Regioselective Domino Metathesis of Unsymmetrical 7‐Oxanorbornenes with Electron‐Rich Vinyl Acetate toward Biologically Active Glutamate Analogues

Abstract

In this article a regioselective domino metathesis reaction of unsymmetrical 7-oxanorbornenes, readily available by a tandem Ugi/Diels-Alder reaction as a key step, promoted by the HoveydaGrubbs second-generation catalyst in the presence of electron-rich vinyl acetate as a cross metathesis (CM) substrate is reported. The mechanism for the unusually high regioselectivity observed in the CM reaction was investigated, and a reaction course where a Fischer-type carbene ["Ru"= CH(OAc)] generates a steric interaction is proposed. The metathesis products were further converted to four artificial glutamate analogues whose structures were inspired by naturally derived excitatory glutamate analogues, dysiherbaine and neodysiherbaine. Interestingly, one of the synthetic analogues (28a) induced a cataleptic state in mice. Further electrophysiological studies suggest that 28a might inhibit excitatory synaptic transmission by a yet unknown indirect pathway.

Improved synthesis and in vitro/in vivo activities of natural product-inspired, artificial glutamate analogs

“…Without purification, the imidates were reduced with NaBH 3 CN under acidic conditions (TFA, MeOH) to provide the corresponding pyrrolidines,16 which were subsequently protected by Boc group (Boc 2 O, TEA) to furnish advanced intermediates 6a–6d in 59–86% yields over three steps. As compared to the first-generation synthesis (see Scheme 1),11 the yields and reproducibility of the deoxygenation steps were improved satisfactorily. For a convenient, one-step deprotection at the final stage of the synthesis, 2-nitrobenzenesulfonyl (Ns)17 group in 6c was replaced with Boc group by two-step transformation (PhSH, Cs 2 CO 3 ; Boc 2 O, TEA) to give 6c ′ in 86% yield.…”

“…Our first-generation synthesis11 of artificial glutamate analogs 1a , 1b , 5a , and 5b is shown in Scheme 1. The 7-oxanorbornenes 2a and 2b , readily available in 50% and 33% yields for two steps, respectively, were subjected to the challenging domino metathesis reaction using Hoveyda–Grubbs second-generation catalyst13 in the presence of electron-rich vinyl acetate as an unprecedented cross metathesis substrate, giving rise to heterotricycles 3a and 3b exclusively in 100% and 84% yields, respectively.…”

“…Scheme 3 depicts synthesis of the common intermediates 4c and 4d , bearing amino groups at the C rings, from known 3c and 3d ,11 respectively, by four-step functional group transformations, which had been developed for the synthesis of 4a and 4b (see Scheme 1). 11 First, N -Boc imides 8c and 8d were prepared by treatment with Boc 2 O, triethylamine (TEA), and 4-(dimethylamino)pyridine (DMAP) in 90% and 83% yields, respectively.…”

“…11 First, N -Boc imides 8c and 8d were prepared by treatment with Boc 2 O, triethylamine (TEA), and 4-(dimethylamino)pyridine (DMAP) in 90% and 83% yields, respectively. Alkaline hydrolysis (K 2 CO 3 , MeOH) was carefully performed on 8c and 8d , giving rise to ester aldehydes 9c and 9d in good yields (81% and 91%) without affecting β-alkoxyaldehyde moiety.…”

“…More recently, we began to pursue the third approach, DOS, and consequently discovered the artificial glutamate analog 1a , which elicits hypoactivity, rather than convulsions, in mice behavioral assays 11. Interestingly, 1a also markedly reduced both action potential firing frequency and spontaneous excitatory synaptic currents in current- and voltage-clamp electrophysiological analyses from cultured hippocampal neurons, although 1a did not displace radioactive ligands for the ( S )-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA), kainate (KA), or N -methyl- D -aspartate (NMDA) receptors that are constituent members of the ionotropic GluR superfamily.…”