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Starting from benzaldehyde derivatives, the corresponding dibenzocycloheptenol could be prepared in five steps. Under both substrate (secondary vs tertiary alcohol and the substituents on the aromatic ring(s)) and condition control, the subsequent epoxidation and acid-catalyzed epoxide opening/semipinacol rearrangement/aromatization afforded the corresponding 9-anthraldehydes in good yields, up to 88% over two steps. The presence of the electron-withdrawing group(s) on the aromatic ring(s) suppressed the rate of the epoxidation while the subsequent semipinacol rearrangement step required heating; the presence of the electron-donating group(s), on the other hand, frequently led to the decomposition during the epoxidation. From the mechanistic studies, the semipinacol rearrangement of the epoxide could precede the ionization at the bisbenzylic position, yielding the aldehyde intermediate. The ensuing dehydrative aromatization led to the formation of 9-anthraldehyde. Conversely, nucleophilic addition to the aldehyde and dehydrative aromatization with concomitant loss of formic acid led to anthracene.

4‐Aryl‐1H‐isochromene derivatives have been successfully synthesized by Brønsted acid‐catalyzed pinacol rearrangement/intramolecular cyclization of the substituted 1‐(2‐(hydroxymethyl)phenyl)‐2‐arylethane‐1,2‐diols. The reaction generally proceeded with low catalyst loading of trifluoromethanesulfonic acid (5 mol%) for short reaction times (10‐20 min) to furnish the desired 4‐aryl‐1H‐isochromenes which were subsequently hydrogenated to 4‐aryl‐isochromans with up to 90 % yield. Moreover, oxidation of the resulting 4‐aryl‐isochroman provided the desired 4‐aryl‐isochroman‐1‐one in good yield. A transition metal‐free procedure for the synthesis of 4‐aryl‐1H‐isochromene derivatives viaa pinacol rearrangement/intramolecular cyclization has been reported. Moreover, their synthetic applications are allowed for the preparation of the corresponding 4‐aryl‐isochroman and 4‐aryl‐isochroman‐1‐one skeletons.

An efficient scandium(III)‐triflate‐catalyzed pinacol‐pinacolone rearrangement and cyclization of 1,2‐diaryl‐1,2‐ethanediol has been developed, providing a variety of 2,3‐dihydro‐1H‐3‐benzazepine derivatives in good yields. The obtained products could be transformed to other valuable building blocks for the synthesis of some biologically active compounds or natural products. Moreover, this protocol was also successfully employed for the synthesis of the corresponding 1‐phenyl‐3,4,5,6‐tetrahydrobenzo[d]azocine and 3‐phenylisoquinoline products. Practical with wide application: A convenient protocol for the preparation of 1‐aryl‐2,3‐dihydro‐1H‐3‐benzazepines via a cascade pinacol‐pinacolone rearrangement and cyclization reaction of 1,2‐diaryl‐1,2‐ethanediol using scandium(III) triflate as the catalyst is described. Moreover, this methodology is also applicable for the synthesis of 3‐substituted isoquinoline and 1‐substituted 3,4,5,6‐tetrahydrobenzo[d]azocine derivatives.

Reported herein is the development of a normal electron‐demand, three‐component aza‐Diels‐Alder reaction between sultines, aldehydes, and amines. In the presence of Cu(OTf)2as a Lewis acid catalyst, the use of sultines as o‐quinodimethane precursors in conjunction with the in situ generation of imines enables the facile preparation of various polysubstituted tetrahydro‐isoquinoline derivatives from readily available substrates. The synthetic utility of these products was further explored through a number of product transformations, including the syntheses of tricyclic N‐heterocycles. A series of tetrahydroisoquinoline derivatives were prepared via a three‐component aza‐Diels‐Alder reaction. Keys to the success of this reaction are a) the utilization of sultines as masked o‐quinodimethanes, b) the facile, in situ generation of imine dienophiles, and c) the presence of Cu(OTf)2as a Lewis acid to promote the desired reactivity.

Five and six: 3,4‐Cyclopentyl‐ and cyclohexyl‐fused 2‐arylchromans could be readily prepared from the intramolecular hetero‐Diels–Alder reactions of the corresponding ortho‐quinone methide (o‐QM) precursors tethered to the styrenes under mild reaction conditions. The products were obtained with good to excellent diastereoselectivity (up to>99:1 dr; see scheme; MOM=methoxymethyl).

The syntheses and in vitro antimalarial screening of 50 bridged, bicyclic endoperoxides of types 9−13 are reported. In contrast to antimalarial trioxanes of the artemisinin family, but like yingzhaosu A and arteflene, the peroxide function of compounds 9−13 is contained in a 2,3-dioxabicyclo[3.3.1]nonane system 6. Peroxides 9 and 10 (R¹ = OH) are readily available through a multicomponent, sequential, free-radical reaction involving thiol-monoterpenes co-oxygenation (a TOCO reaction). β-Sulfenyl peroxides 9 and 10 (R¹ = OH) are converted into β-sulfinyl and β-sulfonyl peroxides of types 11−13 by controlled S-oxidation and manipulation of the tert-hydroxyl group through acylation, alkylation, or dehydration followed by selective hydrogenation. Ten enantiopure β-sulfonyl peroxides of types 12 and 13 exhibit in vitro antimalarial activity comparable to that of artemisinin (IC50 = 6−24 nM against Plasmodium falciparum NF54). In vivo testing of a few selected peroxides against Plasmodium berghei N indicates that the antimalarial efficacies of β-sulfonyl peroxides 39a, 46a, 46b, and 50a are comparable to those of some of the best antimalarial drugs and are higher than artemisinin against chloroquine-resistant Plasmodium yoelii ssp. NS. In view of the nontoxicity of β-sulfonyl peroxides 39a, 46a, and 46b in mice, at high dosing, these compounds are regarded as promising antimalarial drug candidates.

Short chemical syntheses of four new antimalarial trioxanes are presented, starting with inexpensive and commercially available cyclohexanone. Almost exclusive formation of the trioxane 12α-stereoisomers simplifies product purification. Carboxyphenyltrioxanes 3 and 5 are thermally stable in air even at 60 °C for 24 h. When administered orally, these new carboxyphenyltrioxanes are highly efficacious in curing malaria-infected mice. Important for their practical in vivo administration, these new synthetic antimalarial trioxanes 3 and 5 are 14−20 times more soluble in water at pH 7.4 than is artelinic acid (1), a leading semisynthetic, herb-derived antimalarial trioxane drug candidate.

Nine C-10 non-acetal derivatives of the natural trioxane artemisinin (1) were prepared as dimers using some novel chemistry. As designed, each dimer was stable chemically. C-10 Olefinic dimers 7 and C-10 saturated dimers 8−13 all showed good to excellent antimalarial and antiproliferative activities in vitro. Dimers 8, 10, and 12 were especially potent and selective at inhibiting growth of some human cancer cell lines in the NCI in vitro 60-cell line assay.

In only three chemical operations, natural trioxane lactone artemisinin (1) was converted into a series of C-10 carbon-substituted 10-deoxoartemisinin compounds 4−9. The three steps involved lactone reduction, replacement of the anomeric lactol OH by F using diethylaminosulfur trifluoride, and finally boron trifluoride-promoted substitution of F by aryl, heteroaryl, and acetylide nucleophiles. All of these C-10 nonacetal, chemically robust, enantiomerically pure compounds 4−9 have high antimalarial potencies in vitro against Plasmodium falciparum malaria parasites, and furans 5a and 5b and pyrrole 7a are antimalarially potent also in vivo even when administered to rodents orally.

Over 20 new, cyclic, peroxy ketals have been prepared via a two-step protocol starting with readily available aryl methyl ketones. Structure−activity correlations using in vitro antimalarial data as a guide for optimization of potency have led to the design and synthesis of seven new peroxides that have IC50 values of 31−85 nM (artemisinin IC50 = 8.4 nM). Some SAR generalizations are discussed.

On the basis of a mechanistic understanding of the mode of action of artemisinin-like antimalarials, a series of structurally simple 3-aryl-1,2,4-trioxanes 5 was designed and was prepared in three to five operations from commercial reactants. The 3-aryl group was attached in each case as a nucleophile. In an electronically complementary fashion, 3-(fluoroalkyl)trioxanes 6 were prepared via attachment of electrophilic fluoroalkyl esters. Both in vitro and in vivo antimalarial evaluations of these new trioxanes showed 12β-methoxy-3-aryltrioxanes 5g, 5j, 5k, and 5l to be highly potent, with crystalline fluorobenzyl ether trioxane 5k especially potent even when administered to rodents orally. As shown by rearrangement of hexamethyl Dewar benzene into hexamethylbenzene, iron-induced degradation of some of these 3-aryltrioxanes 5 involves generation of high-valent iron oxo species that might kill malaria parasites.

A series of new sulfide and sulfone 1,2,4-trioxanes was prepared in only a few steps from commercial reactants. The sulfone trioxanes were found to have higher in vitroantimalarial potencies than the sulfides, with 12β-arylsulfone trioxanes 1β being from 13to 14as potent as the complex natural antimalarial trioxane artemisinin ( 2). A tentative chemical mechanism is proposed to account for the great difference in antimalarial activity of the 12α- vs. 12β-sulfide trioxanes.

Eleven examples form the basis of a short and effective synthetic method for replacement of an anomeric fluorine atom by saturated, unsaturated, aryl and heteroaryl carbon nucleophiles to prepare α- or β-oriented C 10-R derivatives of the trioxane 10-deoxoartemisinin.

Palodesangrens A and C along with the common tetracyclic core are prepared from simple benzaldehyde and acetophenone derivatives in a 10-step longest linear sequence which featured the Diels–Alder reaction forming the cyclohexene moiety, LiAlH4isomerization, stereoselective acid-catalyzed cyclization forming the chroman moiety, regioselective iodination/vinyl Suzuki cross-coupling reaction, and ring-closing metathesis (RCM) forming the 2H-pyran-2-one. Overall, the desired palodesangrens A and C are obtained in 6.1% and 6.4% yields, respectively.