A practical synthesis of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane

Article abstract of DOI:10.1016/j.tetlet.2013.07.092

The rigid piperazine homologue 2,5-diazabicyclo[2.2.1]heptane (DBH) finds extensive application in medicinal chemistry and pharmaceutical research, but access to this scaffold is non-trivial. This letter details a concise synthetic sequence that gives ready access to DBH on gram scale. The route features a Staudinger reduction of an azide to facilitate a transannular cyclisation.

Full text of DOI:10.1016/j.tetlet.2013.07.092

Tetrahedron Letters 54 (2013) 5345–5347
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A practical synthesis of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane
Corinne Beinat a, Samuel D. Banister a,b, Christopher S. P. McErlean a, Michael Kassiou a,b,c,
⇑
a School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia
b Brain and Mind Research Institute, Sydney, NSW 2050, Australia
c Discipline of Medical Radiation Sciences, The University of Sydney, Sydney, NSW 2006, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
The rigid piperazine homologue 2,5-diazabicyclo[2.2.1]heptane (DBH) finds extensive application in
medicinal chemistry and pharmaceutical research, but access to this scaffold is non-trivial. This letter
details a concise synthetic sequence that gives ready access to DBH on gram scale. The route features
a Staudinger reduction of an azide to facilitate a transannular cyclisation
Received 6 June 2013
Revised 9 July 2013
Accepted 19 July 2013
Available online 27 July 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
2,5-Diazabicyclo[2.2.1]heptane
Amines
Transannular cyclisation
Heterocycles
Nicotinic acetylcholine receptors
The importance of nitrogen-containing heterocycles in the field
of drug discovery is highlighted by the fact that ‘heterocycle syn-
thesis’ is the second most frequently performed reaction in phar-
maceutical laboratories, and the synthesis of N-heterocycles
accounts for more than 89% of those reactions.1 One such N-het-
erocycle that has found extensive use in medicinal chemistry is
the rigid piperazine homologue (1S,4S)-2,5-diazabicyclo[2.2.1]hep-
tane (DBH, 1, Fig. 1). Some prominent examples of DBH-containing
molecules are shown in Figure 1 and include the fluoroquinolone
antibiotic danofloxacin (2). (2) is a bacterial DNA-gyrase inhibitor
that is widely administered in veterinary medicine as its mesylate
salt.2,3 Researchers at Abbott Laboratories have used the DBH ster-
a DBH unit, exemplified by 5, as potent and selective histone
deacetylase 1 (HDAC) inhibitors with antitumor activities.9
Beyond medicinal chemistry, N,N0-dimethyl-DBH (6) has found
application as a potential ligand for asymmetric catalysis.10 Mel-
gar-Fernández and co-workers reported the synthesis and evalua-
tion of various DBH-containing molecules as potential ligands for
the enantioselective addition of diethylzinc to aldehydes as well
as chiral Lewis acid activators for asymmetric Diels–Alder
reactions.
The utility of this compound has inspired several groups to de-
vise synthetic strategies to 1, but none of these are entirely satis-
factory, due to problems with reproducibility and scalability. For
instance, the first synthesis of 1, reported by Portoghese and Mik-
eoisomers to develop a series of potent
tylcholine receptor (nAChR) ligands, such as pyridazine 3, which
exhibit selectivity over the
4b2 subtype.4 Interestingly, 3 was
shown to bind at the 7 nAChR with 23 times greater affinity than
the corresponding (1R,4R) enantiomer, highlighting the specificity
of this rigid piperazine homologue. Selective activation of 7 nAC-
a7 neuronal nicotinic ace-
hail in 1966 (Scheme 1), started from trans-4-hydroxy-L-proline
a
a
a
hRs represents a potential therapeutic strategy for the treatment of
cognitive deficits associated with Alzheimer’s disease (AD) and
schizophrenia, and several a7 nAChR agonists have entered clinical
trials.5–7 Similarly, chemists at Wyeth have used DBH to confer po-
tency and selectivity to a series of pyrazolopyrimidine type I B-Raf
kinase inhibitors including 4, which displays effective antiprolifer-
ative activity against multiple tumor cell lines.8 Researchers at
Merck have investigated 6-aminonicotinamides that incorporate
⇑
Corresponding author. Tel.: +61 2 9351 2745; fax: +61 2 9351 3329.
E-mail address: michael.kassiou@sydney.edu.au (M. Kassiou).
Figure 1. (1S,4S)-2,5-Diazabicyclo[2.2.1]heptane (DBH, 1), and several bioactive
DBH-containing molecules.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.092

5346
C. Beinat et al. / Tetrahedron Letters 54 (2013) 5345–5347
HO
HO
HO
HO
TsO
4 steps
CO2H
Bn
N
b,c.
a.
OH
OTs
CO2H
CO2Me
HCl
14 HCl
100%
91%
N
H
7
N
H
N
N
H
7
N
N
Ts
Ts
10 g scale
12 g scale
Boc
9
8
•
15
low yield
< 30%
d,e. 53%
7 g scale
MsO
HO
Bn
g.
HN
HN
•
f.
•
2 steps
high pressure
N
2HI
2HCl
NH
N3
N3
N
NH
71%
N
Boc
95%
N
Boc
1 g scale
Boc
3 g scale
•
18
1 2HCl
•
17
10 2HI
16
Scheme 1. Portoghese’s synthesis of DBH (1).
Scheme 3. Gram-scale synthesis of protected DBH 18. Reagents and conditions: (a)
MeOH, HCl; (b) (Boc)2O, Et3N; (c) LiBH4; (d) TsCl, py; (e) TMSN3, TBAF; (f) MsCl,
Et3N; (g) PPh3, H2O.
(7). After several functional group manipulations, compound 8 was
generated and subjected to a double displacement reaction with
benzylamine to give 9.11 Although that key cyclisation step was
accomplished smoothly, unveiling 1 proved highly problematic.
Concomitant removal of the toluenesulfonamide and benzyl pro-
tecting groups of 9 using sodium in liquid ammonia delivered
the desired product 1 in low yield (<30%), a stepwise deprotection
regime was therefore investigated. Subjecting 8 to the action of
concentrated hydroiodic acid and red phosphorus in refluxing ace-
tic acid gave the expected benzylated product as its dihydroiodide
salt (10ꢀ2HI) in 76% yield. However, 10 proved resistant to subse-
quent hydrogenolysis, necessitating conversion into the corre-
sponding dihydrochloride, which underwent hydrogenolysis to
give 1 as its dihydrochloride salt (1ꢀ2HCl). Attempts to remove
the benzyl protecting group of 9 prior to sulfonamide cleavage
gave poor yields of the corresponding product.
range of conditions never gave yields exceeding 29% (see Supple-
mentary data). Furthermore, formation of the ditosylate 11 was it-
self problematic, and substantial quantities of the product arising
from monotosylation of the primary hydroxyl group were always
obtained.
Our ongoing interest in the medicinal chemistry of DBH deriv-
atives for use as
a
7 nAChR agonists16 prompted the development
of a new synthetic route to 1, starting from inexpensive 7
(Scheme 3).
Methyl esterification of 7 quantitatively afforded 14 as its
hydrochloride salt. Protection of the amino group of 14 as its
tert-butyl carbamate followed by chemoselective reduction of the
ester, gave diol 15 in excellent yield over two steps, without the
need for chromatography. Selective tosylation of the primary hy-
droxyl group of 15 followed by azide displacement gave 16. The
secondary hydroxyl group of 16 was then activated by treatment
with mesyl chloride to give 17. Staudinger reduction of azide 17 re-
sulted in spontaneous transannular cyclisation as the liberated pri-
mary amino group displaced the mesyl group, furnishing the
mono-protected DBH building block 18 in excellent yield. (An in-
creased yield of 97% was achieved when conducting the cyclisation
on a 200 mg scale). Although this route employs trimethylsilyl
azide, it avoids high reaction temperatures and pressures, and
has the advantage of short reaction times. Trimethylsilyl azide is
generally considered a safer alternative to sodium azide and has
been used in the one pot multigram synthesis of the antiviral agent
(ꢁ)-oseltamivir (TamifluÒ).17 The great advantage of this sequence
is that each operation can be performed on multigram scale, pro-
viding synthetically useful quantities of 18 in short order. Com-
pound 18 is amenable to storage at 0 °C for at least 3 months
prior to use.
Other synthetic efforts towards 1 have built upon Portoghese’s
general strategy with attempted improvements of individual steps,
and/or alternative protecting group strategies.12,13 Jordis and co-
workers reported the synthesis of 1 from 7 using an N-Boc protect-
ing group strategy (Scheme 2). Boc-protected distosylate 11 was
synthesized in moderate yield over 4 steps from 7.14 The key dou-
ble displacement cyclisation of 11 with benzylamine to give 12
was reported to proceed under autoclave conditions of high tem-
perature and pressure, and in refluxing toluene. However, subse-
quent attempts by Yakovlev and co-workers to replicate the
double displacement cyclisation of 11 gave DBH 1 in low yield.
The major reaction product was identified as 13 (Scheme 2),15
a
finding confirmed in our laboratory. Yakovlev and co-workers pro-
posed that under the forcing reaction conditions, thermolysis of
the Boc protecting group gave an intermediate that underwent
dimerization to 13.15 By lowering the reaction temperature to
40–45 °C (in benzene), compound 12 was obtained in good yield
(78%), albeit after 45 days. Additionally, the 20 °C difference in
melting point range reported for compound 12 by the two research
groups pointed to a discrepancy in the synthetic outcome of the
reactions. In our hands, attempts to transform 11 into 12 under a
Finally, unlike previously reported DBH building blocks, re-
moval of the carbamate protecting group is facile (Scheme 4).
Treatment of 18 with hydrochloric acid gave 1 as its dihydrochlo-
ride salt in quantitative yield.
In summary, our need for gram quantities of rigid piperazine
homologue 1, has led us to develop a highly practical, gram-scale
synthesis of the mono-protected DBH compound 18. This molecule
is available as a single stereoisomer, is amenable to synthetic
manipulation, and can be stored for extended periods. This new
•
2HCl
a
HN
HN
NH
N
100%
Boc
•
1 2HCl
18
Scheme 2. Refined syntheses of DBH (1).
Scheme 4. Carbamate deprotection of 18. Reagents: (a) MeOH, HCl.

C. Beinat et al. / Tetrahedron Letters 54 (2013) 5345–5347
5347
5. Martin, L. F.; Freedman, R. Int. Rev. Neurobiol. 2007, 78, 225–246.
synthetic strategy should enable expanded application of this rigid
piperazine homologue.
6. Berman, J. A.; Talmage, D. A.; Role, L. W. Int. Rev. Neurobiol. 2007, 78, 193–223.
7. Mazurov, A.; Hauser, T.; Miller, C. H. Curr. Med. Chem. 2006, 13, 1567–1584.
8. Wang, X.; Berger, D. M.; Salaski, E. J.; Torres, N.; Hu, Y.; Levin, J. I.; Powell, D.;
Wojciechowicz, D.; Collins, K.; Frommer, E. Bioorg. Med. Chem. Lett. 2009, 19,
6571–6574.
Acknowledgments
9. Hamblett, C. L.; Methot, J. L.; Mampreian, D. M.; Sloman, D. L.; Stanton, M. G.;
Kral, A. M.; Fleming, J. C.; Cruz, J. C.; Chenard, M.; Ozerova, N.; Hitz, A. M.;
Wang, H.; Deshmukh, S. V.; Nazef, N.; Harsch, A.; Hughes, B.; Dahlberg, W. K.;
Szewczak, A. A.; Middleton, R. E.; Mosley, R. T.; Secrist, J. P.; Miller, T. A. Bioorg.
Med. Chem. Lett. 2007, 17, 5300–5309.
10. Melgar-Fernández, R.; González-Olvera, R.; Olivares-Romero, J. L.; González-
López, V.; Romero-Ponce, L.; Del Refugio Ramírez-Zárate, M.; Demare, P.; Regla,
I.; Juaristi, E. Eur. J. Org. Chem. 2008, 655–672.
11. Portoghese, P. S.; Mikhail, A. A. J. Org. Chem. 1966, 31, 1059–1062.
12. Braish, T. F.; Fox, D. E. J. Org. Chem. 1990, 55, 1684–1687.
13. Jordis, U.; Sauter, F.; Siddiqi, S. M.; Küenburg, B.; Bhattacharya, K. Synthesis
1990, 925–930.
C.B. acknowledges receipt of an Australian Postgraduate Award
and a John A. Lamberton Research Scholarship.
Supplementary data
Supplementary data associated with this article can be found, in
the
online
version,
at
http://dx.doi.org/10.1016/
j.tetlet.2013.07.092.
14. Baker, G. L.; Fritschel, S. J.; Stille, J. R.; Stille, J. K. J. Org. Chem. 1981, 46, 2954–
2960.
References and notes
15. Yakovlev, M. E.; Lobanov, P. S.; Potekhin, A. A. Chem. Heterocycl. Compd. 2000,
36, 429–431.
16. Beinat, C.; Banister, S. D.; Van Prehn, S.; Doddareddy, M. R.; Hibbs, D.; Sako, M.;
Chebib, M.; Tran, T.; Al-Muhtasib, N.; Xiao, Y.; Kassiou, M. Bioorg. Med. Chem.
Lett. 2012, 22, 2380–2384.
1. Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011, 54, 3451–3479.
2. Giles, C. J.; Magonigle, R. A.; Grimshaw, W. T. R.; Tanner, A. C.; Risk, J. E.; Lynch,
M. J.; Rice, J. R. J. Vet. Pharmacol. Ther. 1991, 14, 400–410.
3. Braish, T. F. Org. Process Res. Dev. 2009, 13, 336–340.
4. Li, T.; Bunnelle, W. H.; Ryther, K. B.; Anderson, D. J.; Malysz, J.; Helfrich, R.;
Grønlien, J. H.; Håkerud, M.; Peters, D.; Schrimpf, M. R.; Gopalakrishnan, M.; Ji,
J. Bioorg. Med. Chem. Lett. 2010, 20, 3636–3639.
17. Ishikawa, H.; Bondzic, B. P.; Hayashi, Y. Eur. J. Org. Chem. 2011, 6020–6031.