A Versatile Synthesis of (±)-Deoxyfebrifugine, an Antimalarial Alkaloid Analogue, and Related Compounds

Abstract

The title compound was prepared by a simple route involving Eschenmoser sulfide contraction between 3-(3-bromo-2-oxopropyl)quinazolin-4(3H)-one (11) and piperidine-2-thione (13) followed by chemoselective catalytic hydrogenation. This short but flexible procedure also permitted access to N-alkyl analogues, and to analogues in which the piperidine ring was replaced by other saturated nitrogen-containing heterocycles.

Intrinsic Organic‐Based Synthetic/Artificial Antiferromagnets

“…The method presented herein provides a new rapid access to various enantiopure pyrrolidine vinylogous amides in good yields. Such compounds, which can be prepared by Eschenmoser coupling17 or Knoevenagel‐type reactions,18 have been used as intermediates in the synthesis of many natural compounds,19 such as anisomycin,20a apomitomycin,20b mesembrenone,20c desoxoprosophylline,20d cassine,19c pinidinone,20e deoxyfebrifugine,20f and sedacryptine 20g. Optimised conditions have allowed the efficient production of 4a – c .…”

Asymmetric Construction of Alkaloids by Employing a Key ω‐Transaminase Cascade

“…β‐Enaminones are vinylogous amides with unique reactivity and represent important intermediates in the synthesis of a variety of N ‐heterocyclic compounds . Specifically, six‐membered cyclic variants have been exploited for the preparation of a diverse array of bioactive piperidine alkaloids (Figure ), including pinidinone and related 2,6‐piperidine derivatives, apomitomycin, mesembrenone, desoxoprosophylline, cassine, deoxyfebrifugine, sedacryptine, selenopsine and the Coccinellidae defensive alkaloids, including hippodamine . However, despite their importance, there have been limited strategies reported for the enantioselective construction of chiral β‐enaminones.…”

(±)-3-Benzyloxy-1-(4-methoxybenzyl)piperidine-2-thione

“…For the use of related piperidinethiones in the synthesis of febrifugine analogues, see: Michael et al (2006). For information on the biological activity of febrifugine, see: Murata et al (1998).…”

“…The title piperidinethione was prepared as an intermediate for the total synthesis of febrifugine, a quinazoline alkaloid with potent antimalarial activity (Murata et al, 1998). Related thiolactam intermediates have been used in the synthesis of febrifugine analogues in ongoing investigations in our laboratories (Michael et al, 2006). It should be noted that, although an optically pure lactam was used in the synthesis of the title compound, racemization took place during the replacement of oxygen by sulfur with Lawesson's reagent.…”