Cyclobutane Synthesis and Fragmentation. A Cascade Route to the Lycopodium Alkaloid (−)-Huperzine A

Abstract

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 (S)-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.

Photochemical Approaches to Complex Chemotypes: Applications in Natural Product Synthesis

“…An intramolecular aza-Prins reaction with a guided fragmentation of a cyclobutylcarbinyl cation was used as the key step for assembling the bicyclo[3.3.1]nonene core of the nootropic alkaloid (−)-huperzine A ( 160 ). 151 Here, the necessary photoadduct 156 , generated from intramolecular [2 + 2] photocycloaddition in 58% yield from 155 , was converted to cyclohexanone 157 . Condensation of ketone 157 with NH 2 CO 2 Me in the presence of p -TsOH initiated the aza-Prins reation sequence, presumably via carbamate 158 , to afford the desired fragmentation product 159 , which is a known precursor to (−)-huperzine A ( 160 ) ( Scheme 31 ).…”

Cyclobutane based “overbred intermediates” and their exploration in organic synthesis

“…Compound 370 on further imine formation followed by treatment with TMS-I led to the cleavage of another cb overbred intermediate through the aza-Prins cyclobutylcarbinyl cation fragmentation pathway and affords (−) huperzine A ( 374 ) as depicted in Scheme 53. 98…”

Allylic azides: synthesis, reactivity, and the Winstein rearrangement

“…The synthetic utility of this method was demonstrated in White's total synthesis of (−)-huperzine. 112,113 Hartwig and co-workers developed a C─H azidation, which is viable on complex molecules (Scheme 10b). 114 Rather than mix PhIO and TMSN 3 to form a hypervalent iodine reagent in situ, this work uses Zhdankin's reagent.…”