Efficient formal synthesis of the dendrobatid alkaloid, indolizidine (-)-209B

Article abstract of DOI:10.1016/S0957-4166(02)00577-3

Condensation of the β-amino alcohol 7 derived from an enantiopure β-amino ester with the β-keto ester 8 provides the vinylogous urethane 9, which is cyclized to give the dehydropiperidine 10. Hydrogenation of 10 and subsequent cyclization mediated by Ph

Full text of DOI:10.1016/S0957-4166(02)00577-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 2257–2260
Efficient formal synthesis of the dendrobatid alkaloid,
indolizidine (−)-209B
Dawei Ma,* Xiaotao Pu and Jinyi Wang
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Received 26 August 2002; accepted 18 September 2002
Abstract—Condensation of the b-amino alcohol 7 derived from an enantiopure b-amino ester with the b-keto ester 8 provides the
vinylogous urethane 9, which is cyclized to give the dehydropiperidine 10. Hydrogenation of 10 and subsequent cyclization
mediated by Ph3P/CBr4 then afforded the bicyclic product 12, a precursor of indolizidine (−)-209B. © 2002 Elsevier Science Ltd.
All rights reserved.
1. Introduction
octenoate.5 The generated b-amino ester 6 was sub-
jected to Pd/C-catalyzed hydrogenolysis and then LAH
reduction to provide the corresponding amino alcohol
7. Next, we planned to condense 7 with the b-keto ester
86 to obtain the vinylogous urethane 9. Initial attempts
to effect this transformation by acid-catalyzed
azeotropic removal of water in toluene failed.4e After
completing a number of experiments, we found that
mixing the two reactants without solvent at room tem-
perature afforded the desired product 9 in 70% yield.
Obviously, the intramolecular cyclization of 9 to afford
the dehydropiperidine 10 was a key step in the present
synthesis. This transformation was found to be chal-
lenging and therefore many reaction conditions were
explored. The results are summarized in Table 1.
About sixty 5,8-disubstituted indolizidines have been
isolated from the skins of amphibians. Most of them
display interesting biological activities.1 For example,
indolizidines 209B, 207A, 205A and 235B (1–4, Fig. 1)
were found to be an atypical and potent class of
non-competitive blockers for muscle-type and gan-
glionic nicotinic receptor-channels.2 As a result, they
have become target molecules for many synthetic
efforts in the past decade.3 Two years ago Michael and
Gravestock reported a concise synthesis of indolizidine
209B utilizing an enantiopure b-amino ester as a build-
ing block.3b Herein, we wish to describe an alternative
and more efficient route to 5,8-disubstituted indolizidi-
nes from an enantiopure b-amino ester.4 The protocol
is exemplified by a formal synthesis of indolizidine
209B.
Because in Michael’s report3b excellent results were
obtained when I2/imidazole/Ph3P was used to mediate a
similar transformation in refluxing toluene, these reac-
tion conditions were initially applied to our reaction.
Unfortunately, the desired cyclization product 10 was
obtained in only 23% yield (entry 1). At this point we
As outlined in Scheme 1, our synthesis started from the
diastereoselective Michael addition of lithium (R)-N-
benzyl-N-a-methylbenzylamide
to
(E)-methyl
Figure 1.
* Corresponding author.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00577-3

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D. Ma et al. / Tetrahedron: Asymmetry 13 (2002) 2257–2260
Scheme 1.
Table 1. Conversion of the alcohol 9 to the dehydropiperidine 10
Entry
Reaction conditions
Yield of 10 (%)a
1
2
3
4
5
6
I2, imidazole, Ph3P, toluene, reflux
23
CBr4, Ph3P, CH2Cl2, 0°C to rt, then adding Et3N, reflux
CBr4, Ph3P, CH3CN, 0°C to rt, then adding Et3N, reflux
CBr4, Ph3P, DMF, 0°C to rt, then adding Et3N, 100°C
1. CBr4, Ph3P, CH3CN, 0°C to rt; 2. LDA, THF, −78°C to rt
1. CBr4, Ph3P, CH3CN, 0°C to rt; 2. KOH, EtOH, reflux
24b
71
c
–
57
c
–
a Isolated yield.
b The corresponding bromide was isolated in 40% yield.
c A complex product mixture was observed by TLC.
turned our attention to stepwise cyclization. Accord-
ingly, bromination of 9 with CBr4/Ph3P in methylene
chloride provided the corresponding bromide, which
was subjected to cyclization by adding triethylamine in
one-pot at reflux. However, in this case the yield for the
desired product 10 was still lower, mainly because 40%
unconverted bromide was isolated (entry 2). We rea-
soned that the reaction temperature might be too low
for the cyclization step and changed the solvent to
acetonitrile. As we expected, the cyclization reaction
worked well in refluxing acetonitrile to give 10 in 71%
yield (entry 3). Further attempts to improve the yield
by increasing the reaction temperature failed (entry 4).
In addition, using other bases to assist the cyclization
of the bromide were unsuccessful (entries 5 and 6).
benzyl group afforded the desired 2,3,6-trisubstituted
piperidine 11a in 80% yield. No other isomers were
obtained from this reaction. It is notable that hydro-
genation of 10 catalyzed by Pd/C at 50 atm provided
11a in low yield and with poor diastereoselectivity, and
when PtO2 was employed as the catalyst only 11b was
isolated in good yield, which showed that no deprotec-
tion of the benzyloxy group occurred. Finally, treat-
ment of 11a with PPh3/CBr4 furnished 5,8-indolizidine
12, which can be converted to (−)-indolizidine 209B.3b
In conclusion, we have developed an efficient route to
enantiopure 5,8-disubstituted indolizidines using b-
amino esters as the starting material. This protocol
should allow the synthesis of various substituted
indolizidines by varying the b-amino ester and b-keto
ester starting materials. Further application of this
method is in hand.
Hydrogenation of 10 in the presence of Raney Ni at 70
atm to hydrogenate the olefin moiety and deprotect the

D. Ma et al. / Tetrahedron: Asymmetry 13 (2002) 2257–2260
2259
2. Experimental
2.1. (R)-3-Aminooctanol, 7
327, 281, 239, 168, 91; HRMS calcd for C23H35NO3
(M+) 373.2591, found 373.2576.
2.4. (1S,2S,6R)-1-(3-Hydroxypropyl)-2-ethoxycarbonyl-
6-pentylpiperidine, 11a
A mixture of the b-amino ester 6 (5.5 g, 15 mmol),
Pd/C (3 mmol) and acetic acid (1.5 mL) in methanol
(60 mL) was stirred under hydrogen (50 atm) at 50°C
for 20 h. The Pd/C was filtered off and the filtrate was
concentrated to dryness. The residual oil was dissolved
in THF (40 mL) and LAH (2.0 g, 50 mmol) was added
at 0°C in portion. The resulting mixture was stirred at
the same temperature for 2 h and then allowed to warm
to room temperature. The reaction was quenched by
adding water before the mixture was partitioned
between chloroform and water. The organic layer was
separated and the aqueous layer was extracted with
chloroform. The combined organic layers were dried
over Na2SO4, and concentrated to afford 2.0 g (91%) of
crude 7. [h]2D0=−14.4 (c 1.3, CHCl3); IR (KBr) 3554,
To a suspension of Raney Ni (60 mg) in ethanol (20
mL) was added a drop of triethylamine, and a solution
of 10 (150 mg, 0.4 mmol) in ethanol (1 mL). The
resulting mixture was stirred under hydrogen (70 atm)
at 60–70°C for 15 h. The cooled mixture was filtered
and the filtrate was concentrated. The residual oil was
chromatographed eluting with 1/10 methanol/ethyl ace-
tate to afford 11a (92 mg, 80%). [h]2D0=−11 (c 0.97,
1
CHCl3); IR (KBr) 3682, 1721, 11180 cm−1; H NMR
(300 MHz, CDCl3) l 4.21 (q, J=7.3 Hz, 2H), 3.70 (dt,
J=11.6, 3.6 Hz, 1H), 3.51 (dt, J=11.7, 3.6 Hz, 1H), 2.6
(d, J=10.7 Hz, 1H), 2.5 (m, 2H), 2.1 (dq, J=11.9, 2.2
Hz, 1H), 1.81–1.20 (m with t, J=6.5 Hz, 20H), 0.89 (t,
J=7.1 Hz, 3H); ESI-MS m/z 286 (M++H+); HRMS
calcd for C16H31NO3 (M+) 285.2303, found 285.2310.
1
3041, 2910, 1051 cm−1; H NMR (300 MHz, CDCl3) l
3.71–3.60 (m, 3H), 3.14 (br s, 3H), 2.85 (m, 1H),
1.63–1.21 (m, 10H), 0.89 (t, J=6.9 Hz, 3H); EI-MS m/z
146 (M+), 128, 102, 74, 56; HRMS calcd for C8H19NO
(M+) 145.1426, found 145.1428.
2.5. (5R,8S,8aS)-5-Pentyloctahydroindolizidine-8-car-
boxylic acid ethyl ester, 12
To a stirred solution of 11 (15 mg, 0.053 mmol) in
anhydrous methylene chloride (1.5 mL) was added
CBr4 (21 mg, 0.06 mmol) at 0°C. After all of the CBr4
was dissolved, Ph3P (21 mg, 0.06 mmol) was added.
The resulting solution was stirred at room temperature
for 17 h and the solvent was removed in vacuo. The
residue was extracted with n-hexane and the hexane
extract washed with brine. After removal of the solvent,
the residue was chromatographed to afford 12 (9 mg,
67%). [h]2D0=−31.5 (c 0.25, CHCl3); IR (KBr) 2781,
2.2. Condensation of 7 with b-keto ester, 8
A mixture of 7 (4.0 g, 27.6 mmol), b-keto ester 8 (7.3 g,
27.6 mmol) and freshly dried MgSO4 (1.5 g) was stirred
at room temperature for 2 days. Purification of the
resulting mixture directly by column chromatography
eluting with 1/3 ethyl acetate/n-hexane afforded 9 as a
colorless oil (7.5 g, 70%). [h]2D0=+8.9 (c 2.6, CHCl3); IR
(KBr) 3063, 2930, 1742, 1716, 1647 cm−1; 1H NMR
(300 MHz, CDCl3) l 8.51 (br d, J=7.8 Hz, 1H),
7.31–7.20 (m, 5H), 4.51 (s, 2H), 4.40 (s, 1H), 4.11 (q,
J=7.2 Hz, 2H), 3.60 (br m, 3H), 3.52 (m, 2H), 2.31 (m,
2H), 1.82 (m, 2H), 1.61–1.23 (m with t, J=6.3 Hz,
14H), 0.89 (t, J=7.3 Hz, 3H); EI-MS m/z 391 (M+),
341, 301, 213, 170, 156, 91; HRMS calcd for
C23H37NO4 (M+) 391.2721, found 391.2783.
1
1738, 1461 cm−1; H NMR (300 MHz, CDCl3) l 4.2 (q,
J=7.3 Hz, 2H), 3.5 (dt, J=7.7, 2.2 Hz, 1H), 2.67 (m,
1H), 2.15 (m, 2H), 1.91–1.21 (m with t, J=6.5 Hz,
20H), 0.89 (t, J=6.9 Hz, 3H); MS m/z 267 (M+), 197,
196, 238, 222, 168, 122, 70; HRMS calcd for
C16H29NO2 (M+) 267.2198, found 267.2207.
2.3. (R)-2-Pentyl-5-ethoxycarbonyl-6-(3-benzyloxy-
propyl)-1,2,3,4-tetrahydropyridine, 10
Acknowledgements
To a stirred solution of 9 (997 mg, 2.55 mmol) in
anhydrous acetonitrile (2.5 mL) was added CBr4 (1088
mg, 3.28 mmol) at 0°C. After all CBr4 was dissolved,
Ph3P (870 mg, 3.32 mmol) was added slowly. The
resulting mixture was warmed to room temperature and
stirring was continued until 9 disappeared (as indicated
by TLC). To this solution triethylamine (0.5 mL) was
added and the resulting solution was heated under
reflux for 5 h. The solvent was removed in vacuo and
the residue was chromatographed eluting with 1/15
ethyl acetate/n-hexane to afford 10 as a pale yellow oil
(675 g, 71%). [h]2D0=+86.5 (c 1.23, CHCl3); IR (KBr)
The authors are grateful to the Chinese Academy of
Sciences and National Natural Science Foundation of
China (grant 29725205) for their financial support.
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