Microwave-enhanced cross-coupling reactions involving alkynyltrifluoroborates with aryl bromides.

Palladium-catalyzed alkynylation has emerged as one of the most reliable methods for the synthesis of alkynes which are often used in natural product syntheses and material science. An efficient method for coupling alkynyltrifluoroborates with various aryl bromides in the presence of a palladium catalyst has been developed using microwave irradiation. The microwave reactions are rapid and efficient.

Design, synthesis, and biological evaluation of 4-(5-dimethylamino-naphthalene-1-sulfon-amido)-3-(4-iodophenyl)butanoic acid as a novel molecular probe for apoptosis imaging.

Apoptosis (programmed cell death) plays a crucial role in the pathogenesis of many disorders, thus the detection of apoptotic cells can provide the physician with important information to further therapeutic strategies and would substantially advance patient care. A small molecule, 4-(5-dimethylamino-naphthalene-1-sulfonamido)-3-(4-iodo-phenyl)butanoic acid (DNSBA), was designed as a novel probe for imaging apoptosis and synthesized with good yield. The biological characterization demonstrated that DNSBA can be used to specifically and selectively detect apoptotic cancer cells at all stages. DNSBA is also designed as a potential SPECT and PET probe when labeled with radioiodine (I-123, -124, and -131).

Design and synthesis of (E)-1-((3-ethyl-2,4,4-trimethylcyclohex-2-enylidene)methyl-4-substituted benzenes from 1-(2,6,6-trimethylcyclohex-1-enyl)ethanol.

A novel strategy for synthesizing (E)-1-((3-ethyl-2,4,4-trimethylcyclohex-2-enylidene)methyl-4-substituted benzenes from 1-(2,6,6-trimethylcyclohex-1-enyl)ethanol has been developed; the allylic alcohol was treated with PPh(3).HBr in methanol followed by aldehydes in the presence of a base and furnished the 1,3-dienes in moderate to good yields (79-86%).

Identification of a boron-containing intermediate in the boron tribromide mediated aryl propargyl ether cleavage reaction.

An alternate reaction mechanism for the boron tribromide mediated deprotection of aryl propargyl ethers based on the isolation of a key boron-containing byproduct is proposed. On the basis of the new mechanistic insight, we discovered that HBBr(2) x SMe(2) can also be used for cleaving aryl propargyl ethers.

Microwave-enhanced palladium-catalyzed cross-coupling reactions of potassium vinyltrifluoroborates and allyl acetates: a new route to 1,4-pentadienes.

[reaction: see text] A novel and straightforward microwave synthesis of 1,4-pentadienes has been developed involving the cross-coupling of potassium vinyltrifluoroborates and allyl acetates in the presence of a palladium catalyst.

Substitution of hydroxyl groups with alkynyl moieties using alkynylboron dihalides: an efficient approach to secondary alkylacetylene derivatives.

The reaction of alkynylboron dihalides with benzylic, allylic, and propargylic alcohols provides an efficient route to internal acetylenes. Isomerization of the product alkynes does not occur under the reaction conditions.

Substitution of benzylic hydroxyl groups with vinyl moieties using vinylboron dihalides.

[reaction: see text] Substitution of benzylic hydroxyl groups with vinyl moieties using vinylboron dihalides has been achieved. The reaction provides a novel method for preparing stereodefined alkenyl halides.

Alkenylation of allylic alcohols using alkenylboron dihalides: a formal transition-metal free Suzuki reaction.

Carbon-carbon bond formation via substitution of an allylic hydroxide with stereodefined alkenyl groups using alkenylboron dihalides in the absence of transition metals.

Imaging of fluorine and boron from fluorinated boronophenylalanine in the same cell at organelle resolution by correlative ion microscopy and confocal laser scanning microscopy.

PURPOSE: There is a clear need for a technique that provides subcellular locations of fluorine and boron atoms from fluorinated neutron capture agents because positron emission tomography is being tested as a tool for providing tumor boron concentrations in boron neutron capture therapy. EXPERIMENTAL DESIGN: Ion microscopy was used in combination with confocal laser scanning microscopy to investigate the subcellular locations of fluorine and boron from fluorinated p-boronophenylalanine (F-BPA) in human glioblastoma T98G cells. The fluorinated compound was also compared with p-boronophenylalanine (BPA) for delivery of boron after a clinically relevant 6-h exposure. Mitochondria were identified by rhodamine 123 labeling. A strict cryogenic sample preparation was used, and measurements were made in fractured freeze-dried cells. RESULTS: The nucleus, a perinuclear mitochondria-rich cytoplasmic region, and the remaining cytoplasm were the three subcellular regions identified in individual T98G cells. In cells treated with F-BPA, the mitochondria-rich perinuclear cytoplasmic region exhibited significantly lower fluorine and boron signals than the remaining cytoplasm and the nuclei. Ion microscopy observations revealed a nearly 1:1 distribution of fluorine and boron in subcellular compartments. Quantitative subcellular observations indicated that there was no significant difference in boron delivery to subcellular compartments between the F-BPA and nonfluorinated BPA. CONCLUSIONS: These observations provide the first direct evidence that fluorine and boron from fluorinated BPA are cocompartmentalized in cells and that the fluorinated compound is as efficient for boron delivery as the nonfluorinated BPA at a clinically relevant time point. These observations provide strong support for the use of F-BPA in positron emission tomography biodistribution studies for boron neutron capture therapy.

Synthesis of PEG-supported organotrifluoroborates and their applications in palladium-catalyzed homo-coupling reactions.

A general synthetic route to water-soluble PEG-supported organotrifluoroborates has been developed. In the presence of air and catalytic amounts of Pd(OAc)2, the PEG-supported organotrifluoroborates undergo homo-coupling reactions smoothly at room temperature. No additional oxidizing agent, base, or phosphine ligands are required.

Cyclohexenylboration of Aldehydes and Ketones with the Borabicyclo[3.3.2]decanes (BBDs).

Asymmetric hydroboration of 1,3-cyclohexadiene with 4R produces the allylborane 5RR as essentially a single diastereomer (i.e., no observable 5RS), and its addition to representative aldehydes provides 9RS (52-75%) with excellent selectivity (94-99% ee). By contrast, a similar sequence with the 10-Ph-BBD reagent, 14R, results in a ca. 45:55 mixture of 15RR and 15RS. However, their addition to methyl ketones provides the corresponding 3°-homoallylic alcohols (18RS) with excellent selectivity (80-99% ee) but in low yields (15-52%) because 15RS is unreactive toward either allylboration or isomerization to 15RR. Thus, with 2 equiv of 15, the yield of 18 (R = Ph) is increased from 52% to 85%. Boranes 5SS and 15SS provide enantiomeric alcohols.

Synthesis of [(18)F]FMISO in a flow-through microfluidic reactor: Development and clinical application.

INTRODUCTION: The PET radiotracer [(18)F]FMISO has been used in the clinic to image hypoxia in tumors. The aim of the present study was to optimize the radiochemical parameters for the preparation of [(18)F]FMISO using a microfluidic reaction system. The main parameters evaluated were (1) precursor concentration, (2) reaction temperature, and (3) flow rate through the microfluidic reactor. Optimized conditions were then applied to the batch production of [(18)F]FMISO for clinical research use. METHODS: For the determination of optimal reaction conditions within a flow-through microreactor synthesizer, 5-400 µL the precursor and dried [(18)F]fluoride solutions in acetonitrile were simultaneously pushed through the temperature-controlled reactor (60-180 °C) with defined flow rates (20-120 µL/min). Radiochemical incorporation yields to form the intermediate species were determined using radio-TLC. Hydrolysis to remove the protecting group was performed following standard vial chemistry to afford [(18)F]FMISO. RESULTS: Optimum reaction parameters for the microfluidic set-up were determined as follows: 4 mg/mL of precursor, 170 °C, and 100 µL/min pump rate per reactant (200 µL/min reaction overall flow rate) to prepare the radiolabeled intermediate. The optimum hydrolysis condition was determined to be 2N HCl for 5 min at 100 °C. Large-scale batch production using the optimized conditions gave the final, ready for human injection [(18)F]FMISO product in 28.4 ± 3.0% radiochemical yield, specific activity of 119 ± 26 GBq/µmol, and >99% radiochemical and chemical purity at the end of synthesis (n = 4). CONCLUSION: By using the NanoTek microfluidic synthesis system, [(18)F]FMISO was successfully prepared with good specific activity and high radiochemical purity for human use. The product generated from large-scale batch production using flow chemistry is currently being used in clinical research.

Synthesis of (e)- and (z)- alkenylphosphonates using vinylboronates.

(E)- and (Z)-alkenylphosphonates have been prepared stereospecifically via the reaction of vinylboronate esters with triethyl phosphite in the presence of palladium acetate.

Synthesis of diprotected monosubstituted hydrazine derivatives from tert-butyl carbazates and boronic acids.

[reaction: see text]. Diprotected monosubstituted hydrazine derivatives have been prepared via the reaction of tert-butyl carbazates with boronic acids catalyzed by cuprous chloride at room temperature.

A new halopropargylation of alkynes promoted by boron trihalides. highly stereo- and regioselective syntheses of substituted (Z)-1-halo-1,4-enyne derivatives.

[reaction: see text] A new halopropargylation of alkynes promoted by boron trihalides has been developed. Reactions of (Z)-2-halo-1-vinylboron dihalides (generated in situ via reaction of alkynes with boron trihalides) with lithium propargyloxides in CH(2)Cl(2) at room temperature produce the corresponding (Z)-1-halo-1,4-enynes in modest to good yields.

Rhodium-catalyzed cross-coupling of allyl alcohols with aryl- and vinylboronic acids in ionic liquids.

[reaction: see text] The direct coupling of aryl- and vinylboronic acids with allylic alcohols has been achieved in ionic liquids using a rhodium catalyst.

Palladium-catalyzed cross-coupling of acetates of Baylis-Hillman adducts and potassium organotrifluoroborates.

[reaction: see text] The cross-coupling of potassium organotrifluoroborates and acetates of Baylis-Hillman adducts proceeds readily in moderate to excellent yield in the presence of Pd(OAc)(2). The reaction tolerates hindered trifluoroborate salts, and the process is stereoselective.

A novel titanium tetrahalide-mediated carbon-carbon bond-forming reaction: regioselective synthesis of substituted (E,Z)-1,5-dihalo-1,4-dienes.

Reactions of aldehydes with 2 equiv of alkyne in the presence of TiX(4) (X = Cl, Br) regioselectively generated 1,5-dihalo-1,4-dienes in moderate to good yields with high (E,Z)-stereoselectivity. [reaction: see text]

A new reaction of aryl aldehydes with aryl acetylenes in the presence of boron trihalides.

[reaction: see text]. The reactions of aryl aldehydes with 2 equiv of arylacetylenes in the presence of boron trichloride yield (E,Z)-1,3,5-triaryl-1,5-dichloro-1,4-pentadienes. Reactions carried out in the presence of boron tribromide generate the corresponding (Z,Z)-1,3,5-triaryl-1,5-dibromo-1,4-pentadienes.

Improved treatment planning for boron neutron capture therapy for glioblastoma multiforme using fluorine-18 labeled boronophenylalanine and positron emission tomography.

Boron neutron capture therapy (BNCT) is a cancer brachytherapy based upon the thermal neutron reaction: 10B(n,alpha)7Li. The efficacy of the treatment depends primarily upon two conditions being met: (a) the preferential concentration of a boronated compound in the neoplasm and (b) an adequate fluence of thermal neutrons delivered to the neoplasm. The boronated amino acid, para-boronophenylalanine (BPA), is the agent widely used in clinical trials to deliver 10B to the malignancy. Positron emission tomography (PET) can be used to generate in vivo boron distribution maps by labeling BPA with the positron emitting nuclide fluorine-18. The incorporation of the PET-derived boron distribution maps into current treatment planning protocols is shown to provide improved treatment plans. Using previously established protocols, six patients with glioblastoma had 18BPA PET scans. The PET distribution maps obtained were used in the conventional BNCT treatment codes. The isodose curves derived from the PET data are shown to differ both qualitatively and quantitatively from the conventional isodose curves that were derived from calculations based upon the assumption of uniform uptake of the pharmaceutical in tumor and normal brain regions. The clinical course of each of the patients who eventually received BNCT (five of the six patients) was compared using both sets of isodose calculations. The isodose contours based upon PET derived distribution data appear to be more consistent with the patients' clinical course.