Concise Synthesis of dl-Febrifugine

Abstract

Racemic compound (1) of the antimalarial agents febrifugine (d-1) was synthesized using an stereoselective Michael reaction of an w w-amidoenone (5) which was prepared by the Wittig reaction of piperidinediol (7).Key words total synthesis; stereoselective Michael reaction; Wittig reaction; febrifugine; antimalarial activity Febrifugine (d-1) is an antimalarial agent that has been isolated from Dichroa febrifuga and Hydrangea umbellate along with isofebrifugine (d-2).1-4) It is well known that d-1 and d-2 are related to each other's isomerization via waminoenone 5,6) (3) (Chart 1). Among reported methods [7][8][9][10][11][12][13][14][15][16][17][18][19][20] of d-1, we had believed that our method 10,13) was widely applicable to the synthesis of the derivatives needed to study the structure-activity relationship of d-1. However, we could not successfully prepare some derivatives because our method involved uncontrollable trans-cis isomerization in the final step. In recent our study, we found that cis form of N-protected febrifugine derivatives (cis-4) also afforded a mixture of trans-4 and cis-4 form under the presence of acid by the isomerization (Chart 2). 21)From those findings, we planed a synthetic strategy via an w-amidoenone (5) as a key intermediate, which would afford trans piperidine derivative (trans-6) by the intramolecular Michael reaction with the stereoselectivity (Chart 3). In this paper, we describe a novel synthesis of dl-febrifugine (dl-1).The synthesis of the key intermediate, w-amidoenone (5), was achieved to utilize the Wittig reaction of 2-hydroxypiperidine derivative which we have developed in our synthetic study of deoxyfebrifugine.22) The Wittig reaction of 2,3-piperidinediol (7), which was easily prepared in 84% yield from tetrahydropyridine (8) by Oxone ® -acetone oxidation, 23) afforded (E)-w-amidoenone (E-5) in which the double bond had E configuration based on the coupling constant (Jϭ16 Hz) of olefinic protons in 1 H-NMR. The Michael reaction of trans-5 (E-5) with BF 3 · OEt 2 afforded the Michael adduct (trans-6). N-Cbz febrifugine (10) was afforded by successive reactions, silylation of the hydroxy and ketone group, bromination, and coupling with 4(3H)-quinazolinone. Hydrogenolysis of 10 gave dl-1 which was identical with the reported one by mp or 1 H-NMR data (Chart 4). In the Michael reaction of E-5 with BF 3 · OEt 2 , we could obtain the furan derivative (9) and 1,4-diketone derivative (11) along with trans-6. It is known that 9 and 11 can be transformed from cis-6 by acid.24) Decreasing yield of trans-6 with the prolongation of the reaction time or heat of reaction mixture suggests that there is an equilibrium relationship via E-5 between trans-6 and cis-6 in the presence of Lewis acid (Table 1).Herein, we could develop the the synthetic method for dlfebrifugine derivatives in high total yield and short steps without using the very expensive, toxic, or dangerous reagents used in other reports. [25][26][27][28][29][30] We are now progress the asymmetric synthesis using this me...

The cytoplasmic prolyl-tRNA synthetase of the malaria parasite is a dual-stage target of febrifugine and its analogs

“…We proposed that the off-target effects may originate from the ability of the compounds to epimerize in solution through formation of a reactive intermediate enabled by the central ketone common to febrifugine and halofuginone (fig. S10) (33). Previously reported efforts to remove this functionality resulted in loss of activity (34).…”

Stereoselective synthesis of analogues of deoxyfebrifugine

“…1–5 D. febrifuga has been used for centuries in traditional Chinese medicine for the treatment of a variety of ailments and since the first scientific papers concerning the plant-based active ingredient appeared (approximately 60years ago) febrifugine ( 1 ) and its analogues have received attention 6–8 from both a biological 9–22 and a chemical standpoint. 23–48 In relation to the latter, the precise structure of naturally occurring febrifugine ( 1 ) was only finally confirmed in 1999—partly due to complications in structure analysis as a result of its isomerisation into isofebrifugine ( 2 ) (Scheme 1). 24,49 Despite the potent antimalarial activity of febrifugine ( 1 ), it proved too toxic to develop as an antimalarial medicine and attempts to mitigate this toxicity led to halofuginone ( 3 ), an analogue in which the metabolically vulnerable aromatic protons are masked.…”

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

“…1 The alkaloids were subsequently isolated from plants of the related genus Hydrangea, including H. umbellata, H. macrophylla and H. chinense. 2 However, their structural and stereochemical elucidation proved to be a convoluted affair, 3 and it was only as recently as 1999 that Kobayashi and co-workers unambiguously demonstrated the absolute configurations depicted in Figure 1. 4…”