Application of Carbohydrate-Templated Asymmetric Diels-Alder Reaction to the Syntheses of ent-Penicillones A and B.

Total syntheses of ent-penicillones A (ent-1) and B (ent-2) from 3,5-dimethylcatechol (3) were accomplished in 10 and 9 synthetic steps, respectively. A carbohydrate-templated asymmetric intramolecular Diels-Alder reaction of a masked o-benzoquinone (MOB) 9 and an aqueous acid-catalyzed intramolecular aldol reaction are the key synthetic steps. In addition, the absolute configurations of the bicyclo[2.2.2]oct-5-en-2-one core obtained from the per-O-benzylated α-d-glucopyranosyl as a carbohydrate template in the intramolecular Diels-Alder reaction of MOBs were revised.

First total synthesis of ganglioside DSG-A possessing neuritogenic activity.

The first total synthesis of ganglioside DSG-A (1) is achieved via chemoselective glycosylation and a [1 + 1 + 2] synthetic strategy. We have also developed an efficient method that can be handled on large scale (50 g) for the synthesis of the phytosphingosine.

First asymmetric total syntheses and determination of absolute configurations of (+)-eudesmadiene-12,6-olide and (+)-frullanolide.

The first asymmetric total syntheses of sesquiterpene lactones (+)-eudesmadiene-12,6-olide (1) and (+)-frullanolide (2) have been accomplished from 4-bromo-2-methoxyphenol (5) in 12 and 13 synthetic steps, respectively, and the absolute configurations of these two natural products were determined.

Intra- and intermolecular hydrogen bonds enhance the fluoride-responsiveness of functionalized glycolipid-based gelators.

We propose a facile approach toward enhancing the efficiency of fluoride-responsive gels through the positioning of functionalized receptor units, allowing tunable intra- and intermolecular hydrogen bonding, in the gelator molecules. We prepared the new glycolipid-based gelator 2 and its hydroxy and methoxy derivatives 2a and 2b, respectively, to study the effects of three types modes of supramolecular assembly: solely intermolecular hydrogen bonding in 2, solely intramolecular hydrogen bonding in 2b, and both inter- and intramolecular hydrogen bonding in 2a. 1H NMR spectra confirmed the self-assembly interactions of these glycolipid-based gelators. We measured the minimum gel concentrations and sol-gel transitions and recorded X-ray diffraction patterns and electron micrographs to characterize the gelation behavior and structural organization of each of these supramolecular gels. Among these three gelators, only 2 and 2a could form organogels in the test solvents, indicating that intermolecular hydrogen bonding plays a determinant role in the supramolecular assemblies leading to gelation. The self-assembly of 2 resulted in a bilayer-packed lamellar structure within ribbon-like fibers, whereas that of 2a resulted in hexagonally packed cylindrical micelles within tree-like fibers. A minimum amount of 0.3 equivalent of F- was required for complete disruption of the gel formed from 2a, which was approximately four times lower than that required for the gel formed from 2. Thus, the incorporation of a ß-hydroxy motif-the only difference in the chemical structures of 2 and 2a-led to interesting variations in the resulting gel morphologies and enhanced the gel's fluoride-responsiveness.

The total synthesis of a ganglioside Hp-s1 analogue possessing neuritogenic activity by chemoselective activation glycosylation.

The total synthesis of ganglioside 2, an analogue of the ganglioside Hp-s1 (1) which displays neuritogenic activity toward the rat pheochromocytoma cell line PC-12 cell in the presence of nerve growth factor (NGF) with an effect (34.0%) greater than that of the mammalian ganglioside GM 1 (25.4%), was accomplished by applying a chemoselective-activation glycosylation strategy. Moreover, we also demonstrate that the synthesized ganglioside 2 exhibited neuritogenic activity toward the human neuroblastoma cell line SH-SY5Y without the presence of NGF.

Scaffold-hopping strategy: synthesis and biological evaluation of 5,6-fused bicyclic heteroaromatics to identify orally bioavailable anticancer agents.

Utilizing scaffold-hopping drug-design strategy, we sought to identify a backup drug candidate for BPR0L075 (1), an indole-based anticancer agent. For this purpose, 5,6-fused bicyclic heteroaromatic scaffolds were designed and synthesized through shuffling of the nitrogen from the N-1 position or by insertion of one or two nitrogen atoms into the indole core of 1. Among these, 7-azaindole core 12 showed potent in vitro anticancer activity and improved oral bioavailability (F = 35%) compared with 1 (F < 10%).

Design and synthesis of tetrahydropyridothieno[2,3-d]pyrimidine scaffold based epidermal growth factor receptor (EGFR) kinase inhibitors: the role of side chain chirality and Michael acceptor group for maximal potency.

HTS hit 7 was modified through hybrid design strategy to introduce a chiral side chain followed by introduction of Michael acceptor group to obtain potent EGFR kinase inhibitors 11 and 19. Both 11 and 19 showed over 3 orders of magnitude enhanced HCC827 antiproliferative activity compared to HTS hit 7 and also inhibited gefitinib-resistant double mutant (DM, T790M/L858R) EGFR kinase at nanomolar concentration. Moreover, treatment with 19 shrinked tumor in nude mice xenograft model.

Fast-forwarding hit to lead: aurora and epidermal growth factor receptor kinase inhibitor lead identification.

A focused library of furanopyrimidine (350 compounds) was rapidly synthesized in parallel reactors and in situ screened for Aurora and epidermal growth factor receptor (EGFR) kinase activity, leading to the identification of some interesting hits. On the basis of structural biology observations, the hit 1a was modified to better fit the back pocket, producing the potent Aurora inhibitor 3 with submicromolar antiproliferative activity in HCT-116 colon cancer cell line. On the basis of docking studies with EGFR hit 1s, introduction of acrylamide Michael acceptor group led to 8, which inhibited both the wild and mutant EGFR kinase and also showed antiproliferative activity in HCC827 lung cancer cell line. Furthermore, the X-ray cocrystal study of 3 and 8 in complex with Aurora and EGFR, respectively, confirmed their hypothesized binding modes. Library construction, in situ screening, and structure-based drug design (SBDD) strategy described here could be applied for the lead identification of other kinases.

Syntheses of optically pure conduramines via the strategy of hetero Diels-Alder reaction of masked o-benzoquinones with homochiral nitroso dienophiles.

Highly stereoselective hetero Diels-Alder reactions of masked o-benzoquinones (MOBs) with homochiral nitroso dienophiles are described along with their application in the syntheses of (+)-ent-conduramine F-1, (+)-conduramine E-1, (-)-conduramine A-1, (+)-conduramine A-1 tetraacetate, and (-)-ent-conduramine A-1 tetraacetate.

Photochemistry of tricyclo[5.2.2.0(2,6)]undeca-4,10-dien-8-ones: an efficient general route to substituted linear triquinanes from 2-methoxyphenols. Total synthesis of (+/-)-Delta(9(12))-capnellene.

An efficient and short entry to polyfunctionalized linear triquinanes from 2-methoxyphenols is described by utilizing the following chemistry. The Diels-Alder reactions of masked o-benzoquinones, derived from 2-methoxyphenols, with cyclopentadiene afford tricyclo[5.2.2.0(2,6)]undeca-4,10-dien-8-ones. Photochemical oxa-di-pi-methane (ODPM) rearrangements and 1,3-acyl shifts of the Diels-Alder adducts are investigated. The ODPM-rearranged products are further converted to linear triquinanes by using an O-stannyl ketyl fragmentation. Application of this efficient strategy to the total synthesis of (+/-)-Delta(9(12))-capnellene was accomplished from 2-methoxy-4-methylphenol in nine steps with 20 % overall yield.

Anti-influenza drug discovery: structure-activity relationship and mechanistic insight into novel angelicin derivatives.

By using a cell-based high throughput screening campaign, a novel angelicin derivative 6a was identified to inhibit influenza A (H1N1) virus induced cytopathic effect in Madin-Darby canine kidney cell culture in low micromolar range. Detailed structure-activity relationship studies of 6a revealed that the angelicin scaffold is essential for activity in pharmacophore B, while meta-substituted phenyl/2-thiophene rings are optimal in pharmacophore A and C. The optimized lead 4-methyl-9-phenyl-8-(thiophene-2-carbonyl)-furo[2,3-h]chromen-2-one (8g, IC(50) = 70 nM) showed 64-fold enhanced activity compared to the high throughput screening (HTS) hit 6a. Also, 8g was found effective in case of influenza A (H3N2) and influenza B virus strains similar to approved anti-influenza drug zanamivir (4). Preliminary mechanistic studies suggest that these compounds act as anti-influenza agents by inhibiting ribonucleoprotein (RNP) complex associated activity and have the potential to be developed further, which could form the basis for developing additional defense against influenza pandemics.

Design and structural analysis of novel pharmacophores for potent and selective peroxisome proliferator-activated receptor gamma agonists.

Utilizing medicinal chemistry design strategies such as benzo splitting and ring expansion, we converted PPARalpha/gamma dual agonist 1 to selective PPARgamma agonists 19 and 20. Compounds 19 and 20 were 2- to 4-fold better than rosiglitazone at PPARgamma receptor, with 80- to 100-fold PPARgamma selectivity over PPARalpha receptor. X-ray cocrystal studies in PPARgamma and modeling studies in PPARalpha give molecular insights for the improved PPARgamma potency and selectivity for 19 when compared to 1.

Efficient synthesis and subsequent transformations of phenylsulfanylbicyclo[2.2.2]octenones and phenylselenylbicyclo[2.2.2]octenones.

Inverse-electron-demand Diels-Alder reactions of masked o-benzoquinones 2 with phenyl vinyl sulfide and phenyl vinyl selenide furnished highly functionalized bicyclo[2.2.2]octenone derivatives 3 and 4, respectively, in excellent regio- and stereoselectivities and yields up to 90%. The bicyclo[2.2.2]octenone derivatives 3 with the sulfur functionality were subjected to an oxidation-elimination process to furnish bicyclo[2.2.2]octadienone systems 7 in good yields. During the reduction process, the Diels-Alder adducts 3e and 4e led to 8, whereas the carbon-centered radicals generated from the other adducts 3a-d and 4a-d provided various rearranged products 9-13 depending on the substitution pattern and reagents utilized (Raney-Ni or n-Bu(3)SnH). Surprisingly these radicals showed preference for the carbonyl functionality to the olefinic double bond, leading to interesting rearrangement reactions of mechanistic importance and possible synthetic utility. Interestingly the alcohols obtained from the reduction of Diels-Alder adducts 3a-d underwent desulfurization smoothly to give desulfurized products in high yields; thus a detoured method of "reduction-desulfurization-oxidation" provides an entry to desulfurized bicyclo[2.2.2]octenones without rearrangement.

1,3- and 1,2-Carbo-migration of 2-vinylbicyclo[2.2.2]octenols: facile and concise synthesis of bicyclo[4.2.2]/[3.2.2] skeleton by two/one-carbon ring expansion.

The synthesis of a series of bicyclo[4.2.2]octenones and bicyclo[3.2.2]heptenones by 1,3- or 1,2-migration reaction from 2-vinylbicyclo[2.2.2]octenols is reported. These ring-expansion reactions were accomplished under basic or neutral conditions. Whether 1,3- or 1,2-migration takes place depends on endo- or exocyclic olefin displacement in the substrates.

Stereocontrolled synthesis of polyfunctionalized cis-decalins from 2-methoxyphenols: total syntheses of (+/-)-eremopetasidione, (+/-)-3 beta-angeloyloxyfuranoeremophilane, and (+/-)-3 beta-methacryloyloxyfuranoeremophilane.

A four-step stereocontrolled synthesis of polyfunctionalized cis-decalins is described, involving oxidation of 2-methoxyphenol, intermolecular Diels-Alder reaction, olefination, and Cope rearrangement. Application of this efficient strategy to the total syntheses of (+/-)-eremopetasidione, (+/-)-3 beta-angeloyloxyfuranoeremophilane, and (+/-)-3 beta-methacryloyloxyfuranoeremophilane was accomplished from creosol and ethyl vinyl ketone via a common intermediate 21.

First total syntheses of (+/-)-annuionone B and (+/-)-tanarifuranonol.

The intramolecular Diels-Alder reaction of o-quinol allyl ether was accomplished and subsequently applied to the first total syntheses of natural products annuionone B (1) and both the proposed and revised structure of tanarifuranonol, 4 and 17.

Chemoselective photorearrangements of diazinobarrelenes. Deuterium labeling study.

Chemoselective photorearrangements of pyrazino-, quinoxalino-, and benzoquinoxalinobarrelenes were investigated by deuterium-labeling experiment. Photolysis of pyrazinobarrelene 4 and quinoxalinobarrelene 5 with 300 nm region light under either direct or sensitized conditions afforded semibullvalenes 7 and 8, respectively; benzoquinoxalinobarrelene 6 was inert to both reaction conditions. Irradiation of deuterated pyrazinobarrelene 4-d4 and quinoxalinobarrelene 5-d4 afforded deuterated semibullvalenes 7-d4-A-7-d4-F and 8-d4-A-8-d4-F, respectively. Of the two a priori possibilities of bridging, the deuterium-labeling experiment has shown that deuterated pyrazinobarrelene 4-d4 afforded 98% (C6D6) and 95% (CD3CN) of semibullvalenes generated through aryl-vinyl (A-V) bridging, whereas the quinoxalinobarrelene 5-d4 furnished 79% (C6D6) and 71% (CD3CN) of semibullvalenes generated through vinyl-vinyl (V-V) bridging. The contrasting photochemical behavior of heteroarene-fused barrelenes 4-6 was explained qualitatively in terms of triplet energy minimization and relative stability of diradicaloid intermediates.