Search

New metal-free one-pot synthesis of α-2-deoxy-ulosides in moderate to good yields by microwave-assisted double Michael addition of various O-nucleophiles to β-enamino ketones in the presence of 12 N HCl. These glycosyl additions occurred with high α-stereoselectivity and were complete in 10-25 min in 51-93% yield. In addition, high α-stereoselectivity was also observed when S-nucleophiles were examined.

Curcumin and curcuminoids have been discussed frequently due to their promising functional groups (such as scaffolds of α,β-unsaturated β-diketone, α,β-unsaturated ketone and β′-hydroxy-α,β-unsaturated ketone connected with aromatic rings on both sides) that play an important role in various bioactivities, including antioxidant, anti-inflammatory, anti-proliferation and anticancer activity. A series of novel curcuminoid derivatives (a total of 55 new compounds) and three reference compounds were synthesized with good yields using three-step organic synthesis. The anti-proliferative activities of curcumin derivatives were examined for six human cancer cell lines: HeLaS3, KBvin, MCF-7, HepG2, NCI-H460 and NCI-H460/MX20. Compared to the IC50 values of all the synthesized derivatives, most α,β-unsaturated ketones displayed potent anti-proliferative effects against all six human cancer cell lines, whereas β′-hydroxy-α,β-unsaturated ketones and α,β-unsaturated β-diketones presented moderate anti-proliferative effects. Two potent curcuminoid derivatives were found among all the novel derivatives and reference compounds: (E)-5-hydroxy-7-phenyl-1-(3,4,5-trimethoxyphenyl)hept-1-en-3-one (compound 3) and (1E,4E)-1,7-bis(3,4,5-trimethoxyphenyl)hepta-1,4-dien-3-one (compound MD12a). These were selected for further analysis after the evaluation of their anti-proliferative effects against all human cancer cell lines. The results of apoptosis assays revealed that the number of dead cells was increased in early apoptosis and late apoptosis, while cell proliferation was also decreased after applying various concentrations of (E)-5-hydroxy-7-phenyl-1-(3,4,5-trimethoxyphenyl)hept-1-en-3-one (compound 3) and (1E,4E)-1,7-bis(3,4,5-trimethoxyphenyl)hepta-1,4-dien-3-one (compound MD12a) to MCF-7 and HpeG2 cancer cells. Analysis of the gene expression arrays showed that three genes (GADD45B, SESN2 and BBC3) were correlated with the p53 pathway. From the quantitative PCR analysis, it was seen that (1E,4E)-1,7-bis(3,4,5-trimethoxyphenyl)hepta-1,4-dien-3-one (compound MD12a) effectively induced the up-regulated expression of GADD45B, leading to the suppression of MCF-7 cancer cell formation and cell death. Molecular docking analysis was used to predict and sketch the interactions of the GADD45B-α,β-unsaturated ketone complex for help in drug design.

Curcumin is proven to have potent anti-inflammatory activity, but its low water solubility and rapid degradation in physiological conditions limit its clinical use, particularly in intravenous drug delivery. In this study, we fabricated rod-shaped, acid-labile nanogels, using high biosafe and biocompatible polymers, for intravenous application in systemic inflammation treatment. The constituent polymers of the nanogels were prepared via the conjugation of vitamin B

Ultraviolet A (UVA) irradiation (320-400 nm range) triggers deleterious consequences in skin cell microenvironment leading to skin damage, photoaging (premature skin aging), and cancer. The accumulation of intracellular reactive oxygen species (ROS) plays a key role in this effect. With rapid progress in cosmetic health and quality of life, use of safe and highly effective phytochemicals has become a need of the hour. Zerumbone (ZER), a natural sesquiterpene, from Zingiber zerumbet rhizomes is well-known for its beneficial effects. We investigated the antiphotoaging and dermatoprotective efficacies of ZER (2-8 μM) against UVA irradiation (3 J/cm2) and elucidated the underlying molecular mechanisms in human skin fibroblast (HSF) cells. ZER treatment prior to low dose of UVA exposure increased cell viability. UVA-induced ROS generation was remarkably suppressed by ZER with parallel inhibition of MMP-1 activation and collagen III degradation. This was due to the inhibition of AP-1 (c-Fos and c-Jun) translocation. Furthermore, ZER alleviated UVA-induced SA-β-galactosidase activity. Dose- or time-dependent increase of antioxidant genes, HO-1 and γ-GCLC by ZER, was associated with increased expression and nuclear accumulation of Nrf2 as well as decreased cytosolic Keap-1 expressions. Altered luciferase activity of ARE could explain the significance of Nrf2/ARE pathway underlying the dermatoprotective properties of ZER. Pharmacological inhibition of various signaling pathways suppressed nuclear Nrf2 activation in HSF cells confirming that Nrf2 translocation was mediated by ERK, JNK, PI3K/AKT, PKC, AMPK, casein kinase II, and ROS signaling pathways. Moreover, increased basal ROS levels and Nrf2 translocation seem crucial in ZER-mediated Nrf2/ARE signaling pathway. This was also evidenced from Nrf2 knocked-out studies in which ZER was not able to suppress the UVA-induced ROS generation in the absence of Nrf2. This study concluded that in the treatment of UVA-induced premature skin aging, ZER may consider as a desirable food supplement for skin protection and/or preparation of skin care products.

A practical Lewis acid-catalyzed Meyer–Schuster rearrangement of fluoroalkylated propargylic alcohols, leading to a series of β-fluoroalkyl-α,β-enones, is developed. The methodology reported herein features moderate to high yields and high stereoselectivity in the synthesis of β-alkyl-β-fluoroalkyl-α,β-enones.

Treatment of cancer patients with chemotherapeutic drugs is often associated with the occurrence of tumors with a multidrug resistance (MDR). Furthermore, the relation between overexpression of P-glycoprotein (P-gp) and resistant cancers has been well established. In this study, novel 2-aminobenzofuran derivatives were synthesized and tested for their ability to modulate P-gp mediated multidrug resistance (MDR) in vitro. The most potent compound, 43, increased P-gp inhibitory activity at 5 μM by 11.12-fold and was 3.6-fold stronger than verapamil. Furthermore, 43 can sensitize Flp-In™-293/MDR cells toward vincristine, paclitaxel and doxorubicin by 17.95-fold, 13.68-fold and 26.43-fold at 2.5 μM, respectively. 43 also can sensitize the resistant cancer cell line KBvin toward vincristine, paclitaxel and doxorubicin by 246.43-fold, 38.72-fold and 5.16-fold at 2.5 μM, respectively. In conclusion, important aspects for developing potent P-gp inhibitors have been emphasized in this study, providing a starting point for the further structural optimization of P-gp inhibitors.

Starting from commercially available 2-chloro-4-fluorobenzoic acid 4, synthesis of fluazolate was achieved in up to 30% overall yield via the key procedure of either regioselective [3+2] cyclocondensation of trifluoromethyl-α,β-ynone 2 with hydrazine hydrate or nucleophilic substitution-cyclization of trifluoromethyl-α,β-dibromoenone 10 with hydrazine hydrate.

Spiro bis-C,C-α-arylglycosides were synthesized in three steps in 78-85% overall yields starting from exo-glycals. The initial Heck type C-aryl addition of exo-glycals with arylboronic acids afforded α-aryl-β-substituted C-glycosides with exclusive α-stereoselectivity. Among the products, β-ethanal α-aryl C-glycosides further reacted with alkylthiol in the presence of InCl3, followed by in situ Friedel-Crafts cyclization to yield the desirable final products. We proposed a mechanism to explain how the α-aryl group serves as a main determinant of the cyclization.

Toona sinensis is a common edible vegetable that is used in certain Chinese dishes and has importance in folk medicine. The leaf extracts of T sinensis possess and exhibit anticancer efficacy against various cancer cell types. In Taiwanese folklore, Antrodia camphorata, also known as “Niu-Cheng-Zi,” is used in traditional medicine to treat various illnesses. Its fruit and mycelium possess various potent antiproliferative properties. Two studies from our group have reported that T sinensis or A camphorata has the ability to cause apoptosis in various cancer cells. Conversely, underlying molecular mechanisms and any beneficial effects remain unknown. This study shows anticancer efficacy for both T sinensis and A camphorata co-treatments that target HL-60 cells. The combination index values indicate that 40 µg/mL of T sinensis and 25 µg/mL of A camphorata as a combined treatment shows a synergetic effect, which reduces HL-60 cell proliferation. Alternately, this treatment exhibited no cytotoxic effects for human umbilical vein endothelial cells. Western blot data showed that T sinensis and A camphorata as a combined treatment result in augmented expression of apoptosis, cytochrome c release, Bcl-2 inhibition, expression of Bax, Fas, and FasL, as well as the cleavage of Bid in HL-60 cells. Moreover, this combined treatment overshadowed monotherapy in its ability to inhibit uPAR, MMP-9, MMP-2, COX-2 expression, and PGE2 secretions. Our study strongly implies that this combined treatment offers more beneficial effects to suppress and treat leukemia due to apoptosis-mediated cell inhibition. Further in vivo studies related to the combined treatment could establish its future potential.

We reported in our previously executed studies that the fermented culture broth of Antrodia salmonea (AS), a mushroom used in Taiwanese folk medicine induced reactive oxygen species (ROS)-mediated apoptosis in human ovarian carcinoma cells. In this study, we studied the anticancer efficacies of AS (0-240 μg/ml) by examining the key molecular events implicated in cell death associated with autophagy in SKOV-3 and A2780 human ovarian carcinoma cells and clarified the fundamental molecular mechanisms. Treatment of ovarian carcinoma cells with AS-induced autophagic cell death mediated by increased microtubule-associated protein LC3-II, GFP-LC3 puncta, and acidic vesicular organelle (AVO) formation. These events are linked with the activation of p62/SQSTM1, the inhibition of ATG4B, the expression of ATG7, and the dysregulation of Beclin-1/Bcl-2 (i.e., B-cell lymphoma 2). N-acetylcysteine inhibited AS-induced ROS generation, which in turn constricted AS-induced LC3 conversion, AVO formation, and ATG4B inhibition, indicating ROS-mediated autophagy cell death. In addition, the 3-methyladenine (3-MA) or chloroquine (CQ)-induced autophagy inhibition decreased AS-induced apoptosis. Additionally, apoptosis inhibition by Z-VAD-FMK, a pan-caspase inhibitor, substantially suppressed AS-induced autophagy. Furthermore, AS-inhibited HER-2/ neu and PI3K/AKT signaling pathways which were reversed by autophagy inhibitors 3-MA and CQ. Thus, A. salmonea is a potential chemopreventive agent that is capable of activating ROS-mediated autophagic cell death in ovarian carcinoma cells.

Amplification of the HER2 gene (also known as neu or ErbB2) or overexpression of HER2 protein has become a solicitous therapeutic target in metastatic and clinical drug-resistance cancer. In our present work, a new series of curcumin derivatives were designed and synthesized using curcumin as model. Here, we evaluated whether curcumin derivatives have better efficiency to degrade HER2 than curcumin. Among these test compounds, pculin02H had better efficiency to inhibit the expression of HER2 than curcumin. Moreover, pculin02H preferentially suppressed the growth of HER2-overexpressing cancer cell lines. Pculin02H induced G2/M cell cycle arrest followed by apoptosis. Interestingly, our results suggested that a posttranslational mechanism contributed to pculin02H-induced HER2 depletion in HER2-overexpressing cancer cells. We found that pculin02H significantly enhanced the antitumor efficacy of clinical drugs on HER2-overexpressing cancer cells as well as efficiently reduced HER2-induced drug resistance. These findings may provide an alternative preventive or therapeutic strategy against HER2-overexpressing cancer cells.

The title cyclocondensation reaction gives 3-trifluoromethylpyrazoles [e.g. (III)] with high regioselectivity in the presence of Cu(OAc)2 in CH2Cl2, while 5-trifluoromethylpyrazoles [e.g. (VII)] are predominantly obtained without catalyst in DMSO.

α-2,3-Unsaturated galactosides were synthesized in good to excellent yields by the initial activation of d-galactals with diethyl phosphorochloridite and the subsequent glycosyl addition via Ferrier rearrangement with various O-nucleophiles in the presence of AlCl3. The two-step reactions were carried out in one-pot and finished within 60 min in 81–95% yield to give the glycoside products with excellent α-stereoselectivity.

α-2-Deoxyulosides were synthesized in moderate to good yields by Michael addition of various O -nucleophiles to hex-1-en-3-ones in the presence of NaOH. These glycosyl additions were complete in 30 min at room temperature with high α-stereoselectivity in 53–92% yield. In addition, high α-stereoselectivity was also observed when S -nucleophiles were examined at 0 °C for 90 min.

We synthesized acetal aza-cage compounds directly via ozonolysis of 2,3-bis- endo -diol- and diacylnorbornenes in dichloromethane at −78 °C. Ozonolysis of the diols followed by addition of amines gave the aza-cage compounds in high yields. The reaction mechanism for the formation of this type of aza-cage compounds is proposed to proceed via the hydroperoxide intermediate. Ozonolysis of the diacetyl norbornene followed by addition of (1) primary amines gave monoaza-cages and diaza-cage, (2) tert -butylamine gave hydroxyl lactone and diaza-cages, and (3) amino acid ester gave optically active aza-cages, in which one compound was converted into chiral aminoalcohol and structure of another was proven by X-ray analysis. A mechanism via the final ozonide and the imine intermediates is proposed for the formation of this type of aza-cages.

Multidrug resistance (MDR) is a phenomenon in which cells become resistant to structurally and mechanistically unrelated drugs, and it is one of the emerging problems in cancer therapy today. The relation between overexpression of the ABC transporter subfamily B member 1 (ABCB1/P-glycoprotein) and resistant cancers has been well characterized. In the present study, we successfully synthesized 52 novel benzodipyranone analogs and evaluated for their P-gp inhibitory activity in a P-gp transfected cell line, ABCB1/Flp-In™-293. Among these derivatives, 5a bearing on the 3-methylphenyl substituent, displayed the most potent P-gp inhibitory activity, which can enable the increase of the intracellular accumulation of P-gp substrate Calcein-AM. 5a exhibited more potency on promoted anticancer drugs cytotoxicity by reversing P-gp-mediated drug resistance in both ABCB1/Flp-In™-293 and KBvin cell lines. In particular, the compound 5a sensitized ABCB1/Flp-In™-293 cells toward paclitaxel, vincristine, and doxorubicin by 16.1, 21.0, and 1.6-fold at 10 μM, respectively. Further, 5a dramatically sensitized the resistant cell line KBvin toward paclitaxel and vincristine by 23.1 and 29.7-fold at 10 μM, respectively. It's possible that its mechanism of MDR inhibition can restore the intracellular accumulation of drugs and eventually chemosensitize cancer cells to anticancer drugs and reduce ABCB1 mRNA expression level.

α-2-Deoxyglycosides were synthesized in good to excellent yields by microwave-assisted reaction of endo -glycals with various O -nucleophiles in the presence of catalytic amount of AlCl 3 . These glycosyl additions occurred with high α-stereoselectivity and were complete in 5–35 min in 65–93% yield.

β-Enamino ketones were successfully synthesized by reaction of endo glycals with primary or secondary amines in the presence of hypervalent iodine reagent in one pot. After the oxidation and protonation taking place on hypervalent iodine agent in acidic condition, endo glucals were effectively converted into the uncyclic β-alkoxyvinyl ketones. Further substitution of β-alkoxyvinyl ketones with primary or secondary amines provided the corresponding β-enamino ketone derivatives in 57–67% yields.

Dibromoisocyanuric acid proves to be a more efficient reagent for the dibromination of the title pyrazole derivatives than NBS.

A new spirocyclization was developed for the synthesis of 1,7-dioxaspiro[5.5]undecanes and 1-oxa-7-thiaspiro[5.5]undecanes by reaction of exo -glycal with aryl alcohols or thiophenols in the presence of Lewis acid BF 3 ·OEt 2 . The reaction proceeded through tandem Ferrier rearrangement, glycosylation, and Friedel–Crafts alkylation to provide the corresponding products in good to excellent yields.

A ‘one-flask’ synthesis of guanidines was developed by reacting isocyanates and isothiocyanates with sodium bis(trimethylsilyl)amide followed by addition of primary or secondary amines with a catalytic amount of AlCl 3 . The desired guanidines were obtained in good yields and the reaction was applicable to aliphatic and aromatic substrates. A plausible mechanism was proposed through the generation of cyanamide anion from isocyanates or isothiocyanates with sodium bis(trimethylsilyl)amide. Addition of amines and catalytic amount of AlCl 3 smoothly converted the cyanamides to the desired guanidines.

An efficient and convenient method for the bromination of pyrazolones and 5-hydroxypyrazoles was developed by using N -bromobenzamide in THF at room temperature. This new method provided di-bromimated pyrazolones in excellent yields (≥90%).

A new safe and convenient transformation has been developed. In the presence of cesium formate in dry MeOH solution, α-haloketones underwent direct conversion reaction to afford α-hydroxyketone in excellent yields. Furthermore, this methodology can be extended and applied in 2-chloro-N-(1,3-diphenyl-1H-pyrazol-5-yl)acetamide, 2-chloro-N-(2,6-dimethylphen-yl)acetamide, 1-(bromomethylsulfonyl)benzene, and N-(bromomethyl)phthalimide to give the corresponding products in moderate to excellent yields.

The synthesis of new dioxa-cage compound 8 and diacetal trioxa-cage compound 17 has been accomplished from dicyclopentadiene in a short sequence. A preliminary study on the π-facial selectivity of 17, which possesses a new rigid skeleton, is also reported.

Amphiphatic Piperazine, Pyrazine, and Pyridine Derivaties as the Thermal Latency for Epoxy-Phenolic Resins

Acid-mediated glycosylations of endo- and exo-glycals have been carried out in good to excellent yields, in which a mixture of two products is often obtained resulting from Ferrier rearrangement and protonation. The former reaction exclusively takes place with the t-butyl carbonate or hydroxyl substituent at the C3 position of endo-glycals, while the latter mainly occurs in the glycosylation of exo-glycals with allyl benzyl ether or acetate. In addition to the substituent effect, protecting groups are critical to determine the activity and favored reaction pathway. Furthermore, the method is applicable to O-, C-, and N-nucleophiles.

exo -Glycosyl carbonates were shown to be efficient glycosyl donors in microwave-assisted glycosylation. In these reactions α-glycosyl additions occurred with excellent stereoselectivity and were complete in 4–8 min with 75–92% yield. Interestingly exo -glycals were found to have higher activity than endo -glycals and common glycosides, the reactions of which can be improved by the addition of Lewis acid to result in a higher yield and enhanced stereoselectivity.

The synthesis of novel acetal thia-cage compounds has been accomplished by the direct substitution for the oxygen atom by the sulfur atom in the reaction of the acetal groups of oxa-cages with Lawesson reagent (LR). Reaction of the tetraoxa-cage compound 2 with LR in dichloromethane at 25 degrees C sequentially gave the monothia-, dithia-, trithia-, and tetrathia-cage compounds 3, 6, 7, and 9. The reaction mechanism for the conversion from oxa-cages into thia-cages was proposed. The diacetal trioxa-cages 18-20 and 24-26 were also transformed into the thia-cages 21-23 and 27-29, respectively. Reaction of the trioxa-cages 34 and 35 with LR under the same reaction conditions gave the thia-cages 36 and 37 with the carbonyl group intact. Treatment of the pentaoxa[5]peristylane 40 with LR in chloroform under supersonic shaking at refluxing temperature gave the monothia[5]peristylane 41 and the dithia[5]peristylane 42. Attempts to synthesize the thia[5]peristylanes from the tetraoxa-cage 51 and the transformation from the parent (unsubstituted) pentaoxa[5]peristylane 46 to the thia-cages have been made. Reaction of the pentaoxa[5]-peristylane 40 with P(2)S(5) in refluxing toluene gave 41, 42, and a rearrangement product 47. The synthesis of new heterocyclic cage compounds 59 and 60, which contain oxygen, nitrogen, and sulfur atoms in the same molecule, was also accomplished.

A new entry for the synthesis of diacetal trioxa-cage compounds via oxirane-induced sequential cyclization reaction of 2,3-bis- endo -diacylbicyclo[2.2.1]-5-heptenes and 2,3-bis- endo -diacylbicyclo[2.2.2]-5-octenes is reported. In the case of bicyclo[2.2.2]octenes, sequential cyclization reaction induced by iodine as electrophile failed. We have also demonstrated that dimethyldioxirane can selectively oxidize hemiacetals to give lactones with the secondary hydroxy group intact.

α-2-Deoxyglycosides were successfully synthesized by means of microwave-assisted glycosylation. Hex-1-en-3-uloses were treated with a catalytic amount of AlCl 3 and various O -nucleophiles including alcohols and sugars under microwave conditions. The desired α-2-deoxy-ulosides products were obtained in good to excellent yields with high stereoselectivity (α/β ⩾ 88/12).

β-Enamino ketones were successfully synthesized in good to excellent yields by reaction of hex-1-en-3-uloses with amines. After hydrogenation on palladium catalyst, β-enamino ketones effectively underwent hydrodeamination and were converted to the corresponding 1,2-dideoxy- d -threo-3-hexulose derivatives in 89–95% yields.

The base-catalyzed intramolecular Diels–Alder reactions of 2-diphenylphosphinyl-5-(propargyloxymethyl)furans 2a–e gave the tetrahydrofuran ring annulated o-diphenylphosphinophenols 3a–e in 70–80% yields, a novel reaction involving an intramolecular Diels–Alder reaction of furan diene with allenyl ether dienophile followed by a nucleophilic 1,2-rearrangement of the diphenylphosphinyl group.

The synthesis of 3,11-dioxatetracyclo[6.3.0.02,6.05,9]undecanes has been accomplished from furans in a short sequence by iodine-induced cyclization reaction. The application of iodine-induced cyclization reaction for the synthesis of 3,5,7-trioxapentacyclo[7.2.1.02,8.04,11.06,10]dodecane itself was also demonstrated.

The synthesis of diacetal trioxa-cage compounds via a sequential cyclization reaction of norbornene derivatives induced by electrophiles in a short sequence is reported. Treatment of the norbornene derivatives 2a−d and 10b with I2 in aqueous THF in the presence of KI at 25 °C regioselectively gave the iodo-cage compounds 3a−d and 11 in 80−90% yields, respectively, via a iodine-induced sequential cyclization reaction. No detectable amount of other regioisomers or monocyclization products was obtained. The synthesis of trioxa-cages 14a−e was accomplished from 3a−d and 11 in a two-step sequence. Treatment of diacylnorbornenes 15a−f with I2 in aqueous THF at 25 °C regioselectively and stereoselectively gave the sequential cyclization products 16a−f, respectively, which were converted in one step to the diacetal trioxa-cages 24a−f in high yields. The structure of these trioxa-cages was proven by X-ray analysis of the crystalline compound 14e. Other electrophiles, such as bromine, m-CPBA, and Hg(OAc)2, were als...

β-Enaminals were successfully synthesized in good to excellent yields by the reaction of C2-formylglycals with primary amines. Subsequent reaction with NaBH4 in HOAc led to unexpected reductive cleavage of allyl ether, i.e., the hydrodealkoxylation took place to produce the corresponding 3-deoxy-β-enaminals. In contrast, the reaction of β-enaminals with Zn/HOAc performed H4-elimination to afford a diene product. The result was attributed to the formation of a common eneiminium ion intermediate, and the different reduction reactivity.

[reaction: see text] Owing to the driving force of the Ferrier-type rearrangement, the exo-glycals are highly reactive with various alcohols to afford glycosides and glycoconjugates with exclusive alpha-configuration. The resulting vinyl group in these glycosylation products can be further elaborated for general applications, including the synthesis of spiro derivatives and glycosylation of 2-ketoaldonic acids.

Microwave-assisted glycosylation of endo-glycals with various O-nucleophiles proceeds smoothly in the presence of catalytic amounts of AlCl3 to give 2-deoxyglycosides, e.g. (III) or (V), with high α-stereoselectivity.

β-Enamino ketones were successfully synthesized by reaction of endo glycals with primary or secondary amines in the presence of hypervalent iodine reagent in one pot. After the oxidation and protonation taking place on hypervalent iodine agent in acidic condition, endo glucals were effectively converted into the uncyclic β-alkoxyvinyl ketones. Further substitution of β-alkoxyvinyl ketones with primary or secondary amines provided the corresponding β-enamino ketone derivatives in 57–67% yields.

Dibromoisocyanuric acid proves to be a more efficient reagent for the dibromination of the title pyrazole derivatives than NBS.

A new spirocyclization was developed for the synthesis of 1,7-dioxaspiro[5.5]undecanes and 1-oxa-7-thiaspiro[5.5]undecanes by reaction of exo -glycal with aryl alcohols or thiophenols in the presence of Lewis acid BF 3 ·OEt 2 . The reaction proceeded through tandem Ferrier rearrangement, glycosylation, and Friedel–Crafts alkylation to provide the corresponding products in good to excellent yields.

The synthesis of diacetal trioxa-cage compounds via a sequential cyclization reaction of norbornene derivatives induced by electrophiles in a short sequence is reported. Treatment of the norbornene derivatives 2a−d and 10b with I2 in aqueous THF in the presence of KI at 25 °C regioselectively gave the iodo-cage compounds 3a−d and 11 in 80−90% yields, respectively, via a iodine-induced sequential cyclization reaction. No detectable amount of other regioisomers or monocyclization products was obtained. The synthesis of trioxa-cages 14a−e was accomplished from 3a−d and 11 in a two-step sequence. Treatment of diacylnorbornenes 15a−f with I2 in aqueous THF at 25 °C regioselectively and stereoselectively gave the sequential cyclization products 16a−f, respectively, which were converted in one step to the diacetal trioxa-cages 24a−f in high yields. The structure of these trioxa-cages was proven by X-ray analysis of the crystalline compound 14e. Other electrophiles, such as bromine, m-CPBA, and Hg(OAc)2, were als...