A straightforward entry to 7-azabicyclo[2.2.1]heptane-l-carbonitriles in the synthesis of novel epibatidine analogues

Article abstract of DOI:10.1002/ejoc.200901277

This paper presents the synthesis of epibatidine analogues by a straightforward one-pot method for the synthesis of 7azabicyclo[2.2.1]heptane-1- carbonitriles, starting from cyclohexanones bearing a leaving group at the 4-position. In situ imine formation

Full text of DOI:10.1002/ejoc.200901277

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200901277
A Straightforward Entry to 7-Azabicyclo[2.2.1]heptane-1-carbonitriles in the
Synthesis of Novel Epibatidine Analogues
Thomas Heugebaert,[a] Joke Van Hevele,[a] Wouter Couck,[a] Vicky Bruggeman,[a]
Sarah Van der Jeught,[a] Kurt Masschelein,[a] and Christian V. Stevens*[a]
Keywords: Cyanides / Cyclization / Natural products / Neurological agents / Nitrogen heterocycles
This paper presents the synthesis of epibatidine analogues
by a straightforward one-pot method for the synthesis of 7-
azabicyclo[2.2.1]heptane-1-carbonitriles, starting from cyclo-
hexanones bearing a leaving group at the 4-position. In situ
imine formation, followed by reversible cyanide addition, al-
lows complete conversion of 4-(mesyloxy)cyclohexanone to
the bicyclic core. Elaboration of the introduced nitrile func-
tionality and deprotection of the tertiary amine leads to five
new epibatidine analogues.
Introduction
Results and Discussion
The alkaloid epibatidine (1) was first isolated in 1974 by
Daly and Myers from the skin of the Ecuadorian frog Epi-
pedobates tricolor.[1] Its remarkable analgesic potency was
shortly afterwards shown to be about 200-fold higher than
that of morphine. Unfortunately, however, the toxicity of
epibatidine is too high for any human therapeutic use. The
unveiling of epibatidine’s mode of action has sparked the
interest of many medicinal chemists: epibatidine is a highly
potent nicotinic acetylcholine receptor agonist.[2] This
membrane-bound pentameric ion channel has been associ-
ated with many neurological disorders such as Alzheimer’s
Disease, Parkinson, neuropathic pain and schizophrenia.[3]
For each of these, there is a shift in the prevalence of the
different nicotinic acetylcholine receptor subtypes. Cur-
rently, the search for more subtype-selective and as such less
toxic epibatidine analogues continues in an effort to provide
treatment for these neurological diseases. Many analogues
have been synthesized, among which epiboxidine[4] (2) and
ABT-594[5] (3) are the most successful examples (Figure 1).
In spite of the high activity in this field, few analogues
bearing the pyridyl moiety at the 1-position of the bicycle
have been reported.[6] We therefore devised a retrosynthetic
approach to compounds 4 and 5 (Scheme 1). To preserve
epibatidine’s highly important internitrogen distance of ap-
proximately 5.5 Å, an extra carbon atom is introduced be-
tween the pyridine substituent and the azabicycle.
Scheme 1. Retrosynthetic approach.
The major problem for the construction of the bicyclic
ring by intramolecular ring closure starting from cycloalk-
anones 8 relates to the fact that the nucleophilic function-
ality and the leaving group in compound 7 need to be posi-
tioned in a trans relationship. Mostly this requires a number
of steps including protection, deprotection strategies or dif-
ficult separation steps in order to avoid that 50% of the
material cannot ring-close. Even in the best enantioselective
syntheses, 25% of starting material is lost due to this
cis/trans selectivity issue.[7]
Figure 1. Epibatidine and analogues.
[a] Research Group SynBioC, Department of Organic Chemistry,
Faculty of Bioscience Engineering, Ghent University,
Coupure links 653, 9000 Ghent, Belgium
Fax: +32-92646243
E-mail: Chris.Stevens@UGent.be
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901277.
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C. V. Stevens et al.
SHORT COMMUNICATION
Scheme 2. Precursor synthesis.
Therefore, the reversible dynamic addition of cyanide to of the compound by flash chromatography lowers the reac-
an imine function, developed in our laboratory, is very ad- tion yield considerably. The polar compounds 6 have a high
vantageous to convert all starting material into the ring- affinity for silica gel, leading to product loss during the pu-
closed product.[8] In this paper, we wish to disclose this rification. Seven 7-azabicyclo[2.2.1]heptane-1-carbonitriles
strategy for the construction of the 7-azabicyclo[2.2.1]hep- could be obtained in reasonable yield after purification.
tane-1-carbonitrile skeleton (from a cyclohexanone precur-
sor) as the key step in the synthesis of epibatidine ana- antiospecific entry to 1-cyano-azabicycles, in which 4-chlo-
logues. rocyclohexanone (12) was treated with an adduct of phen-
Starting from the commercially available protected cyclo- ethylamine and acetone cyanohydrine (13) (Scheme 4).[9]
hexanone 9, the oxo function was reduced with lithium alu- This chloro ketone, however, was shown to isomerize
Our method is closely related to a recently reported en-
minium hydride in good yield, followed by the activation of through a ring contraction to 3-(chloromethyl)cyclopentan-
the hydroxy function as the corresponding mesylate. After one, thus yielding a mixture of 7-azabicyclo[2.2.1]heptane
deprotection of acetal 11 in 86% yield, the precursor for 14 (23%) and 2-azabicyclo[2.2.1]heptanes 15 and 16 (17%)
ring closure was obtained in three steps (Scheme 2).
after ring closure. The use of mesyloxy ketone 8 eliminates
The key step involves the one-pot procedure of imine for- this side reaction and allows the quantitative formation of
mation, addition of cyanide to the imine function, followed the desired 7-azabicycles, increasing the isolated yields con-
by intramolecular nucleophilic substitution (Scheme 3). siderably. Furthermore, the extra step of adduct formation
This could be performed by treating the mesyloxy ketone is eliminated.
8 with 1 equiv. of primary amine, 2 equiv. of triethylamine
Compounds 6a and 6b were selected for the further syn-
(1 equiv. is needed to trap the methylsulfonic acid after ring thesis of epibatidine analogues considering the higher yield
closure) and 2 equiv. of acetone cyanohydrine, the cyanide and the possibility of oxidative and reductive removal of
source, in a closed vessel in methanol for 2 d. The conver- the N-protecting groups.
sion of the mesyloxy ketone 8 to the 7-azabicyclo[2.2.1]hex-
In a first attempt to obtain compound 4, nitrile 6b was
ane-1-carbonitrile (6) is complete; however, the purification submitted to a partial reduction by means of DiBAl
(Scheme 5). Infrared analysis showed that the reduction to
the aldimine proceeded cleanly. Surprisingly, however, the
obtained aldimine was quite resistant to hydrolysis. Even
after careful screening of hydrolysis conditions, chromatog-
raphy was needed to obtain pure aldehyde 17 in 49%
yield.[10] The subsequent addition of the 2-chloropyridyl
group was straightforward and provided racemic alcohol 18
in excellent yields. To avoid the troublesome preparation of
aldehyde 17, the nucleophilic addition of the pyridyl group
was also performed on nitrile 6b. After hydrolysis of the
resulting imine (which proceeded smoothly in this case),
ketone 19 was obtained in 73% yield. Deprotection of these
two substrates 18 and 19 would lead to the proposed epibat-
idine analogue 4. However, in both cases the removal of the
protective benzyl group proved to be extremely difficult. In
Scheme 3. Synthesis of bicycles 6a–6g through reversible cyanide
addition.
Scheme 4. Literature synthesis of 7-azabicyclo[2.2.1]heptanes.
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Synthesis of Novel Epibatidine Analogues
Scheme 5. Synthesis and attempted deprotection of 18 and 19.
order to retain the chlorine group, a mild non-reductive de- alogue 24 could be recovered after crystallization from di-
protection by using ethyl chloroformate was evaluated. Af- ethyl ether (Scheme 7). In a similar fashion, ketone 25 was
ter 16 h at 55 °C, only starting material could be recovered. obtained from 6a in 51% yield. Oxidative deprotection de-
Switching to reductive deprotection, all attempted methods livers epibatidine analogue 26.
yielded a mixture of starting material, dechlorinated, and in
A second series of analogues could be obtained from 6b
some cases dehydroxylated degradation products. Because in three steps. Reduction of 6b to amine 27 by means of
neither dechlorination, nor dehydroxylation nor deben- LiAlH4 was performed quantitatively. Next, the pyridyl
zylation was obtained cleanly, this pathway was not further group was introduced by means of a Pd-catalyzed cross
pursued.
coupling. Standard Buchwald conditions[12] were used to
Subsequently, the troublesome benzyl deprotection was test three different ligands: binap, dppp and di-tert-butyl{1-
circumvented by switching to oxidative deprotection strate- [2-(dicyclohexylphosphanyl)ferrocenyl]ethyl}phosphane
gies. The use of a p-MeO-benzyl protecting group allowed (dfep)[13] provided a conversion of 48, 12 and 10%, respec-
for the synthesis of 21, which could be deprotected by treat- tively. By using binap as ligand, several conditions were
ment with ammonium cerium nitrate (CAN) (Scheme 6).
tested (Table 1). The best results were obtained by using
In the absence of a chlorine substituent, which is in fact 1 equiv. of 2-bromopyridine, 1.4 equiv. of NaOtBu and
not essential to epibatidine’s biological activity,[11] both the 4 mol-% of (dba)3Pd2CHCl3 catalyst.
oxidative and reductive deprotection strategies were suc-
Ligand requirements for this reaction proved to be highly
cessful. Ketone 23 was synthesized from 7-azabicyclo[2.2.1]- dependent upon the substrate. By using 2-bromopyridine
heptane-1-carbonitrile 6b in 48% yield. Refluxing with am- the ligand of choice was binap, giving a conversion of 95%
monium formate in the presence of Pd/C led to complete over 2 d. However, when the same reaction conditions were
removal of the benzyl group within 4 h, and epibatidine an- applied by using 3-bromopyridine, no conversion could be
Scheme 6. Synthesis of 22.
Scheme 7. Synthesis of 24 and 26.
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C. V. Stevens et al.
SHORT COMMUNICATION
Table 1. Optimization of Pd-catalyzed cross-coupling by using binap.
2-Chloropyridine
2-Bromopyridine
1 equiv. amine
1.2 equiv. amine
1.2 equiv. amine
0.8 equiv. amine
2% cat.
4% cat.
56%
62%
59%
77%
91%
95%
85%
N/A[a]
[a] N/A: not available.
detected. Again, all three ligands were tested showing dfep
to be the most efficient. A conversion of 55% could be ob-
tained, and secondary amine 29 was isolated in 47% yield
after column chromatography.
Acknowledgments
Financial support for this research from the Research Fund Ghent
University (BOF, Bijzonder Onderzoeksfonds Universiteit Gent;
K. M.) and the Fund for Scientific Research Flanders (FWO
Vlaanderen; S. V. J. and T. H.) is gratefully acknowledged.
Removal of the protective benzyl group was performed
by refluxing in methanol by using ammonium formate as
reducing agent (Scheme 8). Compound 5 was obtained after
1 h of reflux, whereas for compound 30 a period of 2 h was
necessary to bring the reaction to completion. The low
yields for 30 are attributed to its troublesome purification.
Compound 5 could easily be separated from the excess am-
monium formate by dissolution in dry diethyl ether. Com-
pound 30, however, in spite of its highly similar structure,
does not dissolve in diethyl ether. Eventually, this product
was obtained after preparative TLC with reasonable recov-
ery by using a highly polar mixture of chloroform/triethyl-
amine (93:7).
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Conclusions
We have described the preparation of five new epibatidine ana-
logues by using a short and efficient synthesis of 7-azabicyclo-
[2.2.1]heptane-1-carbonitriles.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, spectroscopic data and copies of 1H
and 13C NMR spectra.
Received: November 7, 2009
Published Online: January 19, 2010
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Eur. J. Org. Chem. 2010, 1017–1020