A new and efficient synthesis of (-)-indolizidine 167B by tandem metathesis

Article abstract of DOI:10.1016/S0040-4039(02)01534-4

An enantioselective synthesis of the natural alkaloid (-)-indolizidine 167B is described. From an easily accessible chiral cycloheptene derivative a 2,5-dihydropyrrolidine was formed via a ruthenium-catalysed tandem ring-rearrangement metathesis. Annellation of the second ring was effected by an intramolecular reductive amination step under complete stereocontrol. (-)-Indolizidine 167B was obtained in 35% overall yield and high optical purity.

Full text of DOI:10.1016/S0040-4039(02)01534-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6739–6741
A new and efficient synthesis of (−)-indolizidine 167B by tandem
metathesis
Jan Zaminer, Christian Stapper and Siegfried Blechert*
Institut fu¨r Chemie, Technische Universita¨t Berlin, Strasse des 17. Juni 135, D-10623 Berlin, Germany
Received 27 June 2002; accepted 22 July 2002
Abstract—An enantioselective synthesis of the natural alkaloid (−)-indolizidine 167B is described. From an easily accessible chiral
cycloheptene derivative a 2,5-dihydropyrrolidine was formed via a ruthenium-catalysed tandem ring-rearrangement metathesis.
Annellation of the second ring was effected by an intramolecular reductive amination step under complete stereocontrol.
(−)-Indolizidine 167B was obtained in 35% overall yield and high optical purity. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
frogs have been recognised to be a rich source of
biologically active substances. Among them, particu-
larly indolizidine alkaloids have been identified as non-
competitive blockers of neuromuscular transmission
useful for pharmaceutical applications.5 Therefore,
much effort has been spent on short and efficient
syntheses of substituted indolizidines. Since 1 has never
been isolated in pure state, its constitution could only
be resolved by mass spectroscopic methods as 5-propyl
indolizidine. Neither the relative nor the absolute
configuration of 1 are known, but were proposed as
(5R,9R) in analogy to the known indolizidine 223AB
2.6 Several total syntheses of (−)-1 have been published
so far.7
During the past decade ruthenium-catalysed olefin
metathesis has proven to be a valuable method in
organic synthesis.1 Especially the ring-closing metathesis
(RCM) has been used in many examples, serving as a
key step in natural product synthesis. In contrast, the
ring-opening metathesis (ROM) has been applied less
frequently because ring-opening metathesis polymerisa-
tions (ROMP) are unwanted side reactions. Only a few
examples of a ROM in natural product synthesis have
been reported in the literature.2 In order to avoid
polymerisation, the ROM is often combined with a
cross metathesis (CM) or an RCM. Intramolecular
RCM-ROM or RCM-ROM-RCM domino processes
are called ring-rearrangement metatheses (RRM). Since
any stereochemical information in the substrate remains
unchanged during the metathesis reaction, ring rear-
rangements occur under conservation of the configura-
tions of the stereocenters (Scheme 1). Starting from
enantiopure carbocycles with olefinic side chains hete-
rocycles of different sizes are easily accessible. A num-
ber of N-heterocyclic natural products have been
synthesised via this methodology.3
2. Results
Compound 1 should be obtainable from pyrrolidine
derivative 3 under stereoselective ring closure after acti-
vation of the homoallylic alcohol moiety and hydro-
genation of the double bonds (Scheme 2). Compound 3
should be accessible from 4 by fluoride induced silyl
ether cleavage and proto-desilylation under double
Herein, we report on the synthesis of indolizidine 167B
(1, Scheme 2) which is one of the simple representatives
of the series of indolizidine alkaloids isolated as trace
components from the skin of a neotropical frog caught
on Isla de Colo´n, Panama´.4 Skin secretions of such
Keywords: asymmetric synthesis; rearrangement; ruthenium; hetero-
cycles.
* Corresponding author. Tel.: +49-30-31422255; fax: +49-30-
31423619; e-mail: blechert@chem.tu-berlin.de
Scheme 1. ROM–RCM sequence.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01534-4

6740
J. Zaminer et al. / Tetrahedron Letters 43 (2002) 6739–6741
H
N
OH
Si
O
N
R
N
PG
nPr
1
3
4
Indolizidine 167B
RCM-ROM-RCM
H
N
R
N
O
HO
OAc
Si
nBu
nPr
6
2
5
Indolizidine 223AB
Scheme 2. Retrosynthetic strategy.
Cbz
R2
N
N
O
OR1
HO
OAc
Si
a
d
7 R1 = Ac, R2 = Ns
8 R1 = Ac, R2 = Cbz
9 R1 = H, R2 = Cbz
6
10
b
c
OH
e
g
f
Si
O
N
N
Cbz
Cbz
11
12
O
h
1
N
Cbz
13
Scheme 3. Reagents and conditions: (a) N-nosyl-N-allylamine,10 PPh3, azodicarboxylic acid diisopropylester, THF, rt, 88%; (b) (i)
PhSH, K2CO3, DMF, 70°C, (ii) benzylchloroformate, 0°C, 84%; (c) NaCN, MeOH, rt, quant.; (d) allyldimethylchlorosilane,
NEt3, DMAP, CH2Cl2, 0°C, 90%; (e) Cl2(Cy3P)2RuꢀCHPh (5 mol%), CH2Cl2, reflux, 4 h; (f) TBAF (1 M in THF), 0°C to rt, 92%
(from 11); (g) Dess–Martin periodinane, CH2Cl2, 2 h, 73%; (h) H2, Pd/C (10%), MeOH, 15 h, 79%.
bond shift.8 In turn, 4 should be obtained from 5 via an
form the N-deprotection and closure of the second ring
in a one pot procedure. Furthermore, past investiga-
tions demonstrated the rate accelerating influence of the
carbamate protecting group in RRM reactions.3d
Cleavage of the acetate 8 and O-silylation of 9 gave the
substrate 10 for the RRM in 90% yield from 8. The
metathesis reaction and the subsequent silyl ether cleav-
age were performed in a one pot procedure: refluxing
10 in dichloromethane with 5 mol% of Grubbs catalyst
for 4 h was followed by the addition of TBAF in THF
at room temperature giving alcohol 12 in 92% yield. In
a similar synthesis, the stereo directing effect of the
stereocenter at C-5 was used to effect a diastereoselec-
tive ring closure.12 Intramolecular reductive amination
RRM key step. The two olefinic side chains required
for the metathesis reaction should be introduced succes-
sively into the chiral cycloheptenediol–monoacetate 6
under inversion of the (S)-configured stereocenter and
retention of the (R)-configured center. Enantiopure 6
can be synthesised in four steps from cycloheptatriene.9
Starting from enantiopure alcohol 6, Mitsunobu reac-
tion with N-nosyl-N-allylamine10 gave protected amine
7 in 88% yield (Scheme 3). The o-nitrobenzenesulfonyl
protecting group required in this step was replaced by a
benzylcarbamate group11 that can easily be removed
under hydrogenolytic conditions. Our plan was, to per-

J. Zaminer et al. / Tetrahedron Letters 43 (2002) 6739–6741
OR
6741
H2, Pd/C (10%)
+
:
1
N
N
H
Cbz
12 R = H
15
b
14 R = Ms
(1
1)
Scheme 4. Attempted hydrogenolytic ring closure of 14.
of ketone 13 should give the correct configuration at C-9.
Thus, oxidation of 12 with Dess–Martin periodinane
afforded ketone 13 in 73% yield. Hydrogenation of 13 on
Pd/C gave the desired (5R,9R)-indolizidine 1 in 79% yield
under complete stereocontrol. The analytical data of 1
(1H NMR (CDCl3): l 3.22 (td, J=8.2, 2.4 Hz, 1H, H-3ax);
[h]2D0=−106.5° (c 0.65, CH2Cl2)) were in accordance with
those reported in the literature7e (1H NMR (CDCl3): l
3.22 (td, J=8.2, 2.4 Hz, 1H, H-3ax), [h]2D0=−111.3° (c 1.3,
CH2Cl2)).
2. For the synthesis of (+)-asteriscanolide, see: Snapper, M.
L.; Limanto, J. J. Am. Chem. Soc. 2000, 122, 8071–8072.
3. (a) Ovaa, H.; Stragies, R.; van der Marel, G. A.; Van
Boom, J. H.; Blechert, S. Chem. Commun. 2000, 1501–
1502; (b) Voigtmann, U.; Blechert, S. Org. Lett. 2000, 2,
3971–3974; (c) Voigtmann, U.; Blechert, S. Synthesis
2000, 6, 893–898; (d) Stragies, R.; Blechert, S. J. Am.
Chem. Soc. 2000, 122, 9584–9591.
4. Daly, J. W.; Spande, T. F. In Alkaloids: Chemical and
Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New
York, 1986; Vol. 4, pp. 1–274.
Several attempts to close the second ring via a sequence
of O-activation, N-deprotection and intramolecular
nucleophilic replacement were not successful. O-Mesyl-
ation of 12 (“14) and subsequent hydrogenation of 14
gave an inseparable 1:1 mixture of 1 and (R)-2-hep-
tylpyrrolidine 15 (Scheme 4). We assumed that in the
course of the hydrogenation elimination of methanesul-
fonic acid occurred giving a 1,3-diene system. This was
then hydrogenated to give the saturated heptylpyrro-
lidine 15.
5. (a) Michael, J. P. In Alkaloids; Cordell, G. A., Ed.;
Academic Press: London, 2001; Vol. 55, pp. 92–258; (b)
Daly, J. W.; Garraffo, H. M.; Spande, T. F. In Alkaloids;
Cordell, G. A., Ed.; Academic Press: London, 1993; Vol.
43, pp. 186–267.
6. (a) Royer, J.; Husson, H.-P. Tetrahedron Lett. 1985, 26,
1515–1518; (b) Tokuyama, T.; Nishimori, N.; Karle, I.
L.; Edwards, M. W.; Daly, J. W. Tetrahedron 1986, 42,
3453–3460.
7. For recent syntheses of (−)-indolizidine 167B (1), see: (a)
Corvo, M. C.; Pareira, M. M. A. Tetrahedron Lett. 2002,
43, 455–458; (b) Kim, G.; Lee, E.-J. Tetrahedron: Asym-
metry 2001, 12, 2073–2076; (c) Peroche, S.; Remuson, R.;
Gelas-Mialhe, Y.; Gramain, J.-C. Tetrahedron Lett. 2001,
42, 4617–4619; (d) Ma, D.; Sun, H. Org. Lett. 2000, 2,
2503–2505; (e) Bach, T. G.; Nakajima, K. J. Org. Chem.
2000, 65, 4543–4552; (f) Yamazaki, N.; Ito, T.;
Kibayashi, C. Org. Lett. 2000, 2, 465–467; (g) Chalard,
P.; Remuson, R.; Gelas-Mialhe, Y.; Gramain, J.-C.;
Canet, I. Tetrahedron Lett. 1999, 40, 1661–1664.
8. A similar strategy was applied in the synthesis of (−)-
halosaline. See: Stragies, R.; Blechert, S. Tetrahedron
1999, 55, 8179–8188.
9. (a) Johnson, C. R.; Bis, S. J. Tetrahedron Lett. 1992, 33,
7287–7290; (b) Bis, S. J.; Whitaker, D. T.; Johnson, C. R.
Tetrahedron: Asymmetry 1993, 4, 875–878; (c)
Dirkzwanger, H.; Nieuwstad, T. J.; van Wijk, A. M.; van
Bekkum, H. Rec. Trav. Chim. Ned. 1973, 35–43.
10. Prepared according to: Beckwith, A. L. J.; Meijs, G. F. J.
Org. Chem. 1987, 52, 1922–1930.
Alternatively, an intramolecular Mitsunobu reaction or
an O-activation with Appels’ reagent13 were attempted
but yielded 1 containing considerable amounts of
triphenylphosphine oxide as impurity. Due to the volatil-
ity of 1 chromatographic purification was difficult result-
ing in low yields.
3. Conclusion
(−)-(5R,9R)-Indolizidine 167B (1) was enantioselectively
prepared in eight steps and an overall yield of 35%
starting from the optically pure cycloheptene derivative
6. The RRM key step demonstrates the high synthetic
value of olefin metathesis in organic synthesis. Further
applications of RCM–ROM and RRM in natural
product syntheses are currently under investigation.
References
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