Synthesis of 6,8-diazabicyclo[3.2.2]nonanes: Conformationally restricted piperazine derivatives

Article abstract of DOI:10.1021/ol990393a

(equation presented) Starting with the proteinogenic amino acid (S)-glutamate, a general method for the synthesis of 3-(piperazin-2-yl)propionic acid esters 7 with various substituents at N-4 of the piperazine ring system is presented. An intramolecular ester condensation of 7 is the key step in the formation of the 6,8-diazabicyclo[3.2.2]nonane derivatives 8-10, which are of interest as conformationally restricted piperazines.

Full text of DOI:10.1021/ol990393a

ORGANIC
LETTERS
2000
Vol. 2, No. 9
1177-1179
Synthesis of
6,8-Diazabicyclo[3.2.2]nonanes:
Conformationally Restricted Piperazine
Derivatives
Manuela Weigl and Bernhard Wu1nsch*
Pharmazeutisches Institut der UniVersita¨t Freiburg i. Br., Hermann-Herder-Strasse 9,
79104 Freiburg i. Br., Germany
wuensch@sun2.ruf.uni-freiburg.de
Received December 9, 1999
ABSTRACT
Starting with the proteinogenic amino acid (S)-glutamate, a general method for the synthesis of 3-(piperazin-2-yl)propionic acid esters 7 with
various substituents at N-4 of the piperazine ring system is presented. An intramolecular ester condensation of 7 is the key step in the
formation of the 6,8-diazabicyclo[3.2.2]nonane derivatives 8−10, which are of interest as conformationally restricted piperazines.
Several compounds with considerable biological activity
belong to the piperazine substance class. The piperazine
derivatives 1-3 depicted in Figure 1 represent three ex-
To study structure-activity relationships, bridges may be
introduced into conformationally flexible receptor ligands.
The enhanced rigidity may result in an increased receptor
affinity, giving insight into the biologically active conforma-
tion.1,4,5
Hence, our interest has been focused on the synthesis of
6,8-diazabicyclo[3.2.2]nonane derivatives (e.g., 10), which
are regarded as conformationally constrained piperazine
derivatives. Suitable nitrogen protective groups (or substi-
tuents) should enable the synthesis of bicyclic analogues of
the biologically active piperazines 1-3. Moreover, bicyclic
piperazinones 10 might be employed for the synthesis of aza
analogues and homologues of bicyclic alkaloids (e.g., epi-
batidine, anatoxine, or cocaine) and antibiotics (e.g., bicy-
clomycine6).
In the literature two procedures for the synthesis of 6,8-
diazabicyclo[3.2.2]nonanes are described: First, 2-fold in-
Figure 1. Piperazines with very high receptor affinities.
(3) Mills, S. G.; Wu, M. T.; MacCoss, M.; Budhu, R. J.; Dorn, C. P.;
Cascieri, M. A.; Sadowski, S.; Strader, C. D.; Greenlee, W. J. Bioorg. Med.
Chem. Lett. 1993, 3, 2707-2712.
amples, which display very high affinity for σ,1κ,2 and
neurokinin3 (NK1) receptors, respectively.
(4) Silverman, R. B. Medizinische Chemie, VCH Verlagsgesellschaft
mbH, Weinheim 1995, pp 12-14 and 86-90.
(1) deCosta, B. R.; He, X.; Linders, J. T. M.; Dominguez, C.; Gu, Z.
Q.; Williams, W.; Bowen, W. D. J. Med. Chem. 1993, 36, 2311-2320.
(2) Naylor, A.; Judd, D. B.; Lloyd, J. E.; Scopes, D. I. C.; Hayes, A. G.;
Birch, P. J. J. Med. Chem. 1993, 36, 2075-2083.
(5) Costantino, G.; Macchiarulo, A.; Pellicciari, R. J. Med. Chem. 1999,
42, 2816-2827.
(6) Williams, R. M.; Armstrong, R. W.; Dung, K.-S. J. Med. Chem. 1985,
28, 733.
10.1021/ol990393a CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/31/2000

tramolecular aminolysis of 2,6-diaminopimelic acid deriva-
tives leads to racemic 6,8-diazabicyclo[3.2.2]nonanes without
further substituents in the propano bridge.7 The second
approach starts with a racemic homoserine derivative using
an intramolecular enolate epoxide cyclization as the key step,
which occurs with unfavorable regioselectivity.8
Therefore, we designed a novel synthesis of the chiral,
nonracemic diazabicyclo[3.2.2]nonane ring system starting
with the proteinogenic amino acid (S)-glutamate (Scheme
1). Esterification followed by N-monobenzylation9 afforded
Having afforded the 3-(piperazinyl)propionic acid esters
7, we next investigated the intramolecular ester condensation.
However, all attempts to obtain cyclization products from
esters 7 under equilibrating conditions (NaOCH3 in methanol,
NaH in toluene) failed. Obviously, an anion to shift the
equilibrium toward the cyclization products could not be
formed due to the low acidity of the bridgehead proton in
position 1 between the carbonyl moieties of 10. This
explanation is supported by the facile ring opening of 10a
with nucleophilic bases (e.g., methanolate) to yield 3-(pip-
erazinyl)propionic acid ester 7a.
Finally, the ester condensation of propionic acid esters 7
succeeded by using the nonnucleophilic base lithium hexa-
methyldisilazane (LiHMDS) and trapping of the primary
cyclization products with trimethylsilyl chloride to furnish
mixed acetals 8 (Scheme 2). By means of methanol and
Scheme 1. Synthesis of 3-(Piperazin-2-yl)propionic Acid
Esters
Scheme 2. Synthesis of 6,8-Diazabicyclo[3.2.2]nonanes
monobenzylamino diester 4, which was acylated with chlo-
roacetyl chloride to yield chloroacetamide 5.10 Reaction of
chloroacetyl derivative 5 with primary amines 6 led to SN2
substitution of the chloro substituent and, subsequently,
intramolecular aminolysis to furnish piperazinediones 7.11
The employment of exactly 1 equiv of the primary amines
6 is crucial for high yields of 7, because an excess of primary
amines would react with the second ester moiety. Thus, we
have developed a facile, high-yielding access to 3-(dioxo-
piperazin-2-yl)propionic acid esters 7. In comparison with
reported procedures,12-14 the presented chiral-pool synthesis
furnishes chiral nonracemic piperazines 7 with various
substituents at both piperazine nitrogen atoms.
p-toluenesulfonic acid, mixed acetal 8a was transformed into
dimethyl acetal 9a. Careful hydrolysis of both, mixed acetals
8 and dimethyl acetal 9a, provided bicyclic ketones 10 in
good yields (82-85% with regard to 7). The structure of
ketones 10 is unequivocally proven by 1H NMR spectroscopy
(singulet at 4.2 ppm caused by 1-H) and IR spectroscopy
(valence bond at 1728 cm-1 for the ketone carbonyl group).
(7) (a) Eastwood, F. W.; Gunawardana, D.; Wernert, G. T. Aust. J. Chem.
1982, 35, 2289-2298. (b) Kiely, J. S.; Hutt, M. P.; Culbertson, T. P.; Bucsh,
R. A.; Worth, D. F.; Lesheski, L. E.; Goglotti, R. D.; Sesnie, J. C.; Solomon,
M.; Mich, T. F. J. Med. Chem. 1991, 34, 656-663.
(8) Williams, R. M.; Maruyama, L. K. J. Org. Chem. 1987, 52, 4044-
4047.
(9) Quitt, P.; Hellerbach, J.; Vogler, K. HelV. Chim. Acta 1963, 46, 327-
333.
(10) All new compounds gave satisfactory spectroscopic and analytical
data.
The enantiomeric purity of the bicyclic products was
shown by NaBH4 reduction of ketone 10a to afford diaste-
reoselectively the (R)-configurated alcohol, which was
subsequently acylated with (R)- and (S)-Mosher’s acid
1
chloride to yield diastereomeric esters. H as well as 19F
NMR spectra of the diastereomeric Mosher acid esters
revealed a diastereomeric ratio of greater than 98:2. There-
fore, racemization at the C-5 position during the base-induced
cyclization can be ruled out.15
(11) An analogous piperazine synthesis is described by: Soukara, S.;
Wu¨nsch, B. Synthesis 1999, 1739-1746.
(12) Williams, L.; Booth, S. E.; Undheim, K. Tetrahedron 1994, 50,
13697-13708.
(13) Fukushi, H.; Mabuchi, H.; Terasgita, Z.; Nishikawa, K.; Sugihara,
H. Chem. Pharm. Bull. 1994, 42, 551-559.
In conclusion, the synthesis of chiral nonracemic 6,8-
diazabicyclo[3.2.2]nonane derivatives 8-10 starting from
(14) Jerumanis, S.; Lefebvre, J. Bull. Soc. Chim. Belg. 1994, 103, 127-
130.
1178
Org. Lett., Vol. 2, No. 9, 2000

(S)-glutamate is presented. Modification of the ketone
functional group of 10 and, subsequently, the nitrogen
protective groups (substituents) will lead to conformationally
restricted receptor ligands (compare 1-3) or aza-analogues
and/or homologues of bicyclic alkaloids.
Acknowledgment. We thank the Deutsche Forschungs-
gemeinschaft and the Fonds der Chemischen Industrie for
financial support and the Degussa AG for donating chemicals.
(15) Typical procedure for the synthesis of 10a from 7a: At -78 °C
a solution of lithium hexamethyldisilazane (LiHMDS, 1 M in THF, 18.5
mL, 18.5 mmol) was added to a solution of 7a (4.92 g, 16.2 mmol) in THF
(100 mL). After 30 min of stirring at -78 °C a solution of trimethylsilyl
chloride (TMSCl, 5.5 g, 50.7 mmol) in THF (14 mL) was added and the
reaction mixture was stirred for 30 min at -78 °C and for 3 h at room
temperature. Then, the solvent was removed in vacuo, the residue was
dissolved in ethyl acetate, and the organic layer was washed with HCl (0.5
M), NaOH (0.5 M), and a saturated solution of NaCl and finally concentrated
OL990393A
in vacuo. Since further purification was not necessary, the residue (8a) was
dissolved in THF/H2O (10:1; 50 mL), p-toluenesulfonic acid (250 mg) was
added, and the mixture was stirred for 12 h at room temperature. The solvent
was removed in vacuo, and the residue was purified by flash chromatography
(ethyl acetate, Rf ) 0.43) to yield a colorless solid (3.62 g, 82%).
Org. Lett., Vol. 2, No. 9, 2000
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