Extension of the “ring switch” approach to glutamate antagonists to δ-lactam urethanes

Investigation of a route to ibotenic acid analogues via a reduced pyroglutamate template

“…These compounds were designed to have potential for activity at individual receptors 5-9 and some have shown interesting CNS activity. The synthesis, shown in Scheme 1, involved reaction of aldehydes 5 of protected pyroglutamic acid (n = 1) 5-8 and of protected 6-oxopipecolic acid (n = 2), 9 with bisnucleophiles and involved a minimum of steps. We have christened this powerful synthetic tool a "ring switching" reaction 5 and recently extended it to the use of b-lactam aldehydes 12 from which a plethora of analogues of ibotenic acid could be obtained 10 (Scheme 2).…”

“…Crystal data for (4S,5S)-N-tert-butoxycarbonyl-5-tert-butyldiphenylsiloxymethyl-4-hydroxymethoxymethylpyrrolidin-2-one (26), † C 28 H 39 NO 6 Si, M = 513.69, monoclinic, space group P2 1 (No. 4), a = 7.6412(4), b = 11.8424 (9), c = 15.8245(7) A ˚, b = 102.434(3) • , V = 1398.37(14) A ˚3, Z = 2, D calc 1.22 mg m −3 , l(Mo Ka) = 0.13 mm −1 , T = 173(2) K, 3805 independent reflections (R int = 0.044). The final R values were R1 = 0.042 (for 3372 reflections with I > 2r(I)) and wR2 = 0.095 (for all reflections).…”

β-Lactams as versatile synthons for homochiral ibotenate analogues with potential for activity at glutamate receptors1

“…2-Aminopyridine (132 mg, 1.40 mmol) was added to a solution of freshly made tert-butyl (3RS,4S )-N-tert-butoxycarbonyl-3formylazetidin-2-one-4-carboxylate 37 (100 mg, 0.334 mmol) in dioxane (2.5 ml) and the reaction was stirred for 20 h at room temperature. The solvents were removed in vacuo and the resulting oily residue was purified by chromatography on silica gel, using a mixture of petroleum ether and ethyl acetate (3 : 2) as eluent to afford tert-butyl (2S)-N-tert-butoxycarbonyl-2-(pyrido[1, 2-a] 9.0, J 8,7 6.6, J 8,6 1.5, H-8), 7.67 (1H, ddd, J 9,8 9.0, J 9, 7 1.7, J 9,6 0.8, H-9), 7.15 (1H, ddd, J 7,6 7.2, J 7,8 6.6, J 7,9 1.7, H-7), 6.04 (1H, d, J NH, 11…”

“…These compounds were designed to have potential for activity at the AMPA receptor 7-11 and some were tested and found to have biological activity at metabotropic receptors. The synthesis, shown in Scheme 1 and 2, involved reaction of aldehydes 6 or their homologues 12 of protected pyroglutamic acid (n = 1) 7-10 or 6-oxopipecolic acid (n = 2) 11 with bisnucleophiles and involved a minimum of steps. We have referred to this powerful synthetic tool as a "ring switching" reaction.…”

An alternative to the use of δ-lactam urethanes in the “ring switch” approach to higher homologues of AMPA-type glutamate antagonists

“…6 We have developed a versatile synthetic approach to homochiral compounds of this type, which is ideally suited to library synthesis. 7, 8 In this method urethanes of aldehydes of activated γ-lactams, 7a-f β-lactams 7g,h and δ-lactams 8 are used as starting materials and homochiral compounds with different numbers of atoms in the chain between the heterocyclic and amino acid moieties are obtained. Use of β-lactam urethanes gives the greatest variety of products in this approach.…”