A convenient allylsilane-N-acyliminium route toward 5-alkylindolizidines. Diastereoselective synthesis of (±)-indolizidine 167B

Article abstract of DOI:10.1016/S0040-4039(01)00822-X

A highly diastereoselective synthesis of 5-alkylindolizidines is described via an intermolecular addition of the allylsilyl functional group of homoallylic alcohols with an N-acyliminium ion derived from pyrrolidin-2-one.

Full text of DOI:10.1016/S0040-4039(01)00822-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4617–4619
A convenient allylsilane-N-acyliminium route toward
5-alkylindolizidines. Diastereoselective synthesis of
( )-indolizidine 167B
Sandrine Peroche, Roland Remuson,* Yvonne Gelas-Mialhe and Jean-Claude Gramain
Chimie des Substances Naturelles, UMR 6504, CNRS et Universite´ Blaise Pascal (Clermont-Ferrand),
63177 Aubie`re Cedex, France
Received 15 May 2001
Abstract—A highly diastereoselective synthesis of 5-alkylindolizidines is described via an intermolecular addition of the allylsilyl
functional group of homoallylic alcohols with an N-acyliminium ion derived from pyrrolidin-2-one. © 2001 Elsevier Science Ltd.
All rights reserved.
Indolizidines constitute a very important class of com-
pounds as they occur in a large number of natural
products and display a variety of physiological activi-
ties. Indolizidines alkaloids have been isolated from the
skin extracts of neotropical frogs of the family Dendro-
bates.1,2 Most of them are monosubstituted by an alkyl
chain in the 5-position or disubstituted in the 3,5- or
5,8-positions. These compounds serve as a defence
against predation. Some of them are non-competitive
blockers of nicotinic receptor channels. Accordingly,
novel strategies for the stereoselective synthesis of
indolizidine ring systems continue to receive consider-
able attention.3
and indolizidine alkaloids.5–7 In this article, we describe
an intermolecular reaction between the allylsilyl func-
tional group of homoallylic alcohols and the
acyliminium ion coming from pyrrolidin-2-one as the
key reaction for a new, general and flexible entry to a
variety of 5-substituted indolizidines (Scheme 1). To
highlight the method, this synthetic strategy was
applied to the synthesis of indolizidine alkaloid ( )-
167B.
Hydroxyallylsilanes 2 were synthesised as described8
(Scheme 2) by reaction of the reagent prepared from
allyltrimethylsilane, sec-butyllithium and titanium tetra-
isopropoxide with aldehydes. Compounds 2b, 2d and 2e
were obtained as a single diastereomer in 54, 76 and
67% yields, respectively, and their spectroscopic data
were in agreement with literature;8–10 compounds 2a
(88% yield) and 2c (64% yield) were identified by com-
parison of their spectroscopic data with those of known
compounds.
The allylsilyl functional group is a weak carbon nucleo-
phile extensively used for trapping N-acyliminium ions,
thus providing an exceptionally useful method for car-
bonꢀcarbon bond formation in both intermolecular and
intramolecular cases.4 We have applied the intramolec-
ular methodology toward the synthesis of quinolizidine
H
+
N
Me3Si
+
N
N
H
R
BnO
O
R
OH
1
2
R = Pr indolizidine 167B
O
R
Scheme 1.
Keywords: silicon and compounds; iminium salts; alkaloids; indolizidines.
* Corresponding author. Tel.: 04-73-40-71-13; fax: 04-73-40-77-17; e-mail: remuson@chisg1.univ-bpclermont.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00822-X

4618
S. Peroche et al. / Tetrahedron Letters 42 (2001) 4617–4619
OH
Li, (Me2CHO) 4Ti
SiMe3
RCHO
+
R
SiMe3
2a R = Me
2b R = Pr
2c R = Bu
2d R = Hex
2e R = Ph
Scheme 2.
The synthesis of indolizidines 8b and 8c was carried out
NMR spectra. Thus, the allylation reaction is
diastereoselective. In the 13C NMR spectra of 5b and
5c, two separate NMR signals are observed for each
carbon nucleus because of hindered rotation due to the
partial CꢀN double bond character of the carbamate
group.
as shown in Scheme 3.
N-Benzyloxycarbonylpyrrolidin-2-one 3 was prepared
as described.11 Reduction of 3 with excess NaBH4 in
ethanol in acidic medium afforded ethoxycarbamate 4
in 83% yield.
Subsequent oxidation of alcohols 5b and 5c with pyri-
dinium dichromate (PDC) in CH2Cl2 afforded a,b-
ethylenic ketones 6b and 6c in 49 and 85% yields,
respectively. The 1H NMR spectrum showed these com-
pounds to have an E configuration for the double bond
(J=15.9 Hz).
The key-step of the synthesis is the intermolecular
addition of the allylsilyl functional group of alcohols 2
on the acyliminium ion derived from ethoxycarbamate
4. Treatment of a mixture of ethoxycarbamate 4 and
hydroxyallylsilane 2b (1.1 equiv.) with 1 equiv. of stan-
nic chloride at low temperature resulted in the forma-
tion of 5b in 47% yield,12 via the acyliminium ion
intermediate 1. In the same way, hydroxyallylsilane 2c
was also reacted with ethoxycarbamate 4 and stannic
chloride to give 5c in 47% yield. These compounds were
Catalytic hydrogenation (H2 over Pd/C in methanol) of
ketones 6b and 6c induced simultaneously hydrogenoly-
sis of the CBz group, reduction of the double bond of
the side chain and reduction of the iminium ion inter-
mediate 7 to give indolizidines 8b and 8c, respectively.
1
obtained as a single diastereomer as shown by their H
(i)
(ii)
(iii)
(v)
N
H
O
N
O
N
OEt
(quantitative)
(83%)
CBz
CBz
4
OH
3
R
+
N
(iv)
N
N
SiMe3
CBz
CBz
CBz
1
O
R
OH
R
5b R = Pr (47%)
5c R = Bu (47%)
6b R = Pr (49%)
6c R = Bu (85%)
H
+
N
N
N
H
R
R
8b R = Pr (95%) indolizidine 167B
8c R = Bu (53%) 5-butylindolizidine
7
O
R
Scheme 3. (i) n-BuLi, THF then PhCH2OCOCl; (ii) NaBH4, H2SO4, EtOH; (iii) SnCl4, CH2Cl2, −78°C; (iv) PDC, CH2Cl2; (v)
H2/Pd/C, MeOH.

S. Peroche et al. / Tetrahedron Letters 42 (2001) 4617–4619
4619
This reaction proceeded with excellent diastereoselectiv-
ity, as only one diastereomer of 8b and 8c was detected
in the crude reaction mixture. This result is in agree-
ment with literature.3h Indolizidine 8b was identified by
stock, D. Eur. J. Org. Chem. 1998, 5, 865–870; (q)
Chenevert, R.; Ziarami, G. M. Heterocycles 1999, 51,
593–598; (r) Yamazaki, N.; Ito, T.; Kibayashi, C. Org.
Lett. 2000, 2, 465–468; (s) Ma, D.; Sun, H. Org. Lett.
2000, 2, 2503–2505.
1
comparison of its H and 13C NMR spectra with those
reported for (−)-indolizidine 167B.
4. Colvin, E. Silicon Organic Synthesis; Butterworth: Lon-
don, 1981; pp. 97–124.
In conclusion, we have developed a concise method for
the synthesis of 5-substituted indolizidines, starting
from readily available materials. The synthesis of ( )-
indolizidine 167B has been achieved in five steps and
18% overall yield from pyrrolidin-2-one. Work is cur-
rently in progress to apply this methodology to the
enantioselective synthesis of indolizidine natural
products.
5. Gelas-Mialhe, Y.; Gramain, J. C.; Perrin, B.; Remuson,
R. Tetrahedron: Asymmetry 1998, 9, 1823.
6. Chalard, P.; Remuson, R.; Gelas-Mialhe, Y.; Gramain, J.
C. Tetrahedron: Asymmetry 1998, 9, 4361–4368.
7. Chalard, P.; Remuson, R.; Gelas-Mialhe, Y.; Gramain, J.
C.; Canet, I. Tetrahedron Lett. 1999, 40, 1661–1664.
8. Reetz, M. T.; Steinbach, R.; Westermann, J.; Peter, R.;
Wenderoth, B. Chem. Ber. 1985, 118, 1441–1454.
9. Yamamoto, Y.; Yatagai, H.; Saito, Y.; Maruyama, K. J.
Org. Chem. 1984, 49, 1096–1104.
10. Shimizu, N.; Shibata, F.; Tsuno, Y. Bull. Chem. Soc. Jpn.
1984, 57, 3017–3018.
11. Giovanni, A.; Savoia, D.; Umani-Ronchi, A. J. Org.
Chem. 1989, 54, 228–234.
12. Typical experimental procedure for preparation of 5: To
a solution of N-benzyloxycarbonyl-2-ethoxypyrrolidone 4
(8 mmol) in dry CH2Cl2 (150 ml) cooled at −78°C under
Ar was added SnCl4 (c=1 M, 8 mmol). The temperature
was then raised to −20°C and 3-trimethylsilylhept-1-ene-
4-ol (8.8 mmol) was added. The reaction mixture was
stirred at this temperature for 1.5 h and was then
quenched with saturated sodium hydrogen carbonate.
The aqueous layer was extracted three times with
CH2Cl2. The combined organic layers were washed with
brine and dried over anhydrous MgSO4, concentrated in
vacuo and purified by flash chromatography on silica gel
(hexane/ethyl acetate, 7:3) to afford the product as a
colourless liquid.
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Representative spectroscopic data for compound 5b: 1H
NMR (CDCl3): l 0.98 (t, 3H), 1.25–1.30 (m, 4H), 1.70–
1.95 (m, 4H), 2.17 and 2.42 (m, 1H), 2.17 and 2.51 (m,
1H), 3.40 (m, 2H), 3.90 (m, 1H), 4.04 (m, 1H), 5.15 (m,
2H), 5.43–5.65 (m, 2H), 7.25–7.40 (m, 5H); 13C NMR
(CDCl3): l 14.0, 18.6, 22.9 and 23.6, 29.7 and 30.1, 36.6
and 37.3, 39.4, 46.5 and 46.8, 56.8 and 57.4, 66.5 and
66.7, 72.5, 127.4, 127.8, 127.9, 128.4, 135.9, 136.1, 137.1,
154.9. Anal. calcd for C19H27NO3: C, 71.89; H, 8.57; N,
4.41. Found: C, 71.72; H, 8.32; N, 4.72.
.