Total synthesis of indolizidine (+)-223A

Article abstract of DOI:10.1002/ejoc.201101530

We described the diastereoselective total synthesis of indolizidine (+)-223A in 10% overall yield over 14 steps starting from 6-chlorohex-2-ynoate. Our strategy involved chain elongation through aldolization, the formation of the indolizidine skeleton by cyclization, and stereocontrolled hydrogenation. We described the diastereoselective total synthesis of indolizidine (+)-223A in 10% overall yield over 14 steps starting from 6-chlorohex-2-ynoate. The influence of theN-protecting group of the starting pyrrolidine to form the indolizidine skeleton was studied. Copyright

Full text of DOI:10.1002/ejoc.201101530

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201101530
Total Synthesis of Indolizidine (+)-223A
Mouloud Fellah,[a] Gérard Lhommet,[a] and Virginie Mouriès-Mansuy*[a]
Keywords: Alkaloids / Total synthesis / Nitrogen heterocycles / Aldol reactions / Protecting groups
We described the diastereoselective total synthesis of indoliz-
idine (+)-223A in 10% overall yield over 14 steps starting
from 6-chlorohex-2-ynoate. Our strategy involved chain
elongation through aldolization, the formation of the indoliz-
idine skeleton by cyclization, and stereocontrolled hydrogen-
ation.
Elaboration of the side chain of 2 could arise from aldehyde
3, which could be obtained from (R)-ethyl 2-{(R)-1-[(S)-1-
phenylethyl]pyrrolidin-2-yl}butanoate [(–)-4].[7]
Introduction
Indolizidine and quinolizidine ring systems constitute the
core of numerous structurally interesting alkaloids ex-
tracted from the skins of amphibians.[1] The small amounts
isolated and the potent biological activities of these natural
products make them attractive targets in organic synthesis.
Among these alkaloids, indolizidine 223A, the first member
of a new trisubstituted indolizidine class of amphibian alka-
loids, was isolated by Daly and co-workers[2] from the skin
extract of a Panamanian population of the frog Dendrob-
ates pumilio Schmidt (Dendrobatidae). The first total syn-
thesis of alkaloid 223A reported by the groups of Toyooka
and Daly[3] allowed the determination of the correct struc-
ture. Recently, this natural product was shown to exhibit
blocking effects on nicotinic acetylcholine receptors.[4]
To date, five syntheses of indolizidine 223A have been
reported.[3,5] Most of them involve the elaboration of a chi-
ral tetrasubstituted piperidine intermediate and its subse-
quent cyclization into the corresponding indolizidine. Re-
cently, Aubé et al.[5d] performed a concise synthesis of alk-
aloid (–)-223A from norbornadiene through ring-opening-
metathesis to form the indolizidine ring system.
Our goal was to develop a simple procedure providing
easy access to alkaloid 223A in sufficient quantities from
readily accessible compounds. In relation to our interest in
the total synthesis of natural products using cyclic amino
esters as versatile intermediates,[6] we report herein a highly
stereoselective synthesis of indolizidine (+)-223A from a
chiral pyrrolidine ester. Our strategy is outlined in
Scheme 1. We envisioned that indolizidine (+)-223A could
stem from pyrrolidine hydroxy ketone 2 by cyclization.
Scheme 1. Retrosynthetic analysis for indolizidine (+)-223A.
Results and Discussion
Compound (–)-4 was easily prepared as outlined in
Scheme 2. Ethyl 6-chlorohex-2-ynoate (5, obtained from
commercially available chloropentyne) was condensed with
(S)-1-phenylethylamine to provide (S,E)-ethyl 2-[1-(1-phen-
ylethyl)pyrrolidin-2-ylidene]acetate [(–)-6][8] in 96% isolated
yield. Catalytic hydrogenation of this compound over PtO2
afforded the expected amino ester as a 90:10 mixture of
diastereomers in 96% isolated yield. Major diastereomer
(–)-7 was isolated in 60% yield after treatment of the mix-
ture with picric acid, subsequent crystallization of the re-
sulting salt, and conversion back to the free base. Com-
pound (–)-7 was alkylated by reaction with LDA followed
by the addition of ethyl iodide to afford pyrrolidine (–)-4 as
a single diastereomer in 92% isolated yield. On the basis of
previously obtained results, the absolute configuration of
(–)-4 was assigned to be (2R,2ЈR).[7]
For initial studies we focused our attention on the con-
struction of a racemic pyrrolidine substituted by an appro-
priate functionalized side chain through an aldolization re-
action, followed by intramolecular cyclization into an
indolizidine. Required aldehyde 3, N-protected by either a
benzyl or a tert-butyl carbamate moiety, was prepared from
pyrrolidine ester 8.[9] The latter was subjected to alkylation
to provide compound 9 in 98% isolated yield.[10] Reduction
of the ester moiety of 9 with lithium aluminum hydride
(LAH) led to alcohol 10 in 96% isolated yield. A debenz-
[a] UPMC Univ Paris 06, Sorbonne Universités,
Institut Parisien de Chimie Moléculaire (UMR CNRS 7201),
4 place Jussieu, C. 229, 75005 Paris, France
Fax: +33-1-44277360
E-mail: virginie.mansuy@upmc.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101530.
Eur. J. Org. Chem. 2012, 463–465
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
463

M. Fellah, G. Lhommet, V. Mouriès-Mansuy
SHORT COMMUNICATION
to the major diastereomer through 13C NMR spectroscopic
analysis of the mixture (see the Supporting Information for
spectroscopic data).[5d,11]
Figure 1. Structure of (Ϯ)-6-epi-indolizidine 223A.
Scheme 2. Synthesis of (R)-ethyl 2-{(R)-1-[(S)-1-phenylethyl]pyrrol-
idin-2-yl}butanoate (4).
To obtain the correct stereochemistry at C6 we thus de-
cided to reduce the alkene moiety of 13 in a first step. We
so examined the selective hydrogenation of the double bond
of N-Boc-pyrrolidine 13b. Numerous attempts did not pro-
duce the expected pyrrolidine. Catalytic hydrogenation (Pd/
C, PtO2, Pt/C), LAH, or metal-catalyzed silicon hydride re-
ylation/carbamation sequence gave either N-Cbz- (12a) or
N-Boc-pyrrolidines (12b) in 82 and 87% isolated yield,
respectively. Swern oxidation of these pyrrolidines provided
corresponding aldehydes 3a (90%) and 3b (97%). These al-
dehydes were then subjected to aldolization with heptan-4-
one. Expected aldol products 2a and 2b were thus obtained
as mixtures of diastereomers in good yield. At this stage,
we first envisaged to transform these compounds into the
corresponding enones by dehydration in acidic medium
[para-toluenesulfonic acid (PTSA) in refluxing toluene].
Pyrrolidines 13a and 13b were thus obtained in similar
yields (92%) and in the same 65:35 ratio of E/Z dia-
stereomers (Scheme 3).
ductions (PdCl2/Et3SiH,[12] IPr-CuCl-tBuONa-PMHS[13]
)
led only to the recovery or decomposition of the starting
material.
In view of these results, we decided to synthesize the
indolizidine core by an alternative route involving the oxi-
dation of the alcohol function before the cyclization step.
Racemic pyrrolidine 2b was therefore submitted to Swern
oxidation providing pyrrolidine 14 as a complex mixture of
diastereomers in 80% isolated yield. Acid-induced removal
of the Boc protecting group and in situ cyclization afforded
tetrahydroindolizinone 15 as a single diastereomer in 95%
isolated yield. Treatment of 15 with various hydrides
(NaBH4, NaBH3CN under neutral or acidic conditions)
only led to intractable mixtures. By contrast, catalytic hy-
drogenation[14] of 15 in the presence of Pd/C (10%) under
100 bar of H2 led to a mixture of indolizidinone 16 and
indolizidinol 17 in a 28:72 ratio. Swern oxidation of this
crude mixture afforded 16 in 78% isolated yield, whereas
reduction by sodium borohydride led to 17 in 74% isolated
yield (Scheme 4). The cis hydrogenation of the double bond
of 15 enabled the formation of the two last stereogenic cen-
ters on indolizidine 223A.
Scheme 3.
With racemic, chain-extended pyrrolidines 13a and 13b
in hand, we turned our attention to the construction of the
indolizidine skeleton. We began our study by catalytic hy-
drogenation of N-Cbz-protected pyrrolidine 13a over Pd/C.
Reduction of the double bond with concomitant N-depro-
tection and intramolecular reductive amination afforded a
75:25 inseparable mixture of indolizidine diastereomers
Scheme 4.
Compounds 16 and 17 were previously involved as inter-
along with material that was not characterized. The config- mediates in the synthesis of indolizidine (–)-223A described
uration of 6-epi-indolizidine 223A (Figure 1) was ascribed by Davis and co-workers.[5c] Therefore, this result allowed
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Eur. J. Org. Chem. 2012, 463–465

Total Synthesis of Indolizidine (+)-223A
us to envisage this route for the formal synthesis of indolizi- indolizidine (+)-223A following the Davis’ route from
dine (+)-223A starting from chiral pyrrolidine 4. Reduction alcohol (+)-17. Finally, expected indolizidine (+)-223A was
of the ester function of pyrrolidine 4 with LAH afforded obtained in 10% yield over 14 steps starting from readily
the corresponding pyrrolidine alcohol (–)-18 in 92% iso- available ethyl 6-chlorohex-2-ynoate (5). Application of this
lated yield. Hydrogenolysis of (–)-18 under a hydrogen at- flexible route to the synthesis of more complex alkaloids is
mosphere in the presence of 10% Pd/C delivered (+)-11 in currently under investigation.
quantitative yield. According to the sequence previously de-
scribed from racemic pyrrolidine 11, chiral indolizidinol
(+)-17 was obtained from N-Boc-protected pyrrolidine (+)-
12b as a single diastereomer (5S,6R, Ͼ98%de) in 42% over-
all yield in seven steps (as described in Schemes 3 and 4).
The spectroscopic data of (+)-17 corresponded to those de-
scribed in the literature. Nevertheless, the sign of the optical
rotation was identical to that reported by Davis and co-
workers for its enantiomer.[15] To secure the absolute config-
uration of the stereogenic centers formed during our se-
quence, we decided to complete the synthesis of (+)-223A
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, characterization data, copies of the
NMR spectra.
Acknowledgments
We thank Dr. Marie-Claude Fargeau-Bellassoued for fruitful dis-
cussions during this work.
[1] J. W. Daly, H. M. Garraffo, T. F. Spande, Alkaloids: Chemical
and Biological Perspectives (Ed.: S. W. Pelletier), 1st ed., Perga-
mon, Oxford, U.K., 1999, vol. 13, ch. 1, pp. 1–161.
from (+)-17 according to Davis’ route for indolizidine (–)- [2] H. M. Garraffo, P. Jain, T. F. Spande, J. W. Daly, J. Nat. Prod.
223A. Conversion of alcohol (+)-17 into the corresponding
phenylthionocarbonate (+)-19 (Scheme 5) followed by radi-
1997, 60, 2–5.
[3] N. Toyooka, A. Fukutome, H. Nemoto, J. W. Daly, T. F.
Spande, H. M. Garraffo, T. Kaneko, Org. Lett. 2002, 4, 1715–
cal deoxygenation led to expected (+)-223A in 45% isolated
1717.
yield.[16] The spectroscopic data and the positive optical ro-
[4] H. Tsuneki, Y. You, N. Toyooka, S. Kagawa, S. Kobayashi, T.
tation value of (+)-223A·DCl {[α]2D0 = +38.0 (c = 0.26,
Sasaoka, H. Nemoto, I. Kimura, J. A. Dani, Mol. Pharmacol.
2004, 66, 1061–1069.
[5] a) X. Pu, D. Ma, J. Org. Chem. 2003, 68, 4400–4405; b) W.
CHCl3)} were in complete agreement with those reported
in the literature for the opposite enantiomer[3,5] {[α]D20
=
Zhu, D. Dong, X. Pu, D. Ma, Org. Lett. 2005, 7, 705–708; c)
F. A. Davis, B. Yang, J. Am. Chem. Soc. 2005, 127, 8398–8407;
d) P. Ghosh, W. R. Judd, T. Ribelin, J. Aubé, Org. Lett. 2009,
11, 4140–4142.
–36.8 (c = 0.45, CHCl3)}.[5c] This result confirmed our con-
figurational assignments for compounds 16 and 17.
[6] a) M. Fellah, M. Santarem, G. Lhommet, V. Mouriès-Mansuy,
J. Org. Chem. 2010, 75, 7803–7808; b) M. Santarem, C. Van-
ucci-Bacqué, G. Lhommet, J. Org. Chem. 2008, 73, 6466–6469;
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soued, G. Lhommet, Tetrahedron 2005, 61, 7774–7782.
[7] A. Bardou, J.-P. Célérier, G. Lhommet, Tetrahedron Lett. 1997,
38, 8507–8510.
[8] a) T. Nikiforov, S. Stanchev, B. Milenkov, V. Dimitrov, Hetero-
cycles 1986, 24, 1825–1829; b) O. David, M.-C. Fargeau-Bellas-
soued, G. Lhommet, Tetrahedron Lett. 2002, 43, 3471–3474.
[9] Compound 8 was prepared in two steps from methyl 6-chlo-
rohex-2-ynoate and benzylamine in 82% overall yield. Spectro-
scopic data of 8 corresponded to those reported: Y. J. Jeon, C.-
P. Lee, P. S. Mariano, J. Am. Chem. Soc. 1991, 113, 8847–8863.
[10] Compound 9 was obtained from 8 in 98% isolated yield under
the same conditions as those used for the obtention of 4
(Scheme 2).
Scheme 5.
[11] J. M. Harris, A. Padwa, J. Org. Chem. 2003, 68, 4371–4381.
[12] M. Mirza-Aghayan, R. Boukherroub, M. Bolourtchian, M.
Rahimifard, J. Organomet. Chem. 2007, 692, 5113–5116.
[13] V. Jurkauskas, J. P. Sadighi, S. L. Buchwald, Org. Lett. 2003, 5,
2417–2420.
Conclusions
In summary, we reported an efficient total formal synthe-
sis of indolizidine (+)-223A, the opposite enantiomer of
natural (–)-223A. Our strategy was based on three major
steps: chain elongation by aldolization, formation of a bi-
cyclic enone by cyclization, and stereocontrolled hydrogen-
ation of the obtained tetrahydroindolizinone. To determi-
nate the absolute configuration of the stereogenic centers
created during our synthesis, we completed the synthesis of
[14] This reaction was sluggish when it was performed under 1 bar
of hydrogen and required an increase in the pressure up to
100 bar to force it to completion.
[15] 17 [α]2D0 = +59.1 (c = 0.69, CHCl3), ref.[5c] [α]2D0 = +56.5 (c =
0.69, CHCl3).
[16] To confirm our results, we performed the total synthesis of (+)-
223A with a unique batch of compound (–)-6.
Received: October 19, 2011
Published Online: December 7, 2011
Eur. J. Org. Chem. 2012, 463–465
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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