Chiral bridged piperazines:
synthesis of (1S,4S) 2,5-diazabicyclo[2.2.2]octane
a Inst. Organic Chemistry, TU Vienna, A-1060 Vienna, Getreidemarkt 9, Austria
bWERFFT-CHEMIE Ges.m.b.H., Landeggerstr. 7, A-2491 Neufeld a.d. Leitha, Austria
Abstract
In the course of the synthesis of quinolone carboxylic acids as potential antibacterials we were interested in conformationally fixed, bridged piperazines.
In addition to the formally methylene bridged piperazines (1R,4R)- and (1S,4S)-2,5-diazabicyclo[2.2.1]heptanes, [2]
we developed a synthesis of the formally ethylene bridged piperazine, the title compound (8), starting from N-Cbz-glycine succinimide ester and
L-homoserine lactone.
(1S,4S) 2,5-Diazabicyclo[2.2.2]octane, 8
Introduction
Piperazine constitutes a partial structure in a surprisingly large number of pharmacologically active compounds.
Examples of such structures are seen within
quinolones,
antipsychotics,
anxiolytics,
antidepressants,
5 HT-antagonists,
calcium antagonists,
antihypertensives,
antineoplastics,
antiallergics,
analgesics,
fungicides and other pharmaceuticals.
Although racemic 2,5-diazabicyclo[2.2.2]octane has been prepared by Strum [3] (click here to see a scheme of Strum`s synthesis) we rationed, that this route would have to include a potentially difficult chiral separation for the preparation of chiral 8.
Discussion
Kemp [4] has reported the preparation of (1S,4S)-3,6-diethoxy-2,5-diazabicyclo[2.2.2]octa-2,5-diene (7). As a literature search including the REACCS reaction databases revealed established methods for the reduction of imidoester to the corresponding amines[5,6] we decided to follow the pathway outlined in the following Scheme:
Kemp starts his synthesis with the reaction of N-CBz-Glycinsuccinimidester (1)
[7]with L-homoserinelactone (2). For the preparation of the commercially available but expensive (2) we chose Baldwin`s method [8]: A champagne bottle served as pressure vessel for the reaction of L-methionine with methyl bromide and 2 was obtained in 82.6%. The following steps to 7 were performed according to Kemp.
7 was then reduced using DIBAL-H. As piperazine-type bases such as 8 are notoriously water soluble the reduction reaction was worked up with a minimum amount of water (see experimental).
Results
A practical synthesis of 8 as a chiral and conformationally fixed piperazine analogue has been described. This building block is now available for lead optimizations in various pharmaceutical targets.
Experimental
(1S,4S) 2,5-Diazabicyclo[2.2.2]octane (8).
To a solution of (1S,4S)-3,6-diethoxy-2,5-diazabicyclo[2.2.2]octa-2,5-diene (7 ) (0.90g, 4.6 mmol) in 20 mL dry toluene DIBAL-H (9.0 mL of 1.5 M solution in toluene) was added at 0 °C and stirred for 1 h at 20 °C. NaOH (15 drops of 40% NaOH) was added, the resulting precipitate was filtered and washed with toluene (3 x 5 mL) and the combined toluene phases treated with dry HCl in diethyl ether. The crystalline product was filtered, washed with diethyl ether (3 x 5 mL) and dried in vacuo to yield 0.37 g (42.3%) of 7 as colourless crystals, mp > 300 °C of uniform TLC behaviour using methylene chloride/ methanol / conc. ammonia (4:4:2) on silica gel.
[a]24: +37.5 (c= 1.28, water)
1H NMR (D2O) d (ppm): 2.35 (m, 4H, H-7,7`, H-8,8`), 3.80 (m, 4H, H-3,3`, H-6,6`), 4.15 (b, 2H, H-1, H-4), 4.85 (HDO).
References
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- U. Jordis, F. Sauter, S.M. Siddiqi, B. Küenburg and K. Bhattacharya, Synthesis 1990, 925-30.
- P. A. Strum, D. W. Henry, P. E. Thompson, J. B. Zeigler and J. W. Call, J. Med. Chem. 17, 481 (1974).
- D. S. Kemp and P. E. McNamara, J. Org. Chem. 49, 2286 (1984).
- A. Hajos "Metallhydride bzw. komplexe Hydride als Reduktionsmittel", in: Houben Weyl, Vol. 4/1d,
G. Thieme Verlag Stuttgart (1981).
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- S. M. Birnbaum and J. P. Greenstein, Arch. Biochem. Biophys. 1952, 213.
