Antimalarial Artemisinin Analogs: Synthesis of 2,3-Desethano-12-deoxoartemisinin-related Compounds

Abstract

Ahnlracl-----2,3-Descthano-I2-deoxoartemisinin-related c o m p o u n d s ((1)-16a) and ((-)-16b) have been synthesized from R-(+)-citronellal (7) by a stereoselective manner, which is applied to the synthesis of various novel antimalarial artemisinin analogs.Artemisinin (qinghaosu, I ) is a clinically useful antimalarial sesquiterpene lactone endoperoxide isolated from the Chinese drug "Qing Hao" (Artemisin ~I I I I U U ~. ) . 2 , 3 Its potent hiological activity and novel chemical structure, coupled with the low yield from natural sources, have prompted synthcscs of 1 and its analogs hy many ~a h o r a t o r i e s .~ Our previous studies 5 on the synthesis and structure-activity relationships among analogs of 1, such as ?a, ?b, 3, Ja and 411, have indicated the importance of a stcric environment of the 1',Zt,4'-lrioxanc ring system as found in I , &I and 411 in contributing to the antimalarial activity.C _ ) HOOC 5 6 16b R=P-Me l l a R=CH2CH2CH2CH3 (a) ZnBr?, 0-5 OC, Benzene; (h) B2H6 (c) NaOH, H?02; (d) C6H5CH2CI, NaH, DMF; (e) Jones oxidation; ( 0 BT, n-BuLi, -70--80 'C;.(p) M ~O I C N -S O ~N + E ~~; (h) n-BuLi; (i) MeOS02F; (I) NaBH4; (k) AgN03; (I) p-TsOH, (MeOhCH, Xylenc, A ; (m) 10% HzSOj, A ; (n) Rase Bengal, M ~c H o , ' ~? , hv .-78 T . Scheme 1Recently, l u n g at a1.6 reported the conversion o f artemisinic acid (3, obtained from A. arrrlua, into (+)-deox<)artemisinin ( 6 ) .which showed scveral fold more activity than 1 in the irr virro antimalarial assay against the chloroquinz-resistant Plurr,~odiaiu fulciparur~t.As a result of our studies aimed at the development of a more practical and stereoselective synthesis of I and 6 ,