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SSJ-127, a novel antimalarial rhodacyanine derivative, has shown potent antimalarial activity against chloroquine-resistant Plasmodium strains in vitro and subcutaneous administration of SSJ-127 results in a complete cure of a mouse malaria model. SSJ-127 was detected by fluorescence microscopy in the mouse malaria parasites Plasmodium berghei after exposure of infected red blood cells to the compound in vitro and in vivo. Selective accumulation of SSJ-127 in an organelle is observed in all blood stages of live malaria parasites. The organelle is clearly different from the mitochondrion and the nucleus in terms of morphology. The shape of the organelle changed during the asexual blood stages of the parasite. There was always a close association between the organelle and the mitochondrion. These results raised the possibility that SSJ-127 accumulates in an apicoplast of the malaria parasite and affects protozoan parasite-specific pathways.

It is clear that the role of 1,2-asymmetric induction on the 1,3-dipolar cycloaddition of nitrones is influenced by the presence of a fluorine atom at the C-2 position. 2-Fluoro nitrones, synthesized by three different methods, have been subjected to the intermolecular 1,3-dipolar cycloaddition with ethyl vinyl ether. The stereostructures of isoxazolidines formed were determined by their conversion into 2,7-dioxa-6-azabicyclo[3.2.1]octanes. The diastereoselectivity of 2-fluoro nitrones was the reverse of that of the corresponding 2-hydro nitrones. This fact supports that the conformation with relief from the dipole repulsion between the fluorine atom and the oxygen atom of the nitrone is a preferred one for 2-fluoro nitrones, while the corresponding 2-hydro nitrones adopt the conformation with the least 1,3-allylic strain.

Total synthesis of (±)-methyl atis-16-en-19-oate (5c), a tetracyclic diterpenoid possessing a bicyclo[2.2.2]octane ring system, was accomplished. Intramolecular Diels−Alder reaction of tetraene 14 was employed in a construction of kaurene skeleton 13. The pivotal step involved a homoallyl−homoallyl radical rearrangement process of (±)-methyl 12-hydroxykaur-16-en-19-oate monothioimidazolide 12, which led to 5c in good yield. Interestingly, treatment of methyl 12-oxo-kaur-16-en-19-oate 30 with hydrazine monohydrate in the presence of KOH in bis(ethylene glycol) at 200 °C resulted in cyclopropanation to furnish, directly, trachyloban-19-oic acid (4b), together with kaur-16-en-19-oic acid (6b).

A novel preparation of (+)-methyl pederate (4), a key intermediate in syntheses of mycalamides (1), marine natural products from a New Zealand sponge of the genus Mycale, is described. The key step involves palladium-catalyzed intramolecular allylic alkylation of the carbonate 21, derived from (+)-(4R,5R,E)-5-(tert-butyldimethylsiloxy)-4-methyl-2-hexenol (13), yielding lactones 5 in 87% yield. Demethoxycarbonylation of the cyclization products 5 and further functional group transformations led to (+)-methyl pederate (4).

The use of palladium complexes as reagents for the synthesis of biologically active natural products has been under development for at least the past three decades, and many elegant total syntheses of structurally complicated natural products, possessing pharmacologically important properties, have been realized employing Heck reaction, cycloisomerization process, and allylic alkylation reaction. In our recent contribution to this area, we would like to describe total syntheses of aphidicolin (diterpene), pumiliotoxin C (alkaloid), methyl pederate (left segment of mycalamides), hirsutene (sesquiterpene), stemodin (diterpene), and methyl atis-16-en-19-oate (diterpene) using palladium-promoted cyclization as key step.Although the palladium-promoted cycloalkenylation reaction of an olefinic silyl enol ether is a powerful strategy for construction of polycyclic system, relatively little is known about successful application of the above reaction to biologically active natural product syntheses. Herein we report the development of novel palladium-catalyzed cycloalkenylation reaction of cross-conjugated silyl enol ethers and its application to a tetracyclic diterpene synthesis.

We designed a sequential three-step, one-pot reaction (homoallyl-homoallyl radical rearrangement reaction) to generate highly functionalized bicyclo[2.2.2]octane ring system, and succeeded in developing a novel synthetic method to bicyclo[2.2.2]octane compounds from simple cyclohexene derivatives.

Total synthesis of 4-deoxyverrucarol ( 4 ), a trichothecane-type sesquiterpene was achieved via two types of ring expansion reaction, 1,2-rearrangement of 18 and palladium mediated ring expansion reaction of 20 , as key steps providing a new route to trichothecanes.

Enantioselective synthesis of (+)-equilenin ( 1 ) utilizing a novel strategy is described. The key steps are two cascade ring expansion reactions of small ring systems; 1) chiral (salen)Mn III complex-catalyzed cascade reaction of cyclopropylidene; 2) Pd II -mediated cascade reaction of the cyclobutanol.

An unusual TBAF-mediated intramolecular cyclisation of diallylsilane derivatives 3 and 12 provided bicyclo[6.2.2]dodecanes 5 and 13 in good yields.

A novel one-pot reaction for the synthesis of exo-olefinated bicyclo[6.4.0]dodecanes 23 has been developed on the basis of an intramolecular Michael reaction of phenylsulfonyl compounds 4 with potassium hexamethyldisilazide (KHMDS) and a sequential reaction with an excess of methoxymethyl chloride (MOMCl). By this reaction, an exo-olefin group was regioselectively introduced at the α-position to the carbonyl group in the 6-membered ring in high yield. The regioselective introduction of the olefin moiety could be envisaged to proceed through a Mannich-type reaction involving the aminomethylating agent 24, which, in turn, is generated in situ by the action of HMDS on MOMCl.

A palladium-catalyzed transformation of 1-(3-methoxycarbonyloxy-1-propynyl)cyclobutanols to cyclo-pentanones on treatment with phenol derivatives is described. This process can be visualized to proceed via nucleophilic attack to allenyl palladium species by phenol, followed by ring expansion reaction of π-allylpalladium complex to form the corresponding cyclopentanone.

Asymmetric intramolecular Michael-aldol reaction of (−)-phenylmenthyl enoates 1 affords tricyclic cyclobutanes 2 in excellent diastereoselectivity. It is made clear that Michael-aldol reaction is reversible under conditions using trimethylsilyl iodide (TMSI) in the presence of hexamethyldisilazane (HMDS) at ambient temperature. The difference of stereoselectivity under kinetic or thermodynamic conditions are reported.

Refixation of the CO2 from a decarboxylation occurs in the palladium-catalyzed domino reaction of 4-methoxycarbonyloxy-2-butyn-1-ols with phenols. The reaction enables the construction of various cyclic carbonates [Eq. (1)] by efficient reincorporation of the CO2 molecule under mild conditions, and is thus a convenient and environmentally friendly method.

Palladium mediated cycloalkenylation reaction of enol silanes of medium and large rings provides concise access to the corresponding bridged bicycloalkenones, a structural unit present in a large number of biologically active natural products.

The radical reaction of 1-iodo-1,5,10-trienoate afforded a linear fused five-membered carbocycle. Another key feature of this reaction is the remarkable acceleration of the reaction rate and enhancement of selectivity caused by the introduction of a conjugated ester moiety at the terminal olefin. This cascade reaction proceeds through three sequential 5-exo cyclizations. The result is in stark contrast with the previously reported radical reaction of 1-iodo-1,5,9,14-tetraenoate, which afforded a linear fused six-membered carbocycle through a 6-endo, 6-endo, 6-exo cyclization.

A novel method for the synthesis of α-substituted cyclopentanones by the ruthenium-catalyzed rearrangement of allenylcyclobutanols with α,β-unsaturated carbonyl compounds has been developed.

Intramolecular Michael−aldol reactions of (−)-phenylmenthyl enoates tethered to cycloalkanone affords tricyclic cyclobutanes with high degrees of diastereochemical control. Kinetic and thermodynamic studies revealed that the Michael−aldol reaction is reversible under conditions in which trimethylsilyl iodide is used in the presence of hexamethyldisilazane at ambient temperature. Different levels of diastereoselectivity are observed when this cyclization process is carried out under kinetic vs thermodynamic conditions. Finally, an influence of added iodonium donors on the reaction rate has been noted.

Biological evaluations of bicyclo[6.4.0]dodecenone derivatives on antimalarial activity in vitro against Plasmodium falciparum and cytotoxicity against human KB cells were made. (±)-(1R*, 4S*, 7R*, 8S*)-4-tert-Butyldimethylsiloxy-5, 5-dimethyl-1-methyl-9-methylene-7-phenylsulfonylbicyclo[6.4.0]dodec-2, 11-dien-10-one (15) exhibited potent antimalarial activity, whereas (±)-(1R*, 7R*, 8S*)-1-methyl-9-methylene-7-phenylsulfonylbicyclo[6.4.0]dodec-2, 11-dien-10-one (14) showed significant cytotoxic activity in human KB cells. Both 14 and 15 possess, as a structural character, the exo-methylene moiety in their 6-membered ring of the 8-6 fused ring system.

The influences of catalysts, substituent groups, and solvents on the palladium-catalyzed cycloalkenylation of cross-conjugated silyl enol ethers of 2-tert-butyldimethylsiloxy-5-(2-propenyl)-1,3-cyclohexadiene derivatives have been investigated. The catalytic reaction proceeded smoothly, even in aqueous media. The product ratios were influenced by the structure of substrates as well as solvents. In addition, it was found that the reaction is applicable to a tandem cyclization for the construction of cedrane skeleton.

To solve the drawback (considerable decrease in yield on a large scale) of cycloalkenylation employing stoichiometric amounts of Pd(OAC) 2 , a novel palladium-catalyzed cycloalkenylation has been developed. Stereoselectivetotal syntheses of several bioactive terpenoids have been achieved by means of the above catalytic reaction.

(1R*,2S*)-2-(2-Oxobut-3-enyl)-1-(1-oxoprop-2-enyl)-1,3,3-trimethylcyclopentane 5 was prepared stereoselectively from 4,4-dimethylcyclopent-2-en-1-one 6 and then converted into the conjugated silyl enol ether 17. Intramolecular cycloaddition of 17, followed by base-catalysed equilibration, provided (1S*,2R*,7R*,9R*)-3-tert-butyldimethylsiloxy-9,12,12-trimethyltricyclo[7.3.0.0]dodec-3-en-8-one 18a, which was transformed, after contraction of the cyclohexene ring, into the synthetic intermediate 32 for (±)-Δ9(12)-capnellene 1.

An enantioselective synthesis of a 6-oxygenated atisine derivative 20 is described. The atisine skeleton 18 was stereoselectively constructed by the intramolecular double Michael reaction of the enone ester 16, derived, through the aldehyde 3, from the symmetrical ketone 4.

Studies about the regiocontrolled addition of arylboronic acids to allenes using a palladium or a platinum catalyst have been described. The selectivity of the reaction can be altered by the choice of the metal reagent and base. Contrary to the formation of endo-olefinic products in the reactions using hydroxopalladium complex, predominant production of exo-olefinic products was observed by the reaction with hydroxoplatinum complex.

We describe here (2+2) cycloaddition reaction of alkyl enol ethers with acrylates catalyzed by triethylsilyl triflic imide (Et3SiNTf2), which was in situ generated from triethylsilane and triflic imide. The reaction efficiently provides substituted cyclobutanes bearing alkoxy function in a stereoselective manner.

A new approach for construction of the A/B ring system of steroids was developed by way of an intramolecular 1,3-dipolar cycloaddition of a nitrile oxide 4, followed by an incorporation of a C3 unit. A highly stereocontrolled synthesis of (+)-testosterone 1 was accomplished by this strategy.

Substitution of the chiral half-esters of monosubstituted malonic acids with halides leads to the formations of mixtures of the diastereoisomeric alkyl- or benzyl-malonic half-esters. The (R)-isomers (13A and 15A–22A) were obtained from the phenylmenthyl half-ester 14 of methylmalonic acid in high diastereoisomeric excess. The same stereoisomers were also produced by reaction of the half-esters 9, 23 and 24 with methyl iodide. Their absolute configurations were determined by transforming the major products into the known α-alkyl α-amino acid derivatives 30, 33 and 35. The major product 43, prepared by allylation of the half-ester 9, was converted into two lactones 41 and 42, key intermediates for synthesis of indole alkaloids of the Hunteria and Aspidosperma types. The mechanism of the above alkylation is discussed.

The first total synthesis of (±)-methyl gummiferolate (1b) has been achieved with a high diastereoselectivity. The key steps included the homoallyl−homoallyl radical rearrangement reaction of the enyne 8 to afford the suitably functionalized bicyclo[2.2.2]octane 9 and the intramolecular Diels−Alder reaction of the tetraene 12 for the construction of the AB ring system of 1b.

In vivo antimalarial drug candidates screening test was carried out on a series of water-soluble 3,7-bis(dialkylamino)phenoxazin-5-ium derivatives. Among them, 3-(diethylamino)-7-(piperidin-1-yl)phenoxazin-5-ium chloride (SSJ-206) showing highest efficacy was chosen for further pharmcodynamics and pharmacokinetics study. It was supported from these data that the phenoxazinium salts, SSJ-206, would be one of hopeful candidates as an oral antimalarial drug.

Studies about the regiocontrolled addition of arylboronic acids to allenes using a palladium or a platinum catalyst have been described. The selectivity of the reaction can be altered by the choice of the metal reagent and base. Contrary to the formation of endo-olefinic products in the reactions using hydroxopalladium complex, predominant production of exo-olefinic products was observed by the reaction with hydroxoplatinum complex.

A CO2-fixation reaction of 4-(benzylamino)-2-butynyl carbonates and benzoates, carried out in the presence of DBU, provides substituted 5-vinylideneoxazolidin-2-ones. The reaction has been successfully applied to the CO2-recycling process and fixation of atmospheric CO2.

We describe here (2+2) cycloaddition reaction of alkyl enol ethers with acrylates catalyzed by triethylsilyl triflic imide (Et3SiNTf2), which was in situ generated from triethylsilane and triflic imide. The reaction efficiently provides substituted cyclobutanes bearing alkoxy function in a stereoselective manner.

A series of novel indoles were designed and their molecular modeling simulation study including fitting to a 3D pharmacophore model using CATALYST program and their docking into the NS3 active site was examined as HCV NS3 protease inhibitor. Several compounds showed significant high simulation docking score and fit values. The designed compounds were synthesized and biologically evaluated in vitro using an NS3 protease binding assay, where compounds 10a – k showed significant inhibitory activity (⩾67% inhibition at 100 μg/mL). Of these, compounds 10c and 10f demonstrated potent HCV NS3 protease inhibitors with IC 50 values of 15 and 13 μM, respectively. Enantio-selective Michael addition of an indole derivative in the presence of catalytic amount of AlCl 3 and quinine at room temperature afforded the adduct 7e in excellent yield with 73% ee. The product was converted into 10l , which showed lower activity than the mixture of the corresponding diastereoisomers.

A CO2-recycling reaction using (E)-4-(benzylamino)-2-butenyl methyl carbonates has been examined and substituted vinyloxazolidinones were obtained via a CO2 fixation–elimination process, carried out in the presence of palladium catalyst with DBU.

The bridged, pentacyclic intermediate 2 for atisine (1) was synthesized in a naturally occurring enantiomeric form from dimethyl cyclohexanone-2,6-dicarboxylate (6). The synthesis is composed of the following key steps: (1) formation of the azabicyclo [3.3.1] nonane by a double Mannich reaction, (2) enantioselective conversion by a lipase-catalyzed acylation, (3) stereoselective hydroboration in the presence of BF 3 .Et 2 O, and (4) construction of the bicyclo [2.2.2] octane ring system by an intramolecular double Michael reaction

Both enantiomers of the menthyl half-esters (10) and (23) of ethylmalonic acid were converted into(+)-(4S,5R)-4-(2-benzyloxyethyl)-5-ethyl-3,4,5,6-tetrahydro-2-pyrone (18). A mixture of the trans-(18) and cis-lactones (19) in a ratio of ca. 4 : 1 was prepared by way of radical cyclisation of the (E)-α,β-unsaturated esters (16), while the former (18) was synthesised with high stereoselection by the cyclisation of the (Z)-esters (26). The lactone (18) was enantioselectively transformed into (–)-protoemetimol (5) and (–)-protoemetine (4), correlated to (–)-emetine (1) and (–)-tubulosine (3).