Enantioselective syntheses of both enantiomers of noranabasamine

Article abstract of DOI:10.1021/ol9002288

Both the R and S enantiomers of the amphibian alkaloid noranabasamine were prepared in >30% overall yield with 80% ee and 86% ee, respectively. An enantioselective iridium-catalyzed N-heterocyclization reaction with either (R)-or (S)-1-phenylethylamine an

Full text of DOI:10.1021/ol9002288

ORGANIC
LETTERS
2009
Vol. 11, No. 7
1579-1582
Enantioselective Syntheses of Both
Enantiomers of Noranabasamine
Lei Miao, Stassi C. DiMaggio, Hong Shu, and Mark L. Trudell*
Department of Chemistry, UniVersity of New Orleans, New Orleans, Louisiana 70148
mtrudell@uno.edu
Received February 2, 2009
ABSTRACT
Both the R and S enantiomers of the amphibian alkaloid noranabasamine were prepared in >30% overall yield with 80% ee and 86% ee,
respectively. An enantioselective iridium-catalyzed N-heterocyclization reaction with either (R)- or (S)-1-phenylethylamine and 1-(5-methoxypyridin-
3-yl)-1,5-pentanediol was employed to generate the 2-(pyridin-3-yl)-piperidine ring system in 69-72% yield.
The pharmacology of amphibian alkaloids has generated
significant interest in these molecules over the past decade.
Many of these compounds have aided in the elucidation of
biological mechanisms and the development of lead com-
pounds for the treatment of a wide variety of pathologies
mediated by nicotinic acetylcholine receptors (nAChRs) and
corresponding ion channels.1 However, the paucity of useful
quantities of isolated amphibian alkaloids has led to a flurry
of synthetic activity to make these compounds available for
biological study. While many of the amphibian alkaloids
possess unique chemical structures,1 the similarity between
noranabasamine (1) isolated from the columbian poison dart
frog Phyllobates terribilis2 and plant alkaloids isolated from
the tobacco species Nicotian tabacum [e.g., nicotine (2),
anabasine (3)],3 as well as the central asian shrub Anabasis
aphylla [anabasamine (4)],4 is noteworthy. The plant-derived
piperidine alkaloids 2 and 3 are widely known to elicit their
pharmacological effects via nAChRs.5 Anabasamine (4) has
been much less studied but has been reported to inhibit
acetylcholine esterase and exhibit anti-inflammatory activity.6
Figure 1. Noranabasamine (1) and related plant alkaloids.
Our interests in the development of new pharmacotherapies
for nAChR mediated disorders and disease states7 prompted
an investigation into the synthesis of the enantiomers of
noranabasamine (1). It was our aim to develop an efficient
synthesis of 1, that would provide sufficient quantities for
(1) For a review see: (a) Daly, J. W.; Spande, T. F.; Garraffo, H. M. J.
Nat. Prod. 2005, 68, 1556. (b) Daly, J. W. J. Med. Chem. 2003, 46, 445.
(c) Gomes, A.; Giri, B.; Saha, A.; Mirsha, R.; Dasgupta, S. C.; Debnath,
A.; Gomes, A. Indian J. Exp. Biol. 2007, 45, 579. (d) Neuronal Nicotinic
Receptors: Pharmacology and Therapeutic Opportunities; Arneric, S. P.,
Brioni, J. D., Eds.; Wiley-Liss Inc.: New York, 1999.
(2) Tokuyama, T.; Daly, J. W. Tetrahedron 1983, 39, 41.
(3) Leete, E.; Mueller, M. E. J. Am. Chem. Soc. 1982, 104, 6440.
(4) Lovkova, M. Y.; Nurimov, E. IsV. Akad. Nauk. SSSR Ser. Biol. 1978,
545.
(7) (a) Cheng, J.; Izenwasser, S.; Zhang, C.; Zhang, S.; Wade, D.;
Trudell, M. L. Bioorg. Med. Chem. Lett. 2004, 14, 1775. (b) Nishiyama,
T.; Gyermek, L.; Trudell, M. L.; Hanaoka, K. Eur. J. Pharmacol. 2003,
470, 27. (c) Cheng, J.; Zhang, C.; Stevens, E. D.; Izenwasser, S.; Wade,
D.; Chen, S.; Paul, D.; Trudell, M. L. J. Med. Chem. 2002, 45, 3041. (d)
Cheng, J.; Izenwasser, S.; Wade, D.; Trudell, M. L. Med. Chem. Res. 2001,
10, 356.
(5) Crooks, P. A.; Dwoskin, L. P. Biochem. Pharmacol. 1997, 54, 743.
(6) (a) Tilyabaev, Z.; Abduvakhabov, A. A. Chem. Nat. Compd. 1998,
34, 295. (b) Tilyabaev, Z.; Aabd Mukhamedzhanova, Kh. S. Dokl. Akad.
Nauk UzSSR 1984, 8, 45. (c) Mukhamedzhanova, Kh. S. Dokl. Akad. Nauk
UzSSR 1983, 7, 47.
10.1021/ol9002288 CCC: $40.75
Published on Web 03/02/2009
2009 American Chemical Society

biological evaluation. In addition, it was envisaged that the
preparation of both antipodes of 1 would aid in the
confirmation of the absolute configuration of the natural
product which has yet to be unequivocally established.4
Herein we describe the first enantioselective syntheses of
both enantiomeric forms of noranabasamine.
of 7 with n-butyllithium followed by addition of δ-valero-
lactone to the lithiated pyridine solution afforded the ketone
8 in 98% yield. The ring-opening reaction proceeded
regioselectively to give 8 without further nucleophilic
addition to the carbonyl. The carbonyl group of 8 was then
reduced to the hydroxyl moiety with BH3·SMe2 to furnish
the diol 9 in 88% yield.
With the diol 9 in hand, our attention focused on the
enantioselective construction of the piperidine ring using
N-heterocyclization chemistry (Scheme 3). The diol 9 was
Our retrosynthetic analysis illustrated in Scheme 1 focused
on the disconnection of the terminal pyridyl group (ring C)
Scheme 1. Retrosynthetic Analysis of Noranabasamine (1)
Scheme 3. Diastereoselective N-Heterocyclization
to afford a 2-substituted piperidine fragment 5 as our initial
target. There are a variety methods for the enantioselective
construction of 2-substituted piperidines,8 but the iridium-
complex-catalyzed N-heterocyclization of primary amines
with diols recently reported by Yamaguchi and co-workers
seemed to be exceptionally well suited for the construction
of the AB-ring system of 5 and has not been explored for
the preparation of natural products.9 A diastereoselective
N-heterocyclization with the appropriate chiral primary amine
was envisaged for introduction of the single stereogenic
carbon atom of the noranabasamine skeleton. The approach
not only was deemed straightforward but also offered the
flexibility for the preparation of various derivatives and
analogues if structure-activity studies were warranted in the
future.
heated at 110 °C in toluene with (R)-1-phenylethylamine10
in the presence of a catalytic amount (1.5 mol%) of
(Cp*IrCl2)2 in a sealed reaction tube. The N-heterocyclization
then proceeded diastereoselectively to provide the 2-substi-
tuted piperidine 10ab in 72% (10a:10b, dr, 95:5). The
diastereoisomers were easily separated by column chroma-
tography. The 2-substituted piperidine 11ab was prepared
in similar fashion from diol 9 using (S)-1-phenylethylamine
(Scheme 3). The piperidine 11ab was obtained in 69% yield
with a diastereomeric ratio of 11a:11b equal to 95:5. On
the basis of the work of Fujita and co-workers, we initially
assigned the stereochemistry at C2 of 10a as possessing an
S-configuration and 11a as having an R-configuration.
Presumably N-heterocyclization proceeds through the
formation of various imine and enamine intermediates.9 To
ensure ourselves that epimerization/racemization of the two
stereogenic centers had not occurred during the ring-
generating process, it would be necessary to establish the
enantiomeric integrity of the piperidine ring. Crooks and co-
As illustrated in Scheme 2, the required diol 9 was
prepared from 5-bromo-2-methoxypyridine (7). Treatment
Scheme 2
1580
Org. Lett., Vol. 11, No. 7, 2009

workers recently reported a procedure for the determination
of the enantiopurity of anabasine and related alkaloids using
NMR spectroscopy and the chiral shift reagent 1,1′-binaph-
thyl-2,2′-diylphosphoric acid (BNPPA).11 With this technique
in mind, it was envisaged that the issue of the enantiopurity
of the piperidine ring system would be more easily resolved
with 1, due to the similar secondary amine structure of
noranabasamine to the anabasine.
Scheme 5. Synthesis of Noranabasamine
With the piperidine ring system 10a in hand, our attention
was directed toward completing the synthesis of norana-
basamine (1). On the basis of the initial stereochemical
assignment of 1,2 it was assumed that the N-heterocyclization
product 10a possessed the correct stereochemistry at C2.
However, the conversion of 10a into 1 would require the
manipulation of the methoxy group into a more suitable
moiety to facilitate an aryl cross-coupling reaction. To this
end, treatment of 10a with POCl3 furnished the 5-chloro-
pyridin-3-yl derivative 12 in 92% yield (Scheme 4). The
Scheme 4
For the final step, the Suzuki-Miyaura coupling conditions
developed by Fu and co-workers were utilized.14 These
conditions for the coupling of 3-pyridineboronic acid with
15 were found to be superior to other methods because of
the ease of the workup and purification steps. This afforded
the (S)-noranabasamine (-)-1 in 84% yield, [R]25D ) -32.9
(c 0.33, CH3OH). The NMR data of (-)-1 was identical to
the reported data of the isolated material, and the optical
rotation was also levorotatory.15 The synthesis of the (R)-
noranabasamine (+)-1 {[R]25D +34.6 (c 0.5, CH3OH) from
17 provided additional support of a 2S-configuration of the
natural antipode of noranabasamine.
Suzuki-Miyaura coupling of 12 with 3-pyridineboronic acid
could be achieved using several different types of palladium/
ligand systems.12 Initially we employed the catalytic system
reported by Nolan and co-workers for the coupling se-
quence.13 This furnished the tricyclic compound 13 in 65%
isolated yield. Unfortunately, despite numerous attempts and
various conditions to remove the N-phenylethyl auxiliary
group, none were successful. The increased basicity of the
molecule and the additional steric hindrance around the
nitrogen atom completely shut down the hydrogenolysis of
the N-1-phenylethyl group. High pressure, high temperature,
and extended reaction times either resulted in recovery of
unreacted starting material or decomposition and formation
of intractable mixtures.
At this point we sought to establish the enantiopurity of
the piperidine ring systems. As expected use of the chiral
(8) (a) Hande, S. M.; Kawai, N.; Uenishi, J. J. Org. Chem. 2009, 74,
244. (b) Spangenberg, T.; Breit, B.; Mann, A. Org. Lett. 2009, 11, 261. (c)
Castro, A.; Ram´ırez, J.; Jua´rez, J.; Tera´n, J. L.; Orea, L.; Galindo, A.;
Gnecco, D. Heterocycles 2007, 71, 2699. (d) Amat, M.; Bassas, O.; Llor,
N.; Canto´, M.; Pere´z, M.; Molins, E.; Bosch, J. Chem. Eur. J. 2006, 12,
7872. (e) Ayers, J. T.; Xu, Rui; Dwoskin, L. P.; Crooks, P. A. AAPS J.
2005, 7, E752. (f) Amat, M.; Canto´, M.; Llor, N.; Bosch, J. Chem. Commun.
2002, 5, 526. (g) Felpin, F.; Girard, S.; Vo-Thanh, G.; Robins, R. J.;
Villieras, J.; Lebreton, J. J. Org. Chem. 2001, 66, 6305. (h) Felpin, F.;
Vo-Thanh, G.; Robins, R. J.; Villieras, J.; Lebreton, J. Synlett 2000, 11,
1646. (i) Hattori, K.; Yamamoto, H. Tetrahedron 1993, 49, 1749–1760. (j)
Kunz, H.; Pfrengle, W. Angew. Chem., Int. Ed. Engl. 1989, 101, 1041. (k)
Pfrengle, W.; Kunz, H. J. Org. Chem. 1989, 54, 4261. (l) Giovannini, A.;
Savoia, D.; Umani-Ronchi, A. J. Org. Chem. 1989, 54, 228.
(9) Fujita, K.; Fujii, T.; Yamaguchi, R. Org. Lett. 2004, 6, 3525.
(10) Commercially available from Alfa Aesar Chemical Co. with
enantiopurity of 99% ee. The (S)-enantiomer was available in 99.5% ee.
(11) Ravard, A.; Crooks, P. A. Chirality 1996, 8, 295.
To avoid the problematic hydrogenolysis of 13, an
alternative sequence of reactions was devised to prepare 1
(Scheme 5). The methoxy derivative 10a was subjected to
hydrogenolysis conditions to furnish 14 and concomitant
treatment with POCl3 provided the chloro analogue 15 in
56% yield over the two-step procedure. This sequence was
also applied to 11a and furnished the corresponding 17 in
60% yield.
(12) For a review, see: Li, J. J.; Gribble, G. W. Palladium in Heterocyclic
Chemistry; Pergamon: Amsterdam, 2000; pp 191-197.
(13) Viciu, M. S.; Germaneau, R. F.; Navarro-Fernandez, O.; Stevens,
E. D.; Nolan, S. P. Organometallics 2002, 21, 5470.
(14) Kudo, N.; Perseghini, M.; Fu, G. C. Angew. Chem., Int. Ed. 2006,
45, 1282.
(15) The specific rotation for the natural material was reported as [R]D
-14.4 (CH3OH). See ref 2.
Org. Lett., Vol. 11, No. 7, 2009
1581

shift reagent BNPPA afforded baseline resolution of the
proton signals for H2, H6, and H2′′ of both enantiomers of
1.16 From the NMR study it was quite clear that the
enantiopurity of (-)-1 was greater than 86% ee, and that of
(+)-1 was greater than 80% ee. From these results it can be
inferred that the diastereoselective N-heterocyclization reac-
tions that furnished 10a and 11a (Scheme 3) are highly
enantioselective (>80% ee) and consistent with previous
studies.9
In summary, we have shown that the iridium-catalyzed
N-heterocyclization reaction is a facile method for the
efficient and enantioselective construction of 2-(pyridin-3-
yl)-piperidine alkaloids. This reaction was a key step in the
first total synthesis of both enantiomers of the amphibian
alkaloid noranabasamine (1) in greater than 30% overall yield
and has allowed us to establish the absolute configuration
of the natural product as levorotatory. Additional studies with
regard to the scope and limitations of this reaction system
are ongoing and will be reported in due course. The
biological evaluation of both enantiomeric forms of norana-
basamine is currently under investigation and will be reported
elsewhere.
Acknowledgment. We thank Prof. Edwin Vedejs at the
University of Michigan for the assistance provided to Mr.
Lei Miao and we thank Prof. Gregory Fu at MIT for the
assistance provided to Ms. Hong Shu during the aftermath
of Hurricane Katrina. This research was funded by the
National Institute on Drug Abuse (DA11528) and the
University of New Orleans.
Supporting Information Available: Full experimental
details and characterization data of all synthetic products.
The material is available free of charge via the Internet at
http://pubs.acs.org.
(16) See Supporting Information for details and spectra.
OL9002288
1582
Org. Lett., Vol. 11, No. 7, 2009