Abstract
Short and efficient syntheses of functionalized (pyrrolidin-2-yl)phosphonate and (5-oxopyrrolidin-2-yl)phosphonate have been developed. The synthetic strategy involved the diastereospecific 1,3-dipolar cycloaddition of N-benzyl-C-(diethoxyphosphoryl)nitrone to cis-1,4-dihydroxybut-2-ene and dimethyl maleate, respectively. O,O-Diethyl 3-carbamoyl-4-hydroxy(5-oxopyrrolidin-2-yl)phosphonate was obtained from O,O-diethyl 2-benzyl-4,5-dimethoxycarbonyl(isoxazolidin-3-yl)phosphonate by hydrogenation and subsequent treatment with ammonia, whereas transformation of O,O-diethyl 2-benzyl-4,5-dihydroxymethyl(isoxazolidin-3-yl)phosphonate into O,O-diethyl 3-aminomethyl-4-hydroxy(pyrrolidin-2-yl)phosphonate was accomplished by mesylation followed by hydrogenolysis to undergo intramolecular cyclization and the introduction of amino group via ammonolysis. Stereochemistry of the isoxazolidine cycloadducts, as well as the final functionalized (pyrrolidin-2-yl)- and (5-oxopyrrolidin-2-yl)phosphonates were established based on conformational analyses using vicinal H–H, H–P, and C–P couplings and supported by the observed diagnostic NOESY correlation signals.
Highlights
Pyrrolidine is an important fragment of many natural products [1,2,3,4] that can be exemplified by complex structures of swainsonin [5], monocotaline [6], lasiocarpine [7], and senecionine [8]
C-phosphorylated nitrones [36] have been successfully applied in the synthesis of variousphosphonates [36,37] we found them suitable for the preparation of isoxazolidines 20 and 21, which could be transformed into the designed compounds 18 and 19 or their functionalized analogues
For transformation of isoxazolidine 21 into functionalized derivative ofphosphonate 28, reaction sequence consisted of a standard mesylation of both hydroxy groups, a hydrogenolytic cleavage of the N–O bond, removal of benzyl group followed by spontaneous formation of the pyrrolidine ring by intramolecular SN2 reaction and exchanging the other mesyloxy group to amino function
Summary
Pyrrolidine is an important fragment of many natural products [1,2,3,4] that can be exemplified by complex structures of swainsonin [5], monocotaline [6], lasiocarpine [7], and senecionine [8]. Pyrrolidine and pyrrolidinone moieties are present in small biologically active molecules. Pyroglutamic acid 3 (Figure 1) is formed as a result of glutamate dehydration [11]. This is an intermediate substrate involved in the glutathione synthesis [12]. The basic structure of pyroglutamic acid has been modified and resulted in the syntheses of pharmacologically active compounds such as piracetam 4, oxiracetam 5, nebracetam 6, and its morpholine derivative 7 (Figure 1), which belong to “nootropic drugs” used in treatment of CNS diseases such as epilepsy and depression [13,14,15,16,17,18]
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