Stereocontrolled Total Synthesis of (+)-Isolaurenidificin and (-)-Bromlaurenidificin.

We report the first total syntheses of (+)-isolaurenidificin (1) and (-)-bromlaurenidificin (2), the latest acetogenins of the 2,6-dioxabicyclo[3.3.0]octane class. The synthesis features a completely stereoselective one-pot epimerization-ring contraction to establish the cis configuration with respect to C10-H and C12-H of the tetrahydrofuran ring. Six stereogenic centers and an olefin geometry were constructed in a highly stereoselective manner. Absolute configurations of the natural products were deduced by the comparison of NMR data and specific rotations.

Syntheses of (-)-Tripterifordin and (-)-Neotripterifordin from Stevioside.

We report short syntheses of (-)-tripterifordin and (-)-neotripterifordin, potent inhibitors of HIV replication, from stevioside, a natural sweetener used worldwide. The key transformations are reduction at C13 through the formation of a tertiary chloride and subsequent three-step lactonization including a selective iodination at C20 by the photoreaction of the C19-alcohol. The title compounds were reliably obtained from stevioside in 9 and 11 steps (with 5-7 isolation steps), respectively. Additionally, the related lactone-containing ent-kaurenes, doianoterpenes A and B, and two more natural products were synthesized.

Stereocontrolled Synthesis of a Possible Stereoisomer of Laurenidificin and a Formal Total Synthesis of (+)-Aplysiallene Featuring a Stereospecific Ring Contraction.

We report a highly stereocontrolled total synthesis of one of the possible stereoisomers of laurenidificin. Highlights of the synthesis include the formation of the 2,6-dioxabicyclo[3.3.0]octane framework by a stereospecific bromolactonization-α-bromination-ring contraction sequence, followed by a stereoselective propargylation, an insertion of the Z-enyne side chain by a hydroindation/cross coupling reaction, and ethylation at C13 with an organocuprate reagent. While the synthetic compound was not identical to the natural product, the absolute stereochemistry of the natural product was proposed on the basis of NMR analyses. Moreover, a formal total synthesis of (+)-aplysiallene was achieved by extending the ring contraction strategy.

Divergent synthesis of bioactive resorcinols isolated from the fruiting bodies of Hericium erinaceum: total syntheses of hericenones A, B, and I, hericenols B-D, and erinacerins A and B.

Total syntheses of 5'- and 7'-oxidized geranyl resorcylates isolated from the fruiting bodies of Hericium erinaceum and the submerged cultures of a Stereum species were achieved. Our synthesis features derivatization of a suitably functionalized 5'-oxidized geranyl phthalide as a common intermediate, which was obtained by Stille coupling between the phthalide core and the side chain, into a series of natural products by divergent functional group manipulations. The crucial C5'-oxygen functionality was installed at the initial stage by alkylation by an α-cyano ethoxyethyl ether. From a common synthetic intermediate, eight total syntheses including hericenones A, B, and I, hericenols B-D, and erinacerins A and B were achieved (hericenol B and erinacerin B were synthesized as racemates). The structure of hericenone B established in the isolation paper was unambiguously revised as the carbonyl regioisomer at the lactam moiety.

Plasmodium falciparum endoplasmic reticulum-resident calcium binding protein is a possible target of synthetic antimalarial endoperoxides, N-89 and N-251.

The endoperoxide artemisinin is a current first-line antimalarial and a critical component of the artemisinin-based combination therapies (ACT) recommended by WHO for treatment of Plasmodium falciparum, the deadliest of malaria parasites. However, recent emergence of the artemisinin-resistant P. falciparum urged us to develop new antimalarial drugs. We have shown that synthetic endoperoxides N-89 and its hydroxyl derivative N-251 had high antimalarial activities both in vivo and in vitro. However, the mechanisms including the cellular targets of the endoperoxide antimalarials are not well understood. Thus, in this study, we employed chemical proteomics to survey potential molecular targets of endoperoxides by evaluating P. falciparum proteins capable to associate with endoperoxide structure (N-346, a carboxyamino derivative of N-89). We also analyzed the protein expression profiles of malaria parasites treated with N-89 or N-251 to explore possible changes associated with the drug action. From these experiments, we found that P. falciparum endoplasmic reticulum-resident calcium binding protein (PfERC) had high affinity to the endoperoxide structure (N-346) and was decreased by treatment with N-89 or N-251. PfERC is a member of CREC protein family, a potential disease marker and also a potential target for therapeutic intervention. We propose that the PfERC is a strong candidate of the endoperoxide antimalarial's target.

Total synthesis and structural revision of hericerin.

The total synthesis of hericerin, a pollen growth inhibitor from Hericium erinaceum, was achieved. We found that the reported structure of hericerin should be revised to be the carbonyl regioisomer.

Optimization of lactobionic acid production by Acetobacter orientalis isolated from Caucasian fermented milk, "Caspian Sea yogurt".

We have reported that lactobionic acid is produced from lactose by Acetobacter orientalis in traditional Caucasian fermented milk. To maximize the application of lactobionic acid, we investigated favorable conditions for the preparation of resting A. orientalis cells and lactose oxidation. The resting cells, prepared under the most favorable conditions, effectively oxidized 2-10% lactose at 97.2 to 99.7 mol % yield.

Improvements in extraction yield by solid phase lipid extraction from liquid infant formula and human milk, and the fatty acid distribution in milk TAG analyzed by joint JOCS/AOCS official method Ch 3a-19.

The Röse-Gottlieb method is one of the most widely used methods for extracting lipids from milk samples. However, we found that lipid recovery from liquid infant formula and human breast milk was lower than expected. Better lipid recovery from these liquid matrices was obtained by solid phase extraction using silica gel; ~10% more could be recovered from liquid infant formula and ruminant milk, and 25% more from human breast milk. However, the method is not recommended for lipid extraction from dried whole milk powders.

Stereocontrolled synthesis of substituted bicyclic ethers through oxy-Favorskii rearrangement: total synthesis of (±)-communiol E.

The potential of the oxy-Favorskii rearrangement to form branched cis-fused bicyclic ethers was explored. Both tertiary and quaternary centers were constructed in highly stereospecific manners. Methanol and primary amines were effective nucleophiles for the rearrangement. The total synthesis of (±)-communiol E was achieved based on this method.

4-Methyltetrahydropyran (4-MeTHP): Application as an Organic Reaction Solvent.

4-Methyltetrahydropyran (4-MeTHP) is a hydrophobic cyclic ether with potential for industrial applications. We herein report, for the first time, a comprehensive study on the performance of 4-MeTHP as an organic reaction solvent. Its broad application to organic reactions includes radical, Grignard, Wittig, organometallic, halogen-metal exchange, reduction, oxidation, epoxidation, amidation, esterification, metathesis, and other miscellaneous organic reactions. This breadth suggests 4-MeTHP can serve as a substitute for conventional ethers and harmful halogenated solvents. However, 4-MeTHP was found incompatible with strong Lewis acids, and the C-O bond was readily cleaved by treatment with BBr3 . Moreover, the radical-based degradation pathways of 4-MeTHP, THP and 2-MeTHF were elucidated on the basis of GC-MS analyses. The data reported herein is anticipated to be useful for a broad range of synthetic chemists, especially industrial process chemists, when selecting the reaction solvent with green chemistry perspectives.

Stage specific activity of synthetic antimalarial endoperoxides, N-89 and N-251, against Plasmodium falciparum.

We have reported that two endoperoxides, N-89 and N-251, synthesized in 2001, possess potent antimalarial activities. Aiming at their eventual use for curing malaria in humans, we have been investigating various aspects of their antimalarial actions. Here we show that N-89 and N-251 inhibit the growth of Plasmodium falciparum within human erythrocytes in vitro at its lifecycle stage 'trophozoite' specifically. It is known that artemisinin compounds, which are currently used for curing malaria, have other stage-specificities. Therefore, it is likely that the antimalarial mechanism of N-89 and N-251 differs from those of artemisinin compounds. As malaria parasites resistant to artemisinin-based combination therapy are currently emerging in some tropical regions, N-89 and N-251 are candidates for overcoming these new problems.

Synthesis and notable antimalarial activity of acyclic peroxides, L-(alkyldioxy)-L-(methyldioxy)cyclododecanes.

Of several bis(alkyldioxy)alkanes and the related acyclic peroxides prepared in this study, 1,1-bis(methyldioxy)cyclododecane showed the most notable antimalarial activity particularly in vivo (almost a half of that of artemisinin).

Antimalarial activity of yingzhaosu A analogues.

Iodonium ion mediated cyclization of unsaturated hydroperoxides 1 afforded the expected yingzhaosu A analogues 2. In some cases, however, the corresponding cyclic ethers 5 were formed competitively with the cyclic peroxides 2, the ratios of these two products being a marked function of the structure of the starting materials. Some of the cyclic peroxides 2 showed significant antimalarial activities in vitro and in vivo.

Antimalarial activity of novel 1,2,5,6-tetraoxacycloalkanes and 1,2,5-trioxacycloalkanes.

Photooxygenation of 2-phenylnorbornene 1 in the presence of 30% aqueous hydrogen peroxide afforded 1,2-bishydroperoxide 3, which could be cycloalkylated on treatment with silver oxide and a 1,omega-diiodoalkane to provide the tricyclic peroxides 12. Trimethylsilylation of 3 followed by TMSOTf-catalyzed cyclocondensation with carbonyl compounds led to the formation of the tricyclic peroxides 14 containing a 1,2,4,5-tetroxepane structure. Photooxygenation of 1 in the presence of either unsaturated hydroperoxides or unsaturated alcohols followed by bis(collidine)iodine hexafluorophosphate promoted cyclization gave the corresponding cyclic peroxides 15-17. Several of these cyclic peroxides showed substantial antimalarial activity particularly in vitro.

Co(III)-alkyl complex- and Co(III)-alkylperoxo complex-catalyzed triethylsilylperoxidation of alkenes with molecular oxygen and triethylsilane.

[reaction: see text] Both a Co(III)-alkyl complex and a Co(III)-alkylperoxo complex were found to catalyze triethylsilylperoxidation of alkenes with O(2) and Et(3)SiH. On this basis, together with the nonstereoselectivity in the Co(II)-catalyzed peroxidation of 3-phenylindene and the formation of the corresponding 1,2-dioxolane from 2-phenyl-1-vinylcyclopropane (a radical clock), we propose a reasonable mechanism for the Co(II)-catalyzed novel autoxidation of alkenes with Et(3)SiH discovered by Isayama and Mukaiyama.

Selective preparation of monobenzyl glyceryl ethers by the condensation reaction of glycerol with benzyl alcohols in the presence of zeolite catalysts.

The selective preparation of monobenzyl glyceryl ethers, which are potential commodity chemicals with special functions, was explored to find new applications for glycerol. Among the acid catalysts investigated (sulfuric acid, heteropoly acid, Nafion(R), and zeolite), Zeolite Socony Mobil-5 (ZSM-5) afforded better results. The reaction of equimolar amounts of glycerol and benzyl alcohol at 150ºC for 7 h in the presence of 2 wt% ZSM-5 selectively afforded 3-(benzyloxy)propane-1,2-diol with a very small amount of the corresponding 2-benzyloxy isomer in 86% gas chromatography yield.

Antimalarial activity of endoperoxide compound 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-1-ol.

Plasmodium falciparum, the major causative parasite for the disease, has acquired resistance to most of the antimalarial drugs used today, presenting an immediate need for new antimalarial drugs. Here, we report the in vitro and in vivo antimalarial activities of 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-1-ol (N-251) against P. falciparum and Plasmodium berghei parasites. The N-251 showed high antimalarial potencies both in the in vitro and the in vivo tests (EC(50) 2.3×10(-8) M; ED(50) 15 mg/kg (per oral)). The potencies were similar to that of artemisinin in vitro and greater than artemisinin's activity in vivo (p.o.). In addition, N-251 has little toxicity: a single oral administration at 2000 mg/kg to a rat gave no health problems to it. Administration of N-251 to mice bearing 1% of parasitemia (per oral 68 mg/kg, 3 times a day for 3 consecutive days) resulted in a dramatic decrease in the parasitemia: all the 5 mice given N-251 were cured without any recurrence, with no diarrhea or weight loss occurring in the 60 days of experiment. N-251 deserves more extensive clinical evaluation, desirably including future trials in the human.

Antimalarial activity of 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-1-ol (N-251) and its carboxylic acid derivatives.

Malaria is one of the world's deadliest diseases and is becoming an increasingly serious problem as malaria parasites develop resistance to most of the antimalarial drugs used today. We previously reported the in vitro and in vivo antimalarial potencies of 1,2,6,7-tetraoxaspiro[7.11]nonadecane (N-89) and 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-1-ol (N-251) against Plasmodium falciparum and Plasmodium berghei parasites. To improve water-solubility for synthetic peroxides, a variety of cyclic peroxides having carboxyl functionality was prepared based on the antimalarial candidate, N-251, and their antimalarial activities were determined. The reactions of N-89 and its derivatives with Fe(II) demonstrated a highly efficient formation of the corresponding carbon radical which may be suspected as a key for the antiparasitic activity.

Proteome analysis of new antimalarial endoperoxide against Plasmodium falciparum.

N-89, a new antimalarial endoperoxide, was selected as a promising antimalarial compound showing high activity and selectivity. To study the mechanism of N-89 action, N-89 resistant strain (NRC10) was obtained by intermittent drug pressure. NRC10 had a tenfold increase in the EC(50) value of N-89. No cross-resistance was obtained with other antimalarial compounds. Comparative proteome analysis of N-89 sensitive and NRC10 strains revealed over-expression of 12 spots and down-regulation of 14 spots in NRC10. Fifteen proteins were identified of Plasmodium falciparum origin. The identified proteins representing several functions, mainly related to the glycolytic pathway, and metabolism of protein and lipid. Our results suggest that identified proteins may be candidates of antimalarial endoperoxide targets.