Tetrahedron Letters

Published by Elsevier
Publications
A microwave-assisted, sequential, one-pot protocol has been developed for the synthesis of a variety of benzothiadiazin-3-one-1,1-dioxides. This protocol utilizes a copper-catalyzed N-arylation of α-bromo-benzenesulfonamides with a number of amines to generate the corresponding 2-aminobenzenesulfonamides, which undergo cyclization to the desired sultams using carbonyl diimidazole (CDI). A range of conditions was evaluated for the key C-N bond formation step with tolerance toward functionalized amines.
 
The regioselective synthesis of 3,5-disubstituted isoxazoles was achieved through the 1,3-dipolar cycloaddition of nitrile oxides with 1,1-disubstituted bromoalkenes. The substituted bromoalkenes function as alkyne synthons which were used to construct 5,5-disubstituted bromoisoxazoline intermediates that aromatize to the analogous isoxazoles through the loss of HBr.
 
In comparison with the NMR data of salvinorin A and its 8-epimer, the published structure of deacetyl-1,10-didehydrosalvinorin G was revised to its 8-epimer. The stereochemistry of 8-epi-deacetyl-1,10-didehydrosalvinorin G was further confirmed by NOESY and chemical synthesis.
 
To unambiguously confirm the actual product in autoxidation of salvinorin A under basic conditions, deacetyl-1,10-didehydrosalvinorin G was synthesized from salvinorin C via intermediate salvinorin H. Furthermore, oxidation of salvinorin D with manganese dioxide gave salvinorin G in good yield.
 
A substituted hydropyrazino[1,2-a]pyrimidin-6-one derivative was synthesized stereoselectively via the intramolecular N-acyliminium ion cyclization between an amide nitrogen and an N(α)-acetal derived from Cbz-protected aminopropyl-phenylalaninamide in very good yields. The formation of a single diastereomer is due to the low energy chairlike conformation of its bicyclic structure. This methodology provides a convenient tool to build internal bicyclic peptidomimetics.
 
An optimized total synthesis of the 2-amino-6-chloro-4-cyclopropyl-7-fluoro-5-methoxy-pyrido[1,2-c]pyrimidine-1,3-dione core structure of a new fluoroquinolone-like class of antibacterial agents is described. This synthesis is highlighted by a nearly quantitative ring-closing reaction to form the pyrido[1,2-c]pyrimidine core. This bicyclic ring system serves as a scaffold for a family of biologically active compounds.
 
A convenient method to prepare a series of benzodithiine derivatives was developed, via the synthesis of cyclic disulfide building blocks containing an amino-group linker. Some of the novel cyclic disulfide compounds are shown to modulate the activity of the redox-enzyme glutathione reductase.
 
A [3+2] 1,3-dipolar cycloaddition reaction of arynes with stable azomethine imines has been developed. The reaction rapidly assembles tricyclic pyrazoloindazolone derivatives in moderate yields under mild reaction conditions.
 
trans-1,2-Diaryloxiranes were conveniently prepared in an one-pot reaction by the direct coupling of benzyl halides in the presence of silver oxide and DMSO under mild conditions.
 
We previously synthesized novel retinoid libraries, and after screening for bioactivity found one compound BT10 that functions as a specific agonist for retinoic acid receptors. This lead compound was further derivatized using SAR and LRD to obtain 3,5-disubstituted-1,2,4-oxadiazole-containing retinoids. The new oxadiazole (amide bioisosters)-containing retinoids (compounds 1, 2, 3, 4, 5, and 6) were synthesized in 42-65% yield by reacting with (E)-4-((3-ethyl,2-4,4,4-trimethylcyclohex-2-enylidene)methyl)benzoic acid and phenyl substituted amidoxime in DMF using CDI as the coupling reagent. The biological activities of the synthesized compounds are currently being evaluated.
 
General, high-yielding MAOS protocols for the expedient synthesis of functionalized 3,6-disubstituted-[1,2,4]triazolo[4,3-b]pyridazines are described amenable to an iterative analog library synthesis strategy for the lead optimization of an M1 antagonist screening hit. Optimized compounds proved to be highly selective M1 antagonists.
 
We have designed and synthesized a small library of 3,5-disubstituted-1,2,4-oxadiazole containing combretastatin A-4 (CA-4) analogs. Our objective is to increase the efficacy of the CA-4 as an anti-tubulin and antimitotic agent by substituting the cis-alkene bond with one of its bioisosteres, the 1,2,4-oxadiazole ring. We also modified the substituents attached to both of the phenyl rings (ring A and B in Fig. 1) of CA-4 for the purpose of diversifying our analogs based on SAR. These compounds were synthesized via a coupling reaction between an amidoxime and a carboxylic acid in DMF solvent, with HOBt as a base, and utilizing EDCI as a coupling reagent. Using this protocol, we synthesized a small library of 10 compounds with moderate to good yields. A detailed biological study is currently undergoing in our laboratory to evaluate the activity of these compounds.
 
A new synthesis of N(1)-(substituted)-pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones, which are analogues of the natural product toxoflavin, is reported. Condensation of preformed alkyl or aryl hydrazones with 6-chloro-3-methyl-5-nitrouracil efficiently provides pyrimidotriazinediones in a three-step process that broadens the scope of R(1) substituents.
 
Aryl thioamides undergo a very rapid condensation in the presence of methyl bromocyanoacetate to provide quantitative yields of 3,5-diaryl-1,2,4-thiadiazoles with easy work-up and a high degree of product purity. The method can be scaled up with no loss in efficiency.
 
Procedures for the synthesis of thirty-six 5-methyl-3-(substituted)-[1,2,4]triazines have been described. These compounds were evaluated for antagonism at metabotropic glutamate receptor subtype 5. Two compounds, 5b and 3c, were determined to be low micromolar inhibitors of mGluR5.
 
Sulfinimine-derived alpha-amino 1,3-dithianes, alpha-amino carbonyl chiral building blocks, are utilized in asymmetric syntheses of (+)-(tetrahydrofuran-2-yl)glycine and the 2,3-disubstituted piperidine (+)-L-733,060.
 
Novel, intramolecular 1,3-dipolar cycloadditions of azomethine ylides have been applied to the synthesis of functionalized core structures of the stemofoline alkaloids. In an effort to maximize the efficiency of this key transformation in the context of an eventual total synthesis of these complex natural products, a number of strategic modifications to the cycloaddition substrate were investigated. These collective efforts have provided useful insights into the operative, regiochemical control elements for 1,3-dipolar cycloadditions leading to stemofoline alkaloids. A potential intermediate in the synthesis of these alkaloids was prepared.
 
A simple two-step procedure for the conversion of readily available phthalides to the corresponding benzoxazinones was developed. Initial ring-opening aminolysis to form a primary 2-hydroxymethylbenzamide, followed by reaction with bis(trifluoroacetoxy)iodobenzene (BTI) conveniently provided a variety of 4-substituted benzoxazinones.
 
The synthesis of a pyrido[3,2-e]-2, 10b-diaza-cyclopenta[c]fluorene-1, 3-dione scaffold is disclosed, which was synthesized using a Suzuki cross-coupling reaction and an intramolecular Heck cyclization as the key steps. This heterocyclic system can serve as a bidentate ligand as demonstrated by the formation and structural analysis of a derived ruthenium complex. The new scaffold constitutes an interesting candidate for the development of organometallic protein kinase inhibitors. (c) 2006 Elsevier Ltd. All rights reserved.
 
The cyclopentane core of palau'amine has been constructed in optically pure form through the use of an asymmetric azomethine ylid [1,3]-dipolar cycloaddition reaction.
 
The synthesized 1,3-dimethylated imidazolium carbaldehydes serves as synthons for incorporating a permanently cationic imidazolium group into molecular framework. The utility of new synthon was demonstrated in a variety of reactions: Knoevenagel, Wittig, Schiff base formation, based mediated electrophilic substitution and oxidation, including synthesis of the natural product norzooanemonin.
 
2-Fluoro-1,3-thiazoles were rapidly and efficiently labeled with no-carrier-added fluorine-18 (t(1/2) = 109.7 min) by treatment of readily prepared 2-halo precursors with cyclotron-produced [(18)F]fluoride ion. The [(18)F]2-fluoro-1,3-thiazolyl moiety constitutes a new and easily-labeled structural motif for prospective molecular imaging radiotracers.
 
The syntheses of an important class of hitherto unreported 1,3,5-pyrazoles, inspired by an unanticipated eliminatory ring opening are described. The reported pyrazole compounds were constructed through the Huisgen cyclization of 2-methylene-1,3,3-trimethylindoline and an in situ generated nitrile imine. The newly formed spiro-pyrazoline intermediate presumably then undergoes a ring opening/elimination process to afford a pyrazole, as evidenced by single X-ray crystal data. The current report constitutes the first formal observation of this kind of ring opening involving a spiro-pyrazoline intermediate.
 
Herein we report a general synthesis of 1,3-diarylsubstituted indazoles utilizing a two-step Suzuki cross-coupling/deprotection/N-arylation sequence. This procedure proceeds in excellent overall yield starting from the 3-iodo-N-Boc indazole derivative allowing for rapid access to these compounds.
 
A solution-phase synthesis of bicyclic prolines containing four points of diversity has been developed by a two-step synthesis involving 1,3-dipolar cycloaddition of perfluoroalkylsulfonyl-protected hydroxybenzaldehydes followed by Pd-catalyzed Suzuki coupling reaction of fluorous sulfonates with boronic acids. Both reactions are conducted under microwave irradiation and reaction mixtures are purified by solid-phase extractions without performing chromatography.
 
Microwave irradiation facilitated the synthesis of 4-arylthio-3-oxazolin-5-ones from ethyl cyanoformate, thiophenol, and cyclic ketones. Subsequent decarboxylation and in situ [3+2] cycloaddition provided novel 2,3,4,5-tetrahydro-1H-pyrrolo[1,2-c][1,3]diazepine scaffolds after a spontaneous retro-Mannich domino reaction.
 
1.3-Dienes derived from (R)-4-t-butyldimethylsilyloxy-2-cyclohexen-1-one react with activated dienophiles to form predominately (or sometimes exclusively) syn/endo products. These controlled [4+2] cycloadditions increase the asymmetric complexity from one asymmetric center in the starting material to five asymmetric centers in the products in a single step, and provide a powerful approach for the asymmetric synthesis of compounds containing the bicyclo[2.2.2]octanone carbon skeleton.
 
No systematic studies appear to have been reported on the synthesis or methods of assigning the stereochemistry of 1,3-disubstituted phthalans such as 1 - 4. As part of pharmaacological studies (3) on the separated cis-trans isomers of 1-(N,N-dimethylaminomethyl)-3-phenylphthalan (3) prepared sequentially from 1 and 2 it was desirable to establish the stereochemical configurations of the cis-trans isomers of 1-4. We report here nonstereospecific syntheses of 1-4, proton and ^(13)C nmr studies which are somewhat indicative of the configurations, stereoselective syntheses of the cis isomers of 2 - 4 from o-benzoylbenzaldehyde and confirmation of the nmr assignments by X-ray diffraction determination of the crystal structure of trans-1.
 
We report the large-scale synthesis of 1,3-cyclooctanedione in five steps with 29% yield. This molecule is a synthetic precurser to difluorinated cyclooctyne, which participates in a bioorthogonal copper-free click reaction with azides. The final step demonstrates the first successful application of the Wacker-Tsuji oxidation to form a cyclic 1,3-dione.
 
Top-cited authors
David A. Evans
  • Harvard University
Rajender S Varma
  • United States Environmental Protection Agency
George Fleet
  • University of Oxford
Jai Singh Yadav
  • Banaras Hindu University
Janmejay Yadav
  • SRM Institute of Science and Technology