Artemisinin Total synthesis

Scheme 10. Total synthesis of artemisinin by Schmid and Hofheinz. Conditions (i) ClCH20Me, PhN(CH3)2, DCM, rt. (ii) B2H6/THF, H2O2 (iii) PhCHzBr, KH, THF/DMF (iv) HCl, MeOH (v) PCC, DCM, rt. (vi) LDA, (E)-(3-iodo-l-methyl-l-propenyl)-trimethylsilane (vii) lithium methoxy(trimethylsily)methyhde (viii) Li/NH3 (ix) PCC DCM (x) m-CPBA, DCM (xi) -Bu4NF, THF, rt. (xii) O2 (methylene blue, DCM, rt.) (xiii) HCOOH, DCM.

The total synthesis of artemisinin via conventional chemistry has also been achieved. In 1983, Schmid and Hofheinz pubhshed a paper showing the complete synthesis of artemisinin from (-)-Isopulegol (Scheme 10), with 5% overall yield. Since then, several other total synthesis of arteminisin... 

Avery MA, Jennings-White C, Chong KM. (1987) The total synthesis of (-i-)-artemisinin and (-i-)-9-desmethyltemesinin. Tetrahedron Lett 28 4629 632. 

The Avery group has produced a large number of artemisinin analogues by semisyntheses and elegant total synthesis . This has enabled Avery to develop predictive 3-D QSAR (CoMFA) analyses for the artemisinin class of antimalarial. This information coupled with the ADME approach described above should permit highly potent and orally bioavailable semi-synthetic analogues to be designed by a truly rational approach. 

Initially, we sought a practical total synthesis of the natural enantiomer (+)-artemisinin (1) to support clinical therapeutic studies with artemisinin and derived prodrug congeners, such as artemether and artesunate, and by providing a radiolabeled version of artemisinin for metabolism and mode of action studies (Eq. 1). Associated model studies from our total synthesis resulted in numerous additional analogues for our fledgling SAR study and the conception of other structural... 

Fig. 38 Examples of molecules prepared following new concepts in total synthesis (a) intricarene (220) generated by protective group-free synthesis and (b) late-stage site-selective C-H oxidations to generate eudesmane-type terpenes like 222 or (c) to prepare the hydroxylated artemisinin derivative 223...

Avery, M. A. Chong, W. K. M. Jennings-White, C. Stereoselective total synthesis of (+)-artemisinin, the antimalarial constituent of Artemisia annua L. /. Am. Chem. Soc. 1992,... 

Some alkoxy-substituted dioxetanes yield a-peroxy ketones and esters via zwitterionic intermediates which are formed by heterolytic C-O bond cleavage as proven by trapping with acetaldehyde [135]. This behavior which has been fully explored by Jefford [135b], has been exploited for the total synthesis of the antimalarial (+)artemisinin [136a-c] and related analogs [136d-f]. One recent example is reported in Sch. 83 [136f ]. 

Recently Avery et al [94] have developed a stereoselective total synthesis of (+)-artemisinine starting from (R)-(+)-pulegone (92). Elaboration of 92 gives the known sulphoxide 93, which was allowed to undergo dianion alkylation and desul-phurisation to yield disubstituted-cyclohexanone (95). Homologation of the latter afforded the aldehyde % in two steps. This product was then converted into the silyl acetate (97), which underwent Tandem Claisen ester-enolate rearrangement to give the vinylsilane 98. Ozonolysis and cyclisation of 98 provided 7 (Scheme 10). 

Bhisutthibhan, J., Pan, X.-O., Hossler, P.A., Walker, D.J., Yowell, C.A., Carlton, J., Dame, J.B., and Meshnick, S.R. The plasmodium falciparum translationally controlled tumor protein homolog and its reaction with the antimalarial drug artemisinin, /. Biol. Chem., 273,16192,1998. 21. Avery, M.A., Chong, W.K.M., and Jennings-White, C. Stereoselective total synthesis of (+)-artemisinin, the antimalarial constituent of Artemisia annua L., /. Am. Chem. Soc., 114,974,1992. Avery, M.A., Bonk, J.D., and Bupp, J. Radiolabeled antimalarials synthesis of 14C-artemisinin, /. Labelled Comp. Radiopharm., 38, 263, 1996. 

The Claisen rearrangement of the enolate of the ester 12 generated with LDA, afforded the y,<5-unsaturated acid 13 which served as an intermediate in the total synthesis of (+)-artemisinin (Scheme 5.1.17) [28]. 

A different application of reagent (5) can be seen in the total synthesis of artemisinin (10). Alkylation of the kinetic enolate of (11), derived from (—)-isopulegol, with (5) gave an 6 1 mixture of epimeric products from which the major isomer (12) was isolated in 62% yield. Further transformations led to vinylsilane (13). Liberation of the latent carbonyl group to provide ketone (14) was again achieved under very mild conditions, although here the possibility of carbonyl participation would seem less likely. Further steps then led to artemisinin (10). 

---