5 research outputs found
A Novel Synthesis of (−)-Huperzine A via Tandem Intramolecular Aza-Prins Cyclization–Cyclobutane Fragmentation
The acetylcholinesterase inhibitor (−)-huperzine A was synthesized from (<i>S</i>)-4-hydroxycyclohex-2-enone in 17 steps by a route that involved two cyclobutane fragmentations. The first of these employed a retro-aldol cleavage to generate the α-pyridone ring of huperzine A, and the second invoked a novel intramolecular aza-Prins reaction in tandem with stereocontrolled scission of a cyclobutylcarbinyl cation to create the aminobicyclo[3.3.1]nonene framework of the natural alkaloid
Cyclobutane Synthesis and Fragmentation. A Cascade Route to the <i>Lycopodium</i> Alkaloid (−)-Huperzine A
An
asymmetric total synthesis of the nootropic alkaloid (−)-huperzine
A was completed using a cascade sequence initiated by an intramolecular
aza-Prins reaction and terminated by a stereoelectronically guided
fragmentation of a cyclobutylcarbinyl cation as the key step in assembling
the bicyclo[3.3.1]nonene core of the natural product. Intramolecular
[2 + 2]-photocycloaddition of the crotyl ether of (<i>S</i>)-4-hydroxycyclohex-2-enone afforded a bicyclo[4.2.0]octanone
containing an embedded tetrahydrofuran in which the cyclohexanone
moiety was converted to a triisopropylsilyl enol ether and functionalized
as an allylic azide. The derived primary amine was acylated with α-phenylselenylacrylic
acid, and the resulting amide was reacted with trimethylaluminum to
give a [2 + 2]-cycloadduct, which underwent retroaldol fission to
produce a fused α-phenylselenyl δ-lactam. Periodate oxidation
of this lactam led directly to an α-pyridone, which was converted
to a fused 2-methoxypyridine. Reductive cleavage of the activated
“pyridylic” C–O bond in this tetracycle and elaboration
of the resultant hydroxy ketone to a diketone was followed by chemoselective
conversion of the methyl ketone in this structure to an endo isopropenyl
group. Condensation of the remaining ketone with methyl carbamate
in the presence of acid initiated the programmed cascade sequence
and furnished a known synthetic precursor to huperzine A. Subsequent
demethylation of the carbamate and the methoxypyridine, accompanied
by in situ decarboxylation of the intermediate carbamic acid, gave
(−)-huperzine A
Système touristique et culture technique dans l'Arc lémanique : analyse d'une success story et de ses effets sur l'économie régionale (1852-1914)
Inhibition of glycosidases has great potential in the quest for highly potent and specific drugs to treat diseases such as diabetes, cancer, and viral infections. One of the most effective ways of designing such compounds is by mimicking the transition state. Here we describe the structural, kinetic, and thermodynamic dissection of binding of two glucoimidazole-derived compounds, which are among the most potent glycosidase inhibitors reported to date, with two family 1 beta-glycosidases. Provocatively, while inclusion of the phenethyl moiety improves binding by a factor of 20-80-fold, this does not appear to result from better noncovalent interactions with the enzyme; instead, improved affinity may be derived from significantly better entropic contributions to binding displayed by the phenethyl-substituted imidazole compound