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Pyrroles and quinolones represent core structures, which are routinely found in both natural and synthetic bioactive substances. Consequently, the development of efficient and regiospecific methods for the preparation of such heterocycles with unique functionality is of some importance. We describe herein the regiospecific synthesis of 1,2,3,4-tetrasubstituted pyrroles containing polar substituents and such products are prepared from vinylogous carbamates and vinylogous aminonitriles. We also describe the regiospecific synthesis of 3-aryl containing 1,3,6trisubstituted quinolones from vinylogous carbamates. The use of an amine exchange reaction to prepare precursors for the pyrrole and quinolone forming cyclizations represents a key factor in the strategy.

Highly functionalized pyrroles with appropriate regiochemical functionality represent an important class of marine natural products and potential drug candidates. We describe herein a detailed study of the reaction of α-aminoacid esters with vinylogous amides and also β-halovinylaldehydes for the regiospecific synthesis of 2,3,4-trisubstituted and 1,2,3,4-tetrasubstituted pyrroles. Since the vinylogous amides and β-halovinylaldehydes are readily available precursors, rapid access to a wide variety of unsymmetrically substituted pyrroles is accomplished via this methodology.

New microtubule depolymerizing agents with potent cytotoxic activities have been prepared with a 5-cyano or 5-oximino group attached to a pyrrole core. The utilization of ortho activation of a bromopyrrole ester to facilitate successful Suzuki-Miyaura cross-coupling reactions was a key aspect of the synthetic methodology. This strategy allows for control of regiochemistry with the attachment of four completely different groups at the 2, 3, 4 and 5 positions of the pyrrole scaffold. Biological evaluations and molecular modeling studies are reported for these examples.

Compounds that bind at the colchicine site of tubulin have drawn considerable attention with studies indicating that these agents suppress microtubule dynamics and inhibit tubulin polymerization. Data for 18 polysubstituted pyrrole compounds are reported, including antiproliferative activity against human MDA-MB-435 cells and calculated free energies of binding following docking the compounds into models of alphabeta-tubulin. These docking calculations coupled with HINT interaction analyses are able to represent the complex structures and the binding modes of inhibitors such that calculated and measured free energies of binding correlate with an r(2) of 0.76. Structural analysis of the binding pocket identifies important intermolecular contacts that mediate binding. As seen experimentally, the complex with JG-03-14 (3,5-dibromo-4-(3,4-dimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester) is the most stable. These results illuminate the binding process and should be valuable in the design of new pyrrole-based colchicine site inhibitors as these compounds have very accessible syntheses.

Studies directed on the synthesis of the pyrrole containing marine natural products Rigidin and Rigidin E via vinylogous iminium salts are described. The successful strategy relies on the formation of a 2,4-disubstituted pyrrole from a vinamidinium salt followed by acylation at the 5-position of pyrrole. Halogenation and aminocarbonylation at the 3-position of pyrrole followed by hydrolysis of the ester group at C-2 and subsequent Curtius rearrangement generates the pyrrolopyrimidine skeleton. A final deprotection step completes the synthesis of Rigidin and Rigidin E.

The highly stereoselective conversions of (Z)-3-aryl-3-chloropropenals to (E)-3-alkoxy-3-arylpropenals, to (E)-3-aryl-3-morphorlinopropenals, and to vinamidinium salts are reported. The stereochemical assignments were based on 2D-NMR experiments.

A new and efficient relay synthesis of the marine natural products polycitone A and B is described. The new strategy relies on the formation of 2,4-disubstituted pyrroles from a vinamidinium salt followed by electrophilic substitution at the 5-position of the pyrrole and Suzuki coupling at the 4-position to produce the tetrasubstituted heterocycle efficiently and with complete control of regiochemistry.

Convenient routes from (Z)-3-aryl-3-chloroenals to (2E,4Z)-5-aryl-5-chloro-2,4-pentadienoates and (2E)-5-aryl-2-penten-4-ynoates are described. The stereochemical assignments are based on NMR spectral data.

A vinylogous iminium salt derivative has been used to prepare a 2,3,4-trisubstituted pyrrole synthon in a regioselective, efficient and convenient manner. This pyrrole synthon was subsequently converted to the multidrug-resistant (MDR) reversal agent, Ningalin B hexamethyl ether, via alkylation, hydrolysis and oxidative lactonization steps. This methodology provides an alternative pathway to this important class of pyrrole containing marine natural products.

A variety of vinylogous iminium salt derivatives have been examined as useful precursors for the regiocontrolled synthesis of heterocyclic appended pyrazoles. The reaction conditions for such processes have been optimized and the regiochemical preferences have been determined. Such reaction sequences represent methodologies which may have useful applications for the preparation of biologically interesting substances.

β-Fluorinated vinamidinium salts ( 1 ) readily reacted with a series of Grignard reagents in tetrahydrofuran, followed by the action of reducing agents at room temperature, to produce stereospecifically the corresponding fluorinated allylamines ( 4 and 5 ) in good to excellent yields.

Numerous novel pyrrole containing marine natural products have been shown to possess interesting biological properties. These compounds have been the synthetic targets of several research groups and we have previously reported synthetic methods which utilize vinylogous iminium salt derivatives as building blocks for analogous pyrrrole systems. We now report a novel and regiocontrolled synthesis of a known pyrrole synthetic precursor to the compounds Lukianol A and Lammelarin O dimethyl ether based on this synthetic methodology.

β-Trifluoromethyl vinamidinium salt 1 reacted cleanly with a variety of Grignard reagents 2 in tetrahydrofuran under reflux for 3 h to produce a mixture of diastereoisomers ( dl and meso ) of the corresponding difluoromethylene compounds 3 in good to excellent yields.

β-Fluorovinamidinium salt ( 1 ) reacted cleanly with a variety of Grignard reagents in tetrahydrofuran at room temperature, followed by acid workup, to produce the corresponding (Z)-α-fluoro-α,β-unsaturated aldehydes ( 3 ) in good to excellent yields.

β-Fluoro vinamidinium salt ( 1 ) reacted with 1.1 equiv. of methylene compounds activated with carbonyl or cyano groups in the presence of lithium diisopropylamide or sodium hydride and triethylamine in tetrahydrofuran at room temperature to give monofluorinated multifunctional dienaminones ( 3 ) and dienaminonitriles ( 5 ) in moderate to good yields. The reactions of 1 with 2.2 equiv. of enolates derived from β-keto esters at 80 °C gave the cyclization products, fluorinated isophthalates ( 6 ) in good yields, while a similar reaction with 2.2 equiv. of cyanoacetate and malononitrile produced the non-cyclic 1, 3-dienecarbonitriles ( 7 ) in excellent yields.

Novel β-polyfluoroalkoxy vinamidinium salts 3 and/or 4 were prepared in good yields by the reaction of N -(2-polyfluoroalkoxy-3,3-difluoro-1-propenyl) trimethylammonium iodides ( 2 ) with secondary amines in acetonitrile at 70 °C for 1 h. These vinamidinium salts readily reacted with bifunctional heteronucleophiles, such as amidines, guanidines and hydrazines, to give regiospecifically polyfluoroalkoxylated pyrimidines ( 6 ) and pyrazoles ( 8 ) in good yields. The one-pot procedure starting from N -(2,3,3-trifluoro-1-propenyl)trimethylammonium iodide ( 1 ), which was the precursor of 2 , was applicable for synthesizing the heterocyclic compounds in almost comparable yields with those obtained by the stepwise procedure using isolated 3 and 4 .

Reactions of 2,3-disubstituted chloropropeniminium salts and related synthons with ethyl glycinate, ethyl N-methylglycinate, and ethyl N-benzylglycinate have been studied under acidic, basic and neutral conditions. Such reactions have resulted in efficient and selective methodology for the synthesis of unsymmetrical 2,3,4-trisubstituted pyrrole systems.

The reaction of 1-substituted vinamidinium salts with sarcosine ethyl ester produced 2,3-disubstituted pyrroles; a similar reaction with glycine ethyl ester gave 2,5-disubstituted pyrroles. Reactions of related three-carbon synthons with sarcosine and glycine were studied under basic, neutral and acidic conditions which demonstrated the utility of these derivatives for the regiocontrolled preparation of disubstituted pyrroles.

β-Trifluoromethylated vinamidinium salt (1) was prepared in high yield by the reaction between 3,3,3-trifluoropropanoic acid and phosphorus oxychloride in N,N-dimethylformamide at 70 °C for 1 h. This salt 1 reacted readily with bifunctional nitrogen nucleophiles, such as amidine and hydrazine derivatives, in acetonitrile or dimethyl sulfoxide to furnish the corresponding trifluoromethylated azaheterocycles in good yields.

The reaction of unsymmetrical vinylogous iminum salts and related analogs with β-aminocrotononitrile to yield 2,3,6-trisubstituted pyridines with regioselective control is described.

β-Fluorovinamidinium salt (2), readily prepared fromN-(2, 3, 3-trifluoro-1-propenyl)trimethyl-ammonium iodide (1) and diethylamine, reacted with bifunctional hetero nucleophiles such as amidine and guanidine hydrochlorides in the presence of a base to afford regiospecifically monofluorinated pyrimidines4 in good yields. The one-pot procedure starting from1 was applicable for synthesizing heterocyclic compounds4 in almost comparable yields.

The reaction of vinylogous iminium salts and related analogs with 3-amino-1,2,4-triazole to yield 7-substituted and 5-substituted triazolo [1,5-a]pyrimidines is described.

A three step synthesis of a novel 2-(1-benzotriazolyl)-vinamidinium salt is described along with its direct conversion to a series of unusual 5-(1-benzotriazolyl) pyrimidines, 4-(1-benzotriazolyl)-pyrazoles, and 4-(1-benzotriazolyl) pyrroles.