidines. Total synthesis of indolizidine (-)-209I

Article abstract of DOI:10.1021/jo051080y

Heating a mixture of substituted N-benzyl γ-chloropropylamines, conjugated alkynoates or alkynones, sodium carbonate, and a catalytic amount of sodium iodide in i-PrOH at 70-83 °C delivers substituted piperidines in good yields. This transformation goes t

Full text of DOI:10.1021/jo051080y

A One-Pot Formal [4 + 2] Cycloaddition Approach to Substituted
Piperidines, Indolizidines, and Quinolizidines. Total Synthesis of
Indolizidine (-)-209I
Shanghai Yu, Wei Zhu, and Dawei Ma*
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
madw@mail.sioc.ac.cn
Received May 30, 2005
Heating a mixture of substituted N-benzyl γ-chloropropylamines, conjugated alkynoates or
alkynones, sodium carbonate, and a catalytic amount of sodium iodide in i-PrOH at 70-83 °C
delivers substituted piperidines in good yields. This transformation goes through a cascade Michael
addition/alkylation process and represents a facile one-pot formal [4 + 2] cycloaddition approach
to piperidine ring. Using secondary cyclic γ-chloropropylamines as substrates, this process produces
substituted indolizidines or quinolizidines. On the basis of this approach, indolizidine (-)-209I is
elaborated in 11 steps from methyl 2-hexenoate.
Introduction
several elegant [3 + 3] formal cycloaddition methodolo-
gies (Figure 1) have been developed.1a,e However, little
attention has been directed to [4 + 2]-type cycloadditions
Piperidine, indolizidine, and quinolizidine are common
skeletons in both natural products1 and artificial com-
pounds1a,2 that possess a wide range of biological activi-
ties. Accordingly, novel strategies for stereoselective
elaboration of these N-heterocycles continued to receive
considerable attention in the past decades.1-7 Since both
indolizidines and quinolizidines could be assembled from
piperidines and piperidones with appropriate substitu-
ents, construction of these six-membered rings has
become the focus in organic synthesis.1 Among the
emerging methods, one-pot, two-component strategies
have been actively pursued because this convergent
manner allows high-throughput synthesis. To this end,
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J. M.; Borcherding, D. R. Tetrahedron 2003, 59, 2953. (b) Daly, J. W.
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21, 625. (d) Buffat, M. G. P. Tetrahedron 2004, 60, 1701. (e) Harrity,
J. P. A.; Provoost, O. Org. Biomol. Chem. 2005, 3, 1349.
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W. S.; Shan, S.; Valenzano, K. J.; Kyle, D. J. Bioorg. Med. Chem. Lett.
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10.1021/jo051080y CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/05/2005
7364
J. Org. Chem. 2005, 70, 7364-7370

Total Synthesis of Indolizidine (-)-209I
TABLE 1. Cascade Reaction Process of
N-Benzyl-3-chloropropylamine 1a and Ethyl 2-Octynoate
4aa
entry
base
solvent
yield (%)b
1
2
3
4
5
6
7
8
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Na2CO3
Na2CO3
MeCN
DMF
0c
0c
benzene
CH2Cl2
i-PrOH
i-PrOH
EtOH
0c
0c
56
91
85
29d
FIGURE 1. [3 + 3] and [4 + 2] cycloadditions to piperidine
i-PrOH
and piperidinone rings.
a Reaction condition: N-benzyl-3-chloropropylamine 1a (0.33
mmol), ethyl 2-octynoate 4a (0.24 mmol), base (0.6 mmol), NaI
(0.03 mmol), solvent (1 mL), refluxed for 15 h. b Isolated yield.c 7a
was recovered almost quantitatively. d Without addition of NaI.
SCHEME 1
reaction system of γ-chloropropylamines 1 and electron-
deficient alkynes 4, halogen exchange of the Michael
addition products 5 would deliver more reactive iodides
6, which would in turn make direct alkylative cyclization
possible (eq 2, Scheme 1). If this process worked well, it
would provide a one-pot formal [4 + 2] cycloaddition
approach to install the piperidine ring. Indeed, our recent
success on elaboration of indolizidines and quinolizidines
from γ-chloropropylamines shed a light on this process.7a
Results and Discussion
With this idea in mind, a reaction of N-benzyl-3-
chloropropylamine 1a with ethyl 2-octynoate 4a under
the action of 0.1 equiv of sodium iodide and 2 equiv of
K2CO3 was conducted. As summarized in Table 1, in
MeCN, DMF, benzene, or CH2Cl2 at reflux temperature,
this reaction did not give any desired cyclization product
7a, while 4a was recovered almost quantitatively (entries
1-4). These results indicated that at these conditions
Michael addition did not occur. Since in Back’s case6 this
step worked well in these solvents, we reasoned that our
problem might result from the relatively poor reactivity
of ester 4a in comparison with acetylenic sulfones.
Consequently, some protic solvents that were favorable
for Michael addition were tested. We were pleased to find
that the reaction in i-PrOH worked to provide cyclization
product 7a in 56% yield (entry 5). Further improvement
by switching the base to Na2CO3 gave the best result
(entry 6), which indicated that this process is very
sensitive to bases. Changing solvent to ethanol gave
slightly low yield (entry 7). Interestingly, without addi-
tion of sodium iodide this reaction still produces 7a, but
low yield and isolation of some unreacted 5a (R′ ) H, R
) n-C5H11, X ) CO2Et) implied that the halogen exchange
was important to ensure this process proceeded well
(entry 8).
except for using imino and azo Diels-Alder reactions.1a,e,4
Recently, Ihara and co-workers described a formal [4 +
2] cycloaddition approach to piperidin-2-ones.5 Herein,
we wish to report a facile one-pot formal [4 + 2]
cycloaddition approach to piperidine ring.
In 1999, Back and Nakajima reported a cycloaddition
strategy to elaborate piperidines 3 via a Michael addition
of secondary acyclic γ-chloropropylamines 1 with acety-
lenic sulfones and subsequent LDA-mediated alkylation
(eq 1, Scheme 1).6 Started from secondary cyclic γ-chloro-
propylamines, both indolizidine and quinolizidine rings
were established via this reaction sequence.6 Although
this two-component methodology showed remarkable
efficiency, it is notable that two working-up operations
for getting the target molecules were required, and only
less conveniently available acetylenic sulfones were
utilized while other electron-deficient alkynes were not
explored.
The γ-chloropropylamines are relatively stable in the
presence of bases compared with the corresponding
bromides and iodides that easily undergo an intra-
molecular or intermolecular SN2 reaction to give the
corresponding substitution products. This is why they
were successfully employed as 1,4-difunctional reagents
in Back’s work.6 However, for further intramolecular
alkylation of their Michael addition products 2, the poor
reactivity of the chloride moiety would be problematic.
We envisaged that by adding sodium iodide to the
In view of the above encouraging result, reaction of
other substituted γ-chloropropylamines with ethyl 2-
octynoate 4a or ethyl 6-benzyloxy-2-hexynoate 4b was
tested for these optimized conditions, and the results
were summarized in Scheme 2. In addition to elaboration
of 1,2,3-trisubstituted piperidines 7a and 7b, this process
J. Org. Chem, Vol. 70, No. 18, 2005 7365

Yu et al.
SCHEME 2a
SCHEME 4a
a Reaction conditions: a. ethyl 2-octynoate 4a or ethyl 6-benz-
yloxy-2-hexynoate 4b (1 mmol), substituted γ-chloropropylamine
hydrochloride salt (1.4 mmol), Na2CO3 (2.5 mmol), NaI (0.1 mmol),
i-PrOH (2 mL), at reflux temperature for 24 h.
SCHEME 3
a Reaction conditions: a. ethyl 2-octynoate 4a or ethyl 6-benz-
yloxy-2-hexynoate 4b (1 mmol), substituted γ-chloropropylamine
hydrochloride salt (1.4 mmol), Na2CO3 (2.5 mmol), NaI (0.1 mmol),
i-PrOH (2 mL), at reflux temperature for 24 h.
was suitable for assembling 1,2,3,6-tetrasubstituted
piperidines as evidenced from the formation of 7c and
7d. In addition, two 3,4-disubstituted quinolizidines 9
were obtained in good yields by employing a piperidine-
embodied γ-chloropropylamine 8 as a building block.
FIGURE 2. NOE correlations of indolizidines 15a and 17b.
favorable for a Michael addition or alkylation step. The
stereochemistry of indolizidines 15a and 17b was estab-
lished by their NOESY studies as indicated in Figure 2.
Through these studies, the configurations at newly
generated chiral centers of 19 and 20 were assigned as
R and S, respectively.
To further demonstrate the usage of our new method-
ology, four enantiopure pyrrolizidine-embodied γ-chloro-
propylamines were prepared. The chlorides 10 and 12
were synthesized by a Wolff rearrangement of Boc-
protected L-proline or trans-4-benzoxy-L-proline8 and
subsequent LAH reduction and chlorination with thionyl
chloride. While chlorides 14 and 16 were constructed
from HCl cleavage of the corresponding N-Boc intermedi-
ates 19 and 20 which were produced by NaBH4 reduction
of N-Boc-L-proline derived chloromethyl ketone 18 as a
separable diastereomer mixture (Scheme 3).9 To our
delight, these enantiopure γ-chloropropylamines all worked
well for this formal [4 + 2] cycloaddition, providing
corresponding 5,6-disubstituted indolizidines 11, 2,5,6-
trisubstituted indolizidines 13, and 5,6,8-trisubstituted
indolizidines 15 and 17 in good to excellent yields
(Scheme 4). Obviously, these products should be useful
for elaboration of more complicated indolizidines because
some of their substituents are ready for further trans-
formations. Noteworthy is that slightly lower yields were
observed for 14 in comparison with those of 16, which
implied that the stereochemistry of 16 might be more
Further scope exploration of this process revealed that
conjugated alkynones were another class of suitable
substrates (Scheme 5). At this time it was found that at
70 °C this process gave best results, which implied that
the conjugated alkynones have better reactivity than the
corresponding alkynoates in this cascade process. Both
aliphatic and aromatic ketones were compatible for these
reaction conditions, providing substituted 3-acylpipe-
ridines 21, 3-acylquinolizidines 22, and 6-acylindoliz-
idines 23 and 24. In most cases, the yields were excellent,
which implied that this process proceeded smoothly.
Since the chain length of the alkynones is tunable at both
terminals, this success would permit assembling various
alkyl-substituted N-heterocycles without requirement of
chain elongation in later stages as described in many
alkaloid synthesis.1c-e
As depicted in Scheme 6, the efficiency of the present
methodology was tested by a total synthesis of indolizi-
dine (-)-209I 32, an alkaloid isolated from poison frog
skins.8 According to Davies’ procedure,11 â-amino ester
25 was prepared from methyl 2-hexenoate in 85% yield.
LAH reduction of 25 followed by treatment with thionyl
(8) Cassal, J. M.; Furst, A.; Meier, W. Helv. Chim. Acta 1976, 59,
1917.
(9) Parkes, K. E. B.; Bushnell, D. J.; Crazkett, P. H.; Dundson, S.
J.; Freeman, A. C.; Gunn, M. P.; Hopkins, R. A.; Lambert, R. W.;
Martin, J. A.; Merrett, J. H.; Redshaw, S.; Spurden, W. C.; Thomas,
G. J. J. Org. Chem. 1994, 59, 3656.
7366 J. Org. Chem., Vol. 70, No. 18, 2005

Total Synthesis of Indolizidine (-)-209I
SCHEME 5a
molecule 32. Its analytical data were identical to those
reported.10
In conclusion, we have demonstrated here a formal
[4 + 2] cycloaddition approach to piperidine rings, which
is based on a cascade reaction process started from
substituted γ-chloropropylamines and two classes of
electron-deficient alkynes. This new approach can con-
struct piperidines, indolizidines, and quinolizidines with
varying substituents at variable positions. Noteworthy,
their benzyloxyl, hydroxyl, ester, and ketone groups are
ready for further transformations, which would allow us
to assess more complex piperidine-embodied molecules.
Further studies toward this goal are in progress.
Experimental Section
General Procedure for Reaction of γ-Chloropropyl-
amines with Conjugated Alkynoates and Alkynones. A
mixture of γ-chloropropylamine hydrochloride salt (1.4 mmol),
alkynoate or alkynone (1.0 mmol), Na2CO3 (2.5 mmol), and NaI
(0.1 mmol) in 2 mL of i-PrOH was heated at reflux (for
alkynoates) or 70 °C (for alkynone) for 24 h. Cooled solution
was filtered, and the filtrate was concentrated. The residual
oil was purified via chromatography eluting with 1:20 to 1:2
ethyl acetate/petroleum ether to afford pure cyclization prod-
uct.
a Reaction conditions: a. substituted γ-chloropropylamine hy-
drochloride salt (1.4 mmol), 4-decyn-3-one, 1-phenyl-2-octyn-1-one,
or 8-benzoxy-4-decyn-3-one (1 mmol), Na2CO3 (2.5 mmol), NaI (0.1
mmol), i-PrOH (2 mL), 70 °C, 24 h.
1-Benzyl-2-pentyl-1,4,5,6-tetrahydropyridine-3-carbox-
ylic Acid Ethyl Ester 7a: 1H NMR (CDCl3, 300 MHz) δ 7.38-
7.17 (m, 5H), 4.44 (s, 2H), 4.13 (q, J ) 7.5 Hz, 2H), 3.12 (t, J
) 5.4 Hz, 2H), 2.86-2.84 (m, 2H), 2.44 (t, J ) 6.3 Hz, 2H),
1.80-1.74 (m, 3H), 1.62-1.49 (m, 2H), 1.35-1.25 (m, 6H),
0.89-0.84 (m, 3H); 13C NMR (CDCl3, 75 MHz) δ 169.0, 159.0,
138.5, 128.8, 127.3, 126.4, 93.2, 58.8, 54.0, 49.4, 32.2, 29.6, 29.2,
SCHEME 6
24.1, 22.7, 21.8, 14.8, 14.2; IR (film) 1710, 1675, 1558 cm-1
;
ESI-MS m/z 316 (M + H)+; HRMS calcd for C20H30NO2 (M +
H)+ 316.2271, found 316.2273.
1-Benzyl-2-(3-benzyloxypropyl)-1,4,5,6-tetrahydro-
pyridine-3-carboxylic Acid Ethyl Ester 7b: 1H NMR
(CDCl3, 300 MHz) δ 7.36-7.13 (m, 10H), 4.51 (s, 2H), 4.45 (s,
2H), 4.11 (q, J ) 7.2 Hz, 2H), 3.54 (t, J ) 6.3 Hz, 2H), 3.14 (t,
J ) 5.4 Hz, 2H), 2.97 (t, J ) 7.5 Hz, 2H), 2.47-2.42 (m, 2H),
1.93-1.88 (m, 2H), 2.00-1.74 (m, 2H), 1.26 (t, J ) 7.2 Hz, 3H);
13C NMR (CDCl3, 75 MHz) δ 168.7, 158.4, 138.6, 138.4, 128.6,
128.2, 127.4, 127.3, 127.0, 126.3, 93.4, 72.8, 70.2, 58.6, 53.9,
49.4, 29.3, 26.3, 23.9, 21.7, 14.6; IR (film) 3031, 2235, 1710,
1673, 1558 cm-1; ESI-MS m/z 394 (M + H)+; HRMS calcd for
C25H32NO3 (M + H)+ 394.2377, found 394.2373.
1-Benzyl-6-methyl-2-pentyl-1,4,5,6-tetrahydropyridine-
3-carboxylic Acid Ethyl Ester 7c: 1H NMR (CDCl3, 300
MHz) δ 7.36-7.24 (m, 3H), 7.19-7.16 (m, 2H), 4.48 (d, J )
17.1 Hz, 1H), 4.47 (d, J ) 17.1 Hz, 1H), 4.20-4.05 (m, 2H),
3.32-3.27 (m, 1H), 3.03-2.97 (m, 1H), 2.93 (m, 1H), 2.8-2.75
(m, 1H), 2.36-2.24 (m, 1H), 1.80-1.51 (m, 4H), 1.37-1.25 (m,
7H), 1.06 (q, J ) 6.9 Hz, 3H), 0.86 (t, 3H); IR (film) 1675, 1555
cm-1; ESI-MS m/z 330 (M + H)+; HRMS calcd for C21H32NO2
(M + H)+ 330.2428, found 330.2430.
1-Benzyl-2-(3-benzyloxypropyl)-6-methyl-1,4,5,6-tet-
rahydropyridine-3-carboxylic Acid Ethyl Ester 7d: 1H
NMR (CDCl3, 300 MHz) δ 7.36-7.11 (m, 10H), 4.55 (d, J )
11.1 Hz, 1H), 4.54 (d, J ) 11.1 Hz, 1H), 4.46-4.44 (m, 2H),
4.25-4.06 (m, 2H), 3.59-3.47 (m, 2H), 3.35-3.25 (m, 1H),
3.05-2.94 (m, 3H), 2.63-2.47 (m, 1H), 2.03-1.90 (m, 1H),
1.80-1.51 (m, 3H), 1.29-1.22 (m, 3H), 1.06 (t, J ) 6.9 Hz, 3H);
IR (film) 3030, 1669, 1550 cm-1; ESI-MS m/z 408 (M + H)+;
HRMS calcd for C26H34NO3 (M + H)+ 408.2533, found 408.2523.
4-Pentyl-1,6,7,8,9,9a-hexahydro-2H-quinolizine-3-car-
chloride and hydrogenolysis provided γ-chloropropyl-
amine 26. Heating a mixture of 26, 8-benzyloxy-4-octyn-
3-one, sodium carbonate, and a catalytic amount of
sodium iodide in i-PrOH produced piperidine 27 in 64%
yield. Next, hydrogenation of 27 over PtO2 in acetic acid
delivered 28, which was treated with sodium methoxide
in methanol at reflux to give its 3-epimer 29. After
removal of the benzyl-protecting group in 29, cyclization
was carried out under the action of Ph3P/I2/imidazole to
afford indolizidine 30. Finally, reduction of ketone moiety
in 30 through its 1,3-dithiolane 31 furnished the target
1
boxylic Acid Ethyl Ester 9a: H NMR (CDCl3, 300 MHz) δ
4.02 (q, J ) 6.9 Hz, 2H), 3.80 (d, J ) 13.5 Hz, 1H), 2.99-2.94
(m, 2H), 2.70-2.61 (m, 2H), 2.33-2.26 (m, 2H), 1.81-1.72 (m,
J. Org. Chem, Vol. 70, No. 18, 2005 7367

Yu et al.
2H), 1.61-1.21 (m, 12H), 1.20 (t, J ) 6.9 Hz, 3H), 0.90 (t, J )
6.6 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 169.0, 158.2, 94.7,
58.7, 57.2, 48.1, 32.7, 32.1, 29.0, 28.8, 28.6, 26.9, 24.8, 22.6,
21.4, 14.7, 14.1; IR (film) 1679, 1560 cm-1; ESI-MS m/z 280
(M + H)+; HRMS calcd for C17H30NO2 (M + H)+ 280.2271,
found 280.2276.
4-(3-Benzyloxy-propyl)-1,6,7,8,9,9a-hexahydro-2H-quin-
olizine-3-carboxylic Acid Ethyl Ester 9b: 1H NMR (CDCl3,
300 MHz) δ 7.34-7.24 (m, 5H), 4.52 (s, 2H), 4.08 (q, J ) 6.6
Hz, 2H), 3.99 (d, J ) 13.2 Hz, 1H), 3.58 (t, J ) 6.0 Hz, 2H),
3.15-3.01 (m, 2H), 2.91-2.80 (m, 1H), 2.71 (t, J ) 7.5 Hz, 1H),
2.43-2.32 (m, 2H), 1.86-1.74 (m, 4H), 1.65-1.1.54 (m, 4H),
1.50-1.33 (m, 2H), 1.24 (t, J ) 6.6 Hz, 3H); 13C NMR (CDCl3,
75 MHz) δ 169.0, 157.8, 138.8, 128.4, 127.6, 127.5, 94.8, 73.0,
70.5, 58.8, 57.2, 48.1, 32.7, 28.9, 28.7, 26.9, 25.9, 24.8, 21.3,
14.7; IR (film) 1674, 1558 cm-1; ESI-MS m/z 358 (M + H)+;
HRMS calcd for C22H32NO3 (M + H)+ 358.2377, found 358.2386.
ESI-MS m/z 282 (M + H)+; HRMS calcd for C16H28NO3 (M +
H)+ 282.2064, found 282.2063.
(8R,9S)-5-(3-Benzyloxypropyl)-8-hydroxy-1,2,3,7,8,8a-
hexahydroindolizine-6-carboxylic Acid Ethyl Ester 15b:
[R]29 -207.9 (c 1.7, CHCl3); 1H NMR (CDCl3, 300 MHz) δ
D
7.34-7.27 (m, 5H), 4.51 (s, 2H), 4.08 (t, J ) 6.9 Hz, 2H), 4.00
(s, 1H), 3.63-3.54 (m, 3H), 3.41-3.35 (m, 2H), 2.63 (AB q, d,
J ) 15.7 Hz, 2H), 2.05-1.59 (m, 9H), 1.26 (t, J ) 6.9 Hz, 3H);
13C NMR (CDCl3, 75 MHz) δ 168.9, 158.1, 138.5, 128.3, 127.7,
127.5, 87.0, 73.0, 70.3, 62.6, 61.5, 58.6, 48.0, 33.1, 28.8, 27.9,
27.0, 23.7, 14.7; IR (film) 3413, 1721, 1551 cm-1; ESI-MS m/z
360 (M + H)+; HRMS calcd for C21H30NO4 (M + H)+ 360.2169,
found 360.2160.
(8S,9S)-8-Hydroxy-5-pentyl-1,2,3,7,8,8a-hexahydroin-
dolizine-6-carboxylic Acid Ethyl Ester 17a: [R]29D -278.6
1
(c 2.0, CHCl3); H NMR (CDCl3, 300 MHz) δ 4.10 (q, J ) 6.3
Hz, 2H), 3.58 (t, J ) 8.4 Hz, 1H), 3.50-3.45 (m, 1H), 3.39-
3.35 (m, 1H), 3.13-3.09 (m, 1H), 2.95-2.88 (m, 2H), 2.60-
2.50 (m, 1H), 2.23-2.15 (m, 1H), 2.05-1.93 (m, 2H), 1.93-
1.75 (m, 2H), 1.67-1.56 (m, 2H), 1.50-1.35 (m, 5H), 1.30-
1.23 (m, 3H), 0.90 (t, J ) 7.2 Hz, 3H); 13C NMR (CDCl3, 75
MHz) δ 170.4, 160.2, 91.7, 72.2, 65.1, 60.6, 49.7, 36.1, 34.2,
32.3, 32.4, 30.2, 25.8, 24.5, 16.6, 16.0; IR (film) 3384, 1718,
1558, 1448 cm-1; ESI-MS m/z 282 (M + H)+; HRMS calcd for
C16H28NO3 (M + H)+ 282.2064, found 282.2067.
(S)-5-Pentyl-1,2,3,7,8,8a-hexahydroindolizine-6-carbox-
1
ylic Acid Ethyl Ester 11a: [R]27 -326.8 (c 1.0, CHCl3); H
D
NMR (CDCl3, 300 MHz) δ 4.10 (q, J ) 6.9 Hz, 2H), 3.56 (t, J
) 8.4 Hz, 1H), 3.44-3.35 (m, 1H), 3.30-3.22 (m, 1H), 3.01-
2.91 (m, 1H), 2.66-2.54 (m, 2H), 2.25-2.03 (m, 3H), 1.96-
1.92 (m, 1H), 1.82-1.78 (m, 1H), 1.63-1.58 (m, 1H), 1.52-
1.18 (m, 10H), 1.95-1.84 (m, 3H); 13C NMR (CDCl3, 75 MHz)
δ 168.4, 158.0, 90.8, 58.0, 57.9, 46.8, 32.3, 32.0, 30.8, 28.0, 27.7,
24.0, 23.4, 22.2, 14.4, 13.7; IR (film) 1674, 1556 cm-1; ESI-MS
m/z 266 (M + H)+; HRMS calcd for C16H28NO2 (M + H)+
266.2115, found 266.2113.
(8S,9S)-5-(3-Benzyloxypropyl)-8-hydroxy-1,2,3,7,8,8a-
hexahydroindolizine-6-carboxylic Acid Ethyl Ester 17b:
[R]29 -235.6 (c 1.9, CHCl3); 1H NMR (CDCl3, 300 MHz) δ
D
7.34-7.27 (m, 5H), 4.52 (s, 2H), 4.09 (q, J ) 7.1 Hz, 2H), 3.73-
3.17 (m, 5H), 3.11-3.06 (m, 2H), 2.90 (dd, J ) 15.4, 5.6 Hz,
1H), 2.80-2.73 (m, 1H), 2.33-2.26 (m, 2H), 2.18 (dd, J ) 15.4,
(S)-5-(3-Benzyloxypropyl)-1,2,3,7,8,8a-hexahydroindoliz-
ine-6-carboxylic Acid Ethyl Ester 11b: [R]23D -120.7 (c 0.2,
CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.34-7.25 (m, 5H), 4.52
(s, 2H), 4.11 (q, J ) 6.9 Hz, 2H), 3.63-3.56 (m, 3H), 3.40-
3.31 (m, 1H), 3.29-3.18 (m, 1H), 3.15-3.03 (m, 1H), 2.80-
2.57 (m, 2H), 2.24-1.75 (m, 8H), 1.47-1.40 (m, 1H), 1.29-
1.20 (m, 3H); 13C NMR (CDCl3, 75 MHz) δ 168.6, 157.8, 138.6,
128.1, 127.4, 127.3, 91.2, 72.7, 70.3, 58.2, 58.1, 47.4, 32.5, 28.6,
27.8, 27.7, 24.2, 23.7, 14.6; IR (film) 1670, 1554 cm-1; ESI-MS
m/z 344 (M + H)+; HRMS calcd for C21H30NO3 (M + H)+
344.2220, found 344.2218.
10.3 Hz, 1H), 1.97-1.55 (m, 5H), 1.23 (t, J ) 7.1 Hz, 3H); 13
C
NMR (CDCl3, 75 MHz) δ 170.3, 159.7, 140.5, 130.2, 129.5,
129.4, 91.9, 74.8, 72.2, 72.1, 65.1, 60.6, 49.8, 36.1, 32.4, 30.6,
29.7, 25.8, 16.6; IR (film) 3405, 1720, 1554, 1454 cm-1; ESI-
MS m/z 360 (M + H)+; HRMS calcd for C21H30NO4 (M + H)+
360.2169, found 360.2161.
1-(1-Benzyl-2-pentyl-1,4,5,6-tetrahydropyridin-3-yl)-
1
propan-1-one 21a: H NMR (CDCl3, 300 MHz) δ 7.38-7.27
(m, 3H), 7.19-7.16 (m, 2H), 4.49 (d, 2H), 3.16-3.12 (m, 2H),
2.91-2.86 (m, 2H), 2.51-2.42 (m, 4H), 1.86-1.80 (m, 2H),
1.64-1.59 (m, 2H), 1.20-1.23 (m, 4H), 1.19-1.06 (m, 3H),
0.93-0.84 (m, 3H); 13C NMR (CDCl3, 75 MHz, for two
conformers) δ 198.3, 198.1, 159.9, 158.9, 137.9, 128.7, 127.2,
126.3, 102.7, 102.6, 53.7, 53.5, 49.2, 49.1, 40.7, 33.6, 32.1, 31.9,
29.7, 28.7, 25.1, 25.0, 24.8, 22.9, 22.6, 22.5, 21.9, 14.0, 13.2,
9.2; IR (film) 2956, 1716, 1632, 1525 cm-1; ESI-MS m/z 300
(M + H)+; Anal. Calcd for C20H29NO: C, 80.22; H, 9.76; N,
4.68. Found: C, 80.21; H, 9.79; N, 4.53.
(2R,9S)-2-Benzyloxy-5-pentyl-1,2,3,7,8,8a-hexahydroin-
dolizine-6- carboxylic Acid Ethyl Ester 13a: [R]24D -111.1
(c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.35-7.29 (m,
5H), 4.61-4.49 (m, 2H), 4.20-4.07 (m, 3H), 3.67-3.55 (m, 3H),
2.99-2.90 (m, 1H), 2.77-2.55 (m, 2H), 2.40-2.17 (m, 2H),
2.15-2.05 (m, 1H), 1.71-1.16 (m, 11H), 0.97-0.84 (m, 3H);
13C NMR (CDCl3, 75 MHz) δ 168.8, 157.9, 138.0, 128.5, 128.4,
127.7, 127.5, 91.6, 76.4, 70.7, 58.5, 56.1, 53.1, 38.2, 32.4, 31.1,
28.4, 27.8, 24.2, 22.6, 14.7, 14.2; IR (film) 1672, 1554 cm-1
;
ESI-MS m/z 372 (M + H)+; HRMS calcd for C23H34NO3 (M +
(1-Benzyl-2-pentyl-1,4,5,6-tetrahydropyridin-3-yl)phen-
H)+ 372.2533, found 372.2538.
1
ylmethanone 21b: H NMR (CDCl3, 300 MHz) δ 7.35-7.14
(2R,9S)-2-Benzyloxy-5-(3-benzyloxypropyl)-1,2,3,7,8,8a-
hexahydroindolizine-6-carboxylic Acid Ethyl Ester 13b:
[R]23D -87.1 (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.33-
7.25 (m, 10H), 4.53-4.50 (m, 4H), 4.12-4.05 (m, 3H), 3.73 (q,
J1 ) 11.7 Hz, J2 ) 3.6 Hz, 1H), 3.60-3.55 (m, 4H), 3.10-2.95
(m, 1H), 2.83-2.70 (m, 1H), 2.70-2.60 (m, 1H), 2.33-2.21 (m,
2H), 2.10-1.81 (m, 4H), 1.58-1.42 (m, 1H), 1.24 (t, J ) 6.6
Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 168.7, 157.6, 138.5,
138.1, 128.5, 128.3, 127.7, 127.6, 127.5, 127.4, 91.8, 76.3, 72.9,
70.6, 70.4, 58.5, 56.1, 53.1, 38.3, 28.8, 27.9, 27.8, 24.2, 14.8;
IR (film) 1745, 1717 cm-1; ESI-MS m/z 450 (M + H)+; HRMS
calcd for C28H36NO4 (M + H)+ 450.2639, found 450.2640.
(m, 10H), 4.02 (s, 2H), 3.18 (t, J ) 4.8 Hz, 2H), 2.54 (t, J ) 6.3
Hz, 2H), 1.77 (t, J ) 5.4 Hz, 2H), 1.67 (t, J ) 7.8 Hz, 2H),
1.34-1.26 (m, 2H), 1.15-1.07 (m, 2H), 0.97-0.90 (m, 2H), 0.78
(t, J ) 7.2 Hz, 3H); 13C NMR (CDCl3, 75 MHz, for two
conformers) δ 201.6, 156.2, 138.1, 137.9, 129.4, 128.9, 128.5,
128.4, 127.2, 127.1, 113.0, 55.5, 48.3, 41.1, 31.5, 25.6, 24.6, 22.3,
21.5, 13.9; IR (film) 3030, 1604, 1548, 1494 cm-1; ESI-MS m/z
348 (M + H)+; Anal. Calcd for C24H29NO: C, 82.95; H, 8.41;
N, 4.03. Found: C, 82.55; H, 8.48; N, 3.95.
1-[1-Benzyl-2-(3-benzyloxypropyl)-1,4,5,6-tetrahydro-
pyridin-3-yl]propan-1-one 21c: 1H NMR (CDCl3, 300 MHz)
δ 7.38-7.12 (m, 10H), 4.55-4.45 (m, 4H), 3.60-3.53 (m, 2H),
3.18-3.13 (m, 2H), 3.00-2.88 (m, 2H), 2.60-2.44 (m, 4H),
1.98-1.81 (m, 4H), 1.19-1.05 (m, 3H); 13C NMR (CDCl3, 75
MHz, for two conformers) δ 198.3, 197.1, 160.2, 158.6, 138.8,
138.7, 138.0, 137.9, 128.7, 128.3, 128.2, 127.6, 127.5, 127.3,
127.2, 126.4, 126.3, 102.7, 72.8, 72.6, 70.4, 70.3, 53.8, 53.6, 49.4,
49.2, 37.1, 33.6, 29.0, 26.8, 25.0, 22.0, 13.3, 9.1; IR (film) 3030,
1716, 1627, 1520 cm-1; ESI-MS m/z 378 (M + H)+; Anal. Calcd
for C25H31NO2: C, 79.54; H, 8.28; N, 3.71. Found: C, 79.24;
H, 8.30; N, 3.79.
(8R,9S)-8-Hydroxy-5-pentyl-1,2,3,7,8,8a-hexahydroin-
dolizine-6-carboxylic Acid Ethyl Ester 15a: [R]29D -241.4
1
(c 1.9, CHCl3); H NMR (CDCl3, 300 MHz) δ 4.10 (q, J ) 7.1
Hz, 2H), 4.00 (s, 1H), 3.59 (t, J ) 6.6 Hz, 1H), 3.39-3.36 (m,
2H), 3.05-2.96 (m, 1H), 2.64 (m, 1H), 2.63 (q, JAB ) 16.8 Hz,
2H), 2.01-1.92 (m, 5H), 1.51-1.23 (m, 6H), 1.25 (t, J ) 7.1
Hz, 3H), 0.91 (t, J ) 7.1 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
δ 168.9, 158.5, 86.6, 62.5, 61.4, 58.6, 47.9, 33.1, 32.3, 31.0, 28.4,
27.0, 23.7, 22.6, 14.6, 14.1; IR (film) 3410, 1674, 1454 cm-1
;
7368 J. Org. Chem., Vol. 70, No. 18, 2005

Total Synthesis of Indolizidine (-)-209I
1-(4-Pentyl-1,6,7,8,9,9a-hexahydro-2H-quinolizin-3-yl)-
propan-1-one 22a: 1H NMR (CDCl3, 300 MHz) δ 3.95 (t, J )
12.0 Hz, 1H), 3.12-3.06 (m, 1H), 3.06-2.96 (m, 1H), 2.76 (t, J
) 12.6 Hz, 2H), 2.47-2.34 (m, 4H), 1.93-1.84 (m, 2H), 1.71-
1.56 (m, 4H), 1.52-1.26 (m, 8H), 1.12-1.04 (m, 3H), 0.92-
0.86 (m, 3H); 13C NMR (CDCl3, 75 MHz, for two conformers)
δ 198.7, 198.5, 159.1, 158.0, 104.0, 103.9, 57.2, 47.8, 47.6, 40.9,
33.8, 32.9, 32.0, 31.9, 29.0, 28.5, 26.9, 26.8, 25.0, 24.7, 22.6,
22.3, 14.1, 14.0, 9.4; IR (film) 1635, 1525, 1443 cm-1; ESI-MS
m/z 264 (M + H)+; Anal. Calcd for C17H29NO: C, 77.51; H,
11.10; N, 5.32. Found: C, 77.61; H, 11.19; N, 5.13.
(4-Pentyl-1,6,7,8,9,9a-hexahydro-2H-quinolizin-3-yl)-
phenylmethanone 22b: 1H NMR (CDCl3, 300 MHz) δ 7.42-
7.35 (m, 3H), 7.27-7.15 (m, 2H), 3.16-3.10 (m, 2H), 2.62-
2.54 (m, 2H), 2.49-2.25 (m, 2H), 2.04-1.98 (m, 1H), 1.86-
1.82 (m, 1H), 1.77-1.68 (m, 2H), 1.65-1.58 (m, 2H), 1.52-
1.40 (m, 3H), 1.34-1.23 (m, 3H), 1.16-1.04 (m, 1H), 0.97-
0.83 (m, 2H), 0.81-0.77 (m, 3H); 13C NMR (CDCl3, 75 MHz,
for two conformers) δ 200.5, 155.5, 138.3, 128.5, 128.4, 127.9,
110.5, 57.7, 49.8, 40.8, 33.1, 31.6, 29.6, 26.5, 25.6, 24.5, 22.3,
21.9, 13.9; IR (film) 1605, 1547 cm-1; ESI-MS m/z 312 (M +
H)+; Anal. Calcd for C21H29NO: C, 80.98; H, 9.38; N, 4.50.
Found: C, 80.69; H, 9.54; N, 4.28.
Calcd for C27H33NO2: C, 80.36; H, 8.24; N, 3.47. Found: C,
80.03; H, 8.41; N, 3.28.
(2R,9S)-1-[2-Benzyloxy-5-(3-benzyloxypropyl)-1,2,3,7,8,-
8a-hexahydroindolizin-6-yl]propan-1-one 24c: [R]24D -136.7
(c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.36-7.24 (m,
10H), 4.54-4.49 (m, 4H), 4.16-4.09 (m, 1H), 3.79-3.68 (m,
1H), 3.64-3.51 (m, 4H), 3.02-2.98 (m, 1H), 2.91-2.82 (m, 1H),
2.58-2.30 (m, 5H), 2.16-2.10 (m, 1H), 2.04-1.78 (m, 2H),
1.54-1.49 (m, 1H), 1.29-1.19 (m, 1H), 1.17-1.03 (m, 3H); IR
(film) 1719, 1623 cm-1; ESI-MS m/z 434 (M + H)+; Anal. Calcd
for C28H35NO3: C, 77.56; H, 8.14; N, 3.23. Found: C, 77.37;
H, 8.36; N, 3.18.
(R)-1-Chloro-3-hexylamine Hydrochloride Salt 26. To
a stirred suspension of LAH (1.63 g, 42.8 mmol) in dry THF
(80 mL) was added dropwise â-amino ester 25 (15.12 g, 42.8
mmol) in dry THF (40 mL) at 0 °C. After the reaction mixture
was stirred at 20 °C for 1 h, water (1.5 mL), 15% NaOH (1.5
mL), and more water (1.5 mL) were added successively.
Stirring was continued until a white precipitate formed, then
it was filtered through Celite, and the filtrate was dried over
MgSO4, concentrated, and purified via chromatography to give
13.24 g (100%) of â-amino alcohol as a viscous oil.
To a stirred solution of the above oil (5.00 g, 16.18 mmol) in
CHCl3 (50 mL) was slowly added a solution of SOCl2 (1.8 mL,
24.3 mmol) in CHCl3 (10 mL) at 0 °C. The reaction mixture
was refluxed for 1 h and then evaporated. The residue was
dissolved directly in methanol (60 mL) and hydrogenated over
20% Pd(OH)2 (1.00 g) under 50 atm hydrogen atmosphere at
30 °C for 48 h. The reaction mixture was filtered off, and the
filtrate was concentrated in a vacuum to afford 2.37 g (85%)
of crude 26 as a light yellow solid, which was used directly
due to its instability. 1H NMR (CDCl3, 300 MHz) δ 8.47-8.42
(m, 3H), 3.86-3.85 (m, 1H), 3.73-3.70 m, 1H), 3.51-3.50 (m,
1H), 2.27-2.25 (m, 1H), 2.15-2.13 (m, 1H), 1.76-1.51 (m, 4H),
0.99 (t, J ) 6.6 Hz, 3H).
1-[4-(3-Benzyloxypropyl)-1,6,7,8,9,9a-hexahydro-2H-
quinolizin-3-yl]propan-1-one 22c: 1H NMR (CDCl3, 300
MHz) δ 7.34-7.24 (m, 5H), 4.52 (AB q, d, J ) 12.0 Hz, 2H),
4.11-3.93 (m, 1H), 3.63-3.50 (m, 2H), 3.12-2.95 (m, 2H),
2.95-2.72 (m, 2H), 2.54-2.34 (m, 4H), 1.95-1.77 (m, 4H),
1.68-1.50 (m, 3H), 1.49-1.38 (m, 3H), 1.12-1.03 (m, 3H); 13
C
NMR (CDCl3, 75 MHz, for two conformers) δ 198.5, 197.2,
159.2, 157.5, 138.8, 128.2, 127.5, 127.4, 127.3, 103.9, 103.8,
72.8, 72.6, 70.5, 70.2, 57.1, 47.7, 47.5, 37.1, 33.7, 32.8, 28.8,
28.7, 26.8, 26.0, 25.1, 24.6, 22.2, 22.1, 12.9, 9.2; IR (film) 3029,
1629, 1523 cm-1; ESI-MS m/z 342 (M + H)+; Anal. Calcd for
C22H31NO2: C, 77.38; H, 9.15; N, 4.10. Found: C, 77.36; H,
9.34; N, 4.02.
(R)-1-[2-(3-Benzyloxypropyl)-6-propyl-1,4,5,6-tetrahy-
dropyridin-3-yl]-propan-1-one 27. A mixture of 26 (347 mg,
2.01 mmol), 7e (331 mg, 1.44 mmol), Na2CO3 (381 mg, 3.60
mmol), and NaI (22 mg, 0.14 mmol) in i-PrOH (5 mL) was
refluxed for 30 h. The precipitate was filtered through Celite.
The residue was concentrated and chromatographed to afford
(S)-1-(5-Pentyl-1,2,3,7,8,8a-hexahydroindolizin-6-yl)-
propan-1-one 23a: [R]19 -232.9 (c 1.4, CHCl3); 1H NMR
D
(CDCl3, 300 MHz) δ 3.66-3.57 (m, 1H), 3.45-3.36 (m, 1H),
3.26-3.18 (m, 1H), 3.11-2.94 (m, 1H), 2.75-2.53 (m, 2H),
2.46-2.30 (m, 3H), 2.19-2.09 (m, 2H), 1.99-1.92 (m, 1H),
1.86-1.79 (m, 1H), 1.63-1.52 (m, 2H), 1.51-1.24 (m, 6H),
1.90-1.03 (m, 3H), 0.95-0.85 (m, 3H); IR (film) 1625, 1516
cm-1; ESI m/z 250 (M + H)+.
312 mg (66%) of 27 as yellow oil. [R]28 +81.1 (c 2.1, CHCl3);
D
1H NMR (CDCl3, 300 MHz) δ 7.37-7.28 (m, 5H), 4.53-4.50
(m, 3H), 3.13 (s, 1H), 2.78-2.72 (m, 2H), 2.45-2.25 (m, 4H),
1.94-1.86 (m, 4H), 1.45-1.26 (m, 5H), 1.10-1.02 (m, 3H), 0.91
(t, J ) 6.9 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 199.9, 158.7,
140.4, 130.3, 129.6, 129.5, 102.6, 74.8, 71.7, 52.8, 39.9, 35.0,
33.8, 30.4, 29.4, 25.0, 20.7, 16.0, 10.7; IR (film) 3301, 1712,
1604, 1455 cm-1; ESI-MS m/z 330 (M + H)+; HRMS calcd for
C21H32NO2 (M + H)+ 330.2428, found 330.2411.
(S)-1-[5-(3-Benzyloxypropyl)-1,2,3,7,8,8a-hexahydroin-
dolizin-6-yl]propan-1-one 23b: [R]24D -269.7 (c 1.7, CHCl3);
1H NMR (CDCl3, 300 MHz) δ 7.38-7.23 (m, 5H), 4.52 (AB q,
d, J ) 12.0 Hz, 2H), 3.69-3.52 (m, 3H), 3.46-3.37 (m, 1H),
3.28-3.20 (m, 1H), 3.10-3.03 (m, 1H), 2.88-2.63 (m, 1H),
2.70-2.23 (m, 4H), 2.16-2.11 (m, 2H), 2.02-1.74 (m, 4H),
1.49-1.39 (m, 1H), 1.37-1.23 (m, 1H), 1.20-1.05 (m, 3H); 13
C
(2S,3S,6R)-1-[2-(3-Benzyloxypropyl)-6-propylpiperidin-
3-yl]propan-1-one 28. To a solution of 28 (260 mg, 0.79 mmol)
in acetic acid (20 mL) was added PtO2 (40 mg). The mixture
was hydrogenated under 1 atm hydrogen atmosphere at room
temperature for 1 h. The catalyst was filtered off, and the
filtrate was concentrated under reduced pressure. To this
residue was added aqueous solution of NaHCO3 and extracted
with ethyl acetate for two times. The combined organic layer
was dried over anhydrous Na2SO4, and the solvent was
removed under reduced pressure. The residue was purified by
NMR (CDCl3, 75 MHz, for two conformers) δ 197.2, 195.9,
160.3, 158.6, 138.9, 138.8, 128.2, 127.6, 127.5, 127.3, 101.3,
72.9, 72.6, 70.6, 70.4, 58.3, 47.2, 46.9, 37.0, 33.5, 32.5, 29.7,
28.6, 28.4, 28.2, 25.5, 25.0, 24.8, 23.6, 22.2, 12.4, 9.1; IR (film)
1621, 1513 cm-1; ESI m/z 328 (M + H)+.
(2R,9S)-1-(2-Benzyloxy-5-pentyl-1,2,3,7,8,8a-hexahy-
droindolizin-6-yl) propan-1-one 24a: [R]24 -164.9 (c 1.0,
D
CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.37-7.26 (m, 5H), 4.54
(AB q, d, J ) 12.0 Hz, 2H), 4.16 (t, J ) 4.2 Hz, 1H), 3.67-3.57
(m, 3H), 2.97-2.85 (m, 1H), 2.75-2.51 (m, 1H), 2.47-2.30 (m,
5H), 2.16-2.12 (m, 1H), 1.64-1.25 (m, 8H), 1.06 (t, J ) 7.2
column chromatography to give 214 mg (82%) of 28. [R]28
D
-26.4 (c 2.2, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.34-7.27
(m, 5H), 4.48 (s, 2H), 3.49-3.41 (m, 2H), 2.68-2.36 (m, 5H),
1.98-1.93 (m, 1H), 1.79-1.64 (m, 4H), 1.50-1.30 (m, 7H),
1.15-1.04 (m, 1H), 1.00 (t, J ) 7.5 Hz, 3H), 0.89 (t, J ) 6.6
Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 217.7, 140.4, 130.2,
129.5, 129.4, 74.8, 72.3, 60.4, 58.2, 49.0, 41.4, 38.8, 33.1, 29.5,
29.1, 21.0, 16.2, 9.5; IR (film) 3032, 1701,1455 cm-1; ESI-MS
m/z 332 (M + H)+; HRMS calcd for C21H34NO2 (M + H)+
332.2584, found 332.2568.
Hz, 3H), 0.89 (t, J ) 7.5 Hz, 3H); IR (film) 1623, 1515 cm-1
;
ESI-MS m/z 356 (M + H)+; Anal. Calcd for C23H33NO2: C,
77.70; H, 9.36; N, 3.94. Found: C, 77.40; H, 9.55; N, 3.69.
(2R,9S)-(2-Benzyloxy-5-pentyl-1,2,3,7,8,8a-hexahydroin-
dolizin-6-yl)-phenylmethanone 24b: [R]24 -124.8 (c 1.0,
D
CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.47-7.26 (m, 10H), 4.56
(AB q, d, J ) 12.0 Hz, 2H), 4.20 (m, 1H), 3.70-3.63 (m, 3H),
2.73-2.46 (m, 3H), 2.42-2.33 (m, 2H), 2.10-2.04 (m, 1H),
1.60-1.43 (m, 4H), 1.29-1.21 (m, 4H), 0.90-0.85 (m, 3H); IR
(film) 1718, 1599, 1498 cm-1; ESI-MS m/z 404 (M + H)+; Anal.
(2S,3R,6R)-1-[2-(3-Benzyloxypropyl)-6-propylpiperidin-
3-yl]propan-1-one 29. A mixture of sodium (18 mg, 0.785
J. Org. Chem, Vol. 70, No. 18, 2005 7369

Yu et al.
mmol) and anhydrous MeOH (10 mL) was stirred for 10 min.
To this solution was added 28 (260 mg, 0.785 mmol). The
reaction mixture was refluxed for 12 h and then cooled to room
temperature. The solvent was removed under reduced pres-
sure, and the residue was purified by column chromatography
to give 196 mg (75%) of 29 as colorless oil. [R]20D -40.7 (c 1.0,
CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.33-7.26 (m, 5H), 4.47
(s, 2H), 3.44 (t, J ) 6.3 Hz, 2H), 2.82 (dt, J ) 9.9, 3.0 Hz, 1H),
2.56-2.41 (m, 3H), 2.38-2.27 (m, 1H), 1.88-1.83 (m, 1H),
1.73-1.55 (m, 4H), 1.49-1.30 (m, 8H), 1.02 (t, J ) 7.5 Hz, 3H),
0.89 (t, J ) 6.3 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 214.9,
138.9, 128.7, 128.0, 127.8, 73.2, 70.7, 57.8, 56.3, 56.2, 39.7, 36.9,
32.3, 31.8, 29.4, 26.4, 19.4, 14.6, 7.9; IR (film) 3032, 1708, 1455
cm-1; ESI-MS m/z 332 (M + H)+; HRMS calcd for C21H34NO2
(M + H)+ 332.2584, found 332.2581.
by column chromatography to give 96 mg (65%) of 31 as
colorless oil. [R]20D -66.2 (c 1.1, CHCl3); 1H NMR (CDCl3, 300
MHz) δ 3.32-3.15 (m, 5H), 2.32-2.17 (m, 1H), 2.00-1.73 (m,
9H), 1.73-1.54 (m, 2H), 1.49-1.23 (m, 6H), 1.11 (t, J ) 6.9
Hz, 3H), 0.91 (t, J ) 6.9 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
δ 69.9, 65.1, 52.6, 52.2, 41.4, 40.8, 37.9, 36.1, 32.3, 31.2, 31.1,
30.9, 21.9, 20.5, 15.9, 12.0; IR (film) 1709 cm-1; ESI-MS m/z
300 (M + H)+; HRMS calcd for C16H30NS2 300.1814, found
300.1822.
(5R,8R,9S)-5,8-Dipropyloctahydroindolizine 32 (In-
dolizidine (-)-209I). To a solution of dithioacetal 31 (88 mg,
0.294 mmol) in i-PrOH (10 mL) was added Raney nickel (1.5
g). The resulting mixture was stirred at 70 °C for 10 h and
then filtered through Celite. The filtrate was concentrated
under reduced pressure, and the residue was purified by
column chromatography to give 49 mg (81%) of 32 as colorless
oil. [R]22 -92.1 (c 1.0, CHCl3); [R]24 -126.5 (c 0.19, CH3-
(5R,8R,9S)-1-(5-Propyloctahydroindolizin-8-yl)propan-
1-one 30. A mixture of 29 (196 mg, 0.592 mmol) in anhydrous
MeOH (10 mL) was hydrogenated over 20% palladium hy-
droxide on charcoal (30 mg) under 1 atm hydrogen atmosphere
at 25 °C for 20 h. After the mixture was filtered, the filtrate
was concentrated in a vacuum to provide the crude alcohol.
To a stirred solution of the above alcohol in dry CH2Cl2 (20
mL) was added triphenylphosphine (465 mg, 1.78 mmol),
imidazole (121 mg, 1.78 mmol), and iodine (300 mg, 1.18 mmol)
at 0 °C. After the reaction mixture was warmed to room
temperature in about 2 h, saturated aqueous NaHCO3 was
added. The aqueous layer was extracted with ethyl acetate,
and the combined organic layers were dried over Na2SO4. The
solution was evaporated in vacuo, and the residue was purified
D
D
COCH3) (lit:10c [R]29 -123.4 (c 0.71, CH3COCH3)); 1H NMR
D
(CDCl3, 500 MHz) δ 3.27 (dt, J ) 8.7, 1.8 Hz, 1H), 2.00-1.87
(m, 2H), 1.87-1.80 (m, 2H), 1.78-1.67 (m, 2H), 1.65-1.59 (m,
2H), 1.50-1.35 (m, 5H), 1.48-1.15 (m, 5H), 1.04 (m, 1H), 0.92-
0.86 (m, 7H); 13C NMR (CDCl3, 75 MHz) δ 70.4, 63.5, 51.8,
41.0, 36.8, 35.6, 31.0, 30.4, 29.1, 20.4, 19.6, 19.1, 14.5, 14.4;
IR (film) 1643 cm-1; ESI-MS m/z 210 (M + H)+; HRMS calcd
for C14H28N (M + H)+ 210.2216, found 210.2221.
Acknowledgment. We are grateful to the Chinese
Academy of Sciences, National Natural Science Founda-
tion of China (Grants 20321202 and 20132030), and
Science and Technology Commission of Shanghai Mu-
nicipality (Grants 04DZ14901 and 03XD14001) for their
financial support.
via chromatography to afford 107 mg (83%) of 30 as colorless
1
oil. [R]20 -84.4 (c 1.0, CHCl3); H NMR (CDCl3, 300 MHz) δ
D
3.24 (dt, J ) 2.7, 9.0 Hz, 1H), 2.55-2.38 (m, 3H), 2.12-1.82
(5H), 1.79-1.62 (m, 3H), 1.46-1.13 (m, 7H), 1.04 (t, J ) 7.5
Hz, 3H), 0.92 (t, J ) 6.3 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
δ 213.5, 65.4, 62.8, 54.7, 51.0, 36.8, 36.0, 30.4, 29.0, 28.4, 20.4,
18.9, 14.5, 7.6; IR (film) 1712 cm-1; ESI-MS m/z 224 (M + H)+;
HRMS calcd for C14H26NO (M + H)+ 224.2009, found 224.2020.
(5R,8R,9S)-8-(2-Ethyl-[1,3]dithiolan-2-yl)-5-propyl-
octahydroindolizine 31. To a solution of 30 (110 mg, 0.493
mmol) in dry CH2Cl2 (10 mL) were added ethane-1,2-dithiol
(0.8 mL) and BF3‚OEt2 (0.36 mL) at 0 °C. After the mixture
was stirred for 30 min, it was warmed to room temperature
and then stirred for an additional 12 h. The suspension was
diluted with CH2Cl2, washed with saturated aqueous NaHCO3,
and dried over anhydrous Na2SO4. The solvent was concen-
trated under reduced pressure, and the residue was purified
1
Supporting Information Available: Copies of H NMR
and 13C NMR spectra for compounds 7, 9, 11, 13, 15, 17, and
21-32. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO051080Y
(10) Isolation: (a) Toyooka, N.; Tanaka, K.; Momose, T.; Daly, J.
W.; Garraffo, H. M. Tetrahedron 1997, 53, 9553. For synthesis, see:
(b) Michel, P.; Rassat, A.; Daly, J. W.; Spande, T. F. J. Org. Chem.
2000, 65, 8908. (c) Enders, D.; Thiebes, C. Synlett 2000, 1745.
(11) Davies, S. G.; Ichihara, O.; Walters, I. S. J. Chem. Soc., Perkin
Trans. 1 1994, 1141.
7370 J. Org. Chem., Vol. 70, No. 18, 2005