A simple enantioselective route to functionalized indolizidines: Synthesis of (+)-ipalbidine and (+)-antofine

Article abstract of DOI:10.1002/ejoc.201100125

An efficient route to functionalized indolizidines from an enantiomerically enriched γ-nitro ketone is described. The nitro ketone is obtained by an organocatalytic, enantioselective ketone-nitro alkene Michael addition. Oxidative ring expansion of the ni

Full text of DOI:10.1002/ejoc.201100125

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100125
A Simple Enantioselective Route to Functionalized Indolizidines: Synthesis of
(+)-Ipalbidine and (+)-Antofine
Sunil V. Pansare,*[a] Rajinikanth Lingampally,[a] and Rajendar Dyapa[a]
Keywords: Organocatalysis / Michael addition / Alkaloids / Ipalbidine / Antofine
An efficient route to functionalized indolizidines from an en-
antiomerically enriched γ-nitro ketone is described. The nitro
ketone is obtained by an organocatalytic, enantioselective
ketone-nitro alkene Michael addition. Oxidative ring expan-
sion of the nitro ketone and subsequent methanolysis pro-
vides a 8-nitro-4-oxooctanoate. This is stereoselectively
transformed to the key, functionalized indolizidine interme-
diate which is readily converted to (+)-ipalbidine and (+)-an-
tofine.
Our interest in indolizidines stems from our studies on
the organocatalytic synthesis of γ-nitro ketones from cyclic
ketones and 2-nitrovinylarenes via an enamine-based
Michael addition reaction.[14] This reaction has been exten-
sively studied and the development of new catalysts for the
process continues at a remarkable pace.[15]
Undoubtedly, the full potential of the organocatalytic
ketone–nitro alkene Michael reaction will be realized only
when the γ-nitro ketone products are utilized in target ori-
ented synthesis, but this has been relatively unexplored.[16]
We therefore chose to examine the application of γ-nitro
ketone 3 (Scheme 1) in the synthesis of ipalbidine and anto-
fine.
Introduction
The indolizidine motif is a prominent structural unit in
numerous alkaloids[1] and also constitutes a major class of
glycosidase inhibitors.[2] In addition, several indolizidines
have an interesting biological profile which includes anti-
bacterial, antiviral, antitumor and antidiabetic properties.[3]
Aryl-substituted indolizidines are also of interest; either as
bioactive natural products[4] or as peptidomimetics.[5] Ac-
cordingly, the synthesis of arylindolizidines continues to be
intensely investigated and general synthetic strategies to-
ward aryl-fused[6a–6c] or aryl-substituted indolizidines[6d–6h]
as well as other, functionalized indolizidines have been re-
ported.[7] Herein, we describe a concise and stereoselective
synthesis of the arylindolizidine alkaloid (+)-ipalbidine (1,
Figure 1),[8] a non-addictive analgesic[9] and oxygen free-
radical scavenger,[10] and the phenanthroindolizidine alka-
loid (+)-antofine (2),[11] the enantiomer of which has potent
anticancer[12] and antiviral acitvity.[13] The syntheses of 1
and 2 are based on a readily available γ-nitro ketone precur-
sor.
Results and Discussion
Our studies began with the synthesis of the appropriate
γ-nitro ketone starting material for (+)-ipalbidine (1).[8] The
organocatalytic Michael addition of cyclohexane-1,4-dione
monoethylene ketal and 4-methoxy-β-nitrostyrene em-
ploying our triamine salt catalyzed protocol[14a] provided
the nitro ketone 3 in good yield and stereoselectivity (er =
96:4, dr Ͼ19:1). Baeyer–Villiger oxidation of 3 provided the
lactone 4 in excellent yield (98%). Methanolysis of 4 and
subsequent hydrolysis of the ketal generated the highly
functionalized octanoate 5 (Scheme 1, 88% over two steps)
that has all the required carbon atoms for the indolizidine
framework.
Partial reduction of the nitro group in 5 provided the
nitrone 6 (Scheme 2) which was anticipated to be subject to
stereoselective reduction due to a 1,3 disposition with the
secondary alcohol stereocenter. Treatment of 6 with l-Se-
lectride® or LAH at –78 °C resulted in reduction of the es-
ter. Reduction with NaBH4 was stereorandom and also led
to reduction of the ester, indicating the need for a milder
reducing agent. Accordingly, we examined Me4NBH-
Figure 1. Arylindolizidine alkaloids synthesized in this study.
[a] Department of Chemistry, Memorial University,
St. John’s, Newfoundland, A1B 3X7, Canada
Fax: +1-709-864-3702
E-mail: spansare@mun.ca
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100125.
Eur. J. Org. Chem. 2011, 2235–2238
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2235

S. V. Pansare, R. Lingampally, R. Dyapa
SHORT COMMUNICATION
1H NMR spectroscopic data of 8 with that of the race-
mate[8f] established its relative stereochemistry, thereby con-
firming the stereochemistry of the reduction of 6 to 7. Oxi-
dation of 8 (DMSO, pyridine·SO3) furnished the amino
ketone 9.[8b–8f] Notably, the conversion of 3 to 9 (9 steps,
18% overall yield) can be conducted without the purifica-
tion of any intermediates.
The conversion of 9 to (+)-ipalbidine (1) was achieved
by employing a modification[8c] of the Govindachari pro-
cedure[8d] described for the racemate. Thus, reaction of 9
with methyllithium and subsequent dehydration of the re-
sulting tertiary alcohol provided ipalbidine methyl ether.
This was demethylated with boron tribromide to provide
(+)-ipalbidine (1, Scheme 3).
Scheme 1. Synthesis of a functionalized octanoate intermediate.
Scheme 3. Conversion of 9 to (+)-ipalbidine.
(OAc)3, which gratifyingly provided the hydroxylamine 7
(83%) as a single diastereomer, presumably via a hydroxy-
directed reduction (Scheme 2). At this stage, 7 was assigned
the shown stereochemistry which was assumed to derive
The synthesis of (+)-antofine was also completed from
from an intramolecular, hydroxy-directed reduction of 6.[17] the lactam 7a that was obtained as an intermediate in the
Reduction of the N–O bond in 7 was achieved with indium preparation of the ketone 9. Oxidation of 7a (DMSO,
metal to provide a mixture of the amino ester and the corre- pyridine·SO3) provided the ketolactam 10 (Scheme 4). Con-
sponding indolizidinone (7a) resulting from cyclization of version of 10 to the enol triflate followed by a Suzuki–Mi-
the amino ester. This product mixture was treated with DI- yaura coupling[18] with (3,4-dimethoxyphenyl)boronic acid
PEA in refluxing isopropyl alcohol to complete the lactam- furnished the lactam 11, which was reduced to secoantofine
ization. Reduction of the lactam (LAH) provided the indol- 12. Oxidative biaryl coupling in 12 provided (+)-antofine
izidine 8 (54% over 3 steps, Scheme 2). Comparison of the (2, 77%).[11]
Scheme 2. Conversion of 5 to amino ketone 9.
2236
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2235–2238

Enantioselective Route to Functionalized Indolizidines
P. Prasanna, V. C. Shekhar, A. Venkateswarlu, S. Rajagopal, R.
Ajaykumar, D. S. Deevi, N. V. S. R. Mamidi, R. Rajagopalan,
Bioorg. Med. Chem. Lett. 2003, 13, 1679; f) W. Zhu, G. Cai,
D. Ma, Org. Lett. 2005, 7, 5545; g) R. T. Yu, T. Rovis, J. Am.
Chem. Soc. 2006, 128, 2782; h) A. Boto, L. De, G. Yolanda, A.
Juan, R. Hernandez, Eur. J. Org. Chem. 2005, 3461.
[7]
For reviews, see: a) A. Brandi, F. Cardona, S. Cicchi, F. M.
Cordero, A. Goti, Chem. Eur. J. 2009, 15, 7808; b) S. Perreault,
T. Rovis, Chem. Soc. Rev. 2009, 38, 3149; c) B. B. Toure, D. G.
Hall, Chem. Rev. 2009, 109, 4439; d) for a thematic series on
indolizidines and quinolizidines, see: Beilstein, J. Org. Chem.
2007, 3, no. 27; e) C. W. Jefford, Curr. Org. Chem. 2000, 4,
205; f) S. Rajeswari, S. Chandrasekharan, T. R. Govindachari,
Heterocycles 1987, 25, 659. Selected recent reports: g) A. Iza,
L. Carrillo, J. L. Vicario, D. Badia, E. Reyes, J. Martinez, Org.
Biomol. Chem. 2010, 8, 2238; h) N. Sirisha, R. Raghunathan,
Tetrahedron Lett. 2010, 51, 2515; i) D. Yang, G. C. Micalizio,
J. Am. Chem. Soc. 2009, 131, 17548; j) R. Affani, S. Comesse,
A. Daich, L. Hamon, C. Kadouri-Puchot, Heterocycles 2009,
78, 2193; k) G. Barbe, G. Pelletier, A. B. Charette, Org. Lett.
2009, 11, 3398; l) M. Katoh, H. Mizutani, T. Honda, Heterocy-
cles 2006, 69, 193.
Scheme 4. Conversion of 10 to (+)-antofine.
Conclusions
[8]
[9]
For a synthesis of (+)-ipalbidine, see: a) T. Honda, H. Namiki,
H. Nagase, H. Mizutani, Tetrahedron Lett. 2003, 44, 3035; b)
L. Zhujin, L. Renrong, C. Qi, H. Hai, Acta Chim. Sinica 1985,
43, 992; c) M. J. Niphakis, G. I. Georg, J. Org. Chem. 2010,
75, 6019. Selected syntheses of racemic ipalbidine: ; d) T. R.
Govindachari, A. R. Sidhaye, N. Viswanathan, Tetrahedron
1970, 26, 3829; e) H. Iida, Y. Watanabe, C. Kibayashi, J. Chem.
Soc. Perkin Trans. 1 1985, 261; f) C. W. Jefford, T. Kubota, A.
Zeslona, Helv. Chim. Acta 1986, 69, 2048.
In conclusion, an organocatalytic Michael-addition-
based enantioselective synthesis of the indolizidine frame-
work was developed. This approach has potential applica-
tions in the synthesis of congeners and analogs of the target
alkaloids[1a] by a) variation in the ketone, nitrostyrene and
the aryl cross-coupling partner, and b) embellishment of the
propanoate side chain in 7. The utility of our strategy is
augmented by the large number of methods available for
J. Zhou, G. Zhao, W. Jin, W. Zheng, Z. Chi, Chin. Acad. Sci.,
Shanghai 1988, 9, 107.
[10]
[11]
the stereoselective synthesis of
a
variety of γ-nitro
X. Chen, Y. Chu, Zhongguo Yaolixue Tongbao 1998, 14, 243.
For synthesis of (+)-antofine, see: a) Ref.[8c]; b) Z. Wang, Z. Li,
K. Wang, Q. Wang, Eur. J. Org. Chem. 2010, 2, 292; c) L. Faber,
W. Wiegrebe, Helv. Chim. Acta 1973, 56, 2882. For synthesis
of (–)-antofine, see: d) M. Cui, H. Song, A. Feng, Z. Wang, Q.
Wang, J. Org. Chem. 2010, 75, 7018; e) X. Yang, Q. Shi, K. F.
Bastow, K.-H. Lee, Org. Lett. 2010, 12, 1416; f) A. Fuerstner,
J. W. Kennedy, Chem. Eur. J. 2006, 12, 7398; g) S. Kim, T. Lee,
E. Lee, J. Lee, G.-J. Fan, S. K. Lee, D. Kim, J. Org. Chem.
2004, 69, 3144; h) S. Kim, J. Lee, T. Lee, H.-G. Park, D. Kim,
Org. Lett. 2003, 5, 2703. For selected syntheses of racemic an-
tofine, see: i) L. M. Ambrosini, T. A. Cernak, T. H. Lambert,
Tetrahedron 2010, 66, 4882; j) K.-L. Wang, M.-Y. Lue, Q.-M.
Wang, R.-Q. Huang, Tetrahedron 2008, 64, 7504; k) C.-R. Su,
A. G. Damu, P.-C. Chiang, K. F. Bastow, S. L. Morris-
Natschke, K.-H. Lee, T.-S. Wu, Bioorg. Med. Chem. 2008, 16,
6233; l) S. Kim, Y. M. Lee, J. Lee, T. Lee, Y. Fu, Y. Song, J.
Cho, D. Kim, J. Org. Chem. 2007, 72, 4886; m) A. Camacho-
Davila, J. W. Herndon, J. Org. Chem. 2006, 71, 6682; n) S. Ya-
mashita, N. Kurono, H. Senboku, M. Tokuda, K. Orito, Eur.
J. Org. Chem. 2009, 8, 1173.
a) H.-Y. Min, H.-J. Chung, E.-H. Kim, S. Kim, E.-J. Park,
S. K. Lee, Biochem. Pharmacol. 2010, 80, 1356; b) W. Gao,
A. P. C. Chen, C. H. Leung, E. A. Gullen, A. Fürstner, Q. Shi,
L. Wei, K. H. Lee, Y. C. Cheng, Bioorg. Med. Chem. Lett. 2008,
18, 704.
K. Wang, B. Su, Z. Wang, M. Wu, Z. Li, Y. Hu, Z. Fan, N.
Mi, Q. Wang, J. Agric. Food Chem. 2010, 58, 2703.
a) S. V. Pansare, K. Pandya, J. Am. Chem. Soc. 2006, 128, 9624;
b) S. V. Pansare, R. L. Kirby, Tetrahedron 2009, 65, 4557.
For reviews, see: a) H. Kotsuki, H. Ikishima, A. Okuyama,
Heterocycles 2008, 75, 757; b) S. Sulzer-Mosse, A. Alexakis,
Chem. Commun. 2007, 30, 3123; c) D. Enders, A. Seki, Eur. J.
Org. Chem. 2002, 1877; d) For a review on enamine catalysis,
see: S. Mukherjee, J. W. Yang, S. Hoffmann, B. List, Chem.
Rev. 2007, 107, 5471. For selected recent reports, see: e) B. Ni,
Q. Zhang, K. Dhungana, A. D. Headley, Org. Lett. 2009, 11,
ketones.[19] We are currently investigating the application of
this methodology in the synthesis of other indolizidines,
quinolizidines and functionalized piperidines.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and spectroscopic data for all com-
pounds.
Acknowledgments
Financial support from the Natural Sciences and Engineering Re-
search Council of Canada and the Canada Foundation for Innova-
tion is gratefully acknowledged.
[1] a) J. P. Michael, Nat. Prod. Rep. 2008, 25, 139, and previous
reviews on indolizidine and quinolizidine alkaloids in the
series; b) J. W. Daly, T. F. Spande, H. M. Garraffo, J. Nat. Prod.
2005, 68,1556.
[12]
[2] a) N. Asano, R. J. Nash, R. J. Molyneux, G. W. J. Fleet, Tetra-
hedron: Asymmetry 2000, 11, 1645; b) Iminosugars as Glycosi-
dase Inhibitors (Ed.: A. E. Stütz), Wiley-VCH, Weinheim, Ger-
many, 1999; c) A. A. Watson, G. W. J. Fleet, N. Asano, R. J.
Molyneux, R. J. Nash, Phytochemistry 2001, 56, 265.
[3] a) C.-H. Wong, R. L. Halcomb, Y. Ichibaka, T. Kajimoto, An-
gew. Chem. 1995, 107, 569; b) P. Compain, O. R. Martin, Curr.
Top. Med. Chem. 2003, 3, 541.
[13]
[14]
[15]
[4] S. R. Chemler, Curr. Bioact. Compd. 2009, 5, 2.
[5] J. Cluzeau, W. D. Lubell, J. Org. Chem. 2004, 69, 1504.
[6] For reviews on phenanthro-indolizidine alkaloids, see: a) Z. Li,
Z. Jin, R. Huang, Synthesis 2001, 2365; b) I. Bick, C. Ralph,
W. Sinchai, Alkaloids 1981, 19, 193; c) T. R. Govindachari, N.
Vishwanathan, Heterocycles 1978, 11, 587. For selected recent
reports, see: d) M. G. Banwell, M. O. Sydnes, Aust. J. Chem.
2004, 57, 537; e) V. M. Sharma, K. V. Adi Seshu, C. V. Krishna,
Eur. J. Org. Chem. 2011, 2235–2238
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2237

S. V. Pansare, R. Lingampally, R. Dyapa
SHORT COMMUNICATION
1041; f) T. Mandal, C.-G. Zhao, Angew. Chem. 2008, 120, 7828;
Angew. Chem. Int. Ed. 2008, 47, 7714; g) D. Almasi, D. A.
Alonso, E. Gomez-Benoga, Y. Nagel, C. Najera, Eur. J. Org.
Chem. 2007, 2328.
P. Kotame, C.-W. Tsai, J.-H. Liao, Org. Lett. 2010, 12, 776; h)
S. V. Pansare, R. Lingampally, R. L. Kirby, Org. Lett. 2010, 12,
556; i) B.-C. Hong, R. Y. Nimje, M.-F. Wu, A. A. Sadani, Eur.
J. Org. Chem. 2008, 1149.
[16] For reports on the application of organocatalytic Michael ad-
dition products in total synthesis, see: a) S. Zhu, S. Yu, Y.
Wang, D. Ma, Angew. Chem. Int. Ed. 2010, 49, 4656; b) H.
Ishikawa, T. Suzuki, Y. Hayashi, Angew. Chem. 2009, 121,
[17] D. A. Evans, K. T. Chapman, E. A. Carriera, J. Am. Chem.
Soc. 1988, 110, 3560.
[18] a) T. Oh-e, N. Miyaura, A. Suzuki, J. Org. Chem. 1993, 58,
2201; b) N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457.
1330; Angew. Chem. Int. Ed. 2009, 48, 1304; c) J. Pavol, D. M. [19] a) M. V. Gill, E. Roman, J. Sorrano, Trends Org. Chem. 2001,
Cockfield, D. J. Dixon, J. Am. Chem. Soc. 2009, 131, 16632; d)
P. Elsner, H. Jiang, J. B. Nielsen, F. Pasi, K. A. Jorgensen,
Chem. Commun. 2008, 5827; e) O. Andrey, A. Vidonne, A.
Alexakis, Tetrahedron Lett. 2003, 44, 7901; f) P. S. Hynes, P. A.
Stupple, D. J. Dixon, Org. Lett. 2008, 10, 1389; g) B.-C. Hong,
9, 17; b) Organocatalytic Enantioselective Conjugate Addition
Reactions (Eds.: J. L. Vicario, D. Badia, L. Carrillo, E. Reyes),
Royal Society, Cambridge, UK, 2010, chapter 2.
Received: January 28, 2011
Published Online: February 18, 2011
2238
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2235–2238