tuted δ-chloropropylamines 5b-5d were assembled.6 It was
found that all of these substrates worked for this process to
provide corresponding polysubstituted indolizidines and
quinolizidines although higher reaction temperature was
required in comparison with 5a (entries 8-11).
When ynone-derived iodide 1g was used, only direct
Michael addition product was isolated (entry 12), which
indicated that ynone moiety of 1g was the target for first
attack. This result implied that its ynone part was more
reactive than its terminal iodide part. However, this priority
was also dependent on the nature of nucleophiles because
when 1g reacted with sterically hindered R-substituted
δ-chloropropylamine 5d, the desired product 6n was obtained
in 55% yield although about 20% direct Michael addition
product was still isolated (entry 13). It was known that
Michael addition of LDA to the R,â-unsaturated ester of
methyl 6-bromo-2-hexenoate or methyl 2-heptenoate could
initiate the ring closure.7 However, in our case no ring closure
products through the direct Michael addition products were
determined, which might result from quick H+ abstract of
the generated carbanion.
Figure 1. Possible reaction course of iodides 1 with â-amino esters
or δ-chloropropylamines 2.
On the basis of the above investigations, we next devel-
oped a concise synthesis of indolizidine 223A (14)8 as
outlined in Scheme 1. The synthesis started from 8, an
enantiopure â-amino ester that was prepared from a com-
mercial available acid 7 in two steps and 67% yield based
on the procedure of Davies.8c,9 Reduction of 8 with LAH
afforded δ-amino alcohol 9, which was exposed to SOCl2,
followed by Pd(OH)2/C-catalyzed hydrogenolysis to provide
δ-chloropropylamine hydrochloride 10. Next, heating a
mixture of 10, 1a, K2CO3 and 4 Å MS in MeCN delivered
indolizidine 11 in 80% yield. Hydrogenation of 11 under
the catalysis of PtO2 worked well to produce a mixture of
8â-isomer 12a and 8R-isomer 12b. This reaction should give
12a initially and then form 12b through C8 epimerization,
which was proved by complete conversion to 12b through
treatment of the above mixture with sodium ethoxide. The
stereochemistry of 12b was assigned by NOESY studies and
the overall yield was 75% from 11. Finally, reduction of
12b produced alcohol 13, which was oxidized to give an
aldehyde. Wittig reaction of this aldehyde followed by
hydrogenation furnished 14. Its analytical data were all-
identical with those reported.8 This protocol consists of 12
linear steps from 7 in 14.5% overall yield, representing the
most efficient one for synthesizing indolizidine 223A to date.
was expected that after the first attack of the amine moiety
of 2b to the terminal carbon of the iodide 1 and subsequent
Michael addition to form the intermediate B, the resultant
iodine anion would undergo a halogen exchange with the
chloride, which in turn would generate a more reactive
species to react with the enolate moiety as depicted in
intermediate C, thereby avoiding the H+ abstraction and
giving bicyclic products exclusively.
With this idea in mind, a reaction of ethyl 6-iodo-2-
hexynoate 1a with 3-chloropropylamine hydrochloride 5a
was conducted in acetonitrile at 60 °C under the action of
3.5 equiv of K2CO3. We were pleased to notice that after 24
h indolizidine 6a was isolated as a sole product in 92% yield
(Table 1, entry 1). In view of this encouraging result, other
iodides with different length of chain or electron-withdrawing
groups and several substituted δ-chloropropylamines
5b-5h were explored for this sequential reaction process.
It was found that in most cases substituted indolizidine
(entries 2 and 3), quinolizidine (entries 4-6), or even
piperidinoazpine ring (entry 7) products were isolated in good
yields. Noteworthy is that several electron-withdrawing
groups of iodides 1 such as carboxylate ester, tosyl, and
phosphonate are compatible with this process and are ready
for further transformations to natural products.4,5 In addition,
successful formation of 6b and 6e indicated that halogen
exchange should be necessary for closure of the second ring
because in a similar case,4 addition of δ-chloropropylamines
to acetylenic sulfones in several refluxed solvents did not
give any cyclization products directly.
Alkaloids incorporating the indolizidine and quinolizidine
skeletons comprise a rather large class of compounds isolated
from diverse natural sources.10 These natural products
displayed a considerable range of biological activity including
(6) They were prepared from corresponding â-amino esters (see refs 3a
and 7c) following a procedure from 9a to 10.
(7) Little, R. D.; Dawson, J. R. Tetrahedron Lett. 1980, 21, 2609.
(8) Isolation: (a) Garraffo, H. M.; Jain, P.; Spande, T. F.; Daly, J. W. J.
Nat. Prod. 1997, 60, 2. For synthesis of indolizidine 223A and its epimer,
see: (b) Toyooka, N.; Fukutome, A.; Nemoto, H.; Daly, J. W.; Spande, T.
F.; Garraffo, H. M.; Kaneko, T. Org. Lett. 2002, 4, 1715. (c) Pu, X.; Ma,
D. J. Org. Chem. 2003, 68, 4400. (d) Harris, J. M.; Padwa, A. J. Org.
Chem. 2003, 68, 4371.
To further explore the scope of this sequential reaction
process, several enantiopure R-substituted or R,â-disubsti-
(5) For other emerging examples, see: (a) Haddad, M.; Celerier, J.-P.;
Lhommet, G. Heterocycles 1987, 26, 2335. (b) Michael, J. P.; Gravestock,
D. J. Chem. Soc., Perkin Trans. 1 2000, 1919. (c) Bates, R. W.; Boonsombat,
J. J. Chem. Soc., Perkin Trans. 1 2001, 654.
(9) Davies, S. G.; Ichihara, O.; Walters, I. S. J. Chem. Soc., Perkin Trans
1 1994, 1141.
706
Org. Lett., Vol. 7, No. 4, 2005