Juan F. Sanz-Cervera

Improved Regioselectivity in Pyrazole Formation through the Use of Fluorinated Alcohols as Solvents: Synthesis and Biological Activity of Fluorinated Tebufenpyrad Analogs

The preparation of N-methylpyrazoles is usually accomplished through reaction of a suitable 1,3-diketone with methylhydrazine in ethanol as the solvent. This strategy, however, leads to the formation of regioisomeric mixtures of N-methylpyrazoles, which sometimes are difficult to separate. We have determined that the use of fluorinated alcohols such as 2,2,2-trifluoroethanol (TFE) and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as solvents dramatically increases the regioselectivity in the pyrazole formation, and we have used this modification in a straightforward synthesis of fluorinated analogs of Tebufenpyrad with acaricide activity.

Recent Advances in the Synthesis of Pyrazoles. A Review

Introduction ..........................................................................................254 I. 1H-Pyrazoles .........................................................................................255 1. 3(5)-Substituted-1H-pyrazoles ...............................................................255 2. 3,4and 3,5-Disubstituted-1H-pyrazoles ................................................256 a. 3,4-Disubstituted-1H-pyrazoles ..........................................................256 b. 3,5-Disubstituted-1H-pyrazoles ..........................................................257 3. 3,4,5-Trisubstituted-1H-pyrazoles ..........................................................261 II. N-Substituted Pyrazoles .......................................................................262 1. 1,3,5-Trisubstituted Pyrazoles................................................................262 a. From 1,3-Dicarbonyl Compounds.......................................................262 b. From α,β-Unsaturated Ketones ..........................................................264 c. From β-Aminoenones and Related Compounds....................................264 d. By 1,3-Dipolar Cycloadditions ...........................................................265 e. Other Methods..................................................................................266 2. 1,3,4,5-Tetrasubstituted Pyrazoles ..........................................................266 3. Miscellaneous Pyrazoles .......................................................................269 III. Substituted Pyrazole-3(5)-carboxylic Acid Derivatives .....................271 1. From 1,3-Diketoesters...........................................................................271 2. From α,β-Unsaturated β-Ketoesters ......................................................271 3. From α-Enamino-β-ketoesters(amides) and Related Compounds ............273 4. Other Methods .....................................................................................274 IV. Fluorinated Pyrazole Derivatives ........................................................275 1. From β-Aminoenones...........................................................................276 2. From β-Alkoxyvinylketones ..................................................................276 3. From 1,3-Dicarbonyl Compounds..........................................................278 Conclusions............................................................................................285 References..............................................................................................285

Synthesis of New Fluorinated Tebufenpyrad Analogs with Acaricidal Activity Through Regioselective Pyrazole Formation

In previous studies, our group has shown that the use of fluorinated alcohols such as trifluoroethanol (TFE) and hexafluoroisopropanol (HFIP) as solvents dramatically increases the regioselectivity in the pyrazole formation from 1,3-diketone with methylhydrazine. We have now applied this synthetic method to the preparation of new fluorinated pyrazoles, which have then been used as synthetic intermediates in the preparation of fluorinated analogs of Tebufenpyrad, a commercial acaricide. These compounds display a strong acaricidal activity that is either comparable to or better than that of the commercial compound.

Solution versus fluorous versus solid-phase synthesis of 2,5-disubstituted 1,3-azoles. Preliminary antibacterial activity studies.

A small library of compounds with an oxa(thia)zole scaffold and structural diversity in both positions 2 and 5 has been synthesized. Double acylation of a protected glycine affords intermediate alpha-amido-beta-ketoesters, which in turn can be dehydrated to afford 1,3-oxazoles or reacted with Lawessons reagent to furnish 1,3-thiazoles. This procedure was designed with its adaptation to fluorous techniques in mind. Thus, when a protected glycine with a fluorous tag in the ester moiety is used as a starting material, the synthesis can be easily completed without column chromatography purification of intermediate compounds with good to excellent yields, thus affording a suitable entry to the preparation of small libraries of these bioactive compounds. The prepared oxa(thia)zoles were assayed for their antibacterial activity, and several of them were active against Staphylococcus aureus.

Synthesis and evaluation of microtubule assembly inhibition and cytotoxicity of prenylated derivatives of cyclo-l-Trp-l-Pro

The synthesis of three isoprenylated derivatives of cyclo-L-Trp-L-Pro is described. These substances have been evaluated for cytotoxic activity in rat normal fibroblast 3Y1 cells and have also been evaluated in vitro for the inhibition of microtubule assembly.

Tricyclic sesquiterpenes from Artemisia chamaemelifolia

The aerial parts of Artemisia chamaemelifolia ssp. chamaemelifolia yielded, in addition to known compounds, four acids with the silphiperfolane framework, a presilphiperfolane derivative, a bicyclic sesquiterpene formed therefrom by oxidative cleavage, a diacetylated monoterpene diol, a cadinane derivative, three acyclic sesquiterpenes and two tetrahydrofurane lignans.

Biomimetic diels–alder cyclizations for the construction of the brevianamide, paraherquamide, sclerotamide, asperparaline and VM55599 ring systems

A potentially bio-mimetic Diels-Alder cyclization to construct the bicyclo[2.2.2] ring system common to the paraherquamides, marcfortines, sclerotamides, brevianamides, VM55599, and asperparaline is reported. Epi-deoxybrevianamide E (22) is converted into the corresponding lactim ether (23) and then oxidized with DDQ to provide an azadiene (24) which is tautomerized in the presence of base to azadiene 25 which, spontaneously cyclizes to give a 2:1 mixture of cycloadducts 26 and 27. These cycloadducts are each in turn, converted into D,L-C-19-epi-brevianamide A (20) and D,L-brevianamide B (6). The stereochemical implications of the [4 + 2] cycloaddition is discussed in the context of a working hypothesis on the biosynthesis of this family, particularly VM55599.

Xanthanolides from Xanthium: Absolute configuration of xanthanol, isoxanthanol and their C-4 epimers

Abstract Three new xanthanolides have been isolated from Xanthium spinosum and X. strumarium subsp. italicum , together with other known compounds. The absolute configurations of xanthanol, isoxanthanol and their C-4 epimers have been established.

Solution-, Solid-Phase, and Fluorous Synthesis of β,β-Difluorinated Cyclic Quaternary α-Amino Acid Derivatives : A Comparative Study

The diastereoselective synthesis of cyclic beta,beta-difluorinated alpha-amino acid derivatives bearing a quaternary stereocenter is described. The process relies on the chemo- and diastereoselective addition of allylic organometallic reagents to fluorinated alpha-imino esters and a subsequent ring-closing metathesis reaction (RCM). Complete selectivity in the nucleophilic addition was achieved with (R)-phenylglycinol methyl ether as a chiral auxiliary. The resulting amino acids were introduced into peptide chains, which could facilitate the preparation of potentially bioactive dipeptide derivatives. In addition, the solution synthesis of these cyclic fluorinated alpha-amino acids was successfully adapted to solid-phase and fluorous-phase techniques. The reaction times and final deprotection were clearly more favorable in the latter, in which a fluorous trimethylsilylethanol (TMSE) tag was used. The tag was then easily removed upon treatment with TBAF in a high-yield transesterification process.

Ingenane and lathyrane diterpenes from the latex of Euphorbia canariensis

The latex of Euphorbia canariensis yielded, in addition to five known ingenol esters, the ingenane derivatives ingenol 3-angelate 5,20-diacetate and 5-deoxyingenol 3-angelate 20-acetate, and the lathyrane derivatives 2,3-diepiingol 7,12-diacetate 8-benzoate, 2,3-diepiingol 7,12-diacetate 8-isobutyrate and 2-epiingol 3,7,12-triacetate 8-benzoate. The structures were established with the aid of spectroscopic methods, mainly NMR, and molecular mechanics calculations. They were also supported by the results of some chemical transformations.