Synthesis of bridged heterocycles from cis-pyrrolidine-2,4-dicarboxylic acids: I. 3,6-Diazabicyclo[3.2.1]octanes

Abstract

cis-5-Arylpyrrolidine-2,4-dicarboxylic acid monoamides undergo thermal intramolecular condensation with formation of bicyclic imides having a 3,6-diazabicyclo[3.2.1]octane skeleton. The use of copper(I) cyanide as catalyst ensures high yields of 3,6-diazabicyclo[3.2.1]octane-2,4-diones substituted at the 3-, 5-, 6-, and 7-positions. (1R*,5R*,7S*)-7-(4-Chlorophenyl)-5,6-dimethyl-3,6-diazabicyclo[3.2.1]octane-2,4-dione was found to inhibit thrombin in a buffer solution at a millimolar concentration.Numerous natural and physiologically active compounds contain a substituted azabicyclo[3.2.1]octane fragment in their molecules. Examples are alkaloids of the tropane [1] and calystegine series [2], which possess a 8-azabicyclo[3.2.1]octane (tropane) structural fragment. (-)-Cocaine (I) is the most known alkaloid of the tropane family. Due to broad spectrum of their neurological and psychiatric effects enantiomerically pure tropane derivatives are targets of synthetic schemes developed by different research teams [3]. 6-Azabicyclo[3.2.1]octane derivatives, e.g., actinobolamine (II) [4], are encountered in nature more rarely, but they also exhibit a broad spectrum of pharmacological activity [5]. Aplaminal (III) which is a functionalized 3,6,8-triazabicyclo[3.2.1]octane derivative was isolated from the sea hare Aplysia kurodai and was found to exhibit cytotoxicity against Hela S 3 tumor cells [6].One of the main approaches to pharmacotherapy of cocaine addiction is based on the use of cocaine antagonists which inhibit cocaine recognition and its binding to dopamine transporter (DAT) but retain other important functions of that membrane protein [7]. The simplest route to the development of cocaine antagonists is synthesis of its structural analogs that are still capable of binding to DAT but exhibit reduced ability to inhibit dopamine transport and low toxicity. Some progress in this line was achieved with the use of structural isomers of tropane and its aza analogs, 3-azabicyclo[3.2.1]octanes IV (X = Y = C; isotropanes) [8] and 3,8-diazabicyclo[3.2.1]octanes IV (X = N, Y = C) [9] as central fragment in cocaine antagonists. The present article reports on a new method of synthesis of 3,6-diazabicyclo[3.2.1]octanes IV (X = C, Y = N) with different substituents in four positions of the bicyclic skeleton. These compounds are isostructural to tropane but are more basic. The products were also tested for inhibitory activity against thrombin (factor IIA).The formation of a substituted 3,6-diazabicyclo-[3.2.1]octane skeleton was revealed when 5-(4-bromophenyl)pyrrolidine-2,4-dicarboxylic acid derivative V was heated in DMF in the presence of copper(I) cyanide (Scheme 1). This reaction was initially carried out with a view to replace the bromine atom in the aromatic ring of V by cyano group (a classical Rosenmund-von Braun procedure for the synthesis of benzonitriles via aromatic nucleophilic substitution of bromine by cyano group [10]) to obtain 5-(4-cyanophenyl)pyrrolidine-2,4-dicarboxylic acid derivative.

Pyrrolidine-2,3,4-tricarboxylic anhydrides: I. Organocatalytic synthesis and fusion of pyrrole ring by the action of p-fluorobenzylamine

“…We previously found conditions for intramolecular condensation involving the carboxy group in cs-5-arylpyrrolidine-2,4-dicarboxylic acid monoamides and obtained bicyclic imides with a 3,6-diazabicyclo[3.2.1]-octane skeleton [8]. Three intramolecular condensation pathways may be proposed for regioisomeric cis-5-arylpyrrolidine-2,3,4-tricarboxylic acid monoamides V and VI: (i) [4,2]-condensation in isomer V, leading to 3,6-diazabicyclo[3.2.1]octane derivative; (ii) [4,3]condensation in isomer V with formation of octahydropyrrolo[3,4-c]pyrrole structure; and (iii) [3,2]-condensation in VI with formation of octahydropyrrolo[3,4-b]-pyrrole skeleton (Fig.…”

Design of small-molecule thrombin inhibitors based on the cis-5-phenylproline scaffold

“…14 Diesters of pyrrolidine 2,4 dicarboxylic acids 5a, 15 5b, 8 and 5c (see Ref. 7) were synthesized from imino esters 4a-c follow ing the known procedures and identified spectroscopically.…”

“…Also, this molecular scaffold was chosen based on the available data on the thrombin inhibiting properties of small molecule compounds containing the structural frag ment 5. 8 To check the possibility of design of thrombin inhibitors with low basicity, we planned to convert pyrrol idine 2,4 dicarboxylic acid derivatives 5 to polysubstitut ed pyrrolidines 6 and 7 (see Scheme 1) in which the 4 chlorophenylsulfanyl fragment should be the P1 frag ment of the ligand and interact with the S1 pocket of thrombin active site. The substituents R 1 and R 2 were chosen taking into account the availability of the starting reactants and the need to assess how structural factors influence the biological activity.…”

syn-3-(4-Chlorobenzyl)-1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-ol

“….1]nonan-9-ols are of interest as a structural motif for enzymes inhibitors. Inhibition of thrombin by substituted 3,6-diazabicyclo[3.2.1]octanes is reported (Kudryavtsev (2010)).…”