Further Investigation of the Intermolecular Diels–Alder Cycloaddition for the Synthesis of Bicyclo[2.2.2]diazaoctane Alkaloids

Abstract

The convergent synthesis of bicyclo[2.2.2]diazaoctane structures using an intermolecular Diels-Alder cycloaddition between a pyrazinone and commercially available fumarate or maleate precursors is reported. High reactivity and stereoselection is observed with both dienophile substrates. Structure validation was achieved by conversion of cycloadducts into known [2.2.2]diazabicyclic compounds or into crystalline derivatives suitable for X-ray analysis. The cycloadduct derived from reaction of pyrazinone and maleic anhydride underwent selective anhydride ring opening and intersected an established precursor in the synthesis of brevianamide B.

Unified total synthesis of the brevianamide alkaloids enabled by chemical investigations into their biosynthesis

“…We found that for the Diels–Alder cyclization of (+)-dehydrodeoxybrevianamide E (9) Williams' conditions of methanolic KOH gave a better result than our aqueous LiOH conditions ( Scheme 9 ). 12 Racemic syn - and anti -configured bicyclo[2.2.2]diazaoctane products, 14 and 6, were isolated in 53% yield with modest syn -diastereoselectivity (d.r. 57 : 43).…”

“…12 Thus, although this strategy hasn't provided a route to brevianamide A ( 1 ), several syntheses of brevianamide B ( 2 ) have been achieved that proceed via intermediate 6 , or protected analogues thereof (see structures in Scheme 1b). 12 Most notably, Williams and co-workers have achieved four syntheses of brevianamide B ( 2 ). In 1988, they reported the first total synthesis of ent -brevianamide B ( ent - 2 ) using a late-stage cationic cyclization, which resulted in an 18-step total synthesis.…”

“…Following the stereospecific [1,2]-shift this then leads to the unnatural enantiomeric framework of brevianamide B ( Scheme 1a ). 12 Thus, although this strategy hasn't provided a route to brevianamide A (1), several syntheses of brevianamide B (2) have been achieved that proceed via intermediate 6, or protected analogues thereof (see structures in Scheme 1b ). 12 Most notably, Williams and co-workers have achieved four syntheses of brevianamide B (2).…”

Chemical Synthesis of (+)-Brevianamide a Supports a Diels–Alderase-Free Biosynthesis

“…16 Furthermore, despite five decades of research, no chemical synthesis of brevianamide A (1) has been achieved, yet several syntheses of the minor diastereomer, brevianamide B (2), have been reported (see SI for a full summary). [17][18][19][20][21][22][23][24][25] Despite the similar structures of the two natural products, none of these strategies have been successfully applied to the synthesis of brevianamide A (1) due to insurmountable issues of stereoselectivity. Following decades of detailed chemical and biochemical studies, the biosynthetic origins of (+)-brevianamide A (1) and B (2) still remain largely unknown.…”