In four or five chemical steps from the 1,2,4-trioxane artemisinin, a new series of 23 trioxane dimers has been prepared. Eleven of these new trioxane dimers cure malaria-infected mice via oral dosing at 3 x 30 mg/kg. The clinically used trioxane drug sodium artesunate prolonged mouse average survival to 7.2 days with this oral dose regimen. In comparison, animals receiving no drug die typically on day 6-7 postinfection. At only 3 x 10 mg/kg oral dosing, seven dimers prolong the lifetime of malaria-infected mice to days 14-17, more than double the chemotherapeutic effect of sodium artesunate. Ten new trioxane dimers at only a single oral dose of 30 mg/kg prolong mouse average survival to days 8.7-13.7, and this effect is comparable to that of the fully synthetic trioxolane drug development candidate OZ277, which is in phase II clinical trials.

An efficient and enantiocontrolled 3-step synthesis of α-hydroxy-(E)-β,γ-unsaturated esters is reported. Enantioenriched α-selenyl aldehydes, prepared in one step by asymmetric, organocatalytic α-selenylation of aldehydes, were directly subjected to a Wittig reaction followed by allylic selenide to selenoxide oxidation and final spontaneous [2,3]-sigmatropic rearrangement to yield the target compounds in 43-65 % overall yield and in 94-97 % ee.Asymmetric synthesis utilizing organoselenium compounds has become increasingly popular in recent years. 1 Selenium incorporation can be done in either a nucleophilic or an electrophilic fashion. 2 Once selenium is introduced into the molecule, many different chemical transformations can occur including oxidations leading to either syn-elimination 3 or, in the case of an allylic selenide, [2,3]-sigmatropic rearrangement to give an allylic alcohol. 4 Pursuing our recently published work preparing chiral non-racemic γ-hydroxy-(E)-α,β-unsaturated sulfones and esters, 5 we have developed a complementary asymmetric synthetic method producing α-hydroxy-(E)-β,γ-unsaturated esters.α-Hydroxy esters and their corresponding acids are key structural units of valuable synthetic intermediates as well as natural products. 1,6 Based on the utility of these structural units, we set out to design a simple, asymmetric general strategy for their synthesis. Suprisingly, most reports of selenium oxidation and [2,3]-sigmatroptic rearrangements have been done utilizing chiral oxidants as opposed to installing chirality prior to oxidation. 7 There have been a few reports involving diastereoselective oxidations of selenides containing chiral moieties, 8 but the scope is quite limited, with low to moderate yields and only modest diastereomeric excess (de). Other methods have also been reported using conformationally locked ring systems to induce stereocontrol. 9 ghp@jhu.edu. Supporting Information Available: Experimental procedures and full spectroscopic data for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org. Recent reports on the organocatalytic, asymmetric α-selenenylation of aldehydes in high yields (> 85 %) and high enantiomeric excess (> 95 %) 10,11 gave an excellent method for controlling the absolute stereochemistry of our α-hydroxy-(E)-β,γ-unsaturated target systems. NIH Public AccessWe chose a variety of aldehydes (3-phenylpropanal, 2-cyclohexylethanal, N-Boc-4-piperidineethanal, hexadecanal, and 6-benzyloxyhexanal) as well as three different ester functional groups (OMe, O-t-butyl, and O-benzyl) to determine the generality of this reaction. α-Selenyl aldehydes 3a-e, prepared according to an Italian protocol, 11 were immediately subjected in situ to a Wittig reaction to give the enantiomerically enriched compounds 5-11 (Scheme 1, A) in 48-83 % yields. Oxidation of the γ-seleneyl-(E)-α,β-unsaturated esters to the selenoxide using hydrogen peroxide caused spontaneous [2,3]-sigmatropic rearrangement to give the final enantioenric...

The method includes preparation of the α‐selenyl aldehydes, Wittig reaction, oxidation and the spontaneous [2,3]‐sigmatropic rearrangement.